本申请是中国发明专利申请(申请日：2012年5月9日；申请号：201510473903.6；发明名称：作为TRKA激酶抑制剂的吡咯烷基脲和吡咯烷基硫脲化合物)的分案申请。This application is a divisional application of a Chinese invention patent application (filing date: May 9, 2012; application number: 201510473903.6; invention name: Pyrrolidinourea and pyrrolidinothiourea compounds as TRKA kinase inhibitors).
发明背景Background of the Invention
本发明涉及新型化合物、包含所述化合物的药物组合物、用于制造所述化合物的方法以及所述化合物在治疗中的用途。更具体地说，本发明涉及吡咯烷基脲和吡咯烷基硫脲化合物，所述化合物显示出TrkA激酶抑制作用并且所述化合物适用于治疗疼痛、癌症、炎症、神经变性疾病以及某些感染性疾病。The present invention relates to novel compounds, pharmaceutical compositions comprising the compounds, methods for making the compounds, and uses of the compounds in therapy. More specifically, the present invention relates to pyrrolidinyl urea and pyrrolidinyl thiourea compounds that exhibit TrkA kinase inhibition and are useful in treating pain, cancer, inflammation, neurodegenerative diseases, and certain infectious diseases.
疼痛病状的当前治疗方案利用若干种类的化合物。阿片样物质(如吗啡)具有若干缺点，包括催吐、便秘和负面呼吸效应，以及成瘾的可能。非类固醇抗炎止痛剂(NSAID，如COX-1型或COX-2型)也具有缺点，包括在治疗严重疼痛中功效不足。另外，COX-1抑制剂可以引起粘膜溃疡。因此，持续存在对用于缓解疼痛尤其慢性疼痛的新型和更有效的治疗的需要。Current treatment options for painful conditions utilize several classes of compounds. Opioids (such as morphine) have several disadvantages, including vomiting, constipation, and negative respiratory effects, as well as the potential for addiction. Nonsteroidal anti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2) also have disadvantages, including insufficient efficacy in treating severe pain. In addition, COX-1 inhibitors can cause mucosal ulcers. Therefore, there is a continuing need for new and more effective treatments for relieving pain, especially chronic pain.
Trk's是由称为神经营养因子(NT)的一群可溶性生长因子所激活的高亲和力受体酪氨酸激酶。Trk受体家族具有三个成员：TrkA、TrkB和TrkC。在神经营养因子之中的是(i)激活TrkA的神经生长因子(NGF)，(ii)激活TrkB的脑衍生神经营养因子(BDNF)和NT-4/5以及(iii)激活TrkC的NT3。Trk's在神经元组织中广泛表达，并且牵涉神经元细胞的维持、信号传递和存活(Patapoutian,A.等,Current Opinion in Neurobiology,2001,11,272-280)。Trks are high-affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NTs). The Trk receptor family has three members: TrkA, TrkB, and TrkC. Among the neurotrophins are (i) nerve growth factor (NGF), which activates TrkA; (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5, which activate TrkB; and (iii) NT3, which activates TrkC. Trks are widely expressed in neuronal tissue and are involved in neuronal cell maintenance, signaling, and survival (Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272-280).
已证明Trk/神经营养因子途径的抑制剂在疼痛的许多临床前动物模型中有效。例如，已示出如RN-624的拮抗性NGF和TrkA抗体在炎症性和神经病性疼痛的动物模型中有效(Woolf,C.J.等(1994)Neuroscience 62,327-331；Zahn,P.K.等(2004)J.Pain 5,157-163；McMahon,S.B.等,(1995)Nat.Med.1,774-780；Ma,Q.P.和Woolf,C.J.(1997)NeuroReport8,807-810；Shelton,D.L.等(2005)Pain 116,8-16；Delafoy,L.等(2003)Pain 105,489-497；Lamb,K.等(2003)Neurogastroenterol.Motil.15,355-361；Jaggar,S.I.等(1999)Br.J.Anaesth.83,442-448)并且在神经病性疼痛动物模型中有效(Ramer,M.S.和Bisby,M.A.(1999)Eur.J.Neurosci.11,837-846；Ro,L.S.等(1999)；Herzberg,U.等,Pain 79,265-274(1997)Neuroreport 8,1613-1618；Theodosiou,M.等(1999)Pain 81,245-255；Li,L.等(2003)Mol.Cell.Neurosci.23,232-250；Gwak,Y.S.等(2003)Neurosci.Lett.336,117-120)。Inhibitors of the Trk/neurotrophic factor pathway have been shown to be effective in many preclinical animal models of pain. For example, antagonist NGF and TrkA antibodies such as RN-624 have been shown to be effective in animal models of inflammatory and neuropathic pain (Woolf, C.J. et al. (1994) Neuroscience 62, 327-331; Zahn, P.K. et al. (2004) J. Pain 5, 157-163; McMahon, S.B. et al. (1995) Nat. Med. 1, 774-780; Ma, Q.P. and Woolf, C.J. (1997) NeuroReport 8, 807-810; Shelton, D.L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al. (2003) Pain 105, 489-497; Lamb, K. et al. (2003) Neurogastroenterol. Motil. 15, 355-361; Jaggar, S.I. et al. (1999) Br. J. Anaesth. 83, 442-448) and is effective in animal models of neuropathic pain (Ramer, M.S. and Bisby, M.A. (1999) Eur. J. Neurosci. 11, 837-846; Ro, L.S. et al. (1999); Herzberg, U. et al., Pain 79, 265-274 (1997) Neuroreport 8, 1613-1618; Theodosiou, M. et al. (1999) Pain 81, 245-255; Li, L. et al. (2003) Mol. Cell. Neurosci. 23, 232-250; Gwak, Y. S. et al. (2003) Neurosci. Lett. 336, 117-120).
还已显示由肿瘤细胞和肿瘤侵入性巨噬细胞所分泌的NGF直接刺激位于周围疼痛纤维上的TrkA。在小鼠和大鼠中使用各种肿瘤模型证实，用单克隆抗体中和NGF将癌症相关的疼痛抑制至类似或超过吗啡的最高耐受剂量的程度。因为TrkA激酶可充当NGF驱动的生物反应的中介者，所以TrkA和/或其它Trk激酶的抑制剂可提供慢性疼痛病况的有效治疗。It has also been shown that NGF, secreted by tumor cells and tumor-invading macrophages, directly stimulates TrkA located on peripheral pain fibers. Using various tumor models in mice and rats, it has been demonstrated that neutralizing NGF with a monoclonal antibody inhibits cancer-related pain to a degree similar to or exceeding the highest tolerated dose of morphine. Because TrkA kinase can act as a mediator of NGF-driven biological responses, inhibitors of TrkA and/or other Trk kinases may provide effective treatments for chronic pain conditions.
近期的文献也已显示，Trk激酶的过度表达、激活、扩增和/或突变与许多癌症相关，包括成神经细胞瘤(Brodeur,G.M.,Nat.Rev.Cancer 2003,3,203-216)、卵巢癌(Davidson.B.等,Clin.Cancer Res.2003,9,2248-2259)、结肠直肠癌(Bardelli,A.,Science 2003,300,949)、黑素瘤(Truzzi,F.等,Dermato-Endocrinology 2008,3(1),第32-36页)、头颈癌(Yilmaz,T.等,Cancer Biology and Therapy 2010,10(6),第644-653页)、胃癌(Du,J.等,World Journal of Gastroenterology 2003,9(7),第1431-1434页)、肺癌(Ricci A.,等,American Journal of Respiratory Cell and Molecular Biology25(4),第439-446页)、乳癌(Jin,W.等,Carcinogenesis 2010,31(11),第1939-1947页)、成胶质细胞瘤(Wadhwa,S.等,Journal of Biosciences 2003,28(2),第181-188页)、成神经管细胞瘤(Gruber-Olipitz,M.等,Journal of Proteome Research 2008,7(5),第1932-1944页)、分泌性乳癌(Euthus,D.M.等,Cancer Cell 2002,2(5),第347-348页)、唾液腺癌(Li,Y.-G.等,Chinese Journal of Cancer Prevention and Treatment 2009,16(6),第428-430页)、乳头状甲状腺癌(Greco,A.等,Molecular and Cellular Endocrinology2010,321(1),第44-49页)以及成人骨髓性白血病(Eguchi,M.等,Blood 1999,93(4),第1355-1363页)。在癌症的临床前模型中，Trk A、Trk B和Trk C的非选择性小分子抑制剂在抑制肿瘤生长和停止肿瘤转移中都有效(Nakagawara,A.(2001)Cancer Letters 169:107-114；Meyer,J.等(2007)Leukemia,1-10；Pierottia,M.A.和Greco A.,(2006)CancerLetters 232:90-98；Eric Adriaenssens,E.等Cancer Res(2008)68:(2)346-351)。Recent literature has also shown that overexpression, activation, amplification and/or mutation of Trk kinases are associated with many cancers, including neuroblastoma (Brodeur, G.M., Nat. Rev. Cancer 2003, 3, 203-216), ovarian cancer (Davidson.B. et al., Clin. Cancer Res. 2003, 9, 2248-2259), colorectal cancer (Bardelli, A., Science 2003, 300, 949), melanoma (Truzzi, F. et al., Dermato-Endocrinology 2008, 3(1), pp. 32-36), head and neck cancer (Yilmaz, T. et al., Cancer Biology and Therapy 2010, 10(6), pp. 644-653), gastric cancer (Du, J. et al., World Journal of Gastroenterology 2010, pp. 644-653), and ovarian cancer (Davidson.B. et al., Clin. Cancer Res. 2003, 9, 2248-2259). 2003, 9(7), pp. 1431-1434), lung cancer (Ricci A., et al., American Journal of Respiratory Cell and Molecular Biology 25(4), pp. 439-446), breast cancer (Jin, W., et al., Carcinogenesis 2010, 31(11), pp. 1939-1947), glioblastoma (Wadhwa, S., et al., Journal of Biosciences 2003, 28(2), pp. 181-188), medulloblastoma (Gruber-Olipitz, M., et al., Journal of Proteome Research 2008, 7(5), pp. 1932-1944), secretory breast cancer (Euthus, D.M., et al., Cancer Cell 2002, 2(5), pp. 347-348), salivary gland cancer (Li, Y.-G., et al., Chinese Journal of Cancer Prevention 2008, pp. 193-1949), and ovarian cancer (Li, Y.-G., et al., Chinese Journal of Cancer Prevention 2008, pp. 193-1949). and Treatment 2009, 16(6), pp. 428-430), papillary thyroid carcinoma (Greco, A. et al., Molecular and Cellular Endocrinology 2010, 321(1), pp. 44-49), and adult myeloid leukemia (Eguchi, M. et al., Blood 1999, 93(4), pp. 1355-1363). In preclinical models of cancer, non-selective small molecule inhibitors of Trk A, Trk B, and Trk C are effective in inhibiting tumor growth and halting tumor metastasis (Nakagawara, A. (2001) Cancer Letters 169:107-114; Meyer, J. et al. (2007) Leukemia, 1-10; Pierottia, M.A. and Greco A., (2006) Cancer Letters 232:90-98; Eric Adriaenssens, E. et al. Cancer Res (2008) 68:(2)346-351).
另外，已显示神经营养因子/Trk途径的抑制在用NGF抗体或Trk A的非选择性小分子抑制剂的炎症性疾病的临床前模型的治疗中有效。例如，神经营养因子/Trk途径的抑制已牵涉以下的临床前模型：包括哮喘的炎症性肺疾病(Freund-Michel,V；Frossard,N.,Pharmacology&Therapeutics(2008)117(1),52-76)、间质性膀胱炎(Hu Vivian Y等TheJournal of Urology(2005),173(3),1016-21)、包括溃疡性结肠炎和克罗恩氏病(Crohn’sdisease)的炎症性肠病(Di Mola,F.F等,Gut(2000)46(5),670-678)和如特应性皮炎(Dou,Y.-C.等Archives of Dermatological Research(2006)298(1),31-37)、湿疹和牛皮癣(Raychaudhuri,S.P.等,J.Investigative Dermatology(2004)122(3),812-819)的炎症性皮肤疾病。Additionally, inhibition of the neurotrophin/Trk pathway has been shown to be effective in the treatment of preclinical models of inflammatory diseases with NGF antibodies or non-selective small molecule inhibitors of Trk A. For example, inhibition of the neurotrophin/Trk pathway has been implicated in preclinical models of inflammatory lung diseases including asthma (Freund-Michel, V; Frossard, N., Pharmacology & Therapeutics (2008) 117(1), 52-76), interstitial cystitis (Hu Vivian Y et al. The Journal of Urology (2005), 173(3), 1016-21), inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Di Mola, F.F et al. Gut (2000) 46(5), 670-678), and diseases such as atopic dermatitis (Dou, Y.-C. et al. Archives of Dermatological Research (2006) 298(1), 31-37), eczema and psoriasis (Raychaudhuri, S.P. et al. J. Investigative Medicine (2006) 48(2), 31-37). Dermatology (2004) 122(3), 812-819).
TrkA受体还被认为对人类宿主中寄生虫感染克氏锥虫(Trypanosoma cruzi)(恰加斯病(Chagas disease))的疾病感染过程是关键的(de Melo-Jorge,M.等,Cell Host&Microbe(2007)1(4),251-261)。The TrkA receptor is also thought to be critical for the disease process of the parasitic infection Trypanosoma cruzi (Chagas disease) in the human host (de Melo-Jorge, M. et al., Cell Host & Microbe (2007) 1(4), 251-261).
Trk抑制剂还可在治疗与骨重塑调节的不平衡相关的疾病中得到使用，如骨质疏松症、风湿性关节炎和骨转移。骨转移是常见的癌症并发症，患有晚期乳癌或前列腺癌的患者中高达70％并且患有肺癌、结肠癌、胃癌、膀胱癌、子宫癌、直肠癌、甲状腺癌或肾癌的患者中大约15％至30％会出现所述并发症。溶骨性转移可以引起严重疼痛、病理性骨折、致命性高钙血症、脊髓压迫以及其它神经压迫综合症。由于这些原因，骨转移为癌症的严重和高代价(costly)并发症。因此，可以诱导增殖性成骨细胞凋亡的药剂将是非常有利。在骨折的小鼠模型中，已在骨形成区中观察到TrkA受体的表达(K.Asaumi,等,Bone(2000)26(6)625-633)。另外，在几乎所有的骨形成细胞中观察到NGF的定位(K.Asaumi等)。最近，证实了Trk抑制剂抑制由结合人hFOB成骨细胞中的所有三种Trk受体的神经营养因子所激活的酪氨酸信号传递(J.Pinski等,(2002)62,986-989)。这些资料支持了在癌症患者中使用Trk抑制剂来治疗如骨转移的骨重塑疾病的基本原理。Trk inhibitors can also be used to treat diseases associated with an imbalance in bone remodeling regulation, such as osteoporosis, rheumatoid arthritis, and bone metastasis. Bone metastasis is a common cancer complication, occurring in up to 70% of patients with advanced breast or prostate cancer and approximately 15% to 30% of patients with lung, colon, stomach, bladder, uterine, rectal, thyroid, or kidney cancer. Osteolytic metastasis can cause severe pain, pathological fractures, fatal hypercalcemia, spinal cord compression, and other nerve compression syndromes. For these reasons, bone metastasis is a serious and costly complication of cancer. Therefore, agents that can induce apoptosis of proliferative osteoblasts would be very advantageous. In a mouse model of bone fracture, expression of the TrkA receptor has been observed in the bone formation zone (K. Asaumi, et al., Bone (2000) 26 (6) 625-633). In addition, localization of NGF has been observed in almost all bone-forming cells (K. Asaumi et al.). Recently, it was demonstrated that Trk inhibitors inhibit tyrosine signaling activated by neurotrophic factors that bind to all three Trk receptors in human hFOB osteoblasts (J. Pinski et al., (2002) 62, 986-989). These data support the rationale for using Trk inhibitors to treat bone remodeling diseases such as bone metastases in cancer patients.
认为适用于治疗疼痛或癌症的若干种类的Trk激酶的小分子抑制剂是已知(Expert Opin.Ther.Patents(2009)19(3),305-319)。Several classes of small molecule inhibitors of Trk kinases that are considered suitable for treating pain or cancer are known (Expert Opin. Ther. Patents (2009) 19(3), 305-319).
发明概述SUMMARY OF THE INVENTION
现已发现吡咯烷基脲、吡咯烷基硫脲和吡咯烷基胍化合物是TrkA的抑制剂，并且可适用于治疗如疼痛(包括慢性疼痛和急性疼痛)的病症和疾病。本发明的化合物可适用于治疗多种类型的疼痛，包括炎症性疼痛、神经病性疼痛以及与癌症、手术和骨折相关的疼痛。另外，本发明的化合物可适用于治疗癌症、炎症、神经变性疾病以及某些感染性疾病。It has been discovered that pyrrolidinyl urea, pyrrolidinyl thiourea, and pyrrolidinyl guanidine compounds are inhibitors of TrkA and are useful in treating conditions and diseases such as pain, including chronic pain and acute pain. The compounds of the present invention are useful in treating various types of pain, including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fractures. In addition, the compounds of the present invention are useful in treating cancer, inflammation, neurodegenerative diseases, and certain infectious diseases.
更具体来说，本文提供式I化合物：More specifically, provided herein are compounds of Formula I:
或其立体异构体、互变异构体或药学上可接受的盐、溶剂合物或前药，其中Y-B部分和NH-C(＝X)-NH部分呈反式构型，并且R1、R2、Ra、Rb、Rc、Rd、X、Y、B和环C如本文所定义。or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the YB moiety and the NH-C(=X)-NH moiety are in trans configuration, and R1 , R2 , Ra,Rb ,Rc,Rd , X, Y, B, and ring C are as defined herein.
在一个实施方案中，本文提供式I'化合物：In one embodiment, provided herein is a compound of formula I':
或其立体异构体、互变异构体或药学上可接受的盐、溶剂合物或前药，其中环B和NH-C(＝X)-NH部分呈反式构型，并且R1、R2、Ra、Rb、Rc、Rd、X、环B和环C如本文所定义。or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Ring B and the NH-C(=X)-NH moiety are in a trans configuration, and R1 , R2 , Ra,Rb ,Rc,Rd , X, Ring B, and Ring C are as defined herein.
本发明的另一方面提供预防或治疗由TrkA调节的疾病或病症的方法，其包括给有此种治疗需要的哺乳动物施用有效量的本发明的化合物或其立体异构体、溶剂合物或药学上可接受的盐。在一个实施方案中，疾病和病症包括慢性疼痛和急性疼痛，包括但不限于炎症性疼痛、神经病性疼痛以及与癌症、手术和骨折相关的疼痛。在另一实施方案中，疾病和病症包括但不限于癌症、炎症、神经变性疾病以及某些感染性疾病。Another aspect of the present invention provides a method for preventing or treating a disease or condition regulated by TrkA, comprising administering to a mammal in need of such treatment an effective amount of a compound of the present invention or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof. In one embodiment, the diseases and conditions include chronic pain and acute pain, including but not limited to inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and fractures. In another embodiment, the diseases and conditions include but are not limited to cancer, inflammation, neurodegenerative diseases, and certain infectious diseases.
本发明的另一方面提供一种包含本发明的化合物或其药学上可接受的盐的药物组合物。Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.
本发明的另一方面提供用于治疗的本发明的化合物。Another aspect of the present invention provides a compound of the invention for use in therapy.
本发明的另一方面提供用于治疗慢性疼痛和急性疼痛的疾病和病症的本发明的化合物，所述慢性疼痛和急性疼痛包括但不限于炎症性疼痛、神经病性疼痛以及与癌症、手术和骨折相关的疼痛。本发明的另一方面提供用于治疗选自癌症、炎症、神经变性疾病以及某些感染性疾病的疾病和病症的本发明的化合物。Another aspect of the present invention provides compounds of the present invention for use in treating diseases and conditions of chronic pain and acute pain, including but not limited to inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fractures. Another aspect of the present invention provides compounds of the present invention for use in treating diseases and conditions selected from cancer, inflammation, neurodegenerative diseases, and certain infectious diseases.
本发明的另一方面提供本发明的化合物在制造用于治疗如慢性疼痛和急性疼痛的疾病和病症的药剂中的用途，所述慢性疼痛和急性疼痛包括但不限于炎症性疼痛、神经病性疼痛以及与癌症、手术和骨折相关的疼痛。Another aspect of the present invention provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of diseases and conditions such as chronic pain and acute pain, including but not limited to inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fractures.
本发明的另一方面提供本发明的化合物在制造用于治疗选自癌症、炎症、神经变性疾病以及某些感染性疾病的疾病和病症的药剂中的用途。Another aspect of the present invention provides the use of a compound of the present invention in the manufacture of a medicament for treating diseases and conditions selected from cancer, inflammation, neurodegenerative diseases, and certain infectious diseases.
本发明的另一方面提供用于制备式I化合物的中间体。Another aspect of the present invention provides intermediates for preparing compounds of formula I.
本发明的另一方面包括本发明的化合物的制备方法、分离方法以及纯化方法。Another aspect of the present invention includes methods for preparing, isolating, and purifying the compounds of the present invention.
发明详述Detailed Description of the Invention
本文提供了潜在适用于治疗由TrkA调节的疾病、病状和/或病症的化合物和其药物制剂。Provided herein are compounds and pharmaceutical formulations thereof that are potentially useful in treating diseases, conditions, and/or disorders modulated by TrkA.
一个实施方案提供式I化合物：One embodiment provides a compound of formula I:
或其立体异构体、互变异构体或药学上可接受的盐、溶剂合物或前药，其中：or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
Y-B部分和NH-C(＝X)-NH部分呈反式构型；The Y-B moiety and the NH-C(=X)-NH moiety are in a trans configuration;
Ra、Rb、Rc和Rd独立地选自H和(1-3C)烷基；Ra ,Rb ,Rc andRd are independently selected from H and (1-3C)alkyl;
X是O、S或NH；X is O, S or NH;
R1是(1-3C烷氧基)(1-6C)烷基、(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、氨基羰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-6C)烷基、(1-3C烷基氨基)(1-3C)烷基、(1-4C烷氧基羰基)(1-6C)烷基、氨基(1-6C)烷基、羟基(1-3C烷氧基)(1-6C)烷基、二(1-3C烷氧基)(1-6C)烷基、(1-3C烷氧基)三氟(1-6C)烷基、羟基三氟(1-6C)烷基、(1-4C烷氧基羰基)(1-3C烷氧基)(1-6C)烷基、羟基羰基(1-3C烷氧基)(1-6C)烷基、hetAr5(CH2)0-1或Ar5(CH2)0-1；R1 is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3C alkyl) alkyl), (1-4C alkoxycarbonyl)(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3C alkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3C alkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4C alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl, hydroxycarbonyl(1-3C alkoxy)(1-6C)alkyl, hetAr5 (CH2 )0-1 or Ar5 (CH2 )0-1 ;
R2是H、F或OH；R2 is H, F or OH;
Y是键、-O-或-OCH2-；Y is a bond, -O- or -OCH2 -;
B是Ar1、hetAr1、1-6C烷基或(1-6C)烷氧基；B is Ar1 , hetAr1 , 1-6C alkyl or (1-6C)alkoxy;
Ar1是苯基，其任选被一个或多个独立地选自以下的取代基取代：卤素、CF3、CF3O-、(1-4C)烷氧基、羟基(1-4C)烷基、(1-6C)烷基和CN；Ar1 is phenyl, optionally substituted with one or more substituents independently selected from halogen, CF3 , CF3 O—, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl, and CN;
hetAr1是5至6元杂芳基，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、卤素、OH、CF3、NH2和羟基(1-2C)烷基；hetAr1 is a 5- to 6-membered heteroaryl group having 1 to 3 ring heteroatoms independently selected from N, S, and O, and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, halogen, OH, CF3 , NH2 , and hydroxy(1-2C)alkyl;
环C是式C-1、C-2或C-3Ring C is of formula C-1, C-2 or C-3
R3是H、(1-6C)烷基、羟基(1-6C)烷基、Ar2、hetCyc1、(3-7C)环烷基或hetAr2；R3 is H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar2 , hetCyc1 , (3-7C)cycloalkyl, or hetAr2 ;
Ar2是苯基，其任选被一个或多个独立地选自以下的基团取代：卤素、(1-6C)烷基和羟甲基；Ar2 is phenyl, optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and hydroxymethyl;
hetCyc1是5至6元饱和的或部分不饱和的杂环，其具有1至2个独立地选自N和O的环杂原子；hetCyc1 is a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O;
hetAr2是5至6元杂芳基环，其具有1至3个独立地选自N、O和S的环杂原子，并且任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基和卤素；hetAr2 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S, and optionally substituted with one or more groups independently selected from: (1-6C)alkyl and halogen;
R4是H、OH、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-3C烷氧基)(1-6C)烷基、氨基(1-6C)烷基、氨基羰基(1-6C)烷基、(1-3C)烷基磺酰胺基(1-6C)烷基、磺酰胺基(1-6C)烷基、羟基羰基(1-6C)烷基、hetAr3(1-6C)烷基、Ar3(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、二氟(1-6C)烷氧基、三氟(1-6C)烷氧基、四氟(2-6C)烷氧基、五氟(2-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、氨基(2-6C)烷氧基、氨基羰基(1-6C)烷氧基、羟基-羰基(1-6C)烷氧基、hetCyc2(1-6C)烷氧基、hetAr3(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基[任选被F、OH、(1-6C烷基)、(1-6C)烷氧基或(1-3C烷氧基)(1-6C)烷基取代]、hetAr4、Ar4、hetCyc2(O)CH2-、(1-4C烷氧基羰基)(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、氨基羰基(1-6C)烷氧基、hetCyc2C(＝O)(1-6C)烷氧基、羟基(1-3C烷氧基)(1-6C)烷氧基、羟基三氟(1-6C)烷氧基、(1-3C)烷基磺酰胺基(1-6C)烷氧基、(1-3C)烷基酰胺基(1-6C)烷氧基、二(1-3C烷基)氨基-羧基、hetCyc2C(＝O)O-、羟基二氟(1-6C)烷基、(1-4C烷基羧基)(1-6C)烷基、(1-6C)烷氧基羰基、羟基/羰基、氨基羰基、(1-3C烷氧基)氨基羰基、hetCyc3、卤素、CN、三氟甲基磺酰基、N-(1-3C烷基)吡啶酮基、N-(1-3C三氟烷基)吡啶酮基、(1-4C烷基硅烷氧基)(1-6C)烷氧基、异吲哚啉-1,3-二酮基(1-6C)烷氧基或N-(1-3C烷基)噁二唑酮基；R4 is H, OH, (1-6C) alkyl, monofluoro(1-6C) alkyl, difluoro(1-6C) alkyl, trifluoro(1-6C) alkyl, tetrafluoro(2-6C) alkyl, pentafluoro(2-6C) alkyl, cyano(1-6C) alkyl, hydroxy(1-6C) alkyl, dihydroxy(2-6C) alkyl, (1-3C alkoxy)(1-6C) alkyl, amino(1-6C) alkyl, aminocarbonyl(1-6C) alkyl, (1-3C) alkylsulfonamido(1-6C) alkyl, sulfonamido(1-6C) alkyl, hydroxycarbonyl(1-6C) alkyl, hetAr3 (1-6C) alkyl, Ar3 (1-6C) alkyl, (1-6C) alkoxy, monofluoro(1-6C) alkoxy, difluoro(1-6C) alkoxy, trifluoro(1-6C) alkoxy, tetrafluoro(2-6C) alkoxy, pentafluoro(2-6C) alkoxy, cyano(1-6C) alkoxy, hydroxy(1-6C) alkoxy, dihydroxy(2-6C) alkoxy, amino(2-6C) alkoxy, aminocarbonyl(1-6C) alkoxy, hydroxy-carbonyl(1-6C) alkoxy, hetCyc2 (1-6C) alkoxy, hetAr3 (1-6C) alkoxy, Ar3 (1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6Calkyl), (1-6C)alkoxy or (1-3Calkoxy)(1-6C)alkyl], hetAr4 , Ar4 , hetCyc2 (O)CH2 -, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc2 C(=O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy, di(1-3Calkyl)amino-carboxyl, hetCyc2 C(=O)O-, hydroxydifluoro(1-6C)alkyl, (1-4Calkylcarboxyl)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxy/carbonyl, aminocarbonyl, (1-3Calkoxy)aminocarbonyl, hetCyc3 , halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)pyridonyl, N-(1-3C trifluoroalkyl)pyridonyl, (1-4C alkylsilyloxy)(1-6C)alkoxy, isoindoline-1,3-dione(1-6C)alkoxy or N-(1-3C alkyl)oxadiazolone;
hetCyc2是4至6元杂环，其具有1至2个独立地选自N和O的环杂原子，并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷基羧基)(1-6C)烷基和(1-6C)酰基；hetCyc2 is a 4- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O, and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxyl)(1-6C)alkyl, and (1-6C)acyl;
hetCyc3是4至7元杂环，其具有1至2个独立地选自N和O的环杂原子，并且任选被一个或多个独立地选自以下的取代基取代：F、CN、CF3、(1-6C)烷基、羟基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)酰基-、(1-6C)烷基磺酰基、三氟甲基磺酰基以及(1-4C烷氧基)羰基；hetCyc3 is a 4- to 7-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O, and optionally substituted with one or more substituents independently selected from F, CN, CF3 , (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl, and (1-4C alkoxy)carbonyl;
hetAr3是5元杂芳基环，其具有1至3个独立地选自N、O和S的环原子，并且任选被(1-6C)烷基取代；hetAr3 is a 5-membered heteroaryl ring having 1 to 3 ring atoms independently selected from N, O and S, and optionally substituted with (1-6C)alkyl;
Ar3是苯基，其任选被(1-4C)烷氧基取代；Ar3 is phenyl, which is optionally substituted with (1-4C)alkoxy;
hetAr4是5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的取代基取代：(1-6C)烷基、卤素、CN、羟基(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、(3-6C环烷基)CH2-、(3-6C环烷基)C(＝O)-、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、(1-6C)烷基磺酰基、NH2、(1-6C烷基)氨基、二(1-6C烷基)氨基、(1-3C三氟烷氧基)、(1-3C)三氟烷基以及甲氧基苯甲基；或是9至10元双环杂芳基，其具有1至3个环氮原子；hetAr4 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S, and O, and optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH2 -, (3-6Ccycloalkyl)C(═O)-, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH2 , (1-6Calkyl)amino, di(1-6Calkyl)amino, (1-3Ctrifluoroalkoxy), (1-3C)trifluoroalkyl, and methoxybenzyl; or a 9- to 10-membered bicyclic heteroaryl having 1 to 3 ring nitrogen atoms;
Ar4是苯基，其任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基、卤素、CN、CF3、CF3O-、(1-6C)烷氧基、(1-6C烷基)OC(＝O)-、氨基羰基、(1-6C)烷基硫基、羟基(1-6C)烷基、(1-6C烷基)SO2-、HOC(＝O)-以及(1-3C烷氧基)(1-3C烷基)OC(＝O)-；Ar4 is phenyl, which is optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF3 , CF3 O-, (1-6C)alkoxy, (1-6C alkyl)OC(═O)-, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO2 -, HOC(═O)-, and (1-3C alkoxy)(1-3C alkyl)OC(═O)-;
R5是H、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、卤素、CN、(1-4C)烷氧基、羟基(1-4C)烷基、(1-3C烷氧基)(1-4C)烷基、(1-4C烷基)OC(＝O)-、(1-6C)烷基硫基、苯基[任选被一个或多个独立地选自卤素、(1-6C)烷基和(1-6C)烷氧基的基团取代]、(3-4C)环烷基、氨基、氨基羰基或三氟(1-3C烷基)酰胺基；或Ris H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3Calkoxy)(1-4C)alkyl, (1-4Calkyl)OC(═O)—, (1-6C)alkylthio, phenyl [optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy], (3-4C)cycloalkyl, amino, aminocarbonyl or trifluoro(1-3Calkyl)amido; or
R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和的或不饱和的碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代，或R4 andR5 together with the atoms to which they are attached form a 5- to 6-membered saturated, partially unsaturated or unsaturated carbocyclic ring, which is optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or
R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和的或不饱和的杂环，其具有选自N、O或S的环杂原子，其中所述杂环任选被一个或两个独立地选自(1-6C烷基)C(＝O)O-、(1-6)酰基、(1-6C)烷基和氧代基的取代基取代，并且所述硫环原子任选被氧化成S(＝O)或SO2；R4 andR5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or unsaturated heterocyclic ring having ring heteroatoms selected from N, O or S, wherein the heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(=O)O-, (1-6)acyl, (1-6C)alkyl and oxo, and the sulfur ring atom is optionally oxidized to S(=O) orSO2 ;
hetAr5是5至6元杂芳基环，其具有1至3个独立地选自N、O或S的环杂原子，其中所述环任选被一个或多个独立地选自以下的取代基取代：卤素、(1-6C)烷基、(1-6C)烷氧基和CF3；hetAr5 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, or S, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, and CF3 ;
Ar5是苯基，其任选被一个或多个独立地选自以下的基团取代：卤素、(1-6C)烷基、(1-6C)烷氧基、CF3O-、(1-4C)烷氧基羰基和氨基羰基；Ar5 is phenyl, optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CF3 O—, (1-4C)alkoxycarbonyl, and aminocarbonyl;
R3a是氢、卤素、(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、任选被一个或多个独立地选自卤素、(1-6C)烷基和羟甲基的取代基取代的苯基，或具有1至3个独立地选自N、O和S的环杂原子并且任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代的5至6元杂芳基环；R3a is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C)alkyl and hydroxymethyl, or a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S and optionally substituted by one or more groups independently selected from (1-6C)alkyl and halogen;
R3b是氢、(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、任选被一个或多个独立地选自卤素、(1-6C)烷基和羟甲基的取代基取代的苯基，或具有1至3个独立地选自N、O和S的环杂原子并且任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代的5至6元杂芳基环；R3b is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C)alkyl and hydroxymethyl, or a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S and optionally substituted by one or more groups independently selected from (1-6C)alkyl and halogen;
R4a是氢、(1-6C)烷基、三氟(1-6C)烷基、苯基[任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基、卤素、CN、CF3、CF3O-、(1-6C)烷氧基、(1-6C烷基)OC(＝O)-、氨基羰基、(1-6C)烷基硫基、羟基(1-6C)烷基、(1-6C烷基)SO2-、HOC(＝O)-以及(1-3C烷氧基)(1-3C烷基)OC(＝O)-]；或5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子并且任选被1至2个独立地选自以下的取代基取代：(1-6C)烷基、羟基(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、(3-6C环烷基)CH2-、(3-6C环烷基)C(＝O)-、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、(1-6C)烷基磺酰基、NH2、(1-6C烷基)氨基、二(1-6C烷基)氨基、(1-3C三氟烷氧基)(1-3C)三氟烷基以及甲氧基苯甲基；并且R4a is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionally substituted by one or more groups independently selected from the group consisting of (1-6C)alkyl, halogen, CN, CF3 , CF3 O-, (1-6C)alkoxy, (1-6C alkyl)OC(═O)-, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO2 -, HOC(═O)-, and (1-3C alkoxy)(1-3C alkyl)OC(═O)-]; or a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S, and O and optionally substituted by 1 to 2 substituents independently selected from the group consisting of (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH2 -, (3-6C cycloalkyl)C(=O)-, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH2 , (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl, and methoxybenzyl; and
R5a是氢、卤素、(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、任选被一个或多个独立地选自卤素、(1-6C)烷基和羟甲基的取代基取代的苯基，或具有1至3个独立地选自N、O和S的环杂原子并且任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代的5至6元杂芳基环。R5a is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C)alkyl and hydroxymethyl, or a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S and optionally substituted by one or more groups independently selected from (1-6C)alkyl and halogen.
在一个实施方案中，式I化合物具有结构I'：In one embodiment, the compound of formula I has structure I':
或其立体异构体、互变异构体或药学上可接受的盐、溶剂合物或前药，其中：or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
环B和NH-C(＝X)-NH部分呈反式构型；Ring B and the NH-C(=X)-NH moiety are in a trans configuration;
Ra、Rb、Rc和Rd独立地选自H和(1-3C)烷基；Ra ,Rb ,Rc andRd are independently selected from H and (1-3C)alkyl;
X是O或S；X is O or S;
R1是(1-3C烷氧基)(1-6C)烷基、(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、氨基羰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-6C)烷基或(1-3C烷基氨基)(1-3C)烷基；Ris (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C)alkyl, or (1-3C alkylamino)(1-3C)alkyl;
R2是H、F或OH；R2 is H, F or OH;
环B是Ar1或hetAr1；Ring B is Ar1 or hetAr1 ;
Ar1是苯基，其任选被一个或多个独立地选自以下的取代基取代：卤素、CF3、CF3O-、(1-4C)烷氧基、羟基(1-4C)烷基和(1-6C)烷基；Ar1 is phenyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, CF3 , CF3 O—, (1-4C)alkoxy, hydroxy(1-4C)alkyl, and (1-6C)alkyl;
hetAr1是5至6元杂芳基，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、卤素、OH、CF3、NH2和羟基((1-2C))烷基；hetAr1 is a 5- to 6-membered heteroaryl group having 1 to 3 ring heteroatoms independently selected from N, S, and O, and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, halogen, OH, CF3 , NH2 , and hydroxy((1-2C))alkyl;
环C是Ring C is
R3是H、(1-6C)烷基、羟基(1-6C)烷基、Ar2、hetCyc1、(3-7C)环烷基或hetAr2；R3 is H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar2 , hetCyc1 , (3-7C)cycloalkyl, or hetAr2 ;
Ar2是苯基，其任选被一个或多个独立地选自以下的基团取代：卤素、(1-6C)烷基和羟甲基；Ar2 is phenyl, optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and hydroxymethyl;
hetCyc1是5至6元饱和或部分不饱和的杂环，其具有1至2个独立地选自N和O的环杂原子；hetCyc1 is a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O;
hetAr2是5至6元杂芳基环，其具有1至3个独立地选自N、O和S的环杂原子并且任选被(1-6C)烷基取代；hetAr2 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;
R4是H、OH、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-3C烷氧基)(1-6C)烷基、氨基(1-6C)烷基、氨基羰基(1-6C)烷基、(1-3C)烷基磺酰胺基(1-6C)烷基、磺酰胺基(1-6C)烷基、羟基羰基(1-6C)烷基、hetAr3(1-6C)烷基、Ar3(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、二氟(1-6C)烷氧基、三氟(1-6C)烷氧基、四氟(2-6C)烷氧基、五氟(2-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、氨基(2-6C)烷氧基、氨基羰基(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、hetCyc2(1-6C)烷氧基、hetAr3(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R4 is H, OH, (1-6C) alkyl, monofluoro(1-6C) alkyl, difluoro(1-6C) alkyl, trifluoro(1-6C) alkyl, tetrafluoro(2-6C) alkyl, pentafluoro(2-6C) alkyl, cyano(1-6C) alkyl, hydroxy(1-6C) alkyl, dihydroxy(2-6C) alkyl, (1-3C alkoxy)(1-6C) alkyl, amino(1-6C) alkyl, aminocarbonyl(1-6C) alkyl, (1-3C) alkylsulfonamido(1-6C) alkyl, sulfonamido(1-6C) alkyl, hydroxycarbonyl(1-6C) alkyl, hetAr3 (1-6C) alkyl, Ar3 (1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc2 (1-6C)alkoxy, hetAr3 (1-6C)alkoxy, Ar3 (1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 or Ar4 ;
hetCyc2是4至6元杂环，其具有1至2个独立地选自N和O的环杂原子并且任选被1至2个独立地选自(1-6C)烷基的基团取代；hetCyc2 is a 4- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl;
hetAr3是5元杂芳基环，其具有1至3个独立地选自N、O和S的环原子并且任选被(1-6C)烷基取代；hetAr3 is a 5-membered heteroaryl ring having 1 to 3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;
Ar3是苯基，其任选被(1-4C)烷氧基取代；Ar3 is phenyl, which is optionally substituted with (1-4C)alkoxy;
hetAr4是5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子并且任选被1至2个独立地选自(1-6C)烷基的取代基取代；或是9至10元双环杂芳基，其具有1至3个环氮原子；hetAr4 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl; or a 9- to 10-membered bicyclic heteroaryl having 1 to 3 ring nitrogen atoms;
Ar4是苯基，其任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基、卤素、CN、CF3、CF3O-、(1-6C)烷氧基、(1-6C烷基)OC(＝O)-、氨基羰基、(1-6C)烷基硫基、羟基(1-6C)烷基、(1-6C烷基)SO2-、HOC(＝O)-和(1-3C烷氧基)(1-3C烷基)OC(＝O)-；并且Ar4 is phenyl, which is optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF3 , CF3 O-, (1-6C)alkoxy, (1-6C alkyl)OC(═O)-, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO2 -, HOC(═O)-, and (1-3C alkoxy)(1-3C alkyl)OC(═O)-; and
R5是H、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、卤素、CN、(1-4C)烷氧基、羟基(1-4C)烷基、(1-3C烷氧基)(1-4C)烷基、(1-4C烷基)OC(＝O)-、(1-6C)烷基硫基，或任选被一个或多个独立地选自以下的基团取代的苯基：卤素、(1-6C)烷基和(1-6C)烷氧基；或Ris H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3Calkoxy)(1-4C)alkyl, (1-4Calkyl)OC(═O)—, (1-6C)alkylthio, or phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; or
R4和R5连同其所连接的原子一起形成5至6元饱和碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代，或R4 andR5 together with the atoms to which they are attached form a 5- to 6-membered saturated carbocyclic ring, which is optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or
R4和R5连同其所连接的原子一起形成5至6元饱和杂环，其具有选自N、O或S的环杂原子，其中所述环氮原子任选被(1-6C烷基)C(＝O)O-或(1-6)酰基取代并且所述硫环原子任选被氧化成S(＝O)或SO2。R4 andR5 together with the atoms to which they are attached form a 5- to 6-membered saturated heterocyclic ring having ring heteroatoms selected from N, O or S, wherein the ring nitrogen atom is optionally substituted with (1-6Calkyl)C(=O)O- or (1-6)acyl and the sulfur ring atom is optionally oxidized to S(=O) orSO2 .
应了解，在连续使用两个或更多个基团定义连接至结构的取代基的情况下，首先提及的基团看作末端并且最后提及的基团看作连接至所述结构。因此，例如，基团“烷氧基烷基”通过烷基连接至所述结构。It will be understood that where two or more groups are used consecutively to define a substituent attached to a structure, the first mentioned group is considered terminal and the last mentioned group is considered attached to the structure. Thus, for example, the group "alkoxyalkyl" is attached to the structure via the alkyl group.
如本文所用的术语“(1-6C)烷基”、“(1-4C)烷基”和“(1-3C)烷基”是指分别具有1至6个碳原子、1至4个碳原子和1至3个碳原子的饱和直链单价烃基或分别具有3至6个碳原子、3至4个碳原子或3个碳原子的支链饱和单价烃基。实例包括但不限于：甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丙基、2-丁基、2-甲基-2-丙基、2,2-二甲基丙基、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基以及3,3-二甲基-2-丁基。As used herein, the terms "(1-6C)alkyl", "(1-4C)alkyl" and "(1-3C)alkyl" refer to a saturated straight-chain monovalent hydrocarbon group having 1 to 6 carbon atoms, 1 to 4 carbon atoms and 1 to 3 carbon atoms, respectively, or a branched-chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, 3 to 4 carbon atoms or 3 carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethylpropyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.
“(1-4C)烷氧基”、“(1-3C)烷氧基”、“(1-6C)烷氧基”和“(2-6C)烷氧基”是指-OR基团，其中R分别是如上文所定义的(1-4C)烷基、(1-3C)烷基、(1-6C)烷基或(2-6C)烷基。实例包括甲氧基、乙氧基以及类似基团。"(1-4C)alkoxy," "(1-3C)alkoxy," "(1-6C)alkoxy," and "(2-6C)alkoxy" refer to -OR groups where R is (1-4C)alkyl, (1-3C)alkyl, (1-6C)alkyl, or (2-6C)alkyl, respectively, as defined above. Examples include methoxy, ethoxy, and the like.
“(1-6)酰基”意指RC(＝O)-基团，其中R是具有1至5个碳原子的直链饱和单价烃基或具有3至5个碳原子的支链饱和单价烃基，例如甲基羰基和类似基团。"(1-6)acyl" means a RC(=O)- group where R is a straight chain saturated monovalent hydrocarbon group having 1 to 5 carbon atoms or a branched chain saturated monovalent hydrocarbon group having 3 to 5 carbon atoms, such as methylcarbonyl and the like.
“(1-3C烷氧基)(1-6C)烷基”和“(1-3C烷氧基)(1-4C)烷基”意指分别具有1至6个碳原子或1至4个碳原子的直链饱和单价烃基或具有3至6个碳原子或3至4个碳原子的支链饱和单价烃基，其中一个碳原子被一个如本文所定义的(1-3C)烷氧基取代。“(1-3C alkoxy)(1-6C)alkyl” and “(1-3C alkoxy)(1-4C)alkyl” mean a straight-chain saturated monovalent hydrocarbon radical having 1 to 6 carbon atoms or 1 to 4 carbon atoms, or a branched-chain saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms or 3 to 4 carbon atoms, respectively, wherein one carbon atom is substituted with one (1-3C)alkoxy radical as defined herein.
“(1-3C烷氧基)(1-6C)烷氧基”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被如本文所定义的(1-3C)烷氧基取代。实例包括甲氧基甲氧基、甲氧基乙氧基以及类似基团。"(1-3C alkoxy)(1-6C)alkoxy" means a (1-6C)alkoxy group as defined herein in which one carbon atom is substituted with a (1-3C)alkoxy group as defined herein. Examples include methoxymethoxy, methoxyethoxy, and the like.
“(1-3C烷氧基)氨基羰基”意指(1-3C烷基)-O-NH-C(＝O)-基团。"(1-3C alkoxy)aminocarbonyl" means a (1-3C alkyl)-O-NH-C(=O)- group.
“(1-6C)烷氧基羰基”和“(1-4C)烷氧基羰基”分别意指(1-6C)-O-C(＝O)-和(1-4C)-O-C(＝O)-基团。"(1-6C)alkoxycarbonyl" and "(1-4C)alkoxycarbonyl" mean (1-6C)-O-C(=O)- and (1-4C)-O-C(=O)- groups, respectively.
“(1-4C烷氧基羰基)(1-6C)烷基”意指如本文所定义的(1-6C)烷基，其中一个碳被如本文所定义的(1-4C烷氧基)羰基取代。"(1-4C alkoxycarbonyl)(1-6C)alkyl" means a (1-6C)alkyl group as defined herein, wherein one carbon is substituted with a (1-4C alkoxy)carbonyl group as defined herein.
“(1-3C烷氧基)三氟(1-6C)烷基”意指如本文所定义的(1-6C)烷基，其中一个碳被三个氟取代，并且另一个碳被如本文所定义的(1-3C)烷氧基取代。"(1-3C alkoxy)trifluoro(1-6C)alkyl" means a (1-6C)alkyl group as defined herein wherein one carbon is substituted with three fluorines and another carbon is substituted with a (1-3C)alkoxy group as defined herein.
“(1-4C烷氧基羰基)(1-6C烷氧基)”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被一个(1-4C)烷氧基羰基(即，烷基-O-C(＝O)-基团)取代。"(1-4C alkoxycarbonyl)(1-6C alkoxy)" means a (1-6C)alkoxy group as defined herein in which one carbon atom is replaced by a (1-4C)alkoxycarbonyl group (i.e., an alkyl-O-C(=O)- group).
“(1-4C烷氧基羰基)(1-3C烷氧基)(1-6C)烷基”意指如本文所定义的(1-3C烷氧基)(1-6C)烷基，其中一个碳原子被一个(1-4C)烷氧基羰基(即，烷基-O-C(＝O)-基团)取代。“(1-4C alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl” means a (1-3C alkoxy)(1-6C)alkyl group as defined herein, in which one carbon atom is replaced by a (1-4C)alkoxycarbonyl group (i.e., an alkyl-O—C(═O)— group).
“(1-3C烷氧基)羟基羰基烷基”意指如本文所定义的羟基羰基烷基，其中一个碳原子被一个(1-3C烷氧基)取代。"(1-3C alkoxy)hydroxycarbonylalkyl" means a hydroxycarbonylalkyl group as defined herein in which one carbon atom is replaced by one (1-3C alkoxy group.
“氨基”意指-NRR'基团，其中R和R'独立地选自氢或如本文所定义的(1-3C)烷基。实例包括H2N-、CH3NH-、(CH3)2N以及类似基团。"Amino" means a -NRR' group where R and R' are independently selected from hydrogen or (1-3C)alkyl as defined herein. Examples includeH2N- ,CH3NH- , (CH3 )2N , and the like.
“氨基(1-6C)烷基”意指具有1至6个碳原子的直链饱和单价烃基或具有3至6个碳原子的支链饱和单价烃基，其中一个碳原子被一个-NRR'基团取代，其中R和R'独立地选自氢或如本文所定义的(1-3C)烷基。实例包括氨基甲基、甲基氨基乙基、2-乙基氨基-2-甲基乙基以及类似基团。"Amino(1-6C)alkyl" means a linear, saturated, monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched, saturated, monovalent hydrocarbon radical having 3 to 6 carbon atoms, one of which is substituted with a -NRR' group, wherein R and R' are independently selected from hydrogen or (1-3C)alkyl as defined herein. Examples include aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, and the like.
“氨基(2-6C)烷氧基”意指如本文所定义的(2-6C)烷氧基，其中一个碳原子被一个-NRR'基团取代，其中R和R'独立地选自氢或如本文所定义的(1-3C)烷基。"Amino(2-6C)alkoxy" means a (2-6C)alkoxy group as defined herein wherein one carbon atom is substituted with a -NRR' group, wherein R and R' are independently selected from hydrogen or (1-3C)alkyl as defined herein.
“氨基羰基”意指RR'NCO-基团，其中R和R'独立地是氢或如本文所定义的(1-6C)烷基。实例包括H2NCO-、二甲基氨基羰基以及类似基团。"Aminocarbonyl" means a RR'NCO- group where R and R' are independently hydrogen or (1-6C)alkyl as defined herein. Examples includeH2NCO- , dimethylaminocarbonyl, and the like.
“氨基羰基(1-6C)烷基”意指具有1至6个碳原子的直链饱和烃基或具有3至6个碳的支链饱和单价烃基，其中一个碳原子被一个如本文所定义的氨基羰基取代，例如2-氨基羰基乙基、1-二甲基氨基羰基丙基、2-二甲基氨基羰基丙基或3-二甲基氨基羰基丙基以及类似基团。"Aminocarbonyl(1-6C)alkyl" means a straight-chain saturated hydrocarbon radical having 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms, in which one carbon atom is substituted with an aminocarbonyl group as defined herein, for example, 2-aminocarbonylethyl, 1-dimethylaminocarbonylpropyl, 2-dimethylaminocarbonylpropyl or 3-dimethylaminocarbonylpropyl and the like.
“氨基羰基(1-6C)烷氧基”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被一个如本文所定义的氨基羰基取代。"Aminocarbonyl(1-6C)alkoxy" means a (1-6C)alkoxy group as defined herein, wherein one carbon atom is substituted by an aminocarbonyl group as defined herein.
“(1-3C)烷基酰胺基(1-6C)烷氧基”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被一个烷基氨基取代，即，被(1-3C)C(＝O)NH-基团取代。"(1-3C)alkylamido(1-6C)alkoxy" means a (1-6C)alkoxy group as defined herein, wherein one carbon atom is substituted by an alkylamino group, ie, by a (1-3C)C(=O)NH- group.
“(1-4C烷基)羧基”意指R'-C(＝O)O-基团，其中R'是(1-4C)烷基。"(1-4C alkyl)carboxy" means an R'-C(=O)O- group where R' is (1-4C)alkyl.
“(1-4C烷基硅烷氧基)(1-6C)烷氧基”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被一个(1-4C烷基)硅烷氧基(例如(1-4C烷基)Si-O-基团，如叔丁基硅烷氧基)取代。“(1-4C alkylsilyloxy)(1-6C)alkoxy” means a (1-6C)alkoxy group as defined herein in which one carbon atom is replaced by a (1-4C alkyl)silyloxy group (e.g., a (1-4C alkyl)Si—O— group, such as tert-butylsilyloxy).
“(1-3C)烷基磺酰胺基”意指(1-3C)烷基SO2NH-基团，其中(1-3C)烷基是如本文所定义。"(1-3C)alkylsulfonamido" means a (1-3C)alkylSO2NH- group, wherein (1-3C)alkyl is as defined herein.
“(1-3C烷基磺酰胺基)(1-6C)烷基”意指被一个如本文所定义的(1-3C)烷基磺酰胺基取代的具有1至6个碳原子的直链饱和烃基或具有3至6个碳的支链饱和单价烃基。"(1-3C alkylsulfonamido)(1-6C)alkyl" means a straight chain saturated hydrocarbon group having 1 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms substituted with one (1-3C)alkylsulfonamido group as defined herein.
“(1-3C)烷基磺酰胺基(1-6C)烷氧基”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被一个如本文所定义的(1-3C)烷基磺酰胺基取代。"(1-3C)alkylsulfonamido(1-6C)alkoxy" means a (1-6C)alkoxy group as defined herein, wherein one carbon atom is substituted by a (1-3C)alkylsulfonamido group as defined herein.
“(1-3C)烷基磺酰基”意指-SO2R基团，其中R是如上文所定义的(1-3C)烷基，例如甲基磺酰基和类似基团。"(1-3C)alkylsulfonyl" means a-SO2R group where R is (1-3C)alkyl as defined above, for example methylsulfonyl and the like.
“(1-3C烷基磺酰基)(1-6C)烷氧基”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被(1-3C)烷基磺酰基取代。"(1-3C alkylsulfonyl)(1-6C)alkoxy" means a (1-6C)alkoxy group as defined herein wherein one carbon atom is replaced by a (1-3C)alkylsulfonyl group.
“羟基羰基”意指HOC(＝O)-。"Hydroxycarbonyl" means HOC(=O)-.
“(1-4C烷基)羧基(1-6C)烷基”意指如本文所定义的(1-6C)烷基，其中一个碳原子被如本文所定义的(1-4C烷基)羧基取代。"(1-4C alkyl)carboxy(1-6C)alkyl" means a (1-6C)alkyl group as defined herein, wherein one carbon atom is substituted by a (1-4C alkyl)carboxy group as defined herein.
“氰基(1-6C)烷基”意指被氰基(CN)取代的具有1至6个碳原子的直链饱和烃基或具有3至6个碳的支链饱和单价烃基。"Cyano(1-6C)alkyl" means a straight-chain saturated hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms substituted with a cyano (CN) group.
“(3-6C)环烷基”意指具有3至6个碳原子的环状饱和单价烃基，例如环丙基、环丁基、环戊基或环己基。The "(3-6C)cycloalkyl group" means a cyclic saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
“二(1-3C烷氧基)(1-6C)烷基”意指如本文所定义的(1-6C)烷基，其中两个碳各自被一个如本文所定义的(1-3C)烷氧基取代。"Di(1-3C alkoxy)(1-6C)alkyl" means a (1-6C)alkyl group as defined herein wherein two carbons are each substituted with one (1-3C)alkoxy group as defined herein.
“二羟基(2-6C)烷基”意指被两个羟基(OH)取代的具有2至6个碳原子的直链饱和烃基或具有3至6个碳的支链饱和单价烃基，其条件是两个羟基并非都处于同一碳原子上。"Dihydroxy(2-6C)alkyl" means a straight chain saturated hydrocarbon group having 2 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms substituted with two hydroxy (OH) groups, provided that the two hydroxy groups are not both on the same carbon atom.
“二羟基(2-6C)烷氧基”意指如本文所定义的(2-6C)烷氧基，其中两个碳原子被羟基取代。"Dihydroxy(2-6C)alkoxy" means a (2-6C)alkoxy group as defined herein wherein two carbon atoms are substituted with hydroxy groups.
如本文所用的“卤素”意指F、Cl、Br或I。As used herein, "halogen" means F, Cl, Br or I.
“杂环”是指具有一个或多个如对于特定杂环基团所述的环杂原子的饱和或部分不饱和的环系统，其中杂环任选被如对于所述特定杂环基团所定义的取代基取代。"Heterocycle" refers to a saturated or partially unsaturated ring system having one or more ring heteroatoms as described for the specific heterocycle group, wherein the heterocycle is optionally substituted with substituents as defined for the specific heterocycle group.
“杂芳基”是指具有一个或多个如对于特定杂芳基所述的环杂原子的5至6元不饱和环系统，其中杂芳基任选被如对于所述特定杂芳基所定义的取代基取代。"Heteroaryl" refers to a 5- to 6-membered unsaturated ring system having one or more ring heteroatoms as described for the specific heteroaryl group, wherein the heteroaryl group is optionally substituted with substituents as defined for the specific heteroaryl group.
“hetCyc2C(＝O)(1-6C)烷氧基”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被hetCyc2C(＝O)基团取代，其中hetCyc2是如本文所定义。"hetCyc2C (=O)(1-6C)alkoxy" means a (1-6C)alkoxy group as defined herein, wherein one carbon atom is substituted by ahetCyc2C (=O) group, whereinhetCyc2 is as defined herein.
“羟基(1-6C)烷基”和“羟基(1-4C)烷基”意指分别具有1至6个碳原子或1至4个碳原子的直链饱和烃基，或分别具有3至6个碳原子或3至4个碳原子的支链饱和单价烃基，其中一个碳原子被羟基(OH)取代。“Hydroxy(1-6C)alkyl” and “hydroxy(1-4C)alkyl” mean a straight-chain saturated hydrocarbon group having 1 to 6 carbon atoms or 1 to 4 carbon atoms, respectively, or a branched-chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms or 3 to 4 carbon atoms, respectively, in which one carbon atom is substituted with a hydroxy (OH) group.
“羟基(1-6C)烷氧基”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被羟基取代。"Hydroxy(1-6C)alkoxy" means a (1-6C)alkoxy group as defined herein in which one carbon atom is replaced by a hydroxy group.
“羟基(1-3C烷氧基)(1-6C)烷基”意指如本文所定义的(1-3C烷氧基)(1-6C)烷基，其中一个碳被羟基取代。"Hydroxy(1-3C alkoxy)(1-6C)alkyl" means a (1-3C alkoxy)(1-6C)alkyl group as defined herein, wherein one carbon is replaced by a hydroxy group.
“羟基(1-3C烷氧基)(1-6C)烷氧基”意指如本文所定义的(1-3C烷氧基)(1-6C)烷氧基，其中一个碳原子被羟基取代。"Hydroxy(1-3C alkoxy)(1-6C)alkoxy" means a (1-3C alkoxy)(1-6C)alkoxy group as defined herein, wherein one carbon atom is replaced by a hydroxy group.
“羟基二氟(1-6C)烷基”意指如本文所定义的二氟(1-6C)烷基，其中一个碳原子被羟基取代。"Hydroxydifluoro(1-6C)alkyl" means a difluoro(1-6C)alkyl group as defined herein, wherein one carbon atom is replaced by a hydroxy group.
“羟基三氟(1-6C)烷氧基”意指如本文所定义的三氟(1-6C)烷氧基，其中一个碳原子被羟基取代。"Hydroxytrifluoro(1-6C)alkoxy" means a trifluoro(1-6C)alkoxy group as defined herein, wherein one carbon atom is replaced by a hydroxy group.
“羟基羰基烷基”意指被一个-COOH基团取代的具有1至6个碳原子的直链饱和烃基或具有3至6个碳的支链饱和单价烃基。实例包括2-羟基羰基乙基、1-羟基羰基丙基、2-羟基羰基丙基或3-羟基羰基丙基以及类似基团。"Hydroxycarbonylalkyl" means a straight-chain saturated hydrocarbon radical having 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms substituted with one -COOH group. Examples include 2-hydroxycarbonylethyl, 1-hydroxycarbonylpropyl, 2-hydroxycarbonylpropyl, or 3-hydroxycarbonylpropyl, and the like.
“异吲哚啉-1,3-二酮基(1-6C)烷氧基”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被异吲哚啉-1,3-二酮基取代。"Isoindoline-1,3-dione (1-6C)alkoxy" means a (1-6C)alkoxy group as defined herein, wherein one carbon atom is substituted with an isoindoline-1,3-dione group.
“单氟(1-6C)烷基”、“二氟(1-6C)烷基”和“三氟(1-6C)烷基”是指如本文所定义的(1-6C)烷基，其中分别有1至3个氢原子被氟基置换。"Monofluoro(1-6C)alkyl", "difluoro(1-6C)alkyl" and "trifluoro(1-6C)alkyl" refer to (1-6C)alkyl groups as defined herein wherein 1 to 3 hydrogen atoms, respectively, are replaced by fluoro groups.
“四氟(2-6C)烷基”和“五氟(2-6C)烷基”是指具有2至6个碳原子的直链饱和单价烃基或具有3至6个碳原子的支链饱和单价烃基，其中分别有4至5个氢原子被氟基置换。“Tetrafluoro(2-6C)alkyl” and “pentafluoro(2-6C)alkyl” refer to a linear saturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, in which 4 to 5 hydrogen atoms are replaced by fluorine groups, respectively.
“(三氟甲氧基)(1-6C)烷基”意指被一个CF3O-基团取代的具有1至6个碳原子的直链饱和烃基或具有3至6个碳的支链饱和单价烃基。"(Trifluoromethoxy)(1-6C)alkyl" means a straight-chain saturated hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms substituted with oneCF3O- group.
“三氟(1-3C烷基)酰胺基”意指(1-3C烷基)C(＝O)NH-基团，其中一个碳被三个氟取代。"Trifluoro(1-3C alkyl)amido" means a (1-3C alkyl)C(=O)NH- group in which one carbon is replaced by three fluorines.
“三氟(1-6C)烷氧基”意指如本文所定义的(1-6C)烷氧基，其中一个碳原子被三个氟取代。"Trifluoro(1-6C)alkoxy" means a (1-6C)alkoxy group as defined herein wherein one carbon atom is replaced by three fluorines.
“磺酰胺基(1-6C)烷基”意指被一个磺酰胺基(H2NSO2NH-)取代的具有1至6个碳原子的直链饱和烃基或具有3至6个碳的支链饱和单价烃基。"Sulfonamido(1-6C)alkyl" means a straight-chain saturated hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms substitutedwith one sulfonamido group (H2NSO2NH- ).
应注意，本发明的化合物可含有可以互变异构形式存在的基团，如被杂原子取代的杂芳基或杂环基团以及类似基团，其在以下一般和特定实例中得以说明：It should be noted that the compounds of the present invention may contain groups that can exist in tautomeric forms, such as heteroaryl or heterocyclic groups substituted with heteroatoms and the like, which are illustrated in the following general and specific examples:
其中Y'＝O、S或NR，并且虽然在本文中命名、描述、呈现和/或要求一种形式，但在此种命名、描述、呈现和/或要求中意图固有地包括所有互变异构形式。wherein Y'=O, S or NR, and although one form is named, described, presented and/or claimed herein, all tautomeric forms are intended to be inherently included in such naming, description, presentation and/or claiming.
在式I的一个实施方案中，Ra、Rb、Rc和Rd独立地选自H和甲基。在一个实施方案中，Ra、Rb、Rc和Rd是氢。在一个实施方案中，Ra是甲基，并且Rb、Rc和Rd是氢。在一个实施方案中，Ra和Rb是甲基，并且Rc和Rd是氢。在一个实施方案中，Ra、Rb和Rc是氢，并且Rd是甲基。在一个实施方案中，Ra和Rb是氢，并且Rc和Rd是甲基。In one embodiment of Formula I,Ra ,Rb ,Rc , andRd are independently selected from H and methyl. In one embodiment,Ra ,Rb ,Rc , andRd are hydrogen. In one embodiment,Ra is methyl, and Rb,Rc , andRd are hydrogen. In one embodiment,Ra andRb are methyl, andRc andRd are hydrogen. In one embodiment,Ra ,Rb, andRc are hydrogen, andRd is methyl. In one embodiment,Ra andRb are hydrogen, andRc andRd are methyl.
在一个实施方案中，X是O。In one embodiment, X is O.
在一个实施方案中，X是S。In one embodiment, X is S.
在一个实施方案中，X是NH。In one embodiment, X is NH.
在一个实施方案中，R1是(1-3C烷氧基)(1-6C)烷基，例如甲氧基乙基、甲氧基丙基、乙氧基乙基和2-甲氧基丙基。具体实例包括具有以下结构的甲氧基乙基和2-甲氧基丙基：In one embodiment, R1 is (1-3C alkoxy)(1-6C)alkyl, such as methoxyethyl, methoxypropyl, ethoxyethyl, and 2-methoxypropyl. Specific examples include methoxyethyl and 2-methoxypropyl having the following structure:
在一个实施方案中，R1是(三氟甲氧基)(1-6C)烷基，例如三氟甲氧基乙基、三氟甲氧基丙基以及类似基团。具体实例是三氟甲氧基乙基。In one embodiment, R1 is (trifluoromethoxy)(1-6C)alkyl, such as trifluoromethoxyethyl, trifluoromethoxypropyl, and the like. A specific example is trifluoromethoxyethyl.
在一个实施方案中，R1是(1-3C硫烷基)(1-6C)烷基，例如甲硫烷基乙基、乙硫烷基乙基以及类似基团。具体实例是甲硫烷基乙基。In one embodiment, R1 is (1-3C sulfanyl)(1-6C)alkyl, such as methylsulfanylethyl, ethylsulfanylethyl, and the like. A specific example is methylsulfanylethyl.
在一个实施方案中，R1是单氟(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基。具体实例包括具有以下结构的1,3-二氟丙-2-基、2,2-二氟乙基、2,2,2-三氟乙基以及2,2,2-三氟丙基：In one embodiment, R1 is monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl. Specific examples include 1,3-difluoroprop-2-yl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoropropyl having the following structure:
在一个实施方案中，R1是四氟(2-6C)烷基或五氟(2-6C)烷基。具体实例是3,3,4,4,4-五氟丁基。In one embodiment, R1 is tetrafluoro(2-6C)alkyl or pentafluoro(2-6C)alkyl. A specific example is 3,3,4,4,4-pentafluorobutyl.
在一个实施方案中，R1是氰基(1-6C)烷基。具体实例是2-氰基乙基。In one embodiment, R1 is cyano(1-6C)alkyl. A specific example is 2-cyanoethyl.
在一个实施方案中，R1是氨基羰基(1-6C)烷基。具体实例是氨基羰基甲基。另一实例是具有式MeNHC(＝O)CH2-的甲基氨基羰基甲基。In one embodiment, R1 is aminocarbonyl(1-6C)alkyl. A specific example is aminocarbonylmethyl. Another example is methylaminocarbonylmethyl having the formula MeNHC(=O)CH2 -.
在一个实施方案中，R1是羟基(1-6C)烷基。具体实例是2-羟基乙基。另一实例是2-羟基丙基。In one embodiment, R1 is hydroxy(1-6C)alkyl. A specific example is 2-hydroxyethyl. Another example is 2-hydroxypropyl.
在一个实施方案中，R1是二羟基(2-6C)烷基。具体实例是以下结构：In one embodiment, R1 is dihydroxy(2-6C)alkyl. Specific examples are the following structures:
在一个实施方案中，R1是(1-6C)烷基。实例包括甲基、乙基和丙基。In one embodiment, R1 is (1-6C)alkyl. Examples include methyl, ethyl and propyl.
在一个实施方案中，R1是(1-3C烷基氨基)(1-3C)烷基，即被(1-3C烷基)氨基(例如(1-3C烷基)NH-基团，如甲基氨基)取代的(1-3C)烷基。具体实例是(2-甲基氨基)乙基。In one embodiment, R1 is (1-3C alkylamino)(1-3C)alkyl, i.e. (1-3C)alkyl substituted by (1-3C alkyl)amino (e.g. a (1-3C alkyl)NH- group, such as methylamino). A specific example is (2-methylamino)ethyl.
在一个实施方案中，R1是(1-4C烷氧基羰基)(1-6C)烷基。具体实例是具有以下结构的甲氧羰基甲基：In one embodiment, R1 is (1-4C alkoxycarbonyl)(1-6C)alkyl. A specific example is methoxycarbonylmethyl having the following structure:
在一个实施方案中，R1是氨基(1-6C)烷基，如甲基氨基(1-6C)烷基。具体实例是2-甲基氨基乙基。In one embodiment, R1 is amino(1-6C)alkyl, such as methylamino(1-6C)alkyl. A specific example is 2-methylaminoethyl.
在一个实施方案中，R1是羟基(1-3C烷氧基)(1-6C)烷基。实例包括羟基甲氧基(1-6C)烷基。具体实例包括以下结构：In one embodiment, R1 is hydroxy(1-3C alkoxy)(1-6C)alkyl. Examples include hydroxymethoxy(1-6C)alkyl. Specific examples include the following structures:
在一个实施方案中，R1是二(1-3C烷氧基)(1-6C)烷基。实例包括二甲氧基(1-6C)烷基。具体实例包括具有以下结构的1,3-二甲氧基丙-2-基：In one embodiment, R1 is di(1-3C alkoxy)(1-6C)alkyl. Examples include dimethoxy(1-6C)alkyl. Specific examples include 1,3-dimethoxyprop-2-yl having the following structure:
在一个实施方案中，R1是(1-3C烷氧基)三氟(1-6C)烷基。实例包括甲氧基三氟(1-6C)烷基。具体实例包括3,3,3-三氟-2-甲氧基丙基。In one embodiment, R1 is (1-3C alkoxy)trifluoro(1-6C)alkyl. Examples include methoxytrifluoro(1-6C)alkyl. Specific examples include 3,3,3-trifluoro-2-methoxypropyl.
在一个实施方案中，R1是羟基三氟(1-6C)烷基。具体实例包括3,3,3-三氟-2-羟基丙基。In one embodiment, R1 is hydroxytrifluoro(1-6C)alkyl. Specific examples include 3,3,3-trifluoro-2-hydroxypropyl.
在一个实施方案中，R1是(1-4C烷氧基羰基)(1-3C烷氧基)(1-6C)烷基。实例包括(甲氧羰基)甲氧基(1-6C)烷基。具体实例包括以下结构：In one embodiment, R1 is (1-4C alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl. Examples include (methoxycarbonyl)methoxy(1-6C)alkyl. Specific examples include the following structures:
在一个实施方案中，R1是羟基羰基(1-3C烷氧基)(1-6C)烷基。实例包括(甲氧羰基)羟基(1-6C)烷基。具体实例包括以下结构：In one embodiment, R1 is hydroxycarbonyl(1-3C alkoxy)(1-6C)alkyl. Examples include (methoxycarbonyl)hydroxy(1-6C)alkyl. Specific examples include the following structures:
在一个实施方案中，R1是hetAr5(CH2)0-1。In one embodiment, R1 is hetAr5 (CH2 )0-1 .
在一个实施方案中，R1是hetAr5，其中hetAr5是5至6元杂芳基环，其具有1至3个独立地选自N、O或S的环杂原子，其中所述环任选被一个或多个独立地选自以下的取代基取代：卤素、(1-6C)烷基、(1-6C)烷氧基和CF3。实例包括吡咯基、吡唑基、咪唑基、呋喃基、异噁唑基、噁唑基、噻吩基、噻唑基、噻二唑基、三唑基、噻二唑基、吡啶基、嘧啶基以及吡嗪基环，其中所述环任选被一个或多个独立地选自以下的取代基取代：卤素、(1-6C)烷基、(1-6C)烷氧基和CF3。In one embodiment, R1 is hetAr5 , wherein hetAr5 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, or S, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, and CF3 . Examples include pyrrolyl, pyrazolyl, imidazolyl, furanyl, isoxazolyl, oxazolyl, thienyl, thiazolyl, thiadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl rings, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, and CF3 .
在一个实施方案中，R1是hetAr5，其中herAr5是吡唑基、吡啶基或吡嗪基，其任选被一个或多个独立地选自以下的取代基取代：卤素、(1-6C)烷基、(1-6C)烷氧基和CF3。在一个实施方案中，herAr5被所述取代基中的一个取代。在一个实施方案中，R1是任选被甲基、三氟甲基、甲氧基或乙氧基取代的吡唑基、吡啶基或吡嗪基。In one embodiment, R1 is hetAr5 , wherein herAr5 is pyrazolyl, pyridinyl or pyrazinyl, which is optionally substituted with one or more substituents independently selected from halogen, (1-6C) alkyl, (1-6C) alkoxy and CF3 . In one embodiment, herAr5 is substituted with one of the substituents. In one embodiment, R1 is pyrazolyl, pyridinyl or pyrazinyl optionally substituted with methyl, trifluoromethyl, methoxy or ethoxy.
R1在由hetAr5表示时的具体实例包括以下结构：Specific examples of R1 when represented by hetAr5 include the following structures:
在一个实施方案中，R1是hetAr5(CH2)-，其中hetAr5是5至6元杂芳基环，其具有1至3个独立地选自N、O或S的环杂原子，其中所述环任选被一个或多个独立地选自以下的取代基取代：卤素、(1-6C)烷基、(1-6C)烷氧基和CF3。实例包括：吡咯基、吡唑基、咪唑基、呋喃基、异噁唑基、噁唑基、噻吩基、噻唑基、噻二唑基、三唑基、噻二唑基、吡啶基、嘧啶基以及吡嗪基环，其中所述环任选被一个或多个独立地选自以下的取代基取代：卤素、(1-6C)烷基、(1-6C)烷氧基和CF3。In one embodiment, R1 is hetAr5 (CH2 )-, wherein hetAr5 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, or S, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, and CF3. Examples include pyrrolyl, pyrazolyl, imidazolyl, furanyl, isoxazolyl, oxazolyl, thienyl, thiazolyl, thiadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl rings, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, and CF3 .
在一个实施方案中，R1是hetAr5(CH2)-，其中hetAr5是咪唑基、噻二唑基或三唑基，其任选被一个或多个独立地选自以下的取代基取代：卤素、(1-6C)烷基、(1-6C)烷氧基和CF3。在一个实施方案中，hetAr5被一个或多个独立地选自以下的取代基取代：甲基、甲氧基、乙氧基和三氟甲基。在一个实施方案中，hetAr5被所述取代基中的一个取代。In one embodiment, R1 is hetAr5 (CH2 )-, wherein hetAr5 is imidazolyl, thiadiazolyl or triazolyl, which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, (1-6C) alkyl, (1-6C) alkoxy and CF3. In one embodiment, hetAr5 is substituted with one or more substituents independently selected from the group consisting of methyl, methoxy, ethoxy and trifluoromethyl. In one embodiment, hetAr5 is substituted with one of the substituents.
R1在由hetAr5(CH2)-表示时的具体实例包括以下结构：Specific examples of R1 when represented by hetAr5 (CH2 )- include the following structures:
在一个实施方案中，R1是Ar5(CH2)0-1。In one embodiment, R1 is Ar5 (CH2 )0-1 .
在一个实施方案中，R1是Ar5，其中Ar5是苯基，其任选被一个或多个独立地选自以下的取代基取代：卤素、(1-6C)烷基、(1-6C)烷氧基、CF3O-、(1-4C)烷氧基羰基以及氨基羰基。在一个实施方案中，Ar5是苯基，其任选被一个或多个独立地选自以下的取代基取代：F、Cl、甲基、甲氧基、三氟甲氧基以及CH3C(＝O)O-。In one embodiment, R1 is Ar5 , wherein Ar5 is phenyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, (1-6C)alkyl, (1-6C)alkoxy, CF3 O—, (1-4C)alkoxycarbonyl, and aminocarbonyl. In one embodiment, Ar5 is phenyl, optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, methyl, methoxy, trifluoromethoxy, and CH3 C(═O)O—.
R1在由Ar5表示时的实例包括：苯基、2-甲氧基苯基、2-氟苯基、2-甲基苯基、2-氯苯基、2-三氟甲氧基苯基、2-(甲氧羰基)苯基、4-氟苯基以及2,6-二氟苯基。Examples of R1 when represented by Ar5 include phenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-methylphenyl, 2-chlorophenyl, 2-trifluoromethoxyphenyl, 2-(methoxycarbonyl)phenyl, 4-fluorophenyl, and 2,6-difluorophenyl.
在一个实施方案中，R1选自：(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基和三氟(1-6C)烷基。In one embodiment, R1 is selected from the group consisting of: (1-3C alkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, and trifluoro(1-6C)alkyl.
在一个实施方案中，R2是H。In one embodiment,R2 is H.
在一个实施方案中，R2是F。In one embodiment,R2 is F.
在一个实施方案中，R2是OH。In one embodiment,R2 is OH.
在一个实施方案中，式I中连接吡咯烷基环与B基团的Y基团是键。In one embodiment, the Y group connecting the pyrrolidinyl ring to the B group in Formula I is a bond.
在一个实施方案中，式I中连接吡咯烷基环与B基团的Y基团是-O-。In one embodiment, the Y group connecting the pyrrolidinyl ring to the B group in Formula I is -O-.
在一个实施方案中，式I中连接吡咯烷基环与B基团的Y基团是-OCH2-，其中Y基团的氧连接至吡咯烷基环。In one embodiment, the Y group connecting the pyrrolidinyl ring to the B group in Formula I is-OCH2- , wherein the oxygen of the Y group is connected to the pyrrolidinyl ring.
在一个实施方案中，B由环B表示，其中环B是Ar1，并且Ar1是苯基，其任选被一个或多个独立地选自以下的取代基取代：卤素、CF3、CF3O-、(1-4C)烷氧基、羟基(1-4C)烷基、(1-6C)烷基以及CN。实例包括苯基、氟苯基、二氟苯基、三氟苯基、氯苯基、三氟甲基苯基、甲氧基苯基、氰基苯基、氯氟苯基、氰基氟苯基以及氯氰基苯基。In one embodiment, B is represented by Ring B, wherein Ring B is Ar1 and Ar1 is phenyl, which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CF3 , CF3 O-, (1-4C) alkoxy, hydroxy (1-4C) alkyl, (1-6C) alkyl, and CN. Examples include phenyl, fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl, trifluoromethylphenyl, methoxyphenyl, cyanophenyl, chlorofluorophenyl, cyanofluorophenyl, and chlorocyanophenyl.
环B在由Ar1表示时的具体实例包括：苯基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、3,5-二氟苯基、2,4-二氟苯基、2,5-二氟苯基、3,4,5-三氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、3-三氟甲基苯基、3-甲氧基苯基、3-氯-4-氟苯基、4-氯-3-氟苯基、3-氯-5-氟苯基、3-氰基-5-氟苯基、2-氰基苯基、4-氰基苯基以及3-氰基-4-氟苯基。Specific examples of ring B when represented by Ar1 include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4,5-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl, 3-cyano-5-fluorophenyl, 2-cyanophenyl, 4-cyanophenyl and 3-cyano-4-fluorophenyl.
在一个实施方案中，B由环B表示，其中环B是Ar1，其中Ar1是苯基，其任选被一个或多个独立地选自以下的取代基取代：卤素、CF3、CF3O-、(1-4C)烷氧基、羟基(1-4C)烷基以及(1-6C)烷基。实例包括苯基、氟苯基、二氟苯基、三氟苯基、氯苯基、三氟甲基苯基以及甲氧基苯基。环B在由Ar1表示时的具体实例包括：苯基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、3,5-二氟苯基、2,4-二氟苯基、2,5-二氟苯基、3,4,5-三氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、3-三氟甲基苯基以及3-甲氧基苯基。In one embodiment, B is represented by ring B, wherein ring B is Ar1 , wherein Ar1 is phenyl, which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CF3 , CF3 O-, (1-4C) alkoxy, hydroxy (1-4C) alkyl, and (1-6C) alkyl. Examples include phenyl, fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl, trifluoromethylphenyl, and methoxyphenyl. Specific examples of ring B when represented by Ar1 include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4,5-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, and 3-methoxyphenyl.
在一个实施方案中，B由环B表示，其中环B是Ar1，其中Ar1是任选被一个或多个卤素取代的苯基。In one embodiment, B is represented by Ring B, wherein Ring B is Ar1 , wherein Ar1 is phenyl optionally substituted with one or more halogens.
在一个实施方案中，B由环B表示，其中环B是如对于式I所定义的Ar1并且Y是键。In one embodiment, B is represented by Ring B, wherein Ring B is Ar1 as defined for Formula I and Y is a bond.
在一个实施方案中，B由环B表示，其中环B是如对于式I所定义的Ar1并且Y是-O-。具体实例包括具有以下结构的-Y-B基团：In one embodiment, B is represented by Ring B, wherein Ring B isAr as defined for Formula I and Y is -O-. Specific examples include -YB groups having the following structure:
在一个实施方案中，B由环B表示，其中环B是如对于式I所定义的Ar1并且Y是-OCH2-。具体实例包括具有以下结构的-Y-B基团：In one embodiment, B is represented by Ring B, wherein Ring B is Ar1 as defined for Formula I and Y is -OCH2 -. Specific examples include -YB groups having the following structure:
在一个实施方案中，B由环B表示，其中环B是hetAr1，并且hetAr1是5至6元杂芳基，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、卤素、OH、CF3、NH2以及羟基(1-2C)烷基。在一个实施方案中，环B是hetAr1，其中hetAr1是5至6元杂芳基，其具有1至2个独立地选自N、O和S的环杂原子并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、卤素、OH、CF3、NH2以及羟基((1-2C))烷基。环B的实例包括吡啶基、噻吩基、噻唑基、噁唑基以及异噁唑基环，其任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、卤素、OH、CF3、NH2以及羟基((1-2C))烷基。在一个实施方案中，环B是吡啶基、噻吩基、噻唑基、噁唑基或异噁唑基环，其任选被1至2个独立地选自卤素和(1-6C)烷基的基团取代。In one embodiment, B is represented by Ring B, wherein Ring B is hetAr1 , and hetAr1 is a 5- to 6-membered heteroaryl group having 1 to 3 ring heteroatoms independently selected from N, S, and O, and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, halogen, OH, CF3 , NH2 , and hydroxy(1-2C)alkyl. In one embodiment, Ring B is hetAr1 , wherein hetAr1 is a 5- to 6-membered heteroaryl group having 1 to 2 ring heteroatoms independently selected from N, O, and S, and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, halogen, OH, CF3 , NH2 , and hydroxy((1-2C))alkyl. Examples of ring B include pyridyl, thienyl, thiazolyl, oxazolyl and isoxazolyl rings, which are optionally substituted with 1 to 2 groups independently selected from (1-6C) alkyl, halogen, OH, CF3 , NH2 and hydroxy((1-2C)) alkyl. In one embodiment, ring B is a pyridyl, thienyl, thiazolyl, oxazolyl or isoxazolyl ring, which is optionally substituted with 1 to 2 groups independently selected from halogen and (1-6C) alkyl.
环B在由hetAr1表示时的实例包括具有以下结构的吡啶-4-基、吡啶-3-基、吡啶-2-基、5-氟吡啶-3-基、噻吩-2-基、噻唑-2-基、2,4-二甲基噻唑-5-基、噁唑-5-基、异噁唑-5-基、噻吩-2-基、5-氯吡啶-3-基、5-氟吡啶-2-基、3-氟吡啶-4-基、1-甲基吡唑-4-基：Examples of ring B when represented byhetAr include pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, 5-fluoropyridin-3-yl, thien-2-yl, thiazol-2-yl, 2,4-dimethylthiazol-5-yl, oxazol-5-yl, isoxazol-5-yl, thien-2-yl, 5-chloropyridin-3-yl, 5-fluoropyridin-2-yl, 3-fluoropyridin-4-yl, 1-methylpyrazol-4-yl having the following structure:
在某些实施方案中，环B在由hetAr1表示时的实例包括具有以下结构的吡啶-4-基、吡啶-3-基、吡啶-2-基、5-氟吡啶-3-基、噻吩-2-基、噻唑-2-基、2,4-二甲基噻唑-5-基、噁唑-5-基以及异噁唑-5-基：In certain embodiments, examples of Ring B when represented byhetAr include pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, 5-fluoropyridin-3-yl, thien-2-yl, thiazol-2-yl, 2,4-dimethylthiazol-5-yl, oxazol-5-yl, and isoxazol-5-yl having the following structures:
在一个实施方案中，环B是任选被1至2个独立地选自(1-6C)烷基和卤素的基团取代的吡啶基环。In one embodiment, Ring B is a pyridyl ring optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl and halogen.
在一个实施方案中，B由环B表示，其中环B是如对于式I所定义的hetAr1并且Y是键。In one embodiment, B is represented by Ring B, wherein Ring B is hetAr1 as defined for formula I and Y is a bond.
在一个实施方案中，B由环B表示，其中环B是如对于式I所定义的hetAr1并且Y是-O-。-Y-B基团的具体实例是以下结构：In one embodiment, B is represented by Ring B, wherein Ring B ishetAr as defined for Formula I and Y is -O-. Specific examples of -YB groups are the following structures:
在一个实施方案中，B由环B表示，其中环B是如对于式I所定义的hetAr1并且Y是-OCH2-。-Y-B基团的具体实例是以下结构：In one embodiment, B is represented by Ring B, wherein Ring B is hetAr1 as defined for Formula I and Y is -OCH2 -. Specific examples of -YB groups are the following structures:
在一个实施方案中，B是(1-6C)烷基。实例包括甲基和乙基、异丙基。In one embodiment, B is (1-6C)alkyl. Examples include methyl and ethyl, isopropyl.
在一个实施方案中，B是(1-6C)烷氧基。实例是异丙氧基。In one embodiment, B is (1-6C)alkoxy. An example is isopropoxy.
现将提及环C。Ring C will now be mentioned.
在一个实施方案中，环C是式C-1：In one embodiment, Ring C is of formula C-1:
其中R3、R4和R5是如对于式I所定义。wherein R3 , R4 and R5 are as defined for formula I.
在一个实施方案中，R3是H。In one embodiment,R3 is H.
在一个实施方案中，R3是(1-6C)烷基。R3的实例包括甲基或乙基。In one embodiment, R3 is (1-6C)alkyl. Examples of R3 include methyl or ethyl.
在一个实施方案中，R3是羟基(1-6C)烷基。R3的实例是2-羟基乙基。In one embodiment, R3 is hydroxy(1-6C)alkyl. An example of R3 is 2-hydroxyethyl.
在一个实施方案中，R3是Ar2，其中Ar2是苯基，其任选被一个或多个独立地选自以下的基团取代：卤素、(1-6C)烷基和羟基甲基。实例包括苯基、氟苯基、甲基苯基和羟基甲基苯基。In one embodiment, R3 is Ar2 , wherein Ar2 is phenyl, optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and hydroxymethyl. Examples include phenyl, fluorophenyl, methylphenyl, and hydroxymethylphenyl.
R3在由Ar2表示时的实例包括苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、3-(羟基甲基)苯基、3-氯苯基、3-氯-4-氟苯基以及3-氯-2-氟苯基。R3在由Ar2表示时的具体实例包括苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基以及3-(羟基甲基)苯基。Examples ofR when represented byAr include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-(hydroxymethyl)phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, and 3-chloro-2-fluorophenyl. Specific examples ofR when represented byAr include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, and 3-(hydroxymethyl)phenyl.
在一个实施方案中，R3是hetCyc1，其中hetCyc1是具有1至2个独立地选自N和O的环杂原子的5至6元饱和或部分不饱和的杂环。在一个实施方案中，R3是吡咯烷基、四氢呋喃基、咪唑烷基、哌啶基、哌嗪基、四氢吡喃基或吗啉基环。R3的实例是四氢-2H-吡喃-4-基。In one embodiment,R ishetCyc , whereinhetCyc is a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O. In one embodiment,R is a pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl ring. An example ofR is tetrahydro-2H-pyran-4-yl.
在一个实施方案中，R3是(3-7C)环烷基。在一个实施方案中，R3是环己基。In one embodiment, R3 is (3-7C)cycloalkyl. In one embodiment, R3 is cyclohexyl.
在一个实施方案中，R3是hetAr2，其中hetAr2是5至6元杂芳基环，其具有1至3个独立地选自N、O和S的环杂原子并且任选被一个或多个独立地选自(1-6C)烷基和卤素的取代基取代。在一个实施方案中，R3是噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基，其任选被一个或多个独立地选自(1-6C)烷基和卤素的取代基取代。在一个实施方案中，R3是吡唑基、吡啶基或哒嗪基，其任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代。在一个实施方案中，R3是任选被(1-6C)烷基或卤素取代的吡唑基、吡啶基或哒嗪基。R3在由hetAr2表示时的实例包括1-甲基-1H-吡唑-4-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、哒嗪基以及3-氯吡啶-5-基。In one embodiment,R ishetAr , whereinhetAr is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, and S and optionally substituted with one or more substituents independently selected from (1-6C)alkyl and halogen. In one embodiment,R is thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, optionally substituted with one or more substituents independently selected from (1-6C)alkyl and halogen. In one embodiment,R is pyrazolyl, pyridinyl, or pyridazinyl, optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen. In one embodiment, R is pyrazolyl, pyridinyl, or pyridazinyl,optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen. Examples of R3 when represented by hetAr2 include 1-methyl-1H-pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazinyl and 3-chloropyridin-5-yl.
在一个实施方案中，R3是hetAr2，其中hetAr2是5至6元杂芳基环，其具有1至3个独立地选自N、O和S的环杂原子并且任选被(1-6C)烷基取代。在一个实施方案中，R3是任选被(1-6C)烷基取代的噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。在一个实施方案中，R3是任选被(1-6C)烷基取代的吡唑基、吡啶基或哒嗪基。R3的实例包括1-甲基-1H-吡唑-4-基、吡啶-2-基、吡啶-3-基、吡啶-4-基以及哒嗪基。In one embodiment,R is hetAr, whereinhetAr is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, and S and optionally substituted with (1-6C)alkyl. In one embodiment,R isthienyl , furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, optionally substituted with (1-6C)alkyl. In one embodiment,R is pyrazolyl, pyridinyl, or pyridazinyl, optionally substituted with (1-6C)alkyl. Examples ofR include 1-methyl-1H-pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyridazinyl.
在一个实施方案中，R3选自H、Ar2、hetAr2和(1-6C)烷基。In one embodiment, R3 is selected from H, Ar2 , hetAr2 and (1-6C)alkyl.
在一个实施方案中，R3选自H、Ar2和(1-6C)烷基。In one embodiment, R3 is selected from H, Ar2 and (1-6C)alkyl.
在一个实施方案中，R3选自Ar2和(1-6C)烷基。In one embodiment, R3 is selected from Ar2 and (1-6C)alkyl.
在一个实施方案中，R3选自Ar2、hetAr2和(1-6C)烷基。In one embodiment, R3 is selected from Ar2 , hetAr2 and (1-6C)alkyl.
在一个实施方案中，R4是H。In one embodiment,R4 is H.
在一个实施方案中，R4是OH。In one embodiment,R4 is OH.
在一个实施方案中，R4是(1-6C)烷基。R4的实例包括甲基、乙基、异丙基和叔丁基。In one embodiment, R4 is (1-6C)alkyl. Examples of R4 include methyl, ethyl, isopropyl and tert-butyl.
在一个实施方案中，R4是单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基或五氟(2-6C)烷基。R4的实例包括氟甲基、2-氟乙基、二氟甲基和2,2-二氟乙基、三氟甲基、2,2,2-三氟乙基、3,3,3-三氟丙基、2,2,3,3-四氟丙基以及2,2,3,3,3-五氟丙基。In one embodiment,R is monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, or pentafluoro(2-6C)alkyl. Examples ofR include fluoromethyl, 2-fluoroethyl, difluoromethyl, and 2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl, and 2,2,3,3,3-pentafluoropropyl.
在一个实施方案中，R4是三氟(1-6C)烷基。R4的实例包括CF3。In one embodiment, R4 is trifluoro(1-6C)alkyl. Examples of R4 include CF3 .
在一个实施方案中，R4是氰基(1-6C)烷基。R4的实例包括氰基甲基和2-氰基丙-2-基。In one embodiment, R4 is cyano(1-6C)alkyl. Examples of R4 include cyanomethyl and 2-cyanoprop-2-yl.
在一个实施方案中，R4是羟基(1-6C)烷基。R4的实例包括羟基甲基、2-羟基乙基、2-羟基丙基、2-羟基-2-甲基丙基以及1-羟基-2-甲基丙-2-基。In one embodiment, R4 is hydroxy(1-6C)alkyl. Examples of R4 include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, and 1-hydroxy-2-methylprop-2-yl.
在一个实施方案中，R4是二羟基(2-6C)烷基。R4的实例包括2,3-二羟基丙基。In one embodiment, R4 is dihydroxy(2-6C)alkyl. Examples of R4 include 2,3-dihydroxypropyl.
在一个实施方案中，R4是(1-3C烷氧基)(1-6C)烷基。R4的实例包括甲氧基甲基、2-甲氧基乙基和3-甲氧基丙基。In one embodiment, R4 is (1-3C alkoxy)(1-6C)alkyl. Examples of R4 include methoxymethyl, 2-methoxyethyl, and 3-methoxypropyl.
在一个实施方案中，R4是氨基(1-6C)烷基。R4的实例包括氨基甲基、2-氨基乙基和3-氨基丙基。In one embodiment, R4 is amino(1-6C)alkyl. Examples of R4 include aminomethyl, 2-aminoethyl, and 3-aminopropyl.
在一个实施方案中，R4是氨基羰基(1-6C)烷基。R4的实例包括氨基羰基甲基和2-(氨基羰基)乙基。In one embodiment, R4 is aminocarbonyl(1-6C)alkyl. Examples of R4 include aminocarbonylmethyl and 2-(aminocarbonyl)ethyl.
在一个实施方案中，R4是(1-3C)烷基磺酰胺基(1-6C)烷基。实例包括CH3SO2NHCH2-和CH3SO2NHCH2CH2-。In one embodiment, R4 is (1-3C)alkylsulfonamido(1-6C)alkyl. Examples include CH3 SO2 NHCH2 — and CH3 SO2 NHCH2 CH2 —.
在一个实施方案中，R4是羟基羰基(1-6C)烷基。实例包括HOC(＝O)CH2-和HOC(＝O)CH2CH2-。In one embodiment, R4 is hydroxycarbonyl(1-6C)alkyl. Examples include HOC(═O)CH2 — and HOC(═O)CH2 CH2 —.
在一个实施方案中，R4是hetAr3(1-6C)烷基，其中hetAr3是5元杂芳基环，其具有1至3个独立地选自N、S和O的环原子并且任选被(1-6C)烷基取代。在一个实施方案中，hetAr3是任选被(1-6C)烷基取代的噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基或噁二唑基环。R4在由hetAr3(1-6C)烷基表示时的实例包括(1-甲基-1H-1,2,4-三唑-3-基)甲基和(5-甲基-1,3,4-噁二唑-2-基)甲基。In one embodiment,R ishetAr (1-6C) alkyl, whereinhetAr is a 5-membered heteroaryl ring having 1 to 3 ring atoms independently selected from N, S, and O and optionally substituted with (1-6C) alkyl. In one embodiment, hetAr is athienyl , furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, or oxadiazolyl ring optionally substituted with (1-6C) alkyl. Examples ofR when represented byhetAr (1-6C) alkyl include (1-methyl-1H-1,2,4-triazol-3-yl)methyl and (5-methyl-1,3,4-oxadiazol-2-yl)methyl.
在一个实施方案中，R4是Ar3(1-6C)烷基，其中苯基任选被(1-4C)烷氧基或羟基(1-4C)烷基取代。在一个实施方案中，Ar3是苯基或4-甲氧基苯基。R4在由Ar3(1-6C)烷基表示时的实例包括苯甲基和4-甲氧基苯甲基。In one embodiment,R4 isAr3 (1-6C) alkyl, wherein phenyl is optionally substituted with (1-4C) alkoxy or hydroxy (1-4C) alkyl. In one embodiment,Ar3 is phenyl or 4-methoxyphenyl. Examples ofR4 when represented byAr3 (1-6C) alkyl include benzyl and 4-methoxybenzyl.
在一个实施方案中，R4是(1-6C)烷氧基。实例包括甲氧基和乙氧基。In one embodiment,R4 is (1-6C)alkoxy. Examples include methoxy and ethoxy.
在一个实施方案中，R4是单氟(1-6C)烷氧基、二氟(1-6C)烷氧基、三氟(1-6C)烷氧基、四氟(2-6C)烷氧基或五氟(2-6C)烷氧基。R4的实例包括氟甲氧基、2-氟乙氧基、2,2-二氟甲氧基、三氟甲氧基、2,2,2-三氟乙氧基以及2,2-二氟乙氧基。在一个实施方案中，R4是2-氟乙氧基。In one embodiment,R is monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy or pentafluoro(2-6C)alkoxy. Examples ofR include fluoromethoxy, 2-fluoroethoxy, 2,2-difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and 2,2-difluoroethoxy. In one embodiment,R is 2-fluoroethoxy.
在一个实施方案中，R4是氰基(1-6C)烷氧基。R4的实例包括氰基甲氧基和2-氰基乙氧基。In one embodiment, R4 is cyano(1-6C)alkoxy. Examples of R4 include cyanomethoxy and 2-cyanoethoxy.
在一个实施方案中，R4是羟基(1-6C)烷氧基。R4的实例包括2-羟基-2-甲基丙氧基、2-羟基乙氧基、2-羟基丙氧基、2-羟基-2-甲基丙氧基以及2-羟基丁氧基。In one embodiment, R4 is hydroxy(1-6C)alkoxy. Examples of R4 include 2-hydroxy-2-methylpropoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxy-2-methylpropoxy, and 2-hydroxybutoxy.
在一个实施方案中，R4是二羟基(2-6C)烷氧基。R4的实例包括2,3-二羟基丙氧基和3-羟基-2-(羟基甲基)丙氧基。In one embodiment, R4 is dihydroxy(2-6C)alkoxy. Examples of R4 include 2,3-dihydroxypropoxy and 3-hydroxy-2-(hydroxymethyl)propoxy.
在一个实施方案中，R4是氨基(2-6C)烷氧基。实例是H2NCH2CH2O-。In one embodiment, R4 is amino(2-6C)alkoxy. An example is H2 NCH2 CH2 O—.
在一个实施方案中，R4是氨基羰基(1-6C)烷氧基。实例包括H2NC(＝O)CH2O-和H2NC(＝O)CH2CH2O-。In one embodiment,R4 is aminocarbonyl(1-6C)alkoxy. Examples includeH2NC (=O)CH2O- andH2NC (=O )CH2CH2O- .
在一个实施方案中，R4是hetCyc2(1-6C)烷氧基，其中hetCyc2是具有1至2个独立地选自N和O的环杂原子的4至6元杂环，其中hetCyc2任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷氧基)羰基和(1-6C)酰基。hetCyc2的实例包括氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基以及1,3-二氧杂环戊基环，其任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷氧基)羰基和(1-6C)酰基。R4在由hetCyc2(1-6C)烷氧基表示时的实例包括氧杂环丁-2-基甲氧基、2-(氧杂环丁-2-基)丙氧基、(2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基、(1,3-二氧杂环戊-4-基)甲氧基、2-吗啉代乙氧基、哌嗪基乙氧基以及哌啶基乙氧基，其任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷氧基)羰基和(1-6C)酰基。具体实例包括以下结构：In one embodiment, R4 is hetCyc2 (1-6C) alkoxy, wherein hetCyc2 is a 4- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O, wherein hetCyc2 is optionally substituted with 1 to 2 groups independently selected from (1-6C) alkyl, (1-4C alkoxy) carbonyl, and (1-6C) acyl. Examples of hetCyc2 include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 1,3-dioxolane rings, which are optionally substituted with 1 to 2 groups independently selected from (1-6C) alkyl, (1-4C alkoxy) carbonyl, and (1-6C) acyl. Examples of R4 when represented by hetCyc2 (1-6C) alkoxy include oxetan-2-ylmethoxy, 2-(oxetan-2-yl)propoxy, (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy, (1,3-dioxolan-4-yl)methoxy, 2-morpholinoethoxy, piperazinylethoxy, and piperidinylethoxy, which are optionally substituted by 1 to 2 groups independently selected from (1-6C) alkyl, (1-4C alkoxy)carbonyl, and (1-6C) acyl. Specific examples include the following structures:
在一个实施方案中，R4是hetCyc2(1-6C)烷氧基，其中hetCyc2是具有1至2个独立地选自N和O的环杂原子的4至6元杂环，其中hetCyc2任选被1至2个独立地选自(1-6C)烷基的基团取代。杂环的实例包括氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基以及1,3-二氧杂环戊基环，其任选被1至2个独立地选自(1-6C)烷基的基团取代。R4在由hetCyc2(1-6C)烷氧基表示时的实例包括任选被(1-6C)烷基取代的氧杂环丁-2-基甲氧基、2-(氧杂环丁-2-基)丙氧基、(2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基、(1,3-二氧杂环戊-4-基)甲氧基和2-吗啉代乙氧基、哌嗪基乙氧基环，如：In one embodiment, R4 is hetCyc2 (1-6C) alkoxy, wherein hetCyc2 is a 4- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O, wherein hetCyc2 is optionally substituted with 1 to 2 groups independently selected from (1-6C) alkyl. Examples of heterocyclic rings include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 1,3-dioxolane rings, which are optionally substituted with 1 to 2 groups independently selected from (1-6C) alkyl. Examples of R4 when represented by hetCyc2 (1-6C) alkoxy include oxetan-2-ylmethoxy, 2-(oxetan-2-yl)propoxy, (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy, (1,3-dioxolan-4-yl)methoxy and 2-morpholinoethoxy, piperazinylethoxy rings optionally substituted with (1-6C) alkyl, such as:
在一个实施方案中，R4在由hetCyc2(1-6C)烷氧基表示时，选自氧杂环丁-2-基甲氧基、2-(氧杂环丁-2-基)丙氧基、(2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基、(1,3-二氧杂环戊-4-基)甲氧基以及2-吗啉代乙氧基。In one embodiment, R4 , when represented by hetCyc2 (1-6C) alkoxy, is selected from oxetan-2-ylmethoxy, 2-(oxetan-2-yl)propoxy, (2,2-dimethyl-1,3-dioxolan-4-yl)methoxy, (1,3-dioxolan-4-yl)methoxy and 2-morpholinoethoxy.
在一个实施方案中，R4是hetAr3(1-6C)烷氧基，其中hetAr3是5元杂芳基环，其具有1至3个独立地选自N、S和O的环原子并且任选被(1-6C)烷基取代。在一个实施方案中，hetAr3是任选被(1-6C)烷基取代的噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基或噁二唑基环。在一个实施方案中，hetAr3是任选被(1-6C)烷基(如甲基)取代的三唑基或噁二唑基环。R4在由hetAr3(1-6C)烷氧基表示时的实例包括(1-甲基-1H-1,2,4-三唑-3-基)甲氧基和(5-甲基-1,3,4-噁二唑-2-基)甲氧基，其可以由以下结构表示：In one embodiment, R4 is hetAr3 (1-6C) alkoxy, wherein hetAr3 is a 5-membered heteroaryl ring having 1 to 3 ring atoms independently selected from N, S and O and optionally substituted with (1-6C) alkyl. In one embodiment, hetAr3 is a thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl or oxadiazolyl ring optionally substituted with (1-6C) alkyl. In one embodiment, hetAr3 is a triazolyl or oxadiazolyl ring optionally substituted with (1-6C) alkyl (such as methyl). Examples of R4 when represented by hetAr3 (1-6C) alkoxy include (1-methyl-1H-1,2,4-triazol-3-yl)methoxy and (5-methyl-1,3,4-oxadiazol-2-yl)methoxy, which can be represented by the following structures:
在一个实施方案中，R4是Ar3(1-6C)烷氧基，其中Ar3是任选被(1-4C)烷氧基取代的苯基。实例包括具有以下结构的苯基甲氧基和(4-甲氧基苯基)甲氧基：In one embodiment, R4 is Ar3 (1-6C) alkoxy, wherein Ar3 is phenyl optionally substituted with (1-4C) alkoxy. Examples include phenylmethoxy and (4-methoxyphenyl)methoxy, having the following structures:
在一个实施方案中，R4是(1-4C烷氧基)(1-6C)烷氧基。实例包括具有以下结构的(2-甲氧基)乙氧基：In one embodiment,R4 is (1-4C alkoxy)(1-6C)alkoxy. Examples include (2-methoxy)ethoxy having the structure:
在一个实施方案中，R4是(1-3C烷基磺酰基)(1-6C)烷氧基。实例包括具有以下结构的(2-甲基磺酰基)乙氧基：In one embodiment,R4 is (1-3C alkylsulfonyl)(1-6C)alkoxy. Examples include (2-methylsulfonyl)ethoxy having the structure:
在一个实施方案中，R4是(3-6C)环烷基，其任选被以下基团取代：F、OH、(1-6C烷基)、(1-6C)烷氧基或(1-3C烷氧基)(1-6C)烷基。实例包括环丙基、环丁基、环戊基、环己基、2-羟基环丁基。在一个实施方案中，R4是环丙基或2-羟基环丁基。在一个实施方案中，R4是环丙基。In one embodiment,R is (3-6C)cycloalkyl, which is optionally substituted with F, OH, (1-6C)alkyl, (1-6C)alkoxy, or (1-3C alkoxy)(1-6C)alkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-hydroxycyclobutyl. In one embodiment,R is cyclopropyl or 2-hydroxycyclobutyl. In one embodiment,R is cyclopropyl.
在一个实施方案中，R4是(3-6C)环烷基。实例包括环丙基、环丁基、环戊基、环己基、2-羟基环丁基。在一个实施方案中，R4是环丙基。In one embodiment, R4 is (3-6C)cycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-hydroxycyclobutyl. In one embodiment, R4 is cyclopropyl.
在一个实施方案中，R4是hetAr4，其中hetAr4是5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的取代基取代：(1-6C)烷基、卤素、CN、羟基(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、(3-6C环烷基)CH2-、(3-6C环烷基)C(＝O)-、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、(1-6C)烷基磺酰基、NH2、(1-6C烷基)氨基、二(1-6C烷基)氨基、(1-3C三氟烷氧基)(1-3C)三氟烷基以及甲氧基苯甲基；或是9至10元双环杂芳基，其具有1至3个环氮原子。In one embodiment,R4 ishetAr4 , whereinhetAr4 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S, and O, and is optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH2- , (3-6Ccycloalkyl)C(=O)-, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl,NH2 , (1-6Calkyl)amino, di(1-6Calkyl)amino, (1-3Ctrifluoroalkoxy)(1-3C)trifluoroalkyl, and methoxybenzyl; or a 9- to 10-membered bicyclic heteroaryl having 1 to 3 ring nitrogen atoms.
实例包括吡啶基、嘧啶基、哒嗪基、吡唑基、咪唑基、噻吩基、1,2,4-三唑基、1,2,3-三唑基、噻唑基、噁唑基、1,3,4-噁二唑基、1,2,4-噁二唑基以及咪唑并[1,2-a]吡啶基环，其任选被1至2个独立地选自以下的取代基取代：(1-6C)烷基、羟基(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、(3-6C环烷基)CH2-、(3-6C环烷基)C(＝O)-、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、(1-6C)烷基磺酰基、NH2、(1-6C烷基)氨基、二(1-6C烷基)氨基、(1-3C三氟烷氧基)(1-3C)三氟烷基以及甲氧基苯甲基。Examples include pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thienyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and imidazo[1,2-a]pyridinyl rings optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH2 —, (3-6Ccycloalkyl)C(═O)—, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH2 , (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl, and methoxybenzyl.
在一个实施方案中，R4是hetAr4，其中hetAr4是吡啶基、嘧啶基、哒嗪基、吡唑基、咪唑基、噻吩基、1,2,4-三唑基、1,2,3-三唑基、噻唑基、噁唑基、1,3,4-噁二唑基、1,2,4-噁二唑基或咪唑并[1,2-a]吡啶基环，其任选被1至2个独立地选自以下的取代基取代：氟、甲基、乙基、异丙基、环丙基甲基、环丙基、三氟甲基、2,2,2-三氟乙基、甲氧基、H2N-、(CH3)2N-、2-羟基乙基、2-甲氧基乙基、1-(2,2,2-三氟乙氧基)-2,2,2-三氟乙基、环丙基羰基、甲基磺酰基以及4-甲氧基苯甲基。In one embodiment,R4 ishetAr4 , whereinhetAr4 is pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thienyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, or an imidazo[1,2-a]pyridinyl ring optionally substituted with 1 to 2 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy,H2N- , (CH3 )2N- , 2-hydroxyethyl, 2-methoxyethyl, 1-(2,2,2-trifluoroethoxy)-2,2,2-trifluoroethyl, cyclopropylcarbonyl, methylsulfonyl, and 4-methoxybenzyl.
在一个实施方案中，R4在由hetAr4表示时的实例包括以下结构：In one embodiment, examples of R4 when represented by hetAr4 include the following structures:
在一个实施方案中，R4是hetAr4，其中hetAr4是5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子并且任选被1至2个独立地选自(1-6C)烷基的取代基取代；或是9至10元双环杂芳基，其具有1至3个环氮原子。在一个实施方案中，hetAr4是5至6元杂芳基环，其具有1至2个独立地选自N和S的环杂原子并且任选被1至2个独立地选自(1-6C)烷基的取代基取代；或是9元双环杂芳基，其具有1至2个环氮原子。实例包括吡啶基、哒嗪基、吡唑基、噻吩基以及咪唑并[1,2-a]吡啶基环，其任选被1至2个独立地选自(1-6C)烷基的取代基取代。In one embodiment, R4 is hetAr4 , wherein hetAr4 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S, and O and optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl; or a 9- to 10-membered bicyclic heteroaryl ring having 1 to 3 ring nitrogen atoms. In one embodiment, hetAr4 is a 5- to 6-membered heteroaryl ring having 1 to 2 ring heteroatoms independently selected from N and S and optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl; or a 9-membered bicyclic heteroaryl ring having 1 to 2 ring nitrogen atoms. Examples include pyridyl, pyridazinyl, pyrazolyl, thienyl, and imidazo[1,2-a]pyridinyl rings, optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl.
在一个实施方案中，R4在由hetAr4表示时的实例包括具有以下结构的吡啶-2-基、吡啶-3-基、吡啶-4-基、5-甲基哒嗪-2-基、哒嗪-2-基、1-甲基吡唑-4-基、噻吩-2-基以及咪唑并[1,2-a]吡啶-5-基：In one embodiment, examples of R4 when represented by hetAr4 include pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 5-methylpyridazin-2-yl, pyridazin-2-yl, 1-methylpyrazol-4-yl, thien-2-yl, and imidazo[1,2-a]pyridin-5-yl having the following structures:
在一个实施方案中，R4是Ar4，其中Ar4是苯基，其任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基、卤素、CN、CF3、CF3O-、(1-6C)烷氧基、(1-6C烷基)OC(＝O)-、氨基羰基、(1-6C)烷基硫基、羟基(1-6C)烷基、(1-6C烷基)SO2-、HOC(＝O)-以及(1-3C烷氧基)(1-3C烷基)OC(＝O)-。实例包括任选被一个或多个独立地选自以下的基团取代的苯基：甲基、F、Cl、CN、甲氧基、CH3OC(＝O)-、氨基羰基、甲基氨基羰基、二甲基氨基羰基、甲硫基、羟基甲基、CH3SO2-、HOC(＝O)-以及CH3OCH2CH2OC(＝O)-。在某些实施方案中，R4是任选被所述取代基中的一个或两个取代的苯基。具体实例包括以下结构：In one embodiment, R4 is Ar4 , wherein Ar4 is phenyl, optionally substituted by one or more groups independently selected from the group consisting of (1-6C)alkyl, halogen, CN, CF3 , CF3 O-, (1-6C)alkoxy, (1-6C alkyl)OC(═O)-, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO2 -, HOC(═O)-, and (1-3C alkoxy)(1-3C alkyl)OC(═O)-. Examples include phenyl optionally substituted by one or more groups independently selected from the group consisting of methyl, F, Cl, CN, methoxy, CH3 OC(═O)-, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylthio, hydroxymethyl, CH3 SO2 -, HOC(═O)-, and CH3 OCH2 CH2 OC(═O)-. In certain embodiments, R4 is phenyl optionally substituted by one or two of the substituents. Specific examples include the following structures:
在一个实施方案中，R4是hetCyc2(O)CH2，其中hetCyc2是4至6元杂环，其具有1至2个独立地选自N和O的环杂原子，其中hetCyc2任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷氧基)羰基和(1-6C)酰基。hetCyc2的实例包括氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基以及1,3-二氧杂环戊基环，其任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷氧基)羰基和(1-6C)酰基。R4在由hetCyc2(1-6C)烷氧基表示时的实例包括哌嗪基乙氧基和哌啶基乙氧基，其任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷氧基)羰基和(1-6C)酰基。具体实例包括以下结构：In one embodiment, R4 is hetCyc2 (O) CH2 , wherein hetCyc2 is a 4- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O, wherein hetCyc2 is optionally substituted with 1 to 2 groups independently selected from (1-6C) alkyl, (1-4C alkoxy) carbonyl, and (1-6C) acyl. Examples of hetCyc2 include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 1,3-dioxolane rings optionally substituted with 1 to 2 groups independently selected from (1-6C) alkyl, (1-4C alkoxy) carbonyl, and (1-6C) acyl. Examples of R4 when represented by hetCyc2 (1-6C) alkoxy include piperazinylethoxy and piperidinylethoxy, which are optionally substituted by 1 to 2 groups independently selected from the group consisting of (1-6C) alkyl, (1-4C alkoxy)carbonyl and (1-6C) acyl. Specific examples include the following structures:
在一个实施方案中，R4是(1-4C烷氧基羰基)(1-6C)烷氧基。实例包括甲氧羰基(1-6C)烷氧基和乙基羰基(1-6C)烷氧基。具体实例是乙氧羰基甲氧基。In one embodiment,R4 is (1-4C alkoxycarbonyl)(1-6C)alkoxy. Examples include methoxycarbonyl(1-6C)alkoxy and ethylcarbonyl(1-6C)alkoxy. A specific example is ethoxycarbonylmethoxy.
在一个实施方案中，R4是羟基羰基(1-6C)烷氧基。具体实例是羟基羰基甲氧基。In one embodiment,R4 is hydroxycarbonyl(1-6C)alkoxy. A specific example is hydroxycarbonylmethoxy.
在一个实施方案中，R4是氨基羰基(1-6C)烷氧基。实例包括H2NC(＝O)(1-6C)烷氧基、(1-6C烷基)NHC(＝O)(1-6C)烷氧基和二(1-6C烷基)NC(＝O)(1-6C)烷氧基。具体实例是CH3CH2NC(＝O)CH2O-。In one embodiment, R4 is aminocarbonyl(1-6C)alkoxy. Examples include H2 NC(═O)(1-6C)alkoxy, (1-6C alkyl)NHC(═O)(1-6C)alkoxy, and di(1-6C alkyl)NC(═O)(1-6C)alkoxy. A specific example is CH3 CH2 NC(═O)CH2 O—.
在一个实施方案中，R4是hetCyc2C(＝O)(1-6C)烷氧基，其中hetCyc2是4至6元杂环，其具有1至2个独立地选自N和O的环杂原子并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷氧基)羰基和(1-6C)酰基。hetCyc2的实例包括氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基以及1,3-二氧杂环戊基环，其任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷氧基)羰基和(1-6C)酰基。在一个实施方案中，hetCyc2是吗啉基。R4在由hetCyc2C(＝O)(1-6C)烷氧基表示时的具体实例是以下结构：In one embodiment, R4 is hetCyc2 C(═O)(1-6C)alkoxy, wherein hetCyc2 is a 4- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyl, and (1-6C)acyl. Examples of hetCyc2 include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 1,3-dioxolane rings optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyl, and (1-6C)acyl. In one embodiment, hetCyc2 is morpholinyl. Specific examples of R4 when represented by hetCyc2 C(═O)(1-6C)alkoxy are the following structures:
在一个实施方案中，R4是羟基(1-3C烷氧基)(1-6C)烷氧基。具体实例是具有以下结构的2-羟基-3-甲氧基丙氧基：In one embodiment, R4 is hydroxy(1-3C alkoxy)(1-6C)alkoxy. A specific example is 2-hydroxy-3-methoxypropoxy having the structure:
在一个实施方案中，R4是羟基三氟(1-6C)烷氧基。具体实例是具有以下结构的3,3,3-二氟-2-羟基丙氧基：In one embodiment, R4 is hydroxytrifluoro(1-6C)alkoxy. A specific example is 3,3,3-difluoro-2-hydroxypropoxy having the following structure:
在一个实施方案中，R4是(1-3C)烷基磺酰胺基(1-6C)烷氧基。实例包括甲磺酰胺基(1-6C)烷氧基。具体实例是具有以下结构的2-甲磺酰胺基乙氧基：In one embodiment, R4 is (1-3C)alkylsulfonamido(1-6C)alkoxy. Examples include methanesulfonamido(1-6C)alkoxy. A specific example is 2-methanesulfonamidoethoxy having the structure:
在一个实施方案中，R4是(1-3C)烷基酰胺基(1-6C)烷氧基。具体实例是具有以下结构的2-(甲基酰胺基)乙氧基：In one embodiment, R4 is (1-3C)alkylamido(1-6C)alkoxy. A specific example is 2-(methylamido)ethoxy having the following structure:
在一个实施方案中，R4是二(1-3C烷基)氨基羧基。具体实例是具有以下结构的二甲基氨基羧基：In one embodiment,R4 is di(1-3C alkyl)aminocarboxyl. A specific example is dimethylaminocarboxyl having the following structure:
在一个实施方案中，R4是hetCyc2C(＝O)O-，其中hetCyc2是4-6元杂环，其具有1至2个独立地选自N和O的环杂原子并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷氧基)羰基和(1-6C)酰基。hetCyc2的实例包括氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基以及1,3-二氧杂环戊基环，其任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷氧基)羰基和(1-6C)酰基。在一个实施方案中，hetCyc2是吗啉基。R4在由hetCyc2C(＝O)O-表示时的具体实例是以下结构：In one embodiment, R4 is hetCyc2 C(═O)O—, wherein hetCyc2 is a 4-6 membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyl, and (1-6C)acyl. Examples of hetCyc2 include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 1,3-dioxolane rings optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, (1-4C alkoxy)carbonyl, and (1-6C)acyl. In one embodiment, hetCyc2 is morpholinyl. Specific examples ofR 4 when represented by hetCyc2 C(═O)O— are the following structures:
在一个实施方案中，R4是羟基二氟(1-6C)烷基。实例包括2,2-二氟-2-羟基乙基。In one embodiment, R4 is hydroxydifluoro(1-6C)alkyl. Examples include 2,2-difluoro-2-hydroxyethyl.
在一个实施方案中，R4是(1-4C烷基羧基)(1-6C)烷基。实例包括甲基羧基(1-6C)烷基。具体实例是2-(甲基羧基)乙基。In one embodiment,R4 is (1-4C alkylcarboxyl)(1-6C)alkyl. Examples include methylcarboxyl(1-6C)alkyl. A specific example is 2-(methylcarboxyl)ethyl.
在一个实施方案中，R4是(1-6C)烷氧基羰基。实例包括甲氧基羰基和乙氧基羰基。In one embodiment,R4 is (1-6C)alkoxycarbonyl. Examples include methoxycarbonyl and ethoxycarbonyl.
在一个实施方案中，R4是羟基羰基。In one embodiment, R4 is hydroxycarbonyl.
在一个实施方案中，R4是氨基羰基，即RR'NCO-基，其中R和R'独立地是氢或如本文所定义的(1-6C)烷基。实例包括氨基羰基、甲基氨基羰基、二甲基氨基羰基、乙基羰基以及异丙基氨基羰基。In one embodiment, R4 is aminocarbonyl, ie, RR'NCO-, wherein R and R' are independently hydrogen or (1-6C)alkyl as defined herein. Examples include aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylcarbonyl, and isopropylaminocarbonyl.
在一个实施方案中，R4是(1-3C烷氧基)氨基羰基。实例包括甲氧基氨基羰基。In one embodiment,R4 is (1-3C alkoxy)aminocarbonyl. Examples include methoxyaminocarbonyl.
在一个实施方案中，R4是hetCyc3，其中hetCyc3是4至7元杂环，其具有1至2个独立地选自N和O的环杂原子并且任选被一个或多个独立地选自以下的取代基取代：F、CN、CF3、(1-6C)烷基、羟基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)酰基-、(1-6C)烷基磺酰基、三氟甲基磺酰基以及(1-4C烷氧基)羰基。在一个实施方案中，hetCyc3是四氢吡喃基、哌啶基、吡咯烷基或氮杂环丁基，其任选被一个或多个独立地选自以下的取代基取代：F、CN、CF3、(1-6C)烷基、羟基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)酰基-、(1-6C)烷基磺酰基、三氟甲基磺酰基以及(1-4C烷氧基)羰基。在一个实施方案中，hetCyc3任选被所述取代基中的一个或两个取代。在一个实施方案中，hetCyc3是四氢吡喃基、哌啶基、吡咯烷基或氮杂环丁基，其任选被以下基团取代：CN、Me、CH3C(＝O)-、MeSO2-、CF3SO2-或(CH3)3COC(＝O)-。R4在由hetCyc3表示时的具体实例包括以下结构：In one embodiment, R4 is hetCyc3 , wherein hetCyc3 is a 4- to 7-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, CF3 , (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl, and (1-4C alkoxy)carbonyl. In one embodiment, hetCyc3 is tetrahydropyranyl, piperidinyl, pyrrolidinyl or azetidinyl, which is optionally substituted with one or more substituents independently selected from the group consisting of F, CN, CF3 , (1-6C) alkyl, hydroxy(1-6C) alkyl, (1-3C alkoxy)(1-6C) alkyl, (1-6C) acyl-, (1-6C) alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl. In one embodiment, hetCyc3 is optionally substituted with one or two of the substituents. In one embodiment, hetCyc3 is tetrahydropyranyl, piperidinyl, pyrrolidinyl or azetidinyl, which is optionally substituted with CN, Me, CH3 C(=O)-, MeSO2 -, CF3 SO2 - or (CH3 )3 COC(=O)-. Specific examples of R4 when represented by hetCyc3 include the following structures:
在一个实施方案中，R4是卤素。在一个实施方案中，R4是Br。In one embodiment, R4 is halogen. In one embodiment, R4 is Br.
在一个实施方案中，R4是CN。In one embodiment, R4 is CN.
在一个实施方案中，R4是三氟甲基磺酰基。In one embodiment, R4 is trifluoromethylsulfonyl.
在一个实施方案中，R4是N-(1-3C烷基)吡啶酮基。实例包括被N-(1-3C烷基)取代的吡啶-2(1H)-酮-4-基和被N-(1-3C烷基)取代的吡啶-2(1H)-酮-5-基。具体实例包括以下结构：In one embodiment, R is N-(1-3C alkyl)pyridin-4- yl substituted with N-(1-3C alkyl) and pyridin-5-yl substituted with N-(1-3C alkyl). Specific examples include the following structures:
在一个实施方案中，R4是N-(1-3C三氟烷基)吡啶酮基。实例包括被N-(1-3C三氟烷基)取代的吡啶-2(1H)-酮-4-基和被N-(1-3C三氟烷基)取代的吡啶-2(1H)-酮-5-基。具体实例包括以下结构：In one embodiment, R is N-(1-3C trifluoroalkyl)pyridin-4- yl substituted with N-(1-3C trifluoroalkyl) and pyridin-5-yl substituted with N-(1-3C trifluoroalkyl). Specific examples include the following structures:
在一个实施方案中，R4是(1-4C烷基硅烷氧基)(1-6C)烷氧基。实例包括叔丁基硅烷氧基(1-6C)烷氧基。具体实例是2-(叔丁基硅烷氧基)丙氧基。In one embodiment,R4 is (1-4C alkylsilyloxy)(1-6C)alkoxy. Examples include tert-butylsilyloxy(1-6C)alkoxy. A specific example is 2-(tert-butylsilyloxy)propoxy.
在一个实施方案中，R4是异吲哚啉-1,3-二酮基(1-6C)烷氧基。具体实例包括以下结构：In one embodiment, R4 is isoindoline-1,3-dione (1-6C) alkoxy. Specific examples include the following structures:
在一个实施方案中，R4是N-(1-3C烷基)噁二唑酮基，具体实例包括以下结构：In one embodiment,R4 is N-(1-3C alkyl)oxadiazolone, specific examples of which include the following structures:
在一个实施方案中，R4选自H、(1-6C)烷基、三氟(1-6C)烷基、羟基(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、hetCyc2(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基[任选被F、(1-6C烷基)、(1-6C)烷氧基或(1-3C烷氧基)(1-6C)烷基取代]、hetAr4、Ar4、(1-4C烷氧基羰基)(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、氨基羰基(1-6C)烷氧基、hetCyc2C(＝O)(1-6C)烷氧基、羟基(1-3C烷氧基)(1-6C)烷氧基、羟基三氟(1-6C)烷氧基、(1-3C)烷基磺酰胺基(1-6C)烷氧基、(1-3C)烷基酰胺基(1-6C)烷氧基、二(1-3C烷基)氨基羧基、hetCyc2C(＝O)O-、羟基二氟(1-6C)烷基、(1-4C烷基羧基)(1-6C)烷基、(1-6C)烷氧基-羰基、羟基羰基、氨基羰基、(1-3C烷氧基)氨基羰基、hetCyc3、卤素、CN、三氟甲基磺酰基、N-(1-3C烷基)吡啶酮基、N-(1-3C三氟烷基)吡啶酮基、(1-4C烷基硅烷氧基)(1-6C)烷氧基、异吲哚啉-1,3-二酮基(1-6C)烷氧基以及N-(1-3C烷基)噁二唑酮基。In one embodiment, R4 is selected from H, (1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, hetCyc2 (1-6C)alkoxy, Ar3 (1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, (1-6C alkyl), (1-6C)alkoxy or (1-3C alkoxy)(1-6C)alkyl], hetAr4 , Ar4 , (1-4C alkoxycarbonyl) (1-6C) alkoxy, hydroxycarbonyl (1-6C) alkoxy, aminocarbonyl (1-6C) alkoxy, hetCyc2 C (= O) (1-6C) alkoxy, hydroxy (1-3C alkoxy) (1-6C) alkoxy, hydroxytrifluoro (1-6C) alkoxy, (1-3C) alkylsulfonamido (1-6C) alkoxy, (1-3C) alkylamido (1-6C) alkoxy, di (1-3C alkyl) aminocarboxyl, hetCyc2 C (= O) O-, hydroxydifluoro (1-6C) alkyl, (1-4C alkylcarboxyl) (1-6C) alkyl, (1-6C) alkoxy-carbonyl, hydroxycarbonyl, aminocarbonyl, (1-3C alkoxy) aminocarbonyl, hetCyc3 , halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)pyridonyl, N-(1-3C trifluoroalkyl)pyridonyl, (1-4C alkylsilyloxy)(1-6C)alkoxy, isoindoline-1,3-dione(1-6C)alkoxy, and N-(1-3C alkyl)oxadiazolone.
在一个实施方案中，R4选自H、(1-6C)烷基、三氟(1-6C)烷基、羟基(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、hetCyc2(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4以及Ar4。In one embodiment, R4 is selected from H, (1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, hetCyc2 (1-6C)alkoxy, Ar3 (1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 and Ar4 .
在一个实施方案中，R4选自H、(1-6C)烷基、三氟(1-6C)烷基、羟基(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、hetCyc2(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4以及Ar4。In one embodiment, R4 is selected from H, (1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, hetCyc2 (1-6C)alkoxy, Ar3 (1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 and Ar4 .
在一个实施方案中，R4选自H、(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4以及Ar4。In one embodiment, R4 is selected from H, (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 and Ar4 .
在一个实施方案中，R4选自(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基以及(3-6C)环烷基。In one embodiment, R4 is selected from (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, and (3-6C)cycloalkyl.
在一个实施方案中，R4选自(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基以及(1-4C烷氧基)(1-6C)烷氧基。In one embodiment, R4 is selected from (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, and (1-4Calkoxy)(1-6C)alkoxy.
在一个实施方案中，R4选自hetAr4和Ar4。In one embodiment, R4 is selected from hetAr4 and Ar4 .
在一个实施方案中，R5是H。In one embodiment,R5 is H.
在一个实施方案中，R5是(1-6C)烷基。实例包括甲基、乙基、丙基、异丙基以及丁基。In one embodiment, R5 is (1-6C)alkyl. Examples include methyl, ethyl, propyl, isopropyl and butyl.
在一个实施方案中，R5是单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基或五氟(2-6C)烷基。实例包括氟甲基、2-氟乙基、二氟甲基、2,2-二氟乙基、1,3-二氟丙-2-基、三氟甲基、2,2,2-三氟乙基、3,3,3-三氟丙基、1,1,2,2-四氟丙烷以及2,2,3,3,3-五氟丙基。In one embodiment,R is monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, or pentafluoro(2-6C)alkyl. Examples include fluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, 1,3-difluoroprop-2-yl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 1,1,2,2-tetrafluoropropane, and 2,2,3,3,3-pentafluoropropyl.
在一个实施方案中，R5是卤素。在一个实施方案中，R5是F。在一个实施方案中，R5是Cl。在一个实施方案中，R5是Br。In one embodiment, R5 is halogen. In one embodiment, R5 is F. In one embodiment, R5 is Cl. In one embodiment, R5 is Br.
在一个实施方案中，R5是CN。In one embodiment, R5 is CN.
在一个实施方案中，R5是(1-4C)烷氧基。实例包括甲氧基和乙氧基。In one embodiment, R5 is (1-4C)alkoxy. Examples include methoxy and ethoxy.
在一个实施方案中，R5是羟基(1-4C)烷基。实例包括羟基甲基和3-羟基丙基。In one embodiment, R5 is hydroxy(1-4C)alkyl. Examples include hydroxymethyl and 3-hydroxypropyl.
在一个实施方案中，R5是(1-4C烷基)OC(＝O)-。实例包括CH3CH2OC(＝O)-。In one embodiment, R5 is (1-4C alkyl)OC(═O)—. Examples include CH3 CH2 OC(═O)—.
在一个实施方案中，R5是(1-6C)烷基硫基。实例是甲硫基(MeS-)。In one embodiment, R5 is (1-6C)alkylthio. An example is methylthio (MeS-).
在一个实施方案中，R5是任选被一个或多个独立地选自以下的基团取代的苯基：卤素、(1-6C)烷基和(1-6C)烷氧基。在一个实施方案中，R5是任选被一个或多个独立地选自以下的基团取代的苯基：F、Cl、甲基、乙基、甲氧基以及乙氧基。在一个实施方案中，R5是苯基。In one embodiment, R5 is phenyl optionally substituted by one or more groups independently selected from the group consisting of halogen, (1-6C) alkyl, and (1-6C) alkoxy. In one embodiment, R5 is phenyl optionally substituted by one or more groups independently selected from the group consisting of F, Cl, methyl, ethyl, methoxy, and ethoxy. In one embodiment, R5 is phenyl.
在一个实施方案中，R5是(3-4C)环烷基。在一个实施方案中，R5是环丙基。在一个实施方案中，R5是环丁基。In one embodiment, R5 is (3-4C)cycloalkyl. In one embodiment, R5 is cyclopropyl. In one embodiment, R5 is cyclobutyl.
在一个实施方案中，R5是氨基。在一个实施方案中，R5是NH2。In one embodiment,R5 is amino. In one embodiment,R5 isNH2 .
在一个实施方案中，R5是氨基羰基。在一个实施方案中，R5是H2NC(＝O)-。In one embodiment,R5 is aminocarbonyl.In one embodiment,R5 isH2NC (=O)-.
在一个实施方案中，R5是三氟(1-3C烷基)酰胺基。在一个实施方案中，R5是CF3C(＝O)NH-。In one embodiment,R5 is trifluoro(1-3C alkyl)amido. In one embodiment,R5 isCF3C (=O)NH-.
在一个实施方案中，R5选自H、卤素、CN、(1-6C)烷基、(1-4C)烷氧基、羟基(1-4C)烷基或任选被一个或多个独立地选自卤素、(1-6C)烷基和(1-6C)烷氧基的基团取代的苯基。In one embodiment, R5 is selected from H, halogen, CN, (1-6C)alkyl, (1-4C)alkoxy, hydroxy(1-4C)alkyl, or phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy.
在一个实施方案中，R5选自H、卤素或(1-6C)烷基。In one embodiment,R5 is selected from H, halogen or (1-6C)alkyl.
在一个实施方案中，R5选自H、甲基、Cl或Br。In one embodiment, R5 is selected from H, methyl, Cl or Br.
在式I的一个实施方案中，R4是H、OH、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-3C烷氧基)(1-6C)烷基、氨基(1-6C)烷基、氨基羰基(1-6C)烷基、(1-3C)烷基磺酰胺基(1-6C)烷基、磺酰胺基(1-6C)烷基、羟基羰基(1-6C)烷基、hetAr3(1-6C)烷基、Ar3(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、二氟(1-6C)烷氧基、三氟(1-6C)烷氧基、四氟(2-6C)烷氧基、五氟(2-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、氨基(2-6C)烷氧基、氨基羰基(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、hetCyc2(1-6C)烷氧基、hetAr3(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基[任选被F、(1-6C烷基)、(1-6C)烷氧基或(1-3C烷氧基)(1-6C)烷基取代]、hetAr4、Ar4、(1-4C烷氧基羰基)(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、氨基羰基(1-6C)烷氧基、hetCyc2C(＝O)(1-6C)烷氧基、羟基(1-3C烷氧基)(1-6C)烷氧基、羟基三氟(1-6C)烷氧基、(1-3C)烷基磺酰胺基(1-6C)烷氧基、(1-3C)烷基酰胺基(1-6C)烷氧基、二(1-3C烷基)氨基羧基、hetCyc2C(＝O)O-、羟基二氟(1-6C)烷基、(1-4C烷基羧基)(1-6C)烷基、(1-6C)烷氧基羰基、羟基羰基、氨基羰基、(1-3C烷氧基)氨基-羰基、hetCyc3、卤素、CN、三氟甲基磺酰基、N-(1-3C烷基)吡啶酮基、N-(1-3C三氟烷基)吡啶酮基、(1-4C烷基硅烷氧基)(1-6C)烷氧基、异吲哚啉-1,3-二酮基(1-6C)烷氧基或N-(1-3C烷基)噁二唑酮基；并且R5是H、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、卤素、CN、(1-4C)烷氧基、羟基(1-4C)烷基、(1-3C烷氧基)(1-4C)烷基、(1-4C烷基)OC(＝O)-、(1-6C)烷基硫基、苯基[任选被一个或多个独立地选自卤素、(1-6C)烷基和(1-6C)烷氧基的基团取代]、(3-4C)环烷基、氨基、氨基羰基或三氟(1-3C烷基)酰胺基。In one embodiment of Formula I, R4 is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl, sulfonamido(1-6C)alkyl, hydroxycarbonyl(1-6C)alkyl, hetAr3 (1-6C)alkyl, Ar3 (1-6C) alkyl, (1-6C) alkoxy, monofluoro(1-6C) alkoxy, difluoro(1-6C) alkoxy, trifluoro(1-6C) alkoxy, tetrafluoro(2-6C) alkoxy, pentafluoro(2-6C) alkoxy, cyano(1-6C) alkoxy, hydroxy(1-6C) alkoxy, dihydroxy(2-6C) alkoxy, amino(2-6C) alkoxy, aminocarbonyl(1-6C) alkoxy, hydroxycarbonyl(1-6C) alkoxy, hetCyc2 (1-6C) alkoxy, hetAr3 (1-6C) alkoxy, Ar3 (1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted by F, (1-6Calkyl), (1-6C)alkoxy or (1-3Calkoxy)(1-6C)alkyl], hetAr4 , Ar4 , (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc2 C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy, di(1-3Calkyl)aminocarboxyl, hetCyc 2 C(═O)(1-6C)alkoxy,2 C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4Calkylcarboxyl)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, (1-3Calkoxy)amino-carbonyl, hetCyc3 , halogen, CN, trifluoromethylsulfonyl, N-(1-3Calkyl)pyridonyl, N-(1-3Ctrifluoroalkyl)pyridonyl, (1-4Calkylsilyloxy)(1-6C)alkoxy, isoindoline-1,3-dione(1-6C)alkoxy, or N-(1-3Calkyl)oxadiazolone; and R5 is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3Calkoxy)(1-4C)alkyl, (1-4Calkyl)OC(═O)—, (1-6C)alkylthio, phenyl [optionally substituted by one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy], (3-4C)cycloalkyl, amino, aminocarbonyl or trifluoro(1-3Calkyl)amido.
在式I的一个实施方案中，R4是H、OH、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-3C烷氧基)(1-6C)烷基、氨基(1-6C)烷基、氨基羰基(1-6C)烷基、(1-3C)烷基磺酰胺基(1-6C)烷基、磺酰胺基(1-6C)烷基、羟基羰基(1-6C)烷基、hetAr3(1-6C)烷基、Ar3(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、二氟(1-6C)烷氧基、三氟(1-6C)烷氧基、四氟(2-6C)烷氧基、五氟(2-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、氨基(2-6C)烷氧基、氨基羰基(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、hetCyc2(1-6C)烷氧基、hetAr3(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；并且R5是H、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、卤素、CN、(1-4C)烷氧基、羟基(1-4C)烷基、(1-3C烷氧基)(1-4C)烷基、(1-4C烷基)OC(＝O)-、(1-6C)烷基硫基或任选被一个或多个独立地选自卤素、(1-6C)烷基和(1-6C)烷氧基的基团取代的苯基。In one embodiment of Formula I, R4 is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl, sulfonamido(1-6C)alkyl, hydroxycarbonyl(1-6C)alkyl, hetAr3 (1-6C)alkyl, Ar3 (1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc2 (1-6C)alkoxy, hetAr3 (1-6C)alkoxy, Ar3 (1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 or Ar4 ; and R5 is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3Calkoxy)(1-4C)alkyl, (1-4Calkyl)OC(═O)—, (1-6C)alkylthio, or phenyl optionally substituted by one or more groups independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy.
在式I的一个实施方案中，R4选自H、(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4以及Ar4，并且R5选自H、卤素、CN、(1-6C)烷基、(1-4C)烷氧基、羟基(1-4C)烷基、(1-6C)烷基硫基或任选被一个或多个独立地选自卤素、(1-6C)烷基和(1-6C)烷氧基的基团取代的苯基。In one embodiment of Formula I, R4 is selected from H, (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 and Ar4 , and R5 is selected from H, halogen, CN, (1-6C)alkyl, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkylthio or phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy.
在一个实施方案中，R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和的或不饱和的碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代；或R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和的或不饱和的杂环，其具有选自N、O或S的环杂原子，其中所述杂环任选被一个或两个独立地选自(1-6C烷基)C(＝O)O-、(1-6)酰基、(1-6C)烷基和氧代基的取代基取代，并且所述硫环原子任选被氧化成S(＝O)或SO2。In one embodiment,R4 andR5, together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or unsaturated carbocyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl; orR4 andR5, together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or unsaturated heterocyclic ring having ring heteroatoms selected from N, O or S, wherein the heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6Calkyl)C(=O)O-, (1-6)acyl, (1-6C)alkyl and oxo, and the sulfur ring atom is optionally oxidized to S(=O) orSO2 .
在一个实施方案中，R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和的或不饱和的碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代。在R4和R5连同其所连接的原子一起形成5至6元饱和或不饱和的碳环时，环C的实例包括以下结构：In one embodiment,R andR together with the atoms to which they are attached form a 5- to 6-membered saturated, partially unsaturated, or unsaturated carbocyclic ring, which is optionally substituted with one or more substituents independently selected from (1-6C)alkyl. When R andR together with the atoms to which they are attached form a 5- to6 -membered saturated or unsaturated carbocyclic ring, examples of ring C include the following structures:
其中R3是如对于式I所定义。wherein R3 is as defined for Formula I.
在一个实施方案中，R4和R5连同其所连接的原子一起形成5至6元饱和碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代，或R4和R5连同其所连接的原子一起形成5至6元饱和杂环，其具有选自N、O或S的环杂原子，其中所述环氮原子任选被(1-6C烷基)C(＝O)O-或(1-6)酰基取代，并且所述硫环原子任选被氧化成S(＝O)或SO2。In one embodiment,R4 andR5, together with the atoms to which they are attached, form a 5- to 6-membered saturated carbocyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, orR4 andR5, together with the atoms to which they are attached, form a 5- to 6-membered saturated heterocyclic ring having ring heteroatoms selected from N, O, or S, wherein the ring nitrogen atom is optionally substituted with (1-6Calkyl)C(=O)O- or (1-6)acyl, and the sulfur ring atom is optionally oxidized to S(=O) orSO2 .
在一个实施方案中，R4和R5连同其所连接的原子一起形成5至6元饱和碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代。在R4和R5连同其所连接的原子一起形成5至6元饱和碳环时，环C的实例包括以下结构：In one embodiment,R andR together with the atoms to which they are attached form a 5- to 6-membered saturated carbocyclic ring, which is optionally substituted with one or more substituents independently selected from (1-6C) alkyl. WhenR andR together with the atoms to which they are attached form a 5- to 6-membered saturated carbocyclic ring, examples of ring C include the following structures:
其中R3是如对于式I所定义。wherein R3 is as defined for Formula I.
在一个实施方案中，R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和的或不饱和的杂环，其具有选自N、O或S的环杂原子，其中所述环N原子任选被(1-6C烷基)C(＝O)O-、(1-6C烷基)C(＝O)-、(1-6C)烷基或氧代基取代，并且所述S环原子任选被氧化成S(＝O)或SO2。在R4和R5连同其所连接的原子一起形成5至6元饱和杂环时，环C的实例包括以下结构：In one embodiment, R4 and R5, together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated, or unsaturated heterocyclic ring having a ring heteroatom selected from N, O, or S, wherein the ring N atom is optionally substituted with (1-6C alkyl)C(═O)O—, (1-6C alkyl)C(═O)—, (1-6C)alkyl, or oxo, and the S ring atom is optionally oxidized to S(═O) or SO2. When R4 and R5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated heterocyclic ring, examples of ring C include the following structures:
其中R3是如对于式I所定义。wherein R3 is as defined for Formula I.
在一个实施方案中，R4和R5连同其所连接的原子一起形成5至6元饱和杂环，其具有选自N、O或S的环杂原子，其中所述环N原子任选被(1-6C烷基)C(＝O)O-或(1-6C烷基)C(＝O)-取代，并且所述S环原子任选被氧化成S(＝O)或SO2。在R4和R5连同其所连接的原子一起形成5至6元饱和杂环时，环C的实例包括以下结构：In one embodiment, R4 and R5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated heterocyclic ring having a ring heteroatom selected from N, O, or S, wherein the ring N atom is optionally substituted with (1-6C alkyl)C(═O)O- or (1-6C alkyl)C(═O)-, and the S ring atom is optionally oxidized to S(═O) or SO2 . When R4 and R5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated heterocyclic ring, examples of ring C include the following structures:
其中R3是如对于式I所定义。wherein R3 is as defined for Formula I.
在一个实施方案中，环C是式C-2In one embodiment, Ring C is of formula C-2
其中R3a、R4a和R5a是如对于式I所定义。wherein R3a , R4a and R5a are as defined for formula I.
在一个实施方案中，R3a是氢。In one embodiment, R3a is hydrogen.
在一个实施方案中，R3a是卤素。In one embodiment, R3a is halogen.
在一个实施方案中，R3a是(1-6C)烷基。在一个实施方案中，R3a是甲基。In one embodiment, R3a is (1-6C)alkyl. In one embodiment, R3a is methyl.
在一个实施方案中，R3a是三氟(1-6C)烷基。在一个实施方案中，R3a是CF3。In one embodiment, R3a is trifluoro(1-6C)alkyl. In one embodiment, R3a is CF3 .
在一个实施方案中，R3a是(3-6C)环烷基。在一个实施方案中，R3a是环丙基。In one embodiment, R3a is (3-6C)cycloalkyl. In one embodiment, R3a is cyclopropyl.
在一个实施方案中，R3a是任选被一个或多个独立地选自以下的取代基取代的苯基：卤素、(1-6C)烷基和羟基甲基。实例包括苯基、氟苯基、甲基苯基以及羟基甲基苯基，例如包括苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、3-(羟基甲基)苯基、3-氯苯基、3-氯-4-氟苯基以及3-氯-2-氟苯基。在一个实施方案中，R3a是苯基。In one embodiment, R3a is optionally substituted by one or more substituents independently selected from phenyl: halogen, (1-6C) alkyl and hydroxymethyl.Example includes phenyl, fluorophenyl, aminomethyl and hydroxymethylphenyl, for example includes phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-aminomethyl, 3-aminomethyl, 4-aminomethyl, 3-(hydroxymethyl) phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl and 3-chloro-2-fluorophenyl.In one embodiment, R3a is phenyl.
在一个实施方案中，R3a是5至6元杂芳基环，其具有1至3个独立地选自N、O和S的环杂原子，并且任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代。在一个实施方案中，R3a是任选被(1-6C)烷基或卤素取代的噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基环。在一个实施方案中，R3a是吡唑基、吡啶基或哒嗪基，其任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代。在一个实施方案中，R3a是任选被(1-6C)烷基或卤素取代的吡唑基、吡啶基或哒嗪基。In one embodiment, R3a is a 5 to 6 yuan heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S, and optionally substituted by one or more groups independently selected from (1-6C) alkyl and halogen. In one embodiment, R3a is a thienyl, furyl, imidazole, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl ring optionally substituted by (1-6C) alkyl or halogen. In one embodiment, R3a is a pyrazolyl, pyridyl or pyridazinyl ring optionally substituted by one or more groups independently selected from (1-6C) alkyl and halogen. In one embodiment, R3a is a pyrazolyl, pyridyl or pyridazinyl ring optionally substituted by (1-6C) alkyl or halogen.
在一个实施方案中，R4a是氢。In one embodiment, R4a is hydrogen.
在一个实施方案中，R4a是(1-6C)烷基。在一个实施方案中，R4a是甲基、乙基或异丙基。In one embodiment, R4a is (1-6C)alkyl. In one embodiment, R4a is methyl, ethyl or isopropyl.
在一个实施方案中，R4a是三氟(1-6C)烷基。在一个实施方案中，R4a是2,2,2-三氟乙基。In one embodiment, R4a is trifluoro(1-6C)alkyl. In one embodiment, R4a is 2,2,2-trifluoroethyl.
在一个实施方案中，R4a是任选被一个或多个独立地选自以下的基团取代的苯基：(1-6C)烷基、卤素、CN、CF3、CF3O-、(1-6C)烷氧基、(1-6C烷基)OC(＝O)-、氨基羰基、(1-6C)烷基硫基、羟基(1-6C)烷基、(1-6C烷基)SO2-、HOC(＝O)-以及(1-3C烷氧基)(1-3C烷基)OC(＝O)-。实例包括任选被一个或多个独立地选自以下的基团取代的苯基：甲基、F、Cl、CN、甲氧基、CH3OC(＝O)-、氨基羰基、甲基氨基羰基、二甲基氨基羰基、甲硫基、羟基甲基、CH3SO2-、HOC(＝O)-以及CH3OCH2CH2OC(＝O)-。在某些实施方案中，R4a是任选被所述取代基中的一个或两个取代的苯基。在一个实施方案中，R4a是苯基。In one embodiment, R4a is phenyl optionally substituted by one or more groups independently selected from the group consisting of (1-6C)alkyl, halogen, CN, CF3 , CF3 O-, (1-6C)alkoxy, (1-6C alkyl)OC(═O)-, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO2 -, HOC(═O)-, and (1-3C alkoxy)(1-3C alkyl)OC(═O)-. Examples include phenyl optionally substituted by one or more groups independently selected from the group consisting of methyl, F, Cl, CN, methoxy, CH3 OC(═O)-, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylthio, hydroxymethyl, CH3 SO2 -, HOC(═O)-, and CH3 OCH2 CH2 OC(═O)-. In certain embodiments, R4a is phenyl optionally substituted with one or two of said substituents. In one embodiment, R4a is phenyl.
在一个实施方案中，R4a是5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的取代基取代：(1-6C)烷基、羟基(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、(3-6C环烷基)CH2-、(3-6C环烷基)C(＝O)-、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、(1-6C)烷基磺酰基、NH2、(1-6C烷基)氨基、二(1-6C烷基)氨基、(1-3C三氟烷氧基)(1-3C)三氟烷基以及甲氧基苯甲基。实例包括吡啶基、嘧啶基、哒嗪基、吡唑基、咪唑基、噻吩基、1,2,4-三唑基、1,2,3-三唑基、噻唑基、噁唑基、1,3,4-噁二唑基、1,2,4-噁二唑基以及咪唑并[1,2-a]吡啶基环，其任选被1至2个独立地选自以下的取代基取代：(1-6C)烷基、羟基(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、(3-6C环烷基)CH2-、(3-6C环烷基)C(＝O)-、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、(1-6C)烷基磺酰基、NH2、(1-6C烷基)氨基、二(1-6C烷基)氨基、(1-3C三氟烷氧基)(1-3C)三氟烷基以及甲氧基苯甲基。在一个实施方案中，R4a是吡嗪基。In one embodiment, R4a is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S, and O, and optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH2 -, (3-6Ccycloalkyl)C(═O)-, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH2 , (1-6Calkyl)amino, di(1-6Calkyl)amino, (1-3Ctrifluoroalkoxy)(1-3C)trifluoroalkyl, and methoxybenzyl. Examples include pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, thienyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and imidazo[1,2-a]pyridinyl rings optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH2 —, (3-6Ccycloalkyl)C(═O)—, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH2 In one embodiment, R4a is pyrazinyl.
在一个实施方案中，R5a是如对于式I所定义。In one embodiment, R5a is as defined for Formula I.
在一个实施方案中，R5a选自氢、卤素、(1-6C)烷基和苯基。In one embodiment, R5a is selected from hydrogen, halogen, (1-6C)alkyl and phenyl.
在一个实施方案中，R5a是氢。In one embodiment, R5a is hydrogen.
在一个实施方案中，R5a是卤素。In one embodiment, R5a is halogen.
在一个实施方案中，R5a是(1-6C)烷基。在一个实施方案中，R5a是甲基。In one embodiment, R5a is (1-6C)alkyl. In one embodiment, R5a is methyl.
在一个实施方案中，R5a是苯基。In one embodiment, R5a is phenyl.
在一个实施方案中，环C是式C-2，其中R3a是(1-6C)烷基、三氟(1-6C)烷基或苯基；R4a是(1-6C)烷基、三氟(1-6C)烷基、苯基或吡嗪基；并且R5a是氢、(1-6C)烷基或苯基。In one embodiment, ring C is of formula C-2, wherein R3a is (1-6C)alkyl, trifluoro(1-6C)alkyl, or phenyl; R4a is (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl, or pyrazinyl; and R5a is hydrogen, (1-6C)alkyl, or phenyl.
在一个实施方案中，环C是式C-3In one embodiment, Ring C is of formula C-3
其中R3b是如对于式I所定义。wherein R3b is as defined for formula I.
在一个实施方案中，R3b是氢。In one embodiment, R3b is hydrogen.
在一个实施方案中，R3b是(1-6C)烷基。在一个实施方案中，R3b是甲基。In one embodiment, R3b is (1-6C)alkyl. In one embodiment, R3b is methyl.
在一个实施方案中，R3b是三氟(1-6C)烷基。在一个实施方案中，R3b是CF3。In one embodiment, R3b is trifluoro(1-6C)alkyl. In one embodiment, R3b is CF3 .
在一个实施方案中，R3b是(3-6C)环烷基。在一个实施方案中，R3b是环丙基。In one embodiment, R3b is (3-6C)cycloalkyl. In one embodiment, R3b is cyclopropyl.
在一个实施方案中，R3b是任选被一个或多个独立地选自以下的取代基取代的苯基：卤素、(1-6C)烷基和羟基甲基。在一个实施方案中，R3b是苯基。In one embodiment, R3b is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, (1-6C)alkyl, and hydroxymethyl. In one embodiment, R3b is phenyl.
在一个实施方案中，R3b是5至6元杂芳基环，其具有1至3个独立地选自N、O和S的环杂原子，并且任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代。在一个实施方案中，R3b是任选被(1-6C)烷基或卤素取代的噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基。在一个实施方案中，R3b是吡唑基、吡啶基或哒嗪基，其任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代。在一个实施方案中，R3b是任选被(1-6C)烷基或卤素取代的吡唑基、吡啶基或哒嗪基。In one embodiment, R3b is a 5 to 6 yuan heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S, and optionally substituted by one or more groups independently selected from (1-6C) alkyl and halogen. In one embodiment, R3b is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl optionally substituted by (1-6C) alkyl or halogen. In one embodiment, R3b is a pyrazolyl, pyridyl or pyridazinyl, and optionally substituted by one or more groups independently selected from (1-6C) alkyl and halogen. In one embodiment, R3b is a pyrazolyl, pyridyl or pyridazinyl optionally substituted by (1-6C) alkyl or halogen.
在一个实施方案中，环C是式C-3，其中R3b是氢或苯基。In one embodiment, Ring C is of formula C-3, wherein R3b is hydrogen or phenyl.
在本发明的另一实施方案中，提供根据式I的化合物，其指定为式I-a，其中：In another embodiment of the present invention, there is provided a compound according to Formula I, designated Formula I-a, wherein:
X是O；X is O;
B是Ar1；B is Ar1 ;
Y是键；Y is a bond;
环C是Ring C is
R4是H、OH、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-3C烷氧基)(1-6C)烷基、氨基(1-6C)烷基、氨基羰基(1-6C)烷基、(1-3C)烷基磺酰胺基(1-6C)烷基、磺酰胺基(1-6C)烷基、羟基羰基(1-6C)烷基、hetAr3(1-6C)烷基、Ar3(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、二氟(1-6C)烷氧基、三氟(1-6C)烷氧基、四氟(2-6C)烷氧基、五氟(2-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、氨基(2-6C)烷氧基、氨基羰基(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、hetCyc2(1-6C)烷氧基、hetAr3(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R4 is H, OH, (1-6C) alkyl, monofluoro(1-6C) alkyl, difluoro(1-6C) alkyl, trifluoro(1-6C) alkyl, tetrafluoro(2-6C) alkyl, pentafluoro(2-6C) alkyl, cyano(1-6C) alkyl, hydroxy(1-6C) alkyl, dihydroxy(2-6C) alkyl, (1-3C alkoxy)(1-6C) alkyl, amino(1-6C) alkyl, aminocarbonyl(1-6C) alkyl, (1-3C) alkylsulfonamido(1-6C) alkyl, sulfonamido(1-6C) alkyl, hydroxycarbonyl(1-6C) alkyl, hetAr3 (1-6C) alkyl, Ar3 (1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc2 (1-6C)alkoxy, hetAr3 (1-6C)alkoxy, Ar3 (1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 or Ar4 ;
R5是H、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、卤素、CN、(1-4C)烷氧基、羟基(1-4C)烷基、(1-3C烷氧基)(1-4C)烷基、(1-4C烷基)OC(＝O)-或任选被一个或多个独立地选自卤素、(1-6C)烷基和(1-6C)烷氧基的基团取代的苯基；并且Ra、Rb、Rc、Rd、R1、R2、Ar1、R3、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。R5 is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3Calkoxy)(1-4C)alkyl, (1-4Calkyl)OC(═O)—, or phenyl optionally substituted by one or more groups independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; andRa ,Rb ,Rc ,Rd ,R1 ,R2 ,Ar1 ,R3 ,hetCyc2 ,hetAr3 ,Ar3 ,hetAr4 , andAr4 are as defined for Formula I.
在式I-a的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；并且R1、Ar1、R3、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ia,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen; andR1 ,Ar1 ,R3 , hetCyc2,hetAr3 ,Ar3 ,hetAr4 ,andAr4 are as defined for Formula I.
在式I-a的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；并且Ar1、R3、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ia,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; andAr1 ,R3 ,hetCyc2 ,hetAr3 ,Ar3 ,hetAr4 , andAr4 are as defined for Formula I.
在式I-a的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R3是Ar2、hetAr2或(1-6C)烷基；并且Ar1、Ar2、hetAr2、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ia,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl;R3 isAr2 ,hetAr2 , or (1-6C)alkyl; andAr1 ,Ar2 ,hetAr2 ,hetCyc2 ,hetAr3 ,Ar3 ,hetAr4 , andAr4 are as defined for Formula I.
在式I-a的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R3是Ar2、hetAr2或(1-6C)烷基；R4是H、(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；并且Ar1、Ar2、hetAr2、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ia,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl;R3 isAr2 ,hetAr2 , or (1-6C)alkyl;R4 is H, (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl,hetAr4 , orAr4 ; andAr1 ,Ar2 ,hetAr2 ,hetCyc2 ,hetAr3 ,Ar3 , hetAr4 and Ar4 are as defined for Formula I.
在式I-a的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R3是Ar2、hetAr2或(1-6C)烷基；R4是hetAr4或Ar4；并且Ar1、Ar2、hetAr2、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ia,Ra ,Rb ,Rc andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl or trifluoro(1-6C)alkyl;R3 isAr2 ,hetAr2 or (1-6C)alkyl;R4 ishetAr4 orAr4 ; andAr1 ,Ar2 ,hetAr2 ,hetCyc2 ,hetAr3 ,Ar3 ,hetAr4 andAr4 are as defined for Formula I.
在式I-a的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R3是Ar2、hetAr2或(1-6C)烷基；R4是H、(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R5是H、卤素、CN、(1-6C)烷基、(1-4C)烷氧基、羟基(1-4C)烷基或任选被一个或多个独立地选自卤素、(1-6C)烷基和(1-6C)烷氧基的基团取代的苯基；并且Ar1、Ar2、hetAr2、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ia,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl;R3 isAr2 ,hetAr2 , or (1-6C)alkyl;R4 is H, (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl,hetAr4 , orAr4 ; R wherein5 is H, halogen, CN, (1-6C)alkyl, (1-4C)alkoxy, hydroxy(1-4C)alkyl, or phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; and Ar1 , Ar2 , hetAr2 , hetCyc2 , hetAr3 , Ar3 , hetAr4 , and Ar4 are as defined for Formula I.
在式I-a的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R3是Ar2、hetAr2或(1-6C)烷基；R4是H、(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R5是H、卤素或(1-6C)烷基；并且Ar1、Ar2、hetAr2、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ia,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; R3 isAr2 , hetAr2, or (1-6C)alkyl;R4 is H, (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl,hetAr4 , or Ar4;R5 is H, halogen, or (1-6C)alkyl; and Ar1, Ar2, hetAr2, hetAr4, or Ar4 are alkyl, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy,hydroxy , hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy,hydroxy ,hydroxy , hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy,hydroxy , hydroxy, hydroxy,hydroxy , hydroxy,hydroxy , hydroxy, hydroxy,Ar 4 and Ar4 are as defined for Formula I.
在式I-a的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R3是Ar2、hetAr2或(1-6C)烷基；R4是hetAr4或Ar4；R5是H、卤素或(1-6C)烷基；并且Ar1、Ar2、hetAr2、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ia,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl;R3 isAr2 ,hetAr2 , or (1-6C)alkyl;R4 ishetAr4 , orAr4 ;R5 is H, halogen, or (1-6C)alkyl; andAr1 ,Ar2 ,hetAr2 ,hetAr4 , andAr4 are as defined for Formula I.
在式I-a的一个实施方案中，R4是(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；并且Ra、Rb、Rc、Rd、R1、R2、R3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ia, R4 is (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 or Ar4 ; and Ra,Rb ,Rc ,Rd ,R1 ,R2 ,R3 , hetAr4 andAr4 are as defined for Formula I.
在式I-a的一个实施方案中，R4是(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R3是H、(1-6C)烷基或Ar2；并且Ra、Rb、Rc、Rd、R1、R2、hetAr4、Ar4和Ar2是如对于式I所定义。In one embodiment of Formula Ia, R4 is (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 , or Ar4 ; R3 is H, (1-6C)alkyl, or Ar2 ; andRa ,Rb ,Rc ,Rd ,R1 ,R2 , hetAr4 , Ar4 , and Ar2 are as defined for Formula I.
在式I-a的一个实施方案中，R4是(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R3是H、(1-6C)烷基或Ar2；R5是H、(1-6C)烷基或卤素；并且Ra、Rb、Rc、Rd、R1、R2、hetAr4、Ar4和Ar2是如对于式I所定义。In one embodiment of Formula Ia, R4 is (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 , or Ar4 ; R3 is H, (1-6C)alkyl, or Ar2 ; R5 is H, (1-6C)alkyl, or halogen; andRa , Rb , Rc , Rd , R1 , R2 , hetAr4 , Ar4 , and Ar2 are as defined for Formula I.
在本发明的另一实施方案中，提供根据式I的化合物，其指定为式I-b，其中：In another embodiment of the present invention, there is provided a compound according to Formula I, designated Formula I-b, wherein:
X是O；X is O;
B是hetAr1；B is hetAr1 ;
Y是一键；Y is a key;
环C是式C-1：Ring C is of formula C-1:
R4是H、OH、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-3C烷氧基)(1-6C)烷基、氨基(1-6C)烷基、氨基羰基(1-6C)烷基、(1-3C)烷基磺酰胺基(1-6C)烷基、磺酰胺基(1-6C)烷基、羟基羰基(1-6C)烷基、hetAr3(1-6C)烷基、Ar3(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、二氟(1-6C)烷氧基、三氟(1-6C)烷氧基、四氟(2-6C)烷氧基、五氟(2-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、氨基(2-6C)烷氧基、氨基羰基(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、hetCyc2(1-6C)烷氧基、hetAr3(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R4 is H, OH, (1-6C) alkyl, monofluoro(1-6C) alkyl, difluoro(1-6C) alkyl, trifluoro(1-6C) alkyl, tetrafluoro(2-6C) alkyl, pentafluoro(2-6C) alkyl, cyano(1-6C) alkyl, hydroxy(1-6C) alkyl, dihydroxy(2-6C) alkyl, (1-3C alkoxy)(1-6C) alkyl, amino(1-6C) alkyl, aminocarbonyl(1-6C) alkyl, (1-3C) alkylsulfonamido(1-6C) alkyl, sulfonamido(1-6C) alkyl, hydroxycarbonyl(1-6C) alkyl, hetAr3 (1-6C) alkyl, Ar3 (1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc2 (1-6C)alkoxy, hetAr3 (1-6C)alkoxy, Ar3 (1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 or Ar4 ;
R5是H、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、卤素、CN、(1-4C)烷氧基、羟基(1-4C)烷基、(1-3C烷氧基)(1-4C)烷基、(1-4C烷基)OC(＝O)-或任选被一个或多个独立地选自卤素、(1-6C)烷基和(1-6C)烷氧基的基团取代的苯基；并且Ra、Rb、Rc、Rd、R1、R2、hetAr1、R3、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。R5 is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3Calkoxy)(1-4C)alkyl, (1-4Calkyl)OC(═O)—, or phenyl optionally substituted by one or more groups independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; andRa ,Rb ,Rc ,Rd ,R1 ,R2 ,hetAr1 ,R3 ,hetCyc2 ,hetAr3 ,Ar3 ,hetAr4 , andAr4 are as defined for Formula I.
在式I-b的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；并且R1、hetAr1、R3、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ib,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen; andR1 ,hetAr1 ,R3 ,hetCyc2 ,hetAr3 ,Ar3 ,hetAr4 , andAr4 are as defined for Formula I.
在式I-b的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；并且hetAr1、R3、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ib,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl; andhetAr1 ,R3 ,hetCyc2 ,hetAr3 ,Ar3 ,hetAr4 , andAr4 are as defined for Formula I.
在式I-b的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R3是Ar2、hetAr2或(1-6C)烷基；并且hetAr1、Ar2、hetAr2、hetCyc2、hetAr3、Ar3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ib,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl;R3 isAr2 ,hetAr2 , or (1-6C)alkyl; andhetAr1 ,Ar2 ,hetAr2 ,hetCyc2 ,hetAr3 ,Ar3 ,hetAr4 , andAr4 are as defined for Formula I.
在式I-b的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R3是Ar2、hetAr2或(1-6C)烷基；R4是H、(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；并且hetAr1、Ar2、hetAr2、hetCyc2、hetAr3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ib,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl;R3 isAr2 ,hetAr2 , or (1-6C)alkyl;R4 is H, (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl,hetAr4 , orAr4 ; andhetAr1 ,Ar2 ,hetAr2 ,hetCyc2 ,hetAr3 , hetArAr 4 and Ar4 are as defined for Formula I.
在式I-b的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R3是Ar2、hetAr2或(1-6C)烷基；R4是H、(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R5是H、卤素、CN、(1-6C)烷基、(1-4C)烷氧基、羟基(1-4C)烷基或任选被一个或多个独立地选自卤素、(1-6C)烷基和(1-6C)烷氧基的基团取代的苯基；并且hetAr1、Ar2、hetAr2、hetCyc2、hetAr3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ib,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl;R3 isAr2 ,hetAr2 , or (1-6C)alkyl;R4 is H, (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl,hetAr4 , orAr4 ; R5 is H, halogen, CN, (1-6C)alkyl, (1-4C)alkoxy, hydroxy(1-4C)alkyl, or phenyl optionally substituted by one or more groups independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; and hetAr1 , Ar2 , hetAr2 , hetCyc2 , hetAr3 , hetAr4 , and Ar4 are as defined for Formula I.
在式I-b的一个实施方案中，Ra、Rb、Rc和Rd是氢；R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R3是Ar2、hetAr2或(1-6C)烷基；R4是H、(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R5是H、卤素或(1-6C)烷基；并且hetAr1、Ar2、hetAr2、hetAr3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ib,Ra ,Rb ,Rc , andRd are hydrogen;R2 is hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl, or trifluoro(1-6C)alkyl;R3 isAr2 ,hetAr2 , or (1-6C)alkyl;R4 is H, (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl,hetAr4 , orAr4 ;R5 is H, halogen, or (1-6C)alkyl; andhetAr1 ,Ar2 ,hetAr2 , hetAr3 , hetAr4 and Ar4 are as defined for formula I.
在式I-b的一个实施方案中，R4是(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；并且Ra、Rb、Rc、Rd、R1、R2、R3、hetAr4和Ar4是如对于式I所定义。In one embodiment of Formula Ib, R4 is (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 or Ar4 ; and Ra,Rb ,Rc ,Rd ,R1 ,R2 ,R3 , hetAr4 andAr4 are as defined for Formula I.
在式I-b的一个实施方案中，R4是(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R3是H、(1-6C)烷基或Ar2；并且Ra、Rb、Rc、Rd、R1、R2、hetAr4、Ar4和Ar2是如对于式I所定义。In one embodiment of Formula Ib, R4 is (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 or Ar4 ; R3 is H, (1-6C)alkyl or Ar2 ; and Ra,R b, Rc , Rd , R1 , R2 , hetAr4 , Ar4 and Ar2 are as defined for Formula I.
在式I-b的一个实施方案中，R4是hetAr4或Ar4；R3是H、(1-6C)烷基或Ar2；R5是H、(1-6C)烷基或卤素；并且Ra、Rb、Rc、Rd、R1、R2、hetAr4、Ar4和Ar2是如对于式I所定义。In one embodiment of Formula Ib, R4 is hetAr4 or Ar4 ; R3 is H, (1-6C)alkyl, or Ar2 ; R5 is H, (1-6C)alkyl, or halogen; and Ra,Rb ,Rc ,Rd ,R1 ,R2 , hetAr4 , Ar4, and Ar2 are as defined for Formula I.
在本发明的另一实施方案中，提供根据式I的化合物，其指定为式I-c，其中：In another embodiment of the present invention, there is provided a compound according to Formula I, which is designated as Formula I-c, wherein:
X是O；X is O;
B是Ar1；B is Ar1 ;
Y是键；Y is a bond;
环C是式C-1：Ring C is of formula C-1:
R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和的或饱和的碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代，或R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和的或饱和的杂环，其具有选自N、O或S的环杂原子，其中所述杂环任选被(1-6C烷基)C(＝O)O-或(1-6)酰基取代，并且所述硫环原子任选被氧化成S(＝O)或SO2；其中Ra、Rb、Rc、Rd、R1、R2、Ar1和R3是如对于式I所定义。R4 and R5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or saturated carbocyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or R4 and R5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or saturated heterocyclic ring having ring heteroatoms selected from N, O or S, wherein the heterocyclic ring is optionally substituted with (1-6C alkyl)C(═O)O— or (1-6)acyl, and the sulfur ring atom is optionally oxidized to S(═O) or SO2 ; whereinRa ,Rb ,Rc ,Rd ,R1 ,R2 ,Ar1 andR3 are as defined for Formula I.
在式I-c的一个实施方案中，R4和R5连同其所连接的原子一起形成5至6元饱和碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代，或R4和R5连同其所连接的原子一起形成5至6元饱和杂环，其具有选自N、O或S的环杂原子，其中所述环氮原子任选被(1-6C烷基)C(＝O)O-或(1-6)酰基取代，并且所述硫环原子任选被氧化成S(＝O)或SO2；其中Ra、Rb、Rc、Rd、R1、R2、Ar1和R3是如对于式I所定义。In one embodiment of Formula Ic,R4 andR5, together with the atoms to which they are attached, form a 5- to 6-membered saturated carbocyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, orR4 andR5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated heterocyclic ring having ring heteroatoms selected from N, O, or S, wherein the ring nitrogen atom is optionally substituted with (1-6Calkyl)C(=O)O- or (1-6)acyl, and the sulfur ring atom is optionally oxidized to S(=O) orSO2 ; whereinRa ,Rb ,Rc ,Rd ,R1 ,R2 ,Ar1 , andR3 are as defined for Formula I.
在式I-c的一个实施方案中，Ra、Rb、Rc、Rd和R2是氢；并且R1、Ar1和R3是如对于式I所定义。In one embodiment of Formula Ic,Ra ,Rb ,Rc ,Rd , andR2 are hydrogen; andR1 ,Ar1 , andR3 are as defined for Formula I.
在式I-c的一个实施方案中，Ra、Rb、Rc、Rd和R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基或(1-3C烷基氨基)(1-3C)烷基；并且Ar1和R3是如对于式I所定义。In one embodiment of Formula Ic,Ra ,Rb ,Rc ,Rd , andR2 are hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or (1-3Calkylamino)(1-3C)alkyl; andAr1 andR3 are as defined for Formula I.
在式I-c的一个实施方案中，Ra、Rb、Rc、Rd和R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基或(1-3C烷基氨基)(1-3C)烷基；R3是H、(1-6C)烷基或任选被一个或多个独立地选自卤素、(1-6C)烷基和羟甲基的基团取代的苯基；并且Ar1是如对于式I所定义。In one embodiment of Formula Ic,Ra ,Rb ,Rc ,Rd , andR2 are hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or (1-3Calkylamino)(1-3C)alkyl;R3 is H, (1-6C)alkyl, or phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and hydroxymethyl; andAr1 is as defined for Formula I.
在式I-c的一个实施方案中，Ra、Rb、Rc、Rd和R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基或(1-3C烷基氨基)(1-3C)烷基；R3是任选被一个或多个独立地选自以下的基团取代的苯基：卤素、(1-6C)烷基和羟甲基；并且Ar1是如对于式I所定义。In one embodiment of Formula Ic,Ra ,Rb ,Rc ,Rd , andR2 are hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or (1-3Calkylamino)(1-3C)alkyl;R3 is phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and hydroxymethyl; andAr1 is as defined for Formula I.
在本发明的另一实施方案中，提供根据式I的化合物，其指定为式I-d，其中：In another embodiment of the present invention, there is provided a compound according to formula I, which is designated as formula I-d, wherein:
X是O；X is O;
B是hetAr1；B is hetAr1 ;
Y是键；Y is a bond;
环C是式C-1：Ring C is of formula C-1:
R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和或饱和的碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代，或R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和或饱和的杂环，其具有选自N、O或S的环杂原子，其中所述杂环任选被(1-6C烷基)C(＝O)O-或(1-6)酰基取代，并且所述硫环原子任选被氧化成S(＝O)或SO2；其中Ra、Rb、Rc、Rd、R1、R2、Ar1和R3是如对于式I所定义。R4 and R5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or saturated carbocyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or R4 and R5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or saturated heterocyclic ring having ring heteroatoms selected from N, O or S, wherein the heterocyclic ring is optionally substituted with (1-6C alkyl)C(═O)O— or (1-6)acyl, and the sulfur ring atom is optionally oxidized to S(═O) or SO2 ; whereinRa ,Rb ,Rc ,Rd ,R1 ,R2 ,Ar1 andR3 are as defined for Formula I.
在式I-d的一个实施方案中，R4和R5连同其所连接的原子一起形成5至6元饱和碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代，或R4和R5连同其所连接的原子一起形成5至6元饱和杂环，其具有选自N、O或S的环杂原子，其中所述环氮原子任选被(1-6C烷基)C(＝O)O-或(1-6)酰基取代，并且所述硫环原子任选被氧化成S(＝O)或SO2；其中Ra、Rb、Rc、Rd、R1、R2、hetAr1和R3是如对于式I所定义。In one embodiment of Formula Id, R4 and R5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated carbocyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or R4 and R5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated heterocyclic ring having ring heteroatoms selected from N, O, or S, wherein the ring nitrogen atom is optionally substituted with (1-6C alkyl)C(═O)O— or (1-6)acyl, and the sulfur ring atom is optionally oxidized to S(═O) or SO2 ; whereinRa ,Rb ,Rc ,Rd ,R1 ,R2 ,hetAr1 , andR3 are as defined for Formula I.
在式I-d的一个实施方案中，Ra、Rb、Rc、Rd和R2是氢；并且R1、hetAr1和R3是如对于式I所定义。In one embodiment of Formula Id,Ra ,Rb ,Rc ,Rd , andR2 are hydrogen; andR1 ,hetAr1 , andR3 are as defined for Formula I.
在式I-d的一个实施方案中，Ra、Rb、Rc、Rd和R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基或(1-3C烷基氨基)(1-3C)烷基；并且hetAr1和R3是如对于式I所定义。In one embodiment of Formula Id,Ra ,Rb ,Rc ,Rd , andR2 are hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or (1-3Calkylamino)(1-3C)alkyl; andhetAr1 andR3 are as defined for Formula I.
在式I-d的一个实施方案中，Ra、Rb、Rc、Rd和R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基或(1-3C烷基氨基)(1-3C)烷基；R3是H、(1-6C)烷基或任选被一个或多个独立地选自卤素、(1-6C)烷基和羟甲基的基团取代的苯基；并且hetAr1是如对于式I所定义。In one embodiment of Formula Id,Ra ,Rb ,Rc ,Rd , andR2 are hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or (1-3Calkylamino)(1-3C)alkyl;R3 is H, (1-6C)alkyl, or phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and hydroxymethyl; andhetAr1 is as defined for Formula I.
在式I-d的一个实施方案中，Ra、Rb、Rc、Rd和R2是氢；R1是(1-3C烷氧基)(1-6C)烷基、(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基或(1-3C烷基氨基)(1-3C)烷基；R3是任选被一个或多个独立地选自以下的基团取代的苯基：卤素、(1-6C)烷基和羟甲基；并且hetAr1是如对于式I所定义。In one embodiment of Formula Id,Ra ,Rb ,Rc ,Rd , andR2 are hydrogen;R1 is (1-3Calkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, or (1-3Calkylamino)(1-3C)alkyl;R3 is phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and hydroxymethyl; andhetAr1 is as defined for Formula I.
如所说明，式I的Y-B部分和-NH-C(＝X)-NH-部分在吡咯烷环上呈反式构型，所述相对立体化学可以由式A或式B说明：As illustrated, the Y-B moiety and the -NH-C(=X)-NH- moiety of Formula I are in a trans configuration on the pyrrolidine ring, and the relative stereochemistry can be illustrated by Formula A or Formula B:
其中粗直线条和虚直线条指示相对立体化学。在上式A和B的一个实施方案中，Y是键并且B是环B，其中环B是Ar1或hetAr1。wherein bold and dashed straight lines indicate relative stereochemistry. In one embodiment of the above formulae A and B, Y is a bond and B is Ring B, wherein Ring B is Ar1 or hetAr1 .
在式I的一个实施方案中，Y-B和-NH-C(＝X)-NH-部分呈可以由式C和式D说明的绝对反式构型：In one embodiment of Formula I, the Y-B and -NH-C(=X)-NH- moieties are in the absolute trans configuration as illustrated by Formula C and Formula D:
其中实心楔形物和虚楔形物指示绝对立体化学。在上式C和D的一个实施方案中，Y是键并且B是环B，其中环B是Ar1或hetAr1。wherein the solid and dashed wedges indicate absolute stereochemistry. In one embodiment of the above formulae C and D, Y is a bond and B is Ring B, wherein Ring B is Ar1 or hetAr1 .
应了解，根据本发明的某些化合物可含有一个或多个不对称中心并且因此可以异构体混合物(如外消旋混合物)形式或以对映异构纯形式制备和分离。It will be appreciated that certain compounds according to the present invention may contain one or more asymmetric centers and can therefore be prepared and isolated as mixtures of isomers (eg, racemic mixtures) or in enantiomerically pure form.
应进一步了解式I化合物或其盐可以溶剂合物形式分离，并且因此任何此种溶剂合物包括在本发明范围内。例如，式I化合物可以非溶剂合物形式以及与药学上可接受的溶剂(如水、乙醇以及类似物)形成的溶剂合物形式存在。It will be further understood that the compounds of Formula I or their salts may be isolated in the form of solvates, and therefore any such solvates are included within the scope of the present invention. For example, the compounds of Formula I may exist in unsolvated form as well as in the form of solvates formed with pharmaceutically acceptable solvents such as water, ethanol, and the like.
式I化合物包括其药学上可接受的盐。另外，式I化合物还包括此类化合物的其它盐，其未必是药学上可接受的盐，而可适用作用于制备和/或纯化式I化合物和/或用于分离式I化合物的对映异构体的中间体。盐的具体实例包括盐酸盐。The compounds of formula I include pharmaceutically acceptable salts thereof. Furthermore, the compounds of formula I also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts but may be useful as intermediates for preparing and/or purifying the compounds of formula I and/or for separating enantiomers of the compounds of formula I. Specific examples of salts include hydrochlorides.
术语“药学上可接受的”指示物质或组合物与构成制剂的其它成分和/或用其所治疗的哺乳动物是化学和/或毒理学相容的。The term "pharmaceutically acceptable" indicates that a substance or composition is chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal to be treated therewith.
本发明还提供一种用于制备如本文所定义的式I化合物或其盐的方法，其包括：The present invention also provides a process for preparing a compound of formula I or a salt thereof as defined herein, comprising:
(a)对于X是O的式I化合物，使具有式II的相应化合物(a) For a compound of formula I wherein X is O, the corresponding compound of formula II
与具有式III的相应化合物With the corresponding compound of formula III
在羰基二咪唑或三光气和碱存在下偶联；或Coupling in the presence of carbonyldiimidazole or triphosgene and a base; or
(b)对于X是S的式I化合物，使具有式II的相应化合物(b) For compounds of formula I where X is S, the corresponding compound of formula II
与具有式III的相应化合物With the corresponding compound of formula III
在二(1H-咪唑-2-基)甲烷硫酮和碱存在下偶联；或Coupling in the presence of bis(1H-imidazol-2-yl)methanethione and a base; or
(c)对于X是O的式I化合物，使具有式II的相应化合物(c) For compounds of formula I where X is O, the corresponding compound of formula II
与具有式IV的相应化合物and the corresponding compound of formula IV
在碱存在下偶联，其中L1是离去基团；或Coupling in the presence of a base, wherein L1 is a leaving group; or
(d)对于X是O的式I化合物，使具有式V的相应化合物(d) For compounds of formula I where X is O, the corresponding compound of formula V
其中L2是离去基团，与具有式III的相应化合物WhereinL2 is a leaving group, and the corresponding compound having formula III
在碱存在下偶联；或Coupling in the presence of a base; or
(e)对于X是O的式I化合物，用二苯基磷酰基叠氮化物使具有式VI的相应化合物活化(e) For compounds of formula I where X is O, activating the corresponding compound of formula VI with diphenylphosphoryl azide
接着使活化的中间体与具有式III的相应化合物The activated intermediate is then reacted with the corresponding compound of formula III
在碱存在下偶联；或Coupling in the presence of a base; or
(f)对于X是O的式I化合物，使具有式II的相应化合物(f) For compounds of formula I where X is O, the corresponding compound of formula II
与具有式VII的相应化合物With the corresponding compound of formula VII
在碱存在下偶联；或Coupling in the presence of a base; or
(g)对于R1是(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基或五氟(2-6C)烷基的式I化合物，使具有式VIII的相应化合物(g) For compounds of formula I wherein R1 is (trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl or pentafluoro(2-6C)alkyl, the corresponding compound of formula VIII is
与具有(三氟甲氧基)(1-6C)烷基-L3、(1-3C硫烷基)(1-6C)烷基-L3、单氟(1-6C)烷基-L3、二氟(1-6C)烷基-L3、三氟(1-6C)烷基-L3、四氟(2-6C)烷基-L3或五氟(2-6C)烷基-L3的相应化合物在碱存在下反应，其中L3是离去原子或离去基团；或with a corresponding compound having (trifluoromethoxy)(1-6C)alkyl-L3 , (1-3Csulfanyl)(1-6C)alkyl-L3 , monofluoro(1-6C)alkyl-L3 , difluoro(1-6C)alkyl-L3 , trifluoro(1-6C)alkyl-L3 , tetrafluoro(2-6C)alkyl-L3 or pentafluoro(2-6C)alkyl-L3 in the presence of a base, wherein L3 is a leaving atom or a leaving group; or
(h)对于X是O，R4是CH3OCH2-并且R5是OHCH2-的式I化合物，用无机酸处理具有通式IX的相应化合物(h) For compounds of formula I wherein X is O, R4 is CH3 OCH2 - and R5 is OHCH2 -, the corresponding compound of formula IX is treated with a mineral acid.
；并且;and
任选去除保护基团并且任选制备其药学上可接受的盐。The protecting groups are optionally removed and a pharmaceutically acceptable salt thereof is optionally prepared.
在上述方法中，除非另有说明，否则术语“相应”意指对于“相应化合物”的定义是如对于式I所定义。In the above methods, the term "corresponding" means that the definition for "corresponding compound" is as defined for Formula I, unless otherwise stated.
在上述任何方法的一个实施方案中，Y是键并且B是环B，其中环B是如对于式I所定义的Ar1或hetAr1。In one embodiment of any of the above methods, Y is a bond and B is Ring B, wherein Ring B is Ar1 or hetAr1 as defined for Formula I.
关于方法(a)，碱可以是胺碱，如三乙胺或二异丙胺。适合的溶剂包括二氯甲烷、二氯乙烷、THF、DMA和DMF。反应宜在环境温度下进行。Regarding method (a), the base can be an amine base, such as triethylamine or diisopropylamine. Suitable solvents include dichloromethane, dichloroethane, THF, DMA and DMF. The reaction is preferably carried out at ambient temperature.
关于方法(b)，碱可以是胺碱，如三乙胺或二异丙胺。适合的溶剂包括二氯甲烷、二氯乙烷、THF、DMA和DMF。反应宜在环境温度下进行。Regarding method (b), the base can be an amine base, such as triethylamine or diisopropylamine. Suitable solvents include dichloromethane, dichloroethane, THF, DMA and DMF. The reaction is preferably carried out at ambient temperature.
关于方法(c)，离去基团可以是例如苯氧基或4-硝基苯氧基。碱可以是胺碱，如三乙胺或二异丙胺。适合的溶剂包括DMA、DMF和DCE。反应宜在环境温度下进行。Regarding method (c), the leaving group can be, for example, phenoxy or 4-nitrophenoxy. The base can be an amine base, such as triethylamine or diisopropylamine. Suitable solvents include DMA, DMF and DCE. The reaction is preferably carried out at ambient temperature.
关于方法(d)，离去基团可以是例如苯氧基或4-硝基苯氧基。碱可以是胺碱，如三乙胺或二异丙胺。适合的溶剂包括DCE、DMA和DMF。反应宜在环境温度下进行。Regarding method (d), the leaving group can be, for example, phenoxy or 4-nitrophenoxy. The base can be an amine base, such as triethylamine or diisopropylamine. Suitable solvents include DCE, DMA and DMF. The reaction is preferably carried out at ambient temperature.
关于方法(e)，碱可以是胺碱，如三乙胺或二异丙胺。适合的溶剂包括甲苯和DMF。反应宜在高温(例如溶剂的回流温度)下进行。Regarding method (e), the base can be an amine base, such as triethylamine or diisopropylamine. Suitable solvents include toluene and DMF. The reaction is preferably carried out at an elevated temperature (e.g., the reflux temperature of the solvent).
关于方法(f)，碱可以是胺碱，如三乙胺或二异丙胺。适合的溶剂包括DCM、DCE、DMF和THF。反应宜在约0℃与环境温度之间的温度下进行。Regarding method (f), the base may be an amine base such as triethylamine or diisopropylamine. Suitable solvents include DCM, DCE, DMF and THF. The reaction is preferably carried out at a temperature between about 0°C and ambient temperature.
式VII化合物可通过使式III化合物与双(三氯甲基)碳酸酯在碱(如胺碱)存在下反应来制备。The compound of formula VII can be prepared by reacting a compound of formula III with bis(trichloromethyl)carbonate in the presence of a base such as an amine base.
关于方法(g)，碱可以是胺碱，如三乙胺或二异丙胺。适合的溶剂包括DMF、DMA和THF。反应宜在环境温度与60℃之间的温度下进行。Regarding method (g), the base may be an amine base such as triethylamine or diisopropylamine. Suitable solvents include DMF, DMA and THF. The reaction is preferably carried out at a temperature between ambient temperature and 60°C.
关于方法(h)，酸可以是例如盐酸。适合的溶剂包括DCM。反应宜在环境温度下进行。Regarding method (h), the acid may be, for example, hydrochloric acid. Suitable solvents include DCM. The reaction is preferably carried out at ambient temperature.
上述任何方法中描述的化合物中的胺基可用任何合宜的胺保护基团保护，例如如Greene和Wuts编,“Protecting Groups in Organic Synthesis”,第2版New York；JohnWiley&Sons,Inc.,1991中所述。胺保护基团的实例包括酰基和烷氧基羰基(如叔丁氧基羰基(BOC))、苯氧基羰基以及[2-(三甲基硅烷基)乙氧基]甲基(SEM)。同样，羧基可用任何合宜的羧基保护基团保护，例如如Greene和Wuts编,“Protecting Groups in OrganicSynthesis”,第2版New York；John Wiley&Sons,Inc.,1991中所述。羧基保护基团的实例包括(1-6C)烷基，如甲基、乙基和叔丁基。醇基可用任何合宜的醇保护基团保护，例如如Greene和Wuts编,“Protecting Groups in Organic Synthesis”,第2版New York；JohnWiley&Sons,Inc.,1991中所述。醇保护基团的实例包括苯甲基、三苯甲基、硅烷基醚以及类似基团。The amine groups in the compounds described in any of the above methods can be protected with any convenient amine protecting group, for example, as described in Greene and Wuts (eds.), "Protecting Groups in Organic Synthesis", 2nd edition New York; John Wiley & Sons, Inc., 1991. Examples of amine protecting groups include acyl and alkoxycarbonyl groups (such as tert-butyloxycarbonyl (BOC)), phenoxycarbonyl, and [2-(trimethylsilyl)ethoxy]methyl (SEM). Similarly, carboxyl groups can be protected with any convenient carboxyl protecting group, for example, as described in Greene and Wuts (eds.), "Protecting Groups in Organic Synthesis", 2nd edition New York; John Wiley & Sons, Inc., 1991. Examples of carboxyl protecting groups include (1-6C)alkyl groups, such as methyl, ethyl, and tert-butyl. Alcohol groups can be protected with any convenient alcohol protecting group, for example as described in Greene and Wuts, eds., "Protecting Groups in Organic Synthesis", 2nd ed., New York; John Wiley & Sons, Inc., 1991. Examples of alcohol protecting groups include benzyl, trityl, silyl ether, and the like.
式II、III、III、IV、V、VI、VII、VIII和IX的化合物也认为是新型化合物并且提供作为本发明的其它方面。Compounds of Formula II, III, III, IV, V, VI, VII, VIII, and IX are also considered novel compounds and are provided as further aspects of the invention.
在上述方法(a)、(b)、(c)和(f)的一个实施方案中，其中B是Ar1并且Ra、Rb、Rc、Rd和R2是氢，中间体II的单个对映异构体(即II-A的对映异构体1)是在使用前通过手性结晶来制备。因此，在一个实施方案中，用于制备II-A的对映异构体1的方法包括：In one embodiment of the above methods (a), (b), (c) and (f), wherein B isAr1 andRa ,Rb ,Rc ,Rd and R2 are hydrogen, asingle enantiomer of intermediate II (i.e., enantiomer 1 of II-A) is prepared by chiral crystallization prior to use. Thus, in one embodiment, the method for preparing enantiomer 1 of II-A comprises:
制备外消旋反式II-APreparation of racemic trans II-A
其中环B和NH2基团呈反式构型；环B是Ar1或hetAr1；Ar1是苯基，其任选被一个或多个独立地选自以下的取代基取代：卤素、CF3、CF3O-、(1-4C)烷氧基、羟基(1-4C)烷基、(1-6C)烷基以及CN；并且hetAr1是5至6元杂芳基，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、卤素、OH、CF3、NH2以及羟基((1-2C))烷基；所述方法包括：wherein Ring B and the NH2 group are in a trans configuration; Ring B is Ar1 or hetAr1 ; Ar1 is phenyl, which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CF3 , CF3 O-, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl, and CN; and hetAr1 is a 5- to 6-membered heteroaryl group having 1 to 3 ring heteroatoms independently selected from N, S, and O, and which is optionally substituted with 1 to 2 groups independently selected from the group consisting of (1-6C)alkyl, halogen, OH, CF3 , NH2 , and hydroxy((1-2C))alkyl; the method comprising:
用二-对甲苯甲酰基-D-酒石酸处理外消旋反式II-A，以提供外消旋反式II-A的二-对甲苯甲酰基-D-酒石酸盐；treating racemic trans II-A with di-p-toluoyl-D-tartaric acid to provide the di-p-toluoyl-D-tartaric acid salt of racemic trans II-A;
使反式II-A的二-对甲苯甲酰基-D-酒石酸盐重结晶，以提供反式II-A的对映异构体1的二-对甲苯甲酰基-D-酒石酸盐；以及recrystallizing the di-p-toluoyl-D-tartrate salt of trans II-A to provide the di-p-toluoyl-D-tartrate salt of enantiomer 1 of trans II-A; and
用无机碱处理反式II-A的对映异构体1的二-对甲苯甲酰基-D-酒石酸盐，以提供具有如所说明的绝对构型的反式II-A的对映异构体1的游离碱：The di-p-toluoyl-D-tartrate salt of enantiomer 1 of trans II-A is treated with an inorganic base to provide the free base of enantiomer 1 of trans II-A having the absolute configuration as illustrated:
在外消旋反式II-A的一个实施方案中，R1是2-甲氧基乙氧基并且环B是4-氟苯基，并且外消旋反式II-A通过以下方法来制备，所述方法包括：In one embodiment of racemic trans II-A, R1 is 2-methoxyethoxy and ring B is 4-fluorophenyl, and racemic trans II-A is prepared by the following process comprising:
使4-氟苯甲醛与硝基甲烷在乙酸和乙酸铵存在下反应，以提供(E)-1-氟-4-(2-硝基乙烯基)苯4-Fluorobenzaldehyde is reacted with nitromethane in the presence of acetic acid and ammonium acetate to provide (E)-1-fluoro-4-(2-nitrovinyl)benzene
使(E)-1-氟-4-(2-硝基乙烯基)苯与2-甲氧基-N-(甲氧基甲基)-N-((三甲基硅烷基)甲基)乙胺在催化量的酸(如TFA)存在下反应，以提供反式-3-(4-氟苯基)-1-(2-甲氧基乙基)-4-硝基吡咯烷(E)-1-Fluoro-4-(2-nitrovinyl)benzene is reacted with 2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine in the presence of a catalytic amount of an acid such as TFA to provide trans-3-(4-fluorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine
以及as well as
在氢气氛围中用氧化铂(IV)或雷尼镍(Raney Nickel)处理反式-3-(4-氟苯基)-1-(2-甲氧基乙基)-4-硝基吡咯烷，以提供反式-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺Trans-3-(4-fluorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine is treated with platinum (IV) oxide or Raney Nickel under a hydrogen atmosphere to provide trans-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine
其中4-氟苯基和氨基呈反式构型。The 4-fluorophenyl group and the amino group are in a trans configuration.
在一个实施方案中，无机碱是碱金属氢氧化物，如氢氧化钠。In one embodiment, the inorganic base is an alkali metal hydroxide, such as sodium hydroxide.
可使用与上述类似的方法，利用二-对甲苯甲酰基-L-酒石酸来提供II-A的对映异构体2：A similar method as described above can be used using di-p-toluoyl-L-tartaric acid to provide enantiomer 2 of II-A:
本发明的化合物充当TrkA抑制剂的能力可通过实例A中所述的测定来证明。The ability of compounds of the present invention to act as TrkA inhibitors can be demonstrated by the assay described in Example A.
式I化合物适用于治疗疼痛，包括慢性疼痛和急性疼痛。例如，式I化合物可适用于治疗多种类型的疼痛，包括炎症性疼痛、神经病性疼痛以及与癌症、手术和骨折相关的疼痛。The compounds of formula I are suitable for treating pain, including chronic pain and acute pain. For example, the compounds of formula I may be suitable for treating various types of pain, including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fractures.
在一个实施方案中，式I化合物适用于治疗急性疼痛。如由国际疼痛研究协会(International Association for the Study of Pain)所定义的急性疼痛由疾病、炎症或组织损伤引起。这种类型的疼痛一般例如在创伤或手术后突然出现并且可能伴有焦虑或压力。病因通常可被诊断和治疗，并且疼痛被局限于给定时段和严重性。在一些情况下，它可以变成慢性疼痛。In one embodiment, the compound of formula I is suitable for treating acute pain. Acute pain as defined by the International Association for the Study of Pain is caused by disease, inflammation or tissue damage. This type of pain generally occurs suddenly, for example, after trauma or surgery and may be accompanied by anxiety or stress. The cause of disease can usually be diagnosed and treated, and the pain is limited to a given period and severity. In some cases, it can become chronic pain.
在一个实施方案中，式I化合物适用于治疗慢性疼痛。如由国际疼痛研究协会所定义的慢性疼痛广泛地被认为代表了疾病本身。它可以因环境和心理因素而变得恶劣得多。慢性疼痛持续的时段比急性疼痛长，并且对大部分医学治疗具有抗性，一般超过3个月或更长。它可以并且常常引起患者的严重问题。In one embodiment, the compounds of Formula I are suitable for treating chronic pain. Chronic pain, as defined by the International Association for the Study of Pain, is widely considered to represent the disease itself. It can be made much worse by environmental and psychological factors. Chronic pain lasts longer than acute pain and is resistant to most medical treatments, generally exceeding three months or longer. It can and often does cause serious problems for patients.
式I化合物还适用于治疗癌症。具体实例包括成神经细胞瘤、卵巢癌、胰腺癌、结肠直肠癌以及前列腺癌。The compounds of formula I are also suitable for treating cancer. Specific examples include neuroblastoma, ovarian cancer, pancreatic cancer, colorectal cancer and prostate cancer.
式I化合物还适用于治疗炎症和某些感染性疾病。The compounds of formula I are also suitable for the treatment of inflammatory and certain infectious diseases.
另外，式I化合物还可用于治疗间质性膀胱炎(IC)、疼痛性膀胱综合症(PBS)、尿失禁、哮喘、厌食、特应性皮炎以及牛皮癣。Additionally, the compounds of formula I may be used to treat interstitial cystitis (IC), painful bladder syndrome (PBS), urinary incontinence, asthma, anorexia, atopic dermatitis, and psoriasis.
式I化合物还适用于在哺乳动物中治疗神经变性疾病，包括给所述哺乳动物施用有效治疗或预防所述神经变性疾病的量的一种或多种式I化合物或其药学上可接受的盐。在一个实施方案中，式I化合物还可通过经由阻断Sp35-TrkA相互作用以促进髓鞘形成、神经元存活和少突胶质细胞分化而用于治疗脱髓鞘和髓鞘形成障碍。在一个实施方案中，神经变性疾病是多发性硬化。在一个实施方案中，神经变性疾病是帕金森氏病(Parkinson'sdisease)。在一个实施方案中，神经变性疾病是阿兹海默氏病(Alzheimer's disease)。The compound of formula I is also suitable for treating neurodegenerative diseases in mammals, including administering to the mammal one or more compounds of formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent the neurodegenerative disease. In one embodiment, the compound of formula I can also be used to treat demyelination and myelination disorders by blocking the Sp35-TrkA interaction to promote myelination, neuronal survival and oligodendrocyte differentiation. In one embodiment, the neurodegenerative disease is multiple sclerosis. In one embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is Alzheimer's disease.
如本文所用的术语“治疗(treat)”或“治疗(treatment)”是指治疗性或缓解性措施。有益或希望的临床结果包括但不限于可检测或不可检测地完全或部分减轻与病症或病状相关的症状、降低疾病程度、使疾病病况稳定(即不恶化)、延迟或减缓疾病进展、改善或缓解疾病病况以及缓和(部分或完全)。“治疗”还可以意指使存活与不接受治疗的情况下的预期存活相比有所延长。As used herein, the term "treat" or "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, detectable or undetectable complete or partial alleviation of symptoms associated with a disorder or condition, reduction in disease severity, stabilization of the disease condition (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease condition, and alleviation (partial or complete). "Treatment" can also mean prolonging survival compared to expected survival in the absence of treatment.
在某些实施方案中，式I化合物适用于预防如本文所定义的疾病和病症。如本文所用的术语“预防”意指完全或部分预防如本文所述的疾病或病状或其症状的发作、复发或传播。In certain embodiments, compounds of Formula I are useful for preventing diseases and conditions as defined herein.The term "preventing" as used herein means completely or partially preventing the onset, recurrence, or spread of a disease or condition as described herein, or its symptoms.
因此，本发明的一个实施方案提供一种在哺乳动物中治疗疼痛的方法，其包括给所述哺乳动物施用有效治疗或预防所述疼痛的量的一种或多种式I化合物或其药学上可接受的盐。在一个实施方案中，疼痛是慢性疼痛。在一个实施方案中，疼痛是急性疼痛。在一个实施方案中，疼痛是炎症性疼痛、神经病性疼痛以及与癌症、手术和骨折相关的疼痛。Therefore, one embodiment of the present invention provides a method for treating pain in a mammal, comprising administering to the mammal one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent the pain. In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and fractures.
本发明的另一实施方案提供一种在哺乳动物中治疗炎症的方法，其包括给所述哺乳动物施用有效治疗或预防所述炎症的量的一种或多种式I化合物或其药学上可接受的盐。Another embodiment of the present invention provides a method of treating inflammation in a mammal, comprising administering to the mammal one or more compounds of Formula I or pharmaceutically acceptable salts thereof in an amount effective to treat or prevent the inflammation.
本发明的另一实施方案提供一种在哺乳动物中治疗神经变性疾病的方法，其包括给所述哺乳动物施用有效治疗或预防所述神经变性疾病的量的一种或多种式I化合物或其药学上可接受的盐。Another embodiment of the present invention provides a method for treating a neurodegenerative disease in a mammal, comprising administering to the mammal one or more compounds of formula I or pharmaceutically acceptable salts thereof in an amount effective to treat or prevent the neurodegenerative disease.
本发明的另一实施方案提供一种在哺乳动物中治疗克氏锥虫感染的方法，其包括给所述哺乳动物施用有效治疗或预防所述克氏锥虫感染的量的一种或多种式I化合物或其药学上可接受的盐。Another embodiment of the present invention provides a method of treating a Trypanosoma cruzi infection in a mammal, comprising administering to the mammal one or more compounds of Formula I or pharmaceutically acceptable salts thereof in an amount effective to treat or prevent the Trypanosoma cruzi infection.
短语“有效量”意指化合物在给有此种治疗需要的哺乳动物施用时足以实现以下的量：(i)治疗或预防可以用式I化合物治疗的具体疾病、病状或病症，(ii)削弱、改善或消除具体疾病、病状或病症中的一个或多个症状，或(iii)预防或延迟本文所述的具体疾病、病状或病症中的一个或多个症状发作。The phrase "effective amount" means an amount of a compound that, when administered to a mammal in need of such treatment, is sufficient to: (i) treat or prevent a specific disease, condition, or disorder that can be treated with a compound of Formula I, (ii) diminish, ameliorate, or eliminate one or more symptoms of a specific disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a specific disease, condition, or disorder as described herein.
对应于这样一种量的式I化合物的量将取决于如具体化合物、疾病病状和其严重度、有治疗需要的哺乳动物本身特点(例如体重)的因素而变化，但仍可以由本领域技术人员常规确定。The amount of a compound of formula I corresponding to such an amount will vary depending on factors such as the specific compound, the disease state and its severity, and the characteristics of the mammal in need of treatment (e.g., body weight), but can be routinely determined by one skilled in the art.
如本文所用的术语“哺乳动物”是指患有本文所述疾病或处于产生本文所述疾病的风险的温血动物，并且包括但不限于豚鼠、犬、猫、大鼠、小鼠、仓鼠以及灵长类动物(包括人)。As used herein, the term "mammal" refers to a warm-blooded animal suffering from or at risk of developing a disease described herein, and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates (including humans).
本发明化合物可以与一种或多种通过相同或不同作用机制起作用的额外药物组合使用。实例包括抗炎化合物、类固醇(例如地塞米松(dexamethasone)、可的松(cortisone)和氟替卡松(fluticasone))、止痛剂(如NSAID(例如阿司匹林(aspirin)、布洛芬(ibuprofen)、吲哚美辛(indomethacin)和酮洛芬(ketoprofen))和阿片样物质(如吗啡)以及化学治疗剂。The compounds of the present invention may be used in combination with one or more additional drugs that act by the same or different mechanisms of action. Examples include anti-inflammatory compounds, steroids (e.g., dexamethasone, cortisone, and fluticasone), analgesics (e.g., NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids (e.g., morphine), as well as chemotherapeutic agents.
本发明化合物可通过任何合宜的途径施用，例如施用至胃肠道(例如经直肠或经口)、鼻、肺、肌肉系统或血管结构中，或经皮或真皮施用。化合物可以任何合宜的施用形式施用，例如片剂、粉剂、胶囊、溶液、分散液、混悬液、糖浆、喷雾、栓剂、凝胶剂、乳液、贴剂等。此类组合物可含有医药制剂中常规的组分，例如稀释剂、载体、pH调节剂、甜味剂、膨胀剂以及另外的活性剂。如果希望肠胃外施用，则组合物将是无菌的并且呈适用于注射或输注的溶液或混悬液形式。此类组合物形成本发明的另一方面。适合的口服剂型的实例是含有以下的片剂：约25mg、50mg、100mg、250mg或500mg本发明的化合物，其与约90mg至30mg无水乳糖、约5mg至40mg交联羧甲基纤维素钠、约5mg至30mg聚乙烯吡咯烷酮(“PVP”)K30以及约1mg至10mg硬脂酸镁混配。首先将粉末状成分混合在一起并且然后与PVP溶液混合。可以干燥所得到的组合物，粒化，与硬脂酸镁混合并且使用常规设备压缩成片剂形式。气溶胶制剂可以通过将例如5mg至400mg本发明的化合物溶解在适合缓冲溶液(例如磷酸盐缓冲液)中，必要时添加张力剂(例如盐，如氯化钠)来制备。通常例如使用0.2微米过滤器过滤溶液以去除杂质和污染物。The compounds of this invention can be applied by any suitable route, for example, applied to the gastrointestinal tract (e.g., rectal or oral), nose, lung, muscle system or vascular structure, or applied transdermally or dermally. The compound can be applied in any suitable form of application, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain conventional components in pharmaceutical preparations, such as diluents, carriers, pH adjusting agents, sweeteners, swelling agents and other active agents. If parenteral administration is desired, the composition will be sterile and in the form of a solution or suspension suitable for injection or infusion. Such compositions form another aspect of the present invention. An example of a suitable oral dosage form is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of the invention mixed with about 90 mg to 30 mg of anhydrous lactose, about 5 mg to 40 mg of croscarmellose sodium, about 5 mg to 30 mg of polyvinylpyrrolidone ("PVP") K30 and about 1 mg to 10 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment. Aerosol formulations can be prepared by dissolving, for example, 5 mg to 400 mg of a compound of the invention in a suitable buffer solution (e.g., phosphate buffer), adding a tonicity agent (e.g., a salt such as sodium chloride) if necessary. The solution is typically filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.
另一种制剂可通过把本文所述的化合物与载体或赋形剂混合来制备。适合的载体和赋形剂是本领域技术人员所熟知的并且在例如以下参考文献中详细描述：Ansel,HowardC.等,Ansel's Pharmaceutical Dosage Forms and DrugDeliverySystems.Philadelphia:Lippincott,Williams&Wilkins,2004；Gennaro,Alfonso R.等,Remington:The Science and Practice of Pharmacy.Philadelphia:Lippincott,Williams&Wilkins,2000；以及Rowe,Raymond C.Handbook ofPharmaceuticalExcipients.Chicago,Pharmaceutical Press,2005。制剂还可包括一种或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、乳浊剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂、稀释剂和其它已知添加剂以提供药物(即本文所述的化合物或其药物组合物)的优良外观或有助于制造医药产品(即药剂)。Another formulation can be prepared by mixing the compound described herein with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, the following references: Ansel, Howard C. et al.,Ansel's Pharmaceutical Dosage Forms and DrugDeliverySystems . Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al.,Remington: The Science and Practice of Pharmacy . Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.Handbook ofPharmaceuticalExcipients . Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromas, flavorings, diluents and other known additives to provide a good appearance of the drug (i.e., the compound described herein or its pharmaceutical composition) or to facilitate the manufacture of a pharmaceutical product (i.e., a medicament).
因此，本发明的另一方面提供一种药物组合物，其包含如上文所定义的式I化合物或其药学上可接受的盐连同药学上可接受的稀释剂或载体。Therefore, another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
根据另一实施方案，本发明提供式I化合物或其药学上可接受的盐用于在哺乳动物中治疗疼痛。在一个实施方案中，疼痛是慢性疼痛。在一个实施方案中，疼痛是急性疼痛。在一个实施方案中，疼痛是炎症性疼痛、神经病性疼痛以及与癌症、手术和骨折相关的疼痛。According to another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating pain in a mammal. In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and fractures.
在另一实施方案中，本发明提供式I化合物或其药学上可接受的盐用于在哺乳动物中治疗炎症。In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating inflammation in a mammal.
在另一实施方案中，本发明提供式I化合物或其药学上可接受的盐用于在哺乳动物中治疗感染性疾病(例如克氏锥虫感染)。In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating an infectious disease (eg, Trypanosoma cruzi infection) in a mammal.
在另一实施方案中，本发明提供式I化合物或其药学上可接受的盐用于在哺乳动物中治疗神经变性疾病。In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating a neurodegenerative disease in a mammal.
根据另一方面，本发明提供式I化合物或其药学上可接受的盐在制造用于治疗选自疼痛、癌症、炎症、神经变性疾病或克氏锥虫感染的病状的药剂的用途。在一个实施方案中，病状是慢性疼痛。在一个实施方案中，病状是急性疼痛。在一个实施方案中，疼痛是炎症性疼痛、神经病性疼痛以及与癌症、手术和骨折相关的疼痛。在一个实施方案中，病状是癌症。在一个实施方案中，病状是炎症。在一个实施方案中，病状是神经变性疾病。在一个实施方案中，病状是克氏锥虫感染。According to another aspect, the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition selected from pain, cancer, inflammation, a neurodegenerative disease, or a Trypanosoma cruzi infection. In one embodiment, the condition is chronic pain. In one embodiment, the condition is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fractures. In one embodiment, the condition is cancer. In one embodiment, the condition is inflammation. In one embodiment, the condition is a neurodegenerative disease. In one embodiment, the condition is a Trypanosoma cruzi infection.
本文所用的缩写具有以下定义：The abbreviations used herein have the following definitions:
实例Examples
以下实例说明本发明。在下文所述实例中，除非另外指示，否则所有温度以摄氏度阐述。试剂购自商业供应商，如Aldrich化学公司、Lancaster、TCI或Maybridge，并且除非另外指示，否则不经进一步纯化即供使用。THF、DCM、甲苯、DMF和二噁烷是在Sure/SealTM瓶中购自Aldrich，并且按原样使用。The following examples illustrate the present invention. In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI, or Maybridge and were used without further purification unless otherwise indicated. THF, DCM, toluene, DMF, and dioxane were purchased from Aldrich in Sure/Seal™ bottles and used as received.
以下所述反应一般在正氮气或氩气压力下或用干燥管(除非另有说明)在无水溶剂中进行，并且反应烧瓶通常装有橡胶隔片以经由注射器引入底物和试剂。玻璃器皿经烘干和/或热干燥。The reactions described below were generally carried out in anhydrous solvents under positive nitrogen or argon pressure or with a drying tube (unless otherwise stated), and the reaction flasks were usually fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven-dried and/or heat-dried.
在具有硅胶或C-18反相柱的Biotage系统(制造商：Dyax公司)上或在二氧化硅SepPak柱体(Waters)上进行柱色谱法。Column chromatography was performed on a Biotage system (manufacturer: Dyax Corporation) with silica gel or C-18 reverse phase columns or on silica SepPak cartridges (Waters).
生物测定Bioassay
实例AExample A
TrkA Omnia测定TrkA Omnia assay
使用来自Invitrogen公司的OmniaTM激酶测定试剂评定Trk酶选择性。在384孔白色聚丙烯板(Nunc目录号267462)中在环境温度下孵育酶(来自Invitrogen公司的TrkA)和测试化合物(各种浓度)10分钟。然后把Omnia Tyr肽4以及ATP添加到板中。最终浓度如下：20nM酶、500μM ATP、10μM肽底物。测定缓冲液由25mM MOPS(pH 7.5)、0.005％(v/v)TritonX-100和5mM MgCl2组成。使用Molecular Devices FlexStation II384微板读取器(激发＝360nm；发射＝485nm)连续监测磷酸化肽的产生，持续70分钟。初始速率由进度曲线计算。IC50值是使用4参数或5参数逻辑曲线拟合由这些速率来计算。Trk enzyme selectivity was assessed using the Omnia™ Kinase Assay Reagent from Invitrogen. Enzyme (TrkA from Invitrogen) and test compounds (various concentrations) were incubated in 384-well white polypropylene plates (Nunc catalog number 267462) at ambient temperature for 10 minutes. Omnia Tyr peptide 4 and ATP were then added to the plates. Final concentrations were as follows: 20 nM enzyme, 500 μM ATP, 10 μM peptide substrate. The assay buffer consisted of 25 mM MOPS (pH 7.5), 0.005% (v/v) Triton X-100, and 5 mMMgCl₂ . Phosphorylated peptide production was monitored continuously for 70 minutes using a Molecular Devices FlexStation II384 microplate reader (excitation = 360 nm; emission = 485 nm). Initial rates were calculated from progress curves.IC₅₀ values were calculated from these rates using a 4-parameter or 5-parameter logistic curve fit.
本发明的化合物在此测定中测试时的平均IC50值低于1000nM。某些化合物在此测定中测试时的平均IC50值低于100nM。Compounds of the invention had meanIC50 values of less than 1000 nM when tested in this assay. Certain compounds had meanIC50 values of less than 100 nM when tested in this assay.
表A提供本发明的化合物在实例A的测定中测试时的平均IC50值，其中A表示平均IC50值<100nM；B表示平均IC50值是100nM至1,000nM；并且C表示平均IC50值是1,000nM至10,000nM。Table A provides the meanIC50 values for compounds of the invention when tested in the assay of Example A, wherein A indicates a meanIC50 value <100 nM; B indicates a meanIC50 value of 100 nM to 1,000 nM; and C indicates a meanIC50 value of 1,000 nM to 10,000 nM.
表ATable A
制备合成中间体Preparation of synthetic intermediates
制备APreparation A
反式-4-苯基吡咯烷-3-基氨基甲酸叔丁酯tert-Butyl trans-4-phenylpyrrolidin-3-ylcarbamate
步骤A：制备反式-1-苯甲基-3-硝基-4-苯基吡咯烷：向(E)-(2-硝基乙烯基)苯(149g，1.00mol)的DCM(2L)溶液中添加TFA(19.5mL，0.250mol)，接着冷却至-15℃，然后经3小时缓慢添加N-甲氧基甲基-N-(三甲基硅烷基甲基)苯甲胺(274g，1.00mol)的DCM(500mL)溶液，同时把反应温度维持在-15℃与-10℃之间。使反应物升温至环境温度并且搅拌18小时，然后用2N NaOH(500mL)洗涤并且用2N HCl(1L)处理。搅拌所得到的白色悬浮液1小时，之后过滤并且用DCM洗涤。然后把DCM(1L)和2N NaOH(750mL)添加到所收集的白色固体中并且搅拌直到所有固体溶解为止。相分离后，用DCM(2×1L)萃取水层。用MgSO4干燥合并的有机层，过滤并且浓缩，得到呈灰白色固体状的标题产物(205g，73％产率)。MS(apci)m/z＝283.1(M+H)。Step A:Preparation of trans-1-benzyl-3-nitro-4-phenylpyrrolidine : To a solution of (E)-(2-nitrovinyl)benzene (149 g, 1.00 mol) in DCM (2 L) was added TFA (19.5 mL, 0.250 mol), followed by cooling to -15°C and then slowly adding a solution of N-methoxymethyl-N-(trimethylsilylmethyl)benzylamine (274 g, 1.00 mol) in DCM (500 mL) over 3 hours while maintaining the reaction temperature between -15°C and -10°C. The reaction was allowed to warm to ambient temperature and stirred for 18 hours before being washed with 2N NaOH (500 mL) and treated with 2N HCl (1 L). The resulting white suspension was stirred for 1 hour before being filtered and washed with DCM. DCM (1 L) and 2N NaOH (750 mL) were then added to the collected white solid and stirred until all the solid had dissolved. After phase separation, the aqueous layer was extracted with DCM (2 x 1 L). The combined organic layers were dried over MgSO4 , filtered and concentrated to afford the title product as an off-white solid (205 g, 73% yield). MS (apci) m/z = 283.1 (M+H).
步骤B：制备反式-1-苯甲基-4-苯基吡咯烷-3-胺：向反式-1-苯甲基-3-硝基-4-苯基-吡咯烷(93.9g，333mmol)在EtOH(1.20L)中的悬浮液中添加浓HCl(450mL)，接着经1.5小时分数小份添加锌粉(173g，2.66mol)，同时把温度维持在55℃至60℃之间。在环境温度下搅拌反应混合物18小时，然后在冰/水浴中冷却，接着添加浓NH4OH(900mL)。过滤混合物(pH＝10至11)并且用CHCl3洗涤所收集的锌。然后对滤液进行相分离，并且用CHCl3(2×400mL)萃取水层。用H2O、盐水洗涤合并的有机物，用MgSO4干燥，过滤并且浓缩，得到呈琥珀色油状的标题化合物(85.0g，100％产率)。MS(apci)m/z＝253.2(M+H)。Step B:Preparation of trans-1-benzyl-4-phenylpyrrolidin-3-amine : To a suspension of trans-1-benzyl-3-nitro-4-phenyl-pyrrolidine (93.9 g, 333 mmol) in EtOH (1.20 L) was added concentrated HCl (450 mL), followed by the addition of zinc powder (173 g, 2.66 mol) in small portions over 1.5 hours while maintaining the temperature between 55° C. and 60° C. The reaction mixture was stirred at ambient temperature for 18 hours, then cooled in an ice/water bath, followed by the addition of concentrated NH4 OH (900 mL). The mixture was filtered (pH = 10 to 11) and the collected zinc was washed with CHCl3. The filtrate was then phase separated, and the aqueous layer was extracted with CHCl3 (2×400 mL). The combined organics were washed withH2O , brine, dried overMgSO4 , filtered and concentrated to give the title compound as an amber oil (85.0 g, 100% yield).MS (apci) m/z = 253.2 (M+H).
步骤C：制备反式-(1-苯甲基-4-苯基-吡咯烷-3-基)-氨基甲酸叔丁酯：经30分钟向反式-1-苯甲基-4-苯基吡咯烷-3-胺(85.0g，333mmol)、THF(750mL)和三乙胺(69.6mL，500mmol)的混合物中逐份缓慢添加(Boc)2O(72.7g，333mmol)。在环境温度下搅拌反应混合物16小时并且在真空中浓缩。把残余物溶解于CHCl3中并且用Na2CO3水溶液和盐水洗涤。用MgSO4干燥有机层，过滤并且浓缩，得到呈浅黄色固体状的标题化合物(116g，99％产率)。MS(apci)m/z＝353.0(M+H)。[0146] Step C:Preparation of trans-(1-benzyl-4-phenyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester : To a mixture of trans-1-benzyl-4-phenylpyrrolidin-3-amine (85.0 g, 333 mmol), THF (750 mL), and triethylamine (69.6 mL, 500 mmol) was slowly added (Boc)2O (72.7 g, 333 mmol) portionwise over 30 minutes. The reaction mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo. The residue was dissolved inCHCl3 and washed withaqueousNa2CO3 and brine. The organic layer was dried overMgSO4 , filtered, and concentrated to give the title compound (116 g, 99% yield) as a light yellow solid. MS (apci) m/z = 353.0 (M+H).
步骤D：制备反式-4-苯基吡咯烷-3-基氨基甲酸叔丁酯：向2加仑帕尔(Parr)反应器中装入反式-(1-苯甲基-4-苯基-吡咯烷-3-基)-氨基甲酸叔丁酯(114g，323mmol)、EtOH(2L)和10％Pd/C(50％湿，11.0g)。用N2吹洗反应器若干次，用H2填充至56psi至57psi并且在80℃下搅动。当根据HPLC分析反应完成时，过滤反应混合物并且浓缩滤液，得到呈黄色固体状的粗产物。把粗物质由甲苯湿磨，得到呈白色固体状的标题产物(68.4g，78％产率)。MS(apci)m/z＝262.9(M+H)。[0146] Step D:Preparation of tert-butyl trans-4-phenylpyrrolidin-3-ylcarbamate : A 2-gallon Parr reactor was charged with tert-butyl trans-(1-benzyl-4-phenyl-pyrrolidin-3-yl)-carbamate (114 g, 323 mmol), EtOH (2 L), and 10% Pd/C (50% wet, 11.0 g). The reactor was purged withN2 several times, filled withH2 to 56 to 57 psi, and stirred at 80°C. When the reaction was complete according to HPLC analysis, the reaction mixture was filtered and the filtrate was concentrated to give the crude product as a yellow solid. The crude material was triturated with toluene to give the title product as a white solid (68.4 g, 78% yield). MS (apci) m/z = 262.9 (M+H).
制备A2Preparation A2
反式-3-氨基-4-苯基吡咯烷-1-甲酸叔丁酯trans-tert-Butyl 3-amino-4-phenylpyrrolidine-1-carboxylate
步骤A：制备反式-N-(1-苯甲基-4-苯基吡咯烷-3-基)-2,2,2-三氟乙酰胺：向反式-1-苯甲基-4-苯基吡咯烷-3-胺(制备A步骤B，61.9g，245mmol)在DCM(400mL)中的溶液中添加DIEA(64.1mL，368mmol)并且在冰浴中冷却混合物。在N2氛围下经30分钟逐滴添加三氟乙酸酐(38.1mL，270mmol)。添加后，搅拌混合物30分钟并且然后在真空中浓缩。把残余物溶解于DCM中并且用饱和NaHCO3水溶液和盐水洗涤。用MgSO4干燥溶液，过滤并且在真空中浓缩。用己烷处理粗物质并且在环境温度下搅拌所得到的黄色悬浮液1小时。通过过滤收集固体，用己烷洗涤并且在真空下干燥，得到呈黄色固体状的标题化合物(78.7g，92％产率)。MS(apci)m/z＝349.1(M+H)。Step A:Preparation of trans-N-(1-benzyl-4-phenylpyrrolidin-3-yl)-2,2,2-trifluoroacetamide : To a solution of trans-1-benzyl-4-phenylpyrrolidin-3-amine (Preparation A, Step B, 61.9 g, 245 mmol) in DCM (400 mL) was added DIEA (64.1 mL, 368 mmol) and the mixture was cooled in an ice bath. Trifluoroacetic anhydride (38.1 mL, 270 mmol) was added dropwise under anN atmosphere over 30 minutes. After the addition, the mixture was stirred for 30 minutes and then concentrated in vacuo. The residue was dissolved in DCM and washed with saturated aqueousNaHCO3 solution and brine. The solution was dried overMgSO4 , filtered, and concentrated in vacuo. The crude material was treated with hexanes and the resulting yellow suspension was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with hexanes, and dried in vacuo to give the title compound (78.7 g, 92% yield) as a yellow solid. MS (apci) m/z = 349.1 (M+H).
步骤B：制备反式-3-苯基-4-(2,2,2-三氟乙酰胺基)吡咯烷-1-甲酸叔丁酯：用N2吹洗反式-N-(1-苯甲基-4-苯基吡咯烷-3-基)-2,2,2-三氟乙酰胺(78.7g，226mmol)在EtOH(400mL)中的溶液并且用活性碳(31.7g，45.2mmol)上的20％Pd(OH)2处理。在帕尔反应器中在环境温度、30psi H2下搅动混合物7小时，并且然后通过GF/F纸过滤并且在真空中浓缩。把残余物溶解于DCM(250mL)中，接着添加TEA(49.4mL，355mmol)并且在冰浴中冷却。经15分钟缓慢添加Boc2O(56.8g，260mmol)并且使反应混合物升温至环境温度并且搅拌1小时。用饱和NaHCO3水溶液和盐水洗涤混合物，然后用MgSO4干燥。过滤溶液，浓缩并且通过二氧化硅柱色谱法用40％EtOAc/己烷洗脱来纯化残余物，得到呈白色固体状的标题化合物(63.2g，75％产率)。1H NMR(CDCl3)δ7.23-7.39(m,5H),6.36(br s,1H),4.47-4.55(m,1H),3.92-4.00(m,1H),3.78-4.00(m,1H),3.50-3.59(m,1H),3.22-3.45(m,2H),1.49(s,9H)。Step B:Preparation of tert-butyl trans-3-phenyl-4-(2,2,2-trifluoroacetamido)pyrrolidine-1- carboxylate: A solution of trans-N-(1-benzyl-4-phenylpyrrolidin-3-yl)-2,2,2-trifluoroacetamide (78.7 g, 226 mmol) in EtOH (400 mL) was purged with N₂ and treated with 20% Pd(OH)₂ on activated carbon (31.7 g, 45.2 mmol). The mixture was stirred in a Parr reactor at ambient temperature under 30 psiH₂ for 7 hours, then filtered through GF/F paper and concentrated in vacuo. The residue was dissolved in DCM (250 mL), followed by the addition of TEA (49.4 mL, 355 mmol) and cooled in an ice bath.Boc₂O (56.8 g, 260 mmol) was added slowly over 15 minutes, and the reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. The mixture was washed with saturated aqueous NaHCO3 and brine, then dried over MgSO4. The solution was filtered, concentrated, and the residue was purified by silica column chromatography eluting with 40% EtOAc/hexanes to give the title compound (63.2 g, 75% yield) as a white solid.1 H NMR (CDCl3 ) δ 7.23-7.39 (m, 5H), 6.36 (br s, 1H), 4.47-4.55 (m, 1H), 3.92-4.00 (m, 1H), 3.78-4.00 (m, 1H), 3.50-3.59 (m, 1H), 3.22-3.45 (m, 2H), 1.49 (s, 9H).
步骤C：制备反式-3-氨基-4-苯基吡咯烷-1-甲酸叔丁酯：在冰浴中冷却反式-3-苯基-4-(2,2,2-三氟乙酰胺基)吡咯烷-1-甲酸叔丁酯(63.2g，176mmol)在MeOH(200mL)中的溶液并且添加2N NaOH(220mL，440mmol)。允许反应混合物升温至环境温度过夜，然后浓缩至约200mL并且用H2O(200mL)稀释。用DCM萃取水性混合物并且用盐水洗涤合并的萃取物并且经Na2SO4干燥。过滤溶液并且浓缩，得到呈淡黄色油状的标题化合物(46.2g，99％产率)。MS(apci)m/z＝163.0(M+H-Boc)。Step C:Preparation of tert-butyl trans-3-amino-4-phenylpyrrolidine-1-carboxylate : A solution of tert-butyl trans-3-phenyl-4-(2,2,2-trifluoroacetamido)pyrrolidine-1-carboxylate (63.2 g, 176 mmol) in MeOH (200 mL) was cooled in an ice bath and 2N NaOH (220 mL, 440 mmol) was added. The reaction mixture was allowed to warm to ambient temperature overnight, then concentrated to approximately 200 mL and diluted with H2 O (200 mL). The aqueous mixture was extracted with DCM and the combined extracts were washed with brine and dried over Na2 SO4. The solution was filtered and concentrated to give the title compound (46.2 g, 99% yield) as a light yellow oil. MS (apci) m/z=163.0 (M+H-Boc).
制备BPreparation B
反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride
步骤A：制备反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯：向反式-4-苯基吡咯烷-3-基氨基甲酸叔丁酯(制备A，4.82g，17.5mmol)在干燥DMF(50mL)中的溶液中依序添加DIEA(9.12mL，52.4mmol)和1-溴-2-甲氧基乙烷(1.97mL，20.9mmol)。在环境温度下搅拌混合物46小时并且然后倒入H2O(300mL)中。用EtOAc(3×150mL)萃取混合物并且用盐水洗涤合并的萃取物，经MgSO4/活性碳干燥，通过盖有填充的MgSO4的SiO2塞过滤，并且用EtOAc洗脱。浓缩溶液并且在真空中干燥，得到呈白色固体状的产物(5.15g，92％产率)。MS(apci)m/z＝321.1(M+H)。Step A:Preparation of tert-butyl trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate : To a solution of tert-butyl trans-4-phenylpyrrolidin-3-ylcarbamate (Preparation A, 4.82 g, 17.5 mmol) in dry DMF (50 mL) was added DIEA (9.12 mL, 52.4 mmol) and 1-bromo-2-methoxyethane (1.97 mL, 20.9 mmol) sequentially. The mixture was stirred at ambient temperature for 46 hours and then poured intoH₂O (300 mL). The mixture was extracted with EtOAc (3×150 mL) and the combined extracts were washed with brine, dried overMgSO₄ /activated carbon, filtered through a plug ofSiO₂ covered withMgSO₄ , and eluted with EtOAc. The solution was concentrated and dried in vacuo to give the product as a white solid (5.15 g, 92% yield). MS (apci) m/z = 321.1 (M+H).
步骤B：制备反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐：向反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯(5.10g，15.9mmol)在2:1 EtOAc-MeOH(150mL)中的溶液中添加4N HCl的二噁烷溶液(59.7mL，239mmol)。在环境温度下搅拌混合物90分钟并且然后在真空中浓缩。用EtOAc(200mL)处理所得到的泡沫状物，超声5分钟并且剧烈搅拌直到精细白色悬浮液形成为止。过滤悬浮液，用EtOAc洗涤并且在真空下干燥，得到呈白色粉末状的标题化合物(5.10g，100％产率)。MS(apci)m/z＝221.1(M+H)。Step B:Preparation of trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride : To a solution of trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamic acid tert-butyl ester (5.10 g, 15.9 mmol) in 2: 1 EtOAc-MeOH (150 mL) was added a solution of 4N HCl in dioxane (59.7 mL, 239 mmol). The mixture was stirred at ambient temperature for 90 minutes and then concentrated in vacuo. The resulting foam was treated with EtOAc (200 mL), sonicated for 5 minutes and stirred vigorously until a fine white suspension formed. The suspension was filtered, washed with EtOAc and dried under vacuum to give the title compound (5.10 g, 100% yield) as a white powder. MS (apci) m/z=221.1 (M+H).
制备CPreparation C
2-甲氧基-N-(甲氧基甲基)-N-((三甲基硅烷基)甲基)乙胺2-Methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethylamine
步骤A：制备2-甲氧基-N-((三甲基硅烷基)甲基)乙胺：在90℃下通过加料漏斗经40分钟向2-甲氧基乙胺(14.2mL，163mmol)的DMSO溶液(15mL)中添加(氯甲基)三甲基硅烷(11.4mL，81.5mmol)的DMSO(10mL)溶液。在90℃下加热混合物3.5小时，然后冷却至环境温度。然后用H2O(150mL)稀释并且用EtOAc(2×150mL)萃取。用盐水(150mL)洗涤合并的有机萃取物，用MgSO4干燥，过滤并且浓缩，得到呈黄色油状的产物(8.14g，62％产率)。MS(apci)m/z＝162.0(M+H)。[0266] Step A:Preparation of 2-methoxy-N-((trimethylsilyl)methyl)ethanamine : To a solution of 2-methoxyethylamine (14.2 mL, 163 mmol) in DMSO (15 mL) was added a solution of (chloromethyl)trimethylsilane (11.4 mL, 81.5 mmol) in DMSO (10 mL) via an addition funnel at 90°C over 40 minutes. The mixture was heated at 90°C for 3.5 hours and then cooled to ambient temperature. It was then diluted withH2O (150 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine (150 mL), dried overMgSO4 , filtered, and concentrated to give the product as a yellow oil (8.14 g, 62% yield). MS (apci) m/z = 162.0 (M+H).
步骤B：制备2-甲氧基-N-(甲氧基甲基)-N-((三甲基硅烷基)甲基)乙胺：把甲醛(37％水溶液，4.91g，60.6mmol)的MeOH(2.45mL)溶液冷却至0℃，并且通过逐滴添加2-甲氧基-N-((三甲基硅烷基)甲基)乙胺(8.14g，50.5mmol)来处理。在0℃下搅拌两相混合物3小时，然后添加K2CO3(6.97g，50.5mmol)并且在0℃下搅拌混合物1小时。把黄色油状物倾析到K2CO3(2.00g，14.4mmol)上，并且在环境温度下搅拌混合物2小时。倾析黄色油状物后，用Et2O(2×10mL)洗涤固体K2CO3，并且把Et2O洗涤液与倾析的黄色油状物合并并且在旋转蒸发仪上浓缩，得到呈黄色油状的产物(9.92g，96％产率)。1H NMR(CDCl3)δ4.00(s,2H),3.37-3.43(m,2H),3.29(s,3H),3.19(s,3H),2.77-2.82(m,2H),2.18(s,2H),0.00(s,9H)。[0146] Step B:Preparation of 2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine : A solution of formaldehyde (37% in water, 4.91 g, 60.6 mmol) in MeOH (2.45 mL) was cooled to 0°C and treated with the dropwise addition of 2-methoxy-N-((trimethylsilyl)methyl)ethanamine (8.14 g, 50.5 mmol). The biphasic mixture was stirred at 0°C for 3 hours, thenK2CO3 (6.97 g, 50.5 mmol) was added and the mixture was stirred at 0°C for 1 hour. The yellow oil was decanted onto K2CO3( 2.00 g, 14.4 mmol) andthe mixture was stirred at ambient temperature for 2 hours. After decanting the yellow oil, the solid K2 CO3 was washed with Et2 O (2×10 mL), and the Et2 O washings were combined with the decanted yellow oil and concentrated on a rotary evaporator to give the product as a yellow oil (9.92 g, 96% yield).1 H NMR (CDCl3 ) δ 4.00 (s, 2H), 3.37-3.43 (m, 2H), 3.29 (s, 3H), 3.19 (s, 3H), 2.77-2.82 (m, 2H), 2.18 (s, 2H), 0.00 (s, 9H).
制备DPreparation D
(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(3S,4R)-1-(2-Methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride
步骤A：制备(R)-3-肉桂酰基-4-苯基噁唑烷-2-酮：把(R)-4-苯基噁唑啶-2-酮(5.90g，36.2mmol)的THF(50mL)溶液冷却至-78℃并且经15分钟逐滴用双(三甲基硅烷基)氨化锂(36.9mL，36.9mmol，1.0M THF溶液)处理。在-78℃下搅拌15分钟后，然后引入肉桂酰氯(6.33g，38.0mmol)的THF(10mL)溶液。在-78℃下搅拌混合物1小时并且在环境温度下搅拌2小时，之后用饱和NaHCO3(50mL)淬灭并且搅拌1小时。用EtOAc(200mL)稀释混合物，用水和盐水洗涤，经MgSO4干燥，过滤并且浓缩，得到呈浅黄色固体状的产物(10.6g，99.9％产率)。MS(apci)m/z＝293.9(M+H)。Step A:Preparation of (R)-3-cinnamoyl-4-phenyloxazolidin-2-one : A solution of (R)-4-phenyloxazolidin-2-one (5.90 g, 36.2 mmol) in THF (50 mL) was cooled to -78°C and treated dropwise with lithium bis(trimethylsilyl)amide (36.9 mL, 36.9 mmol, 1.0 M in THF) over 15 minutes. After stirring at -78°C for 15 minutes, a solution of cinnamoyl chloride (6.33 g, 38.0 mmol) in THF (10 mL) was then introduced. The mixture was stirred at -78°C for 1 hour and at ambient temperature for 2 hours before being quenched with saturatedNaHCO₃ (50 mL) and stirred for 1 hour. The mixture was diluted with EtOAc (200 mL), washed with water and brine, dried overMgSO₄ , filtered, and concentrated to give the product as a light yellow solid (10.6 g, 99.9% yield). MS (apci) m/z = 293.9 (M+H).
步骤B：制备(R)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-羰基)-4-苯基噁唑烷-2-酮：首先把(R)-3-肉桂酰基-4-苯基噁唑烷-2-酮(8.00g，27.3mmol)和TFA(0.210mL，2.73mmol)的甲苯(500mL)溶液冷却至5℃至10℃，接着逐滴添加2-甲氧基-N-(甲氧基甲基)-N-((三甲基硅烷基)甲基)乙胺(制备C，8.40g，40.9mmol)的甲苯(30mL)溶液。使所得到的混合物升温至环境温度并且搅拌3小时，然后用饱和NaHCO3和水洗涤，用MgSO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用16％至20％EtOAc/己烷洗脱来纯化粗物质，得到产物(6.5g，60％产率)。MS(apci)m/z＝395.2(M+H)。[0146] Step B:Preparation of (R)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidine-3-carbonyl)-4-phenyloxazolidin-2-one : A solution of (R)-3-cinnamoyl-4-phenyloxazolidin-2-one (8.00 g, 27.3 mmol) and TFA (0.210 mL, 2.73 mmol) in toluene (500 mL) was first cooled to 5-10°C, followed by the dropwise addition of a solution of 2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine (Preparation C, 8.40 g, 40.9 mmol) in toluene (30 mL). The resulting mixture was allowed to warm to ambient temperature and stirred for 3 hours, then washed with saturatedNaHCO3 and water, dried overMgSO4 , filtered, and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with 16% to 20% EtOAc/hexanes to give the product (6.5 g, 60% yield).MS (apci) m/z = 395.2 (M+H).
步骤C：制备(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-甲酸：在0℃下向1MLiOH水溶液(41.2mL，41.2mmol)中添加H2O2(3.37mL，33.0mmol，30wt％)。然后在0℃下经10分钟把混合物添加到(R)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-羰基)-4-苯基噁唑烷-2-酮(6.50g，16.5mmol)在THF(100mL)中的溶液中。搅拌1小时后，在0℃下引入2.0MNa2SO3水溶液(33.0mL，65.9mmol)并且使反应混合物升温至环境温度。搅拌10分钟后，用EtOAc(50mL)洗涤混合物。用1N HCl酸化水层直至pH为3至5，然后用NaCl(10g)处理，然后用10％iPrOH/DCM萃取。用MgSO4干燥有机层，过滤并且浓缩，得到产物(4.11g，100％产率)。MS(apci)m/z＝250.1(M+H)。Step C:Preparation of (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidine-3-carboxylic acid : To a 1 M aqueous LiOH solution (41.2 mL, 41.2 mmol) was addedH₂O₂( 3.37 mL, 33.0 mmol, 30 wt%) at 0°C. The mixture was then added to a solution of (R)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidine-3-carbonyl)-4-phenyloxazolidin-2-one (6.50 g, 16.5 mmol) in THF (100 mL) at 0°C over 10 minutes. After stirring for 1 hour, a2.0 M aqueousNa₂SO₃ solution (33.0 mL, 65.9 mmol) was introduced at 0°C and the reaction mixture was allowed to warm to ambient temperature. After stirring for 10 minutes, the mixture was washed with EtOAc (50 mL). The aqueous layer was acidified with 1N HCl until the pH was between 3 and 5, then treated with NaCl (10 g), and then extracted with 10% iPrOH/DCM. The organic layer was dried over MgSO4 , filtered, and concentrated to afford the product (4.11 g, 100% yield). MS (apci) m/z=250.1 (M+H).
步骤D：制备(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基氨基甲酸苯甲酯：向(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-甲酸(4.11g，16.5mmol)在甲苯(70mL)中的溶液中添加TEA(5.74mL，41.2mmol)，接着添加二苯基磷酰基叠氮化物(4.99mL，23.1mmol)。在环境温度下搅拌混合物1小时，并且然后加热至回流，持续1小时。然后添加苯甲醇(3.42mL，33.0mmol)并且使反应混合物回流15小时。用EtOAc处理反应混合物，用水洗涤，经MgSO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用1％MeOH/DCM洗脱来纯化粗物质，得到产物(2.5g，43％产率)。MS(apci)m/z＝355.2(M+H)。Step D:Preparation of (3S, 4R) -1- (2-methoxyethyl) -4-phenylpyrrolidin-3-ylcarbamic acid benzyl ester : To a solution of (3S, 4R) -1- (2-methoxyethyl) -4-phenylpyrrolidine -3-carboxylic acid (4.11 g, 16.5 mmol) in toluene (70 mL) was added TEA (5.74 mL, 41.2 mmol), followed by diphenylphosphoryl azide (4.99 mL, 23.1 mmol). The mixture was stirred at ambient temperature for 1 hour, and then heated to reflux for 1 hour. Benzyl alcohol (3.42 mL, 33.0 mmol) was then added and the reaction mixture was refluxed for 15 hours. The reaction mixture was treated with EtOAc, washed with water, dried over MgSO4 , filtered and concentrated in vacuo. The crude material was purified by silica column chromatography using 1% MeOH/DCM as eluent to give the product (2.5 g, 43% yield). MS (apci) m/z = 355.2 (M+H).
步骤E：制备(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐：在60℃下加热(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基氨基甲酸苯甲酯(0.257g，0.725mmol)和TFA(3.91mL，50.8mmol)17小时。在真空中使用甲苯把反应混合物浓缩成共沸物，然后用2N HCl的Et2O溶液处理并且再次浓缩，得到呈灰白色固体状的标题化合物(0.21g，100％产率)。MS(apci)m/z＝221.2(M+H)。[0146] Step E:Preparation of (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride : Heat benzyl (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate (0.257 g, 0.725 mmol) and TFA (3.91 mL, 50.8 mmol) at 60°C for 17 hours. The reaction mixture is concentrated in vacuo with toluene to an azeotrope, then treated with 2N HCl inEt2O and concentrated again to give the title compound as an off-white solid (0.21 g, 100% yield). MS (apci) m/z = 221.2 (M+H).
制备EPreparation E
(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺三氟乙酸盐(3S,4R)-4-(3,5-Difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine trifluoroacetate
步骤A：制备(R,E)-3-(3-(3,5-二氟苯基)丙烯酰基)-4-苯基噁唑烷-2-酮：在0℃下向(E)-3-(3,5-二氟苯基)丙烯酸(10.0g，54.3mmol)在Et2O(150mL)中的溶液中添加DIEA(9.48mL，54.3mmol)，接着添加新戊酰氯(6.69mL，54.3mmol)。在0℃下搅拌混合物1小时并且冷却至-78℃。同时把在THF(200mL)中的(R)-4-苯基噁唑烷-2-酮(8.86g，54.3mmol)冷却至-78℃并且缓慢添加丁基锂(21.7mL，2.5M，54.3mmol)。在-78℃下搅拌混合物20分钟并且通过套管转移到混合酐的溶液中。在-78℃下搅拌合并的混合物15分钟，允许其升温至0℃并且再搅拌30分钟。用饱和NH4Cl(25mL)淬灭反应混合物，用EtOAc(600mL)稀释，用水、NaHCO3和盐水洗涤，经MgSO4干燥，并且在真空中浓缩。通过二氧化硅柱色谱法，用10％至20％乙酸乙酯/己烷洗脱来纯化粗物质，得到产物(11.0g，61.5％产率)。Step A:Preparation of (R,E)-3-(3-(3,5-difluorophenyl)acryloyl)-4-phenyloxazolidin-2-one : To a solution of (E)-3-(3,5-difluorophenyl)acrylic acid (10.0 g, 54.3 mmol) inEt2O (150 mL) at 0°C was added DIEA (9.48 mL, 54.3 mmol) followed by pivaloyl chloride (6.69 mL, 54.3 mmol). The mixture was stirred at 0°C for 1 hour and cooled to -78°C. Simultaneously, (R)-4-phenyloxazolidin-2-one (8.86 g, 54.3 mmol) in THF (200 mL) was cooled to -78°C and butyllithium (21.7 mL, 2.5 M, 54.3 mmol) was slowly added. The mixture was stirred at -78°C for 20 minutes and transferred to the solution of the mixed anhydride via cannula. The combined mixture was stirred at -78 ° C for 15 minutes, allowed to warm to 0 ° C and stirred for an additional 30 minutes. The reaction mixture was quenched with saturated NH4 Cl (25 mL), diluted with EtOAc (600 mL), washed with water, NaHCO3 and brine, dried over MgSO4 , and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with 10% to 20% ethyl acetate/hexane to obtain the product (11.0 g, 61.5% yield).
步骤B：制备(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺三氟乙酸盐：通过制备D步骤B至E中所述的方法，用(R,E)-3-(3-(3,5-二氟苯基)丙烯酰基)-4-苯基噁唑烷-2-酮替代(R)-3-肉桂酰基-4-苯基噁唑烷-2-酮来制备，得到标题化合物(1.70g，102％产率)。MS(apci)m/z＝257.2(M+H)。Step B:Preparation of (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine trifluoroacetate: Prepare by the method described in Preparation D, Steps B through E, substituting (R,E)-3-(3-(3,5-difluorophenyl)acryloyl)-4-phenyloxazolidin-2-one for (R)-3-cinnamoyl-4-phenyloxazolidin-2-one to afford the title compound (1.70 g, 102% yield). MS (apci) m/z = 257.2 (M+H).
制备FPreparation F
(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(3S,4R)-4-(3,4-Difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine
根据制备D中所述的方法，用(E)-3-(3,4-二氟苯基)丙烯酰氯替代肉桂酰氯来制备。MS(apci)m/z＝257.1(M+H)。Prepared according to the method described in Preparation D, substituting (E)-3-(3,4-difluorophenyl)acryloyl chloride for cinnamoyl chloride. MS (apci) m/z = 257.1 (M+H).
制备GPreparation G
(3S,4R)-1-(2-甲氧基乙基)-4-(3-(三氟甲基)苯基)吡咯烷-3-胺二盐酸盐(3S,4R)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-amine dihydrochloride
步骤A：制备(3S,4R)-1-(2-甲氧基乙基)-4-(3-(三氟甲基)-苯基)吡咯烷-3-基氨基甲酸叔丁酯：在环境温度下搅拌(3S,4R)-4-(3-(三氟甲基)苯基)-吡咯烷-3-基氨基甲酸叔丁酯(100mg，0.303mmol，可商购获得)、N,N-二乙基丙-2-胺(0.145mL，0.908mmol)和1-溴-2-甲氧基乙烷(0.0361mL，0.363mmol)在DMF(1mL)中的溶液2小时，然后加热至60℃持续4小时，然后冷却至环境温度过夜。在分配在EtOAc与饱和NaHCO3(各10mL)之间后，用水和盐水(各2×10mL)洗涤有机层，经Na2SO4干燥，过滤并且浓缩，得到呈白色固体状的粗产物(80mg，68％产率)。LCMS(apci)m/z＝389.1(M+H)。Step A:Preparation of tert-butyl (3S,4R)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)-phenyl)pyrrolidin-3-ylcarbamate : A solution of tert-butyl (3S,4R)-4-(3-(trifluoromethyl)phenyl)-pyrrolidin-3-ylcarbamate (100 mg, 0.303 mmol, commercially available), N,N-diethylpropan-2-amine (0.145 mL, 0.908 mmol) and 1-bromo-2-methoxyethane (0.0361 mL, 0.363 mmol) in DMF (1 mL) was stirred at ambient temperature for 2 hours, then heated to 60°C for 4 hours, and then cooled to ambient temperature overnight. After partitioning between EtOAc and saturatedNaHCO3 (10 mL each), the organic layer was washed with water and brine (2 x 10 mL each) , dried overNa2SO4 , filtered and concentrated to give the crude product as a white solid (80 mg, 68% yield).LCMS (apci) m/z = 389.1 (M+H).
步骤B：制备(3S,4R)-1-(2-甲氧基乙基)-4-(3-(三氟甲基)苯基)-吡咯烷-3-胺二盐酸盐：在环境温度下搅拌(3S,4R)-1-(2-甲氧基乙基)-4-(3-(三氟甲基)苯基)吡咯烷-3-基氨基甲酸叔丁酯(80.0mg，0.206mmol)在5N至6N HCl的IPA溶液(4.12mL，20.6mmol)中的溶液1小时，接着在真空中浓缩并且用Et2O湿磨，得到呈米色固体状的产物(74mg，99.5％产率)。LCMS(apci)m/z＝289.1(M+H)。[0266] Step B:Preparation of (3S,4R)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)-pyrrolidin-3-aminedihydrochloride : A solution of tert-butyl (3S,4R)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-ylcarbamate (80.0 mg, 0.206 mmol) in 5N to 6N HCl in IPA (4.12 mL, 20.6 mmol) was stirred at ambient temperature for 1 hour, then concentrated in vacuo and triturated withEt2O to afford the product as a beige solid (74 mg, 99.5% yield). LCMS (apci) m/z = 289.1 (M+H).
制备HPreparation of H
(3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(3S,4R)-4-(3-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride
根据制备G的方法，用(3S,4R)-4-(3-氟苯基)吡咯烷-3-基氨基甲酸叔丁酯替代(3S,4R)-4-(3-(三氟甲基)苯基)-吡咯烷-3-基氨基甲酸叔丁酯来制备，得到标题化合物。LCMS(apci)m/z＝239.1(M+H)。Prepared according to the method of Preparation G, substituting (3S,4R)-4-(3-fluorophenyl)pyrrolidin-3-ylcarbamic acid tert-butyl ester for (3S,4R)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-ylcarbamic acid tert-butyl ester to give the title compound. LCMS (apci) m/z = 239.1 (M+H).
制备IPreparation I
(3S,4R)-4-(2,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(3S,4R)-4-(2,4-Difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride
根据制备G的方法，用(3S,4R)-4-(2,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯替代(3S,4R)-4-(3-(三氟甲基)苯基)-吡咯烷-3-基氨基甲酸叔丁酯来制备，得到标题化合物。LCMS(apci)m/z＝257.1(M+H)。Prepared according to the method of Preparation G, substituting (3S,4R)-4-(2,4-difluorophenyl)pyrrolidin-3-ylcarbamic acid tert-butyl ester for (3S,4R)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-ylcarbamic acid tert-butyl ester to give the title compound. LCMS (apci) m/z = 257.1 (M+H).
制备JPreparation J
(3S,4R)-4-(2,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(3S,4R)-4-(2,5-Difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride
根据制备G的方法，用(3S,4R)-4-(2,5-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯替代(3S,4R)-4-(3-(三氟甲基)苯基)-吡咯烷-3-基氨基甲酸叔丁酯来制备，得到标题化合物。LCMS(apci)m/z＝257.1(M+H)。Prepared according to the method of Preparation G, substituting (3S,4R)-4-(2,5-difluorophenyl)pyrrolidin-3-ylcarbamic acid tert-butyl ester for (3S,4R)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-ylcarbamic acid tert-butyl ester to give the title compound. LCMS (apci) m/z = 257.1 (M+H).
制备KPreparation of K
(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(3S,4R)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride
根据制备D中所述的方法，用(E)-3-(4-氟苯基)丙烯酰氯替代肉桂酰氯来制备。MS(apci)m/z＝239.1(M+H)。Prepared according to the method described in Preparation D, substituting (E)-3-(4-fluorophenyl)acryloyl chloride for cinnamoyl chloride. MS (apci) m/z = 239.1 (M+H).
制备L1Preparation of L1
(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(3S,4R)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine
步骤A：制备(E)-1-氟-4-(2-硝基乙烯基)苯：在环境温度下搅拌乙酸(2.0L，35.5mol)和乙酸铵(310.5g，4.03mol)1小时，然后添加硝基甲烷(611mL，11.3mol)和4-氟苯甲醛(200g，1.61mol)并且把反应混合物加热至90℃持续3小时。允许反应物冷却至环境温度，然后在机械搅拌下经2小时添加H2O(4L)。搅拌悬浮液1小时，然后过滤并且用2:1水/乙酸(500mL)洗涤。在真空烘箱(50℃)中干燥固体，得到呈浅黄色固体状的标题产物(238g，1.42mol，88％产率)。1H NMR(CDCl3)δ7.98(1H),7.55(3H),7.16(2H)。Step A:Preparation of (E)-1-fluoro-4-(2-nitrovinyl)benzene : Acetic acid (2.0 L, 35.5 mol) and ammonium acetate (310.5 g, 4.03 mol) were stirred at ambient temperature for 1 hour, then nitromethane (611 mL, 11.3 mol) and 4-fluorobenzaldehyde (200 g, 1.61 mol) were added and the reaction mixture was heated to 90° C. for 3 hours. The reaction was allowed to cool to ambient temperature, then H2 O (4 L) was added over 2 hours with mechanical stirring. The suspension was stirred for 1 hour, then filtered and washed with 2:1 water/acetic acid (500 mL). The solid was dried in a vacuum oven (50° C.) to give the title product (238 g, 1.42 mol, 88% yield) as a light yellow solid.1 H NMR (CDCl3 ) δ 7.98 (1H), 7.55 (3H), 7.16 (2H).
步骤B：制备反式-3-(4-氟苯基)-1-(2-甲氧基乙基)-4-硝基吡咯烷：经30分钟向(E)-1-氟-4-(2-硝基乙烯基)苯(201g，1.20mol)在DCM(1.09L)和TFA(9.3mL，120mmol)中的悬浮液中逐滴添加2-甲氧基-N-(甲氧基甲基)-N-((三甲基硅烷基)甲基)乙胺(制备C；383g，1.86mol)并且通过在冰浴中冷却把内部反应温度维持在23℃至36℃之间。把反应混合物倒入磷酸盐缓冲水溶液(pH 7，500mL)中并且用DCM(300mL)稀释。分离各相并且用DCM(400mL)萃取水相。合并有机相，用盐水(300mL)洗涤，干燥(MgSO4)，过滤并且在减压下浓缩。通过二氧化硅柱色谱法，用40％EtOAc/庚烷洗脱来纯化粗油状物，得到呈黄色油状的标题化合物(245g，76％产率)。MS(apci)m/z＝269.1(M+H)。Step B:Preparation of trans-3-(4-fluorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine : To a suspension of (E)-1-fluoro-4-(2-nitrovinyl)benzene (201 g, 1.20 mol) in DCM (1.09 L) and TFA (9.3 mL, 120 mmol) was added 2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine (Preparation C; 383 g, 1.86 mol) dropwise over 30 minutes and the internal reaction temperature was maintained between 23° C. and 36° C. by cooling in an ice bath. The reaction mixture was poured into aqueous phosphate buffer (pH 7, 500 mL) and diluted with DCM (300 mL). The phases were separated and the aqueous phase was extracted with DCM (400 mL). The organic phases were combined, washed with brine (300 mL), dried (MgSO4 ), filtered, and concentrated under reduced pressure. The crude oil was purified by silica column chromatography eluting with 40% EtOAc/heptane to give the title compound as a yellow oil (245 g, 76% yield).MS (apci) m/z=269.1 (M+H).
步骤C：制备反式-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯啶-3-胺：在帕尔容器中向反式-3-(4-氟苯基)-1-(2-甲氧基乙基)-4-硝基吡咯烷(289g，1.08mol)在EtOH(1L)中的溶液中添加氧化铂(IV)(24.5g，108mmol)并且安置在帕尔振荡器中。把容器抽真空并且用氮气(3X)回填，然后抽真空并且用氢气(60psi)回填。必要时向容器中再装入氢气直到反应完成为止。通过过滤反应混合物并且用MeOH(50mL)冲洗，然后在减压下浓缩，得到呈黄色油状的标题化合物(243g，95％产率)。MS(apci)m/z＝239.1(M+H)。Step C:Preparation of trans-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine : To a solution of trans-3-(4-fluorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine (289 g, 1.08 mol) in EtOH (1 L) was added platinum (IV) oxide (24.5 g, 108 mmol) in a Parr vessel and placed in a Parr shaker. The vessel was evacuated and backfilled with nitrogen (3X), then evacuated and backfilled with hydrogen (60 psi). Hydrogen was added to the vessel as necessary until the reaction was complete. The title compound (243 g, 95% yield) was obtained by filtering the reaction mixture and rinsing with MeOH (50 mL), then concentrating under reduced pressure. MS (apci) m/z = 239.1 (M+H).
步骤D：制备(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(2S,3S)-2,3-双(4-甲基苯甲酰氧基)琥珀酸盐：向(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(120g，504mmol)在THF(3.0L)和H2O(333mL)中的溶液中添加二-对甲苯甲酰基-D-酒石酸(195g，504mmol)。在环境温度下搅拌1小时，然后在冷冻器(-11℃)中置放18小时。搅拌混合物，得到浆料，过滤并且用Et2O(4×100mL)冲洗。在真空烘箱(40℃)中干燥固体4小时，然后通过以下程序重结晶两次：在加热至45℃下把固体溶解于THF(1.06mL)和H2O(118mL)中，然后经2小时允许冷却至环境温度，然后在冷冻器(-11℃)中置放18小时；搅拌混合物，得到浆料，过滤并且用Et2O(4×100mL)冲洗。两次重结晶后，在真空烘箱(40℃)中干燥固体18小时，得到呈白色结晶固体状的标题化合物(96g，31％产率)。MS(apci)m/z＝239.2(M+H)。Step D:Preparation of (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (2S,3S)-2,3-bis(4-methylbenzoyloxy)succinate : To a solution of (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (120 g, 504 mmol) in THF (3.0 L) and H2 O (333 mL) was added di-p-toluoyl-D-tartaric acid (195 g, 504 mmol). Stir at ambient temperature for 1 hour and then place in a freezer (-11° C.) for 18 hours. The mixture was stirred to give a slurry, filtered, and rinsed with Et2 O (4×100 mL). The solid was dried in a vacuum oven (40°C) for 4 hours and then recrystallized twice by the following procedure: the solid was dissolved in THF (1.06 mL) andH2O (118 mL) while heating to 45°C, then allowed to cool to ambient temperature over 2 hours, and then placed in a freezer (-11°C) for 18 hours; the mixture was stirred to obtain a slurry, which was filtered and rinsed withEt2O (4 x 100 mL). After two recrystallizations, the solid was dried in a vacuum oven (40°C) for 18 hours to provide the title compound (96 g, 31% yield) as a white crystalline solid. MS (apci) m/z = 239.2 (M+H).
步骤E：制备(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺：把(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(2S,3S)-2,3-双(4-甲基苯甲酰氧基)琥珀酸盐(20g，32.0mmol)溶解于DCM(300mL)中并且用1M NaOH(2×200mL)洗涤。用DCM(200mL)萃取合并的水相。用盐水(200mL)洗涤合并的有机萃取物，干燥(MgSO4)，过滤并且浓缩，然后在真空下干燥，得到呈黄色油状的标题化合物(6.17g，81％，>99％ee)。MS(apci)m/z＝239.1(M+H)。[0146] Step E:Preparation of (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine : (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (2S,3S)-2,3-bis(4-methylbenzoyloxy)succinate (20 g, 32.0 mmol) was dissolved in DCM (300 mL) and washed with 1 M NaOH (2 x 200 mL). The combined aqueous phases were extracted with DCM (200 mL). The combined organic extracts were washed with brine (200 mL), dried (MgSO4 ), filtered, and concentrated, then dried under vacuum to afford the title compound as a yellow oil (6.17 g, 81%, >99% ee). MS (apci) m/z = 239.1 (M+H).
根据制备L1的方法，在步骤A中使用适当的苯甲醛并且在步骤C中分别用MeOH和雷尼镍替代EtOH和氧化铂(IV)来制备下列吡咯烷中间体。对于制备L3，在步骤D中用85％MeOH/H2O替代90％THF/H2O。The following pyrrolidine intermediates were prepared according to the procedure for L1 using the appropriate benzaldehyde in step A and MeOH and Raney nickel instead of EtOH and platinum(IV) oxide, respectively, in step C. For the preparation of L3, 85% MeOH/H2O was substituted for 90% THF/H2O in step D.
制备L15Preparation of L15
4-(反式-4-氨基-1-(2-甲氧基乙基)吡咯烷-3-基)苯甲腈4-(trans-4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)benzonitrile
根据制备L1步骤A至C中所述的方法，在步骤A中用4-甲酰基苯甲腈替代4-氟苯甲醛并且在步骤C中分别用MeOH、Zn(粉)和饱和NH4Cl替代EtOH和氧化铂(IV)来制备。MS(apci)m/z＝246.1(M+H)。Prepared according to the method described in Preparation L1 steps A to C, substituting 4-formylbenzonitrile for 4-fluorobenzaldehyde in step A, and substituting MeOH, Zn (powder), and saturatedNH4Cl for EtOH and platinum(IV) oxide, respectively, in step C. MS (apci) m/z = 246.1 (M+H).
制备L16Preparation of L16
3-(反式-4-氨基-1-(2-甲氧基乙基)吡咯烷-3-基)苯甲腈3-(trans-4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)benzonitrile
根据制备L1步骤A至C中所述的方法，在步骤A中用3-甲酰基苯甲腈替代4-氟苯甲醛并且在步骤C中分别用MeOH、Zn(粉)和饱和NH4Cl替代EtOH和氧化铂(IV)来制备。MS(apci)m/z＝246.2(M+H)。Prepared according to the method described in Preparation L1 steps A to C, substituting 3-formylbenzonitrile for 4-fluorobenzaldehyde in step A, and substituting MeOH, Zn (powder), and saturatedNH4Cl for EtOH and platinum(IV) oxide, respectively, in step C. MS (apci) m/z = 246.2 (M+H).
制备MPreparation of M
(3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-胺二盐酸盐(3S,4R)-1-(2-Methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-amine dihydrochloride
根据制备D中所述的方法，用(E)-3-(3,4,5-三氟苯基)丙烯酰氯替代肉桂酰氯来制备。1H NMR(D2O)δ7.06-7.10(m,2H),4.13-4.20(m,1H),3.92-3.99(m,2H),3.71-3.74(m,1H),3.57-3.63(m,3H),3.41-3.49(m,3H),3.25(s,3H)。Prepared according to the method described in Preparation D, substituting (E)-3-(3,4,5-trifluorophenyl)acryloyl chloride for cinnamoyl chloride.1 H NMR (D2 O) δ 7.06-7.10 (m, 2H), 4.13-4.20 (m, 1H), 3.92-3.99 (m, 2H), 3.71-3.74 (m, 1H), 3.57-3.63 (m, 3H), 3.41-3.49 (m, 3H), 3.25 (s, 3H).
制备NPreparation of N
反式-5-(4-氨基-1-(2-甲氧基乙基)吡咯烷-3-基)-2-氟苯甲腈trans-5-(4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)-2-fluorobenzonitrile
步骤A：(E)-2-氟-5-(2-硝基乙烯基)苯甲腈：向2-氟-5-甲酰基苯甲腈(3.84g，25.0mmol)在3:1CH3NO2/CH3CN(25mL)中的溶液中添加DMAP(0.305g，2.50mmol)并且在环境温度下搅拌混合物23小时。在冰浴上冷却混合物，并且添加Ac2O(3.54mL，37.5mmol)。搅拌混合物5分钟，允许其达到环境温度并且搅拌1小时。把混合物浓缩成黄色固体。把固体悬浮于iPrOH(70mL)中并且搅拌10分钟。经由真空过滤收集悬浮液，用iPrOH洗涤滤饼并且在真空中干燥，得到呈淡棕褐色粉末状的标题化合物(3.36g，70％)。1H NMR(CDCl3)δ7.96(d,1H),7.79-7.88(m,2H),7.57(d,1H),7.36(t,1H)。Step A:(E)-2-Fluoro-5-(2-nitrovinyl)benzonitrile : To a solutionof 2-fluoro-5-formylbenzonitrile (3.84 g, 25.0 mmol) in 3:1CH3NO2 /CH3CN (25 mL) was added DMAP (0.305 g, 2.50 mmol) and the mixture was stirred at ambient temperature for 23 hours. The mixture was cooled in an ice bath andAc2O (3.54 mL, 37.5 mmol) was added. The mixture was stirred for 5 minutes, allowed to reach ambient temperature and stirred for 1 hour. The mixture was concentrated to a yellow solid. The solid was suspended in iPrOH (70 mL) and stirred for 10 minutes. The suspension was collected by vacuum filtration, the filter cake was washed with iPrOH and dried in vacuo to give the title compound (3.36 g, 70%) as a light tan powder.1 H NMR (CDCl3 ) δ 7.96 (d, 1H), 7.79-7.88 (m, 2H), 7.57 (d, 1H), 7.36 (t, 1H).
步骤B：反式-2-氟-5-(1-(2-甲氧基乙基)-4-硝基吡咯烷-3-基)苯甲腈：在制备L1中所述程序的步骤B中使用(E)-2-氟-5-(2-硝基乙烯基)苯甲腈，制备呈淡金色糖浆状的标题化合物(1.56g，53％)。MS(apci)m/z＝294.1(M+H)。Step B:trans-2-Fluoro-5-(1-(2-methoxyethyl)-4-nitropyrrolidin-3-yl)benzonitrile : The title compound (1.56 g, 53%) was prepared as a light golden syrup using (E)-2-fluoro-5-(2-nitrovinyl)benzonitrile in step B of the procedure described in Preparation L1. MS (apci) m/z = 294.1 (M+H).
步骤C：反式-5-(4-氨基-1-(2-甲氧基乙基)吡咯烷-3-基)-2-氟苯甲腈：把反式-2-氟-5-(1-(2-甲氧基乙基)-4-硝基吡咯烷-3-基)苯甲腈(450mg，1.53mmol)在MeOH(6.0mL)中的溶液冷却至0℃。依序添加Zn粉(1.00mg，15.3mmol)和饱和NH4Cl水溶液(1.0mL)并且搅拌混合物5分钟。允许混合物达到环境温度并且搅拌直到完成(通过LCMS分析测定)为止。通过填充的使用MeOH进行冲洗和洗脱来过滤混合物，并且把滤液浓缩成无色糖浆状物。用1M K2CO3(15mL)处理糖浆状物，混合并且用CH2Cl2(3X)萃取。经Na2SO4干燥合并的CH2Cl2萃取物，过滤并且浓缩，得到呈无色糖浆状的标题化合物(412mg，100％)。MS(apci)m/z＝264.1(M+H)。[0266] Step C:trans-5-(4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)-2-fluorobenzonitrile : A solution of trans-2-fluoro-5-(1-(2-methoxyethyl)-4-nitropyrrolidin-3-yl)benzonitrile (450 mg, 1.53 mmol) in MeOH (6.0 mL) was cooled to 0°C. Zn powder (1.00 mg, 15.3 mmol) and saturated aqueousNH4Cl (1.0 mL) were added sequentially and the mixture was stirred for 5 minutes. The mixture was allowed to reach ambient temperature and stirred until complete (as determined by LCMS analysis). The mixture was filtered through a packed column using MeOH for rinsing and elution, and the filtrate was concentrated toa colorlesssyrup . The syrup was treated with 1MK2CO3 (15 mL), mixed, and extracted withCH2Cl2 (3X). The combinedCH2Cl2 extracts were driedoverNa2SO4 , filtered and concentrated to give the title compound as a colorless syrup (412 mg, 100%).MS (apci) m/z = 264.1 (M+H).
制备OPreparation of O
反式-3-(4-氨基-1-(2-甲氧基乙基)吡咯烷-3-基)-5-氟苯甲腈trans-3-(4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)-5-fluorobenzonitrile
步骤A：3-氟-5-甲酰基苯甲腈：把3-溴-5-氟苯甲腈(5.00g，25.0mmol)在干燥THF(25mL)中的溶液冷却至0℃并且经5分钟逐滴添加2M iPrMgCl的THF溶液(15.0mL，30.0mmol)。在0℃下搅拌混合物15分钟，然后在环境温度下搅拌1小时。把混合物冷却至0℃并且添加干燥DMF(5.81mL，75.0mmol)。搅拌混合物17小时，期间温度在2小时后达到环境温度。把混合物添加到冰水(150mL)和Et2O(100mL)中。搅拌两相混合物并且用6M HCl处理以使水相达到pH＝3。去除有机层并且用Et2O(2X)萃取水层。用饱和NaCl洗涤合并的Et2O部分并且经MgSO4/活性碳干燥。通过SiO2塞，用Et2O洗脱来过滤干燥的溶液。浓缩滤液，得到呈黄色固体状的标题化合物，把它在真空中干燥(3.68g，99％)。1H NMR(CDCl3)δ10.0(s,1H),8.00(s,1H),7.81-7.86(m,1H),7.62-7.67(m,1H)。Step A:3-Fluoro-5-formylbenzonitrile : A solution of 3-bromo-5-fluorobenzonitrile (5.00 g, 25.0 mmol) in dry THF (25 mL) was cooled to 0°C and a 2M solution of iPrMgCl in THF (15.0 mL, 30.0 mmol) was added dropwise over 5 minutes. The mixture was stirred at 0°C for 15 minutes and then at ambient temperature for 1 hour. The mixture was cooled to 0°C and dry DMF (5.81 mL, 75.0 mmol) was added. The mixture was stirred for 17 hours, during which time the temperature reached ambient temperature after 2 hours. The mixture was added to ice water (150 mL) andEt2O (100 mL). The biphasic mixture was stirred and treated with 6M HCl to bring the aqueous phase to pH 3. The organic layer was removed and the aqueous layer was extracted withEt2O (2x). The combinedEt2O fractions were washed with saturated NaCl and dried overMgSO4 /activated carbon. The dried solution was filtered through a plug of SiO2 eluting with Et2 O. The filtrate was concentrated to give the title compound as a yellow solid which was dried in vacuo (3.68 g, 99%).1 H NMR (CDCl3 ) δ 10.0 (s, 1H), 8.00 (s, 1H), 7.81-7.86 (m, 1H), 7.62-7.67 (m, 1H).
步骤B：反式-3-(4-氨基-1-(2-甲氧基乙基)吡咯烷-3-基)-5-氟苯甲腈：在对于制备反式-5-(4-氨基-1-(2-甲氧基乙基)吡咯烷-3-基)-2-氟苯甲腈(制备N)所述的程序中使用3-氟-5-甲酰基苯甲腈来制备标题化合物。分离呈无色糖浆状的化合物(542mg，93％)。MS(apci)m/z＝264.1(M+H)。Step B:trans-3-(4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)-5-fluorobenzonitrile : The title compound was prepared using 3-fluoro-5-formylbenzonitrile following the procedure described for the preparation of trans-5-(4-amino-1-(2-methoxyethyl)pyrrolidin-3-yl)-2-fluorobenzonitrile (Preparation N). The compound was isolated as a colorless syrup (542 mg, 93%). MS (apci) m/z = 264.1 (M+H).
制备PPreparation of P
反式-1-(2-甲氧基乙基)-4-(4-氯苯基)吡咯烷-3-胺trans-1-(2-methoxyethyl)-4-(4-chlorophenyl)pyrrolidin-3-amine
步骤A：反式-3-(4-氯苯基)-1-(2-甲氧基乙基)-4-硝基吡咯烷：在制备L1中所述程序的步骤B中使用(E)-1-氯-4-(2-硝基乙烯基)苯，制备呈粘性无色油状的标题化合物(5.10g，64％)。MS(apci)m/z＝285.0(M+H)。Step A:trans-3-(4-chlorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine : Using (E)-1-chloro-4-(2-nitrovinyl)benzene in step B of the procedure described in Preparation L1, the title compound (5.10 g, 64%) was prepared as a viscous colorless oil. MS (apci) m/z = 285.0 (M+H).
步骤B：反式-1-(2-甲氧基乙基)-4-(4-氯苯基)吡咯烷-3-胺：向2800雷尼镍(在H2O中50wt％，0.873g，5.10mmol)在MeOH(25mL)中的悬浮液中添加在MeOH(25mL)中的反式-3-(4-氯苯基)-1-(2-甲氧基乙基)-4-硝基吡咯烷(2.90g，10.2mmol)。用H2气体吹拂混合物并且在H2气球氛围下搅拌16小时。用N2气体吹洗混合物并且通过填充的使用MeOH进行冲洗和洗脱来过滤。把滤液浓缩成浑浊油状物。把油状物溶解于CH2Cl2中并且经Na2SO4/活性碳干燥。过滤溶液并且浓缩，得到呈淡金色油状的标题化合物，将其在真空中干燥(2.46g，95％)。MS(apci)m/z＝255.1(M+H)。Step B:trans-1-(2-methoxyethyl)-4-(4-chlorophenyl)pyrrolidin-3-amine : To a suspension of 2800 g of Raney Nickel (50 wt % inH₂O , 0.873 g, 5.10 mmol) in MeOH (25 mL) was added trans-3-(4-chlorophenyl)-1-(2-methoxyethyl)-4-nitropyrrolidine (2.90 g, 10.2 mmol) in MeOH (25 mL). The mixture was purged withH₂ gas and stirred under aH₂ balloon atmosphere for 16 h. The mixture was flushed withN₂ gas and filtered through a pack of Celite®, rinsing and eluting with MeOH. The filtrate was concentrated to a cloudy oil. The oil was dissolved inCH₂Cl₂ and dried overNa₂SO₄ /activatedcharcoal . The solution was filtered and concentrated to give the title compound as a light golden oil, which was dried in vacuo (2.46 g, 95%). MS (apci) m/z = 255.1 (M+H).
表1提供用于合成实例中所述化合物的可商购获得的吡唑中间体的清单。Table 1 provides a list of commercially available pyrazole intermediates used in the synthesis of the compounds described in the Examples.
表1Table 1
N/A＝不可得N/A = Not Available
中间体P1Intermediate P1
3-(5-氨基-3-叔丁基-1H-吡唑-1-基)苯甲酸乙酯Ethyl 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoate
向3-肼基苯甲酸乙酯盐酸盐(500mg，2.31mmol)在EtOH(20mL)中的悬浮液中添加4,4-二甲基-3-氧代戊腈(318mg，2.54mmol)。将反应混合物加热至回流，持续18小时，然后冷却至环境温度并且在真空中浓缩。通过二氧化硅柱色谱法，用0％至5％MeOH/DCM洗脱来纯化粗产物，得到呈黄色油状的产物(154mg，23％产率)。MS(apci)m/z＝288.2(M+H)。To a suspension of ethyl 3-hydrazinobenzoate hydrochloride (500mg, 2.31mmol) in EtOH (20mL) is added 4,4-dimethyl-3-oxopentanonitrile (318mg, 2.54mmol). The reaction mixture is heated to reflux for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The crude product is purified by silica column chromatography using 0% to 5% MeOH/DCM elution to obtain the product (154mg, 23% yield) in a yellow oily form. MS (apci) m/z=288.2 (M+H).
通过如对于中间体P1所述的方法，用适当的氰基酮替代4,4-二甲基-3-氧代戊腈并且用适当的肼替代3-肼基苯甲酸乙酯盐酸盐来制备表2中的化合物。The compounds in Table 2 were prepared by the procedures described for Intermediate P1, substituting the appropriate cyanoketone for 4,4-dimethyl-3-oxopentanonitrile and the appropriate hydrazine for ethyl 3-hydrazinylbenzoate hydrochloride.
表2Table 2
中间体P101Intermediate P101
2-(1-甲基-1H-吡唑-4-基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺2-(1-Methyl-1H-pyrazol-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine
步骤A：制备1-(1-甲基-1H-吡唑-4-基)肼-1,2-二甲酸二叔丁酯：向冷却至-78℃的4-溴-1-甲基-1H-吡唑(1.93mL，18.6mmol)在乙醚(37.3mL)中的溶液中添加nBuLi(23.3mL，37.3mmol)。在-78℃下搅拌30分钟后，逐滴添加偶氮二甲酸二叔丁酯(4.29g，18.6mmol)在Et2O(37.3mL，18.6mmol)中的溶液。1小时后，使反应混合物升温至-20℃并且用冰淬灭。升温至环境温度后，过滤混合物并且用Et2O冲洗。把所得到的固体溶解于DCM和水的混合物中，并且对混合物进行相分离。用MgSO4干燥有机层，过滤并且在真空中浓缩，得到呈白色固体状的第一批产物(1.64g，28％产率)。通过二氧化硅柱色谱法，用40％至60％己烷/EtOAc洗脱而从滤液中回收第二批产物(0.51g，8.8％产率)。MS(apci)m/z＝313.0(M+H)。Step A:Preparation of di-tert-butyl 1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate : To a solution of 4-bromo-1-methyl-1H-pyrazole (1.93 mL, 18.6 mmol) in diethyl ether (37.3 mL) cooled to -78°C was added nBuLi (23.3 mL, 37.3 mmol). After stirring at -78°C for 30 minutes, a solution of di-tert-butyl azodicarboxylate (4.29 g, 18.6 mmol) inEt₂O (37.3 mL, 18.6 mmol) was added dropwise. After 1 hour, the reaction mixture was warmed to -20°C and quenched with ice. After warming to ambient temperature, the mixture was filtered and rinsed withEt₂O . The resulting solid was dissolved in a mixture of DCM and water, and the mixture was phase separated. The organic layer was dried over MgSO4 , filtered, and concentrated in vacuo to afford the first crop of product (1.64 g, 28% yield) as a white solid. A second crop of product (0.51 g, 8.8% yield) was recovered from the filtrate by silica column chromatography eluting with 40% to 60% hexanes/EtOAc. MS (apci) m/z=313.0 (M+H).
步骤B：制备2-(1-甲基-1H-吡唑-4-基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺：向1-(1-甲基-1H-吡唑-4-基)肼-1,2-二甲酸二叔丁酯(103mg，0.330mmol)在EtOH(1.65mL，0.330mmol)中的溶液中添加浓HCl(137μL，1.65mmol)。在环境温度下搅拌混合物5分钟，然后在冰浴中冷却，接着添加2-氧代环戊烷甲腈(36.0mg，0.330mmol)。搅拌5分钟后，使反应混合物升温至环境温度过夜。浓缩反应混合物并且分配在水和DCM中。相分离后，碱化水层(pH10)并且然后用DCM(3×10mL)萃取。用MgSO4干燥合并的有机萃取物，过滤并且在真空中浓缩。通过反相柱色谱法，用0％至100％乙腈/水洗脱来纯化粗物质，得到呈黄色固体状的产物(4.5mg，6.7％产率)。MS(apci)m/z＝204.1(M+H)。Step B:Preparation of 2-(1-methyl-1H-pyrazol-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-amine : To a solution of di-tert-butyl 1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate (103 mg, 0.330 mmol) in EtOH (1.65 mL, 0.330 mmol) was added concentrated HCl (137 μL, 1.65 mmol). The mixture was stirred at ambient temperature for 5 minutes, then cooled in an ice bath, followed by the addition of 2-oxocyclopentanecarbonitrile (36.0 mg, 0.330 mmol). After stirring for 5 minutes, the reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was concentrated and partitioned between water and DCM. After phase separation, the aqueous layer was basified (pH 10) and then extracted with DCM (3 × 10 mL). The combined organic extracts were dried over MgSO4 , filtered, and concentrated in vacuo. The crude material was purified by reverse phase column chromatography eluting with 0% to 100% acetonitrile/water to give the product as a yellow solid (4.5 mg, 6.7% yield).MS (apci) m/z = 204.1 (M+H).
中间体P102Intermediate P102
3-叔丁基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-胺3-tert-Butyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine
步骤A：制备(四氢-2H-吡喃-4-基)肼盐酸盐：使二氢-2H-吡喃-4(3H)-酮(2.00g，20.0mmol)和肼甲酸叔丁酯(2.64g，20.0mmol)在己烷(20.0mL)中的悬浮液回流2小时。冷却后，添加BH3-THF复合物(20.0mL，20.0mmol)并且搅拌反应混合物1小时。然后用4N HCl的二噁烷溶液(20.0mL，79.9mmol)处理混合物，接着用3滴水处理。在环境温度下搅拌1小时后，过滤反应混合物并且用EtOAc冲洗，得到呈固体状的产物(2.39g，78.4％产率)。MS(apci)m/z＝117.0(M+H)。[0146] Step A:Preparation of (tetrahydro-2H-pyran-4-yl)hydrazine hydrochloride : A suspension of dihydro-2H-pyran-4(3H)-one (2.00 g, 20.0 mmol) and tert-butyl hydrazinecarboxylate (2.64 g, 20.0 mmol) in hexanes (20.0 mL) was refluxed for 2 hours. After cooling,BH3 -THF complex (20.0 mL, 20.0 mmol) was added and the reaction mixture was stirred for 1 hour. The mixture was then treated with 4N HCl in dioxane (20.0 mL, 79.9 mmol) followed by 3 drops of water. After stirring at ambient temperature for 1 hour, the reaction mixture was filtered and rinsed with EtOAc to give the product as a solid (2.39 g, 78.4% yield). MS (apci) m/z = 117.0 (M+H).
步骤B：制备3-叔丁基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-胺：通过如对于制备中间体P1所述的方法，用(四氢-2H-吡喃-4-基)肼二盐酸盐替代3-肼基苯甲酸乙酯盐酸盐来制备，得到呈黄色油状的产物(0.472g，99.9％产率)。MS(apci)m/z＝224.1(M+H)。Step B:Preparation of 3-tert-butyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine : Prepared by following the procedure for the preparation of intermediate P1, substituting (tetrahydro-2H-pyran-4-yl)hydrazine dihydrochloride for ethyl 3-hydrazinobenzoate hydrochloride to give the product as a yellow oil (0.472 g, 99.9% yield). MS (apci) m/z = 224.1 (M+H).
中间体P103Intermediate P103
2-(吡啶-2-基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺2-(Pyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine
步骤A：制备2-(2-(吡啶-2-基)亚肼基)环戊烷-甲腈：用浓HCl(0.764mL，9.16mmol)处理2-肼基吡啶(0.200g，1.83mmol)和2-氧代环戊烷甲腈(0.200g，1.83mmol)在MeOH(9.16mL)中的溶液并且使其回流16小时。在真空中浓缩反应混合物，并且然后分配于水与DCM中。相分离后，用DCM洗涤水层，碱化(饱和NaHCO3，pH 10)，并且用DCM萃取。用MgSO4干燥合并的有机层，过滤并且浓缩。通过二氧化硅柱色谱法，用100％EtOAc洗脱来纯化粗物质，得到产物(0.289g，78.6％产率)。MS(apci)m/z＝201.2(M+H)。[0266] Step A:Preparation of 2-(2-(pyridin-2-yl)hydrazono)cyclopentane-carbonitrile : A solution of 2-hydrazinylpyridine (0.200 g, 1.83 mmol) and 2-oxocyclopentanecarbonitrile (0.200 g, 1.83 mmol) in MeOH (9.16 mL) was treated with concentrated HCl (0.764 mL, 9.16 mmol) and refluxed for 16 hours. The reaction mixture was concentrated in vacuo and then partitioned between water and DCM. After phase separation, the aqueous layer was washed with DCM, basified (saturated NaHCO3 , pH 10), and extracted with DCM. The combined organic layers were dried over MgSO4 , filtered, and concentrated. The crude material was purified by silica column chromatography eluting with 100% EtOAc to give the product (0.289 g, 78.6% yield). MS (apci) m/z = 201.2 (M+H).
步骤B：制备2-(吡啶-2-基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺：用6M HCl(0.202mL，1.21mmol)处理2-(2-(吡啶-2-基)亚肼基)环戊烷甲腈(0.243g，1.21mmol)在EtOH(6.06mL，1.21mmol)中的溶液并且使其回流3天。去除溶剂后，把粗残余物稀释在水中，碱化(饱和NaHCO3，pH 10)并且用DCM萃取。用MgSO4干燥合并的有机层，过滤并且浓缩。通过二氧化硅柱色谱法，用50％EtOAc/己烷洗脱来纯化粗物质，得到产物(0.198g，81.6％产率)。MS(apci)m/z＝201.2(M+H)。[0146] Step B:Preparation of 2-(pyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine : A solution of 2-(2-(pyridin-2-yl)hydrazono)cyclopentanecarbonitrile (0.243 g, 1.21 mmol) in EtOH (6.06 mL, 1.21 mmol) was treated with 6 M HCl (0.202 mL, 1.21 mmol) and refluxed for 3 days. After removal of the solvent, the crude residue was diluted in water, basified (saturatedNaHCO₃ , pH 10), and extracted with DCM. The combined organic layers were dried overMgSO₄ , filtered, and concentrated. The crude material was purified by silica column chromatography eluting with 50% EtOAc/hexanes to afford the product (0.198 g, 81.6% yield). MS (apci) m/z = 201.2 (M+H).
中间体P104Intermediate P104
2-(吡啶-3-基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺2-(Pyridin-3-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine
通过以上对于中间体P103所述的方法，用3-肼基吡啶替代2-肼基吡啶来制备，得到标题产物。MS(apci)m/z＝201.1(M+H)。Prepared by the procedure described above for intermediate P103, substituting 3-hydrazinopyridine for 2-hydrazinopyridine, to give the title product.MS (apci) m/z = 201.1 (M+H).
中间体P105Intermediate P105
6,6-二甲基-2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺6,6-Dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine
步骤A：制备5-氯-2,2-二甲基戊腈：在搅拌同时把异丁腈(1.38g，20.0mmol)和1-溴-3-氯丙烷(3.46g，22.0mmol)依序添加到1M双(三甲基硅烷基)氨化锂溶液(20.0mL，20.0mmol)中。在70℃下搅拌16小时后，用水淬灭反应混合物，然后用DCM萃取。用MgSO4干燥合并的有机层，过滤并且在真空中浓缩，得到5-氯-2,2-二甲基戊腈(2.91g，100％产率)。1HNMR(CDCl3)δ3.57-3.61(m,2H),1.94-2.02(m,2H),1.67-1.72(m,2H),1.37(s,6H)。Step A:Preparation of 5-chloro-2,2-dimethylvaleronitrile : Isobutyronitrile (1.38 g, 20.0 mmol) and 1-bromo-3-chloropropane (3.46 g, 22.0 mmol) were added sequentially to a 1 M solution of lithium bis(trimethylsilyl)amide (20.0 mL, 20.0 mmol) with stirring. After stirring at 70°C for 16 hours, the reaction mixture was quenched with water and then extracted with DCM. The combined organic layers were dried overMgSO₄ , filtered, and concentrated in vacuo to afford 5-chloro-2,2-dimethylvaleronitrile (2.91 g, 100% yield).1H NMR (CDCl₃ ) δ 3.57-3.61 (m, 2H), 1.94-2.02 (m, 2H), 1.67-1.72 (m, 2H), 1.37 (s, 6H).
步骤B：制备2,2-二甲基己二腈：在100℃下加热5-氯-2,2-二甲基戊腈(2.91g，20.0mmol)和NaCN(1.57g，32.0mmol)在DMF(20.0mL)与水(1mL)中的悬浮液16小时。冷却后，用水稀释反应混合物并且使其回流30分钟，然后冷却，倒入水中并且搅拌3小时。然后用Et2O萃取溶液。用H2O洗涤合并的Et2O萃取物，用MgSO4干燥，过滤并且在真空中浓缩，得到产物(2.20g，80.7％产率)。1H NMR(CDCl3)δ2.42-2.47(m,2H),1.83-1.92(m,2H),1.67-1.72(m,2H),1.39(s,6H)。Step B:Preparation of 2,2-dimethyladiponitrile : A suspension of 5-chloro-2,2-dimethylvaleronitrile (2.91 g, 20.0 mmol) and NaCN (1.57 g, 32.0 mmol) in DMF (20.0 mL) and water (1 mL) was heated at 100°C for 16 hours. After cooling, the reaction mixture was diluted with water and refluxed for 30 minutes, then cooled, poured into water, and stirred for 3 hours. The solution was then extracted withEt2O . The combinedEt2O extracts were washed withH2O , dried overMgSO4 , filtered, and concentrated in vacuo to give the product (2.20 g, 80.7% yield).1H NMR (CDCl3 ) δ 2.42-2.47 (m, 2H), 1.83-1.92 (m, 2H), 1.67-1.72 (m, 2H), 1.39 (s, 6H).
步骤C：制备3,3-二甲基-2-氧代环戊烷甲腈：用2,2-二甲基己二腈(1.00g，7.34mmol)的甲苯(2.0mL)溶液处理KOtBu(0.511g，4.55mmol)在甲苯(18.4mL)中的悬浮液并且在80℃下加热2小时。然后把反应混合物冷却至环境温度并且用水淬灭。分离混合物并且在2N HCl(20mL)中搅拌有机层16小时。分离混合物并且用MgSO4干燥有机层，过滤并且在真空中浓缩成黄白色固体。通过二氧化硅柱色谱法，用10％至40％EtOAc/己烷洗脱来纯化粗固体，得到产物(0.250g，24.8％产率)。1H NMR(CDCl3)δ3.20-3.26(m,1H),2.38-2.47(m,1H),2.14-2.25(m,1H),1.97-2.05(m,1H),1.74-1.83(m,1H),1.14(s,6H)。Step C:Preparation of 3,3-dimethyl-2-oxocyclopentanecarbonitrile : A suspension of KOtBu (0.511 g, 4.55 mmol) in toluene (18.4 mL) was treated with a solution of 2,2-dimethyladiponitrile (1.00 g, 7.34 mmol) in toluene (2.0 mL) and heated at 80° C. for 2 hours. The reaction mixture was then cooled to ambient temperature and quenched with water. The mixture was separated and the organic layer was stirred in 2N HCl (20 mL) for 16 hours. The mixture was separated and the organic layer was dried over MgSO4 , filtered and concentrated in vacuo to a yellow-white solid. The crude solid was purified by silica column chromatography eluting with 10% to 40% EtOAc/hexane to give the product (0.250 g, 24.8% yield).1 H NMR (CDCl3 ) δ 3.20-3.26 (m, 1H), 2.38-2.47 (m, 1H), 2.14-2.25 (m, 1H), 1.97-2.05 (m, 1H), 1.74-1.83 (m, 1H), 1.14 (s, 6H).
步骤D：制备6,6-二甲基-2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺：通过如对于中间体P1所述的方法，用苯肼替代3-肼基苯甲酸乙酯盐酸盐并且用3,3-二甲基-2-氧代环戊烷甲腈替代4,4-二甲基-3-氧代戊腈来制备，得到呈黄色固体状的产物(0.192g，46.2％产率)。MS(apci)m/z＝228.2(M+H)。Step D:Preparation of 6,6-dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine : Prepared by following the procedure for Intermediate P1, substituting phenylhydrazine for ethyl 3-hydrazinobenzoate hydrochloride and 3,3-dimethyl-2-oxocyclopentanecarbonitrile for 4,4-dimethyl-3-oxopentanonitrile to afford the product as a yellow solid (0.192 g, 46.2% yield). MS (apci) m/z = 228.2 (M+H).
中间体P106Intermediate P106
7,7-二甲基-2-苯基-4,5,6,7-四氢-2H-吲唑-3-胺7,7-Dimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-amine
步骤A：制备2,2-二甲基庚二腈：通过如对于中间体P105步骤A和步骤B所述的方法，用1-溴-4-氯丁烷替代1-溴-3-氯丙烷来制备，得到产物(2.21g，73.7％产率)。1H NMR(CDCl3)δ2.37-2.42(m,2H),1.53-1.77(m,6H),1.36(s,6H)。Step A:Preparation of 2,2-dimethylpimelonitrile : Prepared by the method described for Intermediate P105 Step A and Step B, substituting 1-bromo-4-chlorobutane for 1-bromo-3-chloropropane, to afford the product (2.21 g, 73.7% yield).1 H NMR (CDCl3 ) δ 2.37-2.42 (m, 2H), 1.53-1.77 (m, 6H), 1.36 (s, 6H).
步骤B：制备3,3-二甲基-2-氧代环己烷甲腈：用2,2-二甲基庚二腈(1.00g，6.66mmol)在甲苯(2.0mL)中的溶液处理KOtBu(0.463g，4.13mmol)在甲苯(16.6mL)中的悬浮液并且在80℃下加热48小时。冷却至环境温度后，用水淬灭反应混合物并且进行相分离，并且把有机层与2N HCl(20mL)一起搅拌16小时。相分离后，用MgSO4干燥有机层，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用10％至20％EtOAc/己烷洗脱来纯化粗物质，得到产物(0.374g，37.2％产率)。1H NMR(CDCl3)δ3.72-3.78(m,1H),2.42-2.50(m.1H),1.78-2.04(m,4H),1.60-1.70(m,1H),1.21(s,3H),1.16(s,3H)。Step B:Preparation of 3,3-dimethyl-2-oxocyclohexanecarbonitrile : A suspension of KOtBu (0.463 g, 4.13 mmol) in toluene (16.6 mL) was treated with a solution of 2,2-dimethylpimelane dinitrile (1.00 g, 6.66 mmol) in toluene (2.0 mL) and heated at 80°C for 48 hours. After cooling to ambient temperature, the reaction mixture was quenched with water and the phases were separated, and the organic layer was stirred with 2N HCl (20 mL) for 16 hours. After phase separation, the organic layer was dried overMgSO₄ , filtered, and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with 10% to 20% EtOAc/hexane to give the product (0.374 g, 37.2% yield).1 H NMR (CDCl3 ) δ3.72-3.78(m,1H), 2.42-2.50(m.1H), 1.78-2.04(m,4H), 1.60-1.70(m,1H), 1.21(s,3H), 1.16(s,3H).
步骤C：制备7,7-二甲基-2-苯基-4,5,6,7-四氢-2H-吲唑-3-胺：通过如对于中间体P1所述的方法，用苯肼替代3-肼基苯甲酸乙酯盐酸盐并且用3,3-二甲基-2-氧代环己烷甲腈替代4,4-二甲基-3-氧代戊腈来制备，得到呈灰白色固体状的产物(0.490g，54.2％产率，66％纯度)。MS(apci)m/z＝242.2(M+H)。Step C:Preparation of 7,7-dimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-amine : Prepared by following the procedure for Intermediate P1, substituting phenylhydrazine for ethyl 3-hydrazinobenzoate hydrochloride and 3,3-dimethyl-2-oxocyclohexanecarbonitrile for 4,4-dimethyl-3-oxopentanonitrile to afford the product as an off-white solid (0.490 g, 54.2% yield, 66% purity). MS (apci) m/z=242.2 (M+H).
中间体P107Intermediate P107
3-异丙基-4-甲基-1-苯基-1H-吡唑-5-胺3-Isopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine
步骤A：制备2,4-二甲基-3-氧代戊腈：在-78℃、N2下向丙腈(518mg，9.40mmol)在THF(50mL，7.83mmol)中的溶液中缓慢添加双(三甲基硅烷基)氨化锂(1M THF溶液)(7.83mL，7.83mmol)。30分钟后，逐滴添加异丁酸甲酯(0.898mL，7.83mmol)，并且使反应混合物升温至0℃。形成黄色沉淀物，搅拌反应混合物1小时，然后用H2O(50mL)稀释以溶解固体。用Et2O(25mL)萃取混合物，并且用2M HCl(5mL)酸化碱性水相并且用Et2O(2×50mL)萃取。用盐水(50mL)洗涤合并的有机相，用MgSO4干燥，过滤并且浓缩，得到产物(421mg，42.9％产率)。Step A: Preparation of 2,4-dimethyl-3-oxopentanonitrile : To a solution of propionitrile (518 mg, 9.40 mmol) in THF (50 mL, 7.83 mmol) was slowly added lithium bis(trimethylsilyl)amide (1 M THF solution) (7.83 mL, 7.83 mmol) at -78 ° C under N 2. After 30 minutes, methyl isobutyrate (0.898 mL, 7.83 mmol) was added dropwise and the reaction mixture was warmed to 0 ° C. A yellow precipitate was formed, and the reaction mixture was stirred for 1 hour and then diluted with H2 O (50 mL) to dissolve the solid. The mixture was extracted with Et2 O (25 mL), and the alkaline aqueous phase was acidified with 2M HCl (5 mL) and extracted with Et2 O (2×50 mL). The combined organic phase was washed with brine (50 mL), dried over MgSO4 , filtered and concentrated to give the product (421 mg, 42.9% yield).
步骤B：制备3-异丙基-4-甲基-1-苯基-1H-吡唑-5-胺：通过如对于中间体P1所述的方法，用苯肼替代3-肼基苯甲酸乙酯盐酸盐并且用2,4-二甲基-3-氧代戊腈替代4,4-二甲基-3-氧代戊腈来制备，得到呈黄色糖浆状的产物(0.587g，81.1％产率)。MS(apci)m/z＝216.2(M+H)。Step B:Preparation of 3-isopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine : Prepared by following the procedure for Intermediate P1, substituting phenylhydrazine for ethyl 3-hydrazinobenzoate hydrochloride and 2,4-dimethyl-3-oxopentanonitrile for 4,4-dimethyl-3-oxopentanonitrile, to give the product as a yellow syrup (0.587 g, 81.1% yield). MS (apci) m/z = 216.2 (M+H).
中间体P108Intermediate P108
2-苯基-4,6-二氢-2H-呋喃并[3,4-c]吡唑-3-胺2-Phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-amine
步骤A：制备4-氧代四氢呋喃-3-甲腈：向冷却至0℃的KOtBu(996.6mg，8.881mmol)在THF(640.4mg，8.881mmol)中的悬浮液中逐滴添加2-羟基乙酸甲酯(675.7μL，8.881mmol)并且搅拌10分钟。然后添加丙烯腈(589.1μL，8.881mmol)并且在环境温度下搅拌反应物。3小时后，用H2O(50mL)稀释反应物，然后用Et2O(25mL)萃取以去除任何起始酯。用2M HCl(5mL)酸化碱性水相，然后用Et2O(2×50mL)萃取。用MgSO4干燥合并的有机相，过滤并且浓缩，得到淡棕色油状物(446mg，45.2％产率)。1H NMR(CDCl3)δ4.63(t,1H),4.24(t,1H),4.14(d,1H),4.02(d,1H),3.57(t,1H)。Step A:Preparation of 4-oxotetrahydrofuran-3-carbonitrile : To a suspension of KOtBu (996.6 mg, 8.881 mmol) in THF (640.4 mg, 8.881 mmol) cooled to 0°C was added methyl 2-hydroxyacetate (675.7 μL, 8.881 mmol) dropwise and stirred for 10 minutes. Acrylonitrile (589.1 μL, 8.881 mmol) was then added and the reaction was stirred at ambient temperature. After 3 hours, the reaction was diluted withH₂O (50 mL) and then extracted withEt₂O (25 mL) to remove any starting ester. The basic aqueous phase was acidified with 2M HCl (5 mL) and then extracted withEt₂O (2×50 mL). The combined organic phases were dried overMgSO₄ , filtered, and concentrated to give a light brown oil (446 mg, 45.2% yield).1 H NMR (CDCl3 ) δ 4.63 (t, 1H), 4.24 (t, 1H), 4.14 (d, 1H), 4.02 (d, 1H), 3.57 (t, 1H).
步骤B：制备2-苯基-4,6-二氢-2H-呋喃并[3,4-c]吡唑-3-胺：通过如对于中间体P1所述的方法，用苯肼替代3-肼基苯甲酸乙酯盐酸盐并且用4-氧代四氢呋喃-3-甲腈替代4,4-二甲基-3-氧代戊腈来制备，得到呈红棕色糖浆状的产物(182mg，22.5％产率)。MS(apci)m/z＝202.1(M+H)。Step B:Preparation of 2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-amine : Prepared by following the procedure for Intermediate P1, substituting phenylhydrazine for ethyl 3-hydrazinobenzoate hydrochloride and 4-oxotetrahydrofuran-3-carbonitrile for 4,4-dimethyl-3-oxopentanonitrile, to afford the product as a reddish-brown syrup (182 mg, 22.5% yield). MS (apci) m/z = 202.1 (M+H).
中间体P109Intermediate P109
3-(甲氧基甲基)-1-苯基-1H-吡唑-5-胺3-(Methoxymethyl)-1-phenyl-1H-pyrazol-5-amine
步骤A：制备4-甲氧基-3-氧代丁腈：在-78℃、N2下向2-甲氧基乙酸甲酯(0.4753mL，4.803mmol)在THF(20mL，4.803mmol)中的溶液中添加乙腈(0.3033mL，5.763mmol)，接着添加双(三甲基硅烷基)氨化锂(1M THF溶液)(4.803mL，4.803mmol)。搅拌1小时后，使反应混合物升温至0℃并且搅拌1小时。然后用H2O(25mL)稀释反应混合物，用Et2O(25mL)洗涤，然后用2M HCl(1.5mL)中和。用Et2O(2×25mL)萃取此物质，并且用盐水(25mL)洗涤合并的有机相，用MgSO4干燥，过滤并且浓缩，得到产物(169mg，31.1％产率)。1HNMR(CDCl3)δ4.09(s,2H),3.66(s,2H),3.46(s,3H)。Step A:Preparation of 4-methoxy-3-oxobutanenitrile : To a solution of methyl 2-methoxyacetate (0.4753 mL, 4.803 mmol) in THF (20 mL, 4.803 mmol) at -78°C underN2 was added acetonitrile (0.3033 mL, 5.763 mmol) followed by lithium bis(trimethylsilyl)amide (1 M in THF) (4.803 mL, 4.803 mmol). After stirring for 1 hour, the reaction mixture was warmed to 0°C and stirred for 1 hour. The reaction mixture was then diluted withH2O (25 mL), washed withEt2O (25 mL), and then neutralized with 2M HCl (1.5 mL). This material was extracted withEt2O (2 x 25 mL), and the combined organic phases were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated to afford the product (169 mg, 31.1% yield).1 HNMR (CDCl3 ) δ 4.09 (s, 2H), 3.66 (s, 2H), 3.46 (s, 3H).
步骤B：制备3-(甲氧基甲基)-1-苯基-1H-吡唑-5-胺：通过如对于中间体P1所述的方法，用苯肼替代3-肼基苯甲酸乙酯盐酸盐并且用4-甲氧基-3-氧代丁腈替代4,4-二甲基-3-氧代戊腈来制备，得到呈浅黄色残余物形式的产物(6.0mg，2.0％产率)。MS(apci)m/z＝204.0(M+H)。Step B:Preparation of 3-(methoxymethyl)-1-phenyl-1H-pyrazol-5-amine : Prepared by the method described for Intermediate P1, substituting phenylhydrazine for ethyl 3-hydrazinobenzoate hydrochloride and 4-methoxy-3-oxobutanenitrile for 4,4-dimethyl-3-oxopentanonitrile, to give the product as a light yellow residue (6.0 mg, 2.0% yield). MS (apci) m/z=204.0 (M+H).
中间体P110Intermediate P110
3-(甲氧基甲基)-4-甲基-1-苯基-1H-吡唑-5-胺3-(Methoxymethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine
根据如对于中间体P109所述的方法，用丙腈替代乙腈来制备，得到呈橙色残余物形式的产物。MS(apci)m/z＝218.0(M+H)。Prepared as described for intermediate P109, substituting propionitrile for acetonitrile, to give the product as an orange residue.MS (apci) m/z = 218.0 (M+H).
中间体P111Intermediate P111
2-(5-氨基-1-苯基-1H-吡唑-3-基)-2-甲基丙-1-醇2-(5-Amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol
步骤A：制备3-(叔丁基二甲基硅烷氧基)-2,2-二甲基丙酸甲酯：把3-羟基-2,2-二甲基丙酸甲酯(1.000g，7.567mmol)、TBDMS-Cl(1.140g，7.567mmol)和咪唑(0.5666g，8.323mmol)溶解于DMF(5mL，7.567mmol)中并且在环境温度下搅拌过夜。用H2O(25mL)稀释反应混合物并且用EtOAc(2×25mL)萃取。用盐水(25mL)洗涤合并的有机相，用MgSO4干燥，过滤并且浓缩，得到产物(1.92g，103％产率)。1H NMR(CDCl3)δ3.66(s,3H),3.57(s,2H),1.15(s,6H),0.87(s,9H),0.02(s,6H)。Step A:Preparation of methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate : Methyl 3-hydroxy-2,2-dimethylpropanoate (1.000 g, 7.567 mmol), TBDMS-Cl (1.140 g, 7.567 mmol), and imidazole (0.5666 g, 8.323 mmol) were dissolved in DMF (5 mL, 7.567 mmol) and stirred overnight at ambient temperature. The reaction mixture was diluted withH₂O (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic phases were washed with brine (25 mL), dried over MgSO₄, filtered, and concentrated to afford the product (1.92 g, 103% yield).1 H NMR (CDCl3 ) δ 3.66 (s, 3H), 3.57 (s, 2H), 1.15 (s, 6H), 0.87 (s, 9H), 0.02 (s, 6H).
步骤B：制备5-(叔丁基二甲基硅烷氧基)-4,4-二甲基-3-氧代戊腈：根据对于中间体P109所述的方法，用3-(叔丁基二甲基硅烷氧基)-2,2-二甲基丙酸甲酯替代2-甲氧基乙酸甲酯来制备，得到呈浅黄色残余物形式的产物。1H NMR(CDCl3)δ3.70(s,2H),3.55(s,2H),1.15(s,6H),0.89(s,9H),0.06(s,6H)。Step B:Preparation of 5-(tert-butyldimethylsilyloxy)-4,4-dimethyl-3-oxopentanonitrile : Prepared according to the method described for Intermediate P109, substituting methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate for methyl 2-methoxyacetate, to afford the product as a pale yellow residue.1 H NMR (CDCl3 ) δ 3.70 (s, 2H), 3.55 (s, 2H), 1.15 (s, 6H), 0.89 (s, 9H), 0.06 (s, 6H).
步骤C：制备2-(5-氨基-1-苯基-1H-吡唑-3-基)-2-甲基丙-1-醇：通过如对于中间体P1所述的方法，用苯肼替代3-肼基苯甲酸乙酯盐酸盐并且用3-(叔丁基二甲基硅烷氧基)-2,2-二甲基丙酸甲酯替代4,4-二甲基-3-氧代戊腈来制备，得到呈黄色糖浆状的产物(74mg，66％产率)。MS(apci)m/z＝232.2(M+H)。Step C:Preparation of 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol : Prepared by the method described for Intermediate P1, substituting phenylhydrazine for ethyl 3-hydrazinobenzoate hydrochloride and methyl 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropanoate for 4,4-dimethyl-3-oxopentanonitrile, to give the product as a yellow syrup (74 mg, 66% yield). MS (apci) m/z = 232.2 (M+H).
中间体P112Intermediate P112
2-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)-2-甲基丙-1-醇2-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol
根据对于中间体P111所述的方法，用丙腈替代乙腈来制备，得到呈黄色残余物形式的产物。MS(apci)m/z＝246.2(M+H)。Prepared according to the procedure described for intermediate P111, using propionitrile instead of acetonitrile, to give the product as a yellow residue.MS (apci) m/z = 246.2 (M+H).
中间体P113Intermediate P113
3-(3-甲氧基丙基)-4-甲基-1-苯基-1H-吡唑-5-胺3-(3-Methoxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine
根据对于中间体P109所述的方法，在步骤A中用4-甲氧基丁酸甲酯替代2-甲氧基乙酸甲酯并且用丙腈替代乙腈来制备，得到呈橙棕色糖浆状的产物。MS(apci)m/z＝246.1(M+H)。Prepared according to the procedure described for intermediate P109, substituting methyl 4-methoxybutyrate for methyl 2-methoxyacetate and propionitrile for acetonitrile in step A, to give the product as an orange-brown syrup. MS (apci) m/z = 246.1 (M+H).
中间体P114Intermediate P114
1,1'-二甲基-1H,1'H-3,4'-联吡唑-5-胺1,1'-Dimethyl-1H,1'H-3,4'-bipyrazol-5-amine
步骤A：制备3-(1-甲基-1H-吡唑-4-基)-3-氧代丙腈：一次性用KOtBu(1092mg，9.73mmol)处理1-甲基-1H-吡唑-4-甲酸乙酯(500mg，3.24mmol)、甲苯(7.50mL，70.4mmol)和乙腈(346μL，6.49mmol)的溶液，得到混浊溶液。在环境温度下允许搅拌反应物1小时，并且通过HPLC分析确定完成。用水(7.5mL)处理混合物并且搅拌1分钟，然后用3M HCl(3027μL，9.08mmol)酸化至pH 5.5至6。用乙酸乙酯(3×5mL)萃取水层并且在真空中浓缩合并的有机萃取物，得到黄色粘性油状物，其在高真空下放置时完全凝固，得到产物(102mg，21.1％产率)。1H NMR(CDCl3)δ8.02(s,1H),7.94(s,1H),3.98(s,3H),3.82(s,2H)。Step A:Preparation of 3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropionitrile : A solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate (500 mg, 3.24 mmol), toluene (7.50 mL, 70.4 mmol) and acetonitrile (346 μL, 6.49 mmol) was treated in one portion with KOtBu (1092 mg, 9.73 mmol) to give a cloudy solution. The reaction was allowed to stir at ambient temperature for 1 hour and was determined to be complete by HPLC analysis. The mixture was treated with water (7.5 mL) and stirred for 1 minute, then acidified to pH 5.5 to 6 with 3M HCl (3027 μL, 9.08 mmol). The aqueous layer was extracted with ethyl acetate (3×5 mL) and the combined organic extracts were concentrated in vacuo to give a yellow viscous oil that completely solidified upon placement under high vacuum to give the product (102 mg, 21.1% yield).1 H NMR (CDCl3 ) δ 8.02 (s, 1H), 7.94 (s, 1H), 3.98 (s, 3H), 3.82 (s, 2H).
步骤B：制备1,1'-二甲基-1H,1'H-3,4'-联吡唑-5-胺：通过如对于中间体P1所述的方法，用甲肼替代3-肼基苯甲酸乙酯盐酸盐并且用3-(1-甲基-1H-吡唑-4-基)-3-氧代丙腈替代4,4-二甲基-3-氧代戊腈来制备，得到呈奶白色固体状的产物(45mg，44.6％产率)。MS(apci)m/z＝178.1(M+H)。Step B:Preparation of 1,1'-dimethyl-1H,1'H-3,4'-bipyrazol-5-amine : Prepared by the method described for Intermediate P1, substituting methylhydrazine for ethyl 3-hydrazinobenzoate hydrochloride and 3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropionitrile for 4,4-dimethyl-3-oxopentanonitrile to give the product as a cream solid (45 mg, 44.6% yield). MS (apci) m/z = 178.1 (M+H).
中间体P115Intermediate P115
4-氯-1,3-二苯基-1H-吡唑-5-胺4-Chloro-1,3-diphenyl-1H-pyrazol-5-amine
向1,3-二苯基-1H-吡唑-5-胺(表1；0.100g，0.425mmol)在乙腈(2mL)中的溶液中添加N-氯代琥珀酰亚胺(0.0568g，0.425mmol)。在环境温度下搅拌浅黄色溶液3小时，然后在真空中浓缩并且通过二氧化硅柱色谱法用20％EtOAc/己烷洗脱来纯化，得到呈淡棕色油状的产物(0.10g，87％产率)。MS(apci)m/z＝270.0(M+H)。To a solution of 1,3-diphenyl-1H-pyrazol-5-amine (Table 1; 0.100 g, 0.425 mmol) in acetonitrile (2 mL) was added N-chlorosuccinimide (0.0568 g, 0.425 mmol). The pale yellow solution was stirred at ambient temperature for 3 hours, then concentrated in vacuo and purified by silica column chromatography eluting with 20% EtOAc/hexanes to give the product as a light brown oil (0.10 g, 87% yield). MS (apci) m/z = 270.0 (M+H).
中间体P116Intermediate P116
4-溴-1,3-二苯基-1H-吡唑-5-胺4-Bromo-1,3-diphenyl-1H-pyrazol-5-amine
根据对于中间体P115所述的程序，用N-溴代琥珀酰亚胺替代N-氯代琥珀酰亚胺来制备。MS(apci)m/z＝313.9(M+H)。Prepared according to the procedure described for intermediate P115, substituting N-bromosuccinimide for N-chlorosuccinimide. MS (apci) m/z = 313.9 (M+H).
中间体P117Intermediate P117
4-氯-3-甲基-1-苯基-1H-吡唑-5-胺4-Chloro-3-methyl-1-phenyl-1H-pyrazol-5-amine
根据对于中间体P115所述的程序，用3-甲基-1-苯基-1H-吡唑-5-胺替代1,3-二苯基-1H-吡唑-5-胺来制备。MS(apci)m/z＝207.9(M+H)。Prepared according to the procedure described for intermediate P115, substituting 3-methyl-1-phenyl-1H-pyrazol-5-amine for 1,3-diphenyl-1H-pyrazol-5-amine. MS (apci) m/z = 207.9 (M+H).
中间体P118Intermediate P118
4-溴-3-甲基-1-苯基-1H-吡唑-5-胺4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine
根据对于中间体P117所述的程序，用N-溴代琥珀酰亚胺替代N-氯代琥珀酰亚胺来制备。MS(apci)m/z＝251.9(M+H)。Prepared according to the procedure described for intermediate P117, substituting N-bromosuccinimide for N-chlorosuccinimide. MS (apci) m/z = 251.9 (M+H).
中间体P119Intermediate P119
4-氯-1-甲基-3-苯基-1H-吡唑-5-胺4-Chloro-1-methyl-3-phenyl-1H-pyrazol-5-amine
根据对于中间体P115所述的程序，用1-甲基-3-苯基-1H-吡唑-5-胺(表1)替代1,3-二苯基-1H-吡唑-5-胺来制备。MS(apci)m/z＝208.0(M+H)。Prepared according to the procedure described for intermediate P115, substituting 1-methyl-3-phenyl-1H-pyrazol-5-amine (Table 1) for 1,3-diphenyl-1H-pyrazol-5-amine. MS (apci) m/z = 208.0 (M+H).
中间体P120Intermediate P120
4-溴-1-甲基-3-苯基-1H-吡唑-5-胺4-Bromo-1-methyl-3-phenyl-1H-pyrazol-5-amine
根据对于中间体P119所述的程序，用N-溴代琥珀酰亚胺替代N-氯代琥珀酰亚胺来制备。MS(apci)m/z＝251.9(M+H)。Prepared according to the procedure described for intermediate P119, substituting N-bromosuccinimide for N-chlorosuccinimide. MS (apci) m/z = 251.9 (M+H).
中间体P121Intermediate P121
1-甲基-3-(4-(甲硫基)苯基)-1H-吡唑-5-胺1-Methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-amine
步骤A：制备3-(4-(甲硫基)苯基)-3-氧代丙腈：向NaH(在矿物油中60％154mg，3.84mmol)在二噁烷(25.0mL，2.74mmol)中的悬浮液中添加乙腈(0.217mL，4.12mmol)。在环境温度下搅拌反应混合物30分钟，然后用4-(甲硫基)苯甲酸甲酯(500mg，2.74mmol)处理并且加热至回流，持续15小时。冷却悬浮液，然后用水(25mL)稀释并且用Et2O(25mL)洗涤。用2M HCl(1.8mL)中和水层并且用Et2O(2×25mL)萃取。用盐水(25mL)洗涤合并的有机相，用MgSO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用0％至5％MeOH/DCM洗脱来纯化所得到的残余物，得到产物(317mg，60.4％产率)。1H NMR(CDCl3)δ7.82(d,2H),7.30(d,2H),4.02(s,2H),2.54(s,3H)。Step A:Preparation of 3-(4-(methylthio)phenyl)-3-oxopropionitrile : To a suspension of NaH (60% in mineral oil 154 mg, 3.84 mmol) in dioxane (25.0 mL, 2.74 mmol) was added acetonitrile (0.217 mL, 4.12 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes, then treated with methyl 4-(methylthio)benzoate (500 mg, 2.74 mmol) and heated to reflux for 15 hours. The suspension was cooled, then diluted with water (25 mL) and washed withEt2O (25 mL). The aqueous layer was neutralized with 2M HCl (1.8 mL) and extracted withEt2O (2 x 25 mL). The combined organic phases were washed with brine (25 mL), dried overMgSO4 , filtered, and concentrated in vacuo. The resulting residue was purified by silica column chromatography eluting with 0% to 5% MeOH/DCM to give the product (317 mg, 60.4% yield).1 H NMR (CDCl3 ) δ 7.82 (d, 2H), 7.30 (d, 2H), 4.02 (s, 2H), 2.54 (s, 3H).
步骤B：制备1-甲基-3-(4-(甲硫基)苯基)-1H-吡唑-5-胺：通过如中间体P1中所述的方法，用甲肼替代3-肼基苯甲酸乙酯盐酸盐并且用3-(4-(甲硫基)苯基)-3-氧代丙腈替代4,4-二甲基-3-氧代戊腈来制备，得到呈黄色固体状的产物(0.307g，96.7％产率)。MS(apci)m/z＝220.0(M+H)。Step B:Preparation of 1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-amine : Prepared by the method described in Intermediate P1, substituting methylhydrazine for ethyl 3-hydrazinobenzoate hydrochloride and 3-(4-(methylthio)phenyl)-3-oxopropionitrile for 4,4-dimethyl-3-oxopentanonitrile to give the product as a yellow solid (0.307 g, 96.7% yield). MS (apci) m/z = 220.0 (M+H).
中间体P122Intermediate P122
2-(5-氨基-1-苯基-1H-吡唑-3-基)-2-甲基丙腈2-(5-Amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropionitrile
根据用于中间体P121的程序，在步骤A中用2-氰基-2-甲基丙酸乙酯替代4-(甲硫基)苯甲酸甲酯并且在步骤B中用苯肼盐酸盐替代甲肼来制备。MS(apci)m/z＝227.1(M+H)。Prepared according to the procedure for Intermediate P121, substituting ethyl 2-cyano-2-methylpropanoate for methyl 4-(methylthio)benzoate in Step A and phenylhydrazine hydrochloride for methylhydrazine in Step B. MS (apci) m/z = 227.1 (M+H).
中间体P123Intermediate P123
3-(4-(2-甲氧基乙氧基)苯基)-1-甲基-1H-吡唑-5-胺3-(4-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrazol-5-amine
步骤A：制备3-(4-(苯甲基氧基)苯基)-3-氧代丙腈：根据对于中间体P121所述的程序，在步骤A中用4-(苯甲基氧基)苯甲酸甲酯替代4-(甲硫基)苯甲酸甲酯来制备。1H NMR(CDCl3)δ7.90(d,2H),7.42(m,4H),7.37(m,1H),7.05(d,2H),5.16(s,2H),4.00(s,2H)。Step A:Preparation of 3-(4-(benzyloxy)phenyl)-3-oxopropionitrile : Prepared according to the procedure described for Intermediate P121, substituting methyl 4-(benzyloxy)benzoate for methyl 4-(methylthio)benzoate in Step A.1 H NMR (CDCl3 ) δ 7.90 (d, 2H), 7.42 (m, 4H), 7.37 (m, 1H), 7.05 (d, 2H), 5.16 (s, 2H), 4.00 (s, 2H).
步骤B：制备3-(4-(苯甲基氧基)苯基)-1-甲基-1H-吡唑-5-胺：通过如对于中间体P1所述的方法，用甲肼替代3-肼基苯甲酸乙酯盐酸盐并且用3-(4-(苯甲基氧基)苯基)-3-氧代丙腈替代4,4-二甲基-3-氧代戊腈来制备，得到呈黄色固体状的产物。MS(apci)m/z＝280.1(M+H)。Step B:Preparation of 3-(4-(benzyloxy)phenyl)-1-methyl-1H-pyrazol-5-amine : Prepared by the procedure described for Intermediate P1, substituting methylhydrazine for ethyl 3-hydrazinobenzoate hydrochloride and 3-(4-(benzyloxy)phenyl)-3-oxopropionitrile for 4,4-dimethyl-3-oxopentanonitrile to give the product as a yellow solid. MS (apci) m/z = 280.1 (M+H).
步骤C：制备4-(5-氨基-1-甲基-1H-吡唑-3-基)苯酚：向3-(4-(苯甲基氧基)苯基)-1-甲基-1H-吡唑-5-胺(47mg，0.17mmol)在EtOH(5.0mL)中的溶液中添加5％Pd/C(9.0mg，0.0084mmol)并且在H2气球下搅拌17小时。通过过滤反应混合物，用EtOH冲洗并且在真空中浓缩，得到产物(28mg，88％产率)。MS(apci)m/z＝190.1(M+H)。Step C:Preparation of 4-(5-amino-1-methyl-1H-pyrazol-3-yl)phenol : To a solution of 3-(4-(benzyloxy)phenyl)-1-methyl-1H-pyrazol-5-amine (47 mg, 0.17 mmol) in EtOH (5.0 mL) was added 5% Pd/C (9.0 mg, 0.0084 mmol) and stirred under aH2 balloon for 17 hours. The reaction mixture was filtered through a column, rinsed with EtOH, and concentrated in vacuo to afford the product (28 mg, 88% yield). MS (apci) m/z = 190.1 (M+H).
步骤D：制备3-(4-(2-甲氧基乙氧基)苯基)-1-甲基-1H-吡唑-5-胺：向4-(5-氨基-1-甲基-1H-吡唑-3-基)苯酚(14mg，0.074mmol)在DMSO(0.50mL，7.0mmol)中的溶液中添加Cs2CO3(48mg，0.15mmol)和1-溴-2-甲氧基乙烷(9.7μL，0.10mmol)。搅拌反应混合物16小时，然后用水(10mL)稀释并且用DCM(3×10mL)萃取。用盐水(10mL)洗涤合并的有机萃取物，用MgSO4干燥，过滤并且浓缩，得到粗产物(22mg，120％产率)。粗产物不经纯化即用于后续步骤中。MS(apci)m/z＝248.0(M+H)。[0266] Step D:Preparation of 3-(4-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrazol-5-amine : To a solution of 4-(5-amino-1-methyl-1H-pyrazol-3-yl)phenol (14 mg, 0.074 mmol) in DMSO (0.50 mL, 7.0 mmol) was addedCsCO (48mg , 0.15 mmol) and 1-bromo-2-methoxyethane (9.7 μL, 0.10 mmol). The reaction mixture was stirred for 16 hours, then diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO, filtered, and concentrated to give the crude product (22 mg, 120% yield). The crude product was used in the subsequent step without purification. MS (apci) m/z = 248.0 (M+H).
中间体P124Intermediate P124
1'-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-胺1'-Methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-amine
根据对于中间体P114所述的程序，在步骤B中用苯肼替代甲肼来制备。MS(apci)m/z＝240.0(M+H)。Prepared according to the procedure described for Intermediate P114, substituting phenylhydrazine for methylhydrazine in Step B. MS (apci) m/z = 240.0 (M+H).
中间体P125Intermediate P125
4-甲氧基-3-甲基-1-苯基-1H-吡唑-5-胺4-Methoxy-3-methyl-1-phenyl-1H-pyrazol-5-amine
根据用于中间体P121的程序，在步骤A中用乙酸乙酯替代4-(甲硫基)苯甲酸甲酯并且用2-甲氧基乙腈替代乙腈并且在步骤B中用苯肼盐酸盐替代甲肼来制备。MS(apci)m/z＝204.0(M+H)。Prepared according to the procedure for Intermediate P121, substituting ethyl acetate for methyl 4-(methylthio)benzoate and 2-methoxyacetonitrile for acetonitrile in Step A and phenylhydrazine hydrochloride for methylhydrazine in Step B. MS (apci) m/z = 204.0 (M+H).
中间体P126Intermediate P126
(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)甲醇(5-Amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)methanol
根据用于中间体P112的程序，在步骤A中用2-羟基乙酸乙酯替代3-羟基-2,2-二甲基丙酸甲酯来制备。MS(apci)m/z＝204.1(M+H)。Prepared according to the procedure for Intermediate P112, substituting ethyl 2-hydroxyacetate for methyl 3-hydroxy-2,2-dimethylpropanoate in Step A. MS (apci) m/z = 204.1 (M+H).
中间体P127Intermediate P127
2-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)乙醇2-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)ethanol
根据用于中间体P112的程序，在步骤A中用3-羟基丙酸甲酯替代3-羟基-2,2-二甲基丙酸甲酯来制备。MS(apci)m/z＝218.0(M+H)。Prepared according to the procedure for Intermediate P112, substituting methyl 3-hydroxypropionate for methyl 3-hydroxy-2,2-dimethylpropionate in Step A. MS (apci) m/z = 218.0 (M+H).
中间体P128Intermediate P128
3-(2-甲氧基乙基)-4-甲基-1-苯基-1H-吡唑-5-胺3-(2-Methoxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine
步骤A：制备5-甲氧基-2-甲基-3-氧代戊腈：在N2、-78℃下向NaNH2(在甲苯中的50wt％悬浮液)(330mg，4.23mmol)在THF(25mL，4.23mmol)中的悬浮液中添加丙腈(0.448mL，6.35mmol)，并且搅拌反应混合物30分钟。添加3-甲氧基丙酸甲酯(0.495mL，4.23mmol)并且在-78℃下搅拌反应混合物1小时，然后在0℃下搅拌2.5小时。用H2O(25mL)稀释反应混合物并且用Et2O(25mL)洗涤。用2M HCl(1.6mL)中和碱性水相，然后用Et2O(3×25mL)萃取。用盐水(25mL)洗涤合并的有机相，用MgSO4干燥，过滤并且浓缩，得到呈浅绿色油状的粗产物(171mg)。粗混合物直接用于下一步骤中。Step A: Preparation of 5-methoxy-2-methyl-3-oxopentanonitrile : To a suspension of NaNH2 (50 wt% suspension in toluene) (330 mg, 4.23 mmol) in THF (25 mL, 4.23 mmol) was added propionitrile (0.448 mL, 6.35 mmol) at -78°C under N 2 and the reaction mixture was stirred for 30 minutes. Methyl 3-methoxypropionate (0.495 mL, 4.23 mmol) was added and the reaction mixture was stirred at -78°C for 1 hour and then at 0°C for 2.5 hours. The reaction mixture was diluted with H2 O (25 mL) and washed with Et2 O (25 mL). The basic aqueous phase was neutralized with 2M HCl (1.6 mL) and then extracted with Et2 O (3×25 mL). The combined organic phases were washed with brine (25 mL), dried over MgSO4 , filtered and concentrated to give the crude product (171 mg) as a light green oil. The crude mixture was used directly in the next step.
步骤B：制备3-(2-甲氧基乙基)-4-甲基-1-苯基-1H-吡唑-5-胺：通过如对于中间体P1所述的方法，用5-甲氧基-2-甲基-3-氧代戊腈替代4,4-二甲基-3-氧代戊腈并且用苯肼盐酸盐替代3-肼基苯甲酸乙酯盐酸盐来制备，得到呈黄色固体状的产物(56mg，20％产率)。MS(apci)m/z＝232.0(M+H)。Step B:Preparation of 3-(2-methoxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-amine : Prepared by following the procedure for Intermediate P1, substituting 5-methoxy-2-methyl-3-oxopentanonitrile for 4,4-dimethyl-3-oxopentanonitrile and phenylhydrazine hydrochloride for ethyl 3-hydrazinobenzoate hydrochloride to afford the product as a yellow solid (56 mg, 20% yield). MS (apci) m/z=232.0 (M+H).
中间体P129Intermediate P129
(5-氧化-2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基)氨基甲酸苯酯Phenyl (5-oxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate
用外部干冰/MeCN浴把2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基氨基甲酸苯酯(中间体P130步骤B；50mg，0.15mmol)的THF(4mL)溶液冷却至-50℃并且用3-氯过氧苯甲酸(33mg，0.13mmol)的THF(2mL)溶液处理。搅拌1小时后，用Na2S2O3和水淬灭混合物，用EtOAc萃取，用NaHCO3和盐水洗涤，用MgSO4干燥，过滤并且浓缩，得到产物，其不经进一步纯化即直接用于下一步骤中。MS(apci)m/z＝354.1(M+H)。A solution of phenyl 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate (Intermediate P130, Step B; 50 mg, 0.15 mmol) in THF (4 mL) was cooled to -50°C using an external dry ice/MeCN bath and treated with a solution of3 -chloroperoxybenzoic acid (33 mg, 0.13 mmol) in THF (2mL ). After stirring for 1 hour, the mixture was quenched withNa2S2O3 and water, extracted with EtOAc, washed withNaHCO3 and brine, dried overMgSO4 , filtered, and concentrated to give the product, which was used directly in the next step without further purification. MS (apci) m/z = 354.1 (M+H).
中间体P130Intermediate P130
(5,5-二氧化-2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基)氨基甲酸苯酯Phenyl (5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate
步骤A：制备2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-胺：使4-氧代四氢噻吩-3-甲腈(1.00g，7.86mmol)和苯肼盐酸盐(1.25g，8.65mmol)在绝对EtOH(40mL)中的悬浮液回流2小时。在减压下去除溶剂后，用1N NaOH(40mL)湿磨白色固体残余物。通过过滤收集固体，用0.1N NaOH、水和己烷(各约10mL)洗涤，然后在高真空下干燥，得到呈白色固体状的产物(1.6g，95％产率)。MS(apci正离子)m/z＝218.1(M+H)。Step A:Preparation of 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazole-3-amine : A suspension of 4-oxotetrahydrothiophene-3-carbonitrile (1.00 g, 7.86 mmol) and phenylhydrazine hydrochloride (1.25 g, 8.65 mmol) in absolute EtOH (40 mL) was refluxed for 2 hours. After removing the solvent under reduced pressure, the white solid residue was triturated with 1N NaOH (40 mL). The solid was collected by filtration, washed with 0.1N NaOH, water, and hexane (about 10 mL each), and then dried under high vacuum to give the product as a white solid (1.6 g, 95% yield). MS (apci positive ion) m/z=218.1 (M+H).
步骤B：制备2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基氨基甲酸苯酯：向2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-胺(500mg，2.30mmol)在EtOAc(10mL)中的悬浮液中添加NaOH(2M水溶液，2.3mL，4.60mmol)，接着逐滴添加氯甲酸苯酯(0.400mL，3.22mmol)。在环境温度下搅拌2小时后，逐滴添加另一部分氯甲酸苯酯(0.16mL，1.3mmol)，并且在环境温度下搅拌反应物15小时。用EtOAc(20mL)稀释反应混合物并且进行相分离。用H2O、盐水(各25mL)洗涤有机相，然后用Na2SO4干燥，过滤并且浓缩。通过反相柱色谱法，用5％至70％乙腈/水洗脱来纯化粗物质，得到呈白色固体状的产物(0.5g，64％产率)。MS(apci正离子)m/z＝338.1(M+H)。Step B:Preparation of phenyl 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate : To a suspension of 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine (500 mg, 2.30 mmol) in EtOAc (10 mL) was added NaOH (2M in water, 2.3 mL, 4.60 mmol) followed by dropwise addition of phenyl chloroformate (0.400 mL, 3.22 mmol). After stirring at ambient temperature for 2 hours, another portion of phenyl chloroformate (0.16 mL, 1.3 mmol) was added dropwise and the reaction was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with EtOAc (20 mL) and the phases were separated. The organic phase was washed withH₂O , brine (25 mL each), then dried overNa₂SO₄ ,filtered , and concentrated. The crude material was purified by reverse phase column chromatography eluting with 5% to 70% acetonitrile/water to give the product as a white solid (0.5 g, 64% yield).MS (apci positive ion) m/z = 338.1 (M+H).
步骤C：制备(5,5-二氧化-2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基)氨基甲酸苯酯：在0℃下向2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基氨基甲酸苯酯(50mg，0.15mmol)在DCM(1.5mL)中的的混浊溶液中添加MCPBA(91mg，0.37mmol，70％至75％水复合物)，并且在环境温度下搅拌混合物10分钟。然后用DCM(3mL)稀释混合物并且用饱和NaHCO3水溶液(3×2mL)和饱和Na2S2O3水溶液(3×2mL)洗涤。用MgSO4干燥有机层，过滤并且在减压下浓缩，得到呈淡黄色泡沫状固体状的标题产物(31mg，57％产率，95％纯)。MS(apci正离子)m/z＝371.0(M+H)。Step C:Preparation of phenyl (5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate : To a cloudy solution of phenyl 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate (50 mg, 0.15 mmol) in DCM (1.5 mL) was added MCPBA (91 mg, 0.37 mmol, 70% to 75% aqueous complex) at 0 ° C., and the mixture was stirred at ambient temperature for 10 minutes. The mixture was then diluted with DCM (3 mL) and washed with saturated aqueous NaHCO3 solution (3×2 mL) and saturated aqueous Na2 S2 O3 solution (3×2 mL). The organic layer was dried over MgSO4 , filtered and concentrated under reduced pressure to give the title product (31 mg, 57% yield, 95% pure) as a pale yellow foamy solid. MS (apci positive ion) m/z = 371.0 (M+H).
中间体P131Intermediate P131
3-(咪唑并[1,2-a]吡啶-5-基)-1-甲基-1H-吡唑-5-胺3-(Imidazolo[1,2-a]pyridin-5-yl)-1-methyl-1H-pyrazol-5-amine
步骤A：咪唑并[1,2-a]吡啶-5-甲酸甲酯：向6-氨基吡啶甲酸甲酯(1.52g，10.0mmol)在iPrOH(10mL)中的悬浮液中添加2-氯乙醛(2.57mL，20.0mmol)并且在环境温度下搅拌混合物30分钟。在70℃下加热所得到的溶液16小时，然后冷却至环境温度并且在真空中浓缩。用H2O(40mL)稀释残余物并且用1M K2CO3处理直到pH＝10为止。用EtOAc(3X)萃取混合物并且用饱和NaCl洗涤合并的萃取物并且经MgSO4/活性碳干燥。通过盖有MgSO4层的SiO2塞，使用EtOAc进行洗脱来洗脱干燥的溶液。浓缩溶液，得到呈奶白色固体状的标题化合物(1.73g，98.2％产率)。MS(apci)m/z＝177.0(M+H)。Step A:Methyl imidazo[1,2-a]pyridine-5-carboxylate : To a suspension of methyl 6-aminopicolinate (1.52 g, 10.0 mmol) in iPrOH (10 mL) was added 2-chloroacetaldehyde (2.57 mL, 20.0 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The resulting solution was heated at 70 ° C for 16 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with H2 O (40 mL) and treated with 1M K2 CO3 until pH = 10. The mixture was extracted with EtOAc (3X) and the combined extracts were washed with saturated NaCl and dried over MgSO4 / activated carbon. The dried solution was eluted using EtOAc through a SiO2 plug covered with a MgSO4 layer. The solution was concentrated to give the title compound (1.73 g, 98.2% yield) as a milky white solid. MS (apci) m/z = 177.0 (M+H).
步骤B：3-(咪唑并[1,2-a]吡啶-5-基)-3-氧代丙腈：把1M LiHMDS(3.15mL，3.15mmol)在干燥THF中的溶液冷却至-78℃并且经1分钟逐滴添加乙腈(0.172mL，3.30mmol)。在-78℃下搅拌混合物1小时并且添加咪唑并[1,2-a]吡啶-5-甲酸甲酯(0.529g，3.00mmol)在干燥THF(2.0mL)中的溶液。允许混合物达到环境温度并且搅拌2.5小时。把混合物倒入冷却的H2O(30mL)中并且用Et2O(3X)萃取所得到的水溶液。把水性部分冷却至0℃并且缓慢添加6M HCl直到pH＝6为止。过滤所得到的黄色悬浮液并且用H2O和EtOAc洗涤所收集的固体。在真空中干燥固体，得到呈黄色固体状的标题化合物(317mg，57.1％产率)。MS(apci)m/z＝186.0(M+H)。Step B:3-(Imidazolo[1,2-a]pyridin-5-yl)-3-oxopropionitrile : A 1M solution of LiHMDS (3.15 mL, 3.15 mmol) in dry THF was cooled to -78°C and acetonitrile (0.172 mL, 3.30 mmol) was added dropwise over 1 minute. The mixture was stirred at -78°C for 1 hour and a solution of methyl imidazo[1,2-a]pyridine-5-carboxylate (0.529 g, 3.00 mmol) in dry THF (2.0 mL) was added. The mixture was allowed to reach ambient temperature and stirred for 2.5 hours. The mixture was poured into cooledH₂O (30 mL) and the resulting aqueous solution was extracted withEt₂O (3×). The aqueous portion was cooled to 0°C and 6M HCl was slowly added until pH = 6. The resulting yellow suspension was filtered and the collected solid was washed withH₂O and EtOAc. The solid was dried in vacuo to give the title compound as a yellow solid (317 mg, 57.1% yield).MS (apci) m/z = 186.0 (M+H).
步骤C：3-(咪唑并[1,2-a]吡啶-5-基)-1-甲基-1H-吡唑-5-胺：向3-(咪唑并[1,2-a]吡啶-5-基)-3-氧代丙腈(229mg，1.24mmol)在绝对EtOH(4mL)中的精细悬浮液中添加甲肼(78.1μL，1.45mmol)并且在环境温度下搅拌所得到的溶液2小时。在回流下加热反应混合物5小时并且再添加甲肼(200μL)。在回流下加热混合物15小时，冷却至环境温度并且浓缩。将残余棕褐色固体溶解于5％MeOH/CH2Cl2中并且通过SiO2塞用5％MeOH/CH2Cl2进行洗脱来洗脱。浓缩洗脱液并且用MTBE洗涤残余黄色固体并且在真空中干燥，得到呈淡黄色粉末状的标题化合物(150mg，56.9％产率)。MS(apci)m/z＝214.0(M+H)。Step C:3-(imidazo[1,2-a]pyridin-5-yl)-1-methyl-1H-pyrazol-5-amine : To a fine suspension of 3-(imidazo[1,2-a]pyridin-5-yl)-3-oxopropionitrile (229 mg, 1.24 mmol) in absolute EtOH (4 mL) was added methylhydrazine (78.1 μL, 1.45 mmol) and the resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was heated at reflux for 5 hours and methylhydrazine (200 μL) was added again. The mixture was heated at reflux for 15 hours, cooled to ambient temperature and concentrated. The residual tan solid was dissolved in 5% MeOH/CH2 Cl2 and eluted with 5% MeOH/CH2 Cl2 through a SiO2 plug. The eluent was concentrated and the residual yellow solid was washed with MTBE and dried in vacuo to give the title compound (150 mg, 56.9% yield) as a light yellow powder. MS (apci) m/z = 214.0 (M+H).
中间体P132Intermediate P132
1-甲基-3-(吡嗪-2-基)-1H-吡唑-5-胺1-Methyl-3-(pyrazin-2-yl)-1H-pyrazol-5-amine
步骤A：制备3-氧代-3-(吡嗪-2-基)丙腈：向NaH(在矿物油中60％，81.1mg，2.03mmol)在二噁烷(15mL)中的悬浮液中添加乙腈(0.114mL，2.17mmol)，接着添加吡嗪-2-甲酸甲酯(200mg，1.45mmol)并且把反应物加热至回流，持续2.5小时。把反应混合物冷却至环境温度并且用H2O(25mL)稀释并且用Et2O(25mL)萃取。用2M HCl水溶液(0.7mL)中和水相，然后用10％MeOH/DCM(3×25mL)萃取。用盐水(25mL)洗涤合并的有机相，用MgSO4干燥，过滤并且浓缩，得到呈橙色糖浆状的粗产物(134mg，62.9％产率)。1H NMR(CDCl3)δ9.32(d,1H),8.87(d,1H),8.68(dd,1H),4.34(s,2H)。[0146] Step A:Preparation of 3-oxo-3-(pyrazin-2-yl)propionitrile : To a suspension of NaH (60% in mineral oil, 81.1 mg, 2.03 mmol) in dioxane (15 mL) was added acetonitrile (0.114 mL, 2.17 mmol) followed by methyl pyrazine-2-carboxylate (200 mg, 1.45 mmol) and the reaction was heated to reflux for 2.5 hours. The reaction mixture was cooled to ambient temperature and diluted withH2O (25 mL) and extracted withEt2O (25 mL). The aqueous phase was neutralized with 2M aqueous HCl (0.7 mL) and then extracted with 10% MeOH/DCM (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried overMgSO4 , filtered and concentrated to give the crude product as an orange syrup (134 mg, 62.9% yield).1 H NMR (CDCl3 ) δ 9.32 (d, 1H), 8.87 (d, 1H), 8.68 (dd, 1H), 4.34 (s, 2H).
步骤B：制备1-甲基-3-(吡嗪-2-基)-1H-吡唑-5-胺：向3-氧代-3-(吡嗪-2-基)丙腈(67.0mg，0.455mmol)在EtOH(5mL)中的悬浮液中添加甲肼(0.024mL，0.455mmol)。使反应混合物回流15小时，然后在真空中浓缩。通过二氧化硅柱色谱法，用0％至5％MeOH/DCM洗脱来纯化粗产物，得到呈棕色残余物形式的产物(33mg，41％产率)。MS(apci)m/z＝176.2(M+H)。Step B:Preparation of 1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-5-amine : To a suspension of 3-oxo-3-(pyrazin-2-yl)propionitrile (67.0 mg, 0.455 mmol) in EtOH (5 mL) was added methylhydrazine (0.024 mL, 0.455 mmol). The reaction mixture was refluxed for 15 hours and then concentrated in vacuo. The crude product was purified by silica column chromatography eluting with 0% to 5% MeOH/DCM to give the product (33 mg, 41% yield) as a brown residue. MS (apci) m/z=176.2 (M+H).
中间体P133Intermediate P133
1-甲基-3-(5-甲基吡嗪-2-基)-1H-吡唑-5-胺1-Methyl-3-(5-methylpyrazin-2-yl)-1H-pyrazol-5-amine
通过如对于中间体P107所述的方法，在步骤A中用5-甲基吡嗪-2-甲酸甲酯替代异丁酸甲酯并且用乙腈替代丙腈来制备，得到3-(5-甲基吡嗪-2-基)-3-氧代丙腈。在步骤B中，用甲肼替代苯肼，得到标题吡唑。MS(apci)m/z＝190.2(M+H)。Prepared by the procedure described for Intermediate P107, substituting methyl 5-methylpyrazine-2-carboxylate for methyl isobutyrate and acetonitrile for propionitrile in Step A to give 3-(5-methylpyrazin-2-yl)-3-oxopropionitrile. Substituting methylhydrazine for phenylhydrazine in Step B gave the title pyrazole. MS (apci) m/z = 190.2 (M+H).
中间体P134Intermediate P134
1,4-二甲基-3-(5-甲基吡嗪-2-基)-1H-吡唑-5-胺1,4-Dimethyl-3-(5-methylpyrazin-2-yl)-1H-pyrazol-5-amine
通过如对于中间体P107所述的方法，在步骤A中用5-甲基吡嗪-2-甲酸甲酯替代异丁酸甲酯来制备，得到2-甲基-3-(5-甲基吡嗪-2-基)-3-氧代丙腈。在步骤B中，用甲肼替代苯肼，得到标题化合物。MS(apci)m/z＝204.1(M+H)。Prepared by the procedure described for Intermediate P107, substituting methyl 5-methylpyrazine-2-carboxylate for methyl isobutyrate in Step A to afford 2-methyl-3-(5-methylpyrazine-2-yl)-3-oxopropionitrile. Substituting methylhydrazine for phenylhydrazine in Step B afforded the title compound. MS (apci) m/z = 204.1 (M+H).
中间体P135Intermediate P135
3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-胺3-Ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine
步骤A：制备5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮：在110℃下加热2-氰基丙酸乙酯(5.0g，46mmol)和苯肼(5.9g，46mmol)在二噁烷(10mL)中的混合物17小时。把粗物质冷却至环境温度，浓缩并且用冷EtOH和Et2O湿磨。过滤所得到的固体，用Et2O洗涤，并且在真空下干燥，得到呈白色固体状的产物(3.4g，39％产率)。MS(apci)m/z＝190.0(M-H)。[0266] Step A:Preparation of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one : A mixture of ethyl 2-cyanopropionate (5.0 g, 46 mmol) and phenylhydrazine (5.9 g, 46 mmol) in dioxane (10 mL) was heated at 110°C for 17 hours. The crude material was cooled to ambient temperature, concentrated, and triturated with cold EtOH andEt2O . The resulting solid was filtered, washed withEt2O , and dried under vacuum to give the product as a white solid (3.4 g, 39% yield). MS (apci) m/z = 190.0 (MH).
步骤B：制备3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-胺：在环境温度下向5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮(10.0g，52.9mmol)在DMF(100mL)中的悬浮液中添加K2CO3(14.6g，106mmol)和溴乙烷(4.34mL，58.1)。搅拌17小时后，用EtOAc处理反应混合物并且用水(3×，以获得N-烷基化产物)和盐水洗涤，用MgSO4干燥，过滤并且浓缩，得到产物(5.35g，47％产率)。MS(apci)m/z＝218.1(M+H)。[0146] Step B:Preparation of 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-amine : To a suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (10.0 g, 52.9 mmol) in DMF (100 mL) was addedK2CO3 (14.6 g, 106 mmol) and bromoethane (4.34 mL, 58.1) at ambient temperature. After stirring for 17 h, the reaction mixture was treated with EtOAc and washed with water (3x to obtain the N-alkylated product) and brine, dried over MgSO4, filtered, and concentrated to afford the product (5.35 g, 47% yield). MS (apci) m/z = 218.1 (M+H).
通过如对于中间体P135所述的方法，用适当的烷基卤化物或甲磺酸烷基酯替代溴乙烷来制备表3中的化合物。The compounds in Table 3 were prepared by the procedure described for intermediate P135, substituting the appropriate alkyl halide or alkyl methanesulfonate for ethyl bromide.
表3：Table 3:
中间体P136Intermediate P136
3-(苯甲基氧基)-1-甲基-1H-吡唑-5-胺3-(Benzyloxy)-1-methyl-1H-pyrazol-5-amine
步骤A：制备5-氨基-1-甲基-4-苯基-1H-吡唑-3(2H)-酮：向2-氰基-2-苯基乙酸乙酯(2.56g，13.3mmol)在EtOH(10mL)中的悬浮液中逐滴添加甲肼(1.09mL，19.9mmol)。在85℃下加热反应物15小时。把反应混合物冷却至0℃并且过滤。用冷EtOH(20mL)和Et2O(20mL)洗涤所得到的固体，得到希望的产物(2.10g，83.7％产率)。MS(apci)m/z＝190.2(M+H)。Step A:Preparation of 5-amino-1-methyl-4-phenyl-1H-pyrazol-3(2H)-one : To a suspension of ethyl 2-cyano-2-phenylacetate (2.56 g, 13.3 mmol) in EtOH (10 mL) was added methylhydrazine (1.09 mL, 19.9 mmol) dropwise. The reaction was heated at 85°C for 15 hours. The reaction mixture was cooled to 0°C and filtered. The resulting solid was washed with cold EtOH (20 mL) andEt2O (20 mL) to give the desired product (2.10 g, 83.7% yield). MS (apci) m/z = 190.2 (M+H).
步骤B：制备3-(苯甲基氧基)-1-甲基-1H-吡唑-5-胺：在70℃下加热5-氨基-1-甲基-1H-吡唑-3(2H)-酮(0.35g，3.1mmol)、苯甲基氯(0.43g，3.4mmol)和K2CO3(1.3g，9.3mmol)在DMF(4mL)中的悬浮液17小时。冷却后，用EtOAc处理反应混合物，用水和盐水洗涤，用MgSO4干燥并且在真空中浓缩。通过二氧化硅柱色谱法，用2％至6％MeOH/DCM洗脱来纯化粗产物，得到标题化合物(0.16g，25％产率)。MS(apci)m/z＝204.0(M+H)。[0266] Step B:Preparation of 3-(benzyloxy)-1-methyl-1H-pyrazol-5-amine : A suspension of 5-amino-1-methyl-1H-pyrazol-3(2H)-one (0.35 g, 3.1 mmol), benzyl chloride (0.43 g, 3.4 mmol) andK2CO3( 1.3 g, 9.3 mmol) in DMF (4 mL) was heated at 70°C for 17 hours. After cooling, the reaction mixture was treated with EtOAc, washed with water and brine, dried overMgSO4 and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with 2% to 6% MeOH/DCM to give the title compound (0.16 g, 25% yield). MS (apci) m/z = 204.0 (M+H).
中间体P137Intermediate P137
3-甲氧基-1-甲基-4-苯基-1H-吡唑-5-胺3-Methoxy-1-methyl-4-phenyl-1H-pyrazol-5-amine
向5-氨基-1-甲基-4-苯基-1H-吡唑-3(2H)-酮(制备中间体P136的步骤A；208mg，1.10mmol)和K2CO3(456mg，3.30mmol)在DMF(5mL)中的悬浮液中逐滴添加碘代甲烷(172mg，1.21mmol)。搅拌反应混合物15小时。在减压下去除溶剂并且通过二氧化硅柱色谱法用33％EtOAc/己烷洗脱来纯化残余物，得到标题吡唑(66.0mg，30.4％产率)。MS(apci)m/z＝204.1(M+H)。To a suspensionof 5-amino-1-methyl-4-phenyl-1H-pyrazol-3(2H)-one (Step A of the preparation of intermediate P136; 208 mg, 1.10 mmol) andK2CO3 (456 mg, 3.30 mmol) in DMF (5 mL) was added iodomethane (172 mg, 1.21 mmol) dropwise. The reaction mixture was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography eluting with 33% EtOAc/hexanes to give the title pyrazole (66.0 mg, 30.4% yield). MS (apci) m/z = 204.1 (M+H).
中间体P138Intermediate P138
3-乙氧基-1-甲基-4-苯基-1H-吡唑-5-胺3-Ethoxy-1-methyl-4-phenyl-1H-pyrazol-5-amine
如中间体P137中所述，在步骤B中用碘乙烷替代碘代甲烷来制备，得到标题化合物。MS(apci)m/z＝218.2(M+H)。Prepared as described in Intermediate P137, substituting iodoethane for iodomethane in Step B, to give the title compound. MS (apci) m/z = 218.2 (M+H).
中间体P139Intermediate P139
3-乙氧基-1-苯基-1H-吡唑-5-胺3-Ethoxy-1-phenyl-1H-pyrazol-5-amine
根据对于中间体135所述的程序，在步骤A中用2-氰基乙酸乙酯替代2-氰基丙酸乙酯来制备。MS(apci)m/z＝204.0(M+H)。Prepared according to the procedure described for Intermediate 135, substituting ethyl 2-cyanoacetate for ethyl 2-cyanopropionate in Step A. MS (apci) m/z = 204.0 (M+H).
通过如对于中间体P135所述的方法，用适当的烷基卤化物、甲磺酸烷基酯或环氧化物替代溴乙烷来制备下表中的化合物。The compounds in the following table were prepared by the procedure described for intermediate P135, substituting the appropriate alkyl halide, alkyl methanesulfonate, or epoxide for ethyl bromide.
中间体151Intermediate 151
1'-(2-甲氧基乙基)-1-苯基-1H,1'H-[3,4'-联吡唑]-5-胺1'-(2-methoxyethyl)-1-phenyl-1H,1'H-[3,4'-bipyrazolyl]-5-amine
步骤A：制备1-甲基-1H-1,2,4-三唑-3-甲酸甲酯：在0℃、氮气下向NaH(60％油分散液，0.346g，8.66mmol)在DMF(20mL)中的经搅拌悬浮液中逐滴添加1H-1,2,4-三唑-3-甲酸甲酯(1.00g，7.87mmol)在DMF(20mL)中的溶液。在0℃下搅拌反应混合物1小时。逐滴添加MeI(0.982mL，15.7mmol)。在环境温度下搅拌反应混合物过夜。把反应物倒入冷水中并且用EtOAc萃取。用盐水洗涤合并的有机层，干燥并且浓缩。通过柱色谱法(3:1己烷/EtOAc)纯化残余物，得到呈白色固体状的标题化合物(0.380g，34％产率)。MS(apci)m/z＝142.1(M+H)。Step A:Preparation of 1-methyl-1H-1,2,4-triazole-3-carboxylic acid methyl ester : To a stirred suspension of NaH (60% oil dispersion, 0.346 g, 8.66 mmol) in DMF (20 mL) at 0 ° C under nitrogen was added a solution of 1H-1,2,4-triazole-3-carboxylic acid methyl ester (1.00 g, 7.87 mmol) in DMF (20 mL) dropwise. The reaction mixture was stirred at 0 ° C for 1 hour. MeI (0.982 mL, 15.7 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature overnight. The reactant was poured into cold water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography (3: 1 hexane / EtOAc) to give the title compound (0.380 g, 34% yield) as a white solid. MS (apci) m / z = 142.1 (M + H).
步骤B：制备1'-(2-甲氧基乙基)-1-苯基-1H,1'H-[3,4'-联吡唑]-5-胺：根据对于中间体P109所述的方法，在步骤A中使用1-甲基-1H-1,2,4-三唑-3-甲酸甲酯作为2-甲氧基乙酸甲酯的替代物并且用丙腈替代乙腈来制备。MS(apci)m/z＝255.1(M+H)。Step B:Preparation of 1'-(2-methoxyethyl)-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-amine : Prepared according to the procedure for intermediate P109 using 1-methyl-1H-1,2,4-triazole-3-carboxylic acid methyl ester as a substitute for methyl 2-methoxyacetate and propionitrile instead of acetonitrile in step A. MS (apci) m/z = 255.1 (M+H).
中间体152Intermediate 152
1'-(2-甲氧基乙基)-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-胺1'-(2-methoxyethyl)-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazolyl]-5-amine
根据对于中间体P109所述的方法，在步骤A中使用1-(2-甲氧基乙基)-1H-吡唑-4-甲酸乙酯作为2-甲氧基乙酸甲酯的替代物并且用丙腈替代乙腈来制备。Prepared according to the procedure described for intermediate P109 using ethyl 1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate as a substitute for methyl 2-methoxyacetate and propionitrile in place of acetonitrile in step A.
中间体153Intermediate 153
5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲腈5-Amino-4-methyl-1-phenyl-1H-pyrazole-3-carbonitrile
在0℃至5℃下向苯胺(2.02g，21.7mmol)在6N HCl(22mL)中的经搅拌溶液中逐滴添加NaNO2(1.50g，21.7mmol)在水(20mL)中的溶液。在0℃下搅拌反应混合物15分钟。添加乙酸(10mL)。在0℃下将此溶液逐滴添加至2,3-二氰基丁酸乙酯(根据Bioorganic&Medicinal Chemistry,2004,12,3345-3356中所述的程序制备，3.60g，21.7mmol)在乙酸(12mL)和水(18mL)中的经搅拌溶液中。搅拌1小时后，逐滴添加浓氢氧化铵(50mL)，接着添加THF(50mL)。在环境温度下搅拌反应物过夜。分离有机层。用EtOAc萃取水层。用盐水洗涤合并的有机层，干燥并且浓缩。通过硅胶快速色谱法(3:1己烷/EtOAc)纯化残余物，得到标题化合物(2.95g，69％产率)。MS(apci)m/z＝198.9(M+H)。To a stirred solution of aniline (2.02 g, 21.7 mmol) in 6N HCl (22 mL) was added dropwise a solution of NaNO2 (1.50 g, 21.7 mmol) in water (20 mL) at 0 to 5 ° C. The reaction mixture was stirred for 15 minutes at 0 ° C. Acetic acid (10 mL) was added. This solution was added dropwise to a stirred solution of ethyl 2,3-dicyanobutyrate (prepared according to the procedure described in Bioorganic & Medicinal Chemistry, 2004, 12, 3345-3356, 3.60 g, 21.7 mmol) in acetic acid (12 mL) and water (18 mL) at 0 ° C. After stirring for 1 hour, concentrated ammonium hydroxide (50 mL) was added dropwise, followed by THF (50 mL). The reaction mixture was stirred overnight at ambient temperature. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (3:1 hexanes/EtOAc) to give the title compound (2.95 g, 69% yield).MS (apci) m/z=198.9 (M+H).
中间体154Intermediate 154
2-(5-氨基-4-甲基-1-苯基-1H,1'H-3,4'-联吡唑-1'-基)乙醇2-(5-amino-4-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-1'-yl)ethanol
步骤A：制备1-(2-((叔丁基二甲基硅烷基)氧基)乙基)-1H-吡唑-4-甲酸乙酯：根据对于实例556所述的方法，在步骤A中用(2-溴乙氧基)(叔丁基)二甲基硅烷替代1-溴-2-甲氧基乙烷来制备。MS(apci)m/z＝298.9(M+H)。Step A:Preparation of ethyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-4-carboxylate : Prepared according to the procedure for Example 556, substituting (2-bromoethoxy)(tert-butyl)dimethylsilane for 1-bromo-2-methoxyethane in Step A. MS (apci) m/z = 298.9 (M+H).
步骤B：制备2-(5-氨基-4-甲基-1-苯基-1H,1'H-3,4'-联吡唑-1'-基)乙醇：根据对于中间体P109所述的方法，在步骤A中使用1-(2-((叔丁基二甲基硅烷基)氧基)乙基)-1H-吡唑-4-甲酸乙酯作为2-甲氧基乙酸甲酯的替代物并且用丙腈替代乙腈来制备。MS(apci)m/z＝283.9(M+H)。Step B:Preparation of 2-(5-amino-4-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-1'-yl)ethanol : Prepared according to the procedure described for intermediate P109 using ethyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-4-carboxylate as a substitute for methyl 2-methoxyacetate and propionitrile instead of acetonitrile in step A. MS (apci) m/z = 283.9 (M+H).
中间体155Intermediate 155
4-甲基-3-(2-甲基-2H-1,2,3-三唑-4-基)-1-苯基-1H-吡唑-5-胺4-Methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-amine
步骤A：制备2-甲基-2H-1,2,3-三唑-4-甲酸乙酯：在50℃、氮气下搅拌2H-1,2,3-三唑-4-甲酸乙酯(2.00g，14.2mmol)、K2CO3(3.53g，25.5mmol)和碘代甲烷(3.54mL，56.7mmol)在乙腈(40mL)中的混合物过夜。冷却至环境温度后，通过过滤混合物。在真空中浓缩滤液。通过硅胶快速色谱法(4:1己烷/EtOAc)纯化残余物，得到标题化合物(0.780g，35％产率)。MS(apci)m/z＝156.0(M+H)。Step A:Preparation of ethyl 2-methyl-2H-1,2,3-triazole-4-carboxylate : A mixtureof ethyl 2H-1,2,3-triazole-4-carboxylate (2.00 g, 14.2 mmol),K2CO3 (3.53 g, 25.5 mmol), and iodomethane (3.54 mL, 56.7 mmol) in acetonitrile (40 mL) was stirred at 50°C under nitrogen overnight. After cooling to ambient temperature, the mixture was filtered through Celite®. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (4:1 hexanes/EtOAc) to give the title compound (0.780 g, 35% yield). MS (apci) m/z = 156.0 (M+H).
步骤B：制备4-甲基-3-(2-甲基-2H-1,2,3-三唑-4-基)-1-苯基-1H-吡唑-5-胺：根据对于中间体P109所述的方法，在步骤A中使用2-甲基-2H-1,2,3-三唑-4-甲酸乙酯作为2-甲氧基乙酸甲酯的替代物并且用丙腈替代乙腈来制备。MS(apci)m/z＝254.9(M+H)。Step B:Preparation of 4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-amine : Prepared according to the procedure for intermediate P109 using ethyl 2-methyl-2H-1,2,3-triazole-4-carboxylate as a substitute for methyl 2-methoxyacetate and propionitrile instead of acetonitrile in step A. MS (apci) m/z = 254.9 (M+H).
中间体156Intermediate 156
3-溴-4-甲基-1-苯基-1H-吡唑-5-胺3-Bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine
向5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮(中间体P135步骤A，1.00g，5.29mmol)在MeCN(20mL)中的经搅拌溶液中添加POBr3(2.27g，7.93mmol)。在回流下加热反应混合物3小时。在真空中浓缩反应物。把残余物溶解于DCM中。小心添加饱和NaHCO3水溶液。用DCM萃取水层。用盐水洗涤合并的有机层，干燥并且浓缩。通过硅胶快速色谱法(1:2己烷/EtOAc)纯化残余物，得到标题化合物(0.23g，17％产率)。MS(apci)m/z＝251.8(M+H)。To a stirred solution of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate P135, Step A, 1.00 g, 5.29 mmol) in MeCN (20 mL) was addedPOBr (2.27 g, 7.93 mmol). The reaction mixture was heated at reflux for 3 hours. The reaction was concentrated in vacuo. The residue was dissolved in DCM. Saturated aqueousNaHCO solution was carefully added. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by flash chromatography on silica gel (1:2 hexanes/EtOAc) to give the title compound (0.23 g, 17% yield). MS (apci) m/z = 251.8 (M+H).
中间体157Intermediate 157
3-氨基-5-甲基-2-苯基-4,5-二氢吡咯并[3,4-c]吡唑-6(2H)-酮3-Amino-5-methyl-2-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one
步骤A：制备5-氨基-4-((甲基氨基)甲基)-1-苯基-1H-吡唑-3-甲酸乙酯：向5-氨基-4-甲酰基-1-苯基-1H-吡唑-3-甲酸乙酯(根据J.Heterocyclic Chemistry,2010,47,第287-291页中所述的程序制备，142mg，0.548mmol)在DCM(3mL)中的经搅拌溶液中添加2.0MMeNH2的THF溶液(0.822mL，1.64mmol)。添加两滴乙酸。在环境温度下搅拌反应混合物过夜。添加MeOH(0.4mL)，接着逐份添加NaBH4(31mg，0.82mmol)。通过缓慢添加水淬灭反应。用DCM萃取混合物。用盐水洗涤合并的有机层，干燥并且浓缩。粗物质不经进一步纯化即用于下一步骤中。MS(apci)m/z＝275.0(M+H)。Step A:Preparation of ethyl 5-amino-4-((methylamino)methyl)-1-phenyl-1H-pyrazole-3-carboxylate : To a stirred solution of ethyl 5-amino-4-formyl-1-phenyl-1H-pyrazole-3-carboxylate (prepared according to the procedure described in J. Heterocyclic Chemistry, 2010, 47, pp. 287-291, 142 mg, 0.548 mmol) in DCM (3 mL) was added 2.0 M MeNH2 in THF (0.822 mL, 1.64 mmol). Two drops of acetic acid were added. The reaction mixture was stirred at ambient temperature overnight. MeOH (0.4 mL) was added followed by portionwise addition of NaBH4 (31 mg, 0.82 mmol). The reaction was quenched by the slow addition of water. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The crude material was used in the next step without further purification. MS (apci) m/z = 275.0 (M+H).
步骤B：制备3-氨基-5-甲基-2-苯基-4,5-二氢吡咯并[3,4-c]吡唑-6(2H)-酮：向5-氨基-4-((甲基氨基)甲基)-1-苯基-1H-吡唑-3-甲酸乙酯(粗，65mg，0.24mmol)在MeOH(0.5mL)和THF(0.5mL)中的经搅拌溶液中添加2N NaOH(0.24mL，0.47mmol)。在环境温度下搅拌反应混合物4小时并且然后在真空中浓缩。向残余物中添加水。使用1N HCl把pH调节到4至5。在减压下蒸发水。把粗酸(58mg)溶解于DMF(3mL)中。添加Et3N(66μL，0.47mmol)，接着添加EDCI(90mg，0.47mmol)和HOBt(32mg，0.24mmol)。在环境温度下搅拌反应混合物过夜并且然后分配于EtOAc与水之间。用EtOAc萃取水层。用水和盐水洗涤合并的有机层，干燥并且浓缩。通过硅胶快速色谱法(含2％MeOH的DCM)纯化残余物，得到呈白色固体状的标题化合物(15mg，28％)。MS(apci)m/z＝228.9(M+H)。Step B:Preparation of 3-amino-5-methyl-2-phenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one : To a stirred solution of ethyl 5-amino-4-((methylamino)methyl)-1-phenyl-1H-pyrazole-3-carboxylate (crude, 65 mg, 0.24 mmol) in MeOH (0.5 mL) and THF (0.5 mL) was added 2N NaOH (0.24 mL, 0.47 mmol). The reaction mixture was stirred at ambient temperature for 4 hours and then concentrated in vacuo. Water was added to the residue. The pH was adjusted to 4-5 using 1N HCl. The water was evaporated under reduced pressure. The crude acid (58 mg) was dissolved in DMF (3 mL).Et3N (66 μL, 0.47 mmol) was added, followed by EDCI (90 mg, 0.47 mmol) and HOBt (32 mg, 0.24 mmol). The reaction mixture was stirred at ambient temperature overnight and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (2% MeOH in DCM) to give the title compound (15 mg, 28%) as a white solid. MS (apci) m/z = 228.9 (M+H).
中间体158Intermediate 158
3-甲基-4-(甲硫基)-1-苯基-1H-吡唑-5-胺3-Methyl-4-(methylthio)-1-phenyl-1H-pyrazol-5-amine
根据对于中间体P109所述的方法，在步骤A中用乙酸乙酯替代2-甲氧基乙酸甲酯并且用2-(甲硫基)乙腈替代乙腈来制备，得到呈棕色油状的产物。MS(apci)m/z＝220.1(M+H)。Prepared according to the procedure described for Intermediate P109, substituting ethyl acetate for methyl 2-methoxyacetate and 2-(methylthio)acetonitrile for acetonitrile in Step A, to give the product as a brown oil. MS (apci) m/z = 220.1 (M+H).
中间体159Intermediate 159
2-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)-2,2-二氟乙醇2-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2,2-difluoroethanol
根据对于中间体P111所述的方法，用丙腈替代乙腈并且用2,2-二氟-3-羟基丙酸乙酯替代3-羟基-2,2-二甲基丙酸甲酯来制备，得到呈浅黄色固体状的产物。MS(apci)m/z＝254.1(M+H)。Prepared according to the procedure described for intermediate P111, substituting propionitrile for acetonitrile and ethyl 2,2-difluoro-3-hydroxypropionate for methyl 3-hydroxy-2,2-dimethylpropionate, to afford the product as a pale yellow solid.MS (apci) m/z=254.1 (M+H).
中间体160Intermediate 160
2-(5-氨基-1-苯基-1H-吡唑-3-基)-2,2-二氟乙醇2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2,2-difluoroethanol
根据对于中间体P111所述的方法，用2,2-二氟-3-羟基丙酸乙酯替代3-羟基-2,2-二甲基丙酸甲酯来制备，得到呈浅黄色固体状的产物。MS(apci)m/z＝240.0(M+H)。Prepared according to the method described for intermediate P111, substituting ethyl 2,2-difluoro-3-hydroxypropionate for methyl 3-hydroxy-2,2-dimethylpropionate, to afford the product as a light yellow solid. MS (apci) m/z = 240.0 (M+H).
中间体161Intermediate 161
2-(5-氨基-1-苯基-1H-吡唑-3-基)乙醇2-(5-amino-1-phenyl-1H-pyrazol-3-yl)ethanol
根据中间体P111中所述的方法，在步骤A中用3-羟基丙酸甲酯替代3-羟基-2,2-二甲基丙酸甲酯来制备。MS(apci)m/z＝204.1(M+H)。Prepared according to the method described in Intermediate P111, substituting methyl 3-hydroxypropionate for methyl 3-hydroxy-2,2-dimethylpropionate in Step A. MS (apci) m/z = 204.1 (M+H).
中间体162Intermediate 162
1-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)-2-甲基丙-2-醇1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-2-ol
步骤A：制备3-羟基-3-甲基丁酸乙酯：向处于N2下并且冷却至-78℃的双(三甲基硅烷基)氨化锂(1M THF溶液)(100mL，100mmol)在THF(100mL)中的溶液中添加乙酸乙酯(9.74mL，100mmol)。搅拌反应混合物30分钟，并且然后添加丙酮(8.81mL，120mmol)。搅拌反应混合物10分钟，并且然后用HCl(2M水溶液，70mL，140mmol)淬灭并且允许其升温至环境温度。用EtOAc(2×150mL)萃取反应混合物。合并有机相并且用饱和NaHCO3水溶液(2×50mL)洗涤，干燥(MgSO4)，过滤并且浓缩，得到呈黄色油状的产物(12.8g，88％产率)。1H NMR(CDCl3)δ4.18(q,3H),2.49(s,2H),1.29(m,9H)。Step A:Preparation of ethyl 3-hydroxy-3-methylbutanoate : To a solution of lithium bis(trimethylsilyl)amide (1M THF solution) (100 mL, 100 mmol) in THF (100 mL) under N2 and cooled to -78°C, ethyl acetate (9.74 mL, 100 mmol) was added. The reaction mixture was stirred for 30 minutes, and then acetone (8.81 mL, 120 mmol) was added. The reaction mixture was stirred for 10 minutes, and then quenched with HCl (2M aqueous solution, 70 mL, 140 mmol) and allowed to warm to ambient temperature. The reaction mixture was extracted with EtOAc (2 × 150 mL). The organic phases were combined and washed with saturated NaHCO3 aqueous solution (2 × 50 mL), dried (MgSO4 ), filtered and concentrated to give the product (12.8 g, 88% yield) as a yellow oil.1 H NMR (CDCl3 ) δ 4.18 (q, 3H), 2.49 (s, 2H), 1.29 (m, 9H).
步骤B：制备5-羟基-5-甲基-3-氧代己腈：在N2、-78℃下向丙腈(1.77mL，30.5mmol)在THF(100mL)中的溶液中添加双(三甲基硅烷基)氨化锂(1M THF溶液)(27.9mL，27.9mmol)。搅拌1小时，然后添加3-羟基-3-甲基丁酸乙酯(1.86g，12.7mmol)。在-78℃下搅拌反应混合物1小时，然后在0℃下搅拌1.5小时，然后用H2O(100mL)稀释并且用Et2O(50mL)萃取。分离各相并且用HCl(6M水溶液，4.5mL)中和碱性水相，然后用Et2O(3×75mL)萃取。用盐水(75mL)洗涤合并的有机相，干燥(MgSO4)，过滤并且浓缩，得到呈浅黄色油状的产物(1.24g，63％产率)。1H NMR(CDCl3)δ3.54(m,1H),2.89(s,2H),1.50(d,3H),1.32(s,3H),1.31(s,3H)。[0146] Step B: Preparation of 5-hydroxy-5-methyl-3-oxohexanenitrile : To a solution of propionitrile (1.77 mL, 30.5 mmol) in THF (100 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF) (27.9 mL, 27.9 mmol) at -78°C under N2. Stir for 1 hour, then add ethyl 3-hydroxy-3-methylbutanoate (1.86 g, 12.7 mmol). The reaction mixture was stirred at -78°C for 1 hour, then at 0°C for 1.5 hours, then diluted withH2O (100 mL) and extracted withEt2O (50 mL). The phases were separated and the basic aqueous phase was neutralized with HCl (6 M aqueous solution, 4.5 mL), then extracted withEt2O (3 x 75 mL). The combined organic phases were washed with brine (75 mL), dried (MgSO4 ), filtered and concentrated to give the product as a pale yellow oil (1.24 g, 63% yield).1 H NMR (CDCl3 ) δ 3.54 (m, 1H), 2.89 (s, 2H), 1.50 (d, 3H), 1.32 (s, 3H), 1.31 (s, 3H).
步骤C：制备1-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)-2-甲基丙-2-醇：向苯肼(0.793mL，7.99mmol)和HCl(5M至6M iPrOH溶液，1.60mL，7.99mmol)在EtOH(25mL)中的悬浮液中添加5-羟基-2,5-二甲基-3-氧代己腈(1.24g，7.99mmol)在EtOH(25mL)中的溶液。使反应混合物回流17小时，然后冷却至环境温度，用饱和NaHCO3水溶液(10mL)稀释，用10:90MeOH/DCM(3×25mL)萃取，并且干燥(MgSO4)合并的有机相，过滤并且浓缩。通过二氧化硅柱色谱法，用0％至75％丙酮/己烷洗脱来纯化，得到呈橙色油状的标题化合物(1.13g，58％产率)。MS(apci)m/z＝246.1(M+H)。Step C:Preparation of 1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-2-ol : To a suspension of phenylhydrazine (0.793 mL, 7.99 mmol) and HCl (5M to 6M solution in iPrOH, 1.60 mL, 7.99 mmol) in EtOH (25 mL) was added a solution of 5-hydroxy-2,5-dimethyl-3-oxohexanenitrile (1.24 g, 7.99 mmol) in EtOH (25 mL). The reaction mixture was refluxed for 17 hours, then cooled to ambient temperature, diluted with saturated aqueousNaHCO3 (10 mL), extracted with 10:90 MeOH/DCM (3×25 mL), and the combined organic phases were dried (MgSO4 ), filtered, and concentrated. Purification by silica column chromatography eluting with 0% to 75% acetone/hexanes gave the title compound as an orange oil (1.13 g, 58% yield).MS (apci) m/z=246.1 (M+H).
根据用于制备中间体162(步骤B和步骤C)的方法，使用适当的起始物质制备下列吡唑中间体。为制备中间体168和中间体169，起始物质(购自Oakwood)为顺式和反式非对映异构体的混合物。The following pyrazole intermediates were prepared using the appropriate starting materials according to the procedure used to prepare Intermediate 162 (Step B and Step C). For the preparation of Intermediate 168 and Intermediate 169, the starting materials (purchased from Oakwood) were a mixture of cis and trans diastereomers.
中间体170Intermediate 170
5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酸乙酯5-Amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester
根据对于中间体P109所述的方法，在步骤A中用草酸二乙酯替代2-甲氧基乙酸甲酯并且用丙腈替代乙腈来制备，得到呈黄色固体状的产物。MS(apci)m/z＝246.1(M+H)。Prepared according to the procedure described for intermediate P109, substituting diethyl oxalate for methyl 2-methoxyacetate and propionitrile for acetonitrile in step A, to give the product as a yellow solid. MS (apci) m/z = 246.1 (M+H).
中间体171Intermediate 171
5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酸5-Amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid
向5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酸乙酯(中间体170，1.52mg，6.21mmol)在THF(12mL)和MeOH(6mL)中的溶液中添加LiOH(2M水溶液，9.31mL，18.6mmol)。在环境温度下搅拌反应混合物19小时，然后在减压下部分浓缩，然后用6M HCl(3.2mL)中和，用10:90MeOH/DCM(3×25mL)萃取，并且用盐水(50mL)洗涤合并的有机萃取物，干燥(MgSO4)，过滤并且浓缩，得到呈黄色固体状的标题化合物(1.3g，96％产率)。MS(apci)m/z＝218.1(M+H)。To a solution of ethyl 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170, 1.52 mg, 6.21 mmol) in THF (12 mL) and MeOH (6 mL) was added LiOH (2 M aqueous solution, 9.31 mL, 18.6 mmol). The reaction mixture was stirred at ambient temperature for 19 hours, then partially concentrated under reduced pressure, then neutralized with 6 M HCl (3.2 mL), extracted with 10:90 MeOH/DCM (3×25 mL), and the combined organic extracts washed with brine (50 mL), dried (MgSO4 ), filtered, and concentrated to afford the title compound as a yellow solid (1.3 g, 96% yield). MS (apci) m/z=218.1 (M+H).
中间体172Intermediate 172
5-氨基-N,4-二甲基-1-苯基-1H-吡唑-3-甲酰胺5-Amino-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide
向5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酸(中间体171，223mg，1.02mmol)在乙腈(10mL)中的溶液中添加DIEA(0.71mL，4.10mmol)、甲胺盐酸盐(138mg，2.05mmol)、DMF(2mL)并且然后添加HATU(428mg，1.13mmol)。在环境温度下搅拌反应混合物19小时并且然后在减压下部分浓缩。通过反相柱色谱法，用5％至60％乙腈/水洗脱来纯化混合物，得到呈浅黄色固体状的标题化合物(182mg，77％产率)。MS(apci)m/z＝231.1(M+H)。To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (Intermediate 171, 223 mg, 1.02 mmol) in acetonitrile (10 mL) was added DIEA (0.71 mL, 4.10 mmol), methylamine hydrochloride (138 mg, 2.05 mmol), DMF (2 mL) and then HATU (428 mg, 1.13 mmol). The reaction mixture was stirred at ambient temperature for 19 hours and then partially concentrated under reduced pressure. The mixture was purified by reverse phase column chromatography eluting with 5% to 60% acetonitrile/water to give the title compound (182 mg, 77% yield) as a light yellow solid. MS (apci) m/z=231.1 (M+H).
中间体173Intermediate 173
5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酰胺5-Amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide
在环境温度下搅拌5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲腈(150mg，0.757mmol)在浓H2SO4(0.5mL)中的溶液17小时。冷却反应混合物并且通过添加NaOH水溶液(2M，11mL)中和，然后用10％MeOH/DCM(5×10mL)萃取，并且用盐水洗涤合并的有机萃取物，干燥(MgSO4)，过滤并且在减压下浓缩，得到呈白色固体状的标题化合物(151mg，95％产率)。MS(apci)m/z＝239.1(M+Na)。A solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbonitrile (150 mg, 0.757 mmol) in concentrated H2 SO4 (0.5 mL) was stirred at ambient temperature for 17 hours. The reaction mixture was cooled and neutralized by the addition of aqueous NaOH (2 M, 11 mL), then extracted with 10% MeOH/DCM (5×10 mL), and the combined organic extracts were washed with brine, dried (MgSO4 ), filtered, and concentrated under reduced pressure to afford the title compound (151 mg, 95% yield) as a white solid. MS (apci) m/z=239.1 (M+Na).
中间体174Intermediate 174
5-氨基-3-乙氧基-1-苯基-1H-吡唑-4-甲酸乙酯5-Amino-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester
步骤A：制备2-氰基丙二酸二乙酯：在N2、0℃下向NaH(在矿物油中60wt％，499mg，12.49mmol)在THF(100mL)中的悬浮液中添加丙二酸二乙酯(1.90mL，12.49mmol)。去除冰浴并且在环境温度下搅拌反应混合物30分钟，然后冷却至0℃并且添加溴化氰(5M MeCN溶液，2.5mL，12.49mmol)。在环境温度下搅拌反应混合物19小时，然后用H2O(50mL)稀释，用Et2O(50mL)萃取。用HCl(2M水溶液，3mL)中和水相，然后用DCM(2×50mL)萃取。干燥(MgSO4)合并的DCM萃取物，过滤并且浓缩，得到呈黄色油状的产物(837mg，36％产率)。1H NMR(CDCl3)δ4.46(s,1H),4.35(q,4H),1.35(t,6H)。Step A:Preparation of diethyl 2-cyanomalonate : To a suspension of NaH (60 wt %, 499 mg, 12.49 mmol in mineral oil) in THF (100 mL) under N at0 °C was added diethyl malonate (1.90 mL, 12.49 mmol). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 30 minutes, then cooled to 0°C and cyanogen bromide (5M solution in MeCN, 2.5 mL, 12.49 mmol) was added. The reaction mixture was stirred at ambient temperature for 19 hours, then diluted withH₂O (50 mL) and extracted withEt₂O (50 mL). The aqueous phase was neutralized with HCl (2M aqueous solution, 3 mL) and then extracted with DCM (2×50 mL). The combined DCM extracts were dried (MgSO₄ ), filtered, and concentrated to give the product (837 mg, 36% yield) as a yellow oil. 1H NMR (CDCl3 ) δ 4.46 (s, 1H), 4.35 (q, 4H), 1.35 (t, 6H).
步骤B：制备5-氨基-3-乙氧基-1-苯基-1H-吡唑-4-甲酸乙酯：根据对于中间体P135所述的方法，在步骤A中用2-氰基丙二酸二乙酯替代2-氰基丙酸乙酯来制备，得到呈棕色糖浆状的产物(400mg，32％产率)。MS(apci)m/z＝276.1(M+H)。Step B:Preparation of ethyl 5-amino-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate : Prepared according to the procedure described for intermediate P135, substituting diethyl 2-cyanomalonate for ethyl 2-cyanopropionate in Step A to give the product as a brown syrup (400 mg, 32% yield). MS (apci) m/z = 276.1 (M+H).
中间体175Intermediate 175
4-甲基-3-(5-甲基-1,3,4-噁二唑-2-基)-1-苯基-1H-吡唑-5-胺4-Methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-amine
步骤A：制备N'-乙酰基-5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酰肼：向5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酸(中间体171，93mg，0.428mmol)在DCM(5mL)和DIEA(0.149mL，0.856mmol)中的溶液中添加氯甲酸异丁酯(0.061mL，0.471mmol)。在环境温度下搅拌反应混合物1小时，然后添加乙酰肼(48mg，0.642mmol)。在环境温度下搅拌反应混合物18小时，然后用H2O(10mL)稀释，用DCM(2×10mL)萃取，干燥(MgSO4)，过滤并且在减压下浓缩，得到呈浅黄色固体状的产物(119mg，101％产率)。MS(apci)m/z＝274.1(M+H)。[0266] Step A:Preparation of N'-acetyl-5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid hydrazide: To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (Intermediate 171, 93 mg, 0.428 mmol) in DCM (5 mL) and DIEA (0.149 mL, 0.856 mmol) was added isobutyl chloroformate (0.061 mL, 0.471 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then acetohydrazide (48 mg, 0.642 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours, then diluted withH2O (10 mL), extracted with DCM (2 x 10 mL), dried (MgSO4 ), filtered, and concentrated under reduced pressure to give the product as a light yellow solid (119 mg, 101% yield). MS (apci) m/z = 274.1 (M+H).
步骤B：制备4-甲基-3-(5-甲基-1,3,4-噁二唑-2-基)-1-苯基-1H-吡唑-5-胺：在压力管中把N'-乙酰基-5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酰肼(117mg，0.428mmol)和POCl3(0.5mL)的混合物加热至90℃，持续1小时。用EtOAc(5mL)把反应混合物转移至分液漏斗中，然后用饱和NaHCO3水溶液(20mL)稀释，用EtOAc(2×15mL)萃取，干燥(MgSO4)，过滤并且浓缩。通过二氧化硅柱色谱法，用0％至75％丙酮/己烷洗脱来纯化残余物，得到呈黄色固体状的标题化合物(19.6mg，18％产率)。MS(apci)m/z＝256.1(M+H)。[0146] Step B:Preparation of 4-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-amine : A mixture of N'-acetyl-5-amino-4-methyl-1-phenyl-1H -pyrazole-3 -carboxylic acid hydrazide (117 mg, 0.428 mmol) and POCl3 (0.5 mL) was heated to 90°C in a pressure tube for 1 hour. The reaction mixture was transferred to a separatory funnel with EtOAc (5 mL), then diluted with saturated aqueous NaHCO3 (20 mL), extracted with EtOAc (2 x 15 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica column chromatography eluting with 0% to 75% acetone/hexanes to give the title compound (19.6 mg, 18% yield) as a yellow solid. MS (apci) m/z = 256.1 (M+H).
中间体176Intermediate 176
4-甲基-3-(3-甲基-1,2,4-噁二唑-5-基)-1-苯基-1H-吡唑-5-胺4-Methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-amine
在N2下向NaH(在矿物油中60％，36mg，0.897mmol)在THF(5mL)中的悬浮液中添加N-羟基乙脒(66mg，0.897mmol)。把反应混合物加热至回流，持续1小时，然后冷却至环境温度并且添加5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酸乙酯(中间体170，200mg，0.815mmol)。把反应混合物加热至回流，持续18小时，然后冷却至环境温度并且再添加NaH(在矿物油中60％，18mg，0.449mmol)。把反应混合物加热至回流，持续4小时，然后用H2O(10mL)稀释，用DCM(2×15mL)萃取，并且干燥(MgSO4)合并的有机萃取物，过滤并且在减压下浓缩。通过二氧化硅柱色谱法，用0％至50％丙酮/己烷洗脱来纯化残余物，得到呈橙色固体状的标题化合物(84mg，40％产率)。MS(apci)m/z＝256.1(M+H)。To a suspension of NaH (60% in mineral oil, 36 mg, 0.897 mmol) in THF (5 mL) underN2 was added N-hydroxyacetamidine (66 mg, 0.897 mmol). The reaction mixture was heated to reflux for 1 hour, then cooled to ambient temperature and ethyl 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170, 200 mg, 0.815 mmol) was added. The reaction mixture was heated to reflux for 18 hours, then cooled to ambient temperature and more NaH (60% in mineral oil, 18 mg, 0.449 mmol) was added. The reaction mixture was heated to reflux for 4 hours, then diluted withH2O (10 mL), extracted with DCM (2 x 15 mL), and the combined organic extracts were dried (MgSO4 ), filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 0% to 50% acetone/hexanes to give the title compound as an orange solid (84 mg, 40% yield).MS (apci) m/z=256.1 (M+H).
中间体177Intermediate 177
3-(3-甲基-1,2,4-噁二唑-5-基)-1-苯基-1H-吡唑-5-胺3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-amine
根据中间体176中所述的方法，用5-氨基-1-苯基-1H-吡唑-3-甲酸乙酯南京Chemlin化学公司)替代5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酸乙酯来制备，得到呈棕褐色固体状的产物(83mg，53％产率)。MS(apci)m/z＝242.1(M+H)。Prepared according to the method described in Intermediate 176, substituting 5-amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (Nanjing Chemlin Chemical Co., Ltd.) for 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester, to give the product as a tan solid (83 mg, 53% yield). MS (apci) m/z = 242.1 (M+H).
中间体178Intermediate 178
4-甲基-1-苯基-3-(3-(三氟甲基)-1,2,4-噁二唑-5-基)-1H-吡唑-5-胺4-Methyl-1-phenyl-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-amine
步骤A：制备2,2,2-三氟-N'-羟基乙脒：向盐酸羟胺(5.45g，78.4mmol)在MeOH(100mL)中的悬浮液中添加NaOMe(25wt％MeOH溶液，17.9mL，78.4mmol)并且在环境温度下搅拌混合物10分钟，然后过滤并且用MeOH洗涤固体。把滤液冷却至0℃并且然后使2,2,2-三氟乙腈(7.45g，78.4mmol)气体经30分钟鼓泡进入溶液中。然后允许反应混合物升温至环境温度，持续19小时。在减压下把溶液浓缩至50mL并且过滤固体。浓缩滤液，将其重新悬浮于冷MeOH中并且过滤。浓缩滤液，再次将其重新悬浮于冷MeOH中并且过滤。浓缩滤液，得到呈蜡状白色固体状的产物(6.7g，67％产率)。1H NMR(CD3CN)δ8.32(s,1H),5.25(br s,2H)。19FNMR(CD3CN)δ-71.8(s)。Step A:Preparation of 2,2,2-trifluoro-N'-hydroxyacetamidine : To a suspension of hydroxylamine hydrochloride (5.45 g, 78.4 mmol) in MeOH (100 mL) was added NaOMe (25 wt% MeOH solution, 17.9 mL, 78.4 mmol) and the mixture was stirred at ambient temperature for 10 minutes, then filtered and the solid washed with MeOH. The filtrate was cooled to 0 ° C and then 2,2,2-trifluoroacetonitrile (7.45 g, 78.4 mmol) gas was bubbled into the solution over 30 minutes. The reaction mixture was then allowed to warm to ambient temperature for 19 hours. The solution was concentrated to 50 mL under reduced pressure and the solid was filtered. The filtrate was concentrated, resuspended in cold MeOH and filtered. The filtrate was concentrated, resuspended in cold MeOH again and filtered. The filtrate was concentrated to obtain the product (6.7 g, 67% yield) as a waxy white solid.1 H NMR (CD3 CN) δ 8.32 (s, 1H), 5.25 (br s, 2H).19 FNMR (CD3 CN) δ - 71.8 (s).
步骤B：制备4-甲基-1-苯基-3-(3-(三氟甲基)-1,2,4-噁二唑-5-基)-1H-吡唑-5-胺：在N2下向NaH(在矿物油中60％，356mg，0.897mmol)在THF(5mL，0.815mmol)中的悬浮液中添加2,2,2-三氟-N'-羟基乙脒(115mg，0.897mmol)。将反应混合物加热至回流，持续1小时，然后冷却至环境温度并且添加粉末状4A分子筛(200mg)和5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酸乙酯(中间体170；200mg，0.815mmol)并且加热至回流。将反应混合物加热至回流，持续18小时，然后过滤，用H2O(15mL)稀释，用DCM(2×25mL)萃取，并且用盐水(25mL)洗涤合并的有机萃取物，干燥(MgSO4)，过滤并且在减压下浓缩。通过二氧化硅柱色谱法，用0％至50％丙酮/己烷洗脱来纯化残余物，得到呈白色固体状的标题化合物(44mg，17％产率)。MS(apci)m/z＝310.1(M+H)。Step B:Preparation of 4-methyl-1-phenyl-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-amine : To a suspension of NaH (60% in mineral oil, 356 mg, 0.897 mmol) in THF (5 mL, 0.815 mmol) underN was added 2,2,2-trifluoro-N'-hydroxyacetamidine (115 mg, 0.897 mmol). The reaction mixture was heated to reflux for 1 hour, then cooled to ambient temperature and powdered 4A molecular sieves (200 mg) and ethyl 5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 170; 200 mg, 0.815 mmol) were added and heated to reflux. The reaction mixture was heated to reflux for 18 hours, then filtered, diluted with H2 O (15 mL), extracted with DCM (2×25 mL), and the combined organic extracts washed with brine (25 mL), dried (MgSO4 ), filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with 0% to 50% acetone/hexanes to give the title compound (44 mg, 17% yield) as a white solid. MS (apci) m/z=310.1 (M+H).
中间体179Intermediate 179
2-苯基-2H-吲唑-3-胺2-Phenyl-2H-indazol-3-amine
步骤A：制备1-(2-碘苯基)-2-苯基二氮烯：向2-碘苯胺(1.00g，4.57mmol)在乙酸(46mL)中的溶液中添加亚硝基苯(0.880g，8.22mmol)并且在85℃下加热混合物16小时。将混合物冷却至环境温度，将其倒入水中并且缓慢地用饱和NaHCO3处理直到呈碱性为止。用EtOAc(3X)萃取混合物并且用水、饱和NaCl洗涤合并的萃取物并且经MgSO4干燥。过滤溶液，浓缩并且通过反相色谱法纯化残余物，得到呈红色固体状的标题化合物(0.880g，63％产率)。1H NMR(CDCl3)δ7.23-7.39(m,3H),7.64(d,1H),7.56-7.51(m,3H),7.45(t,1H),7.1(t,1H)。Step A:Preparation of 1-(2-iodophenyl)-2-phenyldiazene : To a solution of 2-iodoaniline (1.00 g, 4.57 mmol) in acetic acid (46 mL) was added nitrosobenzene (0.880 g, 8.22 mmol) and the mixture was heated at 85° C. for 16 hours. The mixture was cooled to ambient temperature, poured into water and slowly treated with saturated NaHCO3 until basic. The mixture was extracted with EtOAc (3×) and the combined extracts were washed with water, saturated NaCl and dried over MgSO4. The solution was filtered, concentrated and the residue was purified by reverse phase chromatography to give the title compound (0.880 g, 63% yield) as a red solid.1 H NMR (CDCl3 ) δ7.23-7.39(m,3H),7.64(d,1H),7.56-7.51(m,3H),7.45(t,1H),7.1(t,1H).
步骤B：2-(苯基二氮烯基)苯甲腈：向1-(2-碘苯基)-2-苯基二氮烯(0.44g，1.4mmol)在1-丙醇(14mL)中的溶液中添加CuCN(0.900g，10.0mmol)并且在回流下加热反应物16小时。将混合物冷却至环境温度，过滤并且用CH2Cl2洗涤所收集的固体。浓缩合并的滤液和洗涤液，得到呈红橙色固体状的标题化合物，将其在真空中干燥(0.280g，95％产率)。1H NMR(CDCl3)δ8.03-8.06(m,2H),7.88(dd,2H),7.71(t,1H),7.54-7.58(m,4H)。Step B:2-(Phenyldiazenyl)benzonitrile : To a solution of 1-(2-iodophenyl)-2-phenyldiazene (0.44 g, 1.4 mmol) in 1-propanol (14 mL) was added CuCN (0.900 g, 10.0 mmol) and the reaction was heated at reflux for 16 hours. The mixture was cooled to ambient temperature, filtered, and the collected solid was washed withCH2Cl2 .The combined filtrate and washings were concentrated to give the title compound as a reddish-orange solid, which was dried in vacuo (0.280 g, 95% yield).1H NMR (CDCl3 ) δ 8.03-8.06 (m, 2H), 7.88 (dd, 2H), 7.71 (t, 1H), 7.54-7.58 (m, 4H).
步骤C：2-苯基-2H-吲唑-3-胺：在回流下加热2-(苯基二氮烯基)苯甲腈(0.28g，1.35mmol)和二水合SnCl2(0.562mL，6.76mmol)在EtOH(14mL)中的混合物16小时。将混合物冷却至环境温度并且浓缩。用EtOAc和水稀释残余物并且过滤。去除水层并且用水洗涤EtOAc层。用饱和NaHCO3碱化合并的水性部分并且用CH2Cl2(2X)萃取。经MgSO4干燥合并的有机层，过滤并且浓缩，得到呈淡紫色固体状的标题化合物，将其在真空中干燥(0.241g，85％产率)。1H NMR(CDCl3)δ7.69(d,2H),7.52-7.58(m,3H),7.47(d,2H),7.26(t,1H),6.90(t,1H),4.28(br s,2H)。Step C:2-phenyl-2H-indazole-3-amine : A mixture of 2-(phenyldiazenyl)benzonitrile (0.28 g, 1.35 mmol) andSnCl dihydrate (0.562 mL, 6.76 mmol) in EtOH (14 mL) was heated at reflux for 16 hours. The mixture was cooled to ambient temperature and concentrated. The residue was diluted with EtOAc and water and filtered. The aqueous layer was removed and the EtOAc layer was washed with water. The combined aqueous portion wasbasified with saturated NaHCO and extracted with CHCl (2X ). The combined organic layers were dried overMgSO , filtered and concentrated to give the title compound as a pale purple solid, which was dried in vacuo (0.241 g, 85% yield).1 H NMR (CDCl3 ) δ 7.69 (d, 2H), 7.52-7.58 (m, 3H), 7.47 (d, 2H), 7.26 (t, 1H), 6.90 (t, 1H), 4.28 (br s, 2H).
中间体180Intermediate 180
3-乙氧基-4-甲基-1-(吡嗪-2-基)-1H-吡唑-5-胺3-Ethoxy-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-5-amine
步骤A：5-胺基-4-甲基-1-(吡嗪-2-基)-1H-吡唑-3(2H)-酮：向2-肼基吡嗪(0.551g，5.00mmol)和2-氰基丙酸乙酯(0.669g，5.00mmol)在绝对EtOH(10mL)中的混合物中添加3M NaOEt的EtOH溶液(0.167mL，0.501mmol)并且在回流下加热混合物64小时。浓缩混合物并且用EtOAc(30mL)处理残余黄棕色固体并且进行超声。剧烈搅拌所得到的棕褐色悬浮液8小时。经由真空过滤收集固体，用EtOAc洗涤并且在真空中干燥，得到呈淡棕褐色粉末状的标题化合物(682mg，71％)。1H NMR(DMSO d6)δ10.3(br s,1H),8.82(s,1H),8.30(d,2H),6.55(s,2H),1.71(s,3H)。Step A:5-amino-4-methyl-1-(pyrazine-2-yl)-1H-pyrazole-3 (2H) -one : to a mixture of 2-hydrazinopyrazine (0.551 g, 5.00 mmol) and ethyl 2-cyanopropionate (0.669 g, 5.00 mmol) in absolute EtOH (10 mL), 3M NaOEt in EtOH solution (0.167 mL, 0.501 mmol) was added and the mixture was heated under reflux for 64 hours. The mixture was concentrated and the residual yellow-brown solid was treated with EtOAc (30 mL) and ultrasonicated. The obtained tan suspension was stirred vigorously for 8 hours. The solid was collected via vacuum filtration, washed with EtOAc and dried in vacuo to give the title compound (682 mg, 71%) as a light tan powder.1 H NMR (DMSO d6 ) δ 10.3 (br s, 1H), 8.82 (s, 1H), 8.30 (d, 2H), 6.55 (s, 2H), 1.71 (s, 3H).
步骤B：3-乙氧基-4-甲基-1-(吡嗪-2-基)-1H-吡唑-5-胺：在环境温度下搅拌5-氨基-4-甲基-1-(吡嗪-2-基)-1H-吡唑-3(2H)-酮(382mg，2.00mmol)和粉末状K2CO3(552mg，4.00mmol)在干燥DMF(3.0mL)中的混合物10分钟。将混合物冷却至0℃并且添加溴乙烷(229mg，2.10mmol)。允许混合物达到环境温度并且搅拌24小时。将反应混合物倒入冷H2O(12mL)中，允许其达到环境温度并且用EtOAc(3X)萃取。用饱和NaCl(2X)洗涤合并的萃取物，经MgSO4和活性碳干燥。用等体积的己烷稀释干燥的溶液并且通过盖有MgSO4层的SiO2塞，用50％EtOAc-己烷洗脱来过滤。浓缩滤液并且用己烷(3X)洗涤残余黄色固体，并且在真空中干燥，得到呈淡黄色结晶固体状的标题化合物(195mg，45％)。1H NMR(CDCl3)δ9.10(s,1H),8.23(s,1H),8.14(s,1H),5.50(br s,2H),4.33(q,2H),1.80(s,3H),1.42(t,3H)。Step B:3-Ethoxy-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-5-amine : A mixture of 5-amino-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-3 (2H)-one (382 mg, 2.00 mmol) and powderedK2CO3 (552 mg, 4.00 mmol) in dry DMF (3.0 mL) was stirred at ambient temperature for 10 minutes. The mixture was cooled to 0°C and bromoethane (229 mg, 2.10 mmol) was added. The mixture was allowed to reach ambient temperature and stirred for 24 hours. The reaction mixture was poured into coldH2O (12 mL), allowed to reach ambient temperature and extracted with EtOAc (3X). The combined extracts were washed with saturated NaCl (2X), dried overMgSO4 and activated carbon. The dried solution was diluted with an equal volume of hexanes and filtered through a plug of SiO2 covered with a layer of MgSO4 , eluting with 50% EtOAc-hexanes. The filtrate was concentrated and the residual yellow solid was washed with hexanes (3×) and dried in vacuo to afford the title compound (195 mg, 45%) as a pale yellow crystalline solid.1 H NMR (CDCl3) δ 9.10 (s, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 5.50 (br s, 2H), 4.33 (q, 2H), 1.80 (s, 3H), 1.42 (t, 3H).
中间体181Intermediate 181
2-(哒嗪-4-基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺2-(Pyridazin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine
用2-氧代环戊烷甲腈(0.191g，1.75mmol)处理4-肼基哒嗪氢溴酸盐(0.368g，1.93mmol)在绝对EtOH(5mL)中的悬浮液并且在回流下加热混合物22小时。将混合物冷却至环境温度并且浓缩成橙色固体。将固体悬浮于1M NaOH中并且搅拌10分钟。收集固体，用H2O和Et2O充分洗涤并且在真空中干燥，得到呈棕褐色粉末状的标题化合物(.323g，92％)。MS(apci)m/z＝202.1(M+H)。A suspension of 4-hydrazinopyridazine hydrobromide (0.368 g, 1.93 mmol) in absolute EtOH (5 mL) was treated with 2-oxocyclopentanecarbonitrile (0.191 g, 1.75 mmol) and the mixture was heated at reflux for 22 hours. The mixture was cooled to ambient temperature and concentrated to an orange solid. The solid was suspended in 1 M NaOH and stirred for 10 minutes. The solid was collected, washed thoroughly withH₂O andEt₂O , and dried in vacuo to give the title compound (0.323 g, 92%) as a tan powder. MS (apci) m/z = 202.1 (M+H).
中间体182Intermediate 182
(5-氨基-1-苯基-1H-吡唑-3-基)甲醇(5-Amino-1-phenyl-1H-pyrazol-3-yl)methanol
步骤A：2-(叔丁基二甲基硅烷氧基)乙酸乙酯：在环境温度下搅拌2-羟基乙酸乙酯(3.00g，28.8mmol)、TBDMS-Cl(5.21g，34.6mmol)和咪唑(2.55g，37.5mmol)的混合物60小时。浓缩混合物并且通过SiO2色谱法用10％EtOAc-己烷洗脱来纯化残余物，得到呈无色油状的标题化合物(4.12g，65％)。1H NMR(CDCl3)δ4.12(s,2H),4.09(q,2H),1.17(t,3H),0.18(s,9H),0.00(s,6H)。[0146] Step A:Ethyl 2-(tert-butyldimethylsilyloxy)acetate : A mixture of ethyl 2-hydroxyacetate (3.00 g, 28.8 mmol), TBDMS-Cl (5.21 g, 34.6 mmol), and imidazole (2.55 g, 37.5 mmol) was stirred at ambient temperature for 60 h. The mixture was concentrated and the residue was purified bySiO2 chromatography eluting with 10% EtOAc-hexanes to give the title compound as a colorless oil (4.12 g, 65%).1H NMR (CDCl3 ) δ 4.12 (s, 2H), 4.09 (q, 2H), 1.17 (t, 3H), 0.18 (s, 9H), 0.00 (s, 6H).
步骤B：(5-氨基-1-苯基-1H-吡唑-3-基)甲醇：将乙腈(0.526mL，10.1mmol)在干燥THF(20.4mL，9.16mmol)中的溶液冷却至-78℃并且逐滴添加2.5M nBuLi的己烷溶液(4.21mL，10.5mmol)。搅拌反应混合物15分钟并且添加2-(叔丁基二甲基硅烷氧基)乙酸乙酯(2.00g，9.16mmol)。允许反应混合物升温至环境温度并且搅拌2小时。用冰水稀释反应混合物并且浓缩。将残余水性混合物酸化至pH＝5并且用EtOAc(3X)萃取。用盐水洗涤合并的有机物，经MgSO4干燥，过滤并且浓缩。把残余棕色油状物溶解于MeOH(23mL)中并且添加苯肼(0.907mL，9.14mmol)。用浓HCl(3.81mL，45.7mmol)处理混合物并且在回流下加热18小时。冷却后，浓缩混合物并且将残余物分配于H2O与CH2Cl2中。过滤混合物并且把有机层从滤液中去除。用CH2Cl2洗涤水性部分并且用饱和NaHCO3处理直到呈碱性为止。用CH2Cl2(3X)萃取水性混合物并且经MgSO4干燥合并的有机部分，过滤并且浓缩。通过二氧化硅柱色谱法使用70％至100％EtOAc/己烷梯度洗脱，接着使用0％至5％MeOH/EtOAc洗脱来纯化残余物。合并产物汇集物并且浓缩，得到呈黄色泡沫状的标题化合物(0.760g，44％产率)。MS(apci)m/z＝190.1(M+H)。Step B:(5-Amino-1-phenyl-1H-pyrazol-3-yl)methanol : A solution of acetonitrile (0.526 mL, 10.1 mmol) in dry THF (20.4 mL, 9.16 mmol) was cooled to -78°C and a 2.5 M solution of nBuLi in hexanes (4.21 mL, 10.5 mmol) was added dropwise. The reaction mixture was stirred for 15 minutes and ethyl 2-(tert-butyldimethylsilyloxy)acetate (2.00 g, 9.16 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was diluted with ice water and concentrated. The residual aqueous mixture was acidified to pH = 5 and extracted with EtOAc (3X). The combined organics were washed with brine, dried overMgSO4 , filtered and concentrated. The residual brown oil was dissolved in MeOH (23 mL) and phenylhydrazine (0.907 mL, 9.14 mmol) was added. The mixture was treated with concentrated HCl (3.81 mL, 45.7 mmol) and heated at reflux for 18 hours. After cooling, the mixture was concentrated and the residue was partitioned betweenH₂OandCH₂Cl₂ . The mixture was filteredand the organic layer was removed from the filtrate. The aqueous portion was washed withCH₂Cl₂ and treated with saturatedNaHCO₃ until basic. The aqueous mixture was extracted withCH₂Cl₂ (3X) andthe combined organic portions were dried overMgSO₄ , filtered, and concentrated. The residue was purified by silica column chromatography using a 70% to 100% EtOAc/hexane gradient followed by a 0% to 5% MeOH/EtOAc eluent. The product pools were combined and concentrated to give the title compound (0.760 g, 44% yield) as a yellow foam. MS (apci) m/z = 190.1 (M+H).
中间体183Intermediate 183
4-甲基-3-((1-甲基-1H-1,2,4-三唑-3-基)甲氧基)-1-苯基-1H-吡唑-5-胺4-Methyl-3-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)-1-phenyl-1H-pyrazol-5-amine
通过如对于中间体P135所述的方法，用3-(氯甲基)-1-甲基-1H-1,2,4-三唑盐酸盐替代溴乙烷来制备标题化合物。分离呈金色糖浆状的产物(110mg，27％)。MS(apci)m/z＝285.1(M+H)。The title compound was prepared by the method described for intermediate P135, substituting 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride for bromoethane. The product was isolated as a golden syrup (110 mg, 27%). MS (apci) m/z = 285.1 (M+H).
中间体184Intermediate 184
5-氨基-4-甲基-1-苯基-1H-吡唑-3-基二甲基氨基甲酸酯5-Amino-4-methyl-1-phenyl-1H-pyrazol-3-yldimethylcarbamate
在环境温度下搅拌5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮(中间体P135步骤A，0.378g，2.00mmol)和粉末状K2CO3(0.553g，4.00mmol)在干燥DMF(4mL)中的混合物5分钟。添加二甲基氨基甲酰氯(0.206mL，2.20mmol)并且搅拌混合物6小时。将混合物倒入冷却的H2O(40mL)中并且用EtOAc(3X)萃取。用饱和NaCl(2X)洗涤合并的萃取物，经MgSO4干燥并且通过盖有MgSO4层的SiO2塞(EtOAc洗脱)过滤。浓缩滤液并且在真空中干燥残余物，得到呈淡金色糖浆状的标题化合物(.507g，97％)。MS(apci)m/z＝261.1(M+H)。A mixture of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate P135, Step A, 0.378 g, 2.00 mmol) and powderedK2CO3( 0.553 g, 4.00 mmol) in dry DMF (4 mL) was stirred at ambient temperature for 5 minutes. Dimethylcarbamoyl chloride (0.206 mL, 2.20 mmol) was added and the mixture was stirred for 6 hours. The mixture was poured into cooledH2O (40 mL) and extracted with EtOAc (3X). The combined extracts were washed with saturated NaCl (2X), dried overMgSO4 and filtered through a plugof SiO2 covered witha layer of MgSO4 (EtOAc elution). The filtrate was concentrated and the residue was dried in vacuo to give the title compound (0.507 g, 97%) as a light golden syrup. MS (apci) m/z = 261.1 (M+H).
中间体185Intermediate 185
5-氨基-4-甲基-1-苯基-1H-吡唑-3-基吗啉-4-甲酸酯5-Amino-4-methyl-1-phenyl-1H-pyrazol-3-ylmorpholine-4-carboxylate
在对于5-氨基-4-甲基-1-苯基-1H-吡唑-3-基二甲基氨基甲酸酯(中间体184)所述的程序中使用吗啉-4-羰基氯来制备标题化合物。分离呈淡黄色蜡状的化合物(0.285g，47％)。1H NMR(CDCl3)δ7.54(d,2H),7.43(t,2H),7.31(t,1H),3.66-3.78(m,8H),3.57(brs,2H),1.85(s,3H)。The title compound was prepared using morpholine-4-carbonyl chloride according to the procedure described for 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yldimethylcarbamate (Intermediate 184). The compound was isolated as a pale yellow wax (0.285 g, 47%).1 H NMR (CDCl3 ) δ 7.54 (d, 2H), 7.43 (t, 2H), 7.31 (t, 1H), 3.66-3.78 (m, 8H), 3.57 (brs, 2H), 1.85 (s, 3H).
中间体186Intermediate 186
(S)-3-(2-((叔丁基二甲基硅烷基)氧基)-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-(S)-3-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-吡唑-5-胺Pyrazole-5-amine
步骤A：(S)-1-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基氧基)-3-甲氧基丙-2-醇：在环境温度下搅拌5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮(P135步骤A，1.21g，6.40mmol)和粉末状K2CO3(1.77g，12.8mmol)在干燥DMF(12mL)中的混合物10分钟。添加(S)-2-(甲氧基甲基)环氧乙烷(0.622mL，6.72mmol)并且在80℃下搅拌混合物6小时。将混合物冷却至环境温度，将其倒入冷却的H2O(25mL)中并且用EtOAc(3X)萃取。用饱和NaCl(2X)洗涤合并的萃取物，经MgSO4干燥并且通过盖有MgSO4层的SiO2塞，用EtOAc洗脱来过滤。浓缩滤液，得到呈无色粘性油状的标题化合物(701mg，40％)。MS(apci)m/z＝278.1(M+H)。[0266] Step A:(S)-1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)-3-methoxypropan-2- ol: A mixture of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (P135, Step A, 1.21 g, 6.40 mmol) and powderedK2CO3 (1.77g , 12.8 mmol) in dry DMF (12 mL) was stirred at ambient temperature for 10 minutes. (S)-2-(Methoxymethyl)oxirane (0.622 mL, 6.72 mmol) was added and the mixture was stirred at 80°C for 6 hours. The mixture was cooled to ambient temperature, poured into cooledH2O (25 mL) and extracted with EtOAc (3X). The combined extracts were washed with saturated NaCl (2X), dried overMgSO4 and filtered through aSiO2 plug capped with aMgSO4 layer, eluting with EtOAc. The filtrate was concentrated to give the title compound (701 mg, 40%) as a colorless viscous oil. MS (apci) m/z = 278.1 (M+H).
步骤B：(S)-3-(2-((叔丁基二甲基硅烷基)氧基)-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-胺：向TBDMS-Cl(725mg，4.81mmol)和咪唑(390mg，5.72mmol)在干燥DMF(7.0mL)中的溶液中添加在干燥DMF(2mL)中的(S)-1-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基氧基)-3-甲氧基丙-2-醇(635mg，2.29mmol)。在环境温度下搅拌混合物2.5小时。将混合物添加至H2O(70mL)中，混合5分钟并且用Et2O(3X)萃取。用饱和NaCl(2X)洗涤合并的萃取物，并且经MgSO4干燥。通过盖有MgSO4层的SiO2塞(Et2O洗脱)过滤干燥的溶液。浓缩滤液，得到呈无色油状的标题化合物，将其在真空中干燥(940mg，105％)。MS(apci)m/z＝392.2(M+H)。1H NMR(CDCl3)δ7.50(d,2H),7.40(t,2H),7.23(t,1H),4.09-4.30(m,3H),3.57(br s,2H),3.38-3.44(m,2H),3.32(s,3H),1.83(s,3H),0.88(s,9H),0.11(s,6H)。[0266] Step B:(S)-3-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl -1H-pyrazol-5-amine: To a solution of TBDMS-Cl (725 mg, 4.81 mmol) and imidazole (390 mg, 5.72 mmol) in dry DMF (7.0 mL) was added (S)-1-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)-3-methoxypropan-2-ol (635 mg, 2.29 mmol) in dry DMF (2 mL). The mixture was stirred at ambient temperature for 2.5 hours. The mixture was added toH2O (70 mL), mixed for 5 minutes and extracted withEt2O (3X). The combined extracts were washed with saturated NaCl (2X) and dried overMgSO4 . The dried solution was filtered through a plug of SiO2 capped with a layer of MgSO4 (Et2 O elution). The filtrate was concentrated to give the title compound as a colorless oil, which was dried in vacuo (940 mg, 105%). MS (apci) m/z = 392.2 (M+H).1 H NMR (CDCl3 ) δ 7.50 (d, 2H), 7.40 (t, 2H), 7.23 (t, 1H), 4.09-4.30 (m, 3H), 3.57 (br s, 2H), 3.38-3.44 (m, 2H), 3.32 (s, 3H), 1.83 (s, 3H), 0.88 (s, 9H), 0.11 (s, 6H).
中间体187Intermediate 187
(R)-3-(2-((叔丁基二甲基硅烷基)氧基)-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-(R)-3-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-吡唑-5-胺Pyrazole-5-amine
使用对于(S)-3-(2-((叔丁基二甲基硅烷基)氧基)-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-胺(中间体186)所述的程序，在步骤A中用(R)-2-(甲氧基甲基)环氧乙烷替代(S)-2-(甲氧基甲基)环氧乙烷来制备标题化合物。得到呈无色糖浆状的产物(921mg，38％(经过2个步骤))。MS(apci)m/z＝392.2(M+H)。1H NMR(CDCl3)δ7.50(d,2H),7.40(t,2H),7.23(t,1H),4.09-4.30(m,3H),3.57(br s,2H),3.38-3.44(m,2H),3.32(s,3H),1.83(s,3H),0.88(s,9H),0.11(s,6H)。The title compound was prepared using the procedure described for (S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine (Intermediate 186), substituting (R)-2-(methoxymethyl)oxirane for (S)-2-(methoxymethyl)oxirane in step A. The product was obtained as a colorless syrup (921 mg, 38% over 2 steps). MS (apci) m/z = 392.2 (M+H).1 H NMR(CDCl3 )δ7.50(d,2H),7.40(t,2H),7.23(t,1H),4.09-4.30(m,3H),3.57(br s,2H),3.38-3.44(m,2H),3.32(s,3H),1.83(s,3H),0.88(s,9H),0.11(s,6H).
中间体188Intermediate 188
4-((5-氨基-1-苯基-1H-吡唑-3-基)甲氧基)哌啶-1-甲酸叔丁酯tert-Butyl 4-((5-amino-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate
步骤A：4-(2-乙氧基-2-氧代乙氧基)哌啶-1-甲酸叔丁酯：将4-羟基哌啶-1-甲酸叔丁酯(2.00g，9.94mmol)在干燥THF(25mL)中的溶液冷却至0℃并且添加KOtBu(1.12g，9.94mmol)。允许混合物达到环境温度并且搅拌10分钟。将混合物冷却至0℃并且逐滴添加2-溴乙酸乙酯(1.65mL，14.9mmol)。允许反应物达到环境温度并且搅拌17小时。将混合物分配于H2O与EtOAc中，混合并且去除有机层。经MgSO4干燥有机层，过滤并且浓缩。通过二氧化硅色谱法，使用10％至25％EtOAc/己烷梯度洗脱来纯化残余稠厚的黄色油状物，得到呈无色油状的标题化合物(0.967g，34％产率)。1H NMR(CDCl3)δ4.22(q,2H),4.12(s,2H),3.67-3.84(m,2H),3.52-3.63(m,1H),3.05-3.11(m,2H),1.81-1.90(m,2H),1.53-1.62(m,2H),1.45(s,9H),1.29(t,3H)。Step A:tert-Butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate : A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.94 mmol) in dry THF (25 mL) was cooled to 0 ° C and KOtBu (1.12 g, 9.94 mmol) was added. The mixture was allowed to reach ambient temperature and stirred for 10 minutes. The mixture was cooled to 0 ° C and ethyl 2-bromoacetate (1.65 mL, 14.9 mmol) was added dropwise. The reactants were allowed to reach ambient temperature and stirred for 17 hours. The mixture was partitioned between H2 O and EtOAc, mixed and the organic layer was removed. The organic layer was dried over MgSO4 , filtered and concentrated. The residual thick yellow oil was purified by silica chromatography using a 10% to 25% EtOAc/hexane gradient to give the title compound (0.967 g, 34% yield) as a colorless oil.1 H NMR (CDCl3 )δ4.22(q,2H),4.12(s,2H),3.67-3.84(m,2H),3.52-3.63(m,1H),3.05-3. 11(m,2H),1.81-1.90(m,2H),1.53-1.62(m,2H),1.45(s,9H),1.29(t,3H).
步骤B：4-((5-氨基-1-苯基-1H-吡唑-3-基)甲氧基)哌啶-1-甲酸叔丁酯：将二异丙胺(1.08mL，7.74mmol)在干燥THF(5mL)中的溶液冷却至0℃并且缓慢添加2.5M nBuLi的己烷溶液(2.96mL，7.41mmol)。在0℃下搅拌混合物10分钟并且冷却至-78℃。添加乙腈(0.404mL，7.74mmol)并且搅拌混合物15分钟。添加4-(2-乙氧基-2-氧代乙氧基)哌啶-1-甲酸叔丁酯(0.967g，3.37mmol)在THF(2.5mL)中的溶液并且在-78℃下搅拌混合物1小时。允许混合物达到环境温度，用冰水淬灭并且浓缩。用2M HCl中和残余水性混合物并且用CH2Cl2(3X)萃取。经MgSO4干燥合并的有机部分，过滤并且浓缩，得到呈黄色油状的粗氰基酮，其直接用于下一步骤中。Step B:tert-Butyl 4-((5-amino-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate : A solution of diisopropylamine (1.08 mL, 7.74 mmol) in dry THF (5 mL) was cooled to 0° C. and a 2.5 M solution of nBuLi in hexanes (2.96 mL, 7.41 mmol) was slowly added. The mixture was stirred at 0° C. for 10 minutes and cooled to −78° C. Acetonitrile (0.404 mL, 7.74 mmol) was added and the mixture was stirred for 15 minutes. A solution of tert-butyl 4-(2-ethoxy-2-oxoethoxy)piperidine-1-carboxylate (0.967 g, 3.37 mmol) in THF (2.5 mL) was added and the mixture was stirred at −78° C. for 1 hour. The mixture was allowed to reach ambient temperature, quenched with ice-water and concentrated. The residual aqueous mixture was neutralized with 2 M HCl and extracted with CH2 Cl2 (3×). The combined organic fractions were dried over MgSO4 , filtered and concentrated to give the crude cyanoketone as a yellow oil which was used directly in the next step.
步骤C：4-((5-氨基-1-苯基-1H-吡唑-3-基)甲氧基)哌啶-1-甲酸叔丁酯：将在步骤B中获得的粗油状物溶解于EtOH(17mL)中并且添加苯肼(0.396mL，3.99mmol)。在60℃下加热混合物60小时，冷却至环境温度并且浓缩。将残余物分配于EtOAc与水中，混合并且去除有机层。用EtOAc(2X)萃取水层并且经MgSO4干燥合并的EtOAc部分，过滤并且浓缩。通过二氧化硅色谱法，使用10％至100％EtOAc/己烷梯度洗脱来纯化残余橙色油状物。浓缩汇集的产物部分并且通过反相HPLC使用0％至100％乙腈/水梯度再纯化残余黄橙色油状物，得到呈橙色泡沫状的标题化合物(0.264g，21％产率)。MS(apci)m/z＝373.2(M+H)。Step C:tert-Butyl 4-((5-amino-1-phenyl-1H-pyrazole-3-yl)methoxy)piperidine-1-carboxylate : The crude oil obtained in step B is dissolved in EtOH (17 mL) and phenylhydrazine (0.396 mL, 3.99 mmol) is added. The mixture is heated at 60 ° C for 60 hours, cooled to ambient temperature and concentrated. The residue is distributed in EtOAc and water, mixed and the organic layer is removed. The aqueous layer is extracted with EtOAc (2X) and the combined EtOAc portions are dried over MgSO4 , filtered and concentrated. The residual orange oil is purified by silica chromatography using a 10% to 100% EtOAc/hexane gradient elution. The product portion collected is concentrated and the residual yellow-orange oil is purified again by reversed-phase HPLC using a 0% to 100% acetonitrile/water gradient to give the title compound (0.264 g, 21% yield) as an orange foam. MS (apci) m/z = 373.2 (M+H).
中间体189Intermediate 189
1-苯基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-5-胺1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine
步骤A：3-氧代-3-(四氢-2H-吡喃-4-基)丙腈：将1M LHMDS(26.3mL，26.3mmol)在干燥THF中的溶液冷却至-78℃并且经2分钟逐滴添加乙腈(1.43mL，27.5mmol)。在-78℃下搅拌混合物1小时并且添加四氢-2H-吡喃-4-甲酸甲酯(3.41mL，25.0mmol)在干燥THF(12mL)中的溶液。搅拌混合物1小时，去除干冰浴并且允许混合物达到环境温度。将混合物倒入冷却的H2O(250mL)中并且用Et2O(3X)萃取。将水性部分冷却至0℃并且逐滴添加6M HCl至pH＝3(起始pH＝12)。用EtOAc(3X)萃取混合物并且经MgSO4干燥合并的萃取物。通过SiO2塞，用EtOAc进行洗脱来洗脱溶液。浓缩滤液，得到呈无色油状的标题化合物(2.52g，66％)。1H NMR(CDCl3)δ3.99-4.06(m,2H),3.54(s,2H),3.46(t,2H),2.76-2.86(m,1H),1.70-1.86(m,4H)。Step A:3-Oxo-3-(tetrahydro-2H-pyran-4-yl)propionitrile : A solution of 1M LHMDS (26.3 mL, 26.3 mmol) in dry THF was cooled to -78°C and acetonitrile (1.43 mL, 27.5 mmol) was added dropwise over 2 minutes. The mixture was stirred at -78°C for 1 hour and a solution of methyl tetrahydro-2H-pyran-4-carboxylate (3.41 mL, 25.0 mmol) in dry THF (12 mL) was added. The mixture was stirred for 1 hour, the dry ice bath was removed and the mixture was allowed to reach ambient temperature. The mixture was poured into cooledH2O (250 mL) and extracted withEt2O (3X). The aqueous portion was cooled to 0°C and 6M HCl was added dropwise to pH = 3 (initial pH = 12). The mixture was extracted with EtOAc (3X) and the combined extracts were dried overMgSO4 . The solution was eluted through a plug ofSiO2 with EtOAc. The filtrate was concentrated to give the title compound as a colorless oil (2.52 g, 66%).1H NMR (CDCl3 ) δ 3.99-4.06 (m, 2H), 3.54 (s, 2H), 3.46 (t, 2H), 2.76-2.86 (m, 1H), 1.70-1.86 (m, 4H).
步骤B：1-苯基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-5-胺：向3-氧代-3-(四氢-2H-吡喃-4-基)丙腈(2.30g，12.8mmol)在绝对EtOH(35mL)中的溶液中添加苯肼盐酸盐(2.21g，15.3mmol)并且在回流下加热混合物直到完成(通过TLC测定)为止(5小时)。将混合物冷却至环境温度并且浓缩。将残余物分配于H2O(75mL)与EtOAc(40mL)中。在剧烈混合下添加2MNaOH至pH＝5，去除有机层并且用EtOAc(2X)萃取水层。用H2O和饱和NaCl洗涤合并的EtOAc部分。用等体积的己烷稀释溶液，经MgSO4/活性碳干燥并且通过SiO2塞，用50％EtOAc-己烷进行洗脱来洗脱。浓缩滤液，得到金色糖浆状物。用Et2O处理糖浆状物并且搅拌直到精细颗粒悬浮液形成为止。收集固体，用Et2O洗涤并且在真空中干燥，得到呈白色固体状的标题化合物(2.01g，65％)。1H NMR(CDCl3)δ7.55(d,2H),7.46(t,2H),7.32(t,1H),5.49(s,1H),4.00-4.08(m,2H),3.97(br s,2H),3.52(dt,2H),2.86(m,1H)1.73-1.93(m,4H)。Step B:1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine : To a solution of 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propionitrile (2.30 g, 12.8 mmol) in absolute EtOH (35 mL) was added phenylhydrazine hydrochloride (2.21 g, 15.3 mmol) and the mixture was heated at reflux until complete (as determined by TLC) (5 hours). The mixture was cooled to ambient temperature and concentrated. The residue was partitioned betweenH2O (75 mL) and EtOAc (40 mL). 2M NaOH was added with vigorous mixing to pH = 5, the organic layer was removed and the aqueous layer was extracted with EtOAc (2X). The combined EtOAc fractions were washed withH2O and saturated NaCl. The solution was diluted with an equal volume of hexanes, dried over MgSO4 /activated carbon and passed through a plug of SiO2 , eluting with 50% EtOAc-hexanes. The filtrate was concentrated to give a golden syrup. The syrup was treated with Et2 O and stirred until a fine particle suspension formed. The solid was collected, washed with Et2 O and dried in vacuo to give the title compound (2.01 g, 65%) as a white solid.1 H NMR (CDCl3 ) δ 7.55 (d, 2H), 7.46 (t, 2H), 7.32 (t, 1H), 5.49 (s, 1H), 4.00-4.08 (m, 2H), 3.97 (br s, 2H), 3.52 (dt, 2H), 2.86 (m, 1H) 1.73-1.93 (m, 4H).
根据用于制备1-苯基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-5-胺(中间体189)的方法，在步骤A中使用乙腈或丙腈连同适当的酯来制备下列化合物。The following compounds were prepared according to the procedure used to prepare 1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (Intermediate 189) using acetonitrile or propionitrile together with the appropriate ester in step A.
中间体199Intermediate 199
1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯1',4-Dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamic acid phenyl ester
步骤A：1-甲基-1H-吡唑-4-甲酸乙酯：向3000-mL三颈烧瓶中添加2-甲酰基-3-氧代丙酸乙酯(100g，694mmol)，接着添加无水200标准酒精度EtOH(694mL)，得到澄清黄色溶液。将反应物在冰浴中冷却至5℃，并且然后逐滴添加甲肼(35.8mL，680mmol)。在添加肼期间观测到剧烈放热，并且通过控制添加速率保持温度低于12℃。在肼添加完成后，去除冰浴，并且在环境温度下允许反应搅拌过夜。在旋转蒸发仪上将反应物浓缩成粗橙色油状物。将粗物质溶解于DCM中并且再浓缩，然后在高真空下浓缩2天，得到棕褐橙色油状物。LC/MS和1H NMR展示基本上纯的1-甲基-1H-吡唑-4-甲酸乙酯(106g，99.1％)。Step A:1-Methyl-1H-pyrazole-4-ethyl carboxylate : In a 3000-mL three-necked flask, 2-formyl-3-oxopropionic acid ethyl ester (100g, 694mmol) was added, followed by anhydrous 200 proof alcohol EtOH (694mL) to obtain a clear yellow solution. The reactant was cooled to 5°C in an ice bath, and then methyl hydrazine (35.8mL, 680mmol) was added dropwise. A vigorous exotherm was observed during the addition of hydrazine, and the temperature was kept below 12°C by controlling the addition rate. After the hydrazine addition was complete, the ice bath was removed, and the reaction was allowed to stir overnight at ambient temperature. The reactant was concentrated into a thick orange oil on a rotary evaporator. The crude material was dissolved in DCM and reconcentrated, then concentrated under high vacuum for 2 days to obtain a brownish-orange oil. LC/MS and1H NMR showed substantially pure 1-methyl-1H-pyrazole-4-ethyl carboxylate (106g, 99.1%).
步骤B：2-甲基-3-(1-甲基-1H-吡唑-4-基)-3-氧代丙腈：向装有顶置式搅拌器和加料漏斗的四颈5升圆底烧瓶中装入LHMDS(1444mL，1444mmol)(1.0M THF溶液)。首先在氮气下在丙酮/干冰浴中冷却溶液(-79℃的内部温度)，接着经由滴液漏斗缓慢添加丙腈(103mL，1444mmol)。在-80℃下搅拌混合物90分钟。然后经由加料漏斗逐滴引入1-甲基-1H-吡唑-4-甲酸乙酯(106g，688mmol)在无水THF(500mL)中的溶液(添加时间：约45分钟；在添加期间保持内部温度低于-76℃)。添加完成后，允许反应物缓慢升温至环境温度并且搅拌过夜。橙色玻璃状物沉积在烧瓶底部。倾析有机物并且将玻璃状物溶解于温水中。用乙醚(3×1000mL)洗涤混合物。然后使用浓HCl和饱和碳酸氢钠溶液将水相的pH调节至5(pH试纸)。用DCM(3×1000mL)萃取水层。经MgSO4干燥合并的有机萃取物，过滤并且浓缩，得到呈琥珀色油状的2-甲基-3-(1-甲基-1H-吡唑-4-基)-3-氧代丙腈(92g，82％)。MS(apci)m/z＝162.1(M-H)。Step B:2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropionitrile : LHMDS (1444mL, 1444mmol) (1.0M THF solution) was charged into a four-necked 5-liter round-bottom flask equipped with an overhead stirrer and an addition funnel. The solution was first cooled in an acetone/dry ice bath under nitrogen (-79°C internal temperature), followed by the slow addition of propionitrile (103mL, 1444mmol) via a dropping funnel. The mixture was stirred at -80°C for 90 minutes. A solution of 1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (106g, 688mmol) in anhydrous THF (500mL) was then introduced dropwise via an addition funnel (addition time: approximately 45 minutes; the internal temperature was kept below -76°C during the addition). After the addition was complete, the reactants were allowed to slowly warm to ambient temperature and stirred overnight. An orange glass was deposited at the bottom of the flask. The organic matter is decanted and the glass is dissolved in warm water. The mixture is washed with ether (3×1000mL). The pH of the aqueous phase is then adjusted to 5 (pH test paper) using concentrated HCl and saturated sodium bicarbonate solution. The aqueous layer is extracted with DCM (3×1000mL). The combined organic extracts are dried over MgSO4 , filtered and concentrated to give 2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropionitrile (92g, 82%) as an amber oil. MS (apci) m/z=162.1 (MH).
步骤C：1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-胺：在环境温度下向3L 3颈圆底烧瓶中装入2-甲基-3-(1-甲基-1H-吡唑-4-基)-3-氧代丙腈(60g，368mmol)、绝对无水乙醇(1000mL)和苯肼盐酸盐(58g，404mmol)，形成黄色悬浮液。反应容器装备有水冷凝器并且回流(使用加热罩)过夜。浓缩反应物并且添加1M NaOH(1L)并且破碎固体并且收集。用水和己烷洗涤固体。第二批产物在滤液中析出并且收集。压碎合并的固体并且用乙醚(500mL)湿磨。过滤收集固体，用己烷洗涤并且在真空下空气干燥，得到1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-胺(93g，100％)。Step C:1', 4-dimethyl-1-phenyl-1H, 1'H-3, 4'-bipyrazole-5-amine : Into a 3L 3-neck round-bottom flask, 2-methyl-3-(1-methyl-1H-pyrazole-4-yl)-3-oxopropionitrile (60g, 368mmol), absolute anhydrous ethanol (1000mL) and phenylhydrazine hydrochloride (58g, 404mmol) were loaded at ambient temperature to form a yellow suspension. The reaction vessel was equipped with a water condenser and refluxed (using a heating mantle) overnight. The reaction was concentrated and 1M NaOH (1L) was added and the solid was broken and collected. The solid was washed with water and hexane. The second batch of product was separated out and collected in the filtrate. The combined solid was crushed and wet-triturated with ether (500mL). The solid was collected by filtration, washed with hexanes and air dried under vacuum to give 1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-amine (93 g, 100%).
步骤D：1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯：在3L圆底烧瓶中装入1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-胺(50g，197.4mmol)和EtOAc(1000mL)，得到澄清棕色溶液。向其中一次性添加NaOH(2M水溶液)(500mL)，得到混浊混合物(水层和有机层都澄清，但在两层之间观测到沉淀物)。3分钟后，在环境温度下(放热至33℃)缓慢添加氯甲酸苯酯(74.29mL，592.2mmol)。在环境温度下搅拌反应物2小时。再添加氯甲酸苯酯(10mL)。30分钟后，分离有机物，用盐水洗涤并且在真空中浓缩。通过硅胶色谱法(用75％乙酸乙酯的己烷溶液洗脱)纯化产物，得到1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯(60g，81.4％)。Step D:1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazole-5-ylcarbamic acid phenyl ester : In a 3L round-bottom flask, 1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazole-5-amine (50g, 197.4mmol) and EtOAc (1000mL) were charged to give a clear brown solution. NaOH (2M aqueous solution) (500mL) was added thereto in one go to give a cloudy mixture (both the aqueous and organic layers were clear, but a precipitate was observed between the two layers). After 3 minutes, phenyl chloroformate (74.29mL, 592.2mmol) was slowly added at ambient temperature (exothermic to 33°C). The reaction was stirred at ambient temperature for 2 hours. Phenyl chloroformate (10mL) was then added. After 30 minutes, the organic matter was separated, washed with brine and concentrated in vacuo. The product was purified by silica gel chromatography (eluting with 75% ethyl acetate in hexanes) to give phenyl 1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamate (60 g, 81.4%).
中间体200Intermediate 200
1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯1',4-Dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamic acid phenyl ester
向3L圆底烧瓶中装入1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-胺(50g，197.4mmol)和EtOAc(1000mL)，得到澄清棕色溶液。向其中一次性添加NaOH(2M水溶液)(500mL)，得到混浊混合物(水层和有机层澄清，但在两层之间观测到沉淀物)。3分钟后，在环境温度下缓慢添加氯甲酸苯酯(74.29mL，592.2mmol)(在添加期间反应混合物的温度升高至33℃)。在环境温度下搅拌反应物2小时。再添加氯甲酸苯酯(10mL)。30分钟后，分离有机层，用盐水洗涤并且在真空中浓缩。通过硅胶色谱法(用75％乙酸乙酯的己烷溶液洗脱)纯化残余物，得到1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯(60g，81.4％)。1', 4-dimethyl-1-phenyl-1H, 1'H-3,4'-bipyrazole-5-amine (50g, 197.4mmol) and EtOAc (1000mL) are loaded into a 3L round-bottom flask to obtain a clear brown solution. NaOH (2M aqueous solution) (500mL) is added thereto once to obtain a turbid mixture (the aqueous layer and the organic layer are clear, but a precipitate is observed between the two layers). After 3 minutes, phenyl chloroformate (74.29mL, 592.2mmol) is slowly added at ambient temperature (the temperature of the reaction mixture rises to 33°C during the addition). The reactant is stirred at ambient temperature for 2 hours. Phenyl chloroformate (10mL) is added again. After 30 minutes, the organic layer is separated, washed with salt water and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 75% ethyl acetate in hexanes) to give phenyl 1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamate (60 g, 81.4%).
中间体201Intermediate 201
(4-氯-3-乙氧基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯Phenyl (4-chloro-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)carbamate
步骤A：制备(3-乙氧基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯：在0℃下向3-乙氧基-1-苯基-1H-吡唑-5-胺(中间体P139，169mg，0.832mmol)在EtOAc(5mL)中的悬浮液中添加2.0M NaOH水溶液(1.25mL，2.50mmol)，接着逐滴添加氯甲酸苯酯(0.178mL，1.41mmol)。在环境温度下搅拌反应物15小时。用EtOAc稀释反应混合物并且进行相分离。用水和盐水洗涤有机层，经MgSO4干燥并且浓缩。通过硅胶快速色谱法(6:1己烷:EtOAc)纯化残余物，得到标题化合物(219mg，81％产率)。MS(apci)m/z＝324.1(M+H)。Step A:Preparation of phenyl (3-ethoxy-1-phenyl-1H-pyrazol-5-yl)carbamate : To a suspension of 3-ethoxy-1-phenyl-1H-pyrazol-5-amine (Intermediate P139, 169 mg, 0.832 mmol) in EtOAc (5 mL) at 0°C was added 2.0 M aqueous NaOH (1.25 mL, 2.50 mmol) followed by dropwise addition of phenyl chloroformate (0.178 mL, 1.41 mmol). The reaction was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with EtOAc and the phases were separated. The organic layer was washed with water and brine, dried overMgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (6:1 hexanes:EtOAc) to give the title compound (219 mg, 81% yield). MS (apci) m/z = 324.1 (M+H).
步骤B：制备(4-氯-3-乙氧基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯：在环境温度下向3-乙氧基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(92mg，0.28mmol)和4-甲基苯磺酸吡啶盐(7.2mg，0.028mmol)在DCM(2mL)中的溶液中添加N-氯代琥珀酰亚胺(42mg，0.31mmol)。在环境温度下搅拌混合物2天并且然后在减压下浓缩。通过硅胶快速色谱法(9:1，己烷/EtOAc)纯化残余物，得到标题化合物(76mg，75％产率)。MS(apci)m/z＝358.1(M+H)。Step B:Preparation of phenyl (4-chloro-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)carbamate : To a solution of phenyl 3-ethoxy-1-phenyl-1H-pyrazol-5-ylcarbamate (92 mg, 0.28 mmol) and 4-methylbenzenesulfonic acid pyridinium salt (7.2 mg, 0.028 mmol) in DCM (2 mL) was added N-chlorosuccinimide (42 mg, 0.31 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 2 days and then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (9: 1, hexane/EtOAc) to give the title compound (76 mg, 75% yield). MS (apci) m/z=358.1 (M+H).
中间体202Intermediate 202
(3-乙氧基-4-氟-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯Phenyl (3-ethoxy-4-fluoro-1-phenyl-1H-pyrazol-5-yl)carbamate
根据实例167步骤B中所述的程序，使用3-乙氧基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯作为3-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯的替代物来制备。Prepared according to the procedure described in Example 167, Step B using phenyl 3-ethoxy-1-phenyl-1H-pyrazol-5-ylcarbamate as an alternative to phenyl 3-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate.
中间体203Intermediate 203
(4-溴-3-(2-羟基-2-甲基丙氧基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯Phenyl (4-bromo-3-(2-hydroxy-2-methylpropyloxy)-1-phenyl-1H-pyrazol-5-yl)carbamate
步骤A：制备5-氨基-1-苯基-1H-吡唑-3(2H)-酮：根据对于中间体P1所述的方法，用2-氰基乙酸乙酯替代4,4-二甲基-3-氧代戊腈并且用苯肼替代3-肼基苯甲酸乙酯盐酸盐来制备。MS(apci)m/z＝176.0(M+H)。Step A:Preparation of 5-amino-1-phenyl-1H-pyrazol-3(2H)-one : Prepare according to the method described for intermediate P1, substituting ethyl 2-cyanoacetate for 4,4-dimethyl-3-oxopentanonitrile and phenylhydrazine for ethyl 3-hydrazinobenzoate hydrochloride. MS (apci) m/z = 176.0 (M+H).
步骤B：制备1-((5-氨基-1-苯基-1H-吡唑-3-基)氧基)-2-甲基丙-2-醇：在80℃下加热5-氨基-1-苯基-1H-吡唑-3(2H)-酮(0.330g，1.88mmol)、2,2-二甲基环氧乙烷(0.143g，1.98mmol)和K2CO3(0.521g，3.77mmol)在DMA(5mL)中的混合物3天。冷却后，用EtOAc稀释反应混合物，用水和盐水洗涤并且经MgSO4干燥。通过SiO2垫，用EtOAc洗脱来过滤混合物，得到标题化合物。MS(apci)m/z＝248.1(M+H)。[0266] Step B:Preparation of 1-((5-amino-1-phenyl-1H-pyrazol-3-yl)oxy)-2-methylpropan-2-ol : A mixture of 5-amino-1-phenyl-1H-pyrazol-3(2H)-one (0.330 g, 1.88 mmol), 2,2-dimethyloxirane (0.143 g, 1.98 mmol) andK2CO3 (0.521 g, 3.77 mmol) in DMA (5 mL) was heated at 80°C for 3 days. After cooling, the reaction mixture was diluted with EtOAc, washed with water and brine, and dried overMgSO4 . The mixture was filtered through a pad ofSiO2 , eluting with EtOAc, to give the title compound. MS (apci) m/z = 248.1 (M+H).
步骤C：制备(3-(2-羟基-2-甲基丙氧基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯：根据对于中间体201步骤A所述的方法，使用1-((5-氨基-1-苯基-1H-吡唑-3-基)氧基)-2-甲基丙-2-醇作为3-乙氧基-1-苯基-1H-吡唑-5-胺的替代物来制备。MS(apci)m/z＝368.1(M+H)。Step C:Preparation of phenyl (3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamate : Prepared according to the procedure described for Intermediate 201, Step A, using 1-((5-amino-1-phenyl-1H-pyrazol-3-yl)oxy)-2-methylpropan-2-ol as a substitute for 3-ethoxy-1-phenyl-1H-pyrazol-5-amine. MS (apci) m/z = 368.1 (M+H).
步骤D：制备(4-溴-3-(2-羟基-2-甲基丙氧基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯：根据对于中间体201步骤B所述的方法，使用N-溴代琥珀酰亚胺作为N-氯代琥珀酰亚胺的替代物并且用(3-(2-羟基-2-甲基丙氧基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯替代3-乙氧基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。MS(apci)m/z＝446.1(M+H)。Step D:Preparation of phenyl (4-bromo-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamate: Prepared according to the procedure described for Intermediate 201, Step B, using N-bromosuccinimide as a substitute for N-chlorosuccinimide and phenyl (3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)carbamate in place of phenyl 3-ethoxy-1-phenyl-1H-pyrazol-5-ylcarbamate. MS (apci) m/z = 446.1 (M+H).
根据对于制备中间体200所述的方法，使用适当的氨基吡唑中间体来制备下列化合物：The following compounds were prepared according to the method described for the preparation of intermediate 200 using the appropriate aminopyrazole intermediate:
中间体228Intermediate 228
4-((4-氯-5-((苯氧基羰基)氨基)-1-苯基-1H-吡唑-3-基)甲氧基)哌啶-1-甲酸4-((4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylic acid叔丁酯tert-Butyl ester
向4-((5-(苯氧基羰基氨基)-1-苯基-1H-吡唑-3-基)甲氧基)哌啶-1-甲酸叔丁酯(中间体226，98.5mg，0.200mmol)在DCM(2.0mL)中的悬浮液中添加4-甲基苯磺酸吡啶盐(PPTS)(5.03mg，0.020mmol)和N-氯代琥珀酰亚胺(40.1mg，0.300mmol)。在环境温度下搅拌所得到的溶液8天。用水和CH2Cl2稀释混合物，分离有机层并且用CH2Cl2(2X)萃取水层。经MgSO4干燥合并的有机部分，过滤并且浓缩。通过二氧化硅色谱法，使用30％至40％EtOAc/己烷梯度洗脱来纯化残余物，得到呈橙色油状的标题化合物(73.5mg，70％产率)。MS(apci)m/z＝527.2(M+H)。To a suspension of tert-butyl 4-((5-(phenoxycarbonylamino)-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate (Intermediate 226, 98.5 mg, 0.200 mmol) in DCM (2.0 mL) was added 4-methylbenzenesulfonic acid pyridinium salt (PPTS) (5.03 mg, 0.020 mmol) and N-chlorosuccinimide (40.1 mg,0.300 mmol). The resulting solution was stirred at ambient temperature for 8 days. The mixture was diluted with waterandCH2Cl2 , the organic layer was separated and the aqueous layer was extracted withCH2Cl2 (2X ). The combined organic portions were dried over MgSO4, filtered and concentrated. The residue was purified by silica chromatography using a 30% to 40% EtOAc/hexane gradient to give the title compound (73.5 mg, 70% yield) as an orange oil. MS (apci) m/z = 527.2 (M+H).
中间体229Intermediate 229
(4-氯-3-(羟基甲基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯Phenyl (4-chloro-3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate
使用对于制备4-((4-氯-5-((苯氧基羰基)氨基)-1-苯基-1H-吡唑-3-基)甲氧基)哌啶-1-甲酸叔丁酯(中间体228)所概述的程序，由3-(羟基甲基)-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(中间体227)来制备。在这种情况下，分离呈白色固体状的化合物(108mg，28％)。MS(apci)m/z＝344.0(M+H)。Prepared from phenyl 3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (Intermediate 227) using the procedure outlined for the preparation of tert-butyl 4-((4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate (Intermediate 228). In this case, the compound was isolated as a white solid (108 mg, 28%). MS (apci) m/z = 344.0 (M+H).
中间体230Intermediate 230
(4-溴-3-(羟基甲基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯Phenyl (4-bromo-3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate
向3-(羟基甲基)-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(中间体227，100mg，0.323mmol)在CH2Cl2(1.6mL)中的悬浮液中添加4-甲基苯磺酸吡啶盐(PPTS)(8.12mg，0.0323mmol)和N-溴代琥珀酰亚胺(86.3mg，0.485mmol)。在环境温度下搅拌反应混合物16小时。过滤所得到的悬浮液并且用CH2Cl2短暂洗涤所收集的固体并且在真空中干燥，得到呈白色固体状的标题化合物(48.5mg，39％)。MS(apci)m/z＝388.0(M+H)。To a suspension of phenyl 3-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (Intermediate 227, 100 mg, 0.323mmol ) inCH2Cl2 (1.6 mL) was added 4-methylbenzenesulfonic acid pyridinium salt (PPTS) (8.12 mg, 0.0323 mmol) and N-bromosuccinimide (86.3 mg, 0.485 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The resulting suspension was filtered and the collected solid was washed brieflywithCH2Cl2 and dried in vacuo to give the title compound as a white solid (48.5 mg, 39%). MS (apci) m/z = 388.0 (M+H).
根据对于制备中间体228、229或230所述的方法制备下列吡唑中间体。The following pyrazole intermediates were prepared according to the procedures described for the preparation of intermediates 228, 229 or 230.
中间体244Intermediate 244
2-苯基吡唑并[1,5-a]吡啶-3-胺2-phenylpyrazolo[1,5-a]pyridin-3-amine
步骤A：2-苯基吡唑并[1,5-a]吡啶-3-甲酸乙酯：向1-氨基吡啶碘(2.22g，10.0mmol)在DMF(20mL)中的溶液中添加K2CO3(1.93g，14.0mmol)和3-苯基丙炔酸乙酯(3.30mL，20.0mmol)。在环境温度下搅拌混合物18小时并且倒入冷却水(100mL)中。搅拌混合物30分钟并且通过填充的过滤，用EtOAc和H2O冲洗。去除有机层并且用H2O(4X)洗涤，经MgSO4干燥，过滤并且浓缩。通过二氧化硅色谱法，使用10％至50％EtOAc/己烷梯度洗脱来纯化残余深红橙色油状物，得到呈黄色固体状的标题化合物(1.75g，65.7％产率)。MS(apci)m/z＝267.0(M+H)。Step A:Ethyl 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylate : To a solution of 1-aminopyridine iodine (2.22 g, 10.0 mmol) in DMF (20 mL) was added K2 CO3 (1.93 g, 14.0 mmol) and ethyl 3-phenylpropiolate (3.30 mL, 20.0 mmol). The mixture was stirred at ambient temperature for 18 hours and poured into cooling water (100 mL). The mixture was stirred for 30 minutes and filtered through a column filled with EtOAc, rinsed with EtOAc and H2 O. The organic layer was removed and washed with H2 O (4×), dried over MgSO4 , filtered and concentrated. The residual dark red-orange oil was purified by silica chromatography using a 10% to 50% EtOAc/hexane gradient elution to give the title compound (1.75 g, 65.7% yield) as a yellow solid. MS (apci) m/z = 267.0 (M+H).
步骤B：2-苯基吡唑并[1,5-a]吡啶-3-甲酸盐酸盐：向2-苯基吡唑并[1,5-a]吡啶-3-甲酸乙酯(1.72g，6.46mmol)在EtOH(10mL)中的溶液中添加2M NaOH(16.1mL，32.3mmol)并且在回流下加热反应混合物7小时。将反应混合物冷却至环境温度并且在冰浴中冷却。用浓HCl酸化混合物并且经由真空过滤收集所得到的悬浮液。用水洗涤产物滤饼并且在真空中干燥，得到呈金色固体状的标题化合物(1.69g，95.2％产率)。MS(apci)m/z＝195.2((M+H)-CO2)。Step B:2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid hydrochloride : To a solution of ethyl 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylate (1.72 g, 6.46 mmol) in EtOH (10 mL) was added 2M NaOH (16.1 mL, 32.3 mmol) and the reaction mixture was heated under reflux for 7 hours. The reaction mixture was cooled to ambient temperature and cooled in an ice bath. The mixture was acidified with concentrated HCl and the resulting suspension was collected via vacuum filtration. The product cake was washed with water and dried in vacuo to give the title compound (1.69 g, 95.2% yield) as a golden solid. MS (apci) m/z=195.2 ((M+H)-CO2 ).
步骤C：2-苯基吡唑并[1,5-a]吡啶：在80℃下加热2-苯基吡唑并[1,5-a]吡啶-3-甲酸盐酸盐(1.00g，3.64mmol)在聚磷酸(41.6m:，364mmol)中的混合物17小时。将所得到的凝胶状混合物冷却至环境温度并且添加冰水(150mL)。搅拌混合物直到颗粒悬浮液开始形成为止。将悬浮液转移至水(350mL)中并且搅拌混合物直到精细颗粒悬浮液产生为止。经由真空过滤收集固体，用水洗涤并且在真空中干燥，得到呈橙色固体状的标题化合物(0.84g，118％)，其直接用于下一步骤中。MS(apci)m/z＝195.2(M+H)。Step C:2-phenylpyrazolo [1,5-a] pyridine : A mixture of 2-phenylpyrazolo [1,5-a] pyridine-3-carboxylic acid hydrochloride (1.00 g, 3.64 mmol) in polyphosphoric acid (41.6 mmol, 364 mmol) was heated at 80 ° C for 17 hours. The resulting gel-like mixture was cooled to ambient temperature and ice water (150 mL) was added. The mixture was stirred until a particle suspension began to form. The suspension was transferred to water (350 mL) and the mixture was stirred until a fine particle suspension was produced. The solid was collected via vacuum filtration, washed with water and dried in vacuo to give the title compound (0.84 g, 118%) as an orange solid, which was used directly in the next step. MS (apci) m/z=195.2 (M+H).
步骤D：3-亚硝基-2-苯基吡唑并[1,5-a]吡啶：向2-苯基吡唑并[1,5-a]吡啶(0.84g，2.85mmol)在乙酸(2.85mL，51.4mmol)中的溶液中经10分钟逐滴添加在水(1.43mL)中的NaNO2(0.295g，4.28mmol)(观测到剧烈鼓泡)。搅拌混合物20分钟并且用冰淬灭。使所得到的悬浮液升温至环境温度并且经由真空过滤收集固体。用水洗涤所收集的固体并且在真空中干燥，得到呈深绿色固体状的标题化合物(0.380g，59.6％)。MS(apci)m/z＝224.1(M+H)。Step D:3-nitroso-2-phenylpyrazolo[1,5-a]pyridine : To a solution of 2-phenylpyrazolo[1,5-a]pyridine (0.84 g, 2.85 mmol) in acetic acid (2.85 mL, 51.4 mmol) was added dropwise NaNO2 (0.295 g, 4.28 mmol) in water (1.43 mL) over 10 minutes (vigorous bubbling was observed). The mixture was stirred for 20 minutes and quenched with ice. The resulting suspension was allowed to warm to ambient temperature and the solid was collected via vacuum filtration. The collected solid was washed with water and dried in vacuo to give the title compound (0.380 g, 59.6%) as a dark green solid. MS (apci) m/z=224.1 (M+H).
步骤E：2-苯基吡唑并[1,5-a]吡啶-3-胺：向3-亚硝基-2-苯基吡唑并[1,5-a]吡啶(0.380g，1.70mmol)和Zn粉(0.557g，8.51mmol)在EtOH(3.81mL)中的混合物中添加浓HCl(0.156mL，1.87mmol)。在回流下加热混合物3小时，并且冷却至环境温度。用MeOH稀释混合物，过滤并且用MeOH洗涤Zn滤饼。浓缩合并的滤液和洗涤液并且将残余物分配于水与DCM中。去除有机层并且用饱和NaHCO3处理水性部分以达成pH＝10。用DCM(3X)萃取混合物并且用饱和NaCl洗涤合并的萃取物，经MgSO4干燥，过滤并且浓缩。在真空中干燥残余物，得到呈棕色固体状的标题化合物(0.304g，85.5％产率)。MS(apci)m/z＝210.1(M+H)。1H NMR(CDCl3)δ8.31(d,1H),7.91(d,2H),7.49(t,2H),7.38(t,2H),6.96(dd,1H),6.64(t,1H),3.21(br s,2H)。Step E:2-phenylpyrazolo[1,5-a]pyridin-3-amine : To a mixture of 3-nitroso-2-phenylpyrazolo[1,5-a]pyridine (0.380 g, 1.70 mmol) and Zn powder (0.557 g, 8.51 mmol) in EtOH (3.81 mL) was added concentrated HCl (0.156 mL, 1.87 mmol). The mixture was heated under reflux for 3 hours and cooled to ambient temperature. The mixture was diluted with MeOH, filtered and the Zn filter cake was washed with MeOH. The combined filtrate and washings were concentrated and the residue was partitioned between water and DCM. The organic layer was removed and the aqueous portion was treated with saturated NaHCO3 to achieve pH=10. The mixture was extracted with DCM (3×) and the combined extracts were washed with saturated NaCl, dried over MgSO4 , filtered and concentrated. The residue was dried in vacuo to give the title compound as a brown solid (0.304 g, 85.5% yield). MS (apci) m/z = 210.1 (M+H).1 H NMR (CDCl3 ) δ 8.31 (d, 1H), 7.91 (d, 2H), 7.49 (t, 2H), 7.38 (t, 2H), 6.96 (dd, 1H), 6.64 (t, 1H), 3.21 (br s, 2H).
中间体245Intermediate 245
5-甲基-3-苯基-1-(吡嗪-2-基)-1H-吡唑-4-胺5-Methyl-3-phenyl-1-(pyrazin-2-yl)-1H-pyrazol-4-amine
步骤A：2-(5-甲基-4-亚硝基-3-苯基-1H-吡唑-1-基)吡嗪：向2-肼基吡嗪(0.485g，4.40mmol)在HOAc(6mL)中的溶液中经2分钟分数小份添加(2-(羟基亚氨基)-1-苯基丁烷-1,3-二酮(0.765g，4.00mmol)。搅拌混合物5分钟并且在60℃下搅拌所得到的淡橙色悬浮液6小时。添加EtOH(1mL)并且在60℃下再加热混合物6小时。将所得到的深绿色悬浮液冷却至环境温度并且用H2O(30mL)稀释混合物。搅拌绿色悬浮液1小时并且经由真空过滤收集固体。用H2O洗涤所收集的固体并且在真空中干燥。将固体悬浮于EtOH(25mL)中并且添加浓HCl(500μL)。在回流下加热混合物20小时，冷却至环境温度并且用冷却的H2O(75mL)稀释。用1M NaOH处理混合物至pH＝7并且用Et2O(3X)萃取。用饱和NaCl洗涤合并的萃取物，并且经MgSO4干燥。通过填充的过滤干燥的溶液并且浓缩。在SiO2柱上使用分步梯度洗脱(25％CH2Cl2，50％EtOAc/己烷)纯化残余绿黄色固体，得到呈青绿色固体状的标题化合物(325mg，31％)。MS(apci)m/z＝266.1(M+H)。Step A:2-(5-methyl-4-nitroso-3-phenyl-1H-pyrazol-1-yl)pyrazine : To a solution of 2-hydrazinopyrazine (0.485 g, 4.40 mmol) in HOAc (6 mL) was added (2-(hydroxyimino)-1-phenylbutane-1,3-dione (0.765 g, 4.00 mmol) in small portions over 2 minutes. The mixture was stirred for 5 minutes and the resulting light orange suspension was stirred at 60°C for 6 hours. EtOH (1 mL) was added and the mixture was heated at 60°C for another 6 hours. The resulting dark green suspension was cooled to ambient temperature and the mixture was diluted withH2O (30 mL). The green suspension was stirred for 1 hour and the solid was collected via vacuum filtration. The collected solid was washed withH2O and dried in vacuo. The solid was suspended in EtOH (25 mL) and concentrated HCl (500 μL) was added. The mixture was heated at reflux for 20 hours, cooled to ambient temperature and washed with cooledH2O. The mixture was diluted with Et2O (75 mL). The mixture was treated with 1 M NaOH to pH 7 and extracted withEt2O (3X ). The combined extracts were washed with saturated NaCl and dried overMgSO4 . The dried solution was filtered through a packing and concentrated. The residual green-yellow solid was purified on aSiO2 column using a step gradient elution (25%CH2Cl2 , 50% EtOAc/hexanes) to give the title compound (325 mg, 31%) as a turquoise solid. MS (apci) m/z = 266.1 (M+H).
步骤B：5-甲基-3-苯基-1-(吡嗪-2-基)-1H-吡唑-4-胺：向2-(5-甲基-4-亚硝基-3-苯基-1H-吡唑-1-基)吡嗪(325mg，1.04mmol)和Zn粉(340mg，5.21mmol)在EtOH(10mL)中的混合物中添加浓HCl(95.5μL，1.15mmol)。在环境温度下搅拌混合物17小时，然后在65℃下搅拌3小时。将混合物冷却至环境温度并且通过填充的用MeOH洗脱来过滤。浓缩洗脱液，并且用H2O处理残余物并且混合。用2M HCl处理所得到的橙色悬浮液至pH＝1并且用Et2O(3X)萃取混合物。用2M NaOH处理水性部分至pH＝8并且用EtOAc(3X)萃取。用饱和NaCl洗涤合并的EtOAc萃取物并且经MgSO4/活性碳干燥。通过SiO2塞，用EtOAc进行洗脱来洗脱溶液。浓缩洗脱液，得到呈淡黄色蜡状的标题化合物(33mg，13％)。MS(esi)m/z＝252.2(M+H)。Step B:5-Methyl-3-phenyl-1-(pyrazin-2-yl)-1H-pyrazol-4-amine : To a mixture of 2-(5-methyl-4-nitroso-3-phenyl-1H-pyrazol-1-yl)pyrazine (325 mg, 1.04 mmol) and Zn powder (340 mg, 5.21 mmol) in EtOH (10 mL) was added concentrated HCl (95.5 μL, 1.15 mmol). The mixture was stirred at ambient temperature for 17 hours and then at 65° C. for 3 hours. The mixture was cooled to ambient temperature and filtered through a column filled with MeOH. The eluent was concentrated and the residue was treated with H2 O and mixed. The resulting orange suspension was treated with 2 M HCl to pH = 1 and the mixture was extracted with Et2 O (3×). The aqueous portion was treated with 2 M NaOH to pH = 8 and extracted with EtOAc (3×). The combined EtOAc extracts were washed with saturated NaCl and dried over MgSO4 /activated carbon. The solution was eluted through a SiO2 plug with EtOAc. The eluent was concentrated to give the title compound as a pale yellow wax (33 mg, 13%). MS (esi) m/z = 252.2 (M+H).
中间体246Intermediate 246
1,5-二甲基-3-苯基-1H-吡唑-4-胺1,5-Dimethyl-3-phenyl-1H-pyrazol-4-amine
步骤A：1,5-二甲基-4-亚硝基-3-苯基-1H-吡唑：向甲肼(0.484g，10.5mmol)在HOAc(10mL)中的溶液中经5分钟分数小份添加2-(羟基亚氨基)-1-苯基丁烷-1,3-二酮(2.01g，10.5mmol)。在60℃下加热反应混合物1小时并且冷却至环境温度。将Et2O(50mL)和H2O(10mL)添加至混合物中，接着缓慢添加饱和Na2CO3直到达到pH＝8为止。去除有机层并且用Et2O(2X)萃取水层。经Na2SO4干燥合并的有机部分，过滤并且浓缩。通过硅胶色谱法(1:5EtOAc/己烷)纯化残余物，得到呈绿色固体状的标题化合物(1.32g，63％)。MS(apci)m/z＝202.1(M+H)。Step A:1,5-dimethyl-4-nitroso-3-phenyl-1H-pyrazole : To a solution of methylhydrazine (0.484 g, 10.5 mmol) in HOAc (10 mL) was added 2-(hydroxyimino)-1-phenylbutane-1,3-dione (2.01 g, 10.5 mmol) in small portions over 5 minutes. The reaction mixture was heated at 60 ° C for 1 hour and cooled to ambient temperature. Et2 O (50 mL) and H2 O (10 mL) were added to the mixture, followed by slow addition of saturated Na2 CO3 until pH = 8 was reached. The organic layer was removed and the aqueous layer was extracted with Et2 O (2×). The combined organic fractions were dried over Na2 SO4 , filtered and concentrated. The residue was purified by silica gel chromatography (1:5 EtOAc / hexane) to give the title compound (1.32 g, 63%) as a green solid. MS (apci) m/z = 202.1 (M+H).
步骤B：1,5-二甲基-3-苯基-1H-吡唑-4-胺：向1,5-二甲基-4-亚硝基-3-苯基-1H-吡唑(1.32g，6.60mmol)在MeOH(50mL)中的溶液中添加碳上的Pd(OH)2(200mg，20wt％，0.286mmol)并且在50psi H2、环境温度下振荡反应混合物3小时。将反应混合物抽真空，用N2吹洗，通过垫用MeOH洗脱来过滤。浓缩洗脱液并且在真空中干燥残余物，得到呈棕褐色固体状的标题化合物(1.23g，100％)。MS(apci)m/z＝188.1(M+H)。Step B:1,5-dimethyl-3-phenyl-1H-pyrazol-4-amine : To a solution of 1,5-dimethyl-4-nitroso-3-phenyl-1H-pyrazole (1.32 g, 6.60 mmol) in MeOH (50 mL) was added Pd(OH) oncarbon (200 mg, 20 wt%, 0.286 mmol) and the reaction mixture was shaken at 50 psiH at ambient temperature for 3 hours. The reaction mixture was evacuated, flushed withN , and filtered through a pad of Celite eluting with MeOH. The eluent was concentrated and the residue was dried in vacuo to give the title compound (1.23 g, 100%) as a tan solid. MS (apci) m/z = 188.1 (M+H).
中间体247Intermediate 247
1-异丙基-5-甲基-3-苯基-1H-吡唑-4-胺1-Isopropyl-5-methyl-3-phenyl-1H-pyrazol-4-amine
根据对于中间体246所述的方法，在步骤A中使用异丙基肼盐酸盐替代甲肼来制备标题化合物，经过2个步骤得到620mg(57％)标题化合物。MS(apci)m/z＝216.1(M+H)。The title compound was prepared according to the procedure described for Intermediate 246 using isopropylhydrazine hydrochloride instead of methylhydrazine in Step A to give 620 mg (57%) of the title compound over 2 steps. MS (apci) m/z = 216.1 (M+H).
中间体248Intermediate 248
5-甲基-3-苯基-1-(2,2,2-三氟乙基)-1H-吡唑-4-胺5-Methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine
步骤A：5-甲基-4-亚硝基-3-苯基-1-(2,2,2-三氟乙基)-1H-吡唑：在对于制备1,5-二甲基-3-苯基-1H-吡唑-4-胺(中间体246)所述的程序的步骤A中使用(2,2,2-三氟乙基)肼替代甲肼来制备标题化合物。分离呈绿色固体状的化合物(999mg，71％)。1H NMR(CDCl3)δ7.60-7.73(m,5H),4.70(q,2H),2.27(t,3H)。Step A:5-Methyl-4-nitroso-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole : The title compound was prepared in step A of the procedure described for the preparation of 1,5-dimethyl-3-phenyl-1H-pyrazol-4-amine (Intermediate 246) using (2,2,2-trifluoroethyl)hydrazine instead of methylhydrazine. The compound was isolated as a green solid (999 mg, 71%).1 H NMR (CDCl3 ) δ 7.60-7.73 (m, 5H), 4.70 (q, 2H), 2.27 (t, 3H).
步骤B：5-甲基-3-苯基-1-(2,2,2-三氟乙基)-1H-吡唑-4-胺：向5-甲基-4-亚硝基-3-苯基-1-(2,2,2-三氟乙基)-1H-吡唑(50mg，0.186mmol)和Zn粉(60.7mg，0.929mmol)在EtOH(0.4mL)中的混合物中添加浓HCl(17.0μL，0.204mmol)并且在回流下加热混合物3小时。将混合物冷却至环境温度并且用MeOH稀释并且过滤。浓缩滤液并且在水中稀释残余物。用饱和NaHCO3处理水性混合物直到达到pH＝10为止。用DCM(3X)萃取混合物并且经Na2SO4干燥合并的萃取物，过滤并且浓缩，得到呈黄色油状的标题化合物(47.1mg，99.4％产率)。MS(apci)m/z＝256.1(M+H)。Step B:5-methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine : To a mixture of 5-methyl-4-nitroso-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (50 mg, 0.186 mmol) and Zn powder (60.7 mg, 0.929 mmol) in EtOH (0.4 mL) was added concentrated HCl (17.0 μL, 0.204 mmol) and the mixture was heated under reflux for 3 hours. The mixture was cooled to ambient temperature and diluted with MeOH and filtered. The filtrate was concentrated and the residue was diluted in water. The aqueous mixture was treated with saturated NaHCO3 until pH=10 was reached. The mixture was extracted with DCM (3×) and the combined extracts were dried over Na2 SO4 , filtered and concentrated to give the title compound (47.1 mg, 99.4% yield) as a yellow oil. MS (apci) m/z = 256.1 (M+H).
中间体249Intermediate 249
1-乙基-5-甲基-3-苯基-1H-吡唑-4-胺1-Ethyl-5-methyl-3-phenyl-1H-pyrazol-4-amine
步骤A：1-乙基-5-甲基-4-亚硝基-3-苯基-1H-吡唑：根据对于制备中间体246所述的程序，在步骤A中使用乙肼草酸盐替代甲肼来制备标题化合物。分离呈绿色油状的1-乙基-5-甲基-4-亚硝基-3-苯基-1H-吡唑(288mg，26％)。1H NMR(CDCl3)δ8.19(d,2H),7.46-7.50(m,3H),4.15(q,2H),2.43(s,3H),1.50(t,3H)。还得到呈蓝绿色固体状的次要区位异构体1-乙基-3-甲基-4-亚硝基-5-苯基-1H-吡唑(165mg，15％)。1H NMR(CDCl3)δ7.71(dd,2H),7.59(m,3H),4.17(q,2H),2.28(s,3H),1.51(t,3H)。Step A:1-Ethyl-5-methyl-4-nitroso-3-phenyl-1H-pyrazole : The title compound was prepared according to the procedure described for the preparation of Intermediate 246, using ethylhydrazine oxalate instead of methylhydrazine in Step A. 1-Ethyl-5-methyl-4-nitroso-3-phenyl-1H-pyrazole (288 mg, 26%) was isolated as a green oil.1H NMR (CDCl3 ) δ 8.19 (d, 2H), 7.46-7.50 (m, 3H), 4.15 (q, 2H), 2.43 (s, 3H), 1.50 (t, 3H). The minor regioisomer, 1-ethyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazole (165 mg, 15%), was also obtained as a bluish-green solid.1 H NMR (CDCl3 ) δ 7.71 (dd, 2H), 7.59 (m, 3H), 4.17 (q, 2H), 2.28 (s, 3H), 1.51 (t, 3H).
步骤B：1-乙基-5-甲基-3-苯基-1H-吡唑-4-胺：根据对于制备中间体248所述的程序，在步骤B中使用1-乙基-5-甲基-4-亚硝基-3-苯基-1H-吡唑来制备。分离呈淡紫色固体状的标题化合物(281mg，104％)。MS(apci)m/z＝202.1(M+H)。Step B:1-Ethyl-5-methyl-3-phenyl-1H-pyrazol-4-amine : Prepared according to the procedure described for the preparation of Intermediate 248 using 1-ethyl-5-methyl-4-nitroso-3-phenyl-1H-pyrazole in Step B. The title compound was isolated as a pale purple solid (281 mg, 104%). MS (apci) m/z = 202.1 (M+H).
中间体250Intermediate 250
1-乙基-3-甲基-5-苯基-1H-吡唑-4-胺1-Ethyl-3-methyl-5-phenyl-1H-pyrazol-4-amine
根据对于制备中间体249所述的程序，在步骤A中使用1-乙基-3-甲基-4-亚硝基-5-苯基-1H-吡唑来制备。根据步骤B制备标题化合物。在通过反相色谱法纯化后分离呈无色油状的化合物(82.4mg，52.5％)。MS(apci)m/z＝202.1(M+H)。Prepared according to the procedure described for the preparation of Intermediate 249 using 1-ethyl-3-methyl-4-nitroso-5-phenyl-1H-pyrazole in step A. The title compound was prepared according to step B. The compound was isolated as a colorless oil after purification by reverse phase chromatography (82.4 mg, 52.5%). MS (apci) m/z = 202.1 (M+H).
中间体251Intermediate 251
1-甲基-5-苯基-3-(三氟甲基)-1H-吡唑-4-胺1-Methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine
步骤A：4,4,4-三氟-2-(羟基亚氨基)-1-苯基丁烷-1,3-二酮：将4,4,4-三氟-1-苯基丁烷-1,3-二酮(5.00g，23.1mmol)在HOAc(46.3mL)中的溶液冷却至10℃并且添加在水(6.0mL)中的亚硝酸钠(1.84g，26.6mmol)。在环境温度下搅拌混合物90分钟并且用H2O(150mL)稀释。用Et2O(3X)萃取混合物并且小心地用饱和NaHCO3洗涤合并的有机部分直到pH＝9为止。用H2O和饱和NaCl洗涤Et2O溶液并且经MgSO4干燥。过滤干燥的溶液并且浓缩，得到呈黄色泡沫状的标题化合物(4.21g，74.2％产率)。MS(apci)m/z＝244.1(M-H)。Step A:4,4,4-trifluoro-2-(hydroxyimino)-1-phenylbutane-1,3-dione : A solution of 4,4,4-trifluoro-1-phenylbutane-1,3-dione (5.00 g, 23.1 mmol) in HOAc (46.3 mL) was cooled to 10°C and sodium nitrite (1.84 g, 26.6 mmol) in water (6.0 mL) was added. The mixture was stirred at ambient temperature for 90 minutes and diluted withH2O (150 mL). The mixture was extracted withEt2O (3X) andthe combined organic fractions were carefully washed with saturated NaHCO3 until pH = 9. TheEt2O solution was washed withH2O and saturated NaCl and dried overMgSO4 . The dried solution was filtered and concentrated to give the title compound (4.21 g, 74.2% yield) as a yellow foam. MS (apci) m/z = 244.1 (MH).
步骤B：4-亚硝基-3-苯基-5-(三氟甲基)-1H-吡唑：将一水合肼(0.204g，4.08mmol)在EtOH(5mL)中的溶液冷却至0℃并且添加在EtOH(15mL)中的4,4,4-三氟-2-(羟基亚氨基)-1-苯基丁烷-1,3-二酮(1.00g，4.08mmol)。在环境温度下搅拌反应混合物3小时，添加过量粉末状MgSO4并且在60℃下加热混合物16小时。将混合物冷却至环境温度，过滤并且浓缩，得到呈绿色固体状的粗标题化合物(78.7mg，8.0％)，其直接用于下一步骤。MS(apci)m/z＝240.0(M-H)。Step B:4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole : A solution of hydrazine monohydrate (0.204 g, 4.08 mmol) in EtOH (5 mL) was cooled to 0 ° C and 4,4,4-trifluoro-2-(hydroxyimino)-1-phenylbutane-1,3-dione (1.00 g, 4.08 mmol) in EtOH (15 mL) was added. The reaction mixture was stirred at ambient temperature for 3 hours, excess powdered MgSO4 was added and the mixture was heated at 60 ° C for 16 hours. The mixture was cooled to ambient temperature, filtered and concentrated to give the crude title compound (78.7 mg, 8.0%) as a green solid, which was used directly in the next step. MS (apci) m / z = 240.0 (MH).
步骤C：1-甲基-5-苯基-3-(三氟甲基)-1H-吡唑-4-胺：向4-亚硝基-3-苯基-5-(三氟甲基)-1H-吡唑(78.7mg，0.326mmol)在DMF(1.6mL)中的溶液中添加NaH(14.4mg，0.359mmol)并且在环境温度下搅拌混合物30分钟。用碘代甲烷(40.6μL，0.653mmol)处理混合物并且搅拌17小时。通过反相HPLC使用20％至100％乙腈/水梯度洗脱直接纯化反应混合物，得到淡蓝色固体(40.2mg)。将固体溶解于EtOH(0.35mL)中并且经历制备5-甲基-3-苯基-1-(2,2,2-三氟乙基)-1H-吡唑-4-胺(中间体248)的步骤B中所述的还原程序。得到呈白色固体状的标题化合物(25.1mg，66.1％)。Step C:1-Methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-amine : To a solution of 4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole (78.7 mg, 0.326 mmol) in DMF (1.6 mL) was added NaH (14.4 mg, 0.359 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The mixture was treated with iodomethane (40.6 μL, 0.653 mmol) and stirred for 17 hours. The reaction mixture was directly purified by reverse phase HPLC using a 20% to 100% acetonitrile/water gradient elution to give a light blue solid (40.2 mg). The solid was dissolved in EtOH (0.35 mL) and subjected to the reduction procedure described in step B for the preparation of 5-methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-amine (intermediate 248). The title compound was obtained as a white solid (25.1 mg, 66.1%).
中间体252Intermediate 252
1-甲基-3-苯基-5-(三氟甲基)-1H-吡唑-4-胺1-Methyl-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine
步骤A：1-甲基-4-亚硝基-3-苯基-5-(三氟甲基)-1H-吡唑：向甲肼(0.214mL，4.08mmol)在EtOH(20mL)中的溶液中添加4,4,4-三氟-2-(羟基亚氨基)-1-苯基丁烷-1,3-二酮(中间体251步骤A；1.00g，4.079mmol)。在环境温度下搅拌反应混合物1小时并且添加过量MgSO4。在60℃下搅拌混合物48小时并且冷却至环境温度。过滤混合物并且将滤液浓缩成绿色残余物。通过硅胶色谱法，使用10％至30％EtOAc/己烷梯度进行洗脱来纯化残余物，得到呈绿色固体状的标题化合物(482mg，46％)。1H NMR(CDCl3)δ7.89(d,2H),7.45-7.52(m,3H),4.15(s,3H)。Step A:1-Methyl-4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole : To a solution of methylhydrazine (0.214 mL, 4.08 mmol) in EtOH (20 mL) was added 4,4,4-trifluoro-2-(hydroxyimino)-1-phenylbutane-1,3-dione (Intermediate 251 Step A; 1.00 g, 4.079 mmol). The reaction mixture was stirred at ambient temperature for 1 hour andexcess MgSO was added. The mixture was stirred at 60 ° C for 48 hours and cooled to ambient temperature. The mixture was filtered and the filtrate was concentrated to a green residue. The residue was purified by silica gel chromatography eluting with a 10% to 30% EtOAc/hexane gradient to give the title compound (482 mg, 46%) as a green solid.1 H NMR (CDCl3 ) δ7.89 (d, 2H), 7.45-7.52 (m, 3H), 4.15 (s, 3H).
步骤B：1-甲基-3-苯基-5-(三氟甲基)-1H-吡唑-4-胺：根据对于制备中间体248的步骤B所述的方法，由1-甲基-4-亚硝基-3-苯基-5-(三氟甲基)-1H-吡唑来制备。得到呈白色固体状的标题化合物(309mg，68％)。1H NMR(CDCl3)δ7.65(d,2H),7.45(t,2H),7.35(t,1H),3.93(s,3H),3.52(br s,2H)。Step B:1-Methyl-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-amine : Prepared from 1-methyl-4-nitroso-3-phenyl-5-(trifluoromethyl)-1H-pyrazole according to the procedure described for Step B of Intermediate 248. The title compound was obtained as a white solid (309 mg, 68%).1 H NMR (CDCl3 ) δ 7.65 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 3.93 (s, 3H), 3.52 (br s, 2H).
制备U-1Preparation of U-1
1-(3-(2-(叔丁基二甲基硅烷氧基)乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-1-(3-(2-(tert-Butyldimethylsilyloxy)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲((3S,4R)-4-(3,4-Difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例1的方法，用(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)替代反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备B)并且使用中间体P203来制备。MS(apci)m/z＝630.1(M+H)。Prepared according to the method of Example 1, substituting (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) for trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation B) and using Intermediate P203. MS (apci) m/z = 630.1 (M+H).
制备U-2Preparation of U-2
1-(3-((S)-2-(叔丁基二甲基硅烷氧基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-1-(3-((S)-2-(tert-Butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazole-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例1的方法，用(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)替代反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备B)并且使用中间体P211来制备。MS(apci)m/z＝644.4(M+H)。Prepared according to the method of Example 1, substituting (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) for trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation B) and using Intermediate P211. MS (apci) m/z = 644.4 (M+H).
合成实例Synthetic Example
实例1Example 1
1-(3-叔丁基-1-苯基-1H-吡唑-5-基)-3-(反式-1-(2-甲氧基乙基)-4-苯基吡咯1-(3-tert-Butyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrole烷-3-基)脲alkyl-3-yl)urea
步骤A：制备3-叔丁基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯：向3-叔丁基-1-苯基-1H-吡唑-5-胺(表1；200.0mg，0.9290mmol)在EtOAc(10mL)中的溶液中添加2M NaOH水溶液(0.9290mL，1.858mmol)，接着添加氯甲酸苯酯(0.1632mL，1.301mmol)。在环境温度下搅拌反应物1小时，并且然后分离各相。用H2O(10mL)、盐水(10mL)洗涤有机相，用MgSO4干燥，过滤并且浓缩，得到呈棕色结晶固体状的产物(320mg，103％产率)。MS(apci)m/z＝336.1(M+H)。[0146] Step A:Preparation of phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate : To a solution of 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (Table 1; 200.0 mg, 0.9290 mmol) in EtOAc (10 mL) was added 2M aqueous NaOH (0.9290 mL, 1.858 mmol) followed by phenyl chloroformate (0.1632 mL, 1.301 mmol). The reaction was stirred at ambient temperature for 1 hour, and the phases were then separated. The organic phase was washed withH2O (10 mL), brine (10 mL), dried overMgSO4 , filtered, and concentrated to afford the product as a brown crystalline solid (320 mg, 103% yield). MS (apci) m/z = 336.1 (M+H).
步骤B：制备1-(3-叔丁基-1-苯基-1H-吡唑-5-基)-3-(反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲：向反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备B，30.0mg，0.102mmol)和DIEA(0.0535mL，0.307mmol)在DMA(1mL)中的溶液中添加3-叔丁基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(34.3mg，0.102mmol)，并且在环境温度下搅拌反应混合物1小时。通过反相柱色谱法，用5％至60％乙腈/水洗脱来直接纯化反应混合物，得到呈棕褐色固体状的产物(38mg，81％产率)。MS(apci)m/z＝462.2(M+H)。[0266] Step B:Preparation of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea : To a solution of trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation B, 30.0 mg, 0.102 mmol) and DIEA (0.0535 mL, 0.307 mmol) in DMA (1 mL) was added phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (34.3 mg, 0.102 mmol) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 60% acetonitrile/water to give the product as a tan solid (38 mg, 81% yield). MS (apci) m/z = 462.2 (M+H).
表4的化合物是根据实例1的方法使用适当的起始物质制备。The compounds in Table 4 were prepared according to the method of Example 1 using appropriate starting materials.
表4Table 4
实例20Example 20
1-(反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-甲基-1H-吡唑-5-基)脲1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-1H-pyrazol-5-yl)urea
步骤A：制备反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基氨基甲酸4-硝基苯酯：在0℃下向反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备B；0.180g，0.614mmol)在DCM(3mL)中的悬浮液中添加三乙胺(0.428mL，3.07mmol)，接着逐滴添加氯甲酸4-硝基苯酯(0.136g，0.675mmol)在DCM(0.5mL)中的溶液。去除冰浴，并且在环境温度下搅拌反应混合物1小时。在饱和NaHCO3(30mL)中稀释混合物并且用DCM(3×20mL)萃取。用盐水(20mL)洗涤合并的有机层，用MgSO4干燥，过滤并且在真空中浓缩，得到粗中间体，其不经纯化即用于下一步骤中。MS(apci)m/z＝386.2(M+H)。[0146] Step A:Preparation of 4-nitrophenyl trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate : To a suspension of trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation B; 0.180 g, 0.614 mmol) in DCM (3 mL) at 0°C was added triethylamine (0.428 mL, 3.07 mmol), followed by the dropwise addition of a solution of 4-nitrophenyl chloroformate (0.136 g, 0.675 mmol) in DCM (0.5 mL). The ice bath was removed and the reaction mixture was stirred at ambient temperature for 1 hour. The mixture was diluted in saturatedNaHCO₃ (30 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give the crude intermediate, which was used in the next step without purification. MS (apci) m/z = 386.2 (M+H).
步骤B：制备1-(反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-甲基-1H-吡唑-5-基)脲：向反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基氨基甲酸4-硝基苯酯(80mg，0.21mmol)在DCE(1mL)中的溶液中添加1-甲基-1H-吡唑-5-胺(表1；24mg，0.25mmol)，接着添加DIEA(0.15mL，0.83mmol)。在55℃下加热混合物18小时，然后用1mL DCM稀释，用饱和碳酸氢钠(2×1mL)洗涤并且在真空中浓缩。通过反相柱色谱法，用5％至45％乙腈/水洗脱来纯化粗残余物，得到标题产物(10mg，14％产率)。MS(apci)m/z＝344.2(M+H)。[0266] Step B:Preparation of 1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-1H-pyrazol-5-yl)urea : To a solution of 4-nitrophenyl trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate (80 mg, 0.21 mmol) in DCE (1 mL) was added 1-methyl-1H-pyrazol-5-amine (Table 1; 24 mg, 0.25 mmol) followed by DIEA (0.15 mL, 0.83 mmol). The mixture was heated at 55°C for 18 hours, then diluted with 1 mL of DCM, washed with saturated sodium bicarbonate (2 x 1 mL) and concentrated in vacuo. The crude residue was purified by reverse phase column chromatography eluting with 5% to 45% acetonitrile/water to give the title product (10 mg, 14% yield). MS (apci) m/z = 344.2 (M+H).
实例21Example 21
1-(反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopentyl)-4-nitropropene戊二烯并[c]吡唑-3-基)硫脲Penta[c]pyrazol-3-yl)thiourea
向2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺(表1；45.2mg，0.227mmol)的CHCl3(0.5mL)悬浮液中添加二(1H-咪唑-1-基)甲硫酮(40.4mg，0.227mmol)，接着添加DIEA(0.158mL，0.908mmol)。在环境温度下搅拌16小时后，将反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺(制备B，50.0mg，0.227mmol)一次性添加至反应混合物中。2小时后，通过反相柱色谱法用5％至68％乙腈/水洗脱来直接纯化反应物，得到呈白色固体状的标题产物(70mg，67％产率)。MS(apci)m/z＝462.1(M+H)。To a suspension of 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (Table 1; 45.2 mg, 0.227 mmol) inCHCl₃ (0.5 mL) was added bis(1H-imidazol-1-yl)methanthione (40.4 mg, 0.227 mmol), followed by DIEA (0.158 mL, 0.908 mmol). After stirring at ambient temperature for 16 hours, trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine (Preparation B, 50.0 mg, 0.227 mmol) was added to the reaction mixture in one portion. After 2 hours, the reaction was directly purified by reverse phase column chromatography eluting with 5% to 68% acetonitrile/water to give the title product (70 mg, 67% yield) as a white solid. MS (apci) m/z = 462.1 (M+H).
实例22Example 22
1-(2-(3-氟苯基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)-3-(反式-1-(2-甲氧1-(2-(3-Fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(trans-1-(2-methoxyphenyl)-基乙基)-4-苯基吡咯烷-3-基)脲(ethyl)-4-phenylpyrrolidin-3-yl)urea
用1,1'-羰基二咪唑(18.7mg，0.115mmol)和TEA(32.1μL，0.230mmol)处理2-(3-氟苯基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺(中间体P3；25.0mg，0.115mmol)在DCM(575μL，0.115mmol)中的溶液。在环境温度下搅拌3小时后，添加反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备B，33.7mg，0.115mmol)，接着添加TEA(64.2μL，0.460mmol)。在环境温度下搅拌30分钟后，通过反相柱色谱法用0％至100％乙腈/水洗脱来直接纯化粗反应混合物，得到呈澄清油状的标题化合物(17.6mg，33.0％产率)。MS(apci)m/z＝464.1(M+H)。A solution of 2-(3-fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (Intermediate P3; 25.0 mg, 0.115 mmol) in DCM (575 μL, 0.115 mmol) was treated with 1,1'-carbonyldiimidazole (18.7 mg, 0.115 mmol) and TEA (32.1 μL, 0.230 mmol). After stirring at ambient temperature for 3 hours, trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation B, 33.7 mg, 0.115 mmol) was added, followed by TEA (64.2 μL, 0.460 mmol). After stirring at ambient temperature for 30 minutes, the crude reaction mixture was directly purified by reverse phase column chromatography eluting with 0% to 100% acetonitrile/water to give the title compound (17.6 mg, 33.0% yield) as a clear oil. MS (apci) m/z = 464.1 (M+H).
表5的化合物是根据实例22的方法使用适当的起始物质制备。以1,1'-羰基二咪唑向活化中间体转化的时间不同，并且通过获取等分试样并且在MeOH中淬灭来监测。向氨基甲酸甲酯的完全转化(30分钟至16小时)使用LCMS分析来监测。The compounds in Table 5 were prepared according to the method of Example 22 using appropriate starting materials. The time for conversion of 1,1'-carbonyldiimidazole to the activated intermediate varied and was monitored by obtaining an aliquot and quenching in MeOH. Complete conversion to the methyl carbamate (30 minutes to 16 hours) was monitored using LCMS analysis.
表5Table 5
实例38Example 38
1-(反式-1-(2-甲氧基乙基)-4-(吡啶-4-基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-1-(trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备反式-1-(2-甲氧基乙基)-4-(吡啶-4-基)吡咯烷-3-甲酸乙酯：向冷却至0℃的(E)-3-(吡啶-4-基)丙烯酸乙酯(200mg，1.13mmol)在DCM(10mL)中的溶液中依序一次性添加TFA(0.017mL，0.226mmol)，接着逐滴添加2-甲氧基-N-(甲氧基甲基)-N-((三甲基硅烷基)甲基)乙胺(制备C，278mg，1.35mmol)。在环境温度下搅拌反应物3小时。将其用饱和NaHCO3(10mL)淬灭，分离各相并且用DCM(15mL)萃取水层。用MgSO4干燥合并的有机相，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用0％至5％MeOH/DCM洗脱来纯化粗产物，得到呈无色油状的产物(276mg，88％产率)。MS(apci)m/z＝279.2(M+H)。Step A: Preparation of ethyl trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidine-3-carboxylate : To a solution of ethyl (E)-3-(pyridin-4-yl)acrylate (200 mg, 1.13 mmol) in DCM (10 mL) cooled to 0° C. was added TFA (0.017 mL, 0.226 mmol) in one portion followed by dropwise addition of 2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine (Preparation C, 278 mg, 1.35 mmol). The reaction was stirred at ambient temperature for 3 hours. It was quenched with saturated NaHCO3 (10 mL), the phases were separated and the aqueous layer was extracted with DCM (15 mL). The combined organic phases were dried over MgSO4 , filtered and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with 0% to 5% MeOH/DCM to give the product as a colorless oil (276 mg, 88% yield).MS (apci) m/z=279.2 (M+H).
步骤B：制备反式-1-(2-甲氧基乙基)-4-(吡啶-4-基)吡咯烷-3-甲酸锂：向反式-1-(2-甲氧基乙基)-4-(吡啶-4-基)吡咯烷-3-甲酸乙酯(276mg，0.992mmol)在THF(6mL)和MeOH(3mL)中的溶液中添加2M LiOH水溶液(0.496mL，0.992mmol)。在环境温度下搅拌反应混合物2小时，并且通过真空过滤收集所得到的白色沉淀物，用Et2O冲洗并且空气干燥。将滤液浓缩成黄色固体，用MeOH(1mL)湿磨，过滤并且用Et2O冲洗白色固体并且空气干燥。合并两批固体，得到呈白色固体状的产物(197mg，88％产率)。1H NMR(d6-DMSO)δ8.37-8.39(m,2H),7.26-7.28(m,2H),3.36-3.43(m,3H),3.24(s,3H),2.75-2.86(m,1H),2.41-2.68(m,6H)。Step B:Preparation of lithium trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidine-3-carboxylate : To a solution of ethyl trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidine-3-carboxylate (276 mg, 0.992 mmol) in THF (6 mL) and MeOH (3 mL) was added 2M aqueous LiOH (0.496 mL, 0.992 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, and the resulting white precipitate was collected by vacuum filtration, rinsed withEt2O , and air-dried. The filtrate was concentrated to a yellow solid, triturated with MeOH (1 mL), filtered, and the white solid was rinsed withEt2O and air-dried. The two batches of solid were combined to give the product (197 mg, 88% yield) as a white solid.1 H NMR (d6 -DMSO) δ 8.37-8.39 (m, 2H), 7.26-7.28 (m, 2H), 3.36-3.43 (m, 3H), 3.24 (s, 3H), 2.75-2.86 (m, 1H), 2.41-2.68 (m, 6H).
步骤C：制备反式-1-(2-甲氧基乙基)-4-(吡啶-4-基)吡咯烷-3-基氨基甲酸苯甲酯：向反式-1-(2-甲氧基乙基)-4-(吡啶-4-基)吡咯烷-3-甲酸锂(25mg，0.098mmol)在甲苯(1.8mL)和DMF(0.2mL)中的悬浮液中依序添加DIEA(0.034mL，0.20mmol)和二苯基磷酰基叠氮化物(0.029mL，0.14mmol)。在环境温度下搅拌反应混合物20分钟，然后使其回流10分钟。引入苯甲醇(100mg，0.98mmol)，并且使反应混合物回流17小时。通过二氧化硅柱色谱法，用0％至10％MeOH/DCM洗脱来直接纯化反应混合物，得到呈黄色油状的产物(11mg，32％产率)。MS(apci)m/z＝356.1(M+H)。Step C:Preparation of trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-ylcarbamic acid benzylester : To a suspension of lithium trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidine-3-carboxylate (25 mg, 0.098 mmol) in toluene (1.8 mL) and DMF (0.2 mL) was added DIEA (0.034 mL, 0.20 mmol) and diphenylphosphoryl azide (0.029 mL, 0.14 mmol) in sequence. The reaction mixture was stirred at ambient temperature for 20 minutes and then refluxed for 10 minutes. Benzyl alcohol (100 mg, 0.98 mmol) was introduced and the reaction mixture was refluxed for 17 hours. The reaction mixture was directly purified by silica column chromatography eluting with 0% to 10% MeOH/DCM to give the product as a yellow oil (11 mg, 32% yield). MS (apci) m/z = 356.1 (M+H).
步骤D：制备反式-1-(2-甲氧基乙基)-4-(吡啶-4-基)吡咯烷-3-胺双(2,2,2-三氟乙酸盐)：在密封管中，在60℃下加热反式-1-(2-甲氧基乙基)-4-(吡啶-4-基)吡咯烷-3-基氨基甲酸苯甲酯(11mg，0.031mmol)在TFA(1mL)中的溶液18小时。将反应混合物和EtOH(5mL)一起转移并且浓缩，得到呈棕色油状的粗产物，其在假定定量产率下直接用于步骤F中。MS(apci)m/z＝222.1(M+H)。Step D:Preparation of trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-amine bis(2,2,2-trifluoroacetate) : A solution of trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-ylcarbamic acid benzyl ester (11 mg, 0.031 mmol) in TFA (1 mL) was heated at 60° C. in a sealed tube for 18 hours. The reaction mixture was transferred with EtOH (5 mL) and concentrated to give the crude product as a brown oil, which was used directly in Step F assuming quantitative yield. MS (apci) m/z=222.1 (M+H).
步骤E：制备2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯：逐滴用氯甲酸苯酯(0.088mL，0.70mmol)处理2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺(表1；100mg，0.50mmol)在EtOAc(2.0mL)和2M NaOH水溶液(0.50mL，1.0mmol)中的悬浮液并且在环境温度下搅拌16小时。然后对反应混合物进行相分离，并且用水(5mL)和盐水(5mL)洗涤有机相，经Na2SO4干燥，过滤并且在真空中浓缩，得到产物(160mg，100％产率)。MS(apci)m/z＝320.1(M+H)。Step E:Preparation of phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate : A suspension of 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (Table 1; 100 mg, 0.50 mmol) in EtOAc (2.0 mL) and 2M aqueous NaOH (0.50 mL, 1.0 mmol) was treated dropwise with phenyl chloroformate (0.088 mL, 0.70 mmol) and stirred at ambient temperature for 16 hours. The reaction mixture was then phase separated, and the organic phase was washed with water (5 mL) and brine (5 mL), dried over Na2 SO4 , filtered, and concentrated in vacuo to afford the product (160 mg, 100% yield). MS (apci) m/z=320.1 (M+H).
步骤F：制备1-(反式-1-(2-甲氧基乙基)-4-(吡啶-4-基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：通过如实例1中所述的方法，在步骤B中用2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯替代3-叔丁基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯并且在步骤B中用反式-1-(2-甲氧基乙基)-4-(吡啶-4-基)吡咯烷-3-胺双(2,2,2-三氟乙酸盐)替代反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐来制备，得到呈白色固体状的最终产物(6.0mg，42％产率)。MS(apci)m/z＝447.2(M+H)。Step F:Preparation of 1-(trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-yl)-3-(2-phenyl -2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea: Prepared by the method described in Example 1, replacing phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate with phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate in Step B and replacing trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-amine bis(2,2,2-trifluoroacetate) in Step B to give the final product (6.0 mg, 42% yield) as a white solid. MS (apci) m/z = 447.2 (M+H).
实例39Example 39
反式-1-(4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-trans-1-(4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备反式-3-(3-氟苯基)-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-甲酸叔丁酯：向反式-1-(叔丁氧基羰基)-4-(3-氟苯基)吡咯烷-3-甲酸(购自ChemImpex；100mg，0.32mmol)在无水甲苯(2mL)中的悬浮液中添加三乙胺(180μL，1.29mmol)，接着添加二苯基磷酰基叠氮化物(98μL，0.45mmol)。在环境温度下搅拌所得到的溶液1小时，并且然后在回流下搅拌1小时。冷却后，用2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺(表1；193mg，0.97mmol)处理反应混合物，并且在回流下搅拌15小时。将冷却的混合物分配于饱和NaHCO3(20mL)与EtOAc(20mL)之间并且用EtOAc(2×10mL)萃取水层。用盐水(10mL)洗涤合并的有机相，经Na2SO4干燥并且在真空中浓缩。通过二氧化硅柱色谱法用1％MeOH/DCM，接着用5％MeOH/DCM洗脱来纯化粗物质，得到呈棕色胶状的产物。LCMS分析胶状物指示此物质为希望的产物与2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺起始物质的对称脲的约2:1混合物(由LCMS测定)。混合物直接用于下一步骤中。MS(apci)m/z＝506.2(M+H)。Step A:Preparation of tert-butyl trans-3-(3-fluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate : To a suspension of trans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylic acid (available from ChemImpex; 100 mg, 0.32 mmol) in anhydrous toluene (2 mL) was added triethylamine (180 μL, 1.29 mmol) followed by diphenylphosphoryl azide (98 μL, 0.45 mmol). The resulting solution was stirred at ambient temperature for 1 hour and then at reflux for 1 hour. After cooling, the reaction mixture was treated with 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (Table 1; 193 mg, 0.97 mmol) and stirred at reflux for 15 hours. The cooled mixture was partitioned between saturatedNaHCO₃ (20 mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (10 mL),dried overNa₂SO₄ , and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with 1% MeOH/DCM followed by 5% MeOH/DCM to give the product as a brown gum. LCMS analysis of the gum indicated that this material was an approximately 2:1 mixture (as determined by LCMS) of the desired product and the symmetrical urea of the 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine starting material. The mixture was used directly in the next step. MS (apci) m/z = 506.2 (M+H).
步骤B：制备1-(反式-4-(3-氟苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：向在CH2Cl2(8mL)中的在步骤A中分离的混合物(90mg，0.18mmol)中添加TFA(2mL)。在环境温度下搅拌溶液2小时并且然后浓缩，并且将残余物分配于1NNaOH(20mL)与CH2Cl2(20mL)之间。用CH2Cl2(2×10mL)萃取水层，并且用盐水(10mL)洗涤合并的有机相，经Na2SO4干燥并且浓缩，得到棕色胶状物。通过二氧化硅柱色谱法，用2％MeOH/DCM至10％MeOH/CH2Cl2/0.1％7N NH3/MeOH洗脱来纯化，得到呈浅黄色固体状的产物(31mg，43％产率)。MS(apci)m/z＝406.1(M+H)。[0266 ] Step B:Preparation of 1-(trans-4-(3-fluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : To the mixture isolated inStep A (90 mg, 0.18 mmol) in CH2Cl2 (8 mL) was added TFA (2 mL). The solution was stirred at ambient temperature for 2 hours and then concentrated, and the residue was partitioned between 1 N NaOH (20mL ) andCH2Cl2 (20 mL). The aqueous layer was extracted withCH2Cl2 (2 x 10 mL), and the combined organic phases were washed with brine (10mL ), dried overNa2SO4 , and concentrated to give a brown gum. Purification by silica column chromatography eluting with 2% MeOH/DCM to 10% MeOH/CH2Cl2 /0.1%7NNH3 /MeOH gave the product as a light yellow solid (31 mg, 43% yield).MS (apci) m/z = 406.1 (M+H).
步骤C：制备反式-1-(4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：向1-(反式-4-(3-氟苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲(31mg，0.076mmol)在无水DMF(1mL)中的溶液中添加1-溴-2-甲氧基乙烷(9.1μL，0.09mmol)，接着添加DIEA(40μL，0.23mmol)。使混合物升温至60℃并且搅拌15小时。将冷却的混合物分配于饱和NaHCO3(20mL)与EtOAc(10mL)之间并且用EtOAc(2×10mL)萃取水层。用水(5×10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥并且浓缩。通过二氧化硅柱色谱法，用2.5％MeOH/CH2Cl2洗脱来纯化粗物质，得到呈无色玻璃状的产物(14mg，40％产率)。MS(apci)m/z＝464.1(M+H)。Step C:Preparation of trans-1-(4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl -2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea: To a solution of 1-(trans-4-(3-fluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea (31 mg, 0.076 mmol) in anhydrous DMF (1 mL) was added 1-bromo-2-methoxyethane (9.1 μL, 0.09 mmol) followed by DIEA (40 μL, 0.23 mmol). The mixture was warmed to 60° C. and stirred for 15 hours. The cooled mixture was partitioned between saturatedNaHCO₃ (20 mL) and EtOAc (10 mL), and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic phases were washed with water (5×10 mL) and brine (10 mL), then dried overNa₂SO₄ and concentrated. The crude material was purified by silica column chromatography eluting with 2.5% MeOH/CH₂Cl₂ to give the productasa colorless glass (14 mg, 40% yield). MS (apci) m/z=464.1 (M+H).
实例40Example 40
反式-1-(-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-异丙基-1-苯trans-1-(4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl)基-1H-吡唑-5-基)脲-1H-pyrazol-5-yl)urea
使用如对于实例39所述的程序，在步骤A中用3-异丙基-1-苯基-1H-吡唑-5-胺(表1)替代2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺来制备。MS(apci)m/z＝466.2(M+H)。Prepared using the procedure as described for Example 39, substituting 3-isopropyl-1-phenyl-1H-pyrazol-5-amine (Table 1) for 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine in Step A. MS (apci) m/z = 466.2 (M+H).
实例41Example 41
反式-1-(4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-异丙基-1-苯基-trans-1-(4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-吡唑-5-基)脲1H-pyrazol-5-yl)urea
根据对于实例39所述的程序，在步骤A中用反式-1-(叔丁氧基羰基)-4-(4-氟苯基)吡咯烷-3-甲酸替代反式-1-(叔丁氧基羰基)-4-(3-氟苯基)吡咯烷-3-甲酸来制备。MS(apci)m/z＝466.2(M+H)。Prepared according to the procedure described for Example 39, substituting trans-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)pyrrolidine-3-carboxylic acid for trans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylic acid in Step A. MS (apci) m/z = 466.2 (M+H).
实例42Example 42
反式-1-(4-(3-氯苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-异丙基-1-苯基-trans-1-(4-(3-chlorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-吡唑-5-基)脲1H-pyrazol-5-yl)urea
根据对于实例40所述的程序，在步骤A中用反式-1-(叔丁氧基羰基)-4-(3-氯苯基)吡咯烷-3-甲酸替代反式-1-(叔丁氧基羰基)-4-(3-氟苯基)吡咯烷-3-甲酸来制备。MS(apci)m/z＝482.1(M+H)。Prepared according to the procedure described for Example 40, substituting trans-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylic acid for trans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylic acid in Step A. MS (apci) m/z = 482.1 (M+H).
实例43Example 43
反式-1-(4-(2-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-异丙基-1-苯基-trans-1-(4-(2-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-吡唑-5-基)脲1H-pyrazol-5-yl)urea
根据对于实例40所述的程序，在步骤A中用反式-1-(叔丁氧基羰基)-4-(2-氟苯基)吡咯烷-3-甲酸替代反式-1-(叔丁氧基羰基)-4-(3-氟苯基)吡咯烷-3-甲酸来制备。MS(apci)m/z＝466.2(M+H)。Prepared according to the procedure described for Example 40, substituting trans-1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)pyrrolidine-3-carboxylic acid for trans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylic acid in Step A. MS (apci) m/z = 466.2 (M+H).
实例44Example 44
反式-1-(3-异丙基-1-苯基-1H-吡唑-5-基)-3-(1-(2-甲氧基乙基)-4-(噻吩-2-trans-1-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-(2-methoxyethyl)-4-(thiophene-2-yl)基)吡咯烷-3-基)脲1-[4-(2-Yl)pyrrolidin-3-yl)urea
根据对于实例40所述的程序，在步骤A中用反式-1-(叔丁氧基羰基)-4-(噻吩-2-基)吡咯烷-3-甲酸替代反式-1-(叔丁氧基羰基)-4-(3-氟苯基)吡咯烷-3-甲酸来制备。MS(apci)m/z＝454.1(M+H)。Prepared according to the procedure described for Example 40, substituting trans-1-(tert-butoxycarbonyl)-4-(thiophen-2-yl)pyrrolidine-3-carboxylic acid for trans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylic acid in Step A. MS (apci) m/z = 454.1 (M+H).
实例45Example 45
1-((3,4-反式)-4-(2,4-二甲基噻唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-1-((3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲(2-Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备(E)-3-(2,4-二甲基噻唑-5-基)丙烯酸甲酯：将(三苯基-正膦基亚基)乙酸甲酯(2.61g，7.80mmol)在CH2Cl2(10mL)中的溶液冷却至0℃，并且然后经15分钟时段逐滴添加4-甲基噻唑-4-甲醛(购自Maybridge，1.00g，7.08mmol)在干燥CH2Cl2(10mL)中的溶液。使反应物升温至环境温度并且搅拌24小时。在减压下去除溶剂后，将获得的黄色固体残余物溶解于CH2Cl2中并且通过硅胶快速色谱法用15％EtOAc/己烷洗脱来纯化，得到呈白色粉末状的产物(1.32g，94.5％产率)。1H-NMR(400MHz,DMSO-d6)δ7.73(d,J＝15.62Hz,1H),6.07(d,J＝15.62Hz,1H),3.71(s,3H,OCH3),2.63(s,3H,CH3),2.42(s,3H,CH3)。MS(apci)m/z＝198(M+H)。Step A:Preparation of (E)-3-(2,4-dimethylthiazol-5-yl)acrylate : A solution of methyl (triphenyl-phosphoranylidene)acetate (2.61 g, 7.80 mmol) in CH2 Cl2 (10 mL) was cooled to 0° C., and then a solution of 4-methylthiazole-4-carbaldehyde (available from Maybridge, 1.00 g, 7.08 mmol) in dry CH2 Cl2 (10 mL) was added dropwise over a period of 15 minutes. The reaction was allowed to warm to ambient temperature and stirred for 24 hours. After removing the solvent under reduced pressure, the yellow solid residue obtained was dissolved in CH2 Cl2 and purified by flash chromatography on silica gel eluting with 15% EtOAc/hexane to give the product as a white powder (1.32 g, 94.5% yield).1 H-NMR (400MHz, DMSO-d6 ) δ7.73 (d, J = 15.62 Hz, 1H), 6.07 (d, J = 15.62 Hz, 1H), 3.71 (s, 3H, OCH3 ), 2.63 (s, 3H, CH3 ), 2.42 (s, 3H, CH3 ). MS(apci)m/z=198(M+H).
步骤B：制备(3,4-反式)-4-(2,4-二甲基噻唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-甲酸甲酯：在冰浴中冷却(E)-3-(2,4-二甲基噻唑-5-基)丙烯酸甲酯(200mg，1.01mmol)和TFA(7.81μL，0.101mmol)在甲苯(15mL)中的溶液，接着逐滴添加2-甲氧基-N-(甲氧基甲基)-N-((三甲基硅烷基)甲基)乙胺(312mg，1.52mmol)在甲苯(5mL)中的溶液。使反应物升温至环境温度并且搅拌3天。用饱和NaHCO3(25mL)和水(2×25mL)洗涤反应混合物，用Na2SO4干燥，过滤并且在真空中浓缩。通过反相柱色谱法，用5％至50％乙腈/水洗脱来纯化粗物质，得到呈澄清油状的产物(43mg，14％产率)。MS(apci)m/z＝299.1(M+H)。Step B:Preparation of methyl (3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidine-3-carboxylate : A solution of methyl (E)-3-(2,4-dimethylthiazol-5-yl)acrylate (200 mg, 1.01 mmol) and TFA (7.81 μL, 0.101 mmol) in toluene (15 mL) was cooled in an ice bath, followed by the dropwise addition of a solution of 2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine (312 mg, 1.52 mmol) in toluene (5 mL). The reaction was allowed to warm to ambient temperature and stirred for 3 days. The reaction mixture was washed with saturatedNaHCO₃ (25 mL) and water (2×25 mL),dried overNa₂SO₄ , filtered, and concentrated in vacuo. The crude material was purified by reverse phase column chromatography eluting with 5% to 50% acetonitrile/water to give the product as a clear oil (43 mg, 14% yield).MS (apci) m/z = 299.1 (M+H).
步骤C：制备(3,4-反式)-4-(2,4-二甲基噻唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-甲酸：向(3,4-反式)-4-(2,4-二甲基噻唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-甲酸甲酯(41mg，0.14mmol)在2:2:1THF/MeOH/水的混合溶剂系统(0.7mL)中的溶液中添加LiOH-H2O(17mg，0.41mmol)，并且在环境温度下搅拌混合物过夜。去除溶剂后，将固体残余物溶解于水(0.2mL)中并且用1N HCl酸化直到pH为4至5。通过反相色谱法，用5％至33％乙腈/水洗脱来直接纯化混合物，得到呈澄清油状的产物(30mg，77％产率)。MS(apci)m/z＝285.1(M+H)。Step C:Preparation of (3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidine-3-carboxylic acid : To a solution of methyl (3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidine-3-carboxylate (41 mg, 0.14 mmol) in a mixed solvent system of 2:2:1 THF/MeOH/water (0.7 mL) was added LiOH-H2 O (17 mg, 0.41 mmol) and the mixture was stirred at ambient temperature overnight. After removal of the solvent, the solid residue was dissolved in water (0.2 mL) and acidified with 1N HCl until the pH was 4 to 5. The mixture was directly purified by reverse phase chromatography eluting with 5% to 33% acetonitrile/water to give the product as a clear oil (30 mg, 77% yield). MS (apci) m/z = 285.1 (M+H).
步骤D：制备(3,4-反式)-4-(2,4-二甲基噻唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-基氨基甲酸苯甲酯：向(3,4-反式)-4-(2,4-二甲基噻唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-甲酸(25.6mg，0.09mmol)在甲苯(0.9mL)中的混浊溶液中添加TEA(31μL，0.22mmol)，接着添加叠氮磷酸二苯酯(27μL，0.13mmol)。在环境温度下搅拌混合物1小时，并且然后在100℃下搅拌1小时。添加苯甲醇(19μL，0.18mmol)并且在100℃下加热混合物18小时。冷却后，用EtOAc(2mL)稀释混合物，用水(2×1mL)洗涤，经MgSO4干燥，过滤并且浓缩。通过反相柱色谱法，用5％至60％乙腈/水洗脱来纯化粗残余物，得到呈黄色油状的产物(18mg，51％产率)。MS(apci)m/z＝390.1(M+H)。Step D:Preparation of benzyl (3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-ylcarbamate : To a turbid solution of (3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidine-3-carboxylic acid (25.6 mg, 0.09 mmol) in toluene (0.9 mL) was added TEA (31 μL, 0.22 mmol), followed by diphenylphosphoryl azide (27 μL, 0.13 mmol). The mixture was stirred at ambient temperature for 1 hour, and then at 100 ° C for 1 hour. Benzyl alcohol (19 μL, 0.18 mmol) was added and the mixture was heated at 100 ° C for 18 hours. After cooling, the mixture was diluted with EtOAc (2 mL), washed with water (2×1 mL), dried over MgSO4 , filtered and concentrated. The crude residue was purified by reverse phase column chromatography eluting with 5% to 60% acetonitrile/water to give the product as a yellow oil (18 mg, 51% yield).MS (apci) m/z = 390.1 (M+H).
步骤E：制备(3,4-反式)-4-(2,4-二甲基噻唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-胺双(2,2,2-三氟乙酸盐)：在60℃下加热(3,4-反式)-4-(2,4-二甲基噻唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-基氨基甲酸苯甲酯(18.0mg，0.0462mmol)在TFA(178μL，2.31mmol)中的溶液18小时。用甲苯/EtOH稀释反应混合物并且浓缩。通过反相柱色谱法，用5％至38％乙腈/水洗脱来纯化粗物质，得到呈无色玻璃状固体状的产物(14mg，63％产率)。MS(apci)m/z＝256.1(M+H)。Step E:Preparation of (3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-amine bis(2,2,2-trifluoroacetate) : A solution of (3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-ylcarbamic acid benzyl ester (18.0 mg, 0.0462 mmol) in TFA (178 μL, 2.31 mmol) was heated at 60 ° C for 18 hours. The reaction mixture was diluted with toluene/EtOH and concentrated. The crude material was purified by reverse phase column chromatography eluting with 5% to 38% acetonitrile/water to give the product (14 mg, 63% yield) as a colorless glassy solid. MS (apci) m/z=256.1 (M+H).
步骤F：制备1-((3,4-反式)-4-(2,4-二甲基噻唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：向(3,4-反式)-4-(2,4-二甲基噻唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-胺双(2,2,2-三氟乙酸盐)(14mg，0.029mmol)在DMA(0.3mL)中的澄清溶液中添加2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(11mg，0.035mmol)。在冰浴中冷却混合物，并且添加DIEA(0.020mL，0.12mmol)。使反应物升温至环境温度并且搅拌5分钟，然后通过反相色谱法用5％至50％乙腈/水洗脱来直接纯化，得到呈白色固体状的标题产物(10mg，72％产率)。MS(apci)m/z＝481.2(M+H)。[0266] Step F:Preparation of 1-((3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : To a clear solution of (3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-amine bis(2,2,2-trifluoroacetate) (14 mg, 0.029 mmol) in DMA (0.3 mL) was added phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (11 mg, 0.035 mmol). The mixture was cooled in an ice bath and DIEA (0.020 mL, 0.12 mmol) was added. The reaction was allowed to warm to ambient temperature and stirred for 5 minutes, then directly purified by reverse phase chromatography eluting with 5% to 50% acetonitrile/water to give the title product as a white solid (10 mg, 72% yield).MS (apci) m/z=481.2 (M+H).
实例46Example 46
1-(反式-1-(2-甲氧基乙基)-4-(噁唑-5-基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-1-(trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备(E)-3-(噁唑-5-基)丙烯酸乙酯：在N2、0℃下向NaH(在矿物油中60％，227mg，5.67mmol)在THF(40mL)中的悬浮液中逐滴添加2-(二乙氧基磷酰基)乙酸乙酯(1.12mL，5.67mmol)。在0℃下搅拌混合物30分钟，并且然后添加噁唑-5-甲醛(500mg，5.15mmol)在THF(5mL)中的溶液。去除冰浴，并且在环境温度下搅拌反应物18小时。用H2O(30mL)稀释反应物并且用EtOAc(50mL)萃取。用盐水(50mL)洗涤有机相，用MgSO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用0％至1％MeOH/DCM洗脱来纯化粗产物，得到呈浅黄色油状的产物(354mg，41.1％产率)。1H NMR(CDCl3)δ7.92(s,1H),7.48(d,1H),7.29(s,1H),6.40(d,1H),4.27(q,2H),1.29(t,3H)。Step A:Preparation of (E)-ethyl 3-(oxazol-5-yl)acrylate : To a suspension of NaH (60% in mineral oil, 227 mg, 5.67 mmol) in THF (40 mL) under N at0 °C was added ethyl 2-(diethoxyphosphoryl)acetate (1.12 mL, 5.67 mmol) dropwise. The mixture was stirred at 0°C for 30 minutes, and then a solution of oxazole-5-carboxaldehyde (500 mg, 5.15 mmol) in THF (5 mL) was added. The ice bath was removed, and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted withH2O (30 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine (50 mL), dried overMgSO4 , filtered, and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with 0% to 1% MeOH/DCM to give the product as a light yellow oil (354 mg, 41.1% yield).1 H NMR (CDCl3 ) δ 7.92 (s, 1H), 7.48 (d, 1H), 7.29 (s, 1H), 6.40 (d, 1H), 4.27 (q, 2H), 1.29 (t, 3H).
步骤B：制备反式-1-(2-甲氧基乙基)-4-(噁唑-5-基)吡咯烷-3-甲酸乙酯：在0℃下向(E)-3-(噁唑-5-基)丙烯酸乙酯(354mg，2.12mmol)在DCM(20mL)中的溶液中添加TFA(0.033mL，0.42mmol)，然后逐滴添加2-甲氧基-N-(甲氧基甲基)-N-((三甲基硅烷基)甲基)乙胺(制备C，522mg，2.54mmol)。去除冰浴并且在环境温度下搅拌反应物18小时，然后用饱和NaHCO3水溶液(20mL)稀释反应混合物，分离并且用DCM(20mL)萃取水相。用MgSO4干燥合并的有机相，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用0％至3％MeOH/DCM洗脱来纯化粗产物，得到呈浅黄色油状的产物(321mg，56.5％产率)。MS(apci)m/z＝269.2(M+H)。Step B:Preparation of trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidine-3-carboxylic acid ethyl ester : To a solution of (E)-3-(oxazol-5-yl) ethyl acrylate (354 mg, 2.12 mmol) in DCM (20 mL) at 0°C was added TFA (0.033 mL, 0.42 mmol) followed by dropwise addition of 2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine (Preparation C, 522 mg, 2.54 mmol). The ice bath was removed and the reaction was stirred at ambient temperature for 18 hours, then the reaction mixture was diluted with saturated aqueousNaHCO3 (20 mL), separated, and the aqueous phase extracted with DCM (20 mL). The combined organic phases were dried overMgSO4 , filtered, and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with 0% to 3% MeOH/DCM to give the product as a light yellow oil (321 mg, 56.5% yield).MS (apci) m/z=269.2 (M+H).
步骤C：制备反式-1-(2-甲氧基乙基)-4-(噁唑-5-基)吡咯烷-3-甲酸锂：向反式-1-(2-甲氧基乙基)-4-(噁唑-5-基)吡咯烷-3-甲酸乙酯(321mg，1.20mmol)在THF(6mL)和MeOH(3mL)中的溶液中添加2M LiOH水溶液(0.837mL，1.67mmol)。在环境温度下搅拌反应物1.5小时并且然后浓缩成黄色粘性固体。将粗产物溶解于MeOH(10mL)中并且浓缩，得到呈黄色泡沫状的产物(234mg，79.4％产率)。MS(apci负离子)m/z＝239.2(M-Li)。Step C:Preparation of lithium trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidine-3-carboxylate : To a solution of ethyl trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidine-3-carboxylate (321 mg, 1.20 mmol) in THF (6 mL) and MeOH (3 mL) was added 2M aqueous LiOH (0.837 mL, 1.67 mmol). The reaction was stirred at ambient temperature for 1.5 hours and then concentrated to a yellow sticky solid. The crude product was dissolved in MeOH (10 mL) and concentrated to give the product as a yellow foam (234 mg, 79.4% yield). MS (apci negative ion) m/z = 239.2 (M-Li).
步骤D：制备反式-1-(2-甲氧基乙基)-4-(噁唑-5-基)吡咯烷-3-基氨基甲酸苯甲酯：向反式-1-(2-甲氧基乙基)-4-(噁唑-5-基)吡咯烷-3-甲酸乙酯(234mg，0.872mmol)在DMF(0.8mL)中的溶液中添加DIEA(0.304mL，1.74mmol)，然后添加甲苯(10mL)。添加二苯基磷酰基叠氮化物(0.263mL，1.22mmol)并且在环境温度下搅拌反应物1小时，然后在回流下搅拌1小时。添加苯甲醇(0.903mL，8.72mmol)并且使反应物回流17小时。冷却混合物并且用H2O(25mL)稀释并且用DCM(3×20mL)萃取，并且用盐水(25mL)洗涤合并的有机相，用MgSO4干燥，过滤，浓缩。通过反相柱色谱法，用5％至70％乙腈/水洗脱来纯化粗产物，得到呈浅黄色糖浆状的产物(55mg，18％产率)。MS(apci)m/z＝346.1(M+H)。Step D:Preparation of trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-ylcarbamic acid benzylester : To a solution of trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidine-3-carboxylic acid ethyl ester (234 mg, 0.872 mmol) in DMF (0.8 mL) was added DIEA (0.304 mL, 1.74 mmol) followed by toluene (10 mL). Diphenylphosphoryl azide (0.263 mL, 1.22 mmol) was added and the reaction was stirred at ambient temperature for 1 hour and then at reflux for 1 hour. Benzyl alcohol (0.903 mL, 8.72 mmol) was added and the reaction was refluxed for 17 hours. The mixture was cooled and diluted with H2 O (25 mL) and extracted with DCM (3×20 mL). The combined organic phases were washed with brine (25 mL), dried over MgSO4 , filtered, and concentrated. The crude product was purified by reverse phase column chromatography, eluting with 5% to 70% acetonitrile/water to give the product as a light yellow syrup (55 mg, 18% yield). MS (apci) m/z=346.1 (M+H).
步骤E：制备反式-1-(2-甲氧基乙基)-4-(噁唑-5-基)吡咯烷-3-胺双(2,2,2-三氟乙酸盐)：在密封管中，在60℃下加热反式-1-(2-甲氧基乙基)-4-(噁唑-5-基)吡咯烷-3-基氨基甲酸苯甲酯(55mg，0.16mmol)在TFA(2mL)中的溶液16小时。将反应混合物转移至含有EtOH(10mL)的烧瓶中并且在真空中浓缩。将粗产物溶解于甲苯(15mL)中并且共沸三次，得到呈棕色糖浆状的粗产物(130mg，186％产率)。MS(apci)m/z＝212.1(M+H)。Step E:Preparation of trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-amine bis(2,2,2-trifluoroacetate) : A solution of trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-ylcarbamic acid benzyl ester (55 mg, 0.16 mmol) in TFA (2 mL) was heated at 60 ° C in a sealed tube for 16 hours. The reaction mixture was transferred to a flask containing EtOH (10 mL) and concentrated in vacuo. The crude product was dissolved in toluene (15 mL) and azeotroped three times to give the crude product as a brown syrup (130 mg, 186% yield). MS (apci) m/z=212.1 (M+H).
步骤F：制备1-(反式-1-(2-甲氧基乙基)-4-(噁唑-5-基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：通过如实例45步骤F中所述的方法，使用反式-1-(2-甲氧基乙基)-4-(噁唑-5-基)吡咯烷-3-胺双(2,2,2-三氟乙酸盐)来制备，得到呈无色残余物形式的产物(5.0mg，18％产率)。MS(apci)m/z＝437.3(M+H)。Step F:Preparation of 1-(trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-yl)-3-(2-phenyl -2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea: Prepared by the method described in Example 45, Step F using trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-amine bis(2,2,2-trifluoroacetate) to give the product as a colorless residue (5.0 mg, 18% yield). MS (apci) m/z = 437.3 (M+H).
实例47Example 47
1-(反式-4-(异噁唑-5-基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,1-(trans-4-(isoxazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
通过如实例46中所述的方法，在步骤A中用异噁唑-5-甲醛替代噁唑-5-甲醛来制备。MS(apci)m/z＝437.0(M+H)。Prepared by the method as described in Example 46, substituting isoxazole-5-carboxaldehyde for oxazole-5-carboxaldehyde in Step A. MS (apci) m/z = 437.0 (M+H).
实例48Example 48
1-((3,4-反式)-1-(2-甲氧基乙基)-4-(3-甲氧基苯基)吡咯烷-3-基)-3-(2-苯1-((3,4-trans)-1-(2-methoxyethyl)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备(3,4-反式)-3-(3-甲氧基苯基)-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-甲酸叔丁酯：向(3,4-反式)-3-氨基-4-(3-甲氧基苯基)吡咯烷-1-甲酸叔丁酯(30mg，0.095mmol，购自BroadPharm)和2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(37mg，0.11mmol)的混合物中添加DMA(0.5mL)，在冰浴中冷却，然后添加DIEA(0.050mL，0.29mmol)。去除冰浴，并且在环境温度下搅拌反应物2小时。然后通过反相色谱法，用5％至75％乙腈/水5％至75％洗脱来直接纯化反应混合物，得到呈白色固体状的产物(15mg，30％产率)。MS(apci)m/z＝518.0(M+H)。Step A:Preparation of tert-butyl (3,4-trans)-3-(3-methoxyphenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta [c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate: To a mixture of tert-butyl (3,4-trans)-3-amino-4-(3-methoxyphenyl)pyrrolidine-1-carboxylate (30 mg, 0.095 mmol, purchased from BroadPharm) and phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (37 mg, 0.11 mmol) was added DMA (0.5 mL), cooled in an ice bath, and then DIEA (0.050 mL, 0.29 mmol) was added. The ice bath was removed, and the reaction was stirred at ambient temperature for 2 hours. The reaction mixture was then purified directly by reverse phase chromatography eluting with 5% to 75% acetonitrile/water 5% to 75% to give the product as a white solid (15 mg, 30% yield).MS (apci) m/z = 518.0 (M+H).
步骤B：制备1-((3,4-反式)-4-(3-甲氧基苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲盐酸盐：在环境温度下搅拌(3,4-反式)-3-(3-甲氧基苯基)-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-甲酸叔丁酯(15mg，0.029mmol)在5N至6N HCl的IPA溶液(58μL，0.29mmol)中的溶液3小时，然后在真空中浓缩，用乙醚处理，并且在高真空下干燥，得到呈灰白色固体状的粗产物。固体不经进一步纯化即直接用于下一步骤中。MS(apci)m/z＝418.1(M+H)。[0266] Step B:Preparation of 1-((3,4-trans)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea hydrochloride : A solution of tert-butyl (3,4-trans)-3-(3-methoxyphenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate (15 mg, 0.029 mmol) in 5N to 6N HCl in IPA (58 μL, 0.29 mmol) was stirred at ambient temperature for 3 hours, then concentrated in vacuo, treated with diethyl ether, and dried under high vacuum to give the crude product as an off-white solid. The solid was used directly in the next step without further purification. MS (apci) m/z = 418.1 (M+H).
步骤C：制备1-((3,4-反式)-1-(2-甲氧基乙基)-4-(3-甲氧基苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：向1-((3,4-反式)-4-(3-甲氧基苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲盐酸盐(13mg，0.029mmol)的DMF(0.3mL)溶液中添加N-乙基-N-异丙基丙-2-胺(16μL，0.086mmol)和1-溴-2-甲氧基乙烷(4.8mg，0.034mmol)，并且在环境温度下搅拌反应物3天。通过反相柱色谱法，用5％至55％乙腈/水洗脱来直接纯化反应物，得到呈白色固体状的标题产物(10mg，73％产率)。MS(apci)m/z＝476.2(M+H)。Step C:Preparation of 1-((3,4-trans)-1-(2-methoxyethyl)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : To a solution of 1-((3,4-trans)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea hydrochloride (13 mg, 0.029 mmol) in DMF (0.3 mL) were added N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.086 mmol) and 1-bromo-2-methoxyethane (4.8 mg, 0.034 mmol) and the reaction was stirred at ambient temperature for 3 days. The reaction was directly purified by reverse phase column chromatography eluting with 5% to 55% acetonitrile/water to give the title product as a white solid (10 mg, 73% yield).MS (apci) m/z=476.2 (M+H).
实例49Example 49
1-(1-(2-甲氧基乙基)-4-(噻唑-2-基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢1-(1-(2-methoxyethyl)-4-(thiazol-2-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydro环戊二烯并[c]吡唑-3-基)脲Cyclopenta[c]pyrazol-3-yl)urea
步骤A：制备反式-(1-(2-甲氧基乙基)-4-硝基吡咯烷-3-基)噻唑：将PS-DMAP(3.52g，5.00mmol)分数小份添加至噻唑-2-甲醛(2.83g，25.0mmol)在乙腈(5mL)和硝基甲烷(5mL)中的溶液中。在环境温度下搅拌反应物4小时并且添加乙腈(50mL)，接着添加乙酸酐(2.59mL，27.5mmol)。搅拌反应物1小时，过滤并且在真空中浓缩，得到(E)-2-(2-硝基乙烯基)噻唑(3.99g)。将一部分(E)-2-(2-硝基乙烯基)噻唑(1.00g，6.40mmol)溶解于DCM(5mL)中，冷却至0℃并且用TFA(0.0987mL，1.28mmol)处理，接着逐滴用2-甲氧基-N-(甲氧基甲基)-N-((三甲基硅烷基)甲基)乙胺(1.32g，6.40mmol)处理。允许反应物升温至环境温度过夜。添加1N NaOH(5mL)并且在相分离过滤器板(phase separator frit)中用数份DCM萃取反应物。浓缩合并的DCM萃取物，得到粗标题化合物(1.61g，94.1％产率)。MS(apci)m/z＝258.0(M+H)。Step A:Preparation of trans-(1-(2-methoxyethyl)-4-nitropyrrolidin-3-yl)thiazole : PS-DMAP (3.52 g, 5.00 mmol) was added in small portions to a solution of thiazole-2-carbaldehyde (2.83 g, 25.0 mmol) in acetonitrile (5 mL) and nitromethane (5 mL). The reaction was stirred at ambient temperature for 4 hours and acetonitrile (50 mL) was added followed by acetic anhydride (2.59 mL, 27.5 mmol). The reaction was stirred for 1 hour, filtered and concentrated in vacuo to afford (E)-2-(2-nitrovinyl)thiazole (3.99 g). A portion of (E)-2-(2-nitrovinyl)thiazole (1.00 g, 6.40 mmol) was dissolved in DCM (5 mL), cooled to 0° C. and treated with TFA (0.0987 mL, 1.28 mmol), followed by dropwise treatment with 2-methoxy-N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine (1.32 g, 6.40 mmol). The reaction was allowed to warm to ambient temperature overnight. 1N NaOH (5 mL) was added and the reaction was extracted with several portions of DCM on a phase separator frit. The combined DCM extracts were concentrated to give the crude title compound (1.61 g, 94.1% yield). MS (apci) m/z=258.0 (M+H).
步骤B：制备反式-1-(2-甲氧基乙基)-4-(噻唑-2-基)吡咯烷-3-胺：将反式-1-(2-甲氧基乙基)-4-硝基吡咯烷-3-基)噻唑(80mg，0.31mmol)溶解于1mL MeOH中并且用10％Pd/C(33mg，0.031mmol)处理。在氢气球下搅拌反应混合物过夜，通过过滤并且浓缩，得到粗标题化合物(68mg，96％产率)。MS(apci)m/z＝228.1(M+H)。[0146] Step B:Preparation of trans-1-(2-methoxyethyl)-4-(thiazol-2-yl)pyrrolidin-3-amine : Dissolve trans-1-(2-methoxyethyl)-4-nitropyrrolidin-3-yl)thiazole (80 mg, 0.31 mmol) in 1 mL of MeOH and treat with 10% Pd/C (33 mg, 0.031 mmol). The reaction mixture was stirred under a hydrogen balloon overnight, filtered through Celite®, and concentrated to give the crude title compound (68 mg, 96% yield). MS (apci) m/z = 228.1 (M+H).
步骤C：制备1-(反式-1-(2-甲氧基乙基)-4-(噻唑-2-基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将反式-1-(2-甲氧基乙基)-4-(噻唑-2-基)吡咯烷-3-胺(15.0mg，0.0660mmol)溶解于1mL DCM中并且用DIEA(23.0μL，0.132mmol)处理，接着用2-(环己-1,3-二烯基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(25.4mg，0.0792mmol)处理。在环境温度下搅拌反应混合物18小时，浓缩并且通过反相柱色谱法用0％至50％乙腈/水洗脱来纯化，得到标题化合物(3.2mg，10.7％产率)。MS(apci)m/z＝453.1(M+H)。[0266] Step C:Preparation of 1-(trans-1-(2-methoxyethyl)-4-(thiazol-2-yl)pyrrolidin-3-yl)-3-(2-phenyl -2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea: trans-1-(2-methoxyethyl)-4-(thiazol-2-yl)pyrrolidin-3-amine (15.0 mg, 0.0660 mmol) was dissolved in 1 mL of DCM and treated with DIEA (23.0 μL, 0.132 mmol) followed by phenyl 2-(cyclohexa-1,3-dienyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (25.4 mg, 0.0792 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, concentrated and purified by reverse phase column chromatography eluting with 0% to 50% acetonitrile/water to give the title compound (3.2 mg, 10.7% yield).MS (apci) m/z=453.1 (M+H).
实例50Example 50
1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydro环戊二烯并[c]吡唑-3-基)脲Cyclopenta[c]pyrazol-3-yl)urea
在0℃下向(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备D；0.10g，0.34mmol)在DCM(5mL)中的溶液中依序添加2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(实例38，步骤C；0.13g，0.41mmol)和TEA(0.14mL，1.0mmol)。允许所得到的混合物升温至环境温度并且搅拌2小时。然后将其用EtOAc处理，用饱和NH4Cl、饱和NaHCO3和盐水洗涤。用MgSO4干燥合并的有机层，过滤并且浓缩。通过二氧化硅柱色谱法，用2％至2.5％MeOH/DCM洗脱来纯化粗物质，得到产物(0.11g，72％产率)。MS(apci)m/z＝446.2(M+H)。To a solution of (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation D; 0.10 g, 0.34 mmol) in DCM (5 mL) at 0°C was added phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (Example 38, Step C; 0.13 g, 0.41 mmol) and TEA (0.14 mL, 1.0 mmol) sequentially. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 hours. It was then treated with EtOAc and washed with saturatedNH4Cl , saturatedNaHCO3 , and brine. The combined organic layers were dried overMgSO4 , filtered, and concentrated. The crude material was purified by silica column chromatography eluting with 2% to 2.5% MeOH/DCM to give the product (0.11 g, 72% yield). MS (apci) m/z = 446.2 (M+H).
实例51Example 51
1-(1,3-二苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-1-(1,3-diphenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidine-3-基)脲3-aminomethyl)urea
在密封容器中，将1,3-二苯基-1H-吡唑-5-胺(表1；32.0mg，0.136mmol)、DIEA(35.6μL，0.204mmol)与1,1'-羰基二咪唑(19.3mg，0.119mmol)在CHCl3(0.5mL)中组合并且在60℃下加热4小时。将混合物冷却至环境温度并且添加(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备D；15.0mg，0.0681mmol)。在100℃下加热15小时后，浓缩反应混合物并且通过反相柱色谱法用0％至70％乙腈/水洗脱来直接纯化，得到标题化合物(5.6mg，17％产率)。MS(apci)m/z＝482.2(M+H)。In a sealed vessel, 1,3-diphenyl-1H-pyrazol-5-amine (Table 1; 32.0 mg, 0.136 mmol), DIEA (35.6 μL, 0.204 mmol), and 1,1'-carbonyldiimidazole (19.3 mg, 0.119 mmol) were combined inCHCl₃ (0.5 mL) and heated at 60°C for 4 hours. The mixture was cooled to ambient temperature and (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation D; 15.0 mg, 0.0681 mmol) was added. After heating at 100°C for 15 hours, the reaction mixture was concentrated and directly purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/water to provide the title compound (5.6 mg, 17% yield). MS (apci) m/z = 482.2 (M+H).
实例52Example 52
1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(1-甲基-3-苯基-1H-吡1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrrolidin-唑-5-基)脲oxazol-5-yl)urea
向1-甲基-3-苯基-1H-吡唑-5-胺(表1；49mg，0.28mmol)在DCM(2mL)中的溶液中添加CDI(46mg，0.28mmol)，接着添加DIEA(200μL，1.1mmol)。在环境温度下2小时后，添加(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备D，83mg，0.28mmol)在DCM(0.6mL)中的溶液。搅拌反应物15分钟，然后通过反相柱色谱法用5％至50％乙腈/水洗脱来直接纯化，得到呈白色固体状的标题产物(45mg，38％产率)。MS(apci)m/z＝420.1(M+H)。To a solution of 1-methyl-3-phenyl-1H-pyrazole-5-amine (Table 1; 49 mg, 0.28 mmol) in DCM (2 mL) was added CDI (46 mg, 0.28 mmol) followed by DIEA (200 μL, 1.1 mmol). After 2 hours at ambient temperature, a solution of (3S, 4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation D, 83 mg, 0.28 mmol) in DCM (0.6 mL) was added. The reaction was stirred for 15 minutes and then directly purified by reverse phase column chromatography eluting with 5% to 50% acetonitrile/water to give the title product (45 mg, 38% yield) as a white solid. MS (apci) m/z=420.1 (M+H).
表6的化合物是根据实例52的方法使用适当的起始物质制备。以CDI向活化中间体转化的时间不同，并且通过获取等分试样并且在MeOH中淬灭来监测。向氨基甲酸甲酯的完全转化(30分钟至16小时)使用LCMS分析来监测。The compound of table 6 is prepared according to the method of example 52 using appropriate starting material.The time of conversion to activated intermediate is different with CDI, and is monitored by obtaining aliquots and quenching in MeOH.The complete conversion to methyl carbamate (30 minutes to 16 hours) is monitored using LCMS analysis.
表6Table 6
根据实例1的方法，用制备D、E、F、G、H、J或K的化合物替代制备B的化合物并且使用适当的吡唑中间体来制备表7的化合物。The compounds of Table 7 were prepared according to the method of Example 1, substituting the compound of Preparation D, E, F, G, H, J, or K for the compound of Preparation B and using the appropriate pyrazole intermediate.
表7Table 7
根据实例1的方法，用制备F或K的化合物替代制备B的化合物并且使用适当的吡唑中间体来制备表8的化合物。The compounds of Table 8 were prepared according to the method of Example 1, substituting the compound of Preparation F or K for the compound of Preparation B and using the appropriate pyrazole intermediate.
表8Table 8
根据实例1的方法，用制备E、F、H或K的化合物替代制备B的化合物并且使用适当的吡唑中间体来制备表9的化合物。The compounds of Table 9 were prepared according to the method of Example 1, substituting the compound of Preparation E, F, H, or K for the compound of Preparation B and using the appropriate pyrazole intermediate.
表9Table 9
实例151Example 151
1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(吡啶-4-基)-2,4,1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-(pyridin-4-yl)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲5,6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备2-(吡啶-4-基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺：将2-氧代环戊烷甲腈(0.4g，3.7mmol，购自AAT Pharmaceutical)和4-肼基吡啶盐酸盐(0.53g，3.7mmol)在甲醇(35mL)中的溶液密封于压力容器中并且在80℃下加热过夜。在真空中去除溶剂后，用1N NaOH(20mL)湿磨残余物并且用DCM(3×25mL)萃取。用盐水洗涤合并的有机物，用MgSO4干燥，过滤并且浓缩，得到呈棕色固体状的粗产物，其直接用于下一步中。MS(apci)m/z＝201.2(M+H)。Step A:Preparation of 2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine : A solution of 2-oxocyclopentanecarbonitrile (0.4 g, 3.7 mmol, purchased from AAT Pharmaceutical) and 4-hydrazinopyridine hydrochloride (0.53 g, 3.7 mmol) in methanol (35 mL) was sealed in a pressure vessel and heated at 80 ° C overnight. After removing the solvent in vacuo, the residue was triturated with 1N NaOH (20 mL) and extracted with DCM (3×25 mL). The combined organics were washed with brine, dried over MgSO4 , filtered and concentrated to give the crude product as a brown solid, which was used directly in the next step. MS (apci) m/z=201.2 (M+H).
步骤B：制备1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-(吡啶-4-基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：在0℃下向2-(吡啶-4-基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺(43mg，0.21mmol)在DCM(2mL)中的混合物中添加DIEA(0.075mL，0.43mmol)，接着一次性添加三光气(25mg，0.086mmol)。使反应物升温至环境温度并且搅拌2小时。去除试样量(0.5mL)的反应混合物(含有3-异氰酰基-2-(吡啶-4-基)-2,4,5,6-四氢环戊二烯并[c]吡唑(12.1mg，0.0535mmol))并且依序用(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺双(2,2,2-三氟乙酸盐)(制备D，20mg，0.0446mmol)和N-乙基-N-异丙基丙-2-胺(38.8μL，0.223mmol)处理。搅拌30分钟后，通过反相色谱法用5％至50％乙腈/水洗脱来直接纯化反应混合物，得到呈灰白色固体状的标题最终产物(5mg，25％产率)。MS(apci正离子)m/z＝447.2(M+H)。[0266] Step B:Preparation of 1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : To a mixture of 2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (43 mg, 0.21 mmol) in DCM (2 mL) at 0°C was added DIEA (0.075 mL, 0.43 mmol) followed by triphosgene (25 mg, 0.086 mmol) in one portion. The reaction was allowed to warm to ambient temperature and stirred for 2 hours. A 0.5 mL aliquot of the reaction mixture containing 3-isocyanato-2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole (12.1 mg, 0.0535 mmol) was removed and treated sequentially with (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine bis(2,2,2-trifluoroacetate) (Preparation D, 20 mg, 0.0446 mmol) and N-ethyl-N-isopropylpropan-2-amine (38.8 μL, 0.223 mmol). After stirring for 30 minutes, the reaction mixture was directly purified by reverse phase chromatography eluting with 5% to 50% acetonitrile/water to provide the title product as an off-white solid (5 mg, 25% yield). MS (apci positive ion) m/z = 447.2 (M+H).
根据实例151的方法，用适当的类似物替代吡唑输入物并且用制备F的化合物替代制备D的化合物来制备表10的化合物。The compounds of Table 10 were prepared according to the procedure of Example 151, substituting the appropriate analog for the pyrazole input and substituting the compound of Preparation F for the compound of Preparation D.
表10Table 10
实例158Example 158
1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydro吡咯并[3,4-c]吡唑-3-基)脲二盐酸盐Pyrrolo[3,4-c]pyrazol-3-yl) urea dihydrochloride
用4N HCl的二噁烷溶液(2.0mL，0.017mmol)处理3-(3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲基)-2-苯基-4,6-二氢吡咯并[3,4-c]吡唑-5(2H)-甲酸叔丁酯(实例79)并且在环境温度下搅拌30分钟。过滤所得到的米色悬浮液并且用Et2O冲洗固体，得到呈棕褐色固体状的产物(6.4mg，74％产率)。MS(apci)m/z＝447.1(M+H)。Tert-butyl 3-(3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)ureido)-2-phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (Example 79) was treated with 4N HCl in dioxane (2.0 mL, 0.017 mmol) and stirred at ambient temperature for 30 minutes. The resulting beige suspension was filtered and the solids were rinsed withEt2O to give the product as a tan solid (6.4 mg, 74% yield). MS (apci) m/z = 447.1 (M+H).
实例159Example 159
1-(5-乙酰基-2-苯基-2,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)-3-((3S,4R)-1-1-(5-Acetyl-2-phenyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲(2-Methoxyethyl)-4-phenylpyrrolidin-3-yl)urea
向1-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基)脲二盐酸盐(实例158，2.0mg，0.0039mmol)和DIEA(0.0067mL，0.039mmol)在乙腈(1.0mL，19mmol)中的溶液中添加乙酸(0.0011mL，0.019mmol)，接着添加HATU(2.9mg，0.0077mmol)。在环境温度下搅拌1小时后，通过二氧化硅柱色谱法用0％至10％MeOH/DCM洗脱来直接纯化反应混合物，得到产物(0.7mg，37％产率)。MS(apci)m/z＝489.2(M+H)。To a solution of 1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)urea dihydrochloride (Example 158, 2.0 mg, 0.0039 mmol) and DIEA (0.0067 mL, 0.039 mmol) in acetonitrile (1.0 mL, 19 mmol) was added acetic acid (0.0011 mL, 0.019 mmol) followed by HATU (2.9 mg, 0.0077 mmol). After stirring at ambient temperature for 1 hour, the reaction mixture was directly purified by silica column chromatography eluting with 0% to 10% MeOH/DCM to give the product (0.7 mg, 37% yield). MS (apci) m/z = 489.2 (M+H).
实例160Example 160
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-(羟基甲1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-(hydroxymethyl)基)-3-(甲氧基甲基)-1-苯基-1H-吡唑-5-基)脲1-phenyl-1H-pyrazol-5-yl)urea
用4N HCl/二噁烷(5mL)处理1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2-苯基-4,6-二氢-2H-呋喃并[3,4-c]吡唑-3-基)脲(实例90，250mg，0.517mmol)在DCM(20mL)中的溶液。浓缩至干燥后，通过用1N NaOH和DCM分配使残余物转化成游离碱，然后通过二氧化硅柱色谱法用2％至4％MeOH/DCM洗脱来纯化，得到产物(29mg，11％产率)。MS(apci)m/z＝516.2(M+H)。A solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-yl)urea (Example 90, 250 mg, 0.517 mmol) in DCM (20 mL) was treated with 4N HCl/dioxane (5 mL). After concentration to dryness, the residue was converted to the free base by partitioning with 1N NaOH and DCM, and then purified by silica column chromatography eluting with 2% to 4% MeOH/DCM to give the product (29 mg, 11% yield). MS (apci) m/z=516.2 (M+H).
实例161Example 161
4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-甲基-1H-吡唑-3-基)苯甲酸1-Methyl-1H-pyrazol-3-yl)benzoic acid
在0℃下向4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-甲基-1H-吡唑-3-基)苯甲酸甲酯(实例121，79mg，0.15mmol)在THF(4.0mL，0.15mmol)和MeOH(2.0mL，49mmol)中的溶液中添加LiOH(2M水溶液)(0.15mL，0.31mmol)。在环境温度下搅拌此反应物并且再添加LiOH直到由HPLC分析观测到完全转化(约2天)。用2MHCl(1mL)酸化后，用水(10mL)稀释混合物，用DCM(20mL)萃取，然后用10％MeOH/DCM(3×10mL)萃取。用盐水(25mL)洗涤合并的有机相，用MgSO4干燥，过滤并且浓缩，得到呈白色固体状的产物(70mg，91％产率)。MS(apci)m/z＝500.1(M+H)。To a solution of methyl 4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate (Example 121, 79 mg, 0.15 mmol) in THF (4.0 mL, 0.15 mmol) and MeOH (2.0 mL, 49 mmol) was added LiOH (2M in water) (0.15 mL, 0.31 mmol) at 0°C. The reaction was stirred at ambient temperature and additional LiOH was added until complete conversion was observed by HPLC analysis (approximately 2 days). After acidification with 2M HCl (1 mL), the mixture was diluted with water (10 mL) and extracted with DCM (20 mL), followed by extraction with 10% MeOH/DCM (3×10 mL). The combined organic phases were washed with brine (25 mL), dried over MgSO4 , filtered and concentrated to give the product as a white solid (70 mg, 91% yield). MS (apci) m/z = 500.1 (M+H).
实例162Example 162
4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-甲基-1H-吡唑-3-基)苯甲酰胺1-methyl-1H-pyrazol-3-yl)benzamide
向4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-甲基-1H-吡唑-3-基)苯甲酸(实例161，12mg，0.024mmol)在DMF(0.5mL，0.024mmol)中的溶液中依序添加N-甲基吗啉(0.0079mL，0.072mmol)、NH3(0.5M二噁烷溶液)(0.096mL，0.048mmol)和HATU(10mg，0.026mmol)。在环境温度下搅拌反应混合物过夜并且通过反相柱色谱法用5％至50％乙腈/水洗脱来纯化，得到标题化合物(5.1mg，43％产率)。MS(apci)m/z＝499.1(M+H)。To a solution of 4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoic acid (Example 161, 12 mg, 0.024 mmol) in DMF (0.5 mL, 0.024 mmol) was added N-methylmorpholine (0.0079 mL, 0.072 mmol), followedby NH3 (0.5 M solution in dioxane) (0.096 mL, 0.048 mmol) and HATU (10 mg, 0.026 mmol). The reaction mixture was stirred at ambient temperature overnight and purified by reverse phase column chromatography eluting with 5% to 50% acetonitrile/water to give the title compound (5.1 mg, 43% yield). MS (apci) m/z = 499.1 (M+H).
实例163Example 163
4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-甲基-1H-吡唑-3-基)-N-甲基苯甲酰胺1-methyl-1H-pyrazol-3-yl)-N-methylbenzamide
根据实例162中所述的方法，用甲胺(2M THF溶液)替代NH3来制备。MS(apci)m/z＝513.1(M+H)。Prepared according to the method described in Example 162, substituting methylamine (2M in THF) forNH3 . MS (apci) m/z = 513.1 (M+H).
实例164Example 164
4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-甲基-1H-吡唑-3-基)-N,N-二甲基苯甲酰胺1-methyl-1H-pyrazol-3-yl)-N,N-dimethylbenzamide
根据实例162中所述的方法，用二甲胺(2M THF溶液)替代NH3来制备。MS(apci)m/z＝5527.1(M+H)。Prepared according to the method described in Example 162, substituting dimethylamine (2M in THF) forNH3 . MS (apci) m/z = 5527.1 (M+H).
实例165Example 165
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(4-(羟1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-(hydroxy基甲基)苯基)-1-甲基-1H-吡唑-5-基)脲(methyl)phenyl)-1-methyl-1H-pyrazol-5-yl)urea
在0℃、N2下向4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-甲基-1H-吡唑-3-基)苯甲酸甲酯(实例121；20mg，0.039mmol)在THF(2mL，0.081mmol)中的悬浮液中添加氢化锂铝(1M在甲苯中的双-THF溶液)(0.078mL，0.078mmol)。在0℃下搅拌反应混合物1小时，然后通过添加3μL H2O和3μL 1M NaOH水溶液，接着添加9μL H2O淬灭。在环境温度下搅拌混合物4小时，然后通过针筒过滤器过滤，用THF(2mL)冲洗，并且浓缩成白色固体。通过反相色谱法，用5％至50％乙腈/水洗脱来纯化固体，得到标题化合物(10mg，53％产率)。MS(apci)m/z＝486.1(M+H)。Toa suspension of methyl 4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate (Example 121; 20 mg, 0.039 mmol) in THF (2 mL, 0.081 mmol) was added lithium aluminum hydride (1 M in toluene bis-THF) (0.078 mL, 0.078 mmol) at 0° C. under N 2. The reaction mixture was stirred at 0° C. for 1 hour and then quenched by the addition of 3 μL H2 O and 3 μL 1 M aqueous NaOH solution, followed by 9 μL H2 O. The mixture was stirred at ambient temperature for 4 hours and then filtered through a syringe filter, rinsed with THF (2 mL), and concentrated to a white solid. The solid was purified by reverse phase chromatography eluting with 5% to 50% acetonitrile/water to give the title compound (10 mg, 53% yield).MS (apci) m/z = 486.1 (M+H).
实例166Example 166
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-甲基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(4-(甲基磺酰基)苯基)-1H-吡唑-5-基)脲(4-(Methylsulfonyl)phenyl)-1H-pyrazol-5-yl)urea
步骤A：制备1-甲基-3-(4-(甲硫基)苯基)-1H-吡唑-5-基氨基甲酸苯酯：根据实例1的步骤A，用1-甲基-3-(4-(甲硫基)苯基)-1H-吡唑-5-胺(中间体P121)替代3-叔丁基-1-苯基-1H-吡唑-5-胺来制备，得到产物。MS(apci)m/z＝340.0(M+H)。Step A:Preparation of phenyl 1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-ylcarbamate : Prepared according to Step A of Example 1, substituting 1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-amine (Intermediate P121) for 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine to give the product. MS (apci) m/z = 340.0 (M+H).
步骤B：制备1-甲基-3-(4-(甲基磺酰基)苯基)-1H-吡唑-5-基氨基甲酸苯酯：在0℃下向1-甲基-3-(4-(甲硫基)苯基)-1H-吡唑-5-基氨基甲酸苯酯(110mg，0.324mmol)在DCM(5mL，0.295mmol)中的溶液中一次性添加MCPBA(在H2O中70％至75％)(72.6mg，0.295mmol)。允许反应混合物升温至环境温度并且搅拌2小时，并且然后添加另一部分MCPBA(72.6mg，0.295mmol)。在环境温度下搅拌5小时后，用DCM(25mL)稀释混合物并且用饱和NaHCO3水溶液(2×10mL)和饱和Na2S2O3水溶液(3×10mL)洗涤。用MgSO4干燥有机层，过滤并且在真空中浓缩，得到粗产物(101mg，92.3％产率)。MS(apci)m/z＝372.0(M+H)。[0266] Step B:Preparation of phenyl 1-methyl-3-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-ylcarbamate : To a solution of phenyl 1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-ylcarbamate (110 mg, 0.324 mmol) in DCM (5 mL, 0.295 mmol) was added MCPBA (70% to 75% inH2O ) (72.6 mg, 0.295 mmol) in one portion at 0°C. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours, and then another portion of MCPBA (72.6 mg, 0.295 mmol) was added. After stirring at ambient temperature for 5 hours, the mixture was diluted with DCM (25 mL) and washed with saturated aqueousNaHCO3 (2 x 10 mL) and saturatedaqueousNa2S2O3 (3 x10 mL). The organic layer was dried over MgSO4 , filtered and concentrated in vacuo to give the crude product (101 mg, 92.3% yield).MS (apci) m/z=372.0 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-甲基-3-(4-(甲基磺酰基)苯基)-1H-吡唑-5-基)脲：根据实例1的步骤B，用1-甲基-3-(4-(甲基磺酰基)苯基)-1H-吡唑-5-基氨基甲酸苯酯替代3-叔丁基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯并且用制备F的化合物替代制备B的化合物来制备。MS(apci)m/z＝534.1(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-yl)urea : Prepared according to step B of Example 1, substituting phenyl 1-methyl-3-(4-(methylsulfonyl )phenyl)-1H-pyrazol-5-ylcarbamate for phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate and substituting the compound of Preparation F for the compound of Preparation B. MS (apci) m/z = 534.1 (M+H).
实例167Example 167
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-氟-3-甲1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-3-methyl基-1-苯基-1H-吡唑-5-基)脲1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备3-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯：根据实例1步骤A的方法，用3-甲基-1-苯基-1H-吡唑-5-胺替代3-叔丁基-1-苯基-1H-吡唑-5-胺来制备，得到产物。MS(apci)m/z＝294.1(M+H)。Step A:Preparation of phenyl 3-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate : Following the procedure of Example 1, Step A, substituting 3-methyl-1-phenyl-1H-pyrazol-5-amine for 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine, the product was obtained. MS (apci) m/z = 294.1 (M+H).
步骤B：制备4-氟-3-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯：在环境温度下向3-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(20mg，0.0682mmol)在乙腈(0.5mL)中的溶液中分数小份添加氟试剂(Selectfluor)(26.6mg，0.0750mmol)并且搅拌反应混合物过夜。通过反相柱色谱法，用5％至65％乙腈/水洗脱来直接纯化反应混合物，得到呈白色泡沫状固体状的产物(12.4mg，58.4％产率)。MS(apci)m/z＝312.0(M+H)。Step B:Preparation of 4-fluoro-3-methyl-1-phenyl-1H-pyrazol-5-ylcarbamic acid phenyl ester : To a solution of 3-methyl-1-phenyl-1H-pyrazol-5-ylcarbamic acid phenyl ester (20 mg, 0.0682 mmol) in acetonitrile (0.5 mL) was added fluorine reagent (Selectfluor) (26.6 mg, 0.0750 mmol) in small portions at ambient temperature and the reaction mixture was stirred overnight. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 65% acetonitrile/water to give the product (12.4 mg, 58.4% yield) as a white foamy solid. MS (apci) m/z=312.0 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-氟-3-甲基-1-苯基-1H-吡唑-5-基)脲：根据实例1步骤B的方法，用4-氟-3-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代3-叔丁基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯并且用制备F的化合物替代制备B的化合物来制备。MS(apci)m/z＝474.1(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-3-methyl-1-phenyl-1H-pyrazol-5-yl)urea : Prepared according to the procedure of Example 1, Step B, substituting phenyl 4-fluoro-3-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate and substituting the compound of Preparation F for the compound of Preparation B. MS (apci) m/z=474.1 (M+H).
实例168Example 168
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-氟-1-甲1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-1-methyl基-3-苯基-1H-吡唑-5-基)脲3-phenyl-1H-pyrazol-5-yl)urea
使用与实例167相同的程序，用1-甲基-3-苯基-1H-吡唑-5-胺替代3-甲基-1-苯基-1H-吡唑-5-胺来制备。MS(apci)m/z＝474.1(M+H)。Prepared using the same procedure as Example 167, substituting 1-methyl-3-phenyl-1H-pyrazol-5-amine for 3-methyl-1-phenyl-1H-pyrazol-5-amine. MS (apci) m/z = 474.1 (M+H).
实例169Example 169
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-氟-1,3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-1,3-二苯基-1H-吡唑-5-基)脲diphenyl-1H-pyrazol-5-yl)urea
使用与实例167相同的程序，用1,3-二-苯基-1H-吡唑-5-胺替代3-甲基-1-苯基-1H-吡唑-5-胺来制备。MS(apci)m/z＝536.1(M+H)。Prepared using the same procedure as Example 167, substituting 1,3-diphenyl-1H-pyrazol-5-amine for 3-methyl-1-phenyl-1H-pyrazol-5-amine. MS (apci) m/z = 536.1 (M+H).
实例170Example 170
4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-甲基-1H-吡唑-3-基)苯甲酸2-甲氧基乙酯2-Methoxyethyl 1-methyl-1H-pyrazol-3-yl)benzoate
步骤A：制备4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-甲基-1H-吡唑-3-基)苯甲酸锂：在0℃下向4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-甲基-1H-吡唑-3-基)苯甲酸甲酯(实例121；158mg，0.308mmol)在THF(4mL，0.308mmol)和MeOH(2.00mL，49.4mmol)中的溶液中添加LiOH(2M水溶液)(0.308mL，0.615mmol)。使反应混合物升温至环境温度并且搅拌48小时。添加另一部分LiOH(70μL，0.4当量)并且再搅拌反应混合物4天。将反应混合物浓缩至干燥并且在假定定量产率下直接用于下一步中。MS(apci)m/z＝500.1(M+H)。[0266] Step A:Preparation of lithium 4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate : To a solution of methyl 4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate (Example 121; 158 mg, 0.308 mmol) in THF (4 mL, 0.308 mmol) and MeOH (2.00 mL, 49.4 mmol) was added LiOH (2M in water) (0.308 mL, 0.615 mmol) at 0°C. The reaction mixture was allowed to warm to ambient temperature and stirred for 48 hours. Another portion of LiOH (70 μL, 0.4 eq) was added and the reaction mixture was stirred for another 4 days. The reaction mixture was concentrated to dryness and used directly in the next step assuming quantitative yield. MS (apci) m/z=500.1 (M+H).
步骤B：制备4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-甲基-1H-吡唑-3-基)苯甲酸2-甲氧基乙酯：向4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-甲基-1H-吡唑-3-基)苯甲酸锂(15mg，0.030mmol)在DMF(0.5mL，0.030mmol)中的溶液中添加DIEA(0.016mL，0.089mmol)和2-甲氧基乙醇(9.0mg，0.12mmol)，接着添加HATU(17mg，0.045mmol)。在环境温度下搅拌反应混合物过夜，然后通过反相柱色谱法用5％至65％乙腈/水洗脱来直接纯化，得到呈白色泡沫状固体状的产物(1.8mg，11％产率)。MS(apci)m/z＝558.0(M+H)。Step B:Preparation of 2-methoxyethyl 4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate : To a solution of lithium 4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate (15 mg, 0.030 mmol) in DMF (0.5 mL, 0.030 mmol) was added DIEA (0.016 mL, 0.089 mmol) and 2-methoxyethanol (9.0 mg, 0.12 mmol) followed by HATU (17 mg, 0.045 mmol). The reaction mixture was stirred at ambient temperature overnight and then directly purified by reverse phase column chromatography eluting with 5% to 65% acetonitrile/water to give the product as a white foamy solid (1.8 mg, 11% yield). MS (apci) m/z=558.0 (M+H).
实例171Example 171
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(5,5-二氧1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5,5-difluorophenyl)-化-2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基)脲2-Phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea
步骤A：制备2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-胺：使4-氧代四氢噻吩-3-甲腈(1.00g，7.86mmol)和苯肼盐酸盐(1.25g，8.65mmol)在绝对EtOH(40mL，7.86mmol)中的悬浮液回流2小时。浓缩混合物并且用1N NaOH水溶液(40mL)湿磨残余物。通过过滤收集固体，依序用0.1N NaOH水溶液、水和己烷洗涤，然后在真空中干燥，得到呈白色固体状的产物(1.62g，95％产率)。MS(apci)m/z＝218.1。Step A:Preparation of 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine : A suspension of 4-oxotetrahydrothiophene-3-carbonitrile (1.00 g, 7.86 mmol) and phenylhydrazine hydrochloride (1.25 g, 8.65 mmol) in absolute EtOH (40 mL, 7.86 mmol) was refluxed for 2 hours. The mixture was concentrated and the residue was triturated with 1N aqueous NaOH (40 mL). The solid was collected by filtration, washed sequentially with 0.1N aqueous NaOH, water, and hexanes, and then dried in vacuo to give the product as a white solid (1.62 g, 95% yield). MS (apci) m/z = 218.1.
步骤B：制备2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基氨基甲酸苯酯：在环境温度下向2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-胺(500mg，2.30mmol)在EtOAc(10.0mL，2.30mmol)中的悬浮液中添加NaOH(2.30mL，2M水溶液，4.60mmol)，接着逐滴添加氯甲酸苯酯(0.40mL，3.22mmol)。搅拌2小时后，再添加氯甲酸苯酯(0.14mL)。继续搅拌5分钟，并且然后添加另一部分氯甲酸苯酯(0.081mL)并且再搅拌混合物16小时。用EtOAc稀释反应混合物并且分离各相。用水和盐水(各25mL)洗涤有机相，经Na2SO4干燥，过滤并且浓缩。通过反相柱色谱法，用5％至70％乙腈/水洗脱来纯化残余物，得到呈白色固体状(83％纯度)的产物(0.50g，64％产率)。MS(apci)m/z＝338.1。Step B:Preparation of phenyl 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate : To a suspension of 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine (500 mg, 2.30 mmol) in EtOAc (10.0 mL, 2.30 mmol) was added NaOH (2.30 mL, 2M aqueous solution, 4.60 mmol) at ambient temperature, followed by dropwise addition of phenyl chloroformate (0.40 mL, 3.22 mmol). After stirring for 2 hours, additional phenyl chloroformate (0.14 mL) was added. Stirring was continued for 5 minutes, and then another portion of phenyl chloroformate (0.081 mL) was added and the mixture was stirred for an additional 16 hours. The reaction mixture was diluted with EtOAc and the phases were separated. The organic phase was washed with water and brine (25 mL each), dried over Na2 SO4 , filtered and concentrated. The residue was purified by reverse phase column chromatography eluting with 5% to 70% acetonitrile/water to give the product (0.50 g, 64% yield) as a white solid (83% purity).MS (apci) m/z=338.1.
步骤C：制备(5,5-二氧化-2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基)氨基甲酸苯酯：在0℃下向2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基氨基甲酸苯酯(100mg，0.29mmol)在DCM(5mL)中的乳状溶液中添加MCPBA(170mg，70％至75％水复合物，0.74mmol)。将混合物从浴中去除并且在环境温度下搅拌10分钟，然后用DCM(20mL)稀释并且依序用饱和NaHCO3(3×10mL)、饱和Na2S2O3(2×10mL)和盐水(10mL)洗涤。经Na2SO4干燥有机层并且浓缩，得到呈浅橙色泡沫状的产物(107mg，98％产率)，其未经纯化即供使用。MS(apci)m/z＝371.4。Step C:Preparation of phenyl (5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate: To a milky solution of phenyl 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-ylcarbamate (100 mg, 0.29 mmol) in DCM (5 mL) was added MCPBA (170 mg, 70% to 75% aqueous complex, 0.74 mmol) at 0° C. The mixture was removed from the bath and stirred at ambient temperature for 10 minutes, then diluted with DCM (20 mL) and washed sequentially with saturated NaHCO3 (3×10 mL), saturated Na2 S2 O3 (2×10 mL), and brine (10 mL). The organic layer was dried overNa2SO4 and concentrated to give the product as a light orange foam (107 mg, 98% yield) which was used without purification.MS (apci) m/z = 371.4.
步骤D：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(5,5-二氧化-2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基)脲：向(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺三氟乙酸盐(制备E；60mg，0.12mmol)和(5,5-二氧化-2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基)氨基甲酸苯酯(50.3mg，0.14mmol)在无水DMA(2mL)中的溶液中添加DIEA(97μL，0.56mmol)。在环境温度下搅拌混合物15小时。然后将反应混合物分配于饱和NH4Cl(20mL)与EtOAc(10mL)之间。用EtOAc(2×10mL)萃取水层并且用水(5×10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥并且浓缩。通过二氧化硅柱色谱法，用2％MeOH/DCM洗脱来纯化粗产物，得到呈浅黄色泡沫状的产物(33mg，50％产率)。MS(apci)m/z＝532.1。[0266] Step D:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea : To a solution of (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine trifluoroacetate (Preparation E; 60 mg, 0.12 mmol) and phenyl (5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)carbamate (50.3 mg, 0.14 mmol) in anhydrous DMA (2 mL) was added DIEA (97 μL, 0.56 mmol). The mixture was stirred at ambient temperature for 15 hours. The reaction mixture was then partitioned between saturatedNH4Cl (20 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with water (5 x 10 mL) and brine (10mL ), then dried overNa2SO4 and concentrated. The crude product was purified by silica column chromatography eluting with 2% MeOH/DCM to give the product as a light yellow foam (33 mg, 50% yield). MS (apci) m/z = 532.1.
实例172Example 172
1-(5,5-二氧化-2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基)-3-((3S,4R)-1-(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)-3-((3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)脲1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea
根据用于实例171的程序，在步骤D中用(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备D)替代(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺三氟乙酸盐(制备E)来制备。MS(apci)m/z＝496.0(M+H)。Prepared according to the procedure used for Example 171, substituting (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation D) for (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine trifluoroacetate (Preparation E) in Step D. MS (apci) m/z = 496.0 (M+H).
实例173Example 173
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(5,5-二氧1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5,5-difluorophenyl)-化-2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-基)脲2-Phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea
使用与实例171相同的程序，用(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺三氟乙酸盐(制备E)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。MS(apci)m/z＝532.0(M+H)。Prepared using the same procedure as Example 171, substituting (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine trifluoroacetate (Preparation E) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F). MS (apci) m/z=532.0 (M+H).
实例174Example 174
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-(甲磺酰基)乙氧基)-1-苯基-1H-吡唑-5-基)脲(2-(Methylsulfonyl)ethoxy)-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备4-甲基-3-(2-(甲硫基)乙氧基)-1-苯基-1H-吡唑-5-基氨基甲酸苯酯：根据对于实例171步骤B所述的方法，用4-甲基-3-(2-(甲硫基)乙氧基)-1-苯基-1H-吡唑-5-胺(中间体P206)替代2-苯基-4,6-二氢-2H-噻吩并[3,4-c]吡唑-3-胺来制备。MS(apci)m/z＝384.0(M+H)。Step A:Preparation of phenyl 4-methyl-3-(2-(methylthio)ethoxy)-1-phenyl-1H-pyrazol-5-ylcarbamate: Prepared according to the procedure described for Example 171, Step B, substituting 4-methyl-3-(2-(methylthio)ethoxy)-1-phenyl-1H-pyrazol-5-amine (Intermediate P206) for 2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-amine. MS (apci) m/z = 384.0 (M+H).
步骤B：制备4-甲基-3-(2-(甲基磺酰基)乙氧基)-1-苯基-1H-吡唑-5-基氨基甲酸苯酯：用THF(10mL)处理4-甲基-3-(2-(甲硫基)乙氧基)-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(0.217g，0.566mmol)并且冷却至0℃。将3-氯过氧苯甲酸(MCPBA)与THF(4mL)的溶液添加至反应混合物中。搅拌1小时后，使混合物升温至环境温度并且搅拌2小时。用EtOAc处理反应混合物，用Na2S2O3和水淬灭，用EtOAc萃取，用NaHCO3和盐水洗涤，经MgSO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法纯化所得到的粗产物，得到产物(0.207g，88.0％产率)。MS(apci)m/z＝416.0(M+H)。Step B:Preparation of phenyl 4-methyl-3-(2-(methylsulfonyl)ethoxy)-1-phenyl-1H-pyrazol-5 -ylcarbamate : Phenyl 4-methyl-3-(2-(methylthio)ethoxy)-1-phenyl-1H-pyrazol-5-ylcarbamate (0.217 g, 0.566 mmol) was treated with THF (10 mL) and cooled to 0° C. A solution of 3-chloroperoxybenzoic acid (MCPBA) and THF (4 mL) was added to the reaction mixture. After stirring for 1 hour, the mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was treated with EtOAc, quenched with Na2 S2 O3 and water, extracted with EtOAc, washed with NaHCO3 and brine, dried over MgSO4 , filtered and concentrated in vacuo. The resulting crude product was purified by silica column chromatography to give the product (0.207 g, 88.0% yield). MS (apci) m/z = 416.0 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-(2-(甲基磺酰基)乙氧基)-1-苯基-1H-吡唑-5-基)脲：在0℃下向在DCM(5mL)中的(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F；50mg，0.15mmol)中添加4-甲基-3-(2-(甲基磺酰基)乙氧基)-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(63mg，0.15mmol)，接着添加TEA(0.064mL，0.46mmol)。允许所得到的混合物升温至环境温度并且搅拌17小时。然后用EtOAc处理反应混合物，用饱和NH4Cl、饱和NaHCO3和盐水洗涤，用MgSO4干燥，过滤，浓缩，并且通过二氧化硅柱色谱法用3％MeOH/DCM洗脱来纯化，得到呈白色固体状的标题产物(47mg，53％产率)。MS(apci)m/z＝578.0(M+H)。[0266] Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-(methylsulfonyl)ethoxy)-1-phenyl-1H-pyrazol-5-yl)urea : To (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F; 50 mg, 0.15 mmol) in DCM (5 mL) was added phenyl 4-methyl-3-(2-(methylsulfonyl)ethoxy)-1-phenyl-1H-pyrazol-5-ylcarbamate (63 mg, 0.15 mmol) followed by TEA (0.064 mL, 0.46 mmol) at 0°C. The resulting mixture was allowed to warm to ambient temperature and stirred for 17 hours. The reaction mixture was then treated with EtOAc, washed with saturatedNH4Cl , saturatedNaHCO3 and brine, dried overMgSO4 , filtered, concentrated and purified by silica column chromatography eluting with 3% MeOH/DCM to give the title product as a white solid (47 mg, 53% yield). MS (apci) m/z = 578.0 (M+H).
实例175Example 175
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-(羟基甲1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-(hydroxymethyl)基)-1-苯基-1H-吡唑-5-基)脲1-Phenyl-1H-pyrazol-5-yl)urea
在0℃、N2下向5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯基-1H-吡唑-4-甲酸乙酯(实例154；55mg，0.11mmol)在THF(2mL)中的溶液中逐滴添加氢化锂铝(1M在甲苯中的双-THF溶液，0.21mL，0.21mmol)。在0℃下搅拌反应物1.5小时，然后在环境温度下搅拌3小时。通过依序添加H2O(0.008mL)、1M NaOH水溶液(0.008mL)和H2O(0.024mL)淬灭反应。在环境温度下搅拌2小时后，过滤反应混合物，用THF(2mL)冲洗，并且在真空中浓缩。通过制备型TLC(0.5mm板)，用10％MeOH/DCM洗脱来纯化粗产物，得到呈白色固体状的产物(6mg，11％产率)。MS(apci)m/z＝472.0(M+H)。To a solution of ethyl 5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carboxylate (Example154 ; 55 mg, 0.11 mmol) in THF (2 mL) was added lithium aluminum hydride (1 M in toluene bis-THF, 0.21 mL, 0.21 mmol) dropwise at 0°C under N2. The reaction was stirred at 0°C for 1.5 hours and then at ambient temperature for 3 hours. The reaction was quenched by the sequential addition ofH2O (0.008 mL), 1 M aqueous NaOH (0.008 mL), andH2O (0.024 mL). After stirring at ambient temperature for 2 hours, the reaction mixture was filtered, rinsed with THF (2 mL), and concentrated in vacuo. The crude product was purified by preparative TLC (0.5 mm plate) eluting with 10% MeOH/DCM to give the product as a white solid (6 mg, 11% yield).MS (apci) m/z = 472.0 (M+H).
实例176Example 176
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-((R)-2,1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2,3-二羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
向1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(((S)-2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(实例76；65.0mg，0.111mmol)在THF(2mL)中的溶液中添加1M HCl水溶液(2mL)。在环境温度下搅拌反应混合物75分钟，并且然后浓缩以去除THF。用H2O(2mL)稀释残余水溶液并且用2MNaOH处理至pH＝10。用NaCl处理所得到的乳状混合物至饱和并且用EtOAc(2X)萃取。经MgSO4干燥合并的有机萃取物，并且通过填充的过滤。将洗脱液浓缩成无色凝胶，用Et2O洗涤并且在真空中干燥，得到呈白色固体状的标题化合物(53mg，88％产率)。MS(apci)m/z＝546.1(M+H)。To a solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea (Example 76; 65.0 mg, 0.111 mmol) in THF (2 mL) was added 1 M aqueous HCl (2 mL). The reaction mixture was stirred at ambient temperature for 75 minutes and then concentrated to remove THF. The residual aqueous solution was diluted withH2O (2 mL) and treated with 2M NaOH to pH = 10. The resulting milky mixture was treated with NaCl to saturation and extracted with EtOAc (2X). The combined organic extracts were dried overMgSO4 and filtered through a pack of Celite®. The eluate was concentrated to a colorless gel, washed withEt2O and dried in vacuo to give the title compound as a white solid (53 mg, 88% yield).MS (apci) m/z = 546.1 (M+H).
实例177Example 177
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-((S)-2,1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2,3-二羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据对于实例176所述的程序，由1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(((R)-2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(实例77；50.0mg，0.0854mmol)来制备，得到呈白色固体状的标题化合物(38mg，82％产率)。MS(apci)m/z＝546.2(M+H)。Prepared from 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea (Example 77; 50.0 mg, 0.0854 mmol) to give the title compound as a white solid (38 mg, 82% yield). MS (apci) m/z = 546.2 (M+H).
实例178Example 178
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(2-羟基1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxy乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲盐酸盐(ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea hydrochloride
在环境温度下向在DCM(2mL)中的1-(3-(2-(叔丁基二甲基硅烷氧基)乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(制备U-1；46mg，0.073mmol)中添加2N HCl(22mL，0.44mmol)。搅拌1小时后，在真空中浓缩反应混合物并且用Et2O冲洗，得到呈HCl盐形式的产物(45mg，100％产率)。MS(apci)m/z＝516.1(M+H)。To 1-(3-(2-(tert-butyldimethylsilyloxy)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (Preparation U-1; 46 mg, 0.073 mmol) in DCM (2 mL) was added 2N HCl (22 mL, 0.44 mmol) at ambient temperature. After stirring for 1 hour, the reaction mixture was concentrated in vacuo and rinsed withEt2O to give the product as an HCl salt (45 mg, 100% yield). MS (apci) m/z = 516.1 (M+H).
实例179Example 179
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-((S)-2-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲盐酸盐(hydroxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea hydrochloride
在环境温度下向在DCM(2mL)中的1-(3-((S)-2-(叔丁基二甲基硅烷氧基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(制备U-2；33mg，0.051mmol)中添加2N HCl(0.15mL，0.31mmol)。搅拌1小时后，在真空中浓缩反应混合物并且用Et2O冲洗，得到产物HCl盐(29mg，100％产率)。MS(apci)m/z＝530.3(M+H)。To 1-(3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (Preparation U-2; 33 mg, 0.051 mmol) in DCM (2 mL) was added 2N HCl (0.15 mL, 0.31 mmol) at ambient temperature. After stirring for 1 hour, the reaction mixture was concentrated in vacuo and rinsed withEt2O to give the product HCl salt (29 mg, 100% yield). MS (apci) m/z = 530.3 (M+H).
实例180Example 180
1-((3R,4S)-4-羟基-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,1-((3R,4S)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲5,6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备(3R,4R)-3-叠氮基-4-羟基吡咯烷-1-甲酸叔丁酯：在环境温度、氮气氛围下搅拌6-氧杂-3-氮杂双环[3.1.0]己烷-3-甲酸叔丁酯(15.42g，83.25mmol)、氯化(1S,2S)-(-)-[1,2-环己烷二氨基-N,N'-双(3,5-二-叔丁基亚水杨基)]铬(III)(1.181g，1.665mmol)和叠氮基三甲基硅烷(12.79mL，91.58mmol)18小时。用MeOH(100mL)和K2CO3(13.81g，99.90mmol)处理所得到的暗红棕色混合物并且在环境温度下搅拌反应物5小时。通过垫过滤溶液，浓缩并且将其溶解于EtOAc(100mL)和水(50mL)中。分离各层并且用EtOAc萃取水层。用饱和NaHCO3水溶液、水和盐水洗涤合并的有机萃取物，用MgSO4干燥并且浓缩，得到棕色油状物。通过二氧化硅柱色谱法，用20％EtOAc/己烷洗脱来纯化油状物，得到标题化合物(ee＝93％，3.99g，102％产率)。MS(apci)m/z＝129.0(M+H-Boc)。Step A:Preparation of tert-butyl (3R,4R)-3-azido-4-hydroxypyrrolidine-1-carboxylate : tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (15.42 g, 83.25 mmol), (1S,2S)-(-)-[1,2-cyclohexanediamino-N,N'-bis(3,5-di-tert-butylsalicylene)]chromium(III) chloride (1.181 g, 1.665 mmol) and trimethylsilylazide (12.79 mL, 91.58 mmol) were stirred at ambient temperatureunder nitrogen for 18 hours. The resulting dark red-brown mixture was treated with MeOH (100 mL) andK2CO3 (13.81 g, 99.90 mmol) and the reaction was stirred at ambient temperature for 5 hours. The solution was filtered through a pad, concentrated and dissolved in EtOAc (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with saturated NaHCO3 aqueous solution, water and brine, dried over MgSO4 and concentrated to give a brown oil. The oil was purified by silica column chromatography using 20% EtOAc/hexane elution to give the title compound (ee=93%, 3.99 g, 102% yield). MS (apci) m/z=129.0 (M+H-Boc).
步骤B：制备(3R,4R)-4-叠氮基吡咯烷-3-醇盐酸盐：将(3R,4R)-3-叠氮基-4-羟基吡咯烷-1-甲酸叔丁酯(9.0g，39mmol)和4N HCl的二噁烷溶液(15mL，59mmol)合并在DCM(30mL)中并且在环境温度下搅拌18小时。在真空中浓缩反应物，得到呈黄色油状的标题化合物(6.5g，100％产率)。MS(apci)m/z＝129.0(M+H)。Step B:Preparation of (3R,4R)-4-azidopyrrolidin-3-ol hydrochloride : tert-Butyl (3R,4R)-3-azido-4-hydroxypyrrolidine-1-carboxylate (9.0 g, 39 mmol) and 4N HCl in dioxane (15 mL, 59 mmol) were combined in DCM (30 mL) and stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo to give the title compound (6.5 g, 100% yield) as a yellow oil. MS (apci) m/z = 129.0 (M+H).
步骤C：制备(3R,4R)-4-叠氮基-1-(2-甲氧基乙基)吡咯烷-3-醇：将(3R,4R)-4-叠氮基吡咯烷-3-醇盐酸盐(6.5g，39.5mmol)、1-溴-2-甲氧基乙烷(6.59g，47.4mmol)和DIEA(13.8mL，79.0mmol)合并在10mL DMF中并且在环境温度下搅拌18小时。添加MP-TsOH(39.5g，158mmol)并且振荡反应物1小时，过滤并且用DCM洗涤树脂。通过与7N NH3的MeOH溶液(113mL，790mmol)和DCM(113mL)一起振荡1小时从树脂释放胺。过滤反应物并且用DCM洗涤树脂。浓缩合并的滤液，得到粗标题化合物(7.09g，96.4％产率)。MS(apci)m/z＝187.0(M+H)。Step C:preparation of (3R, 4R)-4-azido-1-(2-methoxyethyl) pyrrolidin-3-ol : (3R, 4R)-4-azido-1-(2-methoxyethyl) pyrrolidin-3-ol hydrochloride (6.5g, 39.5mmol), 1-bromo-2-methoxyethane (6.59g, 47.4mmol) and DIEA (13.8mL, 79.0mmol) are combined in 10mL DMF and stirred at ambient temperature for 18 hours. Add MP-TsOH (39.5g, 158mmol) and oscillate the reaction for 1 hour, filter and wash the resin with DCM. By with 7N NH3 MeOH solution (113mL, 790mmol) and DCM (113mL), oscillate for 1 hour from the resin and release amine. Filter the reaction and wash the resin with DCM. Concentrate the combined filtrate to obtain thick title compound (7.09g, 96.4% yield). MS (apci) m/z = 187.0 (M+H).
步骤D：制备(3R,4R)-4-氨基-1-(2-甲氧基乙基)吡咯烷-3-醇：将(3R,4R)-4-叠氮基-1-(2-甲氧基乙基)吡咯烷-3-醇(3.0g，16.1mmol)与10％Pd/C(1.71g，1.61mmol)合并在40mL MeOH中并且在40psi H2下在帕尔振荡器中振荡反应物三天。通过过滤反应物并且浓缩，得到呈棕色油状的标题化合物(2.53g，98.0％产率)。MS(apci)m/z＝161.1(M+H)。Step D:Preparation of (3R,4R)-4-amino-1-(2-methoxyethyl)pyrrolidin-3-ol : (3R,4R)-4-azido-1-(2-methoxyethyl)pyrrolidin-3-ol (3.0 g, 16.1 mmol) was combined with 10% Pd/C (1.71 g, 1.61 mmol) in 40 mL of MeOH and the reaction was shaken in a Parr shakerunder 40 psi H for three days. The reaction was filtered and concentrated to give the title compound (2.53 g, 98.0% yield) as a brown oil. MS (apci) m/z = 161.1 (M+H).
步骤E：制备(3R,4R)-4-羟基-1-(2-甲氧基乙基)吡咯烷-3-基氨基甲酸叔丁酯：将(3R,4R)-4-氨基-1-(2-甲氧基乙基)吡咯烷-3-醇(2.50g，15.6mmol)、Boc2O(4.09g，18.7mmol)和PS-DMAP(0.191g，1.56mmol)合并在50mL DCM中并且在环境温度下振荡18小时。过滤反应物，浓缩并且通过二氧化硅柱色谱法用5％至20％EtOAc/己烷洗脱来纯化，得到标题化合物(3.17g，78.0％产率)。MS(apci)m/z＝261.0(M+H)。Step E:Preparation of tert-butyl (3R,4R)-4-hydroxy-1-(2-methoxyethyl)pyrrolidin-3-ylcarbamate : (3R,4R)-4-amino-1-(2-methoxyethyl)pyrrolidin-3-ol (2.50 g, 15.6 mmol), Boc2 O (4.09 g, 18.7 mmol) and PS-DMAP (0.191 g, 1.56 mmol) were combined in 50 mL of DCM and shaken at ambient temperature for 18 hours. The reaction was filtered, concentrated and purified by silica column chromatography eluting with 5% to 20% EtOAc/hexanes to give the title compound (3.17 g, 78.0% yield). MS (apci) m/z=261.0 (M+H).
步骤F：制备(R)-1-(2-甲氧基乙基)-4-氧代吡咯烷-3-基氨基甲酸叔丁酯：将乙二酰氯(33.51μL，0.3841mmol)在5mL DCM中的溶液冷却至-78℃并且逐滴添加DMSO(54.52μL，0.7683mmol)。搅拌反应物15分钟并且逐滴添加(3R,4R)-4-羟基-1-(2-甲氧基乙基)吡咯烷-3-基氨基甲酸叔丁酯(50mg，0.1921mmol)在2mL DCM中的溶液。允许反应物经1小时升温至-40℃，并且然后冷却至-78℃。逐滴添加三乙胺(267.7μL，1.921mmol)，并且允许反应物经1小时升温至0℃，然后用水淬灭并且用乙醚(40mL)萃取。经MgSO4干燥有机层，过滤并且浓缩，得到粗标题化合物(32mg，65％产率)。MS(apci)m/z＝259.0(M+H)。Step F:preparation of (R) -1- (2- methoxyethyl) -4- oxopyrrolidin-3-ylcarbamic acid tert-butyl ester : a solution of oxalyl chloride (33.51 μ L, 0.3841 mmol) in 5 mL of DCM was cooled to -78 ° C and DMSO (54.52 μ L, 0.7683 mmol) was added dropwise. The reaction was stirred for 15 minutes and a solution of (3R, 4R) -4- hydroxy -1- (2- methoxyethyl) pyrrolidin-3-ylcarbamic acid tert-butyl ester (50 mg, 0.1921 mmol) in 2 mL of DCM was added dropwise. The reaction was allowed to warm to -40 ° C over 1 hour and then cooled to -78 ° C. Triethylamine (267.7 μ L, 1.921 mmol) was added dropwise and the reaction was allowed to warm to 0 ° C over 1 hour, then quenched with water and extracted with ether (40 mL). The organic layer was dried over MgSO4 , filtered and concentrated to give the crude title compound (32 mg, 65% yield). MS (apci) m/z = 259.0 (M+H).
步骤G：制备(3R,4S)-4-羟基-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯：将(R)-1-(2-甲氧基乙基)-4-氧代吡咯烷-3-基氨基甲酸叔丁酯(17.0mg，0.0658mmol)溶解于THF(2mL)中并且将溶液冷却至-78℃。逐滴添加苯基锂的二丁醚溶液(395μL，0.197mmol)并且在-78℃下搅拌反应物1小时并且然后允许其经1小时升温至环境温度。将反应物倒入盐水(10mL)中并且用数份乙醚萃取。干燥合并的有机萃取物，浓缩并且通过反相柱色谱法用0％至50％乙腈/水洗脱来纯化，得到呈与(3R,4R)-4-羟基-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯约4:1混合物形式的标题化合物(8.5mg，38％产率)。MS(apci)m/z＝337.1(M+H)。Step G:Preparation of tert-butyl (3R, 4S)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate: tert-butyl (R)-1-(2-methoxyethyl)-4-oxopyrrolidin-3-ylcarbamate (17.0 mg, 0.0658 mmol) was dissolved in THF (2 mL) and the solution was cooled to -78 ° C. A solution of phenyllithium in dibutyl ether (395 μL, 0.197 mmol) was added dropwise and the reaction was stirred at -78 ° C for 1 hour and then allowed to warm to ambient temperature over 1 hour. The reaction was poured into brine (10 mL) and extracted with several portions of diethyl ether. The combined organic extracts were dried, concentrated, and purified by reverse phase column chromatography eluting with 0% to 50% acetonitrile/water to afford the title compound (8.5 mg, 38% yield) as a 4:1 mixture with tert-butyl (3R,4R)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate. MS (apci) m/z = 337.1 (M+H).
步骤H：制备(3S,4R)-4-氨基-1-(2-甲氧基乙基)-3-苯基吡咯烷-3-醇二盐酸盐：向来自步骤G的产物(7.0mg，0.0208mmol)在0.1mL异丙醇中的溶液中添加HCl的异丙醇溶液(29.7μL，0.208mmol)。在环境温度下搅拌反应混合物1小时，然后浓缩，得到呈与(3R,4R)-4-氨基-1-(2-甲氧基乙基)-3-苯基吡咯烷-3-醇二盐酸盐约4:1混合物形式的标题化合物(6.5mg，101％产率)。MS(apci)m/z＝237.1(M+H)。Step H:Preparation of (3S,4R)-4-amino-1-(2-methoxyethyl)-3-phenylpyrrolidin-3-ol dihydrochloride : To a solution of the product from Step G (7.0 mg, 0.0208 mmol) in 0.1 mL of isopropanol was added HCl in isopropanol (29.7 μL, 0.208 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated to afford the title compound (6.5 mg, 101% yield) as a approximately 4:1 mixture with (3R,4R)-4-amino-1-(2-methoxyethyl)-3-phenylpyrrolidin-3-ol dihydrochloride. MS (apci) m/z = 237.1 (M+H).
步骤I：制备1-((3R,4S)-4-羟基-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将来自步骤H的产物(6.5mg，0.021mmol)和DIEA(11μL，0.063mmol)合并在0.5mL DCM中并且冷却至0℃。添加2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(7.4mg，0.023mmol)并且允许反应物经1小时升温至环境温度。浓缩反应物并且通过反相柱色谱法用0％至60％乙腈/水洗脱来纯化，得到标题化合物(3.8mg，39％产率)。MS(apci)m/z＝462.2(M+H)。Step I:Preparation of 1-((3R, 4S)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : The product from Step H (6.5 mg, 0.021 mmol) and DIEA (11 μL, 0.063 mmol) were combined in 0.5 mL of DCM and cooled to 0° C. Phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (7.4 mg, 0.023 mmol) was added and the reaction was allowed to warm to ambient temperature over 1 hour. The reaction was concentrated and purified by reverse phase column chromatography eluting with 0% to 60% acetonitrile/water to give the title compound (3.8 mg, 39% yield). MS (apci) m/z = 462.2 (M+H).
实例181Example 181
1-((3R,4S)-4-氟-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,1-((3R,4S)-4-fluoro-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
将1-((3R,4S)-4-羟基-1-(2-甲氧基乙基)-4-苯基-吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲与1-((3R,4R)-4-羟基-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲的约2:1混合物(5.0mg，0.011mmol)(如实例177步骤I中所述获得)溶解于DCM(2mL)中并且冷却至-78℃。添加DAST(1.7mg，0.011mmol)并且允许反应物缓慢地升温至环境温度过夜。用MeOH淬灭反应，浓缩并且通过反相MPLC纯化，得到呈与1-((3R,4R)-4-氟-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲约1:3混合物形式的标题化合物(2.6mg，40％产率)。不分离异构体。MS(apci)m/z＝464.1(M+H)。A 2:1 mixture of 1-((3R,4S)-4-hydroxy-1-(2-methoxyethyl)-4-phenyl-pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea and 1-((3R,4R)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea (5.0 mg, 0.011 mmol) (obtained as described in Example 177, Step 1) was dissolved in DCM (2 mL) and cooled to -78° C. DAST (1.7 mg, 0.011 mmol) was added and the reaction was allowed to slowly warm to ambient temperature overnight. The reaction was quenched with MeOH, concentrated, and purified by reverse-phase MPLC to afford the title compound (2.6 mg, 40% yield) as a 1:3 mixture with 1-((3R,4R)-4-fluoro-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea. Isomers were not separated. MS (apci) m/z = 464.1 (M+H).
实例182Example 182
1-(反式-4-苯基-1-(2-(三氟甲氧基)乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-1-(trans-4-phenyl-1-(2-(trifluoromethoxy)ethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备反式-3-苯基-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-甲酸叔丁酯：向反式-3-氨基-4-苯基吡咯烷-1-甲酸叔丁酯(制备A2；40mg，0.15mmol)在DMA(0.5mL，0.15mmol)中的溶液中添加2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(实例38步骤C；58mg，0.18mmol)，接着在冰浴中冷却。将DIEA(0.080mL，0.46mmol)添加至反应混合物中，然后允许其升温至环境温度过夜。通过反相柱色谱法，用5％至75％乙腈/水洗脱来直接纯化反应混合物，得到呈白色固体状的产物(30mg，41％产率)。MS(apci)m/z＝488.0(M+H)。Step A:Preparation of tert-butyl trans-3-phenyl-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate : To a solution of tert-butyl trans-3-amino-4-phenylpyrrolidine-1-carboxylate (Preparation A2; 40 mg, 0.15 mmol) in DMA (0.5 mL, 0.15 mmol) was added phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (Example 38, Step C; 58 mg, 0.18 mmol) followed by cooling in an ice bath. DIEA (0.080 mL, 0.46 mmol) was added to the reaction mixture which was then allowed to warm to ambient temperature overnight. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 75% acetonitrile/water to give the product as a white solid (30 mg, 41% yield).MS (apci) m/z = 488.0 (M+H).
步骤B：制备1-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)-3-(反式-4-苯基吡咯烷-3-基)脲盐酸盐：用4N HCl的二噁烷溶液处理反式-3-苯基-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-甲酸叔丁酯(30mg，0.062mmol)并且在环境温度下搅拌15小时，然后在真空中浓缩并且在Et2O中湿磨，得到产物(20mg，83％产率)。MS(apci)m/z＝388.1(M+H)。[0266] Step B:Preparation of 1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(trans-4-phenylpyrrolidin -3-yl)urea hydrochloride: tert-Butyl 3-phenyl-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate (30 mg, 0.062 mmol) was treated with 4N HCl in dioxane and stirred at ambient temperature for 15 hours, then concentrated in vacuo and triturated inEt2O to give the product (20 mg, 83% yield). MS (apci) m/z = 388.1 (M+H).
步骤C：制备1-(反式-4-苯基-1-(2-(三氟甲氧基)乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：向1-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)-3-(反式-4-苯基吡咯烷-3-基)脲盐酸盐(16mg，0.038mmol)的DMF(0.5mL)溶液中添加N-乙基-N-异丙基丙-2-胺(21μL，0.11mmol)和1-溴-2-(三氟甲氧基)乙烷(8.7mg，0.045mmol)并且在环境温度下搅拌3小时，然后加热至40℃，持续15小时。通过反相柱色谱法，用5％至75％乙腈/水洗脱来直接纯化反应混合物，得到标题化合物(10mg，50％产率)。MS(apci)m/z＝499.9(M+H)。Step C:Preparation of 1-(trans-4-phenyl-1-(2-(trifluoromethoxy)ethyl)pyrrolidin-3-yl)-3-(2-phenyl -2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea: To a solution of 1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(trans-4-phenylpyrrolidin-3-yl)urea hydrochloride (16 mg, 0.038 mmol) in DMF (0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (21 μL, 0.11 mmol) and 1-bromo-2-(trifluoromethoxy)ethane (8.7 mg, 0.045 mmol) and stirred at ambient temperature for 3 hours, then heated to 40°C for 15 hours. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 75% acetonitrile/water to give the title compound (10 mg, 50% yield).MS (apci) m/z=499.9 (M+H).
实例183Example 183
1-(反式-1-(2-(甲硫基)乙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢1-(trans-1-(2-(methylthio)ethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydro环戊二烯并[c]吡唑-3-基)脲Cyclopenta[c]pyrazol-3-yl)urea
如在实例182中，用(2-氯乙基)(甲基)硫烷替代1-溴-2-(三氟甲氧基)乙烷来制备，得到呈米色固体状的产物(2.6mg，24％产率)。MS(apci)m/z＝462.1(M+H)。Prepared as in Example 182, substituting (2-chloroethyl)(methyl)sulfane for 1-bromo-2-(trifluoromethoxy)ethane, to afford the product as a beige solid (2.6 mg, 24% yield). MS (apci) m/z = 462.1 (M+H).
实例184Example 184
1-((3S,4R)-1-((S)-2-甲氧基丙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-1-((3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：(S)-2-甲氧基丙基甲磺酸酯：将(S)-2-甲氧基丙-1-醇(451mg，5.00mmol)和DIEA(1.74mL，10.0mmol)在干燥CH2Cl2(4mL)中的溶液冷却至0℃并且经2分钟添加MsCl(0.406mL，5.25mmol)。搅拌混合物3小时，期间混合物达到环境温度。用冷却的H2O、饱和NaHCO3洗涤混合物并且经Na2SO4干燥。通过填充的过滤干燥的溶液并且浓缩，得到呈淡金色油状的标题产物(821mg，98％产率)。1H NMR(CDCl3)δ4.22(m,1H),4.13(m,1H),3.63(m,1H),3.40(s,3H),3.06(s,3H),1.20(d,J＝6.4Hz,3H)。Step A:(S)-2-methoxypropyl methanesulfonate : A solutionof (S)-2-methoxypropan-1-ol (451 mg, 5.00 mmol) and DIEA (1.74 mL, 10.0 mmol) in dryCH2Cl2 (4 mL) was cooled to 0°C and MsCl (0.406 mL, 5.25 mmol) was added over 2 minutes. The mixture was stirred for 3 hours, during which time the mixture reached ambient temperature. The mixture was washed with cooledH2O , saturatedNaHCO3 and dried overNa2SO4 . Thedried solution was filtered through a plug of Celite and concentrated to give the title product as a light golden oil (821 mg, 98% yield).1 H NMR (CDCl3 ) δ 4.22 (m, 1H), 4.13 (m, 1H), 3.63 (m, 1H), 3.40 (s, 3H), 3.06 (s, 3H), 1.20 (d, J = 6.4Hz, 3H).
步骤B：(3S,4R)-1-((S)-2-甲氧基丙基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯：向(3S,4R)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯(可商购获得，262mg，1.00mmol)和DIEA(348μL，2.00mmol)在DMF(2.0mL)中的溶液中添加(S)-2-甲氧基丙基甲磺酸酯(252mg，1.50mmol)。在60℃下加热反应物21小时并且再添加(S)-2-甲氧基丙基甲磺酸酯(84.0mg)。在60℃下加热反应混合物2小时，冷却至环境温度并且添加至H2O(8mL)中。用EtOAc(3X)萃取混合物并且用饱和NaCl(2X)洗涤合并的萃取物并且用MgSO4干燥。通过SiO2塞，用EtOAc洗脱来过滤干燥的溶液。浓缩溶液，得到呈淡金色糖浆状的粗标题化合物(462mg，138％产率)，其直接用于下一步骤中。MS(apci)m/z＝335.1(M+H)。Step B:tert-Butyl (3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-ylcarbamate : To a solution of tert-butyl (3S,4R)-4-phenylpyrrolidin-3-ylcarbamate (commercially available, 262 mg, 1.00 mmol) and DIEA (348 μL, 2.00 mmol) in DMF (2.0 mL) was added (S)-2-methoxypropyl methanesulfonate (252 mg, 1.50 mmol). The reaction was heated at 60° C. for 21 hours and additional (S)-2-methoxypropyl methanesulfonate (84.0 mg) was added. The reaction mixture was heated at 60° C. for 2 hours, cooled to ambient temperature and added to H2 O (8 mL). The mixture was extracted with EtOAc (3×) and the combined extracts were washed with saturated NaCl (2×) and dried over MgSO4 . The dried solution was filtered through a plug of SiO2 eluting with EtOAc. The solution was concentrated to give the crude title compound (462 mg, 138% yield) as a light golden syrup, which was used directly in the next step. MS (apci) m/z = 335.1 (M+H).
步骤C：(3S,4R)-1-((S)-2-甲氧基丙基)-4-苯基吡咯烷-3-胺二盐酸盐：向粗(3S,4R)-1-((S)-2-甲氧基丙基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯在EtOAc(10mL)中的溶液中添加4M HCl的二噁烷溶液(10.0mL，40.0mmol)。在环境温度下搅拌反应混合物3小时并且接着用MTBE(50mL)稀释。收集所得到的沉淀物，用MTBE洗涤并且在真空中干燥，得到呈粘性白色固体状的标题化合物(276mg，90％产率)。MS(apci)m/z＝235.1(M+H)。Step C:(3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-amine dihydrochloride : To a solution of crude tert-butyl (3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-ylcarbamate in EtOAc (10 mL) was added 4M HCl in dioxane (10.0 mL, 40.0 mmol). The reaction mixture was stirred at ambient temperature for 3 hours and then diluted with MTBE (50 mL). The resulting precipitate was collected, washed with MTBE and dried in vacuo to give the title compound (276 mg, 90% yield) as a sticky white solid. MS (apci) m/z=235.1 (M+H).
步骤D：1-((3S,4R)-1-((S)-2-甲氧基丙基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：向(3S,4R)-1-((S)-2-甲氧基丙基)-4-苯基吡咯烷-3-胺二盐酸盐(56.2mg，0.240mmol)在干燥DMF(0.8mL)中的溶液中添加DIEA(139μL，0.796mmol)并且在环境温度下搅拌混合物5分钟。添加2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(实例38步骤E；75.1mg，0.200mmol)并且在环境温度下搅拌混合物4小时。将混合物添加至H2O(5mL)中并且用EtOAc(3X)萃取。用1M NaOH(2X)、H2O和饱和NaCl洗涤合并的萃取物。用MgSO4干燥溶液，过滤并且在真空中浓缩。通过二氧化硅色谱法，用EtOAc洗脱来纯化残余物，得到呈蜡状白色固体状的标题化合物(31mg，34％产率)。MS(apci)m/z＝460.1(M+H)。Step D:1-((3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : To a solution of (3S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-amine dihydrochloride (56.2 mg, 0.240 mmol) in dry DMF (0.8 mL) was added DIEA (139 μL, 0.796 mmol) and the mixture was stirred at ambient temperature for 5 minutes. Phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (Example 38, Step E; 75.1 mg, 0.200 mmol) was added and the mixture was stirred at ambient temperature for 4 hours. The mixture was added toH2O (5 mL) and extracted with EtOAc (3X). The combined extracts were washed with 1 M NaOH (2X),H2O , and saturated NaCl. The solution was dried overMgSO4 , filtered, and concentrated in vacuo. The residue was purified by silica chromatography eluting with EtOAc to give the title compound (31 mg, 34% yield) as a waxy white solid. MS (apci) m/z = 460.1 (M+H).
实例185Example 185
1-((3,4-反式)-4-苯基-1-(4,4,4-三氟丁基)吡咯烷-3-基)-3-(2-苯基-2,4,5,1-((3,4-trans)-4-phenyl-1-(4,4,4-trifluorobutyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
如在实例182中，用4-溴-1,1,1-三氟丁烷替代1-溴-2-(三氟甲氧基)乙烷来制备，得到呈白色固体状的产物(10mg，57％产率)。MS(apci)m/z＝498.2(M+H)。Prepared as in Example 182, substituting 4-bromo-1,1,1-trifluorobutane for 1-bromo-2-(trifluoromethoxy)ethane, the product was obtained as a white solid (10 mg, 57% yield).MS (apci) m/z=498.2 (M+H).
实例186Example 186
1-((3S,4R)-1-(氰基甲基)-4-(3,4-二氟苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,1-((3S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备(3S,4R)-1-(氰基甲基)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯：向(3S,4R)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(100.0mg，0.3352mmol，购自ACS Scientific)和TEA(51.39μL，0.3687mmol)在THF(1.5mL)中的溶液中逐滴添加2-溴乙腈(25.68μL，0.3687mmol)。在环境温度下搅拌两小时后，过滤反应混合物并且浓缩。通过二氧化硅柱色谱法，用33％EtOAc/己烷洗脱来纯化粗物质，得到呈白色固体状的产物(98mg，87％产率)。MS(apci正离子)m/z＝338.0(M+H)。Step A:Preparation of tert-butyl (3S, 4R) -1- (cyanomethyl) -4- (3,4-difluorophenyl) pyrrolidin-3-ylcarbamate: To a solution of tert-butyl (3S, 4R) -4- (3,4-difluorophenyl) pyrrolidin-3-ylcarbamate (100.0 mg, 0.3352 mmol, purchased from ACS Scientific) and TEA (51.39 μL, 0.3687 mmol) in THF (1.5 mL) was added 2-bromoacetonitrile (25.68 μL, 0.3687 mmol) dropwise. After stirring for two hours at ambient temperature, the reaction mixture was filtered and concentrated. The crude material was purified by silica column chromatography eluting with 33% EtOAc / hexanes to give the product (98 mg, 87% yield) as a white solid. MS (apci positive ion) m / z = 338.0 (M + H).
步骤B：制备2-((3S,4R)-3-氨基-4-(3,4-二氟苯基)吡咯烷-1-基)乙腈盐酸盐：在环境温度下搅拌(3S,4R)-1-(氰基甲基)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(20mg，0.059mmol)在HCl(150μL，0.59mmol，4N二噁烷)中的混合物15分钟，然后在真空中浓缩，用乙醚湿磨并且在高真空下干燥，得到呈白色固体状的产物(16mg，99％产率)。MS(apci正离子)m/z＝238.0(M+H)。[0266] Step B:Preparation of 2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)acetonitrile hydrochloride : A mixture of tert-butyl (3S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (20 mg, 0.059 mmol) in HCl (150 μL, 0.59 mmol, 4N dioxane) was stirred at ambient temperature for 15 minutes, then concentrated in vacuo, triturated with ether and dried under high vacuum to give the product as a white solid (16 mg, 99% yield). MS (apci positive ion) m/z = 238.0 (M+H).
步骤C：制备1-((3S,4R)-1-(氰基甲基)-4-(3,4-二氟苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：在环境温度下向2-((3S,4R)-3-氨基-4-(3,4-二氟苯基)吡咯烷-1-基)乙腈盐酸盐(16mg，0.058mmol)和2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(19mg，0.058mmol)在DMA(0.5mL)中的澄清溶液中逐滴添加DIEA(0.041mL，0.23mmol)。搅拌1小时后，通过反相柱色谱法，用5％至55％乙腈/水洗脱来直接纯化反应混合物，得到呈白色固体状的产物(18mg，65％产率)。MS(apci正离子)m/z＝463.0(M+H)。Step C:Preparation of 1-((3S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : To a clear solution of 2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)acetonitrile hydrochloride (16 mg, 0.058 mmol) and phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (19 mg, 0.058 mmol) in DMA (0.5 mL) was added DIEA (0.041 mL, 0.23 mmol) dropwise at ambient temperature. After stirring for 1 hour, the reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 55% acetonitrile/water to give the product as a white solid (18 mg, 65% yield).MS (apci positive ion) m/z=463.0 (M+H).
实例187Example 187
1-((3S,4R)-1-(氰基甲基)-4-(3,4-二氟苯基)吡咯烷-3-基)-3-(3-(2-甲氧基乙1-((3S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-(2-methoxyethyl)氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(4-Methyl-1-phenyl-1H-pyrazol-5-yl)urea
在环境温度下向2-((3S,4R)-3-氨基-4-(3,4-二氟苯基)吡咯烷-1-基)乙腈盐酸盐(实例186步骤B，10mg，0.037mmol)和3-(2-甲氧基乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(13mg，0.037mmol)在DMA(180μL，0.037mmol)中的澄清溶液中逐滴添加DIEA(32μL，0.18mmol)。将反应物短暂(约1分钟)加热至约60℃，然后冷却至环境温度并且搅拌20分钟。通过反相柱色谱法，用5％至65％乙腈/水洗脱来直接纯化反应混合物，得到呈白色固体状的产物(12mg，64％产率)。MS(apci正离子)m/z＝511.1(M+H)。To a clear solution of 2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)acetonitrile hydrochloride (Example 186, Step B, 10 mg, 0.037 mmol) and phenyl 3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (13 mg, 0.037 mmol) in DMA (180 μL, 0.037 mmol) was added DIEA (32 μL, 0.18 mmol) dropwise at ambient temperature. The reaction was briefly heated to about 60 ° C. (about 1 minute) and then cooled to ambient temperature and stirred for 20 minutes. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 65% acetonitrile/water to give the product (12 mg, 64% yield) as a white solid. MS (apci positive ion) m/z=511.1 (M+H).
实例188Example 188
1-((3,4-反式)-1-(氰基甲基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢1-((3,4-trans)-1-(cyanomethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydro环戊二烯并[c]吡唑-3-基)脲Cyclopenta[c]pyrazol-3-yl)urea
步骤A：制备(3,4-反式)-1-(氰基甲基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯：向(3,4-反式)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯(206.0mg，0.7852mmol，制备A)和TEA(120.4μL，0.8637mmol)在THF(3mL)中的溶液中逐滴添加2-溴乙腈(60.16μL，0.8637mmol)。在环境温度下搅拌过夜后，过滤反应混合物并且浓缩，得到呈白色固体状的产物(230mg，97％产率)。MS(apci正离子)m/z＝302.1(M+H)。Step A:Preparation of tert-butyl (3,4-trans)-1-(cyanomethyl)-4-phenylpyrrolidin-3-ylcarbamate : To a solution of tert-butyl (3,4-trans)-4-phenylpyrrolidin-3-ylcarbamate (206.0 mg, 0.7852 mmol, Preparation A) and TEA (120.4 μL, 0.8637 mmol) in THF (3 mL) was added 2-bromoacetonitrile (60.16 μL, 0.8637 mmol) dropwise. After stirring overnight at ambient temperature, the reaction mixture was filtered and concentrated to give the product (230 mg, 97% yield) as a white solid. MS (apci positive ion) m/z=302.1 (M+H).
步骤B：制备2-((3,4-反式)-3-氨基-4-苯基吡咯烷-1-基)乙腈盐酸盐：在环境温度下搅拌(3,4-反式)-1-(氰基甲基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯(230mg，0.763mmol)和HCl(4770μL，19.1mmol，4N二噁烷)的混合物2小时，然后在真空中浓缩，用乙醚处理并且在高真空下干燥，得到呈浅黄色固体状的产物(180mg，99％产率)。MS(apci正离子)m/z＝202.1(M+H)。Step B:Preparation of 2-((3,4-trans)-3-amino-4-phenylpyrrolidin-1-yl)acetonitrile hydrochloride : A mixture of tert-butyl (3,4-trans)-1-(cyanomethyl)-4-phenylpyrrolidin-3-ylcarbamate (230 mg, 0.763 mmol) and HCl (4770 μL, 19.1 mmol, 4N dioxane) was stirred at ambient temperature for 2 hours, then concentrated in vacuo, treated with ether and dried under high vacuum to give the product as a light yellow solid (180 mg, 99% yield). MS (apci positive ion) m/z = 202.1 (M+H).
步骤C：制备1-((3,4-反式)-1-(氰基甲基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：在环境温度下向2-(3,4-反式)-3-氨基-4-苯基吡咯烷-1-基)乙腈盐酸盐(33mg，0.14mmol)和2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(40mg，0.13mmol)在DMA(630μL)中的澄清溶液中逐滴添加DIEA(110μL，0.63mmol)。在环境温度下搅拌过夜后，通过反相柱色谱法用5％至55％乙腈/水洗脱来直接纯化反应混合物，得到呈白色固体状的产物(45mg，84％产率)。MS(apci正离子)m/z＝427.1(M+H)。Step C:Preparation of 1-((3,4-trans)-1-(cyanomethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : To a clear solution of 2-(3,4-trans)-3-amino-4-phenylpyrrolidin-1-yl)acetonitrile hydrochloride (33 mg, 0.14 mmol) and phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (40 mg, 0.13 mmol) in DMA (630 μL) was added DIEA (110 μL, 0.63 mmol) dropwise at ambient temperature. After stirring overnight at ambient temperature, the reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 55% acetonitrile/water to give the product as a white solid (45 mg, 84% yield). MS (apci positive ion) m/z = 427.1 (M+H).
实例189Example 189
1-((3S,4R)-1-(氰基甲基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊1-((3S,4R)-1-(cyanomethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopentane二烯并[c]吡唑-3-基)脲Dieno[c]pyrazol-3-yl)urea
步骤A：制备(3S,4R)-1-(氰基甲基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯：向(3S,4R)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯(535mg，2.04mmol，购自ACS Scientific)和TEA(313μL，2.24mmol)在THF(8mL)中的溶液中逐滴添加2-溴乙腈(156μL，2.24mmol)。在环境温度下搅拌过夜后，过滤反应混合物并且在真空中浓缩。通过二氧化硅柱色谱法，用50％己烷/EtOAc洗脱来纯化粗物质，得到呈白色固体状的产物(510mg，83％产率)。MS(apci正离子)m/z＝302.0(M+H)。Step A:Preparation of tert-butyl (3S, 4R) -1- (cyanomethyl) -4-phenylpyrrolidin-3-ylcarbamate : To a solution of tert-butyl (3S, 4R) -4-phenylpyrrolidin-3-ylcarbamate (535 mg, 2.04 mmol, purchased from ACS Scientific) and TEA (313 μL, 2.24 mmol) in THF (8 mL) was added 2-bromoacetonitrile (156 μL, 2.24 mmol) dropwise. After stirring overnight at ambient temperature, the reaction mixture was filtered and concentrated in vacuo. The crude material was purified by silica column chromatography eluting with 50% hexane/EtOAc to give the product (510 mg, 83% yield) as a white solid. MS (apci positive ion) m/z=302.0 (M+H).
步骤B：制备2-((3S,4R)-3-氨基-4-苯基吡咯烷-1-基)乙腈盐酸盐：在环境温度下搅拌(3S,4R)-1-(氰基甲基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯(490mg，1.63mmol)和HCl(20mL，80mmol，4N二噁烷)的混合物2小时。在真空中浓缩反应物，用乙醚湿磨并且在高真空下干燥，得到浅黄色固体。LCMS显示此固体为以下两种产物的约1:2比率的混合物：2-((3S,4R)-3-氨基-4-苯基吡咯烷-1-基)乙腈盐酸盐与2-((3S,4R)-3-氨基-4-苯基吡咯烷-1-基)乙酰胺盐酸盐；MS(apci正离子)m/z分别为202.1和220.1(M+H)。两种产物的此混合物不经进一步纯化即直接用于下一步骤中。Step B:Preparation of 2-((3S,4R)-3-amino-4-phenylpyrrolidin-1-yl)acetonitrile hydrochloride : A mixture of tert-butyl (3S,4R)-1-(cyanomethyl)-4-phenylpyrrolidin-3-ylcarbamate (490 mg, 1.63 mmol) and HCl (20 mL, 80 mmol, 4N dioxane) was stirred at ambient temperature for 2 hours. The reaction was concentrated in vacuo, triturated with diethyl ether, and dried under high vacuum to give a light yellow solid. LCMS showed this solid to be a mixture of the following two products in a ratio of approximately 1:2: 2-((3S,4R)-3-amino-4-phenylpyrrolidin-1-yl)acetonitrile hydrochloride and 2-((3S,4R)-3-amino-4-phenylpyrrolidin-1-yl)acetamide hydrochloride; MS (apci positive ion) m/z 202.1 and 220.1 (M+H), respectively. This mixture of two products was used directly in the next step without further purification.
步骤C：制备1-((3S,4R)-1-(氰基甲基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：在环境温度下，向来自步骤B的粗产物(39mg，0.16mmol)在DMA(420μL，0.13mmol)中的澄清溶液中添加2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(40mg，0.13mmol)，接着添加DIEA(110μL，0.63mmol)并且搅拌反应混合物18小时。通过反相柱色谱法，用5％至54％乙腈/水洗脱来直接纯化反应混合物，得到呈白色固体状的标题产物(11mg，21％产率)。MS(apci正离子)m/z＝427.1(M+H)。Step C:Preparation of 1-((3S,4R)-1-(cyanomethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : To a clear solution of the crude product from Step B (39 mg, 0.16 mmol) in DMA (420 μL, 0.13 mmol) was added phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (40 mg, 0.13 mmol) followed by DIEA (110 μL, 0.63 mmol) at ambient temperature and the reaction mixture was stirred for 18 hours. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 54% acetonitrile/water to give the title product (11 mg, 21% yield) as a white solid. MS (apci positive ion) m/z = 427.1 (M+H).
实例190Example 190
2-((3R,4S)-3-苯基-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲2-((3R,4S)-3-phenyl-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea基)吡咯烷-1-基)乙酰胺1-Yl)pyrrolidin-1-yl)acetamide
在环境温度下向来自实例189步骤B的含有2-((3S,4R)-3-氨基-4-苯基吡咯烷-1-基)乙酰胺盐酸盐的粗产物(39mg，0.16mmol)在DMA(420μL，0.13mmol)中的澄清溶液中添加2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(40mg，0.13mmol)，接着添加DIEA(110μL，0.63mmol)，并且搅拌反应混合物18小时。通过反相柱色谱法，用5％至54％乙腈/水洗脱来直接纯化反应混合物，得到呈白色固体状的标题产物(20mg，36％产率)。MS(apci正离子)m/z＝445.1(M+H)。To a clear solution of 2-((3S,4R)-3-amino-4-phenylpyrrolidin-1-yl)acetamide hydrochloride (39 mg, 0.16 mmol) from Example 189, Step B, in DMA (420 μL, 0.13 mmol) was added phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (40 mg, 0.13 mmol) followed by DIEA (110 μL, 0.63 mmol) at ambient temperature and the reaction mixture was stirred for 18 hours. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 54% acetonitrile/water to give the title product (20 mg, 36% yield) as a white solid. MS (apci positive ion) m/z=445.1 (M+H).
实例191Example 191
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-羟基乙基)吡咯烷-3-基)-3-(3,4-二甲基-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxyethyl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-苯基-1H-吡唑-5-基)脲1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备(3S,4R)-4-(3,4-二氟苯基)-1-(2-羟基乙基)吡咯烷-3-基氨基甲酸叔丁酯：将(3S,4R)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(ACS Scientific，410mg，1.37mmol)、2-溴乙醇(180mg，1.44mmol)和DIEA(533mg，4.12mmol)合并在1mL DMF中并且在环境温度下搅拌72小时。通过反相柱色谱法，用0％至50％乙腈/水洗脱来直接纯化反应混合物，得到标题化合物(290mg，61.6％产率)。MS(apci)m/z＝343.0(M+H)。Step A:Preparation of tert-butyl (3S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxyethyl)pyrrolidin-3-ylcarbamate: tert-butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (ACS Scientific, 410 mg, 1.37 mmol), 2-bromoethanol (180 mg, 1.44 mmol) and DIEA (533 mg, 4.12 mmol) were combined in 1 mL of DMF and stirred at ambient temperature for 72 hours. The reaction mixture was directly purified by reverse phase column chromatography eluting with 0% to 50% acetonitrile/water to give the title compound (290 mg, 61.6% yield). MS (apci) m/z=343.0 (M+H).
步骤B：制备2-((3S,4R)-3-氨基-4-(3,4-二氟苯基)吡咯烷-1-基)乙醇盐酸盐：将(3S,4R)-4-(3,4-二氟苯基)-1-(2-羟基乙基)吡咯烷-3-基氨基甲酸叔丁酯(230mg，0.672mmol)与氯化氢的异丙醇溶液(480μL，3.36mmol)合并，并且在环境温度下搅拌5小时。浓缩反应物，得到标题化合物(166mg，102％产率)。MS(apci)m/z＝243.0(M+H)。Step B:Preparation of 2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)ethanol hydrochloride : Combine tert-butyl (3S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxyethyl)pyrrolidin-3-ylcarbamate (230 mg, 0.672 mmol) with a solution of hydrogen chloride in isopropanol (480 μL, 3.36 mmol) and stir at ambient temperature for 5 hours. The reaction was concentrated to give the title compound (166 mg, 102% yield). MS (apci) m/z = 243.0 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-羟基乙基)吡咯烷-3-基)-3-(3,4-二甲基-1-苯基-1H-吡唑-5-基)脲：将2-((3S,4R)-3-氨基-4-(3,4-二氟苯基)吡咯烷-1-基)乙醇盐酸盐(160mg，0.574mmol)、3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(168mg，0.547mmol)与DIEA(286μL，1.64mmol)合并在0.5mL DMF中并且在环境温度下搅拌1小时。通过反相柱色谱法，用0％至50％乙腈/水洗脱来直接纯化反应物，得到标题化合物(127mg，51.0％产率)。MS(apci)m/z＝456.0(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxyethyl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)urea : 2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)ethanol hydrochloride (160 mg, 0.574 mmol), phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (168 mg, 0.547 mmol) and DIEA (286 μL, 1.64 mmol) were combined in 0.5 mL of DMF and stirred at ambient temperature for 1 hour. The reaction was directly purified by reverse phase column chromatography eluting with 0% to 50% acetonitrile/water to give the title compound (127 mg, 51.0% yield). MS (apci) m/z = 456.0 (M+H).
实例192Example 192
1-((反式)-1-(3,3,4,4,4-五氟丁基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,1-((trans)-1-(3,3,4,4,4-pentafluorobutyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
将1-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)-3-((反式)-4-苯基吡咯烷-3-基)脲(实例182步骤B，8.0mg，0.021mmol)、1,1,1,2,2-五氟-4-碘丁烷(5.7mg，0.021mmol)与DIEA(3.6μL，0.021mmol)合并在0.1mL DMF中并且在60℃下搅拌2小时。通过反相柱色谱法，用0％至65％乙腈/水洗脱来直接纯化反应物，得到标题化合物(3.2mg，29％产率)。MS(apci)m/z＝534.1(M+H)。1-(2-Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-phenylpyrrolidin-3-yl)urea (Example 182, Step B, 8.0 mg, 0.021 mmol), 1,1,1,2,2-pentafluoro-4-iodobutane (5.7 mg, 0.021 mmol) and DIEA (3.6 μL, 0.021 mmol) were combined in 0.1 mL of DMF and stirred at 60° C. for 2 hours. The reaction was directly purified by reverse phase column chromatography eluting with 0% to 65% acetonitrile/water to give the title compound (3.2 mg, 29% yield). MS (apci) m/z=534.1 (M+H).
实例193Example 193
1-((反式)-1-乙基-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并1-((trans)-1-ethyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopentadien-[c]吡唑-3-基)脲[c]pyrazol-3-yl)urea
将1-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)-3-((反式)-4-苯基吡咯烷-3-基)脲(实例182步骤B，5.0mg，0.012mmol)、溴乙烷(1.3mg，0.012mmol)与DIEA(4.1μL，0.024mmol)合并在0.1mL DMF中并且在环境温度下搅拌4小时。通过反相柱色谱法，用0％至65％乙腈/水洗脱来直接纯化反应物，得到标题化合物(4.3mg，88％产率)。MS(apci)m/z＝416.1(M+H)。1-(2-Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-phenylpyrrolidin-3-yl)urea (Example 182, Step B, 5.0 mg, 0.012 mmol), bromoethane (1.3 mg, 0.012 mmol) and DIEA (4.1 μL, 0.024 mmol) were combined in 0.1 mL of DMF and stirred at ambient temperature for 4 hours. The reaction was directly purified by reverse phase column chromatography eluting with 0% to 65% acetonitrile/water to give the title compound (4.3 mg, 88% yield). MS (apci) m/z = 416.1 (M+H).
实例194Example 194
1-((反式)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四1-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrafluoroethyl)pyrrolidin-3-yl氢环戊二烯并[c]吡唑-3-基)脲Hydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备(反式)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基氨基甲酸叔丁酯：将反式-4-苯基吡咯烷-3-基氨基甲酸叔丁酯(1.00g，3.81mmol)、三氟甲磺酸2,2,2-三氟乙酯(1.06g，4.57mmol)与DIEA(1.48g，11.4mmol)合并在2mL DMF中并且在环境温度下搅拌1小时。通过反相柱色谱法，用0％至75％乙腈/水洗脱来直接纯化反应物，得到标题化合物(1.19g，90.7％产率)。MS(apci)m/z＝345.0(M+H)。Step A:Preparation of tert-butyl (trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate : tert-butyl trans-4-phenylpyrrolidin-3-ylcarbamate (1.00 g, 3.81 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.06 g, 4.57 mmol) and DIEA (1.48 g, 11.4 mmol) were combined in 2 mL of DMF and stirred at ambient temperature for 1 hour. The reaction was directly purified by reverse phase column chromatography eluting with 0% to 75% acetonitrile/water to give the title compound (1.19 g, 90.7% yield). MS (apci) m/z=345.0 (M+H).
步骤B：制备(反式)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-胺盐酸盐：将(反式)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基氨基甲酸叔丁酯(1.19g，3.46mmol)与HCl(5N异丙醇溶液，1.48mL，10.4mmol)合并并且在环境温度下搅拌5小时。浓缩反应物，得到标题化合物(0.85g，101％产率)。MS(apci)m/z＝245.0(M+H)。Step B:Preparation of (trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine hydrochloride : Combine tert-butyl (trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (1.19 g, 3.46 mmol) with HCl (5N in isopropanol, 1.48 mL, 10.4 mmol) and stir at ambient temperature for 5 hours. The reaction is concentrated to give the title compound (0.85 g, 101% yield). MS (apci) m/z = 245.0 (M+H).
步骤C：制备1-((反式)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将(反式)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-胺盐酸盐(10.0mg，0.0356mmol)、2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(9.48mg，0.0297mmol)与DIEA(15.5μL，0.0891mmol)合并在0.2mL DMF中并且在环境温度下搅拌1小时。通过反相柱色谱法，用0％至75％乙腈/水洗脱来直接纯化反应物，得到标题化合物(11.5mg，82.5％产率)。MS(apci)m/z＝470.0(M+H)。[0266] Step C:Preparation of 1-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : (trans)-4-Phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine hydrochloride (10.0 mg, 0.0356 mmol), phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (9.48 mg, 0.0297 mmol) and DIEA (15.5 μL, 0.0891 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 1 hour. The reaction was directly purified by reverse phase column chromatography eluting with 0% to 75% acetonitrile/water to give the title compound (11.5 mg, 82.5% yield).MS (apci) m/z=470.0 (M+H).
实例195Example 195
1-(3,4-二甲基-1-苯基-1H-吡唑-5-基)-3-((反式)-4-苯基-1-(2,2,2-三氟乙1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)基)吡咯烷-3-基)脲1-[4-(2-Yl)pyrrolidin-3-yl)urea
通过如实例194中所述的方法，在步骤C中用3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，用0％至70％乙腈/H2O洗脱来纯化物质，得到标题化合物(6.5mg，48％产率)。MS(apci)m/z＝458.1(M+H)。Prepared by the method described in Example 194, substituting phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate in Step C. The material was purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/H2O to give the title compound (6.5 mg, 48% yield). MS (apci) m/z = 458.1 (M+H).
实例196Example 196
1-(3-(2-甲氧基乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((反式)-4-苯基-1-1-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((trans)-4-phenyl-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲(2,2,2-Trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例194中所述的方法，在步骤C中用3-(2-甲氧基乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，用0％至70％乙腈/H2O洗脱来纯化物质，得到标题化合物(9.3mg，61％产率)。MS(apci)m/z＝518.1(M+H)。Prepared by the method described in Example 194, substituting phenyl 3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate in Step C. The material was purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/H2O to give the title compound (9.3 mg, 61% yield). MS (apci) m/z = 518.1 (M+H).
实例197Example 197
1-((反式)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四1-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrafluoroethyl)pyrrolidin-3-yl氢环戊二烯并[c]吡唑-3-基)脲Hydrocyclopenta[c]pyrazol-3-yl)urea
通过如实例194步骤A-C中所述的方法，在步骤A中使用(3S,4R)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯(购自ACS Scientific，目录号：3-1005)替代反式-4-苯基吡咯烷-3-基氨基甲酸叔丁酯来制备。通过反相柱色谱法，用0％至60％乙腈/H2O洗脱来纯化最终产物，得到标题化合物(7.2mg，52％产率)。MS(apci)m/z＝470.0(M+H)。Prepared by the method described in Example 194, Steps AC, using tert-butyl (3S,4R)-4-phenylpyrrolidin-3-ylcarbamate (available from ACS Scientific, catalog number: 3-1005) instead of tert-butyl trans-4-phenylpyrrolidin-3-ylcarbamate in Step A. The final product was purified by reverse phase column chromatography, eluting with 0% to 60% acetonitrile/H2 O to give the title compound (7.2 mg, 52% yield). MS (apci) m/z = 470.0 (M+H).
实例198Example 198
1-(3,4-二甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-苯基-1-(2,2,2-三氟乙1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)基)吡咯烷-3-基)脲1-[4-(2-Yl)pyrrolidin-3-yl)urea
通过如实例197中所述的方法，在步骤C中用3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代2-苯基-2,4,5,6-四氢-环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，用0％至60％乙腈/H2O洗脱来纯化物质，得到标题化合物(10.0mg，脲形成的产率：67.5％)。MS(apci)m/z＝458.0(M+H)。Prepared by the method described in Example 197, substituting 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamic acid phenyl ester for 2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-ylcarbamic acid phenyl ester in Step C. The material was purified by reverse phase column chromatography eluting with 0% to 60% acetonitrile/H2O to give the title compound (10.0 mg, 67.5% yield of urea formation). MS (apci) m/z = 458.0 (M+H).
实例199Example 199
1-(3-(2-甲氧基乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-苯基-1-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-phenyl-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例197中所述的方法，用3-(2-甲氧基乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，用0％至70％乙腈/H2O洗脱来纯化物质，得到标题化合物(8.9mg，53％产率)。MS(apci)m/z＝518.1(M+H)。Prepared by the method described in Example 197, substituting phenyl 3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate. The material was purified by reverse phase column chromatography, eluting with 0% to 70% acetonitrile/H2O to give the title compound (8.9 mg, 53% yield). MS (apci) m/z = 518.1 (M+H).
实例200Example 200
1-((3S,4R)-4-(3-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,1-((3S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲5,6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
通过如实例194步骤A至C中所述的方法，在步骤A中使用(3S,4R)-4-(3-氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(购自ACS Scientific，目录号：3-1029)替代反式-4-苯基吡咯烷-3-基氨基甲酸叔丁酯来制备。通过反相柱色谱法，用0％至75％乙腈/H2O洗脱来纯化最终产物，得到标题化合物(12mg，92％产率)。MS(apci)m/z＝488.1(M+H)。Prepared by the method described in Example 194, steps A to C, using tert-butyl (3S,4R)-4-(3-fluorophenyl)pyrrolidin-3-ylcarbamate (available from ACS Scientific, catalog number: 3-1029) instead of tert-butyl trans-4-phenylpyrrolidin-3-ylcarbamate in step A. The final product was purified by reverse phase column chromatography, eluting with 0% to 75% acetonitrile/H2 O to give the title compound (12 mg, 92% yield). MS (apci) m/z=488.1 (M+H).
实例201Example 201
1-(3,4-二甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3-氟苯基)-1-(2,2,2-1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3-fluorophenyl)-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲(trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例200中所述的方法，在步骤C中用3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代2-苯基-2,4,5,6-四氢-环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，用5％至80％乙腈/H2O洗脱来纯化物质，得到标题化合物(5.3mg，48％产率)。MS(apci)m/z＝476.0(M+H)。Prepared by the method described in Example 200, substituting phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl 2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-ylcarbamate in Step C. The material was purified by reverse phase column chromatography eluting with 5% to 80% acetonitrile/H2O to give the title compound (5.3 mg, 48% yield). MS (apci) m/z = 476.0 (M+H).
实例202Example 202
1-((3S,4R)-4-(3-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(3-(2-甲氧基1-((3S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(3-(2-methoxy乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过如实例200中所述的方法，用3-(2-甲氧基乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，用5％至80％乙腈/H2O洗脱来纯化物质，得到标题化合物(6.6mg，58％产率)。MS(apci)m/z＝536.1(M+H)。Prepared by the method described in Example 200, substituting phenyl 3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate. The material was purified by reverse phase column chromatography eluting with 5% to 80% acetonitrile/H2O to give the title compound (6.6 mg, 58% yield). MS (apci) m/z = 536.1 (M+H).
实例203Example 203
1-((3S,4R)-4-(3-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(1-甲基-3-苯1-((3S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl)基-1H-吡唑-5-基)脲-1H-pyrazol-5-yl)urea
通过如实例200中所述的方法，用1-甲基-3-苯基-1H-吡唑-5-基氨基甲酸苯酯替代2-苯基-2,4,5,6-四氢-环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，用0％至75％乙腈/H2O洗脱来纯化物质，得到标题化合物(6.3mg，64％产率)。MS(apci)m/z＝462.0(M+H)。Prepared by the method described in Example 200, substituting 1-methyl-3-phenyl-1H-pyrazol-5-ylcarbamic acid phenyl ester for 2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-ylcarbamic acid phenyl ester. The material was purified by reverse phase column chromatography, eluting with 0% to 75% acetonitrile/H2O to give the title compound (6.3 mg, 64% yield). MS (apci) m/z = 462.0 (M+H).
实例204Example 204
1-((3R,4S)-4-(3-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,1-((3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲5,6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备(E)-3-(4-氯-3-氟苯基)丙烯酰氯：将(E)-3-(4-氯-3-氟苯基)丙烯酸(28.1g，140mmol)悬浮于氯仿(250mL)中并且添加DMF(0.1mL)，接着添加乙二酰氯(20.0mL，229mmol)。搅拌反应物18小时并且然后蒸发至干燥。添加庚烷并且浓缩混合物，得到呈浅黄色固体状的产物(30.6g，99.7％产率)。Step A:Preparation of (E)-3-(4-chloro-3-fluorophenyl)acryloyl chloride : (E)-3-(4-chloro-3-fluorophenyl)acrylic acid (28.1 g, 140 mmol) was suspended in chloroform (250 mL) and DMF (0.1 mL) was added, followed by oxalyl chloride (20.0 mL, 229 mmol). The reaction was stirred for 18 hours and then evaporated to dryness. Heptane was added and the mixture was concentrated to give the product as a light yellow solid (30.6 g, 99.7% yield).
步骤B：制备(R)-4-苯甲基-3-((3R,4S)-1-苯甲基-4-(4-氯-3-氟苯基)吡咯烷-3-羰基)噁唑烷-2-酮：将(R)-4-苯甲基噁唑烷-2-酮(21.8g，123mmol)溶解于THF(600mL)中并且冷却至-78℃。经15分钟逐滴添加双(三甲基硅烷基)氨化锂的THF溶液(127mL，127mmol)并且在-78℃下再搅拌混合物15分钟。添加(E)-3-(4-氯-3-氟苯基)丙烯酰氯(28.3g，129mmol)在THF(100mL)中的溶液并且在-78℃下搅拌混合物1小时，然后允许其升温至环境温度并且再搅拌1小时。添加饱和碳酸氢钠水溶液(50mL)并且搅拌反应物1小时。然后在真空中去除THF，添加乙酸乙酯(1L)并且用水(2X)和盐水洗涤反应混合物，用MgSO4干燥，过滤并且蒸发，得到呈棕褐色固体状的(R,E)-4-苯甲基-3-(3-(4-氯-3-氟苯基)丙烯酰基)噁唑烷-2-酮(44.3g，100％产率)。将固体溶解于甲苯(500mL)中并且添加2,2,2-三氟乙酸(0.9486mL，12.31mmol)。使温度升温至35℃并且经20分钟添加N-苯甲基-1-甲氧基-N-((三甲基硅烷基)甲基)甲胺(52.50mL，184.7mmol)，同时用外部水浴将温度保持在25℃至30℃。用饱和碳酸氢钠水溶液和水洗涤混合物并且在真空中浓缩，得到油性残余物，将其用己烷湿磨，过滤并且用己烷洗涤，得到白色固体(55.7g)。将此固体(55.7g)悬浮于己烷(200mL)中并且加热至回流。添加苯(220mL)直至固体在回流下溶解。允许溶液缓慢冷却至环境温度并且然后置放于冷冻器中4小时。通过过滤收集所得到的固体并且用100mL冷1:1己烷/苯洗涤。通过二氧化硅柱色谱法，用20％至40％EtOAc/己烷洗脱来纯化所得到的固体(7.6g)。(R)-4-苯甲基-3-((3S,4R)-1-苯甲基-4-(4-氯-3-氟苯基)吡咯烷-3-羰基)噁唑烷-2-酮(3.2g，42％产率)首先洗脱，接着(R)-4-苯甲基-3-((3R,4S)-1-苯甲基-4-(4-氯-3-氟苯基)吡咯烷-3-羰基)噁唑烷-2-酮(3.0g，39％产率)洗脱。MS(apci)m/z＝493.0(M+H)。[0147] Step B:Preparation of (R)-4-benzyl-3-((3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carbonyl)oxazolidin-2-one : (R)-4-Benzyloxazolidin-2-one (21.8 g, 123 mmol) was dissolved in THF (600 mL) and cooled to -78°C. A solution of lithium bis(trimethylsilyl)amide in THF (127 mL, 127 mmol) was added dropwise over 15 minutes and the mixture was stirred at -78°C for an additional 15 minutes. A solution of (E)-3-(4-chloro-3-fluorophenyl)acryloyl chloride (28.3 g, 129 mmol) in THF (100 mL) was added and the mixture was stirred at -78°C for 1 hour, then allowed to warm to ambient temperature and stirred for an additional hour. Saturated aqueous sodium bicarbonate solution (50 mL) was added and the reaction was stirred for 1 hour. The THF was then removed in vacuo, ethyl acetate (1 L) was added, and the reaction mixture was washed with water (2X ) and brine, dried over MgSO , filtered, and evaporated to afford (R,E)-4-benzyl-3-(3-(4-chloro-3-fluorophenyl)acryloyl)oxazolidin-2-one (44.3 g, 100% yield) as a tan solid. The solid was dissolved in toluene (500 mL) and 2,2,2-trifluoroacetic acid (0.9486 mL, 12.31 mmol) was added. The temperature was raised to 35° C. and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (52.50 mL, 184.7 mmol) was added over 20 minutes while maintaining the temperature at 25 to 30° C. with an external water bath. At 4 DEG C, 1H-dextrose (50mL) is stirred for 2 hours at 4 DEG C.With saturated sodium bicarbonate aqueous solution and water washing mixture and in vacuum, concentrate, obtain oily residue, with it hexane wet grinding, filter and wash with hexane, obtain white solid (55.7g).This solid (55.7g) is suspended in hexane (200mL) and is heated to reflux.Add benzene (220mL) until solid dissolves under reflux.Allow solution to slowly cool to ambient temperature and then be placed in freezer 4 hours.Collect obtained solid by filtration and wash with the cold 1:1 hexane/benzene of 100mL.By silica column chromatography, purify obtained solid (7.6g) with 20% to 40%EtOAc/ hexane wash-out. (R)-4-Benzyl-3-((3S,4R)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carbonyl)oxazolidin-2-one (3.2 g, 42% yield) eluted first, followed by (R)-4-benzyl-3-((3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carbonyl)oxazolidin-2-one (3.0 g, 39% yield). MS (apci) m/z = 493.0 (M+H).
步骤C：制备(3R,4S)-1-苯甲基-4-(4-氯-3-氟苯基)吡咯烷-3-甲酸：将过氧化氢(30％水溶液，2.38mL，23.1mmol)逐滴添加至一水合氢氧化锂(0.638g，15.2mmol)和冰水(50g)的混合物中。搅拌混合物30分钟并且将所得到的溶液添加至(R)-4-苯甲基-3-((3R,4S)-1-苯甲基-4-(4-氯-3-氟苯基)吡咯烷-3-羰基)噁唑烷-2-酮(3.00g，6.09mmol)在THF(50mL)中的溶液中。在环境温度下搅拌反应物5小时，通过添加2M Na2SO3水溶液(20mL)淬灭并且搅动过夜。用固体KHSO4将pH调节至6并且用EtOAc(2×100mL)萃取混合物。用盐水洗涤合并的有机萃取物，用MgSO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用10％MeOH/DCM洗脱来纯化残余物，得到呈白色固体状的产物(1.80g，88.6％产率)。MS(apci)m/z＝334.0(M+H)。Step C:Preparation of (3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carboxylic acid : Hydrogen peroxide (30% aqueous solution, 2.38 mL, 23.1 mmol) was added dropwise to a mixture of lithium hydroxide monohydrate (0.638 g, 15.2 mmol) and ice water (50 g). The mixture was stirred for 30 minutes and the resulting solution was added to a solution of (R)-4-benzyl-3-((3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carbonyl)oxazolidin-2-one (3.00 g, 6.09 mmol) in THF (50 mL). The reaction was stirred at ambient temperature for 5 hours, quenched by the addition of 2MaqueousNa2SO3 (20 mL) and stirred overnight. The pH was adjusted to 6 with solid KHSO4 and the mixture was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over MgSO4 , filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 10% MeOH/DCM to give the product (1.80 g, 88.6% yield) as a white solid. MS (apci) m/z=334.0 (M+H).
步骤D：制备(3R,4S)-1-苯甲基-4-(4-氯-3-氟苯基)吡咯烷-3-基氨基甲酸叔丁酯：在密封容器中将(3R,4S)-1-苯甲基-4-(4-氯-3-氟苯基)吡咯烷-3-甲酸(120mg，0.360mmol)、NEt3(150μL，1.08mmol)与二苯基磷酰基叠氮化物(116μL，0.539mmol)合并在2mL甲苯中并且在100℃下搅拌30分钟。允许反应物冷却至环境温度并且添加2-甲基丙-2-醇锂的THF溶液(1.44mL，0.719mmol)。在100℃下搅拌反应物5小时，冷却，浓缩并且通过反相柱色谱法用20％至90％乙腈/H2O洗脱来纯化，得到产物(61.0mg，41.9％产率)。MS(apci)m/z＝405.0(M+H)。Step D:Preparation of tert-butyl (3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidin-3-ylcarbamate : (3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidine-3-carboxylic acid (120 mg, 0.360 mmol),NEt3 (150 μL, 1.08 mmol) and diphenylphosphoryl azide (116 μL, 0.539 mmol) were combined in 2 mL of toluene in a sealed vessel and stirred for 30 minutes at 100° C. The reaction was allowed to cool to ambient temperature and a solution of lithium 2-methylpropan-2-ol in THF (1.44 mL, 0.719 mmol) was added. The reaction was stirred at 100°C for 5 hours, cooled, concentrated and purified by reverse phase column chromatography eluting with 20% to 90% acetonitrile/H2O to give the product (61.0 mg, 41.9% yield).MS (apci) m/z = 405.0 (M+H).
步骤E：制备(3R,4S)-4-(3-氟苯基)吡咯烷-3-基氨基甲酸叔丁酯：将(3R,4S)-1-苯甲基-4-(4-氯-3-氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(60mg，0.15mmol)溶解于5mLMeOH中并且添加10％Pd/C(32mg，0.030mmol)。在填充氢气的气球下搅拌反应物18小时，通过过滤并且然后浓缩，得到标题化合物(36mg，87％产率)。MS(apci)m/z＝281.1(M+H)。Step E:Preparation of tert-butyl (3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-ylcarbamate : tert-butyl (3R,4S)-1-benzyl-4-(4-chloro-3-fluorophenyl)pyrrolidin-3-ylcarbamate (60 mg, 0.15 mmol) was dissolved in 5 mL of MeOH and 10% Pd/C (32 mg, 0.030 mmol) was added. The reaction was stirred under a balloon filled with hydrogen for 18 hours, filtered through Celite®, and then concentrated to give the title compound (36 mg, 87% yield). MS (apci) m/z = 281.1 (M+H).
步骤F：制备(3R,4S)-4-(3-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基氨基甲酸叔丁酯：将(3R,4S)-4-(3-氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(35mg，0.12mmol)、三氟甲磺酸2,2,2-三氟乙酯(38mg，0.16mmol)与DIEA(65μL，0.37mmol)合并在0.5mL DMF中并且在环境温度下搅拌18小时。通过反相柱色谱法，用0％至80％乙腈/H2O洗脱来直接纯化反应物，得到产物(30mg，66％产率)。MS(apci)m/z＝363.0(M+H)。[0266] Step F:Preparation of tert-butyl (3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate : tert-Butyl (3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-ylcarbamate (35 mg, 0.12 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (38 mg, 0.16 mmol) and DIEA (65 μL, 0.37 mmol) were combined in 0.5 mL of DMF and stirred at ambient temperature for 18 hours. The reaction was directly purified by reverse phase column chromatography eluting with 0% to 80% acetonitrile/H2O to give the product (30 mg, 66% yield). MS (apci) m/z = 363.0 (M+H).
步骤G：制备(3R,4S)-4-(3-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-胺盐酸盐：将(3R,4S)-4-(3-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基氨基甲酸叔丁酯(30mg，0.083mmol)与氯化氢的异丙醇溶液(50μL，0.25mmol)合并在1mL异丙醇中并且在环境温度下搅拌4小时。在真空中浓缩反应物，得到产物(21mg，97％产率)。MS(apci)m/z＝263.0(M+H)。Step G:Preparation of (3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine hydrochloride : tert-Butyl (3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (30 mg, 0.083 mmol) was combined with a solution of hydrogen chloride in isopropanol (50 μL, 0.25 mmol) in 1 mL of isopropanol and stirred at ambient temperature for 4 hours. The reaction was concentrated in vacuo to give the product (21 mg, 97% yield). MS (apci) m/z = 263.0 (M+H).
步骤H：制备1-((3R,4S)-4-(3-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将(3R,4S)-4-(3-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-胺(10.0mg，0.0381mmol)、2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(10.1mg，0.0318mmol)与DIEA(16.6μL，0.0953mmol)合并在0.2mLDMF中并且在环境温度下搅拌18小时。通过反相柱色谱法，用0％至70％乙腈/H2O洗脱来纯化反应物，得到标题化合物(12.5mg，80.7％产率)。MS(apci)m/z＝488.1(M+H)。[0266] Step H:Preparation of 1-((3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : (3R,4S)-4-(3-Fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine (10.0 mg, 0.0381 mmol), phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (10.1 mg, 0.0318 mmol) and DIEA (16.6 μL, 0.0953 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 18 hours. The reaction was purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/H2O to give the title compound (12.5 mg, 80.7% yield).MS (apci) m/z = 488.1 (M+H).
实例205Example 205
1-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3R,4S)-4-(3-氟苯基)-1-(2,1-(3-Ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲2,2-trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例204步骤H中所述的方法，用3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，用0％至80％乙腈/H2O洗脱来纯化物质，得到标题化合物(9.3mg，58％产率)。MS(apci)m/z＝476.0(M+H)。Prepared by the method described in Example 204, Step H, substituting phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate for phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate. The material was purified by reverse phase column chromatography, eluting with 0% to 80% acetonitrile/H2O , to give the title compound (9.3 mg, 58% yield). MS (apci) m/z = 476.0 (M+H).
实例206Example 206
1-((反式)-1-(1,3-二氟丙-2-基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四1-((trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrakis氢环戊二烯并[c]吡唑-3-基)脲Hydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备(反式)-1-(1,3-二氟丙-2-基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯：将1,3-二氟丙-2-醇(150.0mg，1.561mmol)溶解于DCM(5mL)中并且将溶液冷却至0℃。添加DIEA(339.9μL，1.952mmol)，接着添加三氟甲磺酸酐(197.0μL，1.171mmol)。在0℃下搅拌反应物1小时并且添加4-苯基吡咯烷-3-基氨基甲酸叔丁酯(102.4mg，0.3903mmol)。允许反应物经2小时升温至环境温度，浓缩，使用MeOH加载至加样装置(samplet)上并且通过反相柱色谱法用0％至70％乙腈/H2O洗脱来纯化，得到产物(119.0mg，89.56％产率)。MS(apci)m/z＝341.1(M+H)。Step A:Preparation of tert-butyl (trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-ylcarbamate : 1,3-Difluoropropan-2-ol (150.0 mg, 1.561 mmol) was dissolved in DCM (5 mL) and the solution was cooled to 0° C. DIEA (339.9 μL, 1.952 mmol) was added, followed by trifluoromethanesulfonic anhydride (197.0 μL, 1.171 mmol). The reaction was stirred at 0° C. for 1 hour and tert-butyl 4-phenylpyrrolidin-3-ylcarbamate (102.4 mg, 0.3903 mmol) was added. The reaction was allowed to warm to ambient temperature over 2 h, concentrated, loaded onto a samplet using MeOH and purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/H2O to give the product (119.0 mg, 89.56% yield).MS (apci) m/z = 341.1 (M+H).
步骤B：制备(反式)-1-(1,3-二氟丙-2-基)-4-苯基吡咯烷-3-胺盐酸盐：将(反式)-1-(1,3-二氟丙-2-基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯(119mg，0.350mmol)与氯化氢(5N异丙醇溶液，210μL，1.05mmol)合并在1mL异丙醇中并且在环境温度下搅拌4小时。在真空中浓缩反应混合物，得到产物(85.0mg，101％产率)。MS(apci)m/z＝241.1(M+H)。Step B:Preparation of (trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-amine hydrochloride : tert-Butyl (trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-ylcarbamate (119 mg, 0.350 mmol) was combined with hydrogen chloride (5N in isopropanol, 210 μL, 1.05 mmol) in 1 mL of isopropanol and stirred at ambient temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the product (85.0 mg, 101% yield). MS (apci) m/z = 241.1 (M+H).
步骤C：制备1-((反式)-1-(1,3-二氟丙-2-基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将(反式)-1-(1,3-二氟丙-2-基)-4-苯基吡咯烷-3-胺盐酸盐(10.0mg，0.0361mmol)、2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(9.62mg，0.0301mmol)与DIEA(15.7μL，0.0903mmol)合并在0.2mL DMF中并且在环境温度下搅拌18小时。通过反相柱色谱法，用0％至70％乙腈/H2O洗脱来纯化反应混合物，得到产物(11.3mg，80.6％产率)。MS(apci)m/z＝466.1(M+H)。[0266] Step C:Preparation of 1-((trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : (trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-amine hydrochloride (10.0 mg, 0.0361 mmol), phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (9.62 mg, 0.0301 mmol) and DIEA (15.7 μL, 0.0903 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 18 hours. The reaction mixture was purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/H2O to give the product (11.3 mg, 80.6% yield).MS (apci) m/z = 466.1 (M+H).
实例207Example 207
(反式)-3-(3-甲氧基苯基)-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-(trans)-3-(3-methoxyphenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-基)脲基)吡咯烷-1-甲酸叔丁酯tert-Butyl)ureido)pyrrolidine-1-carboxylate
步骤A：制备(反式)-1-(1,3-二氟丙-2-基)-4-苯基吡咯烷-3-基氨基甲酸叔丁酯：将反式-3-氨基-4-(3-甲氧基苯基)吡咯烷-1-甲酸叔丁酯(100.0mg，0.3420mmol)、2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(99.30mg，0.3109mmol)与DIEA(162.5μL，0.9328mmol)合并在0.2mL DMF中并且在环境温度下搅拌1小时。通过反相柱色谱法，用0％至80％乙腈/H2O洗脱来纯化反应混合物，得到产物(102.0mg，63.38％产率)。MS(apci)m/z＝518.1(M+H)。[00145] Step A:Preparation of tert-butyl (trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-ylcarbamate : tert-Butyl trans-3-amino-4-(3-methoxyphenyl)pyrrolidine-1-carboxylate (100.0 mg, 0.3420 mmol), phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate (99.30 mg, 0.3109 mmol) and DIEA (162.5 μL, 0.9328 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 1 hour. The reaction mixture was purified by reverse phase column chromatography eluting with 0% to 80% acetonitrile/H2O to give the product (102.0 mg, 63.38% yield). MS (apci) m/z = 518.1 (M+H).
步骤B：制备1-((反式)-4-(3-甲氧基苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲盐酸盐：将(反式)-3-(3-甲氧基苯基)-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-甲酸叔丁酯(102mg，0.197mmol)与氯化氢的异丙醇溶液(118μL，0.591mmol)合并在1mL异丙醇中并且在环境温度下搅拌4小时。在真空中浓缩反应物，得到产物(80.0mg，97.2％产率)。MS(apci)m/z＝418.1(M+H)。[0266] Step B:Preparation of 1-((trans)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta [c]pyrazol-3-yl)urea hydrochloride: tert-Butyl (trans)-3-(3-methoxyphenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea)pyrrolidine-1-carboxylate (102 mg, 0.197 mmol) was combined with a solution of hydrogen chloride in isopropanol (118 μL, 0.591 mmol) in 1 mL of isopropanol and stirred at ambient temperature for 4 hours. The reaction was concentrated in vacuo to afford the product (80.0 mg, 97.2% yield). MS (apci) m/z = 418.1 (M+H).
步骤C：制备1-((反式)-4-(3-甲氧基苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将1-((反式)-4-(3-甲氧基苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲盐酸盐(8.0mg，0.018mmol)、三氟甲磺酸2,2,2-三氟乙酯(6.1mg，0.026mmol)与DIEA(9.2μL，0.053mmol)合并在0.2mL DMF中并且在环境温度下搅拌1小时。通过反相柱色谱法，用0％至80％乙腈/H2O洗脱来直接纯化反应混合物，得到标题化合物(6.7mg，76％产率)。MS(apci)m/z＝500.1(M+H)。[0266] Step C:Preparation of 1-((trans)-4-(3-methoxyphenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : 1-((trans)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea hydrochloride (8.0 mg, 0.018 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.1 mg, 0.026 mmol) and DIEA (9.2 μL, 0.053 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 1 hour. The reaction mixture was directly purified by reverse phase column chromatography eluting with 0% to 80% acetonitrile/H2O to give the title compound (6.7 mg, 76% yield).MS (apci) m/z = 500.1 (M+H).
实例208Example 208
1-((反式)-4-(3-氯苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,1-((trans)-4-(3-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲5,6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备(反式)-3-(3-氯苯基)-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-甲酸叔丁酯：在密封容器中将(反式)-1-(叔丁氧基羰基)-4-(3-氯苯基)吡咯烷-3-甲酸(150mg，0.460mmol)、NEt3(193μL，1.38mmol)与二苯基磷酰基叠氮化物(149μL，0.691mmol)合并在2mL甲苯中并且在100℃下搅拌30分钟。冷却反应物并且添加2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺(表1；183mg，0.921mmol)。在100℃下搅拌反应混合物16小时，冷却，浓缩并且通过反相柱色谱法用0％至60％乙腈/H2O洗脱来纯化，得到产物(42mg，18％产率)。MS(apci)m/z＝522.1(M+H)。[0266] Step A:Preparation of tert-butyl (trans)-3-(3-chlorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate : (trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylic acid (150 mg, 0.460 mmol),NEt3 (193 μL, 1.38 mmol) and diphenylphosphoryl azide (149 μL, 0.691 mmol) were combined in 2 mL of toluene in a sealed vessel and stirred at 100°C for 30 minutes. The reaction was cooled and 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine (Table 1; 183 mg, 0.921 mmol) was added. The reaction mixture was stirred at 100°C for 16 hours, cooled, concentrated and purified by reverse phase column chromatography eluting with 0% to 60% acetonitrile/H2O to give the product (42 mg, 18% yield).MS (apci) m/z = 522.1 (M+H).
步骤B：制备1-((反式)-4-(3-氯苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲盐酸盐：将(反式)-3-(3-氯苯基)-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-甲酸叔丁酯(40mg，0.077mmol)与氯化氢的异丙醇溶液(46μL，0.23mmol)合并在10.1mL IPA中并且在环境温度下搅拌12小时。在真空中浓缩反应混合物，得到产物(32mg，99％产率)。MS(apci)m/z＝422.0(M+H)。[0266] Step B:Preparation of 1-((trans)-4-(3-chlorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta [c]pyrazol-3-yl)urea hydrochloride: tert-Butyl (trans)-3-(3-chlorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea)pyrrolidine-1-carboxylate (40 mg, 0.077 mmol) was combined with a solution of hydrogen chloride in isopropanol (46 μL, 0.23 mmol) in 10.1 mL of IPA and stirred at ambient temperature for 12 hours. The reaction mixture was concentrated in vacuo to afford the product (32 mg, 99% yield). MS (apci) m/z = 422.0 (M+H).
步骤C：制备1-((反式)-4-(3-氯苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将1-((反式)-4-(3-氯苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲盐酸盐(15mg，0.033mmol)、三氟甲磺酸2,2,2-三氟乙酯(11mg，0.049mmol)与DIEA(17μL，0.098mmol)合并在0.2mL DMF中并且在环境温度下搅拌1小时。通过反相柱色谱法，用0％至80％乙腈/H2O洗脱来直接纯化反应混合物，得到标题化合物(8.2mg，50％产率)。MS(apci)m/z＝504.0(M+H)。Step C:Preparation of 1-((trans)-4-(3-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : 1-((trans)-4-(3-chlorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea hydrochloride (15 mg, 0.033 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (11 mg, 0.049 mmol) and DIEA (17 μL, 0.098 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 1 hour. The reaction mixture was directly purified by reverse phase column chromatography eluting with 0% to 80% acetonitrile/H2O to give the title compound (8.2 mg, 50% yield).MS (apci) m/z = 504.0 (M+H).
实例209Example 209
1-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)-3-((反式)-4-(吡啶-2-1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-(pyridine-2-基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例208中所述的方法，在步骤A中用(反式)-1-(叔丁氧基羰基)-4-(2-吡啶基)吡咯烷-3-甲酸替代(反式)-1-(叔丁氧基羰基)-4-(3-氯苯基)吡咯烷-3-甲酸来制备。通过反相柱色谱法，用0％至60％乙腈/H2O洗脱来纯化粗最终产物，得到标题化合物(4.2mg，23％产率(3个步骤))。MS(apci)m/z＝471.1(M+H)。Prepared by the method described in Example 208, substituting (trans)-1-(tert-butoxycarbonyl)-4-(2-pyridyl)pyrrolidine-3-carboxylic acid for (trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylic acid in Step A. The crude final product was purified by reverse phase column chromatography eluting with 0% to 60% acetonitrile/H2O to give the title compound (4.2 mg, 23% yield over 3 steps). MS (apci) m/z = 471.1 (M+H).
实例210Example 210
1-((反式)-4-(4-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,1-((trans)-4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲5,6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
通过如实例208中所述的方法，在步骤A中用(反式)-1-(叔丁氧基羰基)-4-(4-氟苯基)吡咯烷-3-甲酸替代(反式)-1-(叔丁氧基羰基)-4-(3-氯苯基)吡咯烷-3-甲酸来制备。通过反相柱色谱法，用0％至70％乙腈/H2O洗脱来纯化最终产物，得到标题化合物(10.0mg，65％产率(3个步骤))。MS(apci)m/z＝488.2(M+H)。Prepared by the method described in Example 208, substituting (trans)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)pyrrolidine-3-carboxylic acid for (trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylic acid in Step A. The final product was purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/H2O to give the title compound (10.0 mg, 65% yield over 3 steps). MS (apci) m/z = 488.2 (M+H).
实例211Example 211
1-((反式)-4-(4-氯苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,1-((trans)-4-(4-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲5,6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
通过如实例208中所述的方法，在步骤A中使用(反式)-1-(叔丁氧基羰基)-4-(4-氯苯基)吡咯烷-3-甲酸替代(反式)-1-(叔丁氧基羰基)-4-(3-氯苯基)吡咯烷-3-甲酸来制备。通过反相柱色谱法，用0％至70％乙腈/H2O洗脱来纯化最终产物，得到标题化合物(7.3mg，14％产率(3个步骤))。MS(apci)m/z＝504.2(M+H)。Prepared by the method described in Example 208, using (trans)-1-(tert-butoxycarbonyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid instead of (trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylic acid in Step A. The final product was purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/H2O to give the title compound (7.3 mg, 14% yield over 3 steps). MS (apci) m/z = 504.2 (M+H).
实例212Example 212
1-((反式)-4-(2-氯苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,1-((trans)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲5,6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
通过如实例208中所述的方法，在步骤A中用(反式)-1-(叔丁氧基羰基)-4-(2-氯苯基)吡咯烷-3-甲酸替代(反式)-1-(叔丁氧基羰基)-4-(3-氯苯基)吡咯烷-3-甲酸来制备。通过反相柱色谱法，用0％至70％乙腈/H2O洗脱来纯化最终产物，得到标题化合物(5.2mg，34％产率(3个步骤))。MS(apci)m/z＝504.2(M+H)。Prepared by the method described in Example 208, substituting (trans)-1-(tert-butoxycarbonyl)-4-(2-chlorophenyl)pyrrolidine-3-carboxylic acid for (trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylic acid in Step A. The final product was purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/H2O to give the title compound (5.2 mg, 34% yield over 3 steps). MS (apci) m/z = 504.2 (M+H).
实例213Example 213
1-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)-3-((反式)-4-(吡啶-3-1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-(pyridine-3-基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例208中所述的方法，在步骤A中用(反式)-1-(叔丁氧基羰基)-4-(3-吡啶基)吡咯烷-3-甲酸替代(反式)-1-(叔丁氧基羰基)-4-(3-氯苯基)吡咯烷-3-甲酸来制备。通过反相柱色谱法，用0％至60％乙腈/H2O洗脱来纯化最终产物，得到标题化合物(1.2mg，8％产率(3个步骤))。MS(apci)m/z＝471.2(M+H)。Prepared by the method described in Example 208, substituting (trans)-1-(tert-butoxycarbonyl)-4-(3-pyridyl)pyrrolidine-3-carboxylic acid for (trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylic acid in Step A. The final product was purified by reverse phase column chromatography eluting with 0% to 60% acetonitrile/H2O to give the title compound (1.2 mg, 8% yield over 3 steps). MS (apci) m/z = 471.2 (M+H).
实例214Example 214
1-((反式)-4-(2-氟苯基)-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,1-((trans)-4-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲5,6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
通过如实例208中所述的方法，在步骤A中用(反式)-1-(叔丁氧基羰基)-4-(2-氟苯基)吡咯烷-3-甲酸替代(反式)-1-(叔丁氧基羰基)-4-(3-氯苯基)吡咯烷-3-甲酸来制备。通过反相柱色谱法，用0％至70％乙腈/H2O洗脱来纯化最终产物，得到标题化合物(7.7mg，57％产率(3个步骤))。MS(apci)m/z＝488.2(M+H)。Prepared by the method described in Example 208, substituting (trans)-1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)pyrrolidine-3-carboxylic acid for (trans)-1-(tert-butoxycarbonyl)-4-(3-chlorophenyl)pyrrolidine-3-carboxylic acid in Step A. The final product was purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/H2O to give the title compound (7.7 mg, 57% yield over 3 steps). MS (apci) m/z = 488.2 (M+H).
实例215Example 215
1-((反式)-4-(4-氟苯基)-1-(2,2-二氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,1-((trans)-4-(4-fluorophenyl)-1-(2,2-difluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
通过如实例210中所述的方法，用三氟甲磺酸2,2-二氟乙酯替代三氟甲磺酸2,2,2-三氟乙酯来制备。通过反相柱色谱法，用0％至60％乙腈/H2O洗脱来纯化最终产物，得到标题化合物(4.9mg，46％产率(烷基化))。MS(apci)m/z＝471.2(M+H)。Prepared by the method described in Example 210, substituting 2,2-difluoroethyl trifluoromethanesulfonate for 2,2,2-trifluoroethyl trifluoromethanesulfonate. The final product was purified by reverse phase column chromatography, eluting with 0% to 60% acetonitrile/H2O to give the title compound (4.9 mg, 46% yield (alkylation)). MS (apci) m/z = 471.2 (M+H).
实例216Example 216
1-((3S,4R)-4-(3,4-二氟苯基)-1-(1H-吡唑-4-基)吡咯烷-3-基)-3-(3-乙氧基-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-甲基-1-苯基-1H-吡唑-5-基)脲4-Methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备4-碘-1-(4-甲氧基苯甲基)-1H-吡唑：向4-碘-1H-吡唑(5.54g，28.6mmol)和K2CO3(4.74g，34.3mmol)在DMF(20mL)中的溶液中添加1-(氯甲基)-4-甲氧基苯(4.67mL，34.3mmol)并且在环境温度下搅拌2小时。添加乙醚(80mL)和水(30mL)。分离有机相，用盐水洗涤并且经硫酸钠干燥。去除溶剂后，通过二氧化硅柱色谱法用25％EtOAc/己烷洗脱来纯化残余物，得到呈白色固体状的标题化合物(8.0g，89％产率)。1H NMR(d6-DMSO)δ7.97(s,1H),7.52(s,1H),7.21(d,2H),6.89(d,2H),5.24(s,2H),3.73(s,3H)。[0266] Step A:Preparation of 4-iodo-1-(4-methoxybenzyl)-1H-pyrazole : To a solution of 4-iodo-1H -pyrazole (5.54 g, 28.6 mmol) andKCO (4.74 g, 34.3 mmol) in DMF (20 mL) was added 1-(chloromethyl)-4-methoxybenzene (4.67 mL, 34.3 mmol) and stirred at ambient temperature for 2 hours. Diethyl ether (80 mL) and water (30 mL) were added. The organic phase was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica column chromatography eluting with 25% EtOAc/hexane to give the title compound (8.0 g, 89% yield) as a white solid.1 H NMR(d6-DMSO) δ7.97(s,1H),7.52(s,1H),7.21(d,2H),6.89(d,2H),5.24(s,2H),3.73(s,3H).
步骤B：制备(3S,4R)-4-(3,4-二氟苯基)-1-(1-(4-甲氧基苯甲基)-1H-吡唑-4-基)吡咯烷-3-基氨基甲酸叔丁酯：在密封容器中将(3S,4R)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(ACS Scientific，522mg，1.75mmol)、4-碘-1-(4-甲氧基苯甲基)-1H-吡唑(500mg，1.59mmol)、K2CO3(660mg，4.78mmol)、(S)-吡咯烷-2-甲酸(73.3mg，0.637mmol)以及Cu(I)I(60.6mg，0.318mmol)的混合物合并在DMSO(4mL)中并且加热至100℃，持续18小时。用DCM(40mL)稀释反应混合物，用H2O(2×20mL)洗涤，干燥(MgSO4)，过滤并且浓缩。通过二氧化硅柱色谱法，用1％MeOH/DCM洗脱来纯化，得到呈棕色油状的标题化合物(376mg，49％产率)。MS(apci)m/z＝485.2(M+H)。[0266] Step B:Preparation of tert-butyl (3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-ylcarbamate : A mixture of tert-butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (ACS Scientific, 522 mg, 1.75 mmol), 4-iodo-1-(4-methoxybenzyl)-1H-pyrazole (500 mg, 1.59 mmol),K2CO3 (660 mg, 4.78 mmol), (S)-pyrrolidine-2-carboxylic acid (73.3 mg, 0.637 mmol) and Cu(I)I (60.6 mg, 0.318 mmol) were combined in DMSO (4 mL) in asealed vessel and heated to 100°C for 18 hours. The reaction mixture was diluted with DCM (40 mL), washed withH2O (2 x 20 mL), dried (MgSO4 ), filtered and concentrated. Purification by silica column chromatography eluting with 1% MeOH/DCM gave the title compound as a brown oil (376 mg, 49% yield). MS (apci) m/z = 485.2 (M+H).
步骤C：制备(3S,4R)-4-(3,4-二氟苯基)-1-(1-(4-甲氧基苯甲基)-1H-吡唑-4-基)吡咯烷-3-胺二盐酸盐：在环境温度下搅拌(3S,4R)-4-(3,4-二氟苯基)-1-(1-(4-甲氧基苯甲基)-1H-吡唑-4-基)吡咯烷-3-基氨基甲酸叔丁酯(376mg，0.776mmol)在EtOH(2mL)和HCl(5M至6M iPrOH溶液)(3.10mL，15.5mmol)中的溶液19小时。在真空下浓缩，用Et2O(3×20mL)稀释并且浓缩，得到呈绿棕色固体状的产物(401mg，113％)。MS(apci)m/z＝385.2(M+H)。[0266] Step C:Preparation of (3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-amine dihydrochloride : A solution of tert-butyl (3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-ylcarbamate (376 mg, 0.776 mmol) in EtOH (2 mL) and HCl (5 M to 6 M solution in iPrOH) (3.10 mL, 15.5 mmol) was stirred at ambient temperature for 19 hours. Concentrate under vacuum, dilute withEt2O (3 x 20 mL) and concentrate to give the product as a green-brown solid (401 mg, 113%). MS (apci) m/z = 385.2 (M+H).
步骤D：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(1-(4-甲氧基苯甲基)-1H-吡唑-4-基)吡咯烷-3-基)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲：向(3S,4R)-4-(3,4-二氟苯基)-1-(1-(4-甲氧基苯甲基)-1H-吡唑-4-基)吡咯烷-3-胺二盐酸盐(40mg，0.088mmol)在DIEA(0.061mL，0.35mmol)和DMA(1mL)中的溶液中添加3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(以中间体P135为起始物如实例1步骤A中所制备；29.5mg，0.088mmol)并且在环境温度下搅拌反应混合物1小时。通过反相柱色谱法，用5％至70％乙腈/水洗脱来直接纯化反应混合物，得到呈白色固体状的产物(24mg，44％产率)。MS(apci)m/z＝628.3(M+H)。Step D:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazole-[0266] To a solution of (3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl) pyrrolidin-3-amine dihydrochloride (40 mg, 0.088 mmol) in DIEA (0.061 mL, 0.35 mmol) and DMA (1 mL) was added phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as in Example 1, Step A starting with Intermediate P135; 29.5 mg, 0.088 mmol) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 70% acetonitrile/water to give the product (24 mg, 44% yield) as a white solid. MS (apci) m/z = 628.3 (M+H).
步骤E：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(1H-吡唑-4-基)吡咯烷-3-基)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲：在压力管中将1-((3S,4R)-4-(3,4-二氟苯基)-1-(1-(4-甲氧基苯甲基)-1H-吡唑-4-基)吡咯烷-3-基)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲(22mg，0.035mmol)在TFA(2mL)中的溶液加热至60℃，持续18小时。将反应混合物转移至圆底烧瓶中，浓缩并且与甲苯(2×10mL)共沸。将粗产物溶解于MeOH(5mL)中，并且通过穿过聚合物承载型树脂(StratoSpheres PL-HCO3MP)去除残余TFA。通过制备型TLC(0.5mm板，用10％MeOH/DCM洗脱)纯化粗产物，得到呈灰白色固体状的标题化合物(13mg，73％产率)。MS(apci)m/z＝508.2(M+H)。[0266] Step E:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : A solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea (22 mg, 0.035 mmol) in TFA (2 mL) was heated to 60°C in a pressure tube for 18 hours. The reaction mixture was transferred to a round-bottom flask, concentrated and azeotroped with toluene (2 x 10 mL). The crude product was dissolved in MeOH (5 mL) and residual TFA was removed by passing through a polymer-supported resin (StratoSpheres PL-HCO3 MP). The crude product was purified by preparative TLC (0.5 mm plate, eluting with 10% MeOH/DCM) to afford the title compound (13 mg, 73% yield) as an off-white solid. MS (apci) m/z=508.2 (M+H).
实例217Example 217
1-((3S,4R)-4-(3,5-二氟苯基)-1-(1H-吡唑-4-基)吡咯烷-3-基)-3-(3-乙氧基-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-甲基-1-苯基-1H-吡唑-5-基)脲4-Methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据实例216中所述的方法，在步骤B中用(3S,4R)-4-(3,5-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯替代(3S,4R)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯来制备。MS(apci)m/z＝508.2(M+H)。Prepared according to the method described in Example 216, substituting tert-butyl (3S,4R)-4-(3,5-difluorophenyl)pyrrolidin-3-ylcarbamate for tert-butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate in Step B. MS (apci) m/z = 508.2 (M+H).
实例218Example 218
1-((3S,4R)-4-(3,5-二氟苯基)-1-(1H-吡唑-3-基)吡咯烷-3-基)-3-(3-乙氧基-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(1H-pyrazol-3-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-甲基-1-苯基-1H-吡唑-5-基)脲4-Methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据实例216中所述的方法，在步骤A中用3-碘-1H-吡唑替代4-碘-1H-吡唑并且在步骤B中用(3S,4R)-4-(3,5-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯替代(3S,4R)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯来制备。MS(apci)m/z＝508.2(M+H)。Prepared according to the method described in Example 216, substituting 3-iodo-1H-pyrazole for 4-iodo-1H-pyrazole in Step A and substituting tert-butyl (3S,4R)-4-(3,5-difluorophenyl)pyrrolidin-3-ylcarbamate for tert-butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate in Step B. MS (apci) m/z = 508.2 (M+H).
实例219Example 219
1-((3S,4R)-4-(3,4-二氟苯基)-1-(3-甲基-1H-吡唑-4-基)吡咯烷-3-基)-3-(3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(3-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲Ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据实例216中所述的方法，在步骤A中用4-碘-3-甲基-1H-吡唑替代4-碘-1H-吡唑来制备。MS(apci)m/z＝522.2(M+H)。Prepared according to the method described in Example 216, substituting 4-iodo-3-methyl-1H-pyrazole for 4-iodo-1H-pyrazole in Step A. MS (apci) m/z = 522.2 (M+H).
实例220Example 220
1-((3S,4R)-4-(3,4-二氟苯基)-1-(3-(三氟甲基)-1H-吡唑-4-基)吡咯烷-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrrolidine-3-基)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲1-phenyl-1H-pyrazol-5-yl)urea
根据实例216中所述的方法，在步骤A中用4-碘-3-甲基-1H-吡唑替代4-碘-1H-吡唑来制备。MS(apci)m/z＝576.2(M+H)。Prepared according to the method described in Example 216, substituting 4-iodo-3-methyl-1H-pyrazole for 4-iodo-1H-pyrazole in Step A. MS (apci) m/z = 576.2 (M+H).
实例221Example 221
1-((3S,4R)-4-(3,4-二氟苯基)-1-(1H-吡唑-4-基)吡咯烷-3-基)-3-(3-((S)-2-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-((S)-2-羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(hydroxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备1-(3-((S)-2-(叔丁基二甲基硅烷氧基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(1-(4-甲氧基苯甲基)-1H-吡唑-4-基)吡咯烷-3-基)脲：向(3S,4R)-4-(3,4-二氟苯基)-1-(1-(4-甲氧基苯甲基)-1H-吡唑-4-基)吡咯烷-3-胺二盐酸盐(实例216步骤C，35mg，0.077mmol)在DIEA(0.053mL，0.31mmol)和DMA(1mL)中的溶液中添加(S)-3-(2-(叔丁基二甲基硅烷氧基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(以中间体P211为起始物如实例1步骤A中所制备；37mg，0.077mmol)并且在环境温度下搅拌反应混合物1小时。通过反相柱色谱法，用5％至95％乙腈/水洗脱来直接纯化反应混合物，得到呈白色固体状的产物(40mg，68％产率)。MS(apci)m/z＝772.4(M+H)。Step A:Preparation of 1-(3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin -3-yl)urea: To (3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-amine dihydrochloride To a solution of (S)-phenyl 3-(2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as in Example 1, Step A starting with Intermediate P211; 37 mg, 0.077 mmol) in DIEA (0.053 mL, 0.31 mmol) and DMA (1 mL) was added the 4-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate salt (Example 216, Step C, 35 mg, 0.077 mmol) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 95% acetonitrile/water to give the product (40 mg, 68% yield) as a white solid. MS (apci) m/z=772.4 (M+H).
步骤B：制备(S)-1-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(1H-吡唑-4-基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-基氧基)丙-2-基2,2,2-三氟乙酸酯：在压力管中将1-(3-((S)-2-(叔丁基二甲基硅烷氧基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(1-(4-甲氧基苯甲基)-1H-吡唑-4-基)吡咯烷-3-基)脲(39mg，0.051mmol)在TFA(2mL)中的溶液加热至60℃，持续16小时。将反应混合物转移至圆底烧瓶中，浓缩并且与甲苯(2×10mL)共沸，得到呈棕褐色固体状的产物(32mg，99％)。MS(apci)m/z＝634.2(M+H)。[0266] Step B:Preparation of (S)-1-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)propan-2-yl 2,2,2-trifluoroacetate : A solution of 1-(3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)urea (39 mg, 0.051 mmol) in TFA (2 mL) was heated to 60 °C in a pressure tube for 16 hours. The reaction mixture was transferred to a round bottom flask, concentrated and azeotroped with toluene (2 x 10 mL) to give the product as a tan solid (32 mg, 99%).MS (apci) m/z = 634.2 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(1H-吡唑-4-基)吡咯烷-3-基)-3-(3-((S)-2-羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：向(S)-1-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(1H-吡唑-4-基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-基氧基)丙-2-基2,2,2-三氟乙酸酯(32mg，0.051mmol)在MeOH(1mL)和THF(2mL)中的溶液中添加2M LiOH水溶液(0.5mL，1.0mmol)。在环境温度下搅拌反应物3小时，用H2O(20mL)稀释，用10:90MeOH/DCM(2×20mL)萃取并且干燥(MgSO4)合并的有机相，过滤并且在减压下浓缩。通过二氧化硅柱色谱法，用10％MeOH/DCM洗脱来纯化，得到呈白色固体状的标题化合物(19mg，72％产率)。MS(apci)m/z＝538.2(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : To a solution of (S)-1-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)urea)-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)propan-2-yl 2,2,2-trifluoroacetate (32 mg, 0.051 mmol) in MeOH (1 mL) and THF (2 mL) was added 2 M aqueous LiOH (0.5 mL, 1.0 mmol). The reaction was stirred at ambient temperature for 3 hours, diluted withH2O (20 mL), extracted with 10:90 MeOH/DCM (2 x 20 mL) and the combined organic phases dried (MgSO4 ), filtered and concentrated under reduced pressure. Purification by silica column chromatography eluting with 10% MeOH/DCM gave the title compound (19 mg, 72% yield) as a white solid. MS (apci) m/z = 538.2 (M+H).
实例222Example 222
1-((3S,4R)-4-(3,4-二氟苯基)-1-(1H-吡唑-4-基)吡咯烷-3-基)-3-(3-((R)-2,1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-((R)-2,3-二羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据实例221中所述的方法，在步骤A中用(S)-3-((2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(以中间体P209为起始物如实例1步骤A中所制备)替代(S)-3-(2-(叔丁基二甲基硅烷氧基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。MS(apci)m/z＝554.2(M+H)。Prepared according to the method described in Example 221, substituting (S)-phenyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared starting from intermediate P209 as in Example 1, Step A) for (S)-phenyl 3-(2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate in Step A. MS (apci) m/z = 554.2 (M+H).
根据实例216的方法，在步骤A和B中替代用适当的起始物质并且在步骤D中替代用适当的吡唑中间体来制备下表中的化合物。Following the procedure of Example 216, the compounds in the following table were prepared by substituting appropriate starting materials in Steps A and B and appropriate pyrazole intermediate in Step D.
实例248Example 248
1-((3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-基)-1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲3-(2-Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备((3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-基)氨基甲酸叔丁酯：将(3S,4R)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(150mg，0.503mmol)、1,2,3-噻二唑-4-甲醛(68.9mg，0.603mmol)与DIEA(186μL，1.01mmol)合并在1mL DCM中并且在环境温度下搅拌30分钟。添加三乙酰氧基硼氢化钠(213mg，1.01mmol)并且在环境温度下搅拌反应物过夜并且浓缩。通过反相柱色谱法，用0％至50％乙腈/水洗脱来纯化粗物质，得到产物(168mg，0.424mmol，84.3％产率)。MS(apci)m/z＝397.1(M+H)。Step A:Preparation of tert-butyl ((3S, 4R)-1-((1,2,3-thiadiazole-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)carbamate : tert-butyl (3S, 4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (150 mg, 0.503 mmol), 1,2,3-thiadiazole-4-carbaldehyde (68.9 mg, 0.603 mmol) and DIEA (186 μ L, 1.01 mmol) were combined in 1 mL of DCM and stirred at ambient temperature for 30 minutes. Sodium triacetoxyborohydride (213 mg, 1.01 mmol) was added and the reaction was stirred at ambient temperature overnight and concentrated. The crude material was purified by reverse phase column chromatography using 0% to 50% acetonitrile/water elution to give the product (168 mg, 0.424 mmol, 84.3% yield). MS (apci) m/z = 397.1 (M+H).
步骤B：制备(3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-胺二盐酸盐：将(3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(150mg，0.378mmol)与5N HCl的IPA溶液(378μl，1.89mmol)合并在1mLIPA中并且在环境温度下静置过夜。浓缩反应物，得到产物(140mg，0.379mmol，100％产率)。MS(apci)m/z＝297.0(M+H)。Step B:Preparation of (3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-amine dihydrochloride : tert-Butyl (3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (150 mg, 0.378 mmol) was combined with 5N HCl in IPA (378 μl, 1.89 mmol) in 1 mL IPA and allowed to stand overnight at ambient temperature. The reaction was concentrated to afford the product (140 mg, 0.379 mmol, 100% yield). MS (apci) m/z = 297.0 (M+H).
步骤C：制备1-((3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将(3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-胺二盐酸盐(20mg，0.054mmol)、2-苯基-2,4,5,6-四氢-环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(16mg，0.049mmol，如对于实例38步骤E所述制备)与DIEA(26μl，0.15mmol)合并在0.2mL DMF中并且在环境温度下搅拌1小时。将反应物加载至加样装置上并且通过反相柱色谱法用0％至80％乙腈/水洗脱来纯化，得到标题化合物(24mg，0.046mmol，93％产率)。MS(apci)m/z＝522.2(M+H)。[0266] Step C:Preparation of 1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : (3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-amine dihydrochloride (20 mg, 0.054 mmol), phenyl 2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-ylcarbamate (16 mg, 0.049 mmol, prepared as described for Example 38, Step E) and DIEA (26 μl, 0.15 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 1 hour. The reaction was loaded onto an injection device and purified by reverse phase column chromatography eluting with 0% to 80% acetonitrile/water to give the title compound (24 mg, 0.046 mmol, 93% yield).MS (apci) m/z=522.2 (M+H).
实例249Example 249
1-((3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-基)-1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲3-(3-Ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过如实例216步骤C中所述的方法，使用3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(根据实例1步骤A的方法以中间体P135为起始物来制备)替代2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(23mg，0.043mmol，87％产率)。MS(apci)m/z＝540.2(M+H)。Prepared by the method described in Example 216, Step C, using phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared according to the method of Example 1, Step A starting from Intermediate P135) instead of phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate. The material was purified by reverse phase column chromatography using 0% to 80% acetonitrile/H2O as eluent to give the title compound (23 mg, 0.043 mmol, 87% yield). MS (apci) m/z = 540.2 (M+H).
实例250Example 250
1-((3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-基)-1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-(氰基甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲3-(3-(Cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过如实例216步骤C中所述的方法，使用3-(氰基甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(3.4mg，0.0062mmol，50％产率)。MS(apci)m/z＝551.2(M+H)。Prepared by the method described in Example 216, Step C, using phenyl 3-(cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate instead of phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate. The material was purified by reverse phase column chromatography using 0% to 80% acetonitrile/H2O as eluent to give the title compound (3.4 mg, 0.0062 mmol, 50% yield). MS (apci) m/z = 551.2 (M+H).
实例251Example 251
1-((3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-基)-1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)脲3-(1',4-Dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)urea
通过如实例216步骤C中所述的方法，使用1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯(9.2mg，0.025mmol)替代2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至70％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(4.2mg，0.0073mmol，30％产率)。MS(apci)m/z＝576.2(M+H)。Prepared by the method described in Example 216, Step C, using phenyl 1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamate (9.2 mg, 0.025 mmol) instead of phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate. The material was purified by reverse phase column chromatography using 0% to 70% acetonitrile/H2O as eluent to give the title compound (4.2 mg, 0.0073 mmol, 30% yield). MS (apci) m/z = 576.2 (M+H).
实例252Example 252
1-((3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-基)-1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(4-甲基-3-(1-甲基-1H-咪唑-4-基)-1-苯基-1H-吡唑-5-基)脲3-(4-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea
通过如实例216步骤C中所述的方法，使用氯化1-甲基-4-(4-甲基-5-(苯氧羰基氨基)-1-苯基-1H-吡唑-3-基)-3-(苯氧羰基)-1H-咪唑-3-鎓替代2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯并且额外添加1当量(3S,4R)-1-((1,2,3-噻二唑-4-基)甲基)-4-(3,4-二氟苯基)吡咯烷-3-胺二盐酸盐来制备。通过反相柱色谱法，使用0％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(6.2mg，0.011mmol，42％产率)。MS(apci)m/z＝576.2(M+H)。Prepared by the method described in Example 216, Step C, using 1-methyl-4-(4-methyl-5-(phenoxycarbonylamino)-1-phenyl-1H-pyrazol-3-yl)-3-(phenoxycarbonyl)-1H-imidazol-3-ium chloride instead of phenyl 2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-ylcarbamate and adding 1 additional equivalent of (3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-amine dihydrochloride. The material was purified by reverse phase column chromatography using 0% to 80% acetonitrile/H2O as eluent to give the title compound (6.2 mg, 0.011 mmol, 42% yield). MS (apci) m/z = 576.2 (M+H).
实例253Example 253
1-((3S,4R)-4-(3,4-二氟苯基)-1-((1-甲基-1H-1,2,3-三唑-4-基)甲基)吡咯1-((3S,4R)-4-(3,4-difluorophenyl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)pyrrole烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲alkyl-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea
通过如实例216中所述的方法，在步骤A中使用1-甲基-1H-1,2,3-三唑-4-甲醛替代1,2,3-噻二唑-4-甲醛来制备。通过反相柱色谱法，使用0％至80％乙腈/H2O作为洗脱剂来纯化最终产物，得到标题化合物(17mg，0.033mmol，76％产率(3个步骤))。MS(apci)m/z＝519.2(M+H)。Prepared by the method described in Example 216, using 1-methyl-1H-1,2,3-triazole-4-carbaldehyde instead of 1,2,3-thiadiazole-4-carbaldehyde in Step A. The final product was purified by reverse phase column chromatography using 0% to 80% acetonitrile/H2O as eluent to give the title compound (17 mg, 0.033 mmol, 76% yield (3 steps)). MS (apci) m/z = 519.2 (M+H).
实例254Example 254
1-((3S,4R)-4-(3,4-二氟苯基)-1-(1,3-二甲氧基丙-2-基)吡咯烷-3-基)-3-(3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1,3-dimethoxyprop-2-yl)pyrrolidin-3-yl)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲Ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过如实例249中所述的方法，在步骤A中使用1,3-二甲氧基丙-2-酮替代1,2,3-噻二唑-4-甲醛来制备。通过反相柱色谱法，使用5％至80％乙腈/H2O作为洗脱剂来纯化最终产物，得到标题化合物(17.3mg，0.0318mmol，57.4％产率(3个步骤))。MS(apci)m/z＝544.3(M+H)。Prepared by the method described in Example 249, using 1,3-dimethoxypropan-2-one instead of 1,2,3-thiadiazole-4-carbaldehyde in Step A. The final product was purified by reverse phase column chromatography using 5% to 80% acetonitrile/H2O as eluent to give the title compound (17.3 mg, 0.0318 mmol, 57.4% yield (3 steps)). MS (apci) m/z = 544.3 (M+H).
实例255Example 255
1-((3S,4R)-4-(3,4-二氟苯基)-1-(1-甲氧基丙-2-基)吡咯烷-3-基)-3-(3-乙氧1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-methoxyprop-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy)-基-4-甲基-1-苯基-1H-吡唑-5-基)脲4-Methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过如实例249中所述的方法，在步骤A中使用1-甲氧基丙-2-酮替代1,2,3-噻二唑-4-甲醛来制备。通过反相柱色谱法，使用0％至80％乙腈/H2O作为洗脱剂来纯化最终产物，得到标题化合物(8.2mg，0.016mmol，70.1％产率(3个步骤))。MS(apci)m/z＝514.3(M+H)。Prepared by the method described in Example 249, using 1-methoxypropan-2-one instead of 1,2,3-thiadiazole-4-carbaldehyde in Step A. The final product was purified by reverse phase column chromatography using 0% to 80% acetonitrile/H2O as eluent to give the title compound (8.2 mg, 0.016 mmol, 70.1% yield (3 steps)). MS (apci) m/z = 514.3 (M+H).
实例256Example 256
1-((反式)-4-(4-氟苯基)-1-(2-(甲基氨基)乙基)吡咯烷-3-基)-3-(2-苯基-2,1-((trans)-4-(4-fluorophenyl)-1-(2-(methylamino)ethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲4,5,6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
将1-((3S,4R)-4-(4-氟苯基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢-环戊二烯并[c]吡唑-3-基)脲盐酸盐(11mg，0.0249mmol，如实例210所制备)、2-碘-N-甲基-N-三苯甲基乙胺(19.1mg，0.0448mmol)与DIEA(9.65mg，0.0747mmol)合并在0.2mL DMF中并且在环境温度下搅拌过夜。添加HCl(7N IPA溶液，35.6μL，0.249mmol)并且在环境温度下搅拌反应物4小时。添加1N NaOH(2mL)并且在相分离过滤器板中用数份DCM萃取反应物。浓缩合并的有机萃取物并且通过反相柱色谱法使用0％至60％乙腈/H2O作为洗脱剂纯化，得到标题化合物(2.2mg，0.00476mmol，19.1％产率)。MS(apci)m/z＝463.3(M+H)。1-((3S,4R)-4-(4-Fluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-yl)urea hydrochloride (11 mg, 0.0249 mmol, prepared as in Example 210), 2-iodo-N-methyl-N-tritylethylamine (19.1 mg, 0.0448 mmol) and DIEA (9.65 mg, 0.0747 mmol) were combined in 0.2 mL of DMF and stirred overnight at ambient temperature. HCl (7N in IPA, 35.6 μL, 0.249 mmol) was added and the reaction was stirred at ambient temperature for 4 hours. 1N NaOH (2 mL) was added and the reaction was extracted with several portions of DCM on a phase separation filter plate. The combined organic extracts were concentrated and purified by reverse phase column chromatography using 0% to 60% acetonitrile/H2O as eluent to give the title compound (2.2 mg, 0.00476 mmol, 19.1% yield).MS (apci) m/z = 463.3 (M+H).
实例257Example 257
1-((反式)-1-((1H-咪唑-2-基)甲基)-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,1-((trans)-1-((1H-imidazol-2-yl)methyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲6-Tetrahydrocyclopenta[c]pyrazol-3-yl)urea
将1-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)-3-((反式)-4-苯基-吡咯烷-3-基)脲(15mg，0.039mmol，如实例182步骤B中所述制备)、2-(氯甲基)-1H-咪唑盐酸盐(5.9mg，0.039mmol)与DIEA(14μL，0.077mmol)合并在0.2mL DMF中并且在环境温度下搅拌30分钟。将反应物加载至加样装置上并且通过反相柱色谱法使用0％至70％乙腈/H2O作为洗脱剂来纯化，得到标题化合物(7.9mg，0.017mmol，44％产率)。MS(apci)m/z＝468.2(M+H)。1-(2-Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-phenyl-pyrrolidin-3-yl)urea (15 mg, 0.039 mmol, prepared as described in Example 182, Step B), 2-(chloromethyl)-1H-imidazole hydrochloride (5.9 mg, 0.039 mmol) and DIEA (14 μL, 0.077 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 30 minutes. The reaction was loaded onto a loading device and purified by reverse phase column chromatography using 0% to 70% acetonitrile/H2 O as eluent to give the title compound (7.9 mg, 0.017 mmol, 44% yield). MS (apci) m/z=468.2 (M+H).
实例258Example 258
3-甲氧基-2-((反式)-3-苯基-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-Methoxy-2-((trans)-3-phenyl-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-基)脲基)吡咯烷-1-基)丙酸甲酯3-yl)ureido)pyrrolidin-1-yl)propionic acid methyl ester
将1-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)-3-((反式)-4-苯基-吡咯烷-3-基)脲(30mg，0.077mmol，如实例182步骤B中所述来制备)、2-溴-3-甲氧基丙酸甲酯(15mg，0.077mmol)与DIEA(29μL，0.15mmol)合并在0.2mL DCM中并且在环境温度下搅拌3天。将反应物加载至加样装置上并且通过反相柱色谱法使用5％至80％乙腈/H2O作为洗脱剂来纯化，得到呈非对映异构体混合物形式的标题化合物(24mg，0.048mmol，62％产率)。MS(apci)m/z＝504.3(M+H)。1-(2-Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-phenyl-pyrrolidin-3-yl)urea (30 mg, 0.077 mmol, prepared as described in Example 182, Step B), methyl 2-bromo-3-methoxypropanoate (15 mg, 0.077 mmol) and DIEA (29 μL, 0.15 mmol) were combined in 0.2 mL of DCM and stirred at ambient temperature for 3 days. The reaction was loaded onto a loading device and purified by reverse phase column chromatography using 5% to 80% acetonitrile/H2 O as eluent to give the title compound (24 mg, 0.048 mmol, 62% yield) as a mixture of diastereomers. MS (apci) m/z=504.3 (M+H).
实例259Example 259
1-((3S,4R)-4-(3,4-二氟苯基)-1-(1-甲氧基丙-2-基)吡咯烷-3-基)-3-(3-乙氧1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-methoxyprop-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy)-基-4-甲基-1-苯基-1H-吡唑-5-基)脲4-Methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过如实例194中所述的方法，在步骤A中用2-溴-3-甲氧基丙酸甲酯替代三氟甲磺酸2,2,2-三氟乙酯并且搅拌3天而非1小时来制备。通过反相柱色谱法，使用5％至80％乙腈/H2O作为洗脱剂来纯化最终产物，得到呈非对映异构体混合物形式的标题化合物(260mg，0.482mmol，83.5％产率(3个步骤))。MS(apci)m/z＝540.3(M+H)。Prepared as described in Example 194, substituting methyl 2-bromo-3-methoxypropanoate for 2,2,2-trifluoroethyl trifluoromethanesulfonate in Step A and stirring for 3 days instead of 1 hour. The final product was purified by reverse phase column chromatography using 5% to 80% acetonitrile/H2 O as eluent to give the title compound (260 mg, 0.482 mmol, 83.5% yield (3 steps)) as a mixture of diastereomers. MS (apci) m/z=540.3 (M+H).
实例260Example 260
1-((3S,4R)-4-(3,4-二氟苯基)-1-(1-羟基-3-甲氧基丙-2-基)吡咯烷-3-基)-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxyprop-2-yl)pyrrolidin-3-yl)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲(2-Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea
将2-((3R,4S)-3-(3,4-二氟苯基)-4-(3-(2-苯基-2,4,5,6-四氢-环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-基)-3-甲氧基丙酸甲酯(200mg，0.371mmol，如实例259中所述来制备)溶解于5mL THF中并且将溶液冷却至0℃。添加LiAlH4(28.1mg，0.741mmol)并且允许反应物经2小时升温至环境温度。添加十水合硫酸钠(1194mg，3.71mmol)并且在环境温度下搅拌反应物2小时，过滤并且浓缩。通过反相柱色谱法，使用0％至70％乙腈/H2O作为洗脱剂纯化粗产物，得到呈非对映异构体混合物形式的标题化合物(20mg，0.0391mmol，10.5％产率)。MS(apci)m/z＝512.3(M+H)。Methyl 2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)-3-methoxypropanoate (200 mg, 0.371 mmol, prepared as described in Example 259) was dissolved in 5 mL of THF and the solution was cooled to 0°C.LiAlH4 (28.1 mg, 0.741 mmol) was added and the reaction was allowed to warm to ambient temperature over 2 hours. Sodium sulfate decahydrate (1194 mg, 3.71 mmol) was added and the reaction was stirred at ambient temperature for 2 hours, filtered and concentrated. The crude product was purified by reverse phase column chromatography using 0% to 70% acetonitrile/H2O as eluent to give the title compound as a mixture of diastereomers (20 mg, 0.0391 mmol, 10.5% yield).MS (apci) m/z = 512.3 (M+H).
实例261Example 261
1-((3S,4R)-4-(3,4-二氟苯基)-1-(3-羟基-1-甲氧基-3-甲基丁-2-基)吡咯烷-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(3-hydroxy-1-methoxy-3-methylbutan-2-yl)pyrrolidine-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea
将2-((3R,4S)-3-(3,4-二氟苯基)-4-(3-(2-苯基-2,4,5,6-四氢-环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-基)-3-甲氧基丙酸甲酯(20mg，0.037mmol，如实例12中所述制备)溶解于1mL THF中并且冷却至0℃。添加溴化甲基镁(2M THF溶液，93μL，0.19mmol)并且允许反应物升温至环境温度过夜。添加H2O(2mL)并且在相分离过滤器板中用DCM(2×5mL)萃取反应物。浓缩合并的有机萃取物并且通过反相柱色谱法使用0％至70％乙腈/H2O作为洗脱剂来纯化，得到呈非对映异构体混合物形式的标题化合物(7.9mg，0.015mmol，39％产率)。MS(apci)m/z＝539.6(M+H)。Methyl 2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)-3-methoxypropanoate (20 mg, 0.037 mmol, prepared as described in Example 12) was dissolved in 1 mL of THF and cooled to 0°C. Methylmagnesium bromide (2M solution in THF, 93 μL, 0.19 mmol) was added and the reaction was allowed to warm to ambient temperature overnight.H2O (2 mL) was added and the reaction was extracted with DCM (2×5 mL) on a phase separation filter plate. The combined organic extracts were concentrated and purified by reverse phase column chromatography using 0% to 70% acetonitrile/H2O as eluent to give the title compound (7.9 mg, 0.015 mmol, 39% yield) as a mixture of diastereomers. MS (apci) m/z = 539.6 (M+H).
实例262Example 262
2-((3R,4S)-3-(3,4-二氟苯基)-4-(3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyridine唑-3-基)脲基)吡咯烷-1-基)-3-甲氧基丙酸盐酸盐(3-oxazol-3-yl)ureido)pyrrolidin-1-yl)-3-methoxypropionic acid hydrochloride
将2-((3R,4S)-3-(3,4-二氟苯基)-4-(3-(2-苯基-2,4,5,6-四氢-环戊二烯并[c]吡唑-3-基)脲基)吡咯烷-1-基)-3-甲氧基丙酸甲酯(300mg，0.556mmol，如实例259中所述制备)与NaOH(1N水溶液，834μL，0.834mmol)合并在1mL MeOH中并且在环境温度下搅拌过夜。将反应物加载至加样装置上并且通过反相柱色谱法使用0％至50％乙腈/0.01M HCl水溶液作为洗脱剂来纯化，得到呈非对映异构体混合物形式的标题化合物(298mg，0.530mmol，95.4％产率)。MS(apci)m/z＝526.2(M+H)。Methyl 2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydro-cyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)-3-methoxypropanoate (300 mg, 0.556 mmol, prepared as described in Example 259) was combined with NaOH (1N aqueous solution, 834 μL, 0.834 mmol) in 1 mL of MeOH and stirred overnight at ambient temperature. The reaction was loaded onto a loading device and purified by reverse phase column chromatography using 0% to 50% acetonitrile/0.01 M aqueous HCl as eluent to give the title compound (298 mg, 0.530 mmol, 95.4% yield) as a mixture of diastereomers. MS (apci) m/z=526.2 (M+H).
实例263Example 263
1-((3S,4R)-4-(3,4-二氟苯基)-1-(1-羟基-3-甲氧基丙-2-基)吡咯烷-3-基)-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxyprop-2-yl)pyrrolidin-3-yl)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-Ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备(3S,4R)-4-(3,4-二氟苯基)-1-(1-羟基-3-甲氧基丙-2-基)吡咯烷-3-基氨基甲酸叔丁酯：将2-((3S,4R)-3-(叔丁氧基羰基氨基)-4-(3,4-二氟苯基)吡咯烷-1-基)-3-甲氧基丙酸甲酯(220mg，0.531mmol，如实例259步骤A中所述制备)溶解于5mL THF中并且分数小份添加NaBH4(100mg，2.65mmol)。在环境温度下搅拌反应物1小时，在40℃下搅拌3小时，并且然后在50℃下搅拌过夜。过滤反应物，浓缩，并且通过反相柱色谱法用0％至70％乙腈/水洗脱来纯化，得到标题化合物(154mg，0.399mmol，75.1％产率)。MS(apci)m/z＝387.2(M+H)。Step A:Preparation of tert-butyl (3S, 4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxyprop-2-yl)pyrrolidin-3-ylcarbamate : Methyl 2-((3S, 4R)-3-(tert-butoxycarbonylamino)-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3-methoxypropanoate (220 mg, 0.531 mmol, prepared as described in Example 259, Step A) was dissolved in 5 mL of THF and NaBH (100 mg, 2.65mmol ) was added in small portions. The reaction was stirred at ambient temperature for 1 hour, at 40° C. for 3 hours, and then at 50° C. overnight. The reaction was filtered, concentrated, and purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/water to give the title compound (154 mg, 0.399 mmol, 75.1% yield). MS (apci) m/z = 387.2 (M+H).
步骤B：制备2-((3S,4R)-3-氨基-4-(3,4-二氟苯基)吡咯烷-1-基)-3-甲氧基丙-1-醇二盐酸盐：将(3S,4R)-4-(3,4-二氟苯基)-1-(1-羟基-3-甲氧基丙-2-基)吡咯烷-3-基氨基甲酸叔丁酯(120mg，0.311mmol)与HCl(5N IPA溶液，186μl，0.932mmol)合并在5mL DCM中，并且在环境温度下搅拌6小时。浓缩反应物，得到标题化合物(87mg，0.304mmol，97.9％产率)。Step B:Preparation of 2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3-methoxypropan-1-ol dihydrochloride : tert-Butyl (3S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-ylcarbamate (120 mg, 0.311 mmol) was combined with HCl (5N in IPA, 186 μl, 0.932 mmol) in 5 mL of DCM and stirred at ambient temperature for 6 hours. The reaction was concentrated to give the title compound (87 mg, 0.304 mmol, 97.9% yield).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(1-羟基-3-甲氧基丙-2-基)吡咯烷-3-基)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲：将2-((3S,4R)-3-氨基-4-(3,4-二氟苯基)吡咯烷-1-基)-3-甲氧基丙-1-醇二盐酸盐(13.0mg，0.0362mmol)、3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(根据实例1步骤A的方法以中间体P135为起始物来制备；10.2mg，0.0302mmol)与DIEA(11.7mg，0.0905mmol)合并在0.2mL DMF中，并且在环境温度下搅拌1小时。将反应物加载至加样装置上并且通过反相柱色谱法用0％至60％乙腈/水洗脱来纯化，得到标题化合物(10.9mg，0.0206mmol，68.3％产率)。MS(apci)m/z＝530.2(M+H)。[0266] Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : 2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3-methoxypropan-1-ol dihydrochloride (13.0 mg, 0.0362 mmol), phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared according to the method of Example 1, Step A starting from intermediate P135; 10.2 mg, 0.0302 mmol) and DIEA (11.7 mg, 0.0905 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 1 hour. The reaction was loaded onto an injection device and purified by reverse phase column chromatography eluting with 0% to 60% acetonitrile/water to give the title compound (10.9 mg, 0.0206 mmol, 68.3% yield).MS (apci) m/z=530.2 (M+H).
实例264Example 264
1-(4-氯-1'-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)-3-((3S,4R)-4-(3,4-二1-(4-chloro-1'-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)-3-((3S,4R)-4-(3,4-dipyrazol-5-yl)-氟苯基)-1-(1-羟基-3-甲氧基丙-2-基)吡咯烷-3-基)脲(fluorophenyl)-1-(1-hydroxy-3-methoxyprop-2-yl)pyrrolidin-3-yl)urea
通过如实例263中所述的方法，使用4-氯-1'-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯替代3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(17.2mg，0.0293mmol，63.3％产率)。MS(apci)m/z＝586.2(M+H)。Prepared by the method described in Example 263, using 4-chloro-1'-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamic acid phenyl ester instead of 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamic acid phenyl ester. The material was purified by reverse phase column chromatography using 0% to 80% acetonitrile/H2O as eluent to give the title compound (17.2 mg, 0.0293 mmol, 63.3% yield). MS (apci) m/z=586.2 (M+H).
实例265Example 265
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-甲氧基-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-苯基-4-(三氟甲基)-1H-吡唑-5-基)脲1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea
步骤A：分离外消旋(反式)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-胺盐酸盐：通过使用20mm×250mm手性Tech Chiralcell OD-H柱(零件号14345)进行超临界流体色谱法(SFC)来分离(反式)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-胺盐酸盐(3.80g，11.0mmol，根据对于实例194步骤B所述的程序来制备)。洗脱剂为含0.1％NH4OH作为调节剂的9:1超临界CO2:MeOH。分离峰1，得到(3R,4S)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-胺(1.07g，3.81mmol，34.6％产率，98％ee)。MS(apci)m/z＝245.1(M+H)。[0146] Step A:Isolation of racemic (trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine hydrochloride : (trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine hydrochloride (3.80 g, 11.0 mmol, prepared according to the procedure described for Example 194, Step B) was separated by supercritical fluid chromatography (SFC) using a 20 mm x 250 mm Chiral Tech Chiralcell OD-H column (Part No. 14345). The eluent was 9:1 supercriticalCO₂ :MeOH with 0.1%NH₄OH as the modifier. Peak 1 was isolated to give (3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine (1.07 g, 3.81 mmol, 34.6% yield, 98% ee). MS (apci) m/z = 245.1 (M+H).
步骤B：制备1-(3,4-二甲基-1-苯基-1H-吡唑-5-基)-3-((3R,4S)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲：将(3R,4S)-4-苯基-1-(2,2,2-三氟-乙基)吡咯烷-3-胺(15.0mg，0.0614mmol)、3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(17.2mg，0.0558mmol)与DIEA(21.6mg，0.167mmol)合并在0.2mL DMF中并且在环境温度下搅拌1小时。将反应物加载至加样装置上并且通过反相柱色谱法用0％至80％乙腈/水洗脱来纯化，得到标题化合物(7.2mg，0.0157mmol，28.2％产率)。(MS(apci)m/z＝458.2(M+H))。[0266] Step B:Preparation of 1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea : (3R,4S)-4-phenyl-1-(2,2,2-trifluoro-ethyl)pyrrolidin-3-amine (15.0 mg, 0.0614 mmol), phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (17.2 mg, 0.0558 mmol) and DIEA (21.6 mg, 0.167 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 1 hour. The reaction was loaded onto an injection device and purified by reverse phase column chromatography eluting with 0% to 80% acetonitrile/water to give the title compound (7.2 mg, 0.0157 mmol, 28.2% yield) (MS (apci) m/z = 458.2 (M+H)).
实例266Example 266
1-(3-(2-氟乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3R,4S)-4-苯基-1-(2,1-(3-(2-fluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲2,2-trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例1步骤B中所述的方法，使用3-(2-氟乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(2.2mg，0.0044mmol，26％产率)。MS(apci)m/z＝506.2(M+H)。Prepared by the method described in Example 1, Step B, using phenyl 3-(2-fluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate instead of phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate. The material was purified by reverse phase column chromatography using 0% to 80% acetonitrile/H2O as eluent to give the title compound (2.2 mg, 0.0044 mmol, 26% yield). MS (apci) m/z = 506.2 (M+H).
实例267Example 267
1-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3R,4S)-4-苯基-1-(2,2,2-三1-(3-Ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-triphenyl)-氟乙基)吡咯烷-3-基)脲(fluoroethyl)pyrrolidin-3-yl)urea
通过如实例1步骤B中所述的方法，使用3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(根据实例1步骤A的方法以中间体P135为起始物来制备)替代3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(7.1mg，0.0146mmol，42.7％产率)。MS(apci)m/z＝488.2(M+H)。Prepared by the method described in Example 1, Step B, using phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared according to the method of Example 1, Step A starting with Intermediate P135) instead of phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate. The material was purified by reverse phase column chromatography using 0% to 80% acetonitrile/H2O as eluent to give the title compound (7.1 mg, 0.0146 mmol, 42.7% yield). MS (apci) m/z = 488.2 (M+H).
实例268Example 268
1-(3-(氰基甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3R,4S)-4-苯基-1-(2,1-(3-(Cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲2,2-trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例1步骤B中所述的方法，使用3-(氰基甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(11.4mg，0.0229mmol，67.0％产率)。MS(apci)m/z＝499.2(M+H)。Prepared by the method described in Example 1, Step B, using phenyl 3-(cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate instead of phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate. The material was purified by reverse phase column chromatography using 0% to 80% acetonitrile/H2O as eluent to give the title compound (11.4 mg, 0.0229 mmol, 67.0% yield). MS (apci) m/z = 499.2 (M+H).
实例269Example 269
1-(1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)-3-((3R,4S)-4-苯基-1-1-(1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲(2,2,2-Trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例1步骤B中所述的方法，使用1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯替代3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至70％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(6.1mg，0.012mmol，68％产率)。MS(apci)m/z＝524.2(M+H)。Prepared by the method described in Example 1, Step B, using 1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamic acid phenyl ester instead of 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamic acid phenyl ester. The material was purified by reverse phase column chromatography using 0% to 70% acetonitrile/H2O as eluent to give the title compound (6.1 mg, 0.012 mmol, 68% yield). MS (apci) m/z = 524.2 (M+H).
实例270Example 270
1-(4-氯-1'-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)-3-((3R,4S)-4-苯基-1-1-(4-chloro-1'-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲(2,2,2-Trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例1步骤B中所述的方法，使用4-氯-1'-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯替代3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至70％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(11.3mg，0.0208mmol，60.9％产率)。MS(apci)m/z＝488.2(M+H)。Prepared by the method described in Example 1, Step B, using 4-chloro-1'-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamic acid phenyl ester instead of 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamic acid phenyl ester. The material was purified by reverse phase column chromatography using 0% to 70% acetonitrile/H2O as eluent to give the title compound (11.3 mg, 0.0208 mmol, 60.9% yield). MS (apci) m/z = 488.2 (M+H).
实例271Example 271
1-(3-(((S)-2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基)-4-甲基-1-苯基-1H-吡1-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrrolidone唑-5-基)-3-((3R,4S)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲oxazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea
通过如实例1步骤B中所述的方法，使用(S)-3-((2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(5.6mg，0.00976mmol，28.6％产率)。MS(apci)m/z＝574.3(M+H)。Prepared by the method described in Example 1, Step B, using (S)-phenyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate instead of phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate. The material was purified by reverse phase column chromatography using 0% to 80% acetonitrile/H2O as eluent to give the title compound (5.6 mg, 0.00976 mmol, 28.6% yield). MS (apci) m/z = 574.3 (M+H).
实例272Example 272
1-(3-((R)-2,3-二羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3R,4S)-4-1-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲Phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea
将1-(3-(((S)-2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3R,4S)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲(4.4mg，0.0077mmol，如实例7中所述制备)与HCl(7N IPA溶液，3.3μL，0.023mmol)合并在0.2mL IPA中并且在环境温度下搅拌1小时。浓缩反应物并且添加DIEA(1.3μL，0.0077mmol)。通过反相柱色谱法，使用0％至60％乙腈/H2O作为洗脱剂来纯化粗物质，得到标题化合物(3.7mg，0.0069mmol，90％产率)。MS(apci)m/z＝534.2(M+H)。1-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea (4.4 mg, 0.0077 mmol, prepared as described in Example 7) was combined with HCl (7N in IPA, 3.3 μL, 0.023 mmol) in 0.2 mL of IPA and stirred at ambient temperature for 1 hour. The reaction was concentrated and DIEA (1.3 μL, 0.0077 mmol) was added. The crude material was purified by reverse phase column chromatography using 0% to 60% acetonitrile/H2 O as eluent to give the title compound (3.7 mg, 0.0069 mmol, 90% yield). MS (apci) m/z = 534.2 (M+H).
实例273Example 273
(R,S)1-((2α,3β,4α)-2-甲基-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-(R,S)1-((2α,3β,4α)-2-methyl-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea
步骤A：制备N-苯甲基-1-(三甲基硅烷基)乙胺：将(1-氯乙基)三甲基硅烷(6.3g，46.1mmol)与苯甲胺(14.8g，138mmol)合并在压力容器中并且在180℃下加热过夜。将反应物溶解于EtOAc(200mL)中，用1N NaOH(100mL)洗涤，干燥(MgSO4)并且浓缩。通过硅胶柱色谱法，用10％MeOH/CH2Cl2洗脱来纯化粗产物，得到标题化合物(8.10g，39.1mmol，84.7％产率)。(MS(apci)m/z＝208.1(M+H))。[0146] Step A:Preparation of N-benzyl-1-(trimethylsilyl)ethanamine : Combine (1-chloroethyl)trimethylsilane (6.3 g, 46.1 mmol) and benzylamine (14.8 g, 138 mmol) in a pressure vessel and heat at 180°C overnight. The reaction was dissolved in EtOAc (200 mL), washed with 1N NaOH (100 mL), dried (MgSO4 ), and concentrated. The crude product was purified by silica gel column chromatography elutingwith 10% MeOH/CH2Cl2 to give the title compound (8.10 g, 39.1 mmol, 84.7% yield). (MS (apci) m/z = 208.1 (M+H)).
步骤B：制备N-苯甲基-N-(甲氧基甲基)-1-(三甲基硅烷基)乙胺：在0℃下经10分钟用N-苯甲基-1-(三甲基硅烷基)乙胺(8.00g，38.6mmol)分数小份处理甲醛(37％水溶液，3.45mL，46.3mmol)与甲醇(1.88mL，46.3mmol)的混合物。再使用MeOH(2mL)冲洗残余胺。在0℃下搅拌混合物3小时，添加K2CO3(8.00g，57.9mmol)并且允许混合物升温至环境温度过夜。借助于少量Et2O将混合物倒入新烧瓶中并且再添加K2CO3(50g)。搅拌混合物30分钟并且过滤，用少量Et2O洗涤并且小心地浓缩，得到呈浅黄色液体状的标题化合物(9.60g，38.2mmol，99.0％产率)。(MS(apci)m/z＝208.1(M+2H-CH2OCH3))。[0146] Step B:Preparation of N-benzyl-N-(methoxymethyl)-1-(trimethylsilyl)ethanamine : A mixture of formaldehyde (37% in water, 3.45 mL, 46.3 mmol) and methanol (1.88 mL, 46.3 mmol) was treated with N-benzyl-1-(trimethylsilyl)ethanamine (8.00 g, 38.6 mmol) in small portions at 0°C over 10 minutes. Residual amine was rinsed with additional MeOH (2 mL). The mixture was stirred at 0°C for 3 hours,K2CO3 (8.00 g, 57.9 mmol) was added, and themixture was allowed to warm to ambient temperature overnight. The mixture was poured into a new flask with the aid of a small amount ofEt2O , and additionalK2CO3 (50g ) was added. The mixture was stirred for 30 minutes and filtered, washed with a small amount ofEt2O , and carefully concentrated to give the title compound (9.60 g, 38.2 mmol, 99.0% yield) as a light yellow liquid. (MS(apci)m/z=208.1(M+2H-CH2OCH3 )).
步骤C：制备(R,S)(2α,3β,4α)-1-苯甲基-2-甲基-3-硝基-4-苯基吡咯烷和(R,S)(3β,4α,5α)-1-苯甲基-2-甲基-4-硝基-3-苯基吡咯烷：将(E)-(2-硝基乙烯基)苯(0.500g，3.35mmol)和TFA(0.0258mL，0.335mmol)在10mL CH2Cl2中的溶液冷却至0℃并且逐滴添加N-苯甲基-N-(甲氧基甲基)-1-(三甲基硅烷基)乙胺(1.01g，4.02mmol)。在0℃下搅拌反应物2小时并且然后允许其升温至环境温度过夜。浓缩反应物，使用MeOH(2mL)和DIEA(0.584mL，3.35mmol)将其加载至加样装置上并且通过反相柱色谱法用0.1％乙酸铵缓冲的5％至95％乙腈/水洗脱来纯化，得到呈5:3混合物形式的标题化合物(287mg，0.925mmol，56.5％产率)。(MS(apci)m/z＝297.1(M+H))。Step C:Preparation of (R,S)(2α,3β,4α)-1-benzyl-2-methyl-3-nitro-4-phenylpyrrolidine and (R,S)(3β,4α,5α)-1-benzyl-2-methyl-4-nitro-3-phenylpyrrolidine : A solution of (E)-(2-nitrovinyl)benzene (0.500 g, 3.35 mmol) and TFA (0.0258 mL, 0.335 mmol) in 10mL ofCH2Cl2 was cooled to 0°C and N-benzyl-N-(methoxymethyl)-1-(trimethylsilyl)ethanamine (1.01 g, 4.02 mmol) was added dropwise. The reaction was stirred at 0°C for 2 hours and then allowed to warm to ambient temperature overnight. The reaction was concentrated, loaded onto a loading device using MeOH (2 mL) and DIEA (0.584 mL, 3.35 mmol) and purified by reverse phase column chromatography eluting with 5% to 95% acetonitrile/water buffered with 0.1% ammonium acetate to give the title compound (287 mg, 0.925 mmol, 56.5% yield) as a 5:3 mixture (MS (apci) m/z=297.1 (M+H)).
步骤D：制备(R,S)-1-((2α,3β,4α)-1-苯甲基-2-甲基-4-苯基-吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲和(R,S)-1-((3β,4α,5α)-1-苯甲基-5-甲基-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将((2α,3β,4α)-1-苯甲基-2-甲基-3-硝基-4-苯基吡咯烷与(3β,4α,5α)-1-苯甲基-2-甲基-4-硝基-3-苯基吡咯烷(110mg的5:3混合物，0.371mmol)溶解于10mL THF中并且添加雷尼镍(3.18mg，0.0371mmol)。在H2气球下搅拌反应物3天，通过过滤，浓缩并且溶解于0.2mL DMF中。添加2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基氨基甲酸苯酯(149mg，0.467mmol)和DIEA(222μL，1.27mmol)并且在环境温度下搅拌反应物1小时。将反应物加载至加样装置上并且通过反相柱色谱法用0％至80％乙腈/水洗脱来纯化，得到呈约7:3混合物形式的标题化合物(172mg，0.350mmol，82％产率)。(MS(apci)m/z＝492.3(M+H))。Step D:Preparation of (R,S)-1-((2α,3β,4α)-1-benzyl-2-methyl-4-phenyl-pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea and (R,S)-1-((3β,4α,5α)-1-benzyl-5-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : ((2α,3β,4α)-1-benzyl-2-methyl-3-nitro-4-phenylpyrrolidine and (3β,4α,5α)-1-benzyl-2-methyl-4-nitro-3-phenylpyrrolidine (110 mg of a 5:3 mixture, 0.371 mmol) were dissolved in 10 mL of In THF and add Raney nickel (3.18mg, 0.0371mmol).UnderH2 balloon, stir reaction thing 3 days, by filtering, concentrate and be dissolved in 0.2mL DMF.Add 2-phenyl-2,4,5,6-tetrahydrocyclopenta [c] pyrazole-3-ylcarbamic acid phenyl ester (149mg, 0.467mmol) and DIEA (222 μ L, 1.27mmol) and stir reaction thing 1 hour at ambient temperature.Reactant is loaded on sample adding device and eluted with 0% to 80% acetonitrile/water by reverse phase column chromatography and purify, obtain the title compound (172mg, 0.350mmol, 82% yield) in about 7:3 mixture form.(MS (apci) m/z=492.3 (M+H)).
步骤E：制备(R,S)-1-((2α,3β,4α)-2-甲基-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲和1-((3β,4α,5α)-5-甲基-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将1-((2α,3β,4α)-1-苯甲基-2-甲基-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲和1-((3β,4α,5α)-1-苯甲基-5-甲基-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲(170mg的7:3混合物，0.346mmol)溶解于10mL THF中并且添加10％Pd/C(36.8mg，0.0346mmol)。在H2气球下搅拌反应物16小时，通过硅藻土过滤并且浓缩，得到呈约7:3混合物形式的标题化合物(133mg，0.335mmol，96％产率)。(MS(apci)m/z＝402.2(M+H))。Step E:Preparation of (R,S)-1-((2α,3β,4α)-2-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea and 1-((3β,4α,5α)-5-methyl-4-phenylpyrrolidin-3-yl)-3-(2-Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : 1-((2α,3β,4α)-1-benzyl-2-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea and 1-((3β,4α,5α)-1-benzyl-5-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea (170 mg of a 7:3 mixture, 0.346 mmol) were dissolved in 10 mL of THF and 10% Pd/C (36.8 mg, 0.0346 mmol) was added. The reaction was stirred under a balloon ofH2 for 16 h, filtered through celite and concentrated to afford the title compound (133 mg, 0.335 mmol, 96% yield) as a ca. 7:3 mixture (MS (apci) m/z = 402.2 (M+H)).
步骤F：制备(R,S)-1-((2α,3β,4α)-2-甲基-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲：将1-((2α,3β,4α)-2-甲基-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲与1-((3β,4α,5α)-5-甲基-4-苯基吡咯烷-3-基)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲(20mg的7:3混合物，0.050mmol)与DIEA(8.7μL，0.050mmol)合并在0.2mL DMF中并且添加三氟甲磺酸2,2,2-三氟乙酯(35mg，0.15mmol)。在环境温度下搅拌反应物1小时，加载至加样装置上并且通过反相柱色谱法用0％至80％乙腈/水洗脱来分离。分离峰1，得到标题化合物(3.0mg，0.0062mmol，12％产率)。(MS(apci)m/z＝484.2(M+H))。Step F:Preparation of (R,S)-1-((2α,3β,4α)-2-methyl-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidine-[0266] 1-((2α,3β,4α)-2-Methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea : 1-((2α,3β,4α)-2-Methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea and 1-((3β,4α,5α)-5-methyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea (20 mg of a 7:3 mixture, 0.050 mmol) and DIEA (8.7 μL, 0.050 mmol) were combined in 0.2 mL of DMF and 2,2,2-trifluoroethyl trifluoromethanesulfonate (35 mg, 0.15 mmol) was added. The reaction was stirred at ambient temperature for 1 hour, loaded onto a sample loading device, and separated by reverse phase column chromatography eluting with 0% to 80% acetonitrile/water. Peak 1 was isolated to give the title compound (3.0 mg, 0.0062 mmol, 12% yield). (MS (apci) m/z = 484.2 (M+H)).
实例274Example 274
(R,S)-1-((3β,4α,5α)-5-甲基-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)-3-(R,S)-1-((3β,4α,5α)-5-methyl-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-苯基-2,4,5,6-四氢环戊二烯并[c]吡唑-3-基)脲(2-Phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea
通过实例9中所述的方法，在步骤F中分离峰2而非峰1来制备，得到标题化合物(1.9mg，0.0039mmol，7.9％产率)。MS(apci)m/z＝484.2(M+H)。Prepared by the method described in Example 9, isolating Peak 2 instead of Peak 1 in Step F to give the title compound (1.9 mg, 0.0039 mmol, 7.9% yield).MS (apci) m/z=484.2 (M+H).
实例275Example 275
1-((3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-羟基丙-2-基)吡咯烷-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)pyrrolidine-3-基)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备(3S,4R)-4-(3,4-二氟苯基)-1-((R)-3,3,3-三氟-2-羟基丙基)吡咯烷-3-基氨基甲酸叔丁酯：将(3S,4R)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(900mg，3.017mmol)、(R)-2-(三氟甲基)环氧乙烷(338.0mg，3.017mmol)与DIEA(779.8mg，6.034mmol)合并在2mL DMF中并且在环境温度下搅拌过夜。将反应物加载至加样装置上并且通过反相柱色谱法用0％至80％乙腈/水洗脱来纯化，得到标题化合物(1144mg，2.788mmol，92.40％产率)。(MS(apci)m/z＝411.2(M+H))。Step A:Preparation of tert-butyl (3S,4R)-4-(3,4-difluorophenyl)-1-((R)-3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-ylcarbamate : tert-butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (900 mg, 3.017 mmol), (R)-2-(trifluoromethyl)oxirane (338.0 mg, 3.017 mmol) and DIEA (779.8 mg, 6.034 mmol) were combined in 2 mL of DMF and stirred overnight at ambient temperature. The reaction was loaded onto an injection device and purified by reverse phase column chromatography eluting with 0% to 80% acetonitrile/water to give the title compound (1144 mg, 2.788 mmol, 92.40% yield). (MS (apci) m/z = 411.2 (M+H)).
步骤B：制备(R)-3-((3S,4R)-3-(叔丁氧基羰基氨基)-4-(3,4-二氟苯基)吡咯烷-1-基)-1,1,1-三氟丙-2-基甲磺酸酯：将(3S,4R)-4-(3,4-二氟苯基)-1-((R)-3,3,3-三氟-2-羟基丙基)吡咯烷-3-基氨基甲酸叔丁酯(900mg，2.19mmol)溶解于5mL CH2Cl2中并且冷却至0℃。添加DIEA(1146μL，6.58mmol)，接着添加MsCl(204μL，2.63mmol)。允许反应物经1小时升温至环境温度，浓缩并且通过反相柱色谱法用5％至90％乙腈/水洗脱来纯化，得到标题化合物(805mg，1.65mmol，75.1％产率)。(MS(apci)m/z＝489.1(M+H))。Step B:Preparation of (R)-3-((3S,4R)-3-(tert-butoxycarbonylamino)-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-1,1,1-trifluoropropan-2-yl methanesulfonate : tert-Butyl (3S,4R)-4-(3,4-difluorophenyl)-1-((R)-3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-ylcarbamate (900 mg, 2.19 mmol) was dissolved in 5 mLofCH2Cl2 and cooled to 0°C. DIEA (1146 μL, 6.58 mmol) was added, followed by MsCl (204 μL, 2.63 mmol). The reaction was allowed to warm to ambient temperature over 1 hour, concentrated and purified by reverse phase column chromatography eluting with 5% to 90% acetonitrile/water to give the title compound (805 mg, 1.65 mmol, 75.1% yield). (MS (apci) m/z = 489.1 (M+H)).
步骤C：制备(S)-2-((3S,4R)-3-氨基-4-(3,4-二氟苯基)吡咯烷-1-基)-3,3,3-三氟丙-1-醇：将氯化N,N,N-三甲基十六烷-1-铵(25％H2O溶液，3144mg，2.46mmol)与(R)-3-((3S,4R)-3-(叔丁氧基羰基氨基)-4-(3,4-二氟苯基)吡咯烷-1-基)-1,1,1-三氟丙-2-基甲磺酸酯(800mg，1.64mmol)合并在0.5mL THF中并且在150℃下加热3天。将反应物加载至加样装置上并且通过反相柱色谱法用0％至50％乙腈/水洗脱来纯化，得到标题化合物(287mg，0.925mmol，56.5％产率)。(MS(apci)m/z＝311.1(M+H))。[0266] Step C:Preparation of (S)-2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3,3,3-trifluoropropan -1-ol: N,N,N-Trimethylhexadecane-1-ammonium chloride (25% solution inH2O , 3144 mg, 2.46 mmol) and (R)-3-((3S,4R)-3-(tert-butoxycarbonylamino)-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-1,1,1-trifluoropropan-2-yl methanesulfonate (800 mg, 1.64 mmol) were combined in 0.5 mL of THF and heated at 150°C for 3 days. The reaction was loaded onto an injection device and purified by reverse phase column chromatography eluting with 0% to 50% acetonitrile in water to give the title compound (287 mg, 0.925 mmol, 56.5% yield). (MS (apci) m/z = 311.1 (M+H)).
步骤D：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-羟基丙-2-基)吡咯烷-3-基)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲：将(S)-2-((3S,4R)-3-氨基-4-(3,4-二氟苯基)吡咯烷-1-基)-3,3,3-三氟-丙-1-醇(10mg，0.032mmol)、3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(根据实例1步骤A的方法以中间体P135为起始物来制备；9.1mg，0.027mmol)与DIEA(10mg，0.081mmol)合并在0.2mL DMF中并且在环境温度下搅拌1小时。将反应物加载至加样装置上并且通过反相柱色谱法用0％至60％乙腈/水洗脱来纯化，得到标题化合物(8.1mg，0.015mmol，54％产率)。(MS(apci)m/z＝554.2(M+H))。[0266] Step D:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : (S)-2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3,3,3-trifluoro-propan-1-ol (10 mg, 0.032 mmol), phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared according to the method of Example 1, Step A starting with intermediate P135; 9.1 mg, 0.027 mmol) and DIEA (10 mg, 0.081 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for 1 hour. The reaction was loaded onto an injection device and purified by reverse phase column chromatography eluting with 0% to 60% acetonitrile/water to give the title compound (8.1 mg, 0.015 mmol, 54% yield) (MS (apci) m/z = 554.2 (M+H)).
实例276Example 276
1-((3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-1-((3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxyprop-2-yl)pyrrolidine-3-基)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备(3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-羟基丙-2-基)吡咯烷-3-基氨基甲酸叔丁酯：将(S)-2-((3S,4R)-3-氨基-4-(3,4-二氟苯基)吡咯烷-1-基)-3,3,3-三氟丙-1-醇(120mg，0.387mmol，如实例11步骤C中所述制备)、Boc2O(92.9mg，0.425mmol)与PS-DMAP(27.2mg，0.0387mmol)合并在5mL CH2Cl2中并且在环境温度下静置过夜。再添加Boc2O(30mg，0.14mmol)，接着再添加PS-DMAP(27.2mg，0.0387mmol)。静置反应物2小时，过滤，浓缩并且通过反相柱色谱法用5％至95％乙腈/水洗脱来纯化，得到标题化合物(63mg，0.154mmol，39.7％产率)。(MS(apci)m/z＝411.2(M+H))。[0266] Step A:Preparation of tert-butyl (3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl) pyrrolidin-3-ylcarbamate: (S)-2-((3S,4R)-3-amino-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-3,3,3-trifluoropropan-1-ol (120 mg, 0.387 mmol, prepared as described in Example 11, Step C),Boc2O (92.9 mg, 0.425 mmol) and PS-DMAP (27.2 mg, 0.0387 mmol) were combined in 5 mLofCH2Cl2 and allowed to stand at ambient temperature overnight. AdditionalBoc2O (30 mg, 0.14 mmol) was added, followed by additional PS-DMAP (27.2 mg, 0.0387 mmol). The reaction was allowed to stand for 2 hours, filtered, concentrated and purified by reverse phase column chromatography eluting with 5% to 95% acetonitrile/water to give the title compound (63 mg, 0.154 mmol, 39.7% yield) (MS (apci) m/z = 411.2 (M+H)).
步骤B：制备(3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-3-基氨基甲酸叔丁酯：将(3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-羟基丙-2-基)吡咯烷-3-基氨基甲酸叔丁酯(25mg，0.061mmol)与Ag2O(28mg，0.12mmol)合并在1mL甲苯中并且在0℃下搅拌。添加碘代甲烷(10mg，0.073mmol)并且允许反应物升温至环境温度并且搅拌5小时。添加乙腈(0.5mL)并且再添加碘代甲烷(10mg，0.073mmol)并且在环境温度下搅拌反应物过夜，通过过滤，浓缩并且通过反相柱色谱法用5％至95％乙腈/水洗脱来纯化，得到标题化合物(22mg，0.052mmol，85％产率)。(MS(apci)m/z＝425.2(M+H))。Step B:Preparation of tert-butyl (3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-ylcarbamate : tert-Butyl (3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)pyrrolidin-3-ylcarbamate (25 mg, 0.061 mmol) was combined withAg2O (28 mg, 0.12 mmol) in 1 mL of toluene and stirred at 0° C. Iodomethane (10 mg, 0.073 mmol) was added and the reaction was allowed to warm to ambient temperature and stirred for 5 hours. Acetonitrile (0.5 mL) was added and further iodomethane (10 mg, 0.073 mmol) was added and the reaction was stirred at ambient temperature overnight, filtered, concentrated and purified by reverse phase column chromatography eluting with 5% to 95% acetonitrile/water to give the title compound (22 mg, 0.052 mmol, 85% yield). (MS (apci) m/z=425.2 (M+H)).
步骤C：制备(3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-3-胺二盐酸盐：将(3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-3-基氨基甲酸叔丁酯(20mg，0.0471mmol)与HCl(5N IPA溶液，37.7μL，0.188mmol)合并在5mL CH2Cl2中并且在环境温度下搅拌6小时。浓缩反应物，得到标题化合物(15mg，0.0463mmol，98.2％产率)。(MS(apci)m/z＝325.1(M+H))。[0266] Step C:Preparation of (3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-amine dihydrochloride : tert-Butyl (3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-ylcarbamate (20 mg, 0.0471 mmol) was combined with HCl (5N in IPA, 37.7 μL, 0.188 mmol) in 5 mLofCH2Cl2 and stirred at ambient temperature for 6 hours. The reaction was concentrated to afford the title compound (15 mg, 0.0463 mmol, 98.2% yield). (MS (apci) m/z = 325.1 (M+H)).
步骤D：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-3-基)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲：将(3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-3-胺二盐酸盐(7.5mg，0.019mmol)、3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(根据实例1步骤A的方法以中间体P135为起始物来制备；5.8mg，0.017mmol)与DIEA(6.7mg，0.051mmol)合并在0.2mL DMF中并且在环境温度下搅拌1小时。将反应物加载至加样装置上并且通过反相柱色谱法用0％至90％乙腈/水洗脱来纯化，得到标题化合物(6.8mg，0.012mmol，70％产率)。(MS(apci)m/z＝568.2(M+H))。Step D:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : (3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-amine dihydrochloride (7.5 mg, 0.019 mmol), phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared according to the method of Example 1, Step A starting from intermediate P135; 5.8 mg, 0.017 mmol) and DIEA (6.7 mg, 0.051 mmol) were combined in 0.2 mL of The reaction mixture was added to DMF and stirred at ambient temperature for 1 hour. The reaction mixture was loaded onto a sample loading device and purified by reverse phase column chromatography using 0% to 90% acetonitrile/water elution to give the title compound (6.8 mg, 0.012 mmol, 70% yield). (MS (apci) m/z = 568.2 (M+H)).
实例277Example 277
1-((3S,4R)-4-(3,4-二氟苯基)-1-((S)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-1-((3S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxyprop-2-yl)pyrrolidine-3-基)-3-(3-((S)-2-羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲3-(3-((S)-2-hydroxypropyloxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过如实例12步骤D中所述的方法，使用(S)-3-(2-羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至70％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(7.7mg，0.013mmol，75％产率)。MS(apci)m/z＝598.3(M+H)。Prepared by the method described in Example 12, Step D, using (S)-phenyl 3-(2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate instead of phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate. The material was purified by reverse phase column chromatography using 0% to 70% acetonitrile/H2O as eluent to give the title compound (7.7 mg, 0.013 mmol, 75% yield). MS (apci) m/z = 598.3 (M+H).
实例278Example 278
1-(4-氯-1'-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)-3-((3S,4R)-4-(3,4-二1-(4-chloro-1'-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)-3-((3S,4R)-4-(3,4-dipyrazol-5-yl)-氟苯基)-1-((R)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-3-基)脲(fluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxyprop-2-yl)pyrrolidin-3-yl)urea
步骤A：制备(S)-3-((3S,4R)-3-(叔丁氧基羰基氨基)-4-(3,4-二氟苯基)吡咯烷-1-基)-1,1,1-三氟丙-2-基甲磺酸酯：将(3S,4R)-4-(3,4-二氟苯基)吡咯烷-3-基氨基甲酸叔丁酯(1000mg，3.352mmol)、(S)-2-(三氟甲基)环氧乙烷(413.2mg，3.687mmol)与DIEA(866.4mg，6.704mmol)合并在2mL DMF中并且在环境温度下搅拌过夜。添加甲磺酰氯(285.4μL，3.687mmol)并且搅拌反应物1小时。再添加甲磺酰氯(285.4μL，3.687mmol)两次，同时每次搅拌20分钟。将反应物加载至加样装置上并且通过反相柱色谱法用0％至80％乙腈/水洗脱来纯化，得到标题化合物(1194mg，2.444mmol，72.92％产率)。(MS(apci)m/z＝411.1(M+H))。Step A:Preparation of (S)-3-((3S,4R)-3-(tert-butoxycarbonylamino)-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-1,1,1-trifluoropropan-2-yl methanesulfonate : tert-Butyl (3S,4R)-4-(3,4-difluorophenyl)pyrrolidin-3-ylcarbamate (1000 mg, 3.352 mmol), (S)-2-(trifluoromethyl)oxirane (413.2 mg, 3.687 mmol) and DIEA (866.4 mg, 6.704 mmol) were combined in 2 mL of DMF and stirred overnight at ambient temperature. Methanesulfonyl chloride (285.4 μL, 3.687 mmol) was added and the reaction was stirred for 1 hour. Methanesulfonyl chloride (285.4 μL, 3.687 mmol) was added twice more, stirring for 20 minutes each time. The reaction was loaded onto an injection device and purified by reverse phase column chromatography eluting with 0% to 80% acetonitrile/water to give the title compound (1194 mg, 2.444 mmol, 72.92% yield) (MS (apci) m/z = 411.1 (M+H)).
步骤B：制备(3S,4R)-4-(3,4-二氟苯基)-1-((R)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-3-胺：在压力容器中将硫酸氢N,N,N-三甲基十六烷-1-铵(281mg，0.737mmol)与(S)-3-((3S,4R)-3-(叔丁氧基羰基氨基)-4-(3,4-二氟苯基)吡咯烷-1-基)-1,1,1-三氟丙-2-基甲磺酸酯(180mg，0.368mmol)合并在10mL MeOH中并且在170℃下加热20小时。将反应物加载至加样装置上并且通过反相柱色谱法用0％至95％乙腈/水洗脱来纯化，得到标题化合物(67mg，0.207mmol，56.1％产率)。(MS(apci)m/z＝425.1(M+H))。Step B:Preparation of (3S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-amine : N,N,N-trimethylhexadecane-1-ammonium hydrogen sulfate (281 mg, 0.737 mmol) and (S)-3-((3S,4R)-3-(tert-butoxycarbonylamino)-4-(3,4-difluorophenyl)pyrrolidin-1-yl)-1,1,1-trifluoropropan-2-yl methanesulfonate (180 mg, 0.368 mmol) were combined in 10 mL of MeOH in a pressure vessel and heated at 170° C. for 20 hours. The reaction was loaded onto an injection device and purified by reverse phase column chromatography eluting with 0% to 95% acetonitrile in water to give the title compound (67 mg, 0.207 mmol, 56.1% yield). (MS (apci) m/z = 425.1 (M+H)).
步骤C：1-(4-氯-1'-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-((R)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-3-基)脲：将4-氯-1'-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯(25mg，0.0635mmol)、(3S,4R)-4-(3,4-二氟苯基)-1-((R)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-3-胺二盐酸盐(27.7mg，0.069mmol)与DIEA(24.6mg，0.190mmol)合并在0.2mL DMF中并且在环境温度下搅拌1小时。将反应物加载至加样装置上并且通过反相柱色谱法用0％至80％乙腈/水洗脱来纯化，得到标题化合物(17.2mg，0.0276mmol，43.4％产率)。(MS(apci)m/z＝624.2(M+H))。Step C:1-(4-Chloro-1'-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxyprop-2-yl)pyrrolidin-3-yl)urea : Phenyl 4-chloro-1'-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamate (25 mg, 0.0635 mmol), (3S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxyprop-2-yl)pyrrolidin-3-amine dihydrochloride (27.7 mg, 0.069 mmol) and DIEA (24.6 mg, 0.190 mmol) were combined in 0.2 mL of a 5% CO 2 bath. The reaction mixture was added to DMF and stirred at ambient temperature for 1 hour. The reaction was loaded onto a sample loading device and purified by reverse phase column chromatography using 0% to 80% acetonitrile/water elution to give the title compound (17.2 mg, 0.0276 mmol, 43.4% yield). (MS (apci) m/z = 624.2 (M+H)).
实例279Example 279
1-((3S,4R)-4-(3,4-二氟苯基)-1-((R)-1,1,1-三氟-3-甲氧基丙-2-基)吡咯烷-1-((3S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxyprop-2-yl)pyrrolidine-3-基)-3-(3-((S)-2-羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲3-(3-((S)-2-hydroxypropyloxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过如实例14步骤C中所述的方法，使用(S)-3-(2-羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯替代4-氯-1'-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯来制备。通过反相柱色谱法，使用0％至75％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(13.0mg，0.0218mmol，95.1％产率)。MS(apci)m/z＝598.3(M+H)。Prepared by the method described in Example 14, Step C, using (S)-phenyl 3-(2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate instead of phenyl 4-chloro-1'-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamate. The material was purified by reverse phase column chromatography using 0% to 75% acetonitrile/H2O as eluent to give the title compound (13.0 mg, 0.0218 mmol, 95.1% yield). MS (apci) m/z = 598.3 (M+H).
根据实例52的方法使用适当的起始物质来制备下列化合物。The following compounds were prepared according to the method of Example 52 using appropriate starting materials.
根据实例1步骤B的方法使用适当的起始物质来制备下列化合物。The following compounds were prepared according to the procedure of Example 1, Step B using appropriate starting materials.
根据实例1步骤B的方法使用适当的卤化吡唑氨基甲酸酯起始物质来制备下列化合物。The following compounds were prepared according to the procedure of Example 1, Step B using the appropriate halogenated pyrazole carbamate starting material.
实例441Example 441
1-(1',4-二甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(4-氟苯1-(1',4-dimethyl-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
向(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备L1；40mg，0.13mmol)在DMA(428μL)中的悬浮液中添加DIEA(112μL，0.64mmol)，得到澄清溶液。向此溶液中添加1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯(中间体199；53mg，0.14mmol)。搅拌过夜后，通过反相色谱法，(C18，5％至42％乙腈/水)直接纯化反应物，得到呈白色固体状的1-(1',4-二甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(42mg，63％)。MS(apci)m/z＝518.3(M+H)。1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.74(s,1H),7.48-7.5(m,2H),7.34-7.38(m,2H),7.27-7.31(m,1H),7.05-7.1(m,2H),6.81-6.85(m,2H),5.37(br s,1H),4.27(brs,1H),3.96(s,3H),3.33-3.43(m,2H),3.25(br s,3H),3.16-3.19(m,1H),2.98(br s,1H),2.70-2.83(m,2H),2.49-2.65(m,2H),2.27(t,1H),2.09(s,3H)。To a suspension of (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation L1; 40 mg, 0.13 mmol) in DMA (428 μL) was added DIEA (112 μL, 0.64 mmol) to give a clear solution. To this solution was added phenyl 1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamate (Intermediate 199; 53 mg, 0.14 mmol). After stirring overnight, the reaction was directly purified by reverse phase chromatography (C18, 5% to 42% acetonitrile/water) to afford 1-(1',4-dimethyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (42 mg, 63%) as a white solid. MS (apci) m/z = 518.3 (M+H).1 H NMR (400MHz, CDCl3 )δ7.85(s,1H),7.74(s,1H),7.48-7.5(m,2H),7.34-7.38(m,2H),7.27-7.31(m,1H),7.05-7.1(m,2H),6.81-6.85(m,2H),5.37(br s,1H),4.27(brs,1H),3.96(s,3H),3.33-3.43(m,2H),3.25(br s,3H),3.16-3.19(m,1H),2.98(br s,1H),2.70-2.83(m,2H),2.49-2.65(m,2H),2.27(t,1H),2.09(s,3H).
实例442Example 442
1-(1',4-二甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(3,5-二1-(1',4-dimethyl-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(3,5-dimethyl-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(2-(2-(2-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea)
根据实例441中所述的方法，在步骤F中用(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备。MS(apci)m/z＝536.3(M+H)。1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.74(s,1H),7.49-7.52(m,2H),7.36-7.41(m,2H),7.28-7.33(m,1H),6.62-6.70(m,3H),5.33(br s,1H),4.27(br s,1H),3.96(s,3H),3.36-3.45(m,2H),3.27(br s,3H),3.15-3.20(m,1H),2.96(br s,1H),2.72-2.81(m,2H),2.54-2.67(m,2H),2.31(t,1H),2.11(s,3H)。Prepared according to the method described in Example 441, substituting (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride for (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride in Step F. MS (apci) m/z = 536.3 (M+H).1 H NMR (400MHz, CDCl3 ) δ7.86(s,1H),7.74(s,1H),7.49-7.52(m,2H),7.36-7.41(m,2H),7.28-7.33(m,1H),6.62-6.70(m,3H),5.33(br s,1H),4.27(br s,1H),3.96(s,3H),3.36-3.45(m,2H),3.27(br s,3H),3.15-3.20(m,1H),2.96(br s,1H),2.72-2.81(m,2H),2.54-2.67(m,2H),2.31(t,1H),2.11(s,3H).
实例443Example 443
1-(1',4-二甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(3,4,5-1-(1',4-dimethyl-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(3,4,5-三氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲trifluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例441中所述的方法，在步骤F中用(3S,4R)-4-(3,4,5-三氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备。MS(apci)m/z＝554.3(M+H)。Prepared according to the method described in Example 441, substituting (3S,4R)-4-(3,4,5-trifluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride for (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride in Step F. MS (apci) m/z = 554.3 (M+H).
实例444Example 444
1-(1',4-二甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(3,4-二1-(1',4-dimethyl-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(3,4-dipyrazole)氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(2-(2-(2-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea)
根据实例441中所述的方法，在步骤F中用(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代(3S,4R)-4-(2,4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备。MS(apci)m/z＝554.3(M+H)。1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.74(s,1H),7.48-7.52(m,2H),7.34-7.39(m,2H),7.28-7.32(m,1H),6.92-7.04(m,2H),6.81-6.85(m,1H),5.32(br s,1H),4.24(br s,1H),3.96(s,3H),3.38-3.40(m,2H),3.26(br s,3H),3.12-3.17(m,1H),2.91(br s,1H),2.72-2.77(m,2H),2.52-2.66(m,2H),2.27(t,1H),2.1(s,3H)。Prepared according to the method described in Example 441, substituting (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride for (3S,4R)-4-(2,4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride in Step F. MS (apci) m/z = 554.3 (M+H).1 H NMR (400MHz, CDCl3 )δ7.86(s,1H),7.74(s,1H),7.48-7.52(m,2H),7.34-7.39(m,2H),7.28-7.32(m,1H),6.92-7.04(m,2H),6.81-6.85(m,1H),5.32(br s,1H),4.24(br s,1H),3.96(s,3H),3.38-3.40(m,2H),3.26(br s,3H),3.12-3.17(m,1H),2.91(br s,1H),2.72-2.77(m,2H),2.52-2.66(m,2H),2.27(t,1H),2.1(s,3H).
实例445Example 445
1-(1',4-二甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(氟苯1-(1',4-dimethyl-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(fluorophenyl)-基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例441中所述的方法，在步骤F中用(3S,4R)-4-(苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备。MS(apci)m/z＝500.3(M+H)。Prepared according to the method described in Example 441, substituting (3S,4R)-4-(phenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride for (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride in Step F. MS (apci) m/z = 500.3 (M+H).
实例446Example 446
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-(4-甲1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-(4-methoxyphenyl)氧基苯甲基)-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲(4-Methyl-1-phenyl-1H,1'H-[3,4'-bipyrazolyl]-5-yl)urea
根据实例441中所述的方法，在步骤F中用(3S,4R)-4-(3,4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐并且用(1'-(4-甲氧基苯甲基)-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)氨基甲酸苯酯替代1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯来制备。MS(apci)m/z＝642.3(M+H)。Prepared according to the method described in Example 441, substituting (3S,4R)-4-(3,4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride for (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride and phenyl (1'-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)carbamate for phenyl 1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamate in Step F. MS (apci) m/z = 642.3 (M+H).
实例447Example 447
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-(4-甲1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-(4-methoxyphenyl)氧基苯甲基)-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲三氟乙酸盐(4-Methyl-1-phenyl-1H,1'H-[3,4'-bipyrazolyl]-5-yl)uronium trifluoroacetate
在压力容器中密封1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-(4-甲氧基苯甲基)-4-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)脲(300mg，0.468mmol)和TFA(720μL，9.35mmol)的混合物并且在60℃下加热。加热反应物18小时，然后冷却并且添加乙醚(30mL)并且超声所得到的混合物，得到呈米色固体状的粗产物。将固体溶解于极少量的MeOH中并且通过反相色谱法(C18，5％至35％至50％乙腈/水)纯化，得到呈三氟甲磺酸盐形式的1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-(4-甲氧基苯甲基)-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲(135mg，38％)。A mixture of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)urea (300 mg, 0.468 mmol) and TFA (720 μL, 9.35 mmol) was sealed in a pressure vessel and heated at 60° C. The reaction was heated for 18 hours, then cooled and diethyl ether (30 mL) was added and the resulting mixture sonicated to give the crude product as a beige solid. The solid was dissolved in a minimum amount of MeOH and purified by reverse phase chromatography (C18, 5% to 35% to 50% acetonitrile/water) to afford 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea as the triflate salt (135 mg, 38%).
实例448Example 448
乙酸2-(4-氯-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-2-(4-chloro-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidine-3-yl)acetate基)脲基)-1-苯基-1H-吡唑-3-基)乙酯(1-phenyl-1H-pyrazol-3-yl)ethyl)ureido
步骤A：制备乙酸2-(4-氯-5-((苯氧基羰基)氨基)-1-苯基-1H-吡唑-3-基)乙酯和(3-(2-((苯氧基羰基)氧基)乙基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯：向2-(5-氨基-1-苯基-1H-吡唑-3-基)乙醇(中间体161，242mg，1.191mmol)在EtOAc(10mL)中的溶液中添加氢氧化钠水溶液(2M，1.19mL，2.38mmol)，然后添加氯甲酸苯酯(0.179mL，1.43mmol)。在环境温度下搅拌反应物4小时，并且然后分离各相。用H2O(5mL)、盐水(5mL)洗涤有机相，用MgSO4干燥，过滤并且浓缩，得到呈棕褐色固体状的产物(250mg)，其为以下两种组分的混合物：乙酸2-(4-氯-5-((苯氧基羰基)氨基)-1-苯基-1H-吡唑-3-基)乙酯和(3-(2-((苯氧基羰基)氧基)乙基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯，其不经纯化即用于下一步骤中。[0266] Step A:Preparation of 2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethyl acetate and phenyl(3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate : To a solution of 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)ethanol (Intermediate 161, 242 mg, 1.191 mmol) in EtOAc (10 mL) was added aqueous sodium hydroxide (2 M, 1.19 mL, 2.38 mmol) followed by phenyl chloroformate (0.179 mL, 1.43 mmol). The reaction was stirred at ambient temperature for 4 hours and the phases were then separated. The organic phase was washed withH2O (5 mL), brine (5 mL), dried overMgSO4 , filtered and concentrated to give the product as a tan solid (250 mg) which was a mixture of 2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethyl acetate and phenyl (3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate, which was used in the next step without purification.
步骤B：制备乙酸2-(4-氯-5-((苯氧基羰基)氨基)-1-苯基-1H-吡唑-3-基)乙酯和(4-氯-3-(2-((苯氧基羰基)氧基)乙基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯：向乙酸2-(4-氯-5-((苯氧基羰基)氨基)-1-苯基-1H-吡唑-3-基)乙酯和(3-(2-((苯氧基羰基)氧基)乙基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯(250mg，0.773mmol)在DCM(10mL)中的溶液中添加4-甲基苯磺酸吡锭(PPTS)(19.4mg，0.077mmol)和n-氯代琥珀酰亚胺(155mg，1.16mmol)。在环境温度下搅拌反应物4天，然后用H2O(10mL)稀释，分离各相并且用DCM(2×20mL)萃取水相。干燥(MgSO4)合并的有机相，过滤并且浓缩。通过二氧化硅柱色谱法，用40％丙酮/己烷洗脱来纯化粗油状物，得到呈橙色油状的产物(63mg)，其为以下两种组分的混合物：乙酸2-(4-氯-5-((苯氧基羰基)氨基)-1-苯基-1H-吡唑-3-基)乙酯，MS(apci)m/z＝400.1(M+H)；和(4-氯-3-(2-((苯氧基羰基)氧基)乙基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯，MS(apci)m/z＝478.1(M+H)。[0266] Step B:Preparation of 2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethyl acetate andphenyl (4-chloro-3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate : To a solution of 2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethyl acetate and phenyl (3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate (250 mg, 0.773 mmol) in DCM (10 mL) were added pyridinium 4-methylbenzenesulfonate (PPTS) (19.4 mg, 0.077 mmol) and n-chlorosuccinimide (155 mg, 1.16 mmol). The reaction was stirred at ambient temperature for 4 days, then diluted with H2 O (10 mL), the phases separated and the aqueous phase extracted with DCM (2×20 mL). The combined organic phases were dried (MgSO4 ), filtered and concentrated. The crude oil was purified by silica column chromatography eluting with 40% acetone/hexanes to afford the product (63 mg) as an orange oil, which was a mixture of two components: 2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethyl acetate, MS (apci) m/z=400.1 (M+H); and phenyl (4-chloro-3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate, MS (apci) m/z=478.1 (M+H).
步骤C：制备乙酸2-(4-氯-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯基-1H-吡唑-3-基)乙酯：向(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备F，52mg，0.158mmol)在DMA(0.6mL)中的溶液中添加DIEA(0.110mL，0.630mmol)，并且添加乙酸2-(4-氯-5-((苯氧基羰基)氨基)-1-苯基-1H-吡唑-3-基)乙酯和(4-氯-3-(2-((苯氧基羰基)氧基)乙基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯的混合物(63mg)。在环境温度下搅拌反应混合物2小时，然后通过反相柱色谱法用5％至80％乙腈/水洗脱并且收集峰1来直接纯化，得到呈橙色固体状的标题化合物(21.8mg)。MS(apci)m/z＝562.2(M+H)。Step C:Preparation of 2-(4-chloro-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)ethyl acetate : To (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation F, 52 mg, 0.158 mmol) was added. 1) DIEA (0.110 mL, 0.630 mmol) was added to a solution in DMA (0.6 mL), and a mixture of 2-(4-chloro-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl)ethyl acetate and phenyl (4-chloro-3-(2-((phenoxycarbonyl)oxy)ethyl)-1-phenyl-1H-pyrazol-5-yl)carbamate (63 mg) was added. The reaction mixture was stirred at ambient temperature for 2 hours and then directly purified by reverse phase column chromatography eluting with 5% to 80% acetonitrile/water and collecting Peak 1 to give the title compound (21.8 mg) as an orange solid. MS (apci) m/z=562.2 (M+H).
实例449Example 449
1-(4-氯-3-(2-羟基乙基)-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯1-(4-chloro-3-(2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
步骤A：制备2-(4-氯-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯基-1H-吡唑-3-基)乙基苯基碳酸酯：通过反相柱色谱法，用5％至80％乙腈/水洗脱并且收集峰2来直接纯化来自实例448步骤C的反应混合物，得到呈浅黄色胶状的标题化合物(28mg)。MS(apci)m/z＝640.2(M+H)。Step A:Preparation of 2-(4-chloro-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)ethylphenyl carbonate : The reaction mixture from Example 448, Step C, was directly purified by reverse phase column chromatography, eluting with 5% to 80% acetonitrile/water and collecting Peak 2 to give the title compound (28 mg) as a light yellow gum. MS (apci) m/z = 640.2 (M+H).
步骤B：制备1-(4-氯-3-(2-羟基乙基)-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：向2-(4-氯-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯基-1H-吡唑-3-基)乙基苯基碳酸酯(28mg，0.044mmol)在THF(2mL)和MeOH(1mL)中的溶液中添加LiOH水溶液(2M，0.066mL，0.132mmol)。在环境温度下搅拌反应混合物2小时，然后用HCl水溶液(2M，0.06mL)和H2O(5mL)稀释，并且用DCM(10mL)萃取，然后用10:90MeOH/DCM(2×10mL)萃取。干燥(MgSO4)合并的有机萃取物，过滤并且浓缩。通过二氧化硅柱色谱法，用0％至10％MeOH/DCM洗脱来纯化粗产物，得到呈灰白色固体状的产物(14mg，61％产率)。MS(apci)m/z＝520.2(M+H)。Step B:Preparation of 1-(4-chloro-3-(2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : To a solution of 2-(4-chloro-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea)-1-phenyl-1H-pyrazol-3-yl)ethylphenyl carbonate (28 mg, 0.044 mmol) in THF (2 mL) and MeOH (1 mL) was added aqueous LiOH (2 M, 0.066 mL, 0.132 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with aqueous HCl (2M, 0.06 mL) andH₂O (5 mL) and extracted with DCM (10 mL), followed by 10:90 MeOH/DCM (2×10 mL). The combined organic extracts were dried (MgSO₄ ), filtered, and concentrated. The crude product was purified by silica column chromatography eluting with 0% to 10% MeOH/DCM to afford the product as an off-white solid (14 mg, 61% yield). MS (apci) m/z=520.2 (M+H).
实例450Example 450
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(顺式-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备顺式-1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲和反式-1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：向(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备F，67mg，0.204mmol)在DMA(1mL)和DIEA(0.142mL，0.815mmol)中的溶液中添加3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(中间体209；74mg，0.204mmol)并且在环境温度下搅拌反应混合物1小时。通过反相柱色谱法，用5％至70％乙腈/水洗脱来直接纯化反应混合物，得到呈白色固体状的产物(59mg，55％产率)。MS(apci)m/z＝526.3(M+H)。Step A:Preparation of cis-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea and trans-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea1H-pyrazol-5-yl) urea : To a solution of (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation F, 67 mg, 0.204 mmol) in DMA (1 mL) and DIEA (0.142 mL, 0.815 mmol) was added phenyl 3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (Intermediate 209; 74 mg, 0.204 mmol) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 70% acetonitrile/water to give the product (59 mg, 55% yield) as a white solid. MS (apci) m/z = 526.3 (M+H).
步骤B：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(顺式-3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：通过在苯甲酰胺柱(Princeton Analytical，4.6mm×250mm，5μm)上进行制备型HPLC，用10％EtOH/己烷洗脱来分离顺式-1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲和反式-1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲的混合物(55mg，0.105mmol)。收集峰1，得到呈白色固体状的标题化合物(21.1mg，38％产率)。MS(apci)m/z＝526.3(M+H)。1H NMR(d6-DMSO)δ7.79(br s,1H),7.42(m,4H),7.30(m,3H),7.06(m,1H),6.70(d,1H),5.06(d,1H),4.04(m,2H),3.43(t,2H),3.24(s,3H),3.05(m,2H),2.85(m,2H),2.47-2.66(m,6H),2.08(m,2H),1.77(s,3H)。Step B:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : by filtration on a benzamide column (Princeton Preparative HPLC was performed on a 400 nm HPLC column (4.6 mm × 250 mm, 5 μm) eluting with 10% EtOH/hexanes to separate a mixture of cis-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea and trans-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea (55 mg, 0.105 mmol). Peak 1 was collected to give the title compound (21.1 mg, 38% yield) as a white solid. MS(apci)m/z=526.3(M+H).1H NMR(d6 -DMSO)δ7.79(br s,1H),7.42(m,4H),7.30(m,3H),7.06(m,1H),6.70(d,1H),5.06(d,1H),4.04(m,2H),3.43( t,2H),3.24(s,3H),3.05(m,2H),2.85(m,2H),2.47-2.66(m,6H),2.08(m,2H),1.77(s,3H).
实例451Example 451
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(反式-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(trans-3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过在苯甲酰胺柱(Princeton Analytical，4.6mm×250mm，5μm)上进行制备型HPLC，用10％EtOH/己烷洗脱来分离1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲的顺式和反式羟基环丁基非对映异构体的混合物(实例450步骤A，55mg，0.105mmol)。收集峰2，得到呈白色固体状的标题化合物(27.5mg，50％产率)。MS(apci)m/z＝526.3(M+H)。1H NMR(d6-DMSO)δ7.80(br s,1H),7.42(m,4H),7.31(m,3H),7.06(m,1H),6.70(d,1H),5.02(d,1H),4.33(m,1H),4.04(m,1H),3.43(t,2H),3.34(m,1H),3.24(s,3H),3.05(m,2H),2.88(t,1H),2.43-2.67(m,6H),2.19(m,2H),1.74(s,3H)。A mixture of cis and trans hydroxycyclobutyl diastereomers of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea was separated by preparative HPLC on a benzamide column (Princeton Analytical, 4.6 mm x 250 mm, 5 μm) eluting with 10% EtOH/hexanes (Example 450, Step A, 55 mg, 0.105 mmol). Peak 2 was collected to give the title compound (27.5 mg, 50% yield) as a white solid. MS (apci) m/z = 526.3 (M+H).1H NMR(d6 -DMSO)δ7.80(br s,1H),7.42(m,4H),7.31(m,3H),7.06(m,1H),6.70(d,1H),5.02(d,1H),4.33(m,1H),4.04(m,1H),3.43( t,2H),3.34(m,1H),3.24(s,3H),3.05(m,2H),2.88(t,1H),2.43-2.67(m,6H),2.19(m,2H),1.74(s,3H).
实例452Example 452
1-(4-氯-3-(顺式-3-羟基环丁基)-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-1-(4-chloro-3-(cis-3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
步骤A：顺式-1-(4-氯-3-(3-羟基环丁基)-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲和反式-1-(4-氯-3-(3-羟基环丁基)-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：根据实例450步骤A中所述的方法，在步骤A中用(4-氯-3-(3-羟基环丁基)-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯(中间体238)替代3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备，得到呈顺式和反式羟基环丁基非对映异构体的混合物形式的产物。MS(apci)m/z＝546.2(M+H)。Step A:cis-1-(4-chloro-3-(3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea and trans-1-(4-chloro-3-(3-hydroxycyclobutyl )-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (3-Hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : Prepared according to the procedure described in Example 450, Step A, substituting phenyl (4-chloro-3-(3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)carbamate (Intermediate 238) for phenyl 3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate in Step A to afford the product as a mixture of cis and trans hydroxycyclobutyl diastereomers. MS (apci) m/z = 546.2 (M+H).
步骤B：制备1-(4-氯-3-(顺式-3-羟基环丁基)-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：通过在DEAP柱(PrincetonAnalytical，4.6mm×250mm，5μm)上进行制备型HPLC，用10％EtOH/己烷洗脱来分离1-(4-氯-3-(3-羟基环丁基)-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲的顺式和反式羟基环丁基非对映异构体的混合物(41mg，0.075mmol)。收集峰1，得到呈白色固体状的标题化合物(10.2mg，25％产率)。MS(apci)m/z＝546.2(M+H)。1H NMR(CDCl3)7.50(d,2H),7.41(t,2H),7.30(m,1H),7.05(m,1H),6.97(m,1H),6.86(m,1H),5.48(m,1H),4.30(m,1H),3.43(br m,2H),3.33(m,1H),3.25(br m,2H),3.10(m,2H),2.96(br m,1H),2.60-2.83(m 5H),2.33(m,3H)。[0266] Step B:Preparation of 1-(4-chloro-3-(cis-3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : A mixture of cis and trans hydroxycyclobutyl diastereomers of 1-(4-chloro-3-(3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (41 mg, 0.075 mmol) was separated by preparative HPLC on a DEAP column (Princeton Analytical, 4.6 mm x 250 mm, 5 μm) eluting with 10% EtOH/hexanes. Peak 1 was collected to give the title compound as a white solid (10.2 mg, 25% yield). MS (apci) m/z = 546.2 (M+H).1 H NMR (CDCl3 ) 7.50 (d, 2H), 7.41 (t, 2H), 7.30 (m, 1H), 7.05 (m, 1H), 6.97 (m, 1H), 6.86 (m, 1H), 5.48 (m, 1H), 4.30 (m, 1H), 3.43 (br m, 2H), 3.33 (m, 1H), 3.25 (br m, 2H), 3.10 (m, 2H), 2.96 (br m, 1H), 2.60-2.83 (m 5H), 2.33 (m, 3H).
实例453Example 453
1-(4-氯-3-((1r,3S)-3-羟基环丁基)-1-苯基-1H-吡唑-5-基)-3-(反式-4-(3,4-1-(4-chloro-3-((1r,3S)-3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-(trans-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
通过在DEAP柱(Princeton Analytical，4.6mm×250mm，5μm)上进行制备型HPLC，用10％EtOH/己烷洗脱来分离顺式-1-(4-氯-3-(3-羟基环丁基)-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲和反式-1-(4-氯-3-(3-羟基环丁基)-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲的混合物(实例452步骤A，41mg，0.075mmol)。收集峰1，得到呈白色固体状的标题化合物(16.4mg，40％产率)。MS(apci)m/z＝546.2(M+H)。1H NMR(CDCl3)7.51(d,2H),7.41(t,2H),7.33(m,1H),7.04(m,1H),6.96(m,1H),6.85(m,1H),5.53(br d,1H),4.65(m,1H),3.60(m,1H),3.41(br m,2H),3.25(br m,5H),3.08(br m,1H),2.89(br m,1H),2.57-2.77(m,7H),2.37(m,3H)。A mixture of cis-1-(4-chloro-3-(3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea and trans-1-(4-chloro-3-(3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea was separated by preparative HPLC on a DEAP column (Princeton Analytical, 4.6 mm×250 mm, 5 μm) eluting with 10% EtOH/hexanes (Example 452, Step A, 41 mg, 0.075 mmol). Peak 1 was collected to give the title compound as a white solid (16.4 mg, 40% yield). MS (apci) m/z = 546.2 (M+H).1 H NMR (CDCl3 ) 7.51 (d, 2H), 7.41 (t, 2H), 7.33 (m, 1H), 7.04 (m, 1H), 6.96 (m, 1H), 6.85 (m, 1H), 5.53 (br d, 1H), 4.65 (m, 1H), 3.60 (m, 1H), 3.41 (br m, 2H), 3.25 (br m, 5H), 3.08 (br m, 1H), 2.89 (br m, 1H), 2.57-2.77 (m, 7H), 2.37 (m, 3H).
实例454Example 454
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(顺式-3-羟1-((3S,4R)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxy基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(4-(2-Methylcyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备顺式-1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲和反式-1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：根据实例450步骤A中所述的方法，在步骤A中用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备K)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备，得到呈顺式和反式羟基环丁基非对映异构体的混合物形式的产物。MS(apci)m/z＝508.3(M+H)。Step A:Preparation of cis-1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-Hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea and trans-1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5 -yl)urea : Prepared according to the method described in Example 450, Step A, substituting (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation K) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride in Step A to give the product as a mixture of cis and trans hydroxycyclobutyl diastereomers. MS (apci) m/z = 508.3 (M+H).
步骤B：制备1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(顺式-3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：通过在氰基柱(YMC-Pack CN，250×20mm，10μm)上进行超临界流体色谱法(SFC)(流动相为95％CO2和5％80/20/0.1MeOH/IPA/二乙胺)来分离顺式-1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲和反式-1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲的混合物(49mg，0.096mmol)。收集峰1，得到呈白色固体状的标题化合物(16.4mg，34％产率)。MS(apci)m/z＝508.2(M+H)。1H NMR(d6-DMSO)δ7.85(br s,1H),7.42(m,4H),7.28(m,3H),7.10(t,2H),6.75(br d,1H),5.06(br s,1H),4.04(m,2H),3.42(t,2H),3.24(s,3H),3.06(m,2H),2.84(m,2H),2.46-2.64(m,6H),2.08(m,2H),1.76(s,3H)。Step B:Preparation of 1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : The product was purified by supercritical fluid chromatography (SFC) on a cyano column (YMC-Pack CN, 250×20 mm, 10 μm) with a mobile phase of 95% CO A mixture of cis-1 -((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea and trans-1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea (49 mg, 0.096 mmol) was separated by HPLC (5% 80/20/0.1 MeOH/IPA/diethylamine). Peak 1 was collected to give the title compound (16.4 mg, 34% yield) as a white solid. MS (apci) m/z = 508.2 (M+H).1 H NMR(d6 -DMSO) δ7.85(br s,1H),7.42(m,4H),7.28(m,3H),7.10(t,2H),6.75(br d,1H),5.06(br s,1H),4.04(m,2H),3.42(t,2H),3.24(s,3H),3.06(m,2H),2.84(m,2H),2.46-2.64(m,6H),2.08(m,2H),1.76(s,3H).
实例455Example 455
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(反式-3-羟1-((3S,4R)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(trans-3-hydroxy基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(4-Methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过在氰基柱(YMC-Pack CN，250×20mm，10μm)上进行超临界流体色谱法(SFC)(流动相为95％CO2和5％80/20/0.1MeOH/IPA/二乙胺)来分离顺式-1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲和反式-1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲的混合物(实例454步骤A，49mg，0.096mmol)。收集峰2，得到呈白色固体状的标题化合物(19.0mg，39％产率)。MS(apci)m/z＝508.2(M+H)。1H NMR(d6-DMSO)δ7.86(br s,1H),7.42(m,4H),7.28(m,3H),7.10(t,2H),6.75(br d,1H),5.03(br s,1H),4.33(m,1H),4.03(m,1H),3.42(t,2H),3.34(m,1H),3.24(s,3H),3.07(m,2H),2.84(t,1H),2.43-2.64(m,6H),2.19(m,2H),1.73(s,3H)。A mixture of cis-1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea and trans-1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea was separated by supercritical fluid chromatography (SFC) on a cyano column (YMC-Pack CN, 250×20 mm, 10 μm) with a mobile phase of 95% CO2 and 5% 80/20/0.1 MeOH/IPA/diethylamine (Example 454, Step A, 49 mg, 0.096 mmol). Peak 2 was collected to give the title compound (19.0 mg, 39% yield) as a white solid. MS (apci) m/z = 508.2 (M+H).1H NMR (d6 -DMSO) δ 7.86 (br s, 1H), 7.42 (m, 4H), 7.28 (m, 3H), 7.10 (t, 2H), 6.75 (br d, 1H), 5.03 (br s, 1H), 4.33 (m, 1H), 4.03 (m, 1H), 3.42 (t, 2H), 3.34 (m, 1H), 3.24 (s, 3H), 3.07 (m, 2H), 2.84 (t, 1H), 2.43-2.64 (m, 6H), 2.19 (m, 2H), 1.73 (s, 3H).
实例456Example 456
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(顺式-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备顺式-1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲和反式-1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：根据实例450步骤A中所述的方法，在步骤A中用(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备E)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备，得到呈顺式和反式羟基环丁基非对映异构体的混合物形式的产物。MS(apci)m/z＝526.3(M+H)。Step A:Preparation of cis-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea and trans-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea(1H-Pyrazol-5-yl)urea : Prepared according to the method described in Example 450, Step A, substituting (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation E) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride in Step A to give the product as a mixture of cis and trans hydroxycyclobutyl diastereomers. MS (apci) m/z = 526.3 (M+H).
步骤B：制备1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(顺式-3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：通过在氰基柱(YMC-PackCN，250×20mm，10μm)上进行超临界流体色谱法(SFC)(流动相为95％CO2和5％80/20/0.1MeOH/IPA/二乙胺)来分离1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲的顺式和反式羟基环丁基非对映异构体的混合物(53mg，0.10mmol)。收集峰1，得到呈白色固体状的标题化合物(17.6mg，33％产率)。MS(apci)m/z＝526.2(M+H)。1H NMR(d6-DMSO)δ7.95(br s,1H),7.45(d,2H),7.39(t,2H),7.28(t,1H),7.05(tt,1H),6.97(m,2H),6.85(m,1H),5.08(br s,1H),4.05(m,2H),3.43(t,2H),3.24(s,3H),3.08(m,1H),3.02(m,1H),2.89(m,1H),2.84(m,1H),2.45-2.65(m,6H),2.08(m,2H),1.77(s,3H)。Step B:Preparation of 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : The product was purified by supercritical fluid chromatography (SFC) on a cyano column (YMC-PackCN, 250×20 mm, 10 μm) with a mobile phase of 95% CO A mixture ofcis- and trans-hydroxycyclobutyl diastereomers of 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea (53 mg, 0.10 mmol) was separated by HPLC (5% 80/20/0.1 MeOH/IPA/diethylamine). Peak 1 was collected to give the title compound (17.6 mg, 33% yield) as a white solid. MS (apci) m/z = 526.2 (M+H).1 H NMR(d6 -DMSO) δ7.95(br s,1H),7.45(d,2H),7.39(t,2H),7.28(t,1H),7.05(tt,1H),6.97(m,2H),6.85(m,1H),5.08(br s,1H),4.05(m,2H),3.43(t,2H),3.24(s,3H),3.08(m,1H),3.02(m,1H) ,2.89(m,1H),2.84(m,1H),2.45-2.65(m,6H),2.08(m,2H),1.77(s,3H).
实例457Example 457
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(反式-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(trans-3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
通过在氰基柱(YMC-Pack CN，250×20mm，10μm)上进行超临界流体色谱法(SFC)(流动相为95％CO2和5％80/20/0.1MeOH/IPA/二乙胺)来分离1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基环丁基)-4-甲基-1-苯基-1H-吡唑-5-基)脲的顺式和反式羟基环丁基非对映异构体的混合物(实例456步骤A，53mg，0.10mmol)。收集峰2，得到呈白色固体状的标题化合物(20.7mg，39％产率)。MS(apci)m/z＝526.2(M+H)。1H NMR(d6-DMSO)δ7.96(br s,1H),7.46(d,2H),7.40(t,2H),7.28(t,1H),7.05(tt,1H),6.97(m,2H),6.85(m,1H),5.04(br s,1H),4.34(m,1H),4.06(m,1H),3.43(t,2H),3.35(m,1H),3.24(s,3H),3.09(q,1H),3.02(t,1H),2.90(t,1H),2.44-2.66(m,6H),2.19(m,2H),1.74(s,3H)。A mixture of cis and trans hydroxycyclobutyl diastereomers of 1-((3S,4R)-4-(3,5-difluorophenyl)-1- (2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea was separated by supercritical fluid chromatography (SFC) on a cyano column (YMC-Pack CN, 250×20 mm, 10 μm) with a mobile phase of 95% CO₂ and 5% 80/20/0.1 MeOH/IPA/diethylamine (Example 456, Step A, 53 mg, 0.10 mmol). Peak 2 was collected to give the title compound (20.7 mg, 39% yield) as a white solid. MS (apci) m/z=526.2 (M+H).1 H NMR(d6 -DMSO) δ7.96(br s,1H),7.46(d,2H),7.40(t,2H),7.28(t,1H),7.05(tt,1H),6.97(m,2H),6.85(m,1H),5.04(br s,1H),4.34(m,1H),4.06(m,1H),3.43(t,2H),3.35(m,1H),3.24(s,3H),3.09( q,1H),3.02(t,1H),2.90(t,1H),2.44-2.66(m,6H),2.19(m,2H),1.74(s,3H).
实例458Example 458
5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl基-1-苯基-1H-吡唑-3-甲酸1-phenyl-1H-pyrazole-3-carboxylic acid
向5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基-乙基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-甲酸乙酯(实例291；333mg，6.21mmol)在THF(4mL)和MeOH(2mL)中的溶液中添加LiOH水溶液(2M，0.95mL，1.89mmol)。在环境温度下搅拌反应混合物4小时，然后在减压下部分浓缩，然后用HCl水溶液(1M，1mL)中和。过滤悬浮液并且收集白色沉淀物，得到呈白色固体状的标题化合物(247mg，78％产率)。MS(apci)m/z＝500.2(M+H)。To a solution of ethyl 5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxy-ethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate (Example 291; 333 mg, 6.21 mmol) in THF (4 mL) and MeOH (2 mL) was added aqueous LiOH (2 M, 0.95 mL, 1.89 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, then partially concentrated under reduced pressure and then neutralized with aqueous HCl (1 M, 1 mL). The suspension was filtered and the white precipitate was collected to give the title compound (247 mg, 78% yield) as a white solid. MS (apci) m/z=500.2 (M+H).
实例459Example 459
5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-N,4-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N,4-二甲基-1-苯基-1H-吡唑-3-甲酰胺Dimethyl-1-phenyl-1H-pyrazole-3-carboxamide
向5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-甲酸(实例458，25mg，0.050mmol)在DMF(0.5mL)中的溶液中添加DIEA(0.026mL，0.150mmol)、甲胺盐酸盐(6.8mg，0.100mmol)，然后添加HATU(20.9mg，0.055mmol)。在环境温度下搅拌反应混合物19小时。通过反相柱色谱法，用5％至60％乙腈/水洗脱来直接纯化反应混合物，得到呈白色固体状的产物(13.5mg，53％产率)。MS(apci)m/z＝513.3(M+H)。To a solution of 5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 458, 25 mg, 0.050 mmol) in DMF (0.5 mL) was added DIEA (0.026 mL, 0.150 mmol), methylamine hydrochloride (6.8 mg, 0.100 mmol), and then HATU (20.9 mg, 0.055 mmol). The reaction mixture was stirred at ambient temperature for 19 hours. The reaction mixture was directly purified by reverse phase column chromatography eluting with 5% to 60% acetonitrile/water to give the product (13.5 mg, 53% yield) as a white solid. MS (apci) m/z=513.3 (M+H).
实例460Example 460
5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-N,N,5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N,N,4-三甲基-1-苯基-1H-吡唑-3-甲酰胺4-Trimethyl-1-phenyl-1H-pyrazole-3-carboxamide
根据实例459中所述的方法，用二甲胺(2M THF溶液)替代甲胺盐酸盐来制备，得到呈白色固体状的产物(13.0mg，49％产率)。MS(apci)m/z＝527.2(M+H)。Prepared according to the method described in Example 459, substituting dimethylamine (2M in THF) for methylamine hydrochloride, to give the product as a white solid (13.0 mg, 49% yield).MS (apci) m/z=527.2 (M+H).
实例461Example 461
5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-N-乙5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N-ethyl基-4-甲基-1-苯基-1H-吡唑-3-甲酰胺4-Methyl-1-phenyl-1H-pyrazole-3-carboxamide
根据实例459中所述的方法，用乙胺(2M THF溶液)替代甲胺盐酸盐来制备，得到呈白色固体状的产物(11.2mg，48％产率)。MS(apci)m/z＝527.2(M+H)。Prepared according to the method described in Example 459, substituting ethylamine (2M in THF) for methylamine hydrochloride, to give the product as a white solid (11.2 mg, 48% yield).MS (apci) m/z = 527.2 (M+H).
实例462Example 462
5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-N-异5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N-iso丙基-4-甲基-1-苯基-1H-吡唑-3-甲酰胺Propyl-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide
根据实例459中所述的方法，用丙-2-胺替代甲胺盐酸盐来制备，得到呈白色固体状的产物(5.6mg，24％产率)。MS(apci)m/z＝541.3(M+H)。Prepared according to the method described in Example 459, substituting propan-2-amine for methylamine hydrochloride, to give the product as a white solid (5.6 mg, 24% yield).MS (apci) m/z = 541.3 (M+H).
实例463Example 463
5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl基-1-苯基-1H-吡唑-3-甲酰胺1-phenyl-1H-pyrazole-3-carboxamide
在环境温度下搅拌1-(3-氰基-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(实例349，25mg，0.52mmol)在浓H2SO4(0.2mL)中的溶液20小时。将反应混合物冷却至0℃并且通过添加NaOH水溶液(15wt％，4mL)中和，然后用10％MeOH/DCM(3×10mL)萃取，并且用盐水洗涤合并的有机萃取物，干燥(MgSO4)，过滤并且在减压下浓缩。通过反相柱色谱法，用5％至60％乙腈/水洗脱来纯化粗产物，得到呈白色固体状的产物(1.4mg，5％产率)。MS(apci)m/z＝499.2(M+H)。A solution of 1-(3-cyano-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (Example 349, 25 mg, 0.52 mmol) in concentrated H2 SO4 (0.2 mL) was stirred at ambient temperature for 20 hours. The reaction mixture was cooled to 0° C. and neutralized by the addition of aqueous NaOH (15 wt %, 4 mL), then extracted with 10% MeOH/DCM (3×10 mL), and the combined organic extracts were washed with brine, dried (MgSO4 ), filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography eluting with 5% to 60% acetonitrile/water to give the product (1.4 mg, 5% yield) as a white solid. MS (apci) m/z=499.2 (M+H).
实例464Example 464
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-乙氧基-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(羟甲基)-1-苯基-1H-吡唑-5-基)脲4-(Hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备5-(3-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-3-乙氧基-1-苯基-1H-吡唑-4-甲酸乙酯：向5-氨基-3-乙氧基-1-苯基-1H-吡唑-4-甲酸乙酯(中间体174，68mg，0.25mmol)在DCM(1mL)中的溶液中添加DIEA(0.086mL，0.49mmol)，然后添加三光气(26mg，0.086mmol)。在环境温度下搅拌反应混合物2小时，然后再添加三光气(26mg，0.086mmol)。在环境温度下搅拌反应混合物22小时，并且然后再添加三光气(26mg，0.086mmol)。在环境温度下再搅拌反应混合物5小时，然后添加(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备E，81mg，0.25mmol)和DIEA(0.13mL，0.74mmol)在DCM(0.5mL)中的溶液。在环境温度下搅拌反应混合物1小时，然后在减压下浓缩并且通过反相柱色谱法用5％至70％乙腈/水洗脱来纯化，得到呈白色固体状的产物(12mg，9％产率)。MS(apci)m/z＝558.3(M+H)。[0266] Step A:Preparation of ethyl 5-(3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate : To a solution of ethyl 5-amino-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate (Intermediate 174, 68 mg, 0.25 mmol) in DCM (1 mL) was added DIEA (0.086 mL, 0.49 mmol) followed by triphosgene (26 mg, 0.086 mmol). The reaction mixture was stirred at ambient temperature for 2 hours before additional triphosgene (26 mg, 0.086 mmol) was added. The reaction mixture was stirred at ambient temperature for 22 hours and then additional triphosgene (26 mg, 0.086 mmol) was added. The reaction mixture was stirred at ambient temperature for another 5 hours, and then a solution of (3S, 4R) -4- (3,5- difluorophenyl) -1- (2-methoxyethyl) pyrrolidin-3-amine dihydrochloride (Preparation E, 81 mg, 0.25 mmol) and DIEA (0.13 mL, 0.74 mmol) in DCM (0.5 mL) was added. The reaction mixture was stirred at ambient temperature for 1 hour, then concentrated under reduced pressure and purified by reverse phase column chromatography eluting with 5% to 70% acetonitrile / water to give the product (12 mg, 9% yield) as a white solid. MS (apci) m / z = 558.3 (M + H).
步骤B：制备1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-乙氧基-4-(羟甲基)-1-苯基-1H-吡唑-5-基)脲：向N2下冷却至0℃的5-(3-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-3-乙氧基-1-苯基-1H-吡唑-4-甲酸乙酯(18mg，0.032mmol)在THF(2mL)中的溶液中添加LiAlH4(1M双-四氢呋喃的甲苯溶液，0.032mL，0.032mmol)。在0℃下搅拌反应混合物2小时，然后在环境温度下搅拌90分钟，然后冷却至0℃并且通过添加H2O(0.005mL)、5μL NaOH水溶液(1M，0.005mL)，接着添加H2O(0.015mL)来淬灭，搅拌10分钟，然后过滤，用THF(2×5mL)冲洗并且浓缩。通过制备型TLC(0.5mm板，用5％MeOH/DCM洗脱)纯化粗产物，得到呈无色残余物形式的产物(1.6mg，10％产率)。MS(apci)m/z＝516.3(M+H)。Step B:Preparation of 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)urea : To a solution ofethyl 5-(3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea)-3-ethoxy-1-phenyl-1H-pyrazole-4-carboxylate (18 mg, 0.032 mmol) in THF (2 mL) cooled to 0 °C under N2 was addedLiAlH4 (1 M bis-tetrahydrofuran in toluene, 0.032 mL, 0.032 mmol). The reaction mixture was stirred at 0°C for 2 hours, then at ambient temperature for 90 minutes, then cooled to 0°C and quenched by addingH2O (0.005 mL), 5 μL of aqueous NaOH (1 M, 0.005 mL), followed byH2O (0.015 mL), stirred for 10 minutes, then filtered, rinsed with THF (2×5 mL), and concentrated. The crude product was purified by preparative TLC (0.5 mm plate, eluted with 5% MeOH/DCM) to give the product (1.6 mg, 10% yield) as a colorless residue. MS (apci) m/z=516.3 (M+H).
实例465Example 465
1-((3S,4R)-4-(3-氯-4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1',4-二1-((3S,4R)-4-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1',4-dimethoxyphenyl)-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)脲Methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)urea
通过手性HPLC(Chiralcel OD柱)，用10％EtOH/己烷洗脱来分离1-(反式-4-(3-氯-4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)脲的外消旋混合物(实例293，30mg，0.054mmol)。收集峰1，得到呈白色固体状的标题化合物(9.8mg，33％产率)。MS(apci)m/z＝552.2(M+H)。A racemic mixture of 1-(trans-4-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)urea (Example 293, 30 mg, 0.054 mmol) was separated by chiral HPLC (Chiralcel OD column) eluting with 10% EtOH/hexanes. Peak 1 was collected to give the title compound (9.8 mg, 33% yield) as a white solid. MS (apci) m/z = 552.2 (M+H).
实例466Example 466
1-((3S,4R)-4-(4-氯-3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1',4-二1-((3S,4R)-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1',4-dimethoxyphenyl)-甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)脲Methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)urea
通过手性HPLC(Chiralcel OD柱)，用10％EtOH/己烷洗脱来分离1-(反式-4-(4-氯-3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)脲的外消旋混合物(实例294，42mg，0.076mmol)。收集峰1，得到呈白色固体状的标题化合物(17.1mg，41％产率)。MS(apci)m/z＝552.2(M+H)。A racemic mixture of 1-(trans-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)urea (Example 294, 42 mg, 0.076 mmol) was separated by chiral HPLC (Chiralcel OD column) eluting with 10% EtOH/hexanes. Peak 1 was collected to give the title compound (17.1 mg, 41% yield) as a white solid. MS (apci) m/z = 552.2 (M+H).
实例467Example 467
1-((3S,4R)-4-(3-氯-5-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1',4-二1-((3S,4R)-4-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1',4-difluorophenyl)甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)脲Methyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)urea
通过手性HPLC(Chiralpak IA柱)，用15％EtOH/己烷洗脱来分离1-(反式-4-(3-氯-5-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)脲的外消旋混合物(实例295，32mg，0.058mmol)。收集峰2，得到呈白色固体状的标题化合物(12.5mg，39％产率)。MS(apci)m/z＝552.2(M+H)。A racemic mixture of 1-(trans-4-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)urea (Example 295, 32 mg, 0.058 mmol) was separated by chiral HPLC (Chiralpak IA column) eluting with 15% EtOH/hexanes. Peak 2 was collected to give the title compound as a white solid (12.5 mg, 39% yield). MS (apci) m/z = 552.2 (M+H).
实例468Example 468
2-((3R,4S)-3-(3,4-二氟苯基)-4-(3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazole-5-基)脲基)吡咯烷-1-基)乙酸甲酯1-Yl)ureido)pyrrolidin-1-yl)acetic acid methyl ester
根据实例191中所述的方法，在步骤A中用2-溴乙酸甲酯替代2-溴乙醇并且在步骤C中用3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(根据实例1步骤A以中间体P135为起始物制备)替代3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备，得到呈白色固体状的产物(23mg，50％产率)。MS(apci)m/z＝514.2(M+H)。Prepared according to the method described in Example 191, substituting methyl 2-bromoacetate for 2-bromoethanol in Step A and phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared according to Example 1, Step A starting with Intermediate P135) for phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate in Step C, to give the product as a white solid (23 mg, 50% yield). MS (apci) m/z=514.2 (M+H).
实例469Example 469
1-((3S,4R)-4-(3,4-二氟苯基)-1-(3,3,3-三氟-2-羟基丙基)吡咯烷-3-基)-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-yl)-3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-Ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据实例191中所述的方法，在步骤A中用3-溴-1,1,1-三氟丙-2-醇替代2-溴乙醇并且在步骤C中用3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(根据实例1步骤A以中间体P135为起始物制备)替代3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备，得到呈白色固体状的产物(38mg，78％产率)。MS(apci)m/z＝554.2(M+H)。Prepared according to the method described in Example 191, substituting 3-bromo-1,1,1-trifluoropropan-2-ol for 2-bromoethanol in Step A and phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared according to Example 1, Step A starting with Intermediate P135) for phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate in Step C, to give the product as a white solid (38 mg, 78% yield). MS (apci) m/z=554.2 (M+H).
实例470Example 470
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-羟基丙基)吡咯烷-3-基)-3-(3-乙氧基-4-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxypropyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-甲基-1-苯基-1H-吡唑-5-基)脲Methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据实例191中所述的方法，在步骤A中用1-氯丙-2-醇(Aldrich，70％纯度，含<25％的2-氯丙-1-醇)替代2-溴乙醇并且在步骤C中用3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(根据实例1步骤A以中间体P135为起始物制备)替代3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备，得到呈白色固体状的产物(10mg，53％产率)。MS(apci)m/z＝500.2(M+H)。Prepared according to the method described in Example 191, substituting 1-chloropropan-2-ol (Aldrich, 70% purity, containing <25% 2-chloropropan-1-ol) for 2-bromoethanol in Step A and phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared according to Example 1, Step A starting with Intermediate P135) for phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate in Step C to give the product as a white solid (10 mg, 53% yield). MS (apci) m/z = 500.2 (M+H).
实例471Example 471
1-((3S,4R)-1-(2-氰基乙基)-4-(3,4-二氟苯基)吡咯烷-3-基)-3-(3-乙氧基-4-1-((3S,4R)-1-(2-cyanoethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-甲基-1-苯基-1H-吡唑-5-基)脲Methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据实例191中所述的方法，在步骤A中用1-氯丙-2-醇替代丙烯腈并且在步骤C中用3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(根据实例1步骤A以中间体P135为起始物制备)替代3,4-二甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备，得到呈白色固体状的产物(16mg，59％产率)。MS(apci)m/z＝459.3(M+H)。Prepared according to the method described in Example 191, substituting 1-chloropropane-2-ol for acrylonitrile in Step A and phenyl 3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared according to Example 1, Step A starting from Intermediate P135) for phenyl 3,4-dimethyl-1-phenyl-1H-pyrazol-5-ylcarbamate in Step C, to give the product as a white solid (16 mg, 59% yield). MS (apci) m/z = 459.3 (M+H).
实例472Example 472
2-((3R,4S)-3-(3,4-二氟苯基)-4-(3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazole-5-基)脲基)吡咯烷-1-基)-N-甲基乙酰胺(1-yl)ureido)pyrrolidin-1-yl)-N-methylacetamide
步骤A：制备2-((3R,4S)-3-(3,4-二氟苯基)-4-(3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲基)吡咯烷-1-基)乙酸：向2-((3R,4S)-3-(3,4-二氟苯基)-4-(3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲基)吡咯烷-1-基)乙酸甲酯(实例468；15mg，0.029mmol)在THF(0.8mL)和MeOH(0.4mL)中的溶液中添加LiOH水溶液(2M，0.044mL，0.088mmol)。在环境温度下搅拌反应混合物3小时，然后用HCl水溶液(1M，1mL)和盐水(2mL)稀释，并且用DCM(2×5mL)萃取。干燥(MgSO4)合并的有机萃取物，过滤并且浓缩，得到呈灰白色固体状的产物(13.0mg，89％产率)。MS(apci)m/z＝500.2(M+H)。Step A:Preparation of 2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)acetic acid : To a solution of methyl 2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)acetate (Example 468; 15 mg, 0.029 mmol) in THF (0.8 mL) and MeOH (0.4 mL) was added aqueous LiOH (2 M, 0.044 mL, 0.088 mmol). The reaction mixture was stirred at ambient temperature for 3 hours, then diluted with aqueous HCl (1 M, 1 mL) and brine (2 mL), and extracted with DCM (2×5 mL). The combined organic extracts were dried (MgSO4 ), filtered and concentrated to give the product as an off-white solid (13.0 mg, 89% yield).MS (apci) m/z = 500.2 (M+H).
步骤B：制备2-((3R,4S)-3-(3,4-二氟苯基)-4-(3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲基)吡咯烷-1-基)-N-甲基乙酰胺：向2-((3R,4S)-3-(3,4-二氟苯基)-4-(3-(3-乙氧基-4-甲基-1-苯基-1H-吡唑-5-基)脲基)吡咯烷-1-基)乙酸(7.4mg，0.015mmol)在DMF(0.5mL)中的悬浮液中添加N-甲基吗啉(0.005mL，0.044mmol)、甲胺(2MTHF溶液，0.009mL，0.018mmol)，然后添加HATU(6.8mg，0.018mmol)。在环境温度下搅拌反应混合物19小时，然后通过反相柱色谱法用5％至70％乙腈/水洗脱来直接纯化，得到呈浅白色固体状的标题化合物(4.2mg，55％产率)。MS(apci)m/z＝513.3(M+H)。[0266] Step B:Preparation of 2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)-N-methylacetamide : To a suspension of 2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)acetic acid (7.4 mg, 0.015 mmol) in DMF (0.5 mL) was added N-methylmorpholine (0.005 mL, 0.044 mmol), methylamine (2M in THF, 0.009 mL, 0.018 mmol), and then HATU (6.8 mg, 0.018 mmol). The reaction mixture was stirred at ambient temperature for 19 hours and then directly purified by reverse phase column chromatography eluting with 5% to 70% acetonitrile/water to give the title compound (4.2 mg, 55% yield) as a pale white solid. MS (apci) m/z=513.3 (M+H).
实例473Example 473
1-(1-环己基-3,4-二甲基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-1-(1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(2-Methoxyethyl)pyrrolidin-3-yl)urea
步骤A：制备1-环己基-3,4-二甲基-1H-吡唑-5-胺：向环己肼盐酸盐(0.465g，3.09mmol)在乙醇(30mL)中的悬浮液中添加2-氧代环戊烷甲腈(0.30g，3.09mmol)。将混合物加热至回流并维持18小时，然后冷却至环境温度并且在真空中浓缩。将残余物分配于饱和NaHCO3(30mL)与EtOAc(30mL)之间。用EtOAc(2×20mL)萃取水层，并且用盐水(20mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且浓缩，得到呈奶白色固体状的1-环己基-3,4-二甲基-1H-吡唑-5-胺(0.523g，88％产率)。1H NMR(CDCl3)δ3.78-3.93(m,1H),3.13(br s,2H),2.12(s,3H),1.85-1.95(m,6H),1.83(s,3H),1.63-1.73(m,1H),1.18-1.44(m,3H)ppm。Step A:Preparation of 1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-amine : To a suspension of cyclohexylhydrazine hydrochloride (0.465 g, 3.09 mmol) in ethanol (30 mL) was added 2-oxocyclopentanecarbonitrile (0.30 g, 3.09 mmol). The mixture was heated to reflux and maintained for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between saturated NaHCO3 (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic phases were washed with brine (20 mL), dried over Na2 SO4 , filtered and concentrated to give 1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-amine (0.523 g, 88% yield) as a milky white solid.1 H NMR (CDCl3 ) δ3.78-3.93(m,1H),3.13(br s,2H),2.12(s,3H),1.85-1.95(m,6H),1.83(s,3H),1.63-1.73(m,1H),1.18-1.44(m,3H)ppm.
步骤B：制备(1-环己基-3,4-二甲基-1H-吡唑-5-基)氨基甲酸苯酯：向1-环己基-3,4-二甲基-1H-吡唑-5-胺(200mg，1.04mmol)在EtOAc(5mL)中的溶液中添加2N NaOH(1.04mL，2.1mmol)，接着添加氯甲酸苯酯(182μL，1.45mmol)。在环境温度下搅拌混合物5小时，然后用水(30mL)稀释并且用EtOAc(3×20mL)萃取。用饱和NaHCO3(20mL)和盐水(20mL)洗涤合并的有机相，然后经Na2SO4干燥并且在真空中浓缩，得到呈浅紫色泡沫状的(1-环己基-3,4-二甲基-1H-吡唑-5-基)氨基甲酸苯酯，其不经纯化即在假定定量产率的情况下使用。[0146] Step B:Preparation of phenyl (1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)carbamate : To a solution of 1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-amine (200 mg, 1.04 mmol) in EtOAc (5 mL) was added 2N NaOH (1.04 mL, 2.1 mmol) followed by phenyl chloroformate (182 μL, 1.45 mmol). The mixture was stirred at ambient temperature for 5 hours, then diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with saturated NaHCO₃ (20 mL) and brine (20 mL), then dried overNa₂SO₄ and concentrated in vacuo to afford phenyl (1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)carbamate as a light purple foam, which was used without purification assuming a quantitative yield.
步骤C：制备1-(1-环己基-3,4-二甲基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：向(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)(50mg，0.15mmol)和(1-环己基-3,4-二甲基-1H-吡唑-5-基)氨基甲酸苯酯(52mg，0.17mmol)在DMA(2mL)中的溶液中添加DIEA(93μL，0.53mmol)。在环境温度下搅拌混合物18小时，然后将其分配于饱和NH4Cl(20mL)与EtOAc(20mL)之间并且用EtOAc(2×10mL)萃取水层。用水(5×10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2％MeOH/DCM洗脱来纯化残余物，得到呈无色玻璃状的标题化合物(42mg，58％产率)。MS(apci)m/z＝476.3(M+H)。[0266] Step C:Preparation of 1-(1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl )-1-(2-methoxyethyl)pyrrolidin-3-yl)urea: To a solution of (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) (50 mg, 0.15 mmol) and phenyl (1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)carbamate (52 mg, 0.17 mmol) in DMA (2 mL) was added DIEA (93 μL, 0.53 mmol). The mixture was stirred at ambient temperature for 18 h then partitioned between saturatedNH4Cl (20 mL) and EtOAc (20 mL) and the aqueous layer extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with water (5 x 10 mL) and brine (10 mL), then dried overNa2SO4 ,filtered , and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (42 mg, 58% yield) as a colorless glass. MS (apci) m/z = 476.3 (M+H).
实例474Example 474
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxyphenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-基-2-(羟甲基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备(2,2-二甲基-1,3-二噁烷-5-基)甲醇：向2-(羟甲基)丙烷-1,3-二醇(5.0g，47.1mmol)在THF(100mL)中的悬浮液中添加一水合对甲苯磺酸(269mg，1.41mmol)，接着添加2,2-二甲氧基丙烷(6.72mL，54.7mmol)。在环境温度下搅拌混合物3小时，然后再添加200mg一水合对甲苯磺酸并且再继续搅拌60小时。用三乙胺(3mL)处理溶液，然后在真空中浓缩。通过二氧化硅柱色谱法，用5％MeOH/DCM洗脱来纯化残余物，得到呈无色液体状的(2,2-二甲基-1,3-二噁烷-5-基)甲醇(5.04g，73％产率)。1H NMR(CDCl3)δ4.02(dd,J＝12.0,4.1Hz,2H),3.74-3.80(m,4H),1.90(t,J＝5.1Hz,1H),1.80-1.88(m,1H),1.45(s,3H),1.40(s,3H)ppm。Step A:Preparation of (2,2-dimethyl-1,3-dioxane-5-yl)methanol : To a suspension of 2-(hydroxymethyl)propane-1,3-diol (5.0 g, 47.1 mmol) in THF (100 mL) was added p-toluenesulfonic acid monohydrate (269 mg, 1.41 mmol), followed by 2,2-dimethoxypropane (6.72 mL, 54.7 mmol). The mixture was stirred at ambient temperature for 3 hours, then 200 mg of p-toluenesulfonic acid monohydrate was added and stirring was continued for another 60 hours. The solution was treated with triethylamine (3 mL) and then concentrated in vacuo. The residue was purified by silica column chromatography eluting with 5% MeOH/DCM to give (2,2-dimethyl-1,3-dioxane-5-yl)methanol (5.04 g, 73% yield) as a colorless liquid.1 H NMR (CDCl3 ) δ4.02 (dd, J = 12.0, 4.1 Hz, 2H), 3.74-3.80 (m, 4H), 1.90 (t, J = 5.1 Hz, 1H), 1.80-1.88 (m, 1H), 1.45 (s, 3H), 1.40 (s, 3H) ppm.
步骤B：制备甲磺酸(2,2-二甲基-1,3-二噁烷-5-基)甲酯：在0℃下向(2,2-二甲基-1,3-二噁烷-5-基)甲醇(1.0g，6.84mmol)在DCM(30mL)中的溶液中添加三乙胺(1.43mL，10.3mmol)，接着添加甲磺酰氯(0.58mL，7.52mmol)。允许混合物在搅拌下经18小时缓慢升温至环境温度。将混合物分配于0.5M HCl(40mL)与DCM(20mL)之间并且用DCM(2×20mL)萃取水层。用盐水(20mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且浓缩，得到呈无色油状的甲磺酸(2,2-二甲基-1,3-二噁烷-5-基)甲酯(1.29g，84％产率)。1H NMR(CDCl3)δ4.42(d,J＝7.3Hz,2H),4.08(dd,J＝12.5,3.5Hz,2H),3.77(dd,J＝12.5,3.9Hz,2H),3.04(s,3H),1.98-2.03(m,1H),1.46(s,3H),1.39(s,3H)ppm。Step B:Preparation of (2,2-dimethyl-1,3-dioxane-5-yl)methyl methanesulfonate : To a solution of (2,2-dimethyl-1,3-dioxane-5-yl)methanol (1.0 g, 6.84 mmol) in DCM (30 mL) at 0 ° C., triethylamine (1.43 mL, 10.3 mmol) was added, followed by methanesulfonyl chloride (0.58 mL, 7.52 mmol). The mixture was allowed to slowly warm to ambient temperature over 18 hours with stirring. The mixture was partitioned between 0.5 M HCl (40 mL) and DCM (20 mL) and the aqueous layer was extracted with DCM (2×20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2 SO4 , filtered and concentrated to give (2,2-dimethyl-1,3-dioxane-5-yl)methyl methanesulfonate (1.29 g, 84% yield) as a colorless oil.1 H NMR (CDCl3 )δ4.42(d,J＝7.3Hz,2H),4.08(dd,J＝12.5,3.5Hz,2H),3.77(dd,J＝12.5,3.9Hz,2H),3.04(s,3H),1.98-2.03(m,1H),1.46(s,3H),1.39(s,3H)ppm.
步骤C：制备3-((2,2-二甲基-1,3-二噁烷-5-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-胺：向5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮(中间体P135步骤A；500mg，2.64mmol)在DMF(5mL)中的溶液中添加K2CO3(1.10g，7.93mmol)，接着添加甲磺酸(2,2-二甲基-1,3-二噁烷-5-基)甲酯(711mg，3.17mmol)在DMF(2mL)中的溶液。在50℃下搅拌混合物18小时，然后冷却，用水(30mL)处理并且用EtOAc(3×20mL)萃取。用水(5×10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用4:1至2:1己烷/EtOAc洗脱来纯化残余物，得到呈黄色胶状的3-((2,2-二甲基-1,3-二噁烷-5-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-胺(198mg，24％)。MS(apci)m/z＝318.1(M+H)。[0266] Step C:Preparation of 3-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine : To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate P135, Step A; 500 mg, 2.64 mmol) in DMF (5 mL) was addedK2CO3 (1.10 g, 7.93 mmol) followed by a solutionof (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (711 mg, 3.17 mmol) in DMF (2 mL). The mixture was stirred at 50°C for 18 hours, then cooled, treated with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with water (5 x 10 mL) and brine (10 mL), then driedoverNa2SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 4:1 to 2:1 hexanes/EtOAc to afford 3-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine (198 mg, 24%) as a yellow gum. MS (apci) m/z = 318.1 (M+H).
步骤D：制备(3-(3-羟基-2-(羟甲基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯：向3-((2,2-二甲基-1,3-二噁烷-5-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-胺(198mg，0.62mmol)在EtOAc(5mL)中的溶液中添加2M NaOH(780μL，1.56mmol)，接着添加氯甲酸苯酯(117μL，0.94mmol)。在环境温度下搅拌混合物18小时，然后将其分配于水(20mL)与EtOAc(20mL)之间并且用EtOAc(2×20mL)萃取水层。用饱和NaHCO3(20mL)和盐水(20mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2％至4％MeOH/DCM洗脱来纯化残余物，得到呈奶白色泡沫状的(3-(3-羟基-2-(羟甲基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯(75mg，30％产率)。MS(apci)m/z＝398.2(M+H)。[0266] Step D:Preparation ofphenyl (3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl) carbamate: To a solution of 3-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine (198 mg, 0.62 mmol) in EtOAc (5 mL) was added 2M NaOH (780 μL, 1.56 mmol) followed by phenyl chloroformate (117 μL, 0.94 mmol). The mixture was stirred at ambient temperature for 18 hours before being partitioned between water (20 mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with saturatedNaHCO₃ (20 mL) and brine (20 mL) , then dried overNa₂SO₄ , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2% to 4% MeOH/DCM to give phenyl (3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate (75 mg, 30% yield) as a milky white foam. MS (apci) m/z = 398.2 (M+H).
步骤E：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(3-羟基-2-(羟甲基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：根据实例473步骤C的方法，用(3-(3-羟基-2-(羟甲基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯替代(1-环己基-3,4-二甲基-1H-吡唑-5-基)氨基甲酸苯酯来制备。通过二氧化硅柱色谱法，用2％至5％MeOH/DCM洗脱来纯化物质，得到呈无色玻璃状的标题化合物(26mg，55％产率)。MS(apci)m/z＝560.3(M+H)。Step E:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : Prepared according to the procedure of Example 473, Step C, substituting phenyl (3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate for phenyl (1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)carbamate. The material was purified by silica column chromatography eluting with 2% to 5% MeOH/DCM to give the title compound (26 mg, 55% yield) as a colorless glass. MS (apci) m/z = 560.3 (M+H).
实例475Example 475
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-基)脲Phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea
步骤A：制备4-甲基-1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-胺：根据实例474步骤C的方法，用1,1,1-三氟-2-碘乙烷替代甲磺酸(2,2-二甲基-1,3-二噁烷-5-基)甲酯来制备。MS(apci)m/z＝272.1(M+H)。Step A:Preparation of 4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-amine : Prepared according to the procedure of Example 474, Step C, substituting 1,1,1-trifluoro-2-iodoethane for (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate. MS (apci) m/z = 272.1 (M+H).
步骤B：制备(4-甲基-1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-基)氨基甲酸苯酯：根据实例474步骤D的方法，用4-甲基-1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-胺替代3-((2,2-二甲基-1,3-二噁烷-5-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-胺来制备。MS(apci)m/z＝392.1(M+H)。Step B:Preparation of phenyl (4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)carbamate: Prepared according to the procedure of Example 474, Step D, substituting 4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-amine for 3-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-amine. MS (apci) m/z = 392.1 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-基)脲：根据实例473步骤C的方法，用(4-甲基-1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-基)氨基甲酸苯酯替代(1-环己基-3,4-二甲基-1H-吡唑-5-基)氨基甲酸苯酯来制备。通过二氧化硅柱色谱法，用5％MeOH/DCM洗脱来纯化物质，接着通过制备型HPLC(5％至95％ACN/H2O/0.1％TFA，经20分钟)纯化，在萃取处理(DCM/1N NaOH)后得到呈白色固体状的标题化合物(16mg，38％产率)。MS(apci)m/z＝554.2(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea : Prepared according to the method of Step C of Example 473, using (4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)carbamic acid phenyl ester instead of (1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)carbamic acid phenyl ester. The material was purified by silica column chromatography eluting with 5% MeOH/DCM followed by preparative HPLC (5% to 95% ACN/H2O /0.1% TFA over 20 minutes) to afford the title compound (16 mg, 38% yield) as a white solid after extractive workup (DCM/1 N NaOH). MS (apci) m/z = 554.2 (M+H).
实例476Example 476
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl)基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-基)脲3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea
根据实例475的方法，用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备K)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用2％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(56mg，65％产率)。MS(apci)m/z＝536.2(M+H)。Prepared according to the method of Example 475, substituting (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation K) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F). The material was purified by silica column chromatography eluting with 2% MeOH/DCM to give the title compound (56 mg, 65% yield) as a white solid. MS (apci) m/z=536.2 (M+H).
实例477Example 477
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-基)脲Phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea
根据实例475的方法，用(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺三氟乙酸盐(制备E)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用2％MeOH/DCM洗脱来纯化物质，得到呈无色玻璃状的标题化合物(53mg，63％产率)。MS(apci)m/z＝554.2(M+H)。Prepared according to the method of Example 475, substituting (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine trifluoroacetate (Preparation E) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F). The material was purified by silica column chromatography eluting with 2% MeOH/DCM to give the title compound (53 mg, 63% yield) as a colorless glass. MS (apci) m/z=554.2 (M+H).
实例478Example 478
1-(3-(2,2-二氟乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-1-(3-(2,2-difluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例475的方法，在步骤A中用1,1-二氟-2-碘乙烷替代1,1,1-三氟-2-碘乙烷来制备。通过二氧化硅柱色谱法，用2％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(55mg，68％产率)。(MS(apci)m/z＝536.2(M+H)。Prepared according to the method of Example 475, substituting 1,1,1-trifluoro-2-iodoethane for 1,1,1-difluoro-2-iodoethane in step A. The material was purified by silica column chromatography eluting with 2% MeOH/DCM to give the title compound (55 mg, 68% yield) as a white solid. (MS (apci) m/z=536.2 (M+H)
实例479Example 479
1-(4-氯-1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-1-(4-chloro-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
步骤A：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-基)脲：根据实例475的方法，用5-氨基-1-苯基-1H-吡唑-3(2H)-酮(中间体P136步骤A)替代5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮(中间体P135步骤A)来制备。Step A:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea : Prepared according to the method of Example 475, substituting 5-amino-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate P136, Step A) for 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate P135, Step A).
步骤B：制备1-(4-氯-1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：向1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-苯基-3-(2,2,2-三氟乙氧基)-1H-吡唑-5-基)脲(50mg，0.09mmol)在DCM(1mL)中的溶液中添加N-氯代琥珀酰亚胺(15mg，0.11mmol)，接着添加4-甲基苯磺酸吡啶-1-鎓(2mg，0.009mmol)。在环境温度下搅拌混合物18小时，然后再用5mg N-氯代琥珀酰亚胺处理并且搅拌2.5小时。将混合物分配于饱和NaHCO3(20mL)与DCM(20mL)之间并且用DCM(2×10mL)萃取水层。用盐水(10mL)洗涤合并的有机相，经Na2SO4干燥并且在真空中浓缩。通过二氧化硅柱色谱法，用2.5％MeOH/DCM洗脱来纯化残余物，得到呈浅黄色泡沫状的标题化合物(28mg，53％产率)。MS(apci)m/z＝574.2(M+H)。[0266] Step B:Preparation of 1-(4-chloro-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : To a solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea (50 mg, 0.09 mmol) in DCM (1 mL) was added N-chlorosuccinimide (15 mg, 0.11 mmol) followed by pyridin-1-ium 4-methylbenzenesulfonate (2 mg, 0.009 mmol). The mixture was stirred at ambient temperature for 18 hours, then treated with an additional 5 mg of N-chlorosuccinimide and stirred for2.5 hours. The mixture was partitioned between saturatedNaHCO₃ (20 mL) and DCM (20 mL), and the aqueous layer was extracted with DCM (2×10 mL). The combined organic phases were washed with brine (10 mL), dried overNa₂SO₄ , and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2.5% MeOH/DCM to give the title compound (28 mg, 53% yield) as a light yellow foam. MS (apci) m/z=574.2 (M+H).
实例480Example 480
1-(4-氯-1-苯基-3-(吡啶-2-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯1-(4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
步骤A：制备1-苯基-3-(吡啶-2-基)-1H-吡唑-5-胺：根据实例473步骤A的方法，用苯肼盐酸盐替代环己肼盐酸盐并且用3-氧代基-3-(吡啶-2-基)丙腈替代2-氧代环戊烷甲腈来制备。MS(apci)m/z＝237.1(M+H)。Step A:Preparation of 1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine : Prepared according to the procedure of Example 473, Step A, substituting phenylhydrazine hydrochloride for cyclohexylhydrazine hydrochloride and 3-oxo-3-(pyridin-2-yl)propionitrile for 2-oxocyclopentanecarbonitrile. MS (apci) m/z = 237.1 (M+H).
步骤B：制备4-氯-1-苯基-3-(吡啶-2-基)-1H-吡唑-5-胺：将1-苯基-3-(吡啶-2-基)-1H-吡唑-5-胺(300mg，1.27mmol)的溶液溶解于DCM(20mL)中并且用N-氯代琥珀酰亚胺(187mg，1.40mmol)处理，接着用4-甲基苯磺酸吡啶-1-鎓(32mg，0.13mmol)处理。在环境温度下搅拌溶液3小时，然后将其分配于DCM(20mL)与饱和NaHCO3(20mL)之间并且用DCM(2×20mL)萃取水层。用盐水(20mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2:1己烷/EtOAc洗脱来纯化残余物，得到呈粉红色泡沫状的4-氯-1-苯基-3-(吡啶-2-基)-1H-吡唑-5-胺(211mg，61％)。MS(apci)m/z＝271.0(M+H)。Step B:Preparation of 4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine : A solution of 1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (300 mg, 1.27 mmol) was dissolved in DCM (20 mL) and treated with N-chlorosuccinimide (187 mg, 1.40 mmol) followed by pyridin-1-ium 4-methylbenzenesulfonate (32 mg, 0.13 mmol). The solution was stirred at ambient temperature for 3 hours before being partitioned between DCM (20 mL) and saturated NaHCO3 (20 mL) and the aqueous layer was extracted with DCM (2×20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2 SO4 , filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2:1 hexanes/EtOAc to give 4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (211 mg, 61%) as a pink foam. MS (apci) m/z = 271.0 (M+H).
步骤C：制备1-(4-氯-1-苯基-3-(吡啶-2-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：向4-氯-1-苯基-3-(吡啶-2-基)-1H-吡唑-5-胺(37mg，0.14mmol)在DCM(2mL)中的溶液中添加三光气(21mg，0.07mmol)，接着添加DIEA(72μL，0.41mmol)。在环境温度下搅拌混合物1小时，然后用(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)(50mg，0.15mmol)处理，接着用DIEA(72μL，0.41mmol)处理。再搅拌18小时后，将混合物分配于饱和NH4Cl(20mL)与DCM(20mL)之间并且用DCM(2×10mL)萃取水层。用盐水(20mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2.5％MeOH/DCM洗脱来纯化残余物，接着进行反相HPLC纯化(5％至95％ACN/水/0.5％TFA，经20分钟)。在水性处理(1N NaOH/DCM)后得到呈白色固体状的标题化合物(10mg，13％产率)。MS(apci)m/z＝553.2(M+)。[0266] Step C:Preparation of 1-(4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : To a solution of 4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (37 mg, 0.14 mmol) in DCM (2 mL) was added triphosgene (21 mg, 0.07 mmol) followed by DIEA (72 μL, 0.41 mmol). The mixture was stirred at ambient temperature for 1 hour and then treated with (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) (50 mg, 0.15 mmol) followed by DIEA (72 μL, 0.41 mmol). After stirring for an additional 18 hours, the mixture was partitioned between saturatedNH4Cl (20 mL) and DCM (20 mL)and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic phases were washed with brine (20 mL), dried overNa2SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2.5% MeOH/DCM, followed by reverse phase HPLC purification (5% to 95% ACN/water/0.5% TFA over 20 minutes). Aqueous workup (1 N NaOH/DCM) afforded the title compound (10 mg, 13% yield) as a white solid. MS (apci) m/z = 553.2 (M+).
实例481Example 481
1-(4-氯-1-苯基-3-(吡啶-4-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯1-(4-chloro-1-phenyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例480的方法，在步骤A中用3-氧代基-3-(吡啶-4-基)丙腈替代3-氧代基-3-(吡啶-2-基)丙腈来制备。通过二氧化硅柱色谱法，用2％MeOH/DCM洗脱来纯化物质，接着进行反相HPLC纯化(5％至95％ACN/水/0.5％TFA，经20分钟)。在水性处理(1N NaOH/DCM)后得到呈白色固体状的标题化合物(3mg，4％产率)。MS(apci)m/z＝553.2(M+)。Prepared according to the method of Example 480, using 3-oxo-3-(pyridin-4-yl)propionitrile instead of 3-oxo-3-(pyridin-2-yl)propionitrile in step A. The material was purified by silica column chromatography eluting with 2% MeOH/DCM, followed by reverse phase HPLC purification (5% to 95% ACN/water/0.5% TFA over 20 minutes). The title compound (3 mg, 4% yield) was obtained as a white solid after aqueous workup (1N NaOH/DCM). MS (apci) m/z=553.2 (M+).
实例482Example 482
1-(4-氯-1-苯基-3-(吡啶-3-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯1-(4-chloro-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
步骤A：制备1-苯基-3-(吡啶-3-基)-1H-吡唑-5-胺：根据实例480步骤A的方法，用3-氧代基-3-(吡啶-3-基)丙腈替代3-氧代基-3-(吡啶-2-基)丙腈来制备。MS(apci)m/z＝237.1(M+H)。Step A:Preparation of 1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine : Prepared according to the procedure of Example 480, Step A, substituting 3-oxo-3-(pyridin-3-yl)propionitrile for 3-oxo-3-(pyridin-2-yl)propionitrile. MS (apci) m/z = 237.1 (M+H).
步骤B：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-苯基-3-(吡啶-3-基)-1H-吡唑-5-基)脲：向1-苯基-3-(吡啶-3-基)-1H-吡唑-5-胺(50mg，0.21mmol)和CDI(72mg，0.44mmol)在DMF(2mL)中的溶液中添加DIEA(147μL，0.85mmol)并且在50℃下搅拌混合物4小时。向冷却的混合物中添加(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)(146mg，0.44mmol)和DIEA(147μL，0.85mmol)并且在环境温度下继续搅拌18小时。将混合物分配于饱和NH4Cl(20mL)与EtOAc(20mL)之间并且用EtOAc(2×10mL)萃取水层。用水(5×10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用5％MeOH/DCM洗脱来纯化残余物，得到呈白色固体状的1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-苯基-3-(吡啶-3-基)-1H-吡唑-5-基)脲(80mg，73％)。MS(apci)m/z＝519.3(M+H)。[0266] Step B:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea : To a solution of 1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (50 mg, 0.21 mmol) and CDI (72 mg, 0.44 mmol) in DMF (2 mL) was added DIEA (147 μL, 0.85 mmol) and the mixture was stirred at 50°C for 4 hours. To the cooled mixture was added (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) (146 mg, 0.44 mmol) and DIEA (147 μL, 0.85 mmol) and stirring was continued at ambient temperature for 18 hours. The mixture was partitioned between saturated NH4 Cl (20 mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic phases were washed with water (5×10 mL) and brine (10 mL), then dried over Na2 SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 5% MeOH/DCM to afford 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea (80 mg, 73%) as a white solid. MS (apci) m/z=519.3 (M+H).
步骤C：制备1-(4-氯-1-苯基-3-(吡啶-3-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：向1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-苯基-3-(吡啶-3-基)-1H-吡唑-5-基)脲(40mg，0.08mmol)在DCM(1mL)中的溶液中添加N-氯代琥珀酰亚胺(12mg，0.09mmol)，接着添加4-甲基苯磺酸吡啶-1-鎓(2mg，0.008mmol)。在环境温度下搅拌混合物18小时，然后将其分配于饱和NaHCO3(20mL)与DCM(20mL)之间并且用DCM(2×10mL)萃取水层。用盐水(10mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2.5％至5％MeOH/DCM洗脱来纯化残余物，得到呈浅黄色固体状的标题化合物(16mg，38％产率)。MS(apci)m/z＝553.2(M+)。[0149] Step C:Preparation of 1-(4-chloro-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : To a solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea (40 mg, 0.08 mmol) in DCM (1 mL) was added N-chlorosuccinimide (12 mg, 0.09 mmol) followed by pyridin-1-ium 4-methylbenzenesulfonate (2 mg, 0.008 mmol). The mixture was stirred at ambient temperature for 18 hours, then partitioned between saturatedNaHCO₃ (20 mL) and DCM (20 mL) and the aqueous layer was extracted with DCM (2×10 mL). The combined organic phases were washed with brine (10 mL), driedoverNa₂SO₄ , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2.5% to 5% MeOH/DCM to give the title compound (16 mg, 38% yield) as a light yellow solid. MS (apci) m/z=553.2 (M+).
实例483Example 483
1-(4-溴-1-苯基-3-(吡啶-3-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯1-(4-Bromo-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例482的方法，在步骤C中用N-溴代琥珀酰亚胺替代N-氯代琥珀酰亚胺来制备。通过二氧化硅柱色谱法，用3％MeOH/DCM洗脱来纯化物质，得到呈黄色固体状的标题化合物(31mg，67％产率)。MS(apci)m/z＝597.2(M+H)。Prepared according to the method of Example 482, substituting N-bromosuccinimide for N-chlorosuccinimide in step C. The material was purified by silica column chromatography eluting with 3% MeOH/DCM to give the title compound (31 mg, 67% yield) as a yellow solid. MS (apci) m/z=597.2 (M+H).
实例484Example 484
1-(4-溴-1-苯基-3-(吡啶-2-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯1-(4-Bromo-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
步骤A：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-苯基-3-(吡啶-2-基)-1H-吡唑-5-基)脲：根据实例480的方法，在步骤C中用1-苯基-3-(吡啶-2-基)-1H-吡唑-5-胺替代4-氯-1-苯基-3-(吡啶-2-基)-1H-吡唑-5-胺来制备。MS(apci)m/z＝519.2(M+H)。Step A:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)urea : Prepared according to the method of Example 480, substituting 1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine for 4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine in Step C. MS (apci) m/z = 519.2 (M+H).
步骤B：制备1-(4-溴-1-苯基-3-(吡啶-2-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：根据实例483的方法，在步骤C中用1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-苯基-3-(吡啶-2-基)-1H-吡唑-5-基)脲替代1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-苯基-3-(吡啶-3-基)-1H-吡唑-5-基)脲来制备。通过二氧化硅柱色谱法，用2.5％至5％MeOH/DCM洗脱来纯化物质，得到呈无色玻璃状的标题化合物(14mg，40％产率)。MS(apci)m/z＝597.2(M+)。Step B:Preparation of 1-(4-bromo-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : According to the method of Example 483, 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)urea was used to replace 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea in Step C. The material was purified by silica column chromatography eluting with 2.5% to 5% MeOH/DCM to give the title compound as a colorless glass (14 mg, 40% yield).MS (apci) m/z = 597.2 (M+).
实例485Example 485
1-(4-氯-3-苯基-1-(吡啶-3-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯1-(4-chloro-3-phenyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl) ...基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例482的程序，在步骤A中用3-氧代基-3-苯基丙腈替代3-氧代基-3-(吡啶-3-基)丙腈并且用3-肼基吡啶盐酸盐替代苯肼盐酸盐来制备。通过二氧化硅柱色谱法，用2.5％MeOH/DCM洗脱来纯化物质，得到呈米色固体状的标题化合物(22mg，49％产率)。MS(apci)m/z＝553.2(M+)。Prepared according to the procedure of Example 482, using 3-oxo-3-phenylpropionitrile instead of 3-oxo-3-(pyridin-3-yl)propionitrile and 3-hydrazinopyridine hydrochloride instead of phenylhydrazine hydrochloride in step A. The material was purified by silica column chromatography eluting with 2.5% MeOH/DCM to give the title compound (22 mg, 49% yield) as a beige solid. MS (apci) m/z=553.2 (M+).
实例486Example 486
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-苯基-3-(吡啶-3-基)-1H-吡唑-5-基)脲Phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea
步骤A：制备2-甲基-3-氧代基-3-(吡啶-3-基)丙腈：将LiHMDS溶液(13.6mL，1.0M/THF，13.6mmol)在N2氛围下冷却至-78℃并且逐滴用丙腈(991μL，13.9mmol)处理。在此温度下搅拌所得黄色浆料2小时，然后经10分钟逐滴用烟酸乙酯(1.0g，6.62mmol)在THF(5mL)中的溶液处理。允许混合物经18小时缓慢升温至环境温度，然后倒入冰冷水(100mL)中并且用Et2O(2×30mL)萃取。在冰中冷却水相，用1N HCl酸化至pH 5并且用DCM(3×30mL)萃取。用盐水(30mL)洗涤合并的DCM萃取物，经Na2SO4干燥，过滤并且浓缩，得到呈黄色油状的2-甲基-3-氧代基-3-(吡啶-3-基)丙腈(1.06g，100％产率)。MS(apci)m/z＝161.1(M+H)。Step A:Preparation of 2-methyl-3-oxo-3-(pyridin-3-yl)propionitrile : A LiHMDS solution (13.6 mL, 1.0 M/THF, 13.6 mmol) was cooled to -78 ° C under anN atmosphere and treated dropwise with propionitrile (991 μL, 13.9 mmol). The resulting yellow slurry was stirred at this temperature for 2 hours, then treated dropwise with a solution of ethyl nicotinate (1.0 g, 6.62 mmol) in THF (5 mL) over 10 minutes. The mixture was allowed to slowly warm to ambient temperature over 18 hours, then poured into ice-cold water (100 mL) and extracted withEt O (2 × 30 mL). The aqueous phase was cooled in ice, acidified to pH 5 with 1N HCl and extracted with DCM (3 × 30 mL). The combined DCM extracts were washed with brine (30 mL),dried overNa2SO4 , filtered and concentrated to give 2-methyl-3-oxo-3-(pyridin-3-yl)propanenitrile (1.06 g, 100% yield) as a yellow oil. MS (apci) m/z = 161.1 (M+H).
步骤B：制备4-甲基-1-苯基-3-(吡啶-3-基)-1H-吡唑-5-胺：在回流下搅拌2-甲基-3-氧代基-3-(吡啶-3-基)丙腈(1.06g，6.62mmol)和苯肼盐酸盐(1.05g，7.28mmol)在EtOH(30mL)中的悬浮液18小时，然后冷却至环境温度。浓缩混合物，然后用饱和NaHCO3(50mL)处理并且用DCM(3×30mL)萃取。用盐水(30mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用1:1至1:2己烷/EtOAc洗脱来纯化残余物，得到呈浅黄色泡沫状的4-甲基-1-苯基-3-(吡啶-3-基)-1H-吡唑-5-胺(984mg，59％产率)。MS(apci)m/z＝251.1(M+H)。Step B:Preparation of 4-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine : A suspension of 2-methyl-3-oxo-3-(pyridin-3-yl)propionitrile (1.06 g, 6.62 mmol) and phenylhydrazine hydrochloride (1.05 g, 7.28 mmol) in EtOH (30 mL) was stirred at reflux for 18 hours and then cooled to ambient temperature. The mixture was concentrated, then treated with saturated NaHCO3 (50 mL) and extracted with DCM (3×30 mL). The combined organic phases were washed with brine (30 mL), dried over Na2 SO4 , filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 1:1 to 1:2 hexanes/EtOAc to give 4-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (984 mg, 59% yield) as a light yellow foam. MS (apci) m/z = 251.1 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-3-(吡啶-3-基)-1H-吡唑-5-基)脲：向4-甲基-1-苯基-3-(吡啶-3-基)-1H-吡唑-5-胺(100mg，0.40mmol)在DCM(2mL)中的溶液中添加三光气(59mg，0.20mmol)，接着添加DIEA(209uLμL，1.20mmol)。在环境温度下搅拌混合物1小时，然后用(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F；145mg，0.44mmol)和DIEA(209μL，1.20mmol)处理。在环境温度下搅拌18小时后，将混合物分配于饱和NH4Cl(20mL)与DCM(20mL)之间并且用DCM(2×10mL)萃取水层。用盐水(10mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用3％至4％MeOH/DCM洗脱来纯化残余物，得到呈白色固体状的标题化合物(99mg，47％产率)。MS(apci)m/z＝533.2(M+H)。[0266] Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea : To a solution of 4-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (100 mg, 0.40 mmol) in DCM (2 mL) was added triphosgene (59 mg, 0.20 mmol) followed by DIEA (209 uL, 1.20 mmol). The mixture was stirred at ambient temperature for 1 hour and then treated with (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F; 145 mg, 0.44 mmol) and DIEA (209 uL, 1.20 mmol). After stirring at ambient temperature for 18 hours, the mixture was partitioned between saturatedNH4Cl (20 mL) and DCM (20 mL), and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic phases were washed with brine (10 mL), driedoverNa2SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 3% to 4% MeOH/DCM to give the title compound (99 mg, 47% yield) as a white solid. MS (apci) m/z = 533.2 (M+H).
根据实例486，在步骤A中用适当的试剂替代烟酸乙酯并且对于实例490而言，也在步骤B中用3-肼基吡啶盐酸盐替代苯肼盐酸盐来制备下列化合物。The following compounds were prepared according to Example 486 by substituting the appropriate reagent for ethyl nicotinate in Step A and for Example 490 by substituting 3-hydrazinopyridine hydrochloride for phenylhydrazine hydrochloride in Step B.
实例492Example 492
1-(1',4-二甲基-1-苯基-1H,1'H-[3,3'-联吡唑]-5-基)-3-((3S,4R)-4-(4-氟苯1-(1',4-dimethyl-1-phenyl-1H,1'H-[3,3'-bipyrazole]-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例491的程序，在步骤C中用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备K)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用3％MeOH/DCM洗脱来纯化物质，得到呈浅黄色泡沫状的标题化合物(52mg，51％产率)。MS(apci)m/z＝518.2(M+H)。Prepared according to the procedure of Example 491, substituting (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation K) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in Step C. The material was purified by silica column chromatography eluting with 3% MeOH/DCM to give the title compound (52 mg, 51% yield) as a light yellow foam. MS (apci) m/z = 518.2 (M+H).
实例493Example 493
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1',4-二甲1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1',4-dimethyl基-1-苯基-1H,1'H-[3,3'-联吡唑]-5-基)脲1-phenyl-1H,1'H-[3,3'-bipyrazole]-5-yl)urea
根据实例491的程序，在步骤C中用(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺三氟乙酸盐(制备E)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用3％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(33mg，31％产率)。MS(apci)m/z＝536.2(M+H)。Prepared according to the procedure of Example 491, substituting (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine trifluoroacetate (Preparation E) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in Step C. The material was purified by silica column chromatography eluting with 3% MeOH/DCM to give the title compound (33 mg, 31% yield) as a white solid. MS (apci) m/z=536.2 (M+H).
实例494Example 494
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2',4-二甲1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2',4-dimethyl基-1-苯基-1H,2'H-[3,3'-联吡唑]-5-基)脲1-phenyl-1H,2'H-[3,3'-bipyrazole]-5-yl)urea
步骤A：制备2',4-二甲基-1-苯基-1H,2'H-[3,3'-联吡唑]-5-胺：根据实例486步骤A的方法，用1-甲基-1H-吡唑-5-甲酸乙酯替代烟酸乙酯来制备。1H NMR(CDCl3)δ7.55(d,J＝2.2Hz,1H),7.01(d,J＝2.2Hz,1H),4.19(s,3H),4.12(q,J＝7.2Hz,1H),1.65(d,J＝7.2Hz,3H)ppm。Step A:Preparation of 2',4-dimethyl-1-phenyl-1H,2'H-[3,3'-bipyrazol]-5-amine : Prepared according to the procedure of Example 486, Step A, substituting 1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester for nicotinate ethyl ester.1 H NMR (CDCl3 ) δ 7.55 (d, J=2.2 Hz, 1H), 7.01 (d, J=2.2 Hz, 1H), 4.19 (s, 3H), 4.12 (q, J=7.2 Hz, 1H), 1.65 (d, J=7.2 Hz, 3H) ppm.
步骤B：制备(2',4-二甲基-1-苯基-1H,2'H-[3,3'-联吡唑]-5-基)氨基甲酸苯酯：向2',4-二甲基-1-苯基-1H,2'H-[3,3'-联吡唑]-5-胺(100mg，0.39mmol)在EtOAc(2mL)中的溶液中添加2N NaOH(395μL，0.79mmol)，接着添加氯甲酸苯酯(75μL，0.59mmol)。在环境温度下搅拌混合物4小时，然后再用一部分氯甲酸苯酯(50μL)处理，并且搅拌18小时。将混合物分配于水(20mL)与EtOAc(10mL)之间并且用EtOAc(2×10mL)萃取水层。用饱和NaHCO3(10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩，得到呈浅黄色胶状的(2',4-二甲基-1-苯基-1H,2'H-[3,3'-联吡唑]-5-基)氨基甲酸苯酯(140mg，95％产率)。MS(apci)m/z＝374.2(M+H)。Step B:Preparation of phenyl (2',4-dimethyl-1-phenyl-1H,2'H-[3,3'-bipyrazol]-5-yl)carbamate : To a solution of 2',4-dimethyl-1-phenyl-1H,2'H-[3,3'-bipyrazol]-5-amine (100 mg, 0.39 mmol) in EtOAc (2 mL) was added 2N NaOH (395 μL, 0.79 mmol) followed by phenyl chloroformate (75 μL, 0.59 mmol). The mixture was stirred at ambient temperature for 4 hours before being treated with an additional portion of phenyl chloroformate (50 μL) and stirred for 18 hours. The mixture was partitioned between water (20 mL) and EtOAc (10 mL) and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with saturated NaHCO3 (10 mL) and brine (10 mL), then dried over Na2 SO4 , filtered, and concentrated in vacuo to afford phenyl (2',4-dimethyl-1-phenyl-1H,2'H-[3,3'-bipyrazol]-5-yl)carbamate (140 mg, 95% yield) as a light yellow gum. MS (apci) m/z=374.2 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(2',4-二甲基-1-苯基-1H,2'H-[3,3'-联吡唑]-5-基)脲：向(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F；68mg，0.21mmol)和(2',4-二甲基-1-苯基-1H,2'H-[3,3'-联吡唑]-5-基)氨基甲酸苯酯(70mg，0.19mmol)在DCM(2mL)中的溶液中添加DIEA(114μL，0.66mmol)。在环境温度下搅拌3小时后，将混合物分配于饱和NH4Cl(20mL)与DCM(20mL)之间并且用DCM(2×10mL)萃取水层。用盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用1％至3％MeOH/DCM洗脱来纯化残余物，得到呈白色固体状的标题化合物(68mg，68％产率)。MS(apci)m/z＝536.2(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2',4-dimethyl-1-phenyl-1H,2'H-[3,3'-bipyrazol]-5-yl)urea : To a solution of (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F; 68 mg, 0.21 mmol) and phenyl (2',4-dimethyl-1-phenyl-1H,2'H-[3,3'-bipyrazol]-5-yl)carbamate (70 mg, 0.19 mmol) in DCM (2 mL) was added DIEA (114 μL, 0.66 mmol). After stirring at ambient temperature for 3 hours, the mixture was partitioned between saturatedNH4Cl (20 mL) and DCM (20 mL), and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic phases were washed with brine (10 mL), then driedoverNa2SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 1% to 3% MeOH/DCM to give the title compound (68 mg, 68% yield) as a white solid. MS (apci) m/z = 536.2 (M+H).
实例495Example 495
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-(5-氟吡1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(5-fluoropyrrolidin-啶-3-基)-1',4-二甲基-1H,1'H-[3,4'-联吡唑]-5-基)脲pyridin-3-yl)-1',4-dimethyl-1H,1'H-[3,4'-bipyrazol-5-yl)urea
步骤A：制备3-(2-(二苯基亚甲基)肼基)-5-氟吡啶：用N2使3-溴-5-氟吡啶(5.0g，28.4mmol)、二苯甲酮腙(6.13g，31.3mmol)和Xantphos(164mg，0.28mmol)的溶液脱气10分钟，然后用叔丁醇钠(3.82g，39.8mmol)和乙酸钯(II)(64mg，0.28mmol)处理。在密封容器中在85℃下搅拌非均质混合物18小时。将冷却的混合物分配于水(100mL)与EtOAc(100mL)之间并且用EtOAc(2×50mL)萃取水层。用盐水(50mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。用Et2O湿磨残余物，过滤并且在真空中干燥，得到呈米色粉末状的3-(2-(二苯基亚甲基)肼基)-5-氟吡啶(6.3g，72％产率)。MS(apci)m/z＝292.1(M+H)。Step A:Preparation of 3-(2-(diphenylmethylene)hydrazinyl)-5-fluoropyridine :A solution of 3-bromo-5-fluoropyridine (5.0 g, 28.4 mmol), benzophenone hydrazone (6.13 g, 31.3 mmol) and Xantphos (164 mg, 0.28 mmol) was degassed with N for 10 minutes, then treated with sodium tert-butoxide (3.82 g, 39.8 mmol) and palladium(II) acetate (64 mg, 0.28 mmol). The heterogeneous mixture was stirred in a sealed vessel at 85° C. for 18 hours. The cooled mixture was partitioned between water (100 mL) and EtOAc (100 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over Na2 SO4 , filtered and concentrated in vacuo. The residue was triturated withEt2O , filtered and dried in vacuo to give 3-(2-(diphenylmethylene)hydrazino)-5-fluoropyridine (6.3 g, 72% yield) as a beige powder. MS (apci) m/z = 292.1 (M+H).
步骤B：制备1-(5-氟吡啶-3-基)-1',4-二甲基-1H,1'H-[3,4'-联吡唑]-5-胺：在密封的小瓶中在80℃下搅拌2-甲基-3-(1-甲基-1H-吡唑-4-基)-3-氧代丙腈(实例491步骤A；100mg，0.61mmol)、3-(2-(二苯基亚甲基)肼基)-5-氟吡啶(162mg，0.56mmol)和一水合对甲苯磺酸(530mg，2.79mmol)在EtOH(3mL)中的溶液18小时。用饱和NaHCO3(30mL)处理冷却的混合物并且用DCM(3×10mL)萃取。用盐水(10mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用1％至3％MeOH/DCM洗脱来纯化残余物，得到呈浅黄色固体状的1-(5-氟吡啶-3-基)-1',4-二甲基-1H,1'H-[3,4'-联吡唑]-5-胺(71mg，47％)。MS(apci)m/z＝273.1(M+H)。[0266] Step B:Preparation of 1-(5-fluoropyridin-3-yl)-1',4-dimethyl-1H,1'H-[3,4'-bipyrazol]-5-amine : A solution of 2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-3-oxopropionitrile (Example 491, Step A; 100 mg, 0.61 mmol), 3-(2-(diphenylmethylene)hydrazino)-5-fluoropyridine (162 mg, 0.56 mmol) and p-toluenesulfonic acid monohydrate (530 mg, 2.79 mmol) in EtOH (3 mL) was stirred in a sealed vial at80 °C for 18 hours. The cooled mixture was treated with saturated NaHCO3 (30 mL) and extracted with DCM (3 x 10 mL). The combined organic phases were washed with brine (10 mL),dried overNa2SO4 , filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 1% to 3% MeOH/DCM to give 1-(5-fluoropyridin-3-yl)-1',4-dimethyl-1H,1'H-[3,4'-bipyrazol]-5-amine (71 mg, 47%) as a pale yellow solid. MS (apci) m/z = 273.1 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-(5-氟吡啶-3-基)-1',4-二甲基-1H,1'H-[3,4'-联吡唑]-5-基)脲：向1-(5-氟吡啶-3-基)-1',4-二甲基-1H,1'H-[3,4'-联吡唑]-5-胺(35mg，0.13mmol)在DCM(2mL)中的溶液中添加三光气(19mg，0.06mmol)，接着添加DIEA(67μL，0.39mmol)。在环境温度下搅拌混合物1小时，然后用(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F；42mg，0.13mmol)和DIEA(67μL，0.39mmol)处理并且继续搅拌18小时。将混合物分配于饱和NH4Cl(20mL)与DCM(20mL)之间并且用DCM(2×10mL)萃取水层。用盐水(10mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2.5％至4％MeOH/DCM洗脱来纯化残余物，得到呈白色固体状的标题化合物(33mg，46％)。MS(apci)m/z＝555.2(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(5-fluoropyridin-3-yl)-1',4-dimethyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea : To a solution of 1-(5-fluoropyridin-3-yl)-1',4-dimethyl-1H,1'H-[3,4'-bipyrazol]-5-amine (35 mg, 0.13 mmol) in DCM (2 mL) was added triphosgene (19 mg, 0.06 mmol) followed by DIEA (67 μL, 0.39 mmol). The mixture was stirred at ambient temperature for 1 hour, then treated with (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F; 42 mg, 0.13 mmol) and DIEA (67 μL, 0.39 mmol) and stirring was continued for 18 hours. The mixture was partitioned between saturated NH4 Cl (20 mL) and DCM (20 mL) and the aqueous layer was extracted with DCM (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2 SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2.5% to 4% MeOH/DCM to give the title compound (33 mg, 46%) as a white solid. MS (apci) m/z=555.2 (M+H).
实例496Example 496
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1',4-二甲1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1',4-dimethyl基-1-(5-甲基吡啶-3-基)-1H,1'H-[3,4'-联吡唑]-5-基)脲1-(5-methylpyridin-3-yl)-1H,1'H-[3,4'-bipyrazole]-5-yl)urea
根据实例495的程序，在步骤A中用3-溴-5-甲基吡啶替代3-溴-5-氟吡啶来制备。通过二氧化硅柱色谱法，用5％至10％MeOH/DCM洗脱来纯化物质，得到呈奶白色固体状的标题化合物(41mg，56％产率)。MS(apci)m/z＝551.2(M+H)。Prepared according to the procedure of Example 495, substituting 3-bromo-5-methylpyridine for 3-bromo-5-fluoropyridine in step A. The material was purified by silica column chromatography eluting with 5% to 10% MeOH/DCM to give the title compound (41 mg, 56% yield) as a creamy white solid. MS (apci) m/z=551.2 (M+H).
实例497Example 497
1-(1-(5-氯吡啶-3-基)-1',4-二甲基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,1-(1-(5-chloropyridin-3-yl)-1',4-dimethyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例495的程序，在步骤A中用3-溴-5-氯吡啶替代3-溴-5-氟吡啶来制备。通过二氧化硅柱色谱法，用2％至5％MeOH/DCM洗脱来纯化物质，得到呈浅粉红色固体状的标题化合物(85mg，86％产率)。MS(apci)m/z＝571.2(M+)。Prepared according to the procedure of Example 495, substituting 3-bromo-5-chloropyridine for 3-bromo-5-fluoropyridine in step A. The material was purified by silica column chromatography eluting with 2% to 5% MeOH/DCM to give the title compound (85 mg, 86% yield) as a light pink solid. MS (apci) m/z=571.2 (M+).
实例498Example 498
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-苯基-1'-(2,2,2-三氟-1-(2,2,2-三氟乙氧基)乙基)-1H,1'H-[3,4'-联吡唑]-5-基)脲Phenyl-1'-(2,2,2-trifluoro-1-(2,2,2-trifluoroethoxy)ethyl)-1H,1'H-[3,4'-bipyrazol-5-yl)urea
步骤A：制备1-(4-甲氧基苯甲基)-1H-吡唑-4-甲酸乙酯：向1H-吡唑-4-甲酸乙酯(3g，21.4mmol)和K2CO3(3.55g，25.7mmol)在DMF(10mL)中的混合物中添加1-(氯甲基)-4-甲氧基苯(3.50mL，25.7mmol)。在环境温度下搅拌反应物18小时，然后添加乙醚(30mL)和水(10mL)。分离有机层，用盐水洗涤，经Na2SO4干燥并且在真空中浓缩。通过二氧化硅柱色谱法，用3:1己烷/EtOAc洗脱来纯化残余物，得到呈无色油状的1-(4-甲氧基苯甲基)-1H-吡唑-4-甲酸乙酯(5.7g，102％)。1H NMR(CDCl3)δ7.92(m,1H),7.80(m,1H),7.21(m,2H),6.89(m,2H),5.23(s,2H),4.27(m,2H),3.80(s,3H),1.32(m,3H)ppm。[0266] Step A:Preparation of ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate : To a mixture of ethyl 1H-pyrazole- 4-carboxylate (3 g, 21.4 mmol) andK2CO3 (3.55 g, 25.7 mmol) in DMF (10 mL) was added 1-(chloromethyl)-4-methoxybenzene (3.50 mL, 25.7 mmol). The reaction was stirred at ambient temperature for 18 hours, then diethyl ether (30 mL) and water (10 mL) were added. The organic layer was separated, washed with brine, driedoverNa2SO4 , and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 3:1 hexanes/EtOAc to give ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (5.7 g, 102%) as a colorless oil.1 H NMR (CDCl3 ) δ7.92(m,1H),7.80(m,1H),7.21(m,2H),6.89(m,2H),5.23(s,2H),4.27(m,2H),3.80(s,3H),1.32(m,3H)ppm.
步骤B：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-(4-甲氧基苯甲基)-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲：根据实例494的程序，在步骤A中用1-(4-甲氧基苯甲基)-1H-吡唑-4-甲酸乙酯替代1-甲基-1H-吡唑-5-甲酸乙酯来制备。通过二氧化硅柱色谱法，用1:1至1:1.2己烷/丙酮加上0.5％NH4OH洗脱来纯化物质，得到呈白色固体状的1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-(4-甲氧基苯甲基)-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲(800mg，60％产率)。MS(apci)m/z＝642.3(M+H)。Step B:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea : Prepared according to the procedure of Example 494, substituting 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid ethyl ester for 1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester in Step A. The material was purified by silica column chromatography eluting with 1:1 to 1:1.2 hexanes/acetone plus 0.5%NH4OH to afford 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea (800 mg, 60% yield) as a white solid. MS (apci) m/z = 642.3 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲：将1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-(4-甲氧基苯甲基)-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲(241mg，0.38mmol)与TFA(2mL)合并在密封管中并且在70℃下搅拌18小时。在真空中浓缩冷却的混合物并且将残余物分配于1N NaOH(20mL)与DCM(10mL)之间。用DCM(2×10mL)萃取水层并且用饱和NaHCO3(10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2％至5％MeOH/DCM洗脱来纯化残余物，得到呈白色固体状的1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲(144mg，74％产率)。MS(apci)m/z＝522.2(M+)。[0266] Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3- (4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea: 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea (241 mg, 0.38 mmol) was combined with TFA (2 mL) in a sealed tube and stirred at 70°C for 18 hours. The cooled mixture was concentrated in vacuo and the residue was partitioned between 1 N NaOH (20 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (2×10 mL) and the combined organic phases were washed with saturated NaHCO3 (10 mL) and brine (10 mL), then dried over Na2 SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2% to 5% MeOH/DCM to afford 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazole]-5-yl)urea (144 mg, 74% yield) as a white solid. MS (apci) m/z=522.2 (M+).
步骤D：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-1'-(2,2,2-三氟-1-(2,2,2-三氟-乙氧基)乙基)-1H,1'H-[3,4'-联吡唑]-5-基)脲：在-78℃下向1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲(50mg，0.10mmol)在DMF(2.5mL)中的溶液中添加叔丁醇钾(264μL，1M/THF，0.264mmol)。搅拌混合物10分钟，然后用三氟甲磺酸2,2,2-三氟乙酯(13.1μL，0.09mmol)处理。在环境温度下搅拌2小时后，将混合物分配于饱和NH4Cl(20mL)与EtOAc(10mL)之间并且用EtOAc(2×10mL)萃取水层。用水(2×10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2.5％MeOH/DCM洗脱来纯化残余物，得到呈无色玻璃状的标题化合物(29mg，43％产率)。MS(apci)m/z＝702.2(M+H)。Step D:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1'-(2,2,2-trifluoro-1-(2,2,2-trifluoro-ethoxy)ethyl)-1H,1'H-[3,4'-bipyrazol]-5-yl) urea: To a solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea (50 mg, 0.10 mmol) in DMF (2.5 mL) was added potassium tert-butoxide (264 μL, 1 M/THF, 0.264 mmol) at -78 °C. The mixture was stirred for 10 minutes and then treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate (13.1 μL, 0.09 mmol). After stirring at ambient temperature for 2 hours, the mixture was partitioned between saturated NH4 Cl (20 mL) and EtOAc (10 mL) and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic phases were washed with water (2×10 mL) and brine (10 mL), then dried over Na2 SO4 , filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2.5% MeOH/DCM to give the title compound (29 mg, 43% yield) as a colorless glass. MS (apci) m/z=702.2 (M+H).
实例499Example 499
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-苯基-1'-(2,2,2-三氟乙基)-1H,1'H-[3,4'-联吡唑]-5-基)脲Phenyl-1'-(2,2,2-trifluoroethyl)-1H,1'H-[3,4'-bipyrazol-5-yl)urea
向1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲(实例498步骤C；20mg，0.04mmol)在DMF(0.5mL)中的溶液中添加K2CO3(16mg，0.12mmol)，接着添加三氟甲磺酸三氟乙酯(6μL，0.04mmol)。密封混合物并且在环境温度下搅拌5小时。再添加一部分三氟甲磺酸三氟乙酯(30μL)并且继续搅拌18小时。将混合物分配于水(10mL)与EtOAc(10mL)之间并且用EtOAc(2×10mL)萃取水层。用水(4×10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2％至5％MeOH/DCM洗脱来纯化残余物，得到呈无色玻璃状的标题化合物(8mg，35％产率)。MS(apci)m/z＝604.2(M+H)。To a solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea (Example 498, Step C; 20 mg, 0.04 mmol) in DMF (0.5 mL) was addedK2CO3 (16mg , 0.12 mmol) followed by trifluoroethyl triflate (6 μL, 0.04 mmol). The mixture was sealed and stirred at ambient temperature for 5 hours. An additional portion of trifluoroethyl triflate (30 μL) was added and stirring continued for 18 hours. The mixture was partitioned between water (10 mL) and EtOAc (10 mL) and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with water (4 x 10 mL) and brine (10 mL), then driedoverNa2SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2% to 5% MeOH/DCM to afford the title compound (8 mg, 35% yield) as a colorless glass. MS (apci) m/z = 604.2 (M+H).
实例500Instance 500
1-(1'-(环丙基甲基)-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,1-(1'-(cyclopropylmethyl)-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例499的程序，用(溴甲基)环丙烷替代三氟甲磺酸三氟乙酯来制备。通过二氧化硅柱色谱法，用2.5％至5％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(16mg，31％产率)。MS(apci)m/z＝576.3(M+H)。Prepared according to the procedure of Example 499, substituting (bromomethyl)cyclopropane for trifluoroethyl trifluoromethanesulfonate. The material was purified by silica column chromatography eluting with 2.5% to 5% MeOH/DCM to give the title compound (16 mg, 31% yield) as a white solid. MS (apci) m/z=576.3 (M+H).
实例501Example 501
1-(1'-(环丙烷羰基)-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,1-(1'-(cyclopropanecarbonyl)-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
在0℃下向1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲(实例498步骤C；50mg，0.09mmol)在DCM(2mL)中的溶液中添加环丙基羰基氯(13μL，0.14mmol)，接着添加DIEA(67μL，0.38mmol)。允许混合物经18小时缓慢升温至环境温度，然后将其分配于饱和NaHCO3(20mL)与DCM(10mL)之间并且用DCM(2×10mL)萃取水层。用盐水(10mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2.5％MeOH/DCM洗脱来纯化残余物，得到呈白色固体状的标题化合物(26mg，46％产率)。MS(apci)m/z＝590.2(M+H)。To a solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea (Example 498, Step C; 50 mg, 0.09 mmol) in DCM (2 mL) was added cyclopropylcarbonyl chloride (13 μL, 0.14 mmol) followed by DIEA (67 μL, 0.38 mmol) at 0°C. The mixture was allowed to slowly warm to ambient temperature over 18 hours before being partitioned between saturated NaHCO3 (20 mL) and DCM (10 mL) and the aqueous layer extracted with DCM (2×10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2 SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2.5% MeOH/DCM to give the title compound as a white solid (26 mg, 46% yield).MS (apci) m/z=590.2 (M+H).
实例502Example 502
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1'-(甲基磺酰基)-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲1'-(Methylsulfonyl)-1-phenyl-1H,1'H-[3,4'-bipyrazol-5-yl)urea
根据实例501的程序，用甲磺酰氯替代环丙基羰基氯来制备。通过二氧化硅柱色谱法，用2％至5％MeOH/DCM洗脱来纯化物质，得到呈无色玻璃状的标题化合物(39mg，68％产率)。MS(apci)m/z＝600.2(M+H)。Prepared according to the procedure of Example 501, substituting methanesulfonyl chloride for cyclopropylcarbonyl chloride. Purify the material by silica column chromatography eluting with 2% to 5% MeOH/DCM to give the title compound (39 mg, 68% yield) as a colorless glass. MS (apci) m/z = 600.2 (M+H).
实例503Example 503
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-异丙1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-isopropyl基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲4-Methyl-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)urea
步骤A：制备3-溴-4-甲基-1-苯基-1H-吡唑-5-胺：向5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮(中间体P135步骤A；1.60g，8.46mmol)在乙腈(30mL)中的悬浮液中一次性添加氧溴化磷(3.64g，12.7mmol)。在回流下搅拌混合物3小时，然后冷却并且在真空中浓缩。用DCM(50mL)处理残余物，然后缓慢添加饱和NaHCO3(50mL)。搅拌混合物30分钟，然后分离各层并且用DCM(2×50mL)萃取水层。用盐水(20mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2:1己烷/EtOAc洗脱来纯化残余物，得到呈白色固体状的3-溴-4-甲基-1-苯基-1H-吡唑-5-胺(273mg，13％产率)。MS(apci)m/z＝254.0(M+H)。[0266] Step A:Preparation of 3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine : To a suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate P135, Step A; 1.60 g, 8.46 mmol) in acetonitrile (30 mL) was added phosphorus oxybromide (3.64 g, 12.7 mmol) in one portion. The mixture was stirred at reflux for 3 hours, then cooled and concentrated in vacuo. The residue was treated with DCM (50 mL), then saturatedNaHCO₃ (50 mL) was slowly added. The mixture was stirred for 30 minutes, then the layers were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine (20 mL),dried overNa₂SO₄ , filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2:1 hexanes/EtOAc to give 3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine (273 mg, 13% yield) as a white solid. MS (apci) m/z = 254.0 (M+H).
步骤B：制备(3-溴-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯：向3-溴-4-甲基-1-苯基-1H-吡唑-5-胺(339mg，1.34mmol)在EtOAc(10mL)中的溶液中添加2N NaOH(2mL，4.0mmol)，接着添加氯甲酸苯酯(337μL，2.69mmol)。在环境温度下搅拌混合物5小时，然后将其分配于水(30mL)与EtOAc(30mL)之间并且用EtOAc(2×20mL)萃取水层。用饱和NaHCO3(30mL)和盐水(30mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩，得到(3-溴-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯，其在假定定量产率的情况下直接供使用。MS(apci)m/z＝374.0(M+H)。Step B:Preparation of phenyl (3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate : To a solution of 3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine (339 mg, 1.34 mmol) in EtOAc (10 mL) was added 2N NaOH (2 mL, 4.0 mmol) followed by phenyl chloroformate (337 μL, 2.69 mmol). The mixture was stirred at ambient temperature for 5 hours, then partitioned between water (30 mL) and EtOAc (30 mL) and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with saturatedNaHCO₃ (30 mL) and brine (30 mL) , then dried overNa₂SO₄ , filtered, and concentrated in vacuo to afford phenyl (3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate, which was used directly assuming quantitative yield. MS (apci) m/z = 374.0 (M+H).
步骤C：制备1-(3-溴-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：向(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F；464mg，1.41mmol)和(3-溴-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯(500mg，1.34mmol)在DCM(10mL)中的溶液中添加DIEA(819μL，4.7mmol)。在环境温度下搅拌溶液18小时，然后将其分配于饱和NH4Cl(30mL)与DCM(30mL)之间并且用DCM(2×20mL)萃取水层。用盐水(20mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2％MeOH/DCM洗脱来纯化残余物，得到呈白色固体状的1-(3-溴-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(483mg，67％产率)。MS(apci)m/z＝534.1(M+)。[0266] Step C:Preparation of 1-(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl )-1-(2-methoxyethyl)pyrrolidin-3-yl)urea: To a solution of (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F; 464 mg, 1.41 mmol) and phenyl (3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate (500 mg, 1.34 mmol) in DCM (10 mL) was added DIEA (819 μL, 4.7 mmol). The solution was stirred at ambient temperature for 18 hours then partitioned between saturatedNH4Cl (30 mL) and DCM (30 mL) and the aqueous layer extracted with DCM (2 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2 SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2% MeOH/DCM to afford 1-(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (483 mg, 67% yield) as a white solid. MS (apci) m/z=534.1 (M+).
步骤D：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-异丙基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲：将1-(3-溴-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(30mg，0.06mmol)、1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)-1H-吡唑(20mg，0.08mmol)、三环己基膦(3mg，0.01mmol)与Pd2(dba)3(5mg，0.006mmol)合并在密封管中并且添加1,4-二噁烷(561μL)。用N2吹洗溶液30秒，然后用K3PO4(130μL，1.3M，0.17mmol)处理，密封并且在100℃下搅拌1小时。在真空中浓缩冷却的混合物并且通过二氧化硅柱色谱法用2.5％至10％MeOH/DCM洗脱来纯化残余物，得到呈无色玻璃状的标题化合物(12mg，38％产率)。MS(apci)m/z＝564.2(M+H)。Step D:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-isopropyl-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea : 1-(3-Bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (30 mg, 0.06 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20 mg, 0.08 mmol), tricyclohexylphosphine (3 mg, 0.01 mmol) andPd2 (dba) were reacted.3 (5 mg, 0.006 mmol) were combined in a sealed tube and 1,4- dioxane (561 μL) was added. The solution was purged withN2 for 30 seconds, then treated withK3PO4 (130 μL, 1.3 M, 0.17 mmol), sealed and stirred at 100 ° C for 1 hour. The cooled mixture was concentrated in vacuo and the residue was purified by silica column chromatography eluting with 2.5% to 10% MeOH/DCM to give the title compound (12 mg, 38% yield) as a colorless glass. MS (apci) m/z=564.2 (M+H).
根据实例503的方法，在步骤D中用适当的试剂替代1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)-1H-吡唑来制备下列化合物。The following compounds were prepared according to the procedure of Example 503 by substituting the appropriate reagent for 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step D.
实例516Example 516
1-(3-溴-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧1-(3-Bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxy基乙基)吡咯烷-3-基)脲(2-(2-ethyl)pyrrolidin-3-yl)urea
根据实例503步骤C的程序，用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备K)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用2％至3％MeOH/DCM洗脱来纯化物质，得到呈奶白色固体状的标题化合物(526mg，63％)。MS(apci)m/z＝518.1(M+H)。Prepared according to the procedure of Example 503, Step C, substituting (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation K) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F). The material was purified by silica column chromatography eluting with 2% to 3% MeOH/DCM to give the title compound (526 mg, 63%) as a creamy white solid. MS (apci) m/z = 518.1 (M+H).
实例517Example 517
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(6-氧代基-1-(2,2,2-三氟乙基)-1,6-二氢吡啶-3-基)-1-苯基-1H-吡唑-5-基)脲(6-Oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea
根据实例503的程序，在步骤D中用5-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)-1-(2,2,2-三氟乙基)吡啶-2(1H)酮替代1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)-1H-吡唑来制备。通过二氧化硅柱色谱法，用2％MeOH/DCM洗脱来纯化物质，接着进行反相HPLC纯化(5％至95％ACN/水/0.5％TFA，经20分钟)。在水性处理(1N NaOH/DCM)后得到呈白色固体状的标题化合物(5.5mg，9％产率)。MS(apci)m/z＝631.2(M+H)。Prepared according to the procedure of Example 503, using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)one instead of 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step D. The material was purified by silica column chromatography eluting with 2% MeOH/DCM, followed by reverse phase HPLC purification (5% to 95% ACN/water/0.5% TFA over 20 minutes). The title compound (5.5 mg, 9% yield) was obtained as a white solid after aqueous workup (1N NaOH/DCM). MS (apci) m/z=631.2 (M+H).
实例518Example 518
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-异丙基-4-1-((3S,4R)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-isopropyl-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲Methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol-5-yl)urea
根据实例503的程序，在步骤C中用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备K)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用2％至3％MeOH/DCM洗脱来纯化物质，接着进行反相HPLC纯化(5％至95％ACN/水/0.5％TFA，经20分钟)。在水性处理(1N NaOH/DCM)后得到呈无色胶状的标题化合物(37mg，18％产率)。MS(apci)m/z＝546.3(M+H)。Prepared according to the procedure of Example 503, substituting (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation K) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in Step C. The material was purified by silica column chromatography eluting with 2% to 3% MeOH/DCM, followed by reverse phase HPLC purification (5% to 95% ACN/water/0.5% TFA over 20 minutes). After aqueous workup (1N NaOH/DCM), the title compound (37 mg, 18% yield) was obtained as a colorless gum. MS (apci) m/z=546.3 (M+H).
实例519Example 519
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-(1-1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-甲基-6-氧代基-1,6-二氢吡啶-3-基)-1-苯基-1H-吡唑-5-基)脲(methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea
根据实例518的程序，在步骤D中用1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)吡啶-2(1H)-酮替代1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)-1H-吡唑来制备。通过二氧化硅柱色谱法，用2％至5％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题产物(29mg，27％产率)。MS(apci)m/z＝545.2(M+H)。Prepared according to the procedure of Example 518, substituting 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one for 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step D. The material was purified by silica column chromatography eluting with 2% to 5% MeOH/DCM to give the title product (29 mg, 27% yield) as a white solid. MS (apci) m/z=545.2 (M+H).
实例520Example 520
1-(3-溴-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3R,4S)-4-苯基-1-(2,2,2-三氟乙1-(3-Bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)基)吡咯烷-3-基)脲1-[4-(2-Yl)pyrrolidin-3-yl)urea
根据实例516的程序，用(3R,4S)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-胺盐酸盐(实例265步骤A)替代(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备K)来制备。通过二氧化硅柱色谱法，用2:1己烷/EtOAc洗脱来纯化物质，得到呈白色固体状的标题化合物(173mg，62％产率)。MS(apci)m/z＝522.1(M+)。Prepared according to the procedure of Example 516, substituting (3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine hydrochloride (Example 265, Step A) for (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation K). The material was purified by silica column chromatography eluting with 2:1 hexanes/EtOAc to give the title compound (173 mg, 62% yield) as a white solid. MS (apci) m/z=522.1 (M+).
实例521Example 521
1-(4-甲基-3-(1-甲基-6-氧代基-1,6-二氢吡啶-3-基)-1-苯基-1H-吡唑-5-基)-1-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea
根据实例519的程序，在步骤C中用(3R,4S)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-胺盐酸盐(实例265步骤A)替代(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备K)来制备。通过二氧化硅柱色谱法，用2％MeOH/DCM洗脱来纯化物质，得到呈浅黄色固体状的标题产物(28mg，33％产率)。MS(apci)m/z＝550.2(M+)。Prepared according to the procedure of Example 519, substituting (3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-amine hydrochloride (Example 265, Step A) for (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation K) in Step C. The material was purified by silica column chromatography eluting with 2% MeOH/DCM to give the title product (28 mg, 33% yield) as a light yellow solid. MS (apci) m/z=550.2 (M+).
实例522Example 522
1-(3-(2-氨基嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3R,4S)-4-苯基-1-(3-(2-aminopyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-三氟乙基)吡咯烷-3-基)脲双(2,2,2-三氟乙酸盐)1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea bis(2,2,2-trifluoroacetate)
根据实例512的程序，在步骤C中用(3R,4S)-4-苯基-1-(2,2,2-三氟乙基)吡咯烷-3-胺盐酸盐(实例265步骤A)替代(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备K)来制备。通过二氧化硅柱色谱法，用2％至5％MeOH/DCM洗脱来纯化物质，接着进行反相HPLC纯化(5％至95％ACN/水/0.5％TFA，经20分钟)。得到呈白色固体状的呈二TFA盐形式的标题化合物(3mg，3％产率)。MS(apci)m/z＝537.2(M+H)。Prepared according to the procedure of Example 512, (3R, 4S) -4-phenyl -1- (2,2,2- trifluoroethyl) pyrrolidin-3-amine hydrochloride (Example 265, Step A) was substituted for (3S, 4R) -4- (4-fluorophenyl) -1- (2-methoxyethyl) pyrrolidin-3-amine dihydrochloride (Preparation K) in Step C. The material was purified by silica column chromatography eluting with 2% to 5% MeOH / DCM, followed by reverse phase HPLC purification (5% to 95% ACN / water / 0.5% TFA over 20 minutes). The title compound was obtained as a di-TFA salt as a white solid (3 mg, 3% yield). MS (apci) m / z = 537.2 (M + H).
实例523Example 523
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-乙基-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-ethyl-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲4-Methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol-5-yl)urea
步骤A：制备1'-乙基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-胺：将3-溴-4-甲基-1-苯基-1H-吡唑-5-胺(实例503步骤A；100mg，0.39mmol)、1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)-1H-吡唑(176mg，0.79mmol)、K2CO3(219mg，1.59mmol)与Pd(PPh3)4(46mg，0.039mmol)合并在甲苯(2mL)、水(1mL)和EtOH(0.5mL)中并且在密封管中在95℃下搅拌18小时。通过GF滤纸过滤冷却的混合物并且将滤液分配于水(10mL)与EtOAc(10mL)之间。用EtOAc(2×10mL)萃取水层并且用盐水(10mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用1.5％MeOH/DCM洗脱来纯化残余物，得到呈无色胶状的1'-乙基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-胺(78mg，74％产率)。MS(apci)m/z＝268.1(M+H)。[0266] Step A:Preparation of 1'-ethyl-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-amine : 3-Bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine (Example 503, Step A; 100 mg, 0.39 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (176 mg, 0.79 mmol),K2CO3 (219 mg, 1.59 mmol) and Pd(PPh3 )4 (46 mg, 0.039 mmol) were combined in toluene (2 mL), water (1 mL) and EtOH (0.5 mL) and stirred in a sealed tube at 95°C for 18 hours. The cooled mixture was filtered through GF filter paper and the filtrate was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine (10mL ), dried overNa2SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 1.5% MeOH/DCM to afford 1'-ethyl-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazolyl]-5-amine (78 mg, 74% yield) as a colorless gum. MS (apci) m/z = 268.1 (M+H).
步骤B：制备(1'-乙基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)氨基甲酸苯酯：向1'-乙基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-胺(78mg，0.29mmol)在EtOAc(5mL)中的溶液中添加2N NaOH(0.44mL，0.87mmol)，接着添加氯甲酸苯酯(73μL，0.58mmol)。在环境温度下搅拌混合物18小时，然后将其分配于水(20mL)与EtOAc(20mL)之间并且用EtOAc(2×10mL)萃取水层。用饱和NaHCO3(10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩，得到呈浅黄色油状的(1'-乙基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)氨基甲酸苯酯。其在假定定量产率的情况下直接供使用。MS(apci)m/z＝388.2(M+H)。Step B:Preparation of phenyl (1'-ethyl-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)carbamate: To a solution of 1'-ethyl-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-amine (78 mg, 0.29 mmol) in EtOAc (5 mL) was added 2N NaOH (0.44 mL, 0.87 mmol) followed by phenyl chloroformate (73 μL, 0.58 mmol). The mixture was stirred at ambient temperature for 18 hours then partitioned between water (20 mL) and EtOAc (20 mL) and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with saturatedNaHCO₃ (10 mL) and brine (10 mL), then driedoverNa₂SO₄ , filtered, and concentrated in vacuo to afford phenyl (1′-ethyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)carbamate as a light yellow oil. It was used directly assuming quantitative yield. MS (apci) m/z = 388.2 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-乙基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)脲：向(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F；56mg，0.17mmol)和(1'-乙基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)氨基甲酸苯酯(66mg，0.17mmol)在DCM(2mL)中的溶液中添加DIEA(150μL，0.85mmol)。在环境温度下搅拌18小时后，将混合物分配于饱和NH4Cl(10mL)与DCM(10mL)之间并且用DCM(2×10mL)萃取水层。用盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2.5％至3.5％MeOH/DCM洗脱来纯化残余物，得到呈无色玻璃状的标题化合物(35mg，37％产率)。MS(apci)m/z＝550.2(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-ethyl-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)urea : To a solution of (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F; 56 mg, 0.17 mmol) and phenyl (1'-ethyl-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)carbamate (66 mg, 0.17 mmol) in DCM (2 mL) was added DIEA (150 μL, 0.85 mmol). After stirring at ambient temperature for 18 hours, the mixture was partitioned between saturatedNH4Cl (10 mL) and DCM (10 mL), and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic phases were washed with brine (10 mL), then driedoverNa2SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2.5% to 3.5% MeOH/DCM to give the title compound (35 mg, 37% yield) as a colorless glass. MS (apci) m/z = 550.2 (M+H).
实例524Example 524
1-(1'-乙基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(4-1-(1'-ethyl-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(2-(2-(2-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea)
根据实例523的程序，在步骤C中用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备K)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用3％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题产物(29mg，30％产率)。MS(apci)m/z＝532.3(M+H)。Prepared according to the procedure of Example 523, substituting (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation K) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in Step C. The material was purified by silica column chromatography eluting with 3% MeOH/DCM to give the title product (29 mg, 30% yield) as a white solid. MS (apci) m/z=532.3 (M+H).
实例525Example 525
5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl基-1-苯基-1H-吡唑-3-基三氟甲磺酸酯1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate
步骤A：制备5-氨基-4-甲基-1-苯基-1H-吡唑-3-基三氟甲磺酸酯：用DIEA(1.38mL，7.93mmol)处理5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮(中间体P135步骤A；0.50g，2.64mmol)和N-苯基双(三氟甲基磺酰胺)(0.99g，2.77mmol)在DMF(5mL)中的悬浮液并且在环境温度下搅拌混合物64小时。将混合物分配于饱和NaHCO3(30mL)与EtOAc(30mL)之间并且用EtOAc(2×20mL)萃取水层。用水(5×10mL)和盐水(10mL)洗涤合并的有机相，然后经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用2:1己烷/EtOAc洗脱)来纯化残余物，得到呈浅黄色油状的5-氨基-4-甲基-1-苯基-1H-吡唑-3-基三氟甲磺酸酯(817mg，92％产率)。MS(apci)m/z＝322.0(M+H)。[0266] Step A:Preparation of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate : A suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Intermediate P135, Step A; 0.50 g, 2.64 mmol) and N-phenylbis(trifluoromethylsulfonamide) (0.99 g, 2.77 mmol) in DMF (5 mL) was treated with DIEA (1.38 mL, 7.93 mmol) and the mixture was stirred at ambient temperature for 64 hours. The mixture was partitioned between saturatedNaHCO₃ (30 mL) and EtOAc (30 mL) and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (5 x 10 mL) and brine (10 mL), then dried overNa₂SO₄ ,filtered , and concentrated in vacuo. The residue was purified by silica column chromatography (eluting with 2:1 hexanes/EtOAc) to give 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate (817 mg, 92% yield) as a pale yellow oil. MS (apci) m/z = 322.0 (M+H).
步骤B：制备4-甲基-5-((苯氧基羰基)氨基)-1-苯基-1H-吡唑-3-基三氟甲磺酸酯：根据实例503步骤B的程序，用5-氨基-4-甲基-1-苯基-1H-吡唑-3-基三氟甲磺酸酯替代3-溴-4-甲基-1-苯基-1H-吡唑-5-胺来制备。MS(apci)m/z＝442.0(M+H)。Step B:Preparation of 4-methyl-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate: Prepared according to the procedure of Example 503, Step B, substituting 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate for 3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine. MS (apci) m/z = 442.0 (M+H).
步骤C：制备5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-基三氟甲磺酸酯：根据实例503步骤C的程序，用4-甲基-5-((苯氧基羰基)氨基)-1-苯基-1H-吡唑-3-基三氟甲磺酸酯替代(3-溴-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯来制备。通过二氧化硅柱色谱法，用1.5％至4％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(191mg，62％产率)。MS(apci)m/z＝604.2(M+H)。Step C: Preparation of 5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate: Prepared according to the procedure of Example 503, Step C, substituting 4-methyl-5-((phenoxycarbonyl)amino)-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate for phenyl (3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate. The material was purified by silica column chromatography eluting with 1.5% to 4% MeOH/DCM to give the title compound (191 mg, 62% yield) as a white solid. MS (apci) m/z=604.2 (M+H).
实例526Example 526
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(2-甲氧1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxy)基嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(5-pyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备3-(2-甲氧基嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-胺：将5-氨基-4-甲基-1-苯基-1H-吡唑-3-基三氟甲磺酸酯(实例525步骤A；200mg，0.62mmol)、2-甲氧基嘧啶-5-基硼酸(192mg，1.25mmol)、K2CO3(344mg，2.49mmol)与Pd(PPh3)4(72mg，0.06mmol)合并在甲苯(2mL)、水(1mL)和EtOH(0.5mL)中并且在密封管中在95℃下搅拌18小时。通过GF滤纸过滤冷却的混合物并且将滤液分配于水(20mL)与EtOAc(20mL)之间。用EtOAc(2×20mL)萃取水层并且用盐水(20mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用1％MeOH/DCM洗脱来纯化残余物，得到呈奶白色泡沫状的3-(2-甲氧基嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-胺(138mg，79％产率)。MS(apci)m/z＝282.1(M+H)。[0266] Step A:Preparation of 3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine : 5-Amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate (Example 525, Step A; 200 mg, 0.62 mmol), 2-methoxypyrimidin-5-ylboronicacid (192 mg, 1.25 mmol),K2CO3 (344 mg, 2.49 mmol) and Pd(PPh3 )4 (72 mg, 0.06 mmol) were combined in toluene (2 mL), water (1 mL) and EtOH (0.5 mL) and stirred in a sealed tube at 95°C for 18 hours. The cooled mixture was filtered through GF filter paper and the filtrate was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic phases were washed with brine (20mL ), dried overNa2SO4 , filtered, and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 1% MeOH/DCM to afford 3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine (138 mg, 79% yield) as a creamy white foam. MS (apci) m/z = 282.1 (M+H).
步骤B：制备(3-(2-甲氧基嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯：根据实例503步骤B的程序，用3-(2-甲氧基嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-胺替代3-溴-4-甲基-1-苯基-1H-吡唑-5-胺来制备。通过二氧化硅柱色谱法，用1％MeOH/DCM洗脱来纯化物质，得到呈奶白色泡沫状的(3-(2-甲氧基嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯(92mg，47％产率)。MS(apci)m/z＝402.1(M+H)。Step B:Preparation of phenyl (3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate: Prepared according to the procedure of Example 503, Step B, substituting 3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine for 3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine. The material was purified by silica column chromatography eluting with 1% MeOH/DCM to give phenyl (3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate (92 mg, 47% yield) as a creamy white foam. MS (apci) m/z = 402.1 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(2-甲氧基嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：根据实例503步骤C的程序，用(3-(2-甲氧基嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯替代(3-溴-4-甲基-1-苯基-1H-吡唑-5-基)氨基甲酸苯酯来制备。通过二氧化硅柱色谱法，用2.5％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(31mg，48％产率)。MS(apci)m/z＝564.2(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : Prepared according to the procedure of Example 503, Step C, substituting phenyl (3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate for phenyl (3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)carbamate. The material was purified by silica column chromatography eluting with 2.5% MeOH/DCM to give the title compound (31 mg, 48% yield) as a white solid. MS (apci) m/z=564.2 (M+H).
实例527Example 527
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(2-(二1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-甲基氨基)嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(methylamino)pyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据实例526的程序，在步骤A中用N,N-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)嘧啶-2-胺替代2-甲氧基嘧啶-5-基硼酸来制备。通过二氧化硅柱色谱法，用3％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(22mg，32％产率)。MS(apci)m/z＝577.3(M+H)。Prepared according to the procedure of Example 526, substituting N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine for 2-methoxypyrimidin-5-ylboronic acid in Step A. The material was purified by silica column chromatography eluting with 3% MeOH/DCM to give the title compound (22 mg, 32% yield) as a white solid. MS (apci) m/z=577.3 (M+H).
实例528Example 528
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(2-甲氧基嘧1-((3S,4R)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxypyrimidine)啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(4-(2-pyridin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据实例526的程序，在步骤C中用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(2S,3S)-2,3-双((4-甲基苯甲酰基)氧基)琥珀酸盐(制备L1步骤A至D)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用3％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(32mg，51％产率)。MS(apci)m/z＝546.2(M+H)。Prepared according to the procedure of Example 526, using (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (Preparation L1, Steps A to D) instead of (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in Step C. The material was purified by silica column chromatography eluting with 3% MeOH/DCM to give the title compound (32 mg, 51% yield) as a white solid. MS (apci) m/z=546.2 (M+H).
实例529Example 529
1-(3-(2-(二甲基氨基)嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,1-(3-(2-(dimethylamino)pyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4R)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据实例527的程序，在步骤C中用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备K)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用3％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(27mg，40％产率)。MS(apci)m/z＝559.3(M+H)。Prepared according to the procedure of Example 527, substituting (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation K) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in Step C. The material was purified by silica column chromatography eluting with 3% MeOH/DCM to give the title compound (27 mg, 40% yield) as a white solid. MS (apci) m/z=559.3 (M+H).
实例530Example 530
1-(1'-乙基-4-甲基-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(3-1-(1'-ethyl-4-methyl-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(2-(2-(2-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea)
根据实例526的程序，在步骤A中用1-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)-1H-吡唑替代2-甲氧基嘧啶-5-基硼酸，并且在步骤C中用(3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备L11)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用3％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(39mg，57％产率)。MS(apci)m/z＝532.3(M+H)。Prepared according to the procedure of Example 526, substituting 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 2-methoxypyrimidin-5-ylboronic acid in Step A and substituting (3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation L11) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in Step C. The material was purified by silica column chromatography eluting with 3% MeOH/DCM to give the title compound (39 mg, 57% yield) as a white solid. MS (apci) m/z=532.3 (M+H).
实例531Example 531
1-((3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-(1-1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-甲基-2-氧代基-1,2-二氢吡啶-4-基)-1-苯基-1H-吡唑-5-基)脲(methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea
根据实例526的程序，在步骤A中用1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)吡啶-2(1H)-酮替代2-甲氧基嘧啶-5-基硼酸，并且在步骤C中用(3S,4R)-4-(3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备L1)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用3％至8％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(38mg，54％产率)。MS(apci)m/z＝545.2(M+H)。Prepared according to the procedure of Example 526, substituting 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one for 2-methoxypyrimidin-5-ylboronic acid in step A, and substituting (3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation L1) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in step C. The material was purified by silica column chromatography eluting with 3% to 8% MeOH/DCM to give the title compound (38 mg, 54% yield) as a white solid. MS (apci) m/z=545.2 (M+H).
实例532Example 532
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-(1-1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-甲基-2-氧代基-1,2-二氢吡啶-4-基)-1-苯基-1H-吡唑-5-基)脲(methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea
根据实例526的程序，在步骤A中用1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)吡啶-2(1H)-酮替代2-甲氧基嘧啶-5-基硼酸，并且在步骤C中用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(2S,3S)-2,3-双((4-甲基苯甲酰基)氧基)琥珀酸盐(制备L1步骤A至D)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用3％至8％MeOH/DCM洗脱来纯化物质，得到呈白色固体状的标题化合物(34mg，49％产率)。MS(apci)m/z＝545.3(M+H)。Prepared according to the procedure of Example 526, substituting 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one for 2-methoxypyrimidin-5-ylboronic acid in Step A and (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (Preparation L1, Steps A to D) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in Step C. The material was purified by silica column chromatography eluting with 3% to 8% MeOH/DCM to give the title compound (34 mg, 49% yield) as a white solid. MS (apci) m/z = 545.3 (M+H).
实例533Example 533
1-(3-环丙基-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
步骤A：制备3-环丙基-4-甲基-1-苯基-1H-吡唑-5-胺：用氩气使密封管中5-氨基-4-甲基-1-苯基-1H-吡唑-3-基三氟甲磺酸酯(实例525步骤A；200mg，0.62mmol)在甲苯:水(10:1，5.5mL)中的悬浮液脱气5分钟。然后添加环丙基三氟硼酸钾(368mg，2.49mmol)、Pd(OAc)2(21mg，0.09mmol)和K3PO4(396mg，1.87mmol)，接着添加二环己基(2',6'-二异丙基联苯-2-基)膦(87mg，0.19mmol)。再用氩气使混合物脱气5分钟，然后密封并且在110℃下搅拌18小时。用水(30mL)稀释冷却的混合物并且用EtOAc(3×20mL)萃取。用盐水(20mL)洗涤合并的有机相，经Na2SO4干燥，过滤并且在真空中浓缩。通过二氧化硅柱色谱法，用1％MeOH/DCM洗脱来纯化残余物，得到呈黄色油状的3-环丙基-4-甲基-1-苯基-1H-吡唑-5-胺(100mg，75％产率)。MS(apci)m/z＝214.1(M+H)。[0266] Step A:Preparation of 3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine : A suspension of 5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl trifluoromethanesulfonate (Example 525, Step A; 200 mg, 0.62 mmol) in toluene:water (10:1, 5.5 mL) in a sealed tube was degassed with argon for 5 minutes. Potassium cyclopropyltrifluoroborate (368 mg, 2.49 mmol), Pd(OAc)2 (21 mg, 0.09 mmol), andK3PO4 (396 mg, 1.87 mmol) were then added, followedby dicyclohexyl(2',6'-diisopropylbiphenyl-2-yl)phosphine (87 mg, 0.19 mmol). The mixture was degassed with argon for an additional 5 minutes, then sealed and stirred at 110°C for 18 hours. The cooled mixture was diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2 SO4 , filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 1% MeOH/DCM to afford 3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazole-5-amine (100 mg, 75% yield) as a yellow oil. MS (apci) m/z=214.1 (M+H).
步骤B：制备1-(3-环丙基-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：根据实例526步骤B和C的程序，在步骤B中用3-环丙基-4-甲基-1-苯基-1H-吡唑-5-胺替代3-(2-甲氧基嘧啶-5-基)-4-甲基-1-苯基-1H-吡唑-5-胺来制备。通过二氧化硅柱色谱法，用1％至3％MeOH/DCM洗脱来纯化物质，得到呈无色玻璃状的标题产物(29mg，39％产率)。MS(apci)m/z＝496.3(M+H)。Step B:Preparation of 1-(3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : Prepared according to the procedures of Example 526, Steps B and C, substituting 3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-amine for 3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-amine in Step B. The material was purified by silica column chromatography eluting with 1% to 3% MeOH/DCM to give the title product (29 mg, 39% yield) as a colorless glass. MS (apci) m/z=496.3 (M+H).
实例534Example 534
1-(3-环丙基-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(4-氟苯基)-1-(2-1-(3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(methoxyethyl)pyrrolidin-3-yl)urea
根据实例533的程序，在步骤C中用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(2S,3S)-2,3-双((4-甲基苯甲酰基)氧基)琥珀酸盐(制备L1步骤A至D)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用2％至4％MeOH/DCM洗脱来纯化物质，得到呈无色玻璃状的标题化合物(11mg，15％产率)。MS(apci)m/z＝478.3(M+H)。Prepared according to the procedure of Example 533, substituting (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (Preparation L1, Steps A to D) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in Step C. The material was purified by silica column chromatography eluting with 2% to 4% MeOH/DCM to give the title compound (11 mg, 15% yield) as a colorless glass. MS (apci) m/z=478.3 (M+H).
实例535Example 535
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(1-异丙1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(1-isopropyl)-基-6-氧代基-1,6-二氢吡啶-3-基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)吡啶-2(1H)-酮：在密封容器中将5-溴-1-异丙基吡啶-2(1H)-酮(500mg，2.31mmol)、双(频哪醇根基)二硼(881mg，3.47mmol)与乙酸钾(681mg，6.94mmol)合并在1,4-二噁烷(5mL)中并且用氩气吹洗5分钟。然后添加PdCl2(dppf)dcm(189mg，0.23mmol)，继续吹洗1分钟，然后密封容器并且在100℃下加热18小时。通过GF滤纸过滤冷却的混合物并且用EtOAc和DCM冲洗。在真空中浓缩滤液并且通过二氧化硅柱色谱法，用1％MeOH/DCM洗脱来纯化残余物，接着通过第二个柱用1:1己烷/EtOAc洗脱来纯化。用Et2O湿磨所得固体，过滤并且在真空中浓缩滤液，得到呈桃红色固体状的1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)吡啶-2(1H)-酮(308mg，51％产率)。MS(apci)m/z＝264.2(M+H)。Step A:Preparation of 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one : 5-Bromo-1-isopropylpyridin-2(1H)-one (500 mg, 2.31 mmol), bis(pinacolato)diboron (881 mg, 3.47 mmol) and potassium acetate (681 mg, 6.94 mmol) were combined in 1,4-dioxane (5 mL) in a sealed vessel and purged with argon for 5 minutes.PdCl2 (dppf)dcm (189 mg, 0.23 mmol) was then added and purging continued for 1 minute. The vessel was then sealed and heated at 100°C for 18 hours. The cooled mixture was filtered through GF filter paper and rinsed with EtOAc and DCM. The filtrate was concentrated in vacuo and the residue was purified by silica column chromatography eluting with 1% MeOH/DCM, followed by purification by a second column eluting with 1:1 hexanes/EtOAc. The resulting solid was triturated with Et2 O, filtered, and the filtrate was concentrated in vacuo to afford 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (308 mg, 51% yield) as a pink solid. MS (apci) m/z=264.2 (M+H).
步骤B：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(1-异丙基-6-氧代基-1,6-二氢吡啶-3-基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：根据实例526的程序，用1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧环戊硼烷-2-基)吡啶-2(1H)-酮替代2-甲氧基嘧啶-5-基硼酸来制备。通过二氧化硅柱色谱法，用2.5％至4％MeOH/DCM洗脱来纯化物质，得到呈无色玻璃状的标题化合物(37mg，53％产率)。MS(apci)m/z＝591.3(M+H)。Step B:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : Prepared according to the procedure of Example 526, substituting 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one for 2-methoxypyrimidin-5-ylboronic acid. The material was purified by silica column chromatography eluting with 2.5% to 4% MeOH/DCM to give the title compound (37 mg, 53% yield) as a colorless glass. MS (apci) m/z = 591.3 (M+H).
实例536Example 536
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(1-异丙基-1-((3S,4R)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(1-isopropyl-6-氧代基-1,6-二氢吡啶-3-基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据实例535的程序，在最终步骤中用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(2S,3S)-2,3-双((4-甲基苯甲酰基)氧基)琥珀酸盐(制备L1步骤A至D)替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备F)来制备。通过二氧化硅柱色谱法，用3％至5％MeOH/DCM洗脱来纯化物质，得到呈无色玻璃状的标题化合物(34mg，50％产率)。MS(apci)m/z＝573.3(M+H)。Prepared according to the procedure of Example 535, substituting (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (Preparation L1, Steps A to D) for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation F) in the final step. The material was purified by silica column chromatography eluting with 3% to 5% MeOH/DCM to give the title compound (34 mg, 50% yield) as a colorless glass. MS (apci) m/z=573.3 (M+H).
实例537Example 537
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-((S)-2-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲二盐酸盐(hydroxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea dihydrochloride
步骤A：制备1-(3-((S)-2-((叔丁基二甲基硅烷基)氧基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：根据对于实例1所述的方法，在步骤A中使用中间体P211作为3-叔丁基-1-苯基-1H-吡唑-5-胺的替代物并且在步骤B中用(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备B)来制备。MS(apci)m/z＝644.4(M+H)。Step A:Preparation of 1-(3-((S)-2-((tert-butyldimethylsilyl)oxy)propoxy)-4-methyl-1-phenyl -1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea: Prepared according to the method described for Example 1 using intermediate P211 as a substitute for 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine in Step A and substituting (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride for trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation B) in Step B. MS (apci) m/z = 644.4 (M+H).
步骤B：制备1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-((S)-2-羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲二盐酸盐：根据对于实例179所述的程序，使用1-(3-((S)-2-((叔丁基二甲基硅烷基)氧基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲作为1-(3-((S)-2-((叔丁基二甲基硅烷基)氧基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(制备U-2)的替代物来制备。MS(apci)m/z＝530.3(M+H)。Step B:Preparation of 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-Hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea dihydrochloride : Prepared according to the procedure described for Example 179 using 1-(3-((S)-2-((tert-butyldimethylsilyl)oxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea as an alternative to 1-(3-((S)-2-((tert-butyldimethylsilyl)oxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (Preparation U-2). MS (apci) m/z = 530.3 (M+H).
实例538Example 538
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-苯基-3-(2-(哌嗪-1-基)乙氧基)-1H-吡唑-5-基)脲三盐酸盐Phenyl-3-(2-(piperazin-1-yl)ethoxy)-1H-pyrazol-5-yl)urea trihydrochloride
向4-(2-((5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-基)氧基)乙基)哌嗪-1-甲酸叔丁酯(实例388，52mg，0.076mmol)在DCM(3mL)中的经搅拌溶液中添加2N HCl的乙醚溶液(0.15mL)。在环境温度下搅拌1小时后，在减压下蒸发溶剂，得到标题化合物(50mg，110％产率)。MS(apci)m/z＝584.3(M+H)。To a stirred solution of tert-butyl 4-(2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)ethyl)piperazine-1-carboxylate (Example 388, 52 mg, 0.076 mmol) in DCM (3 mL) was added 2N HCl in diethyl ether (0.15 mL). After stirring at ambient temperature for 1 hour, the solvent was evaporated under reduced pressure to give the title compound (50 mg, 110% yield). MS (apci) m/z = 584.3 (M+H).
实例539Example 539
1-(3-(苯甲氧基)-4-氯-1-甲基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯1-(3-(Benzyloxy)-4-chloro-1-methyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorobenzene基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据对于中间体201步骤B所述的方法，使用1-(3-(苯甲氧基)-1-甲基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(实例136)作为3-乙氧基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯的替代物来制备。MS(apci)m/z＝520.2(M+H)。Prepared according to the procedure for Intermediate 201, Step B, using 1-(3-(benzyloxy)-1-methyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (Example 136) as an alternative to phenyl 3-ethoxy-1-phenyl-1H-pyrazol-5-ylcarbamate. MS (apci) m/z = 520.2 (M+H).
实例540Example 540
2-((5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-甲基-1-苯基-1H-吡唑-3-基)氧基)乙酸4-Methyl-1-phenyl-1H-pyrazol-3-yl)oxy)acetic acid
在环境温度下搅拌2-((5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-基)氧基)乙酸乙酯(实例361，190mg，0.341mmol)和1.0N LiOH水溶液(0.682mL，0.682mmol)在THF(4mL)和MeOH(2mL)中的混合物1小时。用水稀释反应混合物。逐滴添加1.0N HCl水溶液(0.8mL)以将pH调节至4。用EtOAc萃取混合物。用盐水洗涤合并的萃取物，经MgSO4干燥，过滤并且浓缩，得到呈灰白色固体状的标题化合物(150mg，83％产率)。MS(apci)m/z＝530.2(M+H)。A mixture of ethyl 2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)acetate (Example 361, 190 mg, 0.341 mmol) and 1.0 N aqueous LiOH solution (0.682 mL, 0.682 mmol) in THF (4 mL) and MeOH (2 mL) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water. 1.0 N aqueous HCl solution (0.8 mL) was added dropwise to adjust the pH to 4. The mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4 , filtered and concentrated to give the title compound (150 mg, 83% yield) as an off-white solid. MS (apci) m/z=530.2 (M+H).
实例541Example 541
2-((5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-甲基-1-苯基-1H-吡唑-3-基)氧基)-N-乙基乙酰胺4-Methyl-1-phenyl-1H-pyrazol-3-yl)oxy)-N-ethylacetamide
向2-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-基氧基)乙酸(实例540，22mg，0.042mmol)在DMF(2mL)中的经搅拌溶液中添加EDCI(24mg，0.12mmol)和HOBt(17mg，0.12mmol)。在环境温度下搅拌所得到的混合物10分钟。添加乙胺(2.0M THF溶液，0.062mL，0.12mmol)，接着添加TEA(0.017mL，0.12mmol)。在环境温度下搅拌反应混合物3天。用EtOAc稀释混合物，依序用饱和NH4Cl水溶液、饱和NaHCO3水溶液和盐水洗涤，经MgSO4干燥并且浓缩。通过硅胶快速色谱法(5％MeOH的DCM)纯化残余物，得到标题化合物(16mg，69％产率)。MS(apci)m/z＝557.3(M+H)。To a stirred solution of 2-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)acetic acid (Example 540, 22 mg, 0.042 mmol) in DMF (2 mL) was added EDCI (24 mg, 0.12 mmol) and HOBt (17 mg, 0.12 mmol). The resulting mixture was stirred at ambient temperature for 10 minutes. Ethylamine (2.0 M solution in THF, 0.062 mL, 0.12 mmol) was added followed by TEA (0.017 mL, 0.12 mmol). The reaction mixture was stirred at ambient temperature for 3 days. The mixture was diluted with EtOAc, washed sequentially with saturated aqueousNH4Cl solution, saturated aqueousNaHCO3 solution, and brine, dried overMgSO4 , and concentrated. The residue was purified by flash chromatography on silica gel (5% MeOH in DCM) to give the title compound (16 mg, 69% yield).MS (apci) m/z = 557.3 (M+H).
实例542Example 542
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-乙基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-ethyl-3-(2-羟基-2-甲基丙氧基)-1-苯基-1H-吡唑-5-基)脲(2-Hydroxy-2-methylpropyloxy)-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备5-氨基-4-乙基-1-苯基-1H-吡唑-3(2H)-酮：在90℃下加热2-氰基丁酸乙酯(10.0g，70.8mmol)、苯肼(7.66g，70.8mmol)、二噁烷(20mL)、EtOH(50mL)和NaOEt(3.0M EtOH溶液，2.36mL，7.08mmol)的混合物7天。冷却后，浓缩反应混合物。用Et2O处理残余物。通过过滤收集固体，用Et2O洗涤并且在真空中干燥，得到标题化合物(7.50g，52％产率)。MS(apci)m/z＝204.1(M+H)。[0148] Step A:Preparation of 5-amino-4-ethyl-1-phenyl-1H-pyrazol-3(2H)-one : A mixture of ethyl 2-cyanobutyrate (10.0 g, 70.8 mmol), phenylhydrazine (7.66 g, 70.8 mmol), dioxane (20 mL), EtOH (50 mL), and NaOEt (3.0 M in EtOH, 2.36 mL, 7.08 mmol) was heated at 90°C for 7 days. After cooling, the reaction mixture was concentrated. The residue was treated withEt2O . The solid was collected by filtration, washed with Et2O, and dried in vacuo to give the title compound (7.50 g, 52% yield). MS( apci) m/z = 204.1 (M+H).
步骤B：制备1-((5-氨基-4-乙基-1-苯基-1H-吡唑-3-基)氧基)-2-甲基丙-2-醇：根据对于中间体203所述的程序，使用5-氨基-4-乙基-1-苯基-1H-吡唑-3(2H)-酮作为5-氨基-1-苯基-1H-吡唑-3(2H)-酮的替代物来制备。MS(apci)m/z＝276.2(M+H)。Step B:Preparation of 1-((5-amino-4-ethyl-1-phenyl-1H-pyrazol-3-yl)oxy)-2-methylpropan-2-ol : Prepared according to the procedure described for Intermediate 203 using 5-amino-4-ethyl-1-phenyl-1H-pyrazol-3(2H)-one as a substitute for 5-amino-1-phenyl-1H-pyrazol-3(2H)-one. MS (apci) m/z = 276.2 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-乙基-3-(2-羟基-2-甲基丙氧基)-1-苯基-1H-吡唑-5-基)脲：根据对于实例1所述的程序，在步骤A中使用1-((5-氨基-4-乙基-1-苯基-1H-吡唑-3-基)氧基)-2-甲基丙-2-醇作为3-叔丁基-1-苯基-1H-吡唑-5-胺的替代物并且在步骤B中用(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备B)来制备。MS(apci)m/z＝558.3(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-ethyl-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)urea : Prepared according to the procedure described for Example 1, using 1-((5-amino-4-ethyl-1-phenyl-1H-pyrazol-3-yl)oxy)-2-methylpropan-2-ol as a substitute for 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine in Step A and (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride in Step B instead of trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation B). MS (apci) m/z = 558.3 (M+H).
实例543Example 543
1-(3-(2-氨基乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二1-(3-(2-aminoethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-dimethyl-1-phenyl-2-nitropropoxy)-2-nitropropoxy)-3-nitropropoxy)-2-nitropropoxy-3-nitropropoxy ...3-nitropropoxy-3-nitropropoxy氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(2-(2-(2-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea)
在环境温度下向1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(2-(1,3-二氧代基异吲哚啉-2-基)乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(实例387，170mg，0.264mmol)在1:1MeOH:THF(10mL)中的溶液中添加一水合肼(132mg，2.64mmol)。在50℃下加热反应物17小时。冷却后，浓缩混合物。用DCM湿磨残余物并且通过过滤去除固体。浓缩滤液，得到标题化合物(106mg，78％产率)。MS(apci)m/z＝515.3(M+H)。To a solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea (Example 387, 170 mg, 0.264 mmol) in 1:1 MeOH:THF (10 mL) was added hydrazine monohydrate (132 mg, 2.64 mmol) at ambient temperature. The reaction was heated at 50° C. for 17 hours. After cooling, the mixture was concentrated. The residue was triturated with DCM and the solids were removed by filtration. The filtrate was concentrated to give the title compound (106 mg, 78% yield). MS (apci) m/z=515.3 (M+H).
实例544Example 544
N-(2-((5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲N-(2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea基)-4-甲基-1-苯基-1H-吡唑-3-基)氧基)乙基)甲磺酰胺(4-Methyl-1-phenyl-1H-pyrazol-3-yl)oxy)ethyl)methanesulfonamide
在环境温度下搅拌1-(3-(2-氨基乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(实例543，30mg，0.058mmol)、甲磺酰氯(7.3mg，0.064mmol)和TEA(0.016mL，0.12mmol)在DCM(3mL)中的混合物1小时。用EtOAc稀释反应混合物，用水和盐水洗涤，经MgSO4干燥并且浓缩。通过硅胶快速色谱法(3％MeOH的DCM溶液)纯化残余物，得到标题化合物(25mg，72％产率)。MS(apci)m/z＝593.2(M+H)。A mixture of 1-(3-(2-aminoethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (Example 543, 30 mg, 0.058 mmol), methanesulfonyl chloride (7.3 mg, 0.064 mmol) and TEA (0.016 mL, 0.12 mmol) in DCM (3 mL) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (3% MeOH in DCM) to give the title compound (25 mg, 72% yield). MS (apci) m/z=593.2 (M+H).
实例545Example 545
N-(2-((5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲N-(2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea基)-4-甲基-1-苯基-1H-吡唑-3-基)氧基)乙基)乙酰胺(4-Methyl-1-phenyl-1H-pyrazol-3-yl)oxy)ethyl)acetamide
根据对于实例544所述的程序，使用乙酸酐作为甲磺酰氯的替代物来制备。MS(apci)m/z＝557.3(M+H)。Prepared according to the procedure described for Example 544 using acetic anhydride as an alternative to methanesulfonyl chloride. MS (apci) m/z = 557.3 (M+H).
实例546Example 546
1-(3-(2-(4-乙酰基哌嗪-1-基)乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-1-(3-(2-(4-acetylpiperazin-1-yl)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲((3S,4R)-4-(3,4-Difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据对于实例544所述的程序，使用乙酸酐作为甲烷磺酰氯的替代物，并且用1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-3-(2-(哌嗪-1-基)乙氧基)-1H-吡唑-5-基)脲三盐酸盐(实例538)替代1-(3-(2-氨基乙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(实例543)来制备。MS(apci)m/z＝626.4(M+H)。Prepared according to the procedure described for Example 544 using acetic anhydride as a substitute for methanesulfonyl chloride and 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2-(piperazin-1-yl)ethoxy)-1H-pyrazol-5-yl)urea trihydrochloride (Example 538) substituting 1-(3-(2-aminoethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (Example 543). MS (apci) m/z = 626.4 (M+H).
实例547Example 547
2-((5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-甲基-1-苯基-1H-吡唑-3-基)氧基)乙酰胺4-Methyl-1-phenyl-1H-pyrazol-3-yl)oxy)acetamide
根据对于实例544所述的程序，使用氯化铵作为乙胺的替代物来制备。MS(apci)m/z＝529.2(M+H)。Prepared according to the procedure described for Example 544 using ammonium chloride as a substitute for ethylamine. MS (apci) m/z = 529.2 (M+H).
实例548Example 548
N-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-N-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-乙氧基-1-苯基-1H-吡唑-4-基)-2,2,2-三氟乙酰胺3-Ethoxy-1-phenyl-1H-pyrazol-4-yl)-2,2,2-trifluoroacetamide
步骤A：制备(5-氨基-3-氧代基-1-苯基-2,3-二氢-1H-吡唑-4-基)氨基甲酸苯甲酯：根据对于实例542步骤A所述的方法，使用2-(苯甲氧基羰基氨基)-2-氰基乙酸乙酯作为2-氰基丁酸乙酯的替代物来制备。MS(apci)m/z＝325.1(M+H)。Step A:Preparation of benzyl (5-amino-3-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbamate : Prepared according to the method described for Example 542, Step A, using ethyl 2-(benzyloxycarbonylamino)-2-cyanoacetate as a substitute for ethyl 2-cyanobutyrate. MS (apci) m/z = 325.1 (M+H).
步骤B：制备(5-氨基-3-乙氧基-1-苯基-1H-吡唑-4-基)氨基甲酸苯甲酯：根据对于中间体P135步骤B所述的方法，使用(5-氨基-3-氧代基-1-苯基-2,3-二氢-1H-吡唑-4-基)氨基甲酸苯甲酯作为5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮的替代物来制备。MS(apci)m/z＝353.1(M+H)。Step B:Preparation of benzyl (5-amino-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)carbamate : Prepared according to the procedure described for Intermediate P135, Step B, using benzyl (5-amino-3-oxo-1-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbamate as a surrogate for 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one. MS (apci) m/z = 353.1 (M+H).
步骤C：制备(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-3-乙氧基-1-苯基-1H-吡唑-4-基)氨基甲酸苯甲酯：根据对于实例151步骤B所述的程序，使用(5-氨基-3-乙氧基-1-苯基-1H-吡唑-4-基)氨基甲酸苯甲酯作为2-(吡啶-4-基)-2,4,5,6-四氢环戊二烯并[c]吡唑-3-胺的替代物，并且用(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代(3S,4R)-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺双(2,2,2-三氟乙酸盐)(制备D)来制备。MS(apci)m/z＝635.3(M+H)。Step C:Preparation of benzyl (5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)carbamate : Following the procedure described for Example 151, Step B, using benzyl (5-amino-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)carbamate as Alternative to 2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-amine, prepared using (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride in place of (3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine bis(2,2,2-trifluoroacetate) (Preparation D). MS (apci) m/z = 635.3 (M+H).
步骤D：制备N-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-3-乙氧基-1-苯基-1H-吡唑-4-基)-2,2,2-三氟-乙酰胺：在60℃下加热(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-3-乙氧基-1-苯基-1H-吡唑-4-基)氨基甲酸苯甲酯(75mg，0.12mmol)在TFA(1mL)中的溶液17小时。在减压下浓缩反应混合物。将5％EtOH的甲苯溶液添加至残余物中并且再次浓缩混合物，得到呈TFA盐形式的粗产物。将粗物质溶解于EtOAc中，用饱和NaHCO3水溶液和盐水洗涤，经MgSO4干燥并且在减压下浓缩。通过硅胶柱色谱法(2％MeOH的DCM溶液)纯化残余物，得到呈次要产物形式的标题化合物(9mg，13％产率)。MS(apci)m/z＝597.2(M+H)。Step D:Preparation of N-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)-2,2,2-trifluoro-acetamide : A solution of benzyl (5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)carbamate (75 mg, 0.12 mmol) in TFA (1 mL) was heated at 60 °C for 17 hours. The reaction mixture was concentrated under reduced pressure. 5% EtOH in toluene was added to the residue and the mixture was concentrated again to give the crude product as a TFA salt. The crude material was dissolved in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2% MeOH in DCM) to give the title compound (9 mg, 13% yield) as a minor product. MS (apci) m/z=597.2 (M+H).
实例549Example 549
1-(4-氨基-3-乙氧基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(4-amino-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据对于实例548步骤C所述的程序来制备。通过硅胶柱色谱法(5％MeOH的DCM溶液)分离呈主要产物形式的标题化合物。MS(apci)m/z＝501.2(M+H)。Prepared according to the procedure described for Example 548, Step C. The title compound was isolated as the major product by silica gel column chromatography (5% MeOH in DCM). MS (apci) m/z = 501.2 (M+H).
实例550Example 550
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-乙氧基-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(2-羟基乙基)-1-苯基-1H-吡唑-5-基)脲4-(2-Hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：制备5-氨基-4-(2,2-二乙氧基乙基)-1-苯基-1H-吡唑-3(2H)-酮：根据对于实例542步骤A所述的方法，使用2-氰基-4,4-二乙氧基丁酸乙酯作为2-氰基丁酸乙酯的替代物来制备。MS(apci)m/z＝292.1(M+H)。Step A:Preparation of 5-amino-4-(2,2-diethoxyethyl)-1-phenyl-1H-pyrazol-3(2H)-one : Prepared according to the method described for Example 542, Step A, using ethyl 2-cyano-4,4-diethoxybutanoate as a substitute for ethyl 2-cyanobutanoate. MS (apci) m/z = 292.1 (M+H).
步骤B：制备4-(2,2-二乙氧基乙基)-3-乙氧基-1-苯基-1H-吡唑-5-胺：根据对于中间体P135步骤B所述的方法，使用5-氨基-4-(2,2-二乙氧基乙基)-1-苯基-1H-吡唑-3(2H)-酮作为5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮的替代物来制备。MS(apci)m/z＝320.2(M+H)。Step B:Preparation of 4-(2,2-diethoxyethyl)-3-ethoxy-1-phenyl-1H-pyrazol-5-amine : Prepared according to the procedure described for Intermediate P135, Step B, using 5-amino-4-(2,2-diethoxyethyl)-1-phenyl-1H-pyrazol-3(2H)-one as a substitute for 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one. MS (apci) m/z = 320.2 (M+H).
步骤C：制备1-(4-(2,2-二乙氧基乙基)-3-乙氧基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：根据对于实例1所述的程序，在步骤A中使用4-(2,2-二乙氧基乙基)-3-乙氧基-1-苯基-1H-吡唑-5-胺作为3-叔丁基-1-苯基-1H-吡唑-5-胺的替代物，并且在步骤B中用(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备B)来制备。MS(apci)m/z＝602.3(M+H)。Step C:Preparation of 1-(4-(2,2-diethoxyethyl)-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : Prepared according to the procedure described for Example 1 using 4-(2,2-diethoxyethyl)-3-ethoxy-1-phenyl-1H-pyrazol-5-amine as a substitute for 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine in Step A and (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride instead of trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation B) in Step B. MS (apci) m/z = 602.3 (M+H).
步骤D：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-乙氧基-4-(2-氧代基乙基)-1-苯基-1H-吡唑-5-基)脲：在环境温度下搅拌1-(4-(2,2-二乙氧基乙基)-3-乙氧基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(0.13g，0.22mmol)、乙酸(1mL)和水(0.2mL)的混合物17小时。通过HPLC测定反应未完成。添加两滴30wt.％HBr的AcOH溶液。再搅拌反应混合物17小时。通过添加饱和NaHCO3水溶液淬灭反应，用EtOAc萃取，用饱和NaHCO3水溶液(2X)和盐水洗涤，经MgSO4干燥，并且浓缩，得到标题化合物，其不经进一步纯化即用于下一步骤中。MS(apci)m/z＝528.2(M+H)。[0266] Step D:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(2-oxoethyl)-1-phenyl-1H-pyrazol-5-yl)urea : A mixture of 1-(4-(2,2-diethoxyethyl)-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (0.13 g, 0.22 mmol), acetic acid (1 mL) and water (0.2 mL) was stirred at ambient temperature for 17 hours. The reaction was determined to be incomplete by HPLC. Two drops of 30 wt.% HBr in AcOH were added. The reaction mixture was stirred for an additional 17 hours. The reaction was quenched by adding saturated aqueous NaHCO3 solution, extracted with EtOAc, washed with saturated aqueous NaHCO3 solution (2×) and brine, dried over MgSO4 , and concentrated to give the title compound, which was used in the next step without further purification. MS (apci) m/z=528.2 (M+H).
步骤E：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-乙氧基-4-(2-羟基乙基)-1-苯基-1H-吡唑-5-基)脲：在0℃下向1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-乙氧基-4-(2-氧代乙基)-1-苯基-1H-吡唑-5-基)脲(40mg，0.076mmol)在THF(1mL)中的经搅拌溶液中逐滴添加2.0M LiBH4的THF溶液(0.038mL，0.076mmol)。允许反应物升温至环境温度并且搅拌3小时。用EtOAc稀释反应物，用0.1N HCl、饱和NaHCO3水溶液和盐水洗涤，经MgSO4干燥并且浓缩。通过硅胶快速色谱法(4％MeOH的DCM溶液)纯化残余物，得到标题化合物(4mg，10％产率)。MS(apci)m/z＝530.3(M+H)。Step E:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)urea : To a stirred solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(2-oxoethyl)-1-phenyl-1H-pyrazol-5-yl)urea (40 mg, 0.076 mmol) in THF (1 mL) was added dropwise a 2.0M solution of LiBH in THF (0.038 mL, 0.076 mmol). The reaction was allowed to warm to ambient temperature and stirred for 3 hours. The reaction was diluted with EtOAc, washed with 0.1N HCl, saturated aqueous NaHCO3 solution, and brine, dried over MgSO4 , and concentrated. The residue was purified by flash chromatography on silica gel (4% MeOH in DCM) to afford the title compound (4 mg, 10% yield). MS (apci) m/z = 530.3 (M+H).
实例551Example 551
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-(4-甲基哌嗪-1-基)乙氧基)-1-苯基-1H-吡唑-5-基)脲三盐酸盐(2-(4-Methylpiperazin-1-yl)ethoxy)-1-phenyl-1H-pyrazol-5-yl)urea trihydrochloride
在0℃下向1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-3-(2-(哌嗪-1-基)乙氧基)-1H-吡唑-5-基)脲三盐酸盐(实例538，50mg，0.086mmol)、NaBH(OAc)3(73mg，0.34mmol)和THF(2mL)的混合物中添加甲醛(37％水溶液，14mg，0.17mmol)。使反应混合物升温至环境温度并且搅拌17小时。用H2O(20mL)稀释混合物并且用DCM萃取。经MgSO4干燥合并的有机层并且浓缩。通过硅胶快速色谱法(3％7N胺-MeOH的DCM溶液)纯化残余物，得到游离碱，将其用2N HCl的乙醚溶液(3滴)处理。浓缩混合物并且用Et2O湿磨，得到标题化合物(22mg，43％产率)。MS(apci)m/z＝598.3(M+H)。To a mixture of 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2-(piperazin-1-yl)ethoxy)-1H-pyrazol-5-yl)urea trihydrochloride (Example 538, 50 mg, 0.086 mmol), NaBH(OAc) (73 mg, 0.34 mmol) and THF (2 mL) was added formaldehyde (37% in water, 14 mg, 0.17 mmol) at 0°C. The reaction mixture was allowed to warm to ambient temperature and stirred for 17 hours. The mixture was diluted withH2O (20 mL) and extracted with DCM. The combined organic layers were dried overMgSO4 and concentrated. The residue was purified by flash chromatography on silica gel (3% 7N amine-MeOH in DCM) to give the free base, which was treated with 2N HCl in diethyl ether (3 drops). The mixture was concentrated and triturated withEt2O to give the title compound (22 mg, 43% yield).MS (apci) m/z = 598.3 (M+H).
实例552Example 552
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-吗啉代-2-氧代乙氧基)-1-苯基-1H-吡唑-5-基)脲(2-Morpholino-2-oxoethoxy)-1-phenyl-1H-pyrazol-5-yl)urea
根据对于实例541所述的程序，使用吗啉作为乙胺的替代物来制备。MS(apci)m/z＝599.3(M+H)。Prepared according to the procedure described for Example 541 using morpholine as a substitute for ethylamine. MS (apci) m/z = 599.3 (M+H).
实例553Example 553
4-溴-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4-Bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea基)-1-苯基-1H-吡唑-3-甲酸1-Phenyl-1H-pyrazole-3-carboxylic acid
根据对于实例540所述的程序，使用4-溴-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯基-1H-吡唑-3-甲酸乙酯(实例381)作为2-((5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-基)氧基)乙酸乙酯(实例361)的替代物来制备。MS(apci)m/z＝564.2(M+H)。Prepared according to the procedure described for Example 540 using ethyl 4-bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-3-carboxylate (Example 381) as an alternative to ethyl 2-((5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)acetate (Example 361). MS (apci) m/z = 564.2 (M+H).
实例554Example 554
4-溴-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4-Bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea基)-N-甲基-1-苯基-1H-吡唑-3-甲酰胺1-H-pyrazole-3-carboxamide
根据对于实例541所述的程序，使用4-溴-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯基-1H-吡唑-3-甲酸(实例553)作为2-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-基氧基)乙酸(实例540)的替代物并且用甲胺替代乙胺来制备。MS(apci)m/z＝577.1(M+H)。Prepared according to the procedure described for Example 541 using 4-bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 553) as a substitute for 2-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)acetic acid (Example 540) and methylamine instead of ethylamine. MS (apci) m/z = 577.1 (M+H).
实例555Example 555
4-溴-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4-Bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea基)-N-甲氧基-1-苯基-1H-吡唑-3-甲酰胺1-H-pyrazole-3-carboxamide
根据对于实例541所述的程序，使用4-溴-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯基-1H-吡唑-3-甲酸(实例553)作为2-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-4-甲基-1-苯基-1H-吡唑-3-基氧基)乙酸(实例540)的替代物并且用O-甲基羟胺盐酸盐替代乙胺来制备。MS(apci)m/z＝593.1(M+H)。Prepared according to the procedure described for Example 541 using 4-bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 553) as a substitute for 2-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yloxy)acetic acid (Example 540) and O-methylhydroxylamine hydrochloride instead of ethylamine. MS (apci) m/z = 593.1 (M+H).
实例556Example 556
1-(4-氯-1'-(2-甲氧基乙基)-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,1-(4-chloro-1'-(2-methoxyethyl)-1-phenyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
步骤A：制备1-(2-甲氧基乙基)-1H-吡唑-4-甲酸乙酯：在80℃下搅拌1H-吡唑-4-甲酸乙酯(5.00g，35.7mmol)、DMF(120mL)、K2CO3(19.7g，143mmol)和1-溴-2-甲氧基乙烷(9.92g，71.4mmol)的混合物4小时。冷却后，将反应混合物倒入水中并且用EtOAc萃取。用水和盐水洗涤合并的萃取物，干燥并且浓缩。通过柱色谱法(4:1己烷/EtOAc)纯化残余物，得到呈无色油状的标题化合物(5.57g，79％产率)。MS(apci)m/z＝199.1(M+H)。[0266] Step A:Preparation of ethyl 1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate : A mixture of ethyl 1H-pyrazole-4-carboxylate (5.00 g, 35.7 mmol), DMF (120 mL),K2CO3 (19.7g , 143 mmol) and 1-bromo-2-methoxyethane (9.92 g, 71.4 mmol) was stirred at 80°C for 4 hours. After cooling, the reaction mixture was poured into water and extracted with EtOAc. The combined extracts were washed with water and brine, dried and concentrated. The residue was purified by column chromatography (4:1 hexanes/EtOAc) to give the title compound (5.57 g, 79% yield) as a colorless oil. MS (apci) m/z = 199.1 (M+H).
步骤B：制备1'-(2-甲氧基乙基)-1-苯基-1H,1'H-[3,4'-联吡唑]-5-胺：根据对于中间体P109所述的方法，在步骤A中用1-(2-甲氧基乙基)-1H-吡唑-4-甲酸乙酯替代2-甲氧基乙酸甲酯来制备。MS(apci)m/z＝284.1(M+H)。Step B:Preparation of 1'-(2-methoxyethyl)-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-amine : Prepare according to the procedure described for Intermediate P109, substituting 1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ester for methyl 2-methoxyacetate in Step A. MS (apci) m/z = 284.1 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-(2-甲氧基乙基)-1-苯基-1H,1'H-3,4'-联吡唑-5-基)脲：根据对于实例1所述的程序，在步骤A中使用1'-(2-甲氧基乙基)-1-苯基-1H,1'H-[3,4'-联吡唑]-5-胺作为3-叔丁基-1-苯基-1H-吡唑-5-胺的替代物，并且在步骤B中用(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代反式-1-(2-甲氧基乙基)-4-苯基吡咯烷-3-胺二盐酸盐(制备B)来制备。MS(apci)m/z＝566.2(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-(2-methoxyethyl)-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)urea : Prepared according to the procedure described for Example 1, using 1'-(2-methoxyethyl)-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-amine as a substitute for 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine in Step A and substituting (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride for trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride (Preparation B) in Step B. MS (apci) m/z = 566.2 (M+H).
步骤D：制备1-(4-氯-1'-(2-甲氧基乙基)-1-苯基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：向1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1'-(2-甲氧基乙基)-1-苯基-1H,1'H-3,4'-联吡唑-5-基)脲(40mg，0.071mmol)在DCM(1mL)中的溶液中添加N-氯代琥珀酰亚胺(11mg，0.085mmol)，接着添加催化量的4-甲基苯磺酸吡啶鎓(PPTS)。在环境温度下搅拌混合物过夜。再添加N-氯代琥珀酰亚胺(4mg)。在环境温度下再搅拌反应物4小时。将反应混合物分配于DCM与饱和NaHCO3水溶液之间。用DCM萃取水层。用盐水洗涤合并的有机层，干燥并且浓缩。通过反相制备型HPLC(5％至95％乙腈的水溶液)纯化残余物，得到呈白色固体状的标题化合物(15mg，35％产率)。MS(apci)m/z＝600.2(M+H)。[0266] Step D:Preparation of 1-(4-chloro-1'-(2-methoxyethyl)-1-phenyl-1H,1'H-[3,4'-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : To a solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1'-(2-methoxyethyl)-1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)urea (40 mg, 0.071 mmol) in DCM (1 mL) was added N-chlorosuccinimide (11 mg, 0.085 mmol) followed by a catalytic amount of pyridinium 4-methylbenzenesulfonate (PPTS). The mixture was stirred at ambient temperature overnight. N-chlorosuccinimide (4 mg) was added. The reaction was stirred for another 4 hours at ambient temperature. The reaction mixture was partitioned between DCM and saturated NaHCO3 aqueous solution. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by reverse phase preparative HPLC (5% to 95% acetonitrile in water) to give the title compound (15 mg, 35% yield) as a white solid. MS (apci) m/z=600.2 (M+H).
实例557Example 557
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-((S)-2,1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2,3-二羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据对于实例176所述的程序，由1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(((R)-2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(实例392；38.0mg，0.065mmol)来制备，得到呈白色固体状的标题化合物(32mg，90％产率)。MS(apci)m/z＝546.2(M+H)。Prepared from 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea (Example 392; 38.0 mg, 0.065 mmol) to give the title compound as a white solid (32 mg, 90% yield). MS (apci) m/z = 546.2 (M+H).
实例558Example 558
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-((R)-2,1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2,3-二羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据对于实例176所述的程序，由1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(((S)-2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(实例393；82.0mg，0.130mmol)来制备，得到呈白色固体状的标题化合物(67mg，97％产率)。MS(apci)m/z＝546.2(M+H)。Prepared from 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea (Example 393; 82.0 mg, 0.130 mmol) to give the title compound as a white solid (67 mg, 97% yield). MS (apci) m/z = 546.2 (M+H).
实例559Example 559
1-(3-((R)-2,3-二羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-1-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲(2-Methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea
根据对于实例176所述的程序，由1-(3-(((S)-2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲(实例398；90.0mg，0.149mmol)来制备，得到呈白色固体状的标题化合物(83mg，99％产率)。MS(apci)m/z＝564.2(M+H)。Prepared according to the procedure described for Example 176 from 1-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea (Example 398; 90.0 mg, 0.149 mmol) to give the title compound as a white solid (83 mg, 99% yield). MS (apci) m/z = 564.2 (M+H).
实例560Example 560
1-(3-((S)-2,3-二羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-1-(3-((S)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲(2-Methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea
根据对于实例176所述的程序，由1-(3-(((R)-2,2-二甲基-1,3-二氧杂环戊-4-基)甲氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲(实例399；64.0mg，0.096mmol)来制备，得到呈白色固体状的标题化合物(44mg，81％产率)。MS(apci)m/z＝564.2(M+H)。Prepared according to the procedure described for Example 176 from 1-(3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea (Example 399; 64.0 mg, 0.096 mmol) to give the title compound as a white solid (44 mg, 81% yield). MS (apci) m/z = 564.2 (M+H).
实例561Example 561
1-(3-((S)-2-羟基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-1-(3-((S)-2-hydroxypropyloxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲(methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea
根据对于实例176所述的程序，由1-(3-((S)-2-(叔丁基二甲基硅烷氧基)丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲(实例400，64.0mg，0.097mmol)来制备，得到呈白色固体状的标题化合物(44mg，83％产率)。MS(apci)m/z＝548.3(M+H)。Prepared according to the procedure described for Example 176 from 1-(3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea (Example 400, 64.0 mg, 0.097 mmol) to give the title compound as a white solid (44 mg, 83% yield). MS (apci) m/z = 548.3 (M+H).
实例562Example 562
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-((S)-2-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-羟基-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
向1-(3-((S)-2-(叔丁基二甲基硅烷氧基)-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(实例402，110mg，0.163mmol)在THF(5mL)中的溶液中添加1M HCl(5mL)并且在环境温度下搅拌混合物90分钟。将混合物浓缩至3mL并且用1M HCl(3mL)稀释。用Et2O(2X)洗涤混合物并且用50％NaOH浆处理水溶液至pH＝7。添加NaCl达饱和并且用EtOAc(3X)萃取混合物。经MgSO4干燥合并的萃取物，通过填充的过滤(EtOAc洗脱)并且浓缩，得到白色固体。粉碎固体并且在真空中干燥，得到呈白色粉末状的标题化合物(64mg，70％)。MS(apci)m/z＝560.3(M+H)。To a solution of 1-(3-((S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (Example 402, 110 mg, 0.163 mmol) in THF (5 mL) was added 1 M HCl (5 mL) and the mixture was stirred at ambient temperature for 90 minutes. The mixture was concentrated to 3 mL and diluted with 1 M HCl (3 mL). The mixture was washed withEt2O (2X) and the aqueous solution was treated with 50% NaOH slurry to pH = 7. NaCl was added to saturation and the mixture was extracted with EtOAc (3X). The combined extracts were dried overMgSO4 , filtered through a plug of Celite (EtOAc elution) and concentrated to give a white solid. The solid was crushed and dried in vacuo to give the title compound as a white powder (64 mg, 70%). MS (apci) m/z = 560.3 (M+H).
实例563Example 563
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-((R)-2-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-羟基-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
根据对于实例564所述的程序，由1-(3-((R)-2-(叔丁基二甲基硅烷氧基)-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(根据实例402的方法制备，104mg，0.154mmol)来制备。得到呈白色固体状的标题化合物(76mg，88％产率)。MS(apci)m/z＝560.3(M+H)。Prepared according to the procedure described for Example 564 from 1-(3-((R)-2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (prepared according to the method of Example 402, 104 mg, 0.154 mmol). The title compound was obtained as a white solid (76 mg, 88% yield). MS (apci) m/z = 560.3 (M+H).
实例564Example 564
1-(3-((S)-2-羟基-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,1-(3-((S)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea
步骤A：1-(3-((S)-2-(叔丁基二甲基硅烷氧基)-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲：根据对于实例1所述的程序使用适当的起始物质来制备。得到呈无色蜡状的标题化合物(122mg，88％产率)。MS(apci)m/z＝692.3(M+H)。Step A:1-(3-((S)-2-(tert-Butyldimethylsilyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl - 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea : Prepared according to the procedure described for Example 1 using appropriate starting materials. The title compound was obtained as a colorless wax (122 mg, 88% yield). MS (apci) m/z = 692.3 (M+H).
步骤B：1-(3-((S)-2-羟基-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲：向1-(3-((S)-2-(叔丁基二甲基硅烷氧基)-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲(120mg，0.173mmol)在THF(5mL)中的溶液中添加1M HCl(5mL)并且在环境温度下搅拌混合物3.5小时。将混合物浓缩至5mL并且用Et2O(3X)洗涤。用50％NaOH浆处理水溶液至pH＝7。添加NaCl至饱和并且用EtOAc(3X)萃取混合物。经MgSO4干燥合并的萃取物，并且通过填充的过滤，用EtOAc洗脱。浓缩滤液并且用Et2O(3X)洗涤残余白色固体，并且在真空中干燥，得到标题化合物(76mg，76％)。MS(apci)m/z＝578.3(M+H)。Step B:1-(3-((S)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea : To a solution of 1-(3-((S)-2-(tert-butyldimethylsilanyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea (120 mg, 0.173 mmol) in THF (5 mL) was added 1 M HCl (5 mL) and the mixture was stirred at ambient temperature for 3.5 hours. The mixture was concentrated to 5 mL and washed withEt2O (3X). The aqueous solution was treated with 50% NaOH slurry to pH = 7. NaCl was added to saturation and the mixture was extracted with EtOAc (3X). The combined extracts were dried overMgSO4 and filtered through a plug of Celite®, eluting with EtOAc. The filtrate was concentrated and the residual white solid was washed withEt2O (3X) and dried in vacuo to give the title compound (76 mg, 76%). MS (apci) m/z = 578.3 (M+H).
实例565Example 565
1-(3-((R)-2-羟基-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,1-(3-((R)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea
步骤A：1-(3-((R)-2-(叔丁基二甲基硅烷氧基)-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲：根据对于实例1所述的程序使用适当的起始物质来制备。得到呈无色蜡状的化合物(131mg，95％产率)。MS(apci)m/z＝692.3(M+H)。Step A:1-(3-((R)-2-(tert-Butyldimethylsilyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl - 1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea : Prepared according to the procedure described for Example 1 using appropriate starting materials. The compound was obtained as a colorless wax (131 mg, 95% yield). MS (apci) m/z = 692.3 (M+H).
步骤B：1-(3-((R)-2-羟基-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲：在对于实例563步骤B所述的程序中使用1-(3-((R)-2-羟基-3-甲氧基丙氧基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)脲，得到呈白色固体状的标题化合物(77mg，73％)。MS(apci)m/z＝578.3(M+H)。[0266] Step B:1-(3-((R)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea : 1-(3-((R)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea was used in the procedure described for Example 563, Step B to give the title compound (77 mg, 73%) as a white solid. MS (apci) m/z = 578.3 (M+H).
实例566Example 566
1-(4-溴-1,1'-二甲基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(3,4-二氟1-(4-Bromo-1,1'-dimethyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(3,4-difluoro苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲phenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
步骤A：1,1'-二甲基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯：将1,1'-二甲基-1H,1'H-3,4'-联吡唑-5-胺(中间体P114，159mg，0.897mmol)在EtOAc(4mL)中的精细悬浮液冷却至0℃。依序添加NaOH(987μL，1.97mmol)和氯甲酸苯酯(135μL，1.08mmol)并且搅拌混合物5分钟。允许混合物达到环境温度并且搅拌24小时。用H2O(2X)和饱和NaCl洗涤混合物。经MgSO4/活性碳干燥溶液并且通过SiO2塞用EtOAc进行洗脱来洗脱。浓缩滤液并且用己烷(3X)洗涤残余物，并且在真空中干燥，得到呈无色蜡状的标题化合物(232mg，87％)。MS(apci)m/z＝298.1(M+H)。Step A:1,1'-dimethyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamic acid phenyl ester : A fine suspension of 1,1'-dimethyl-1H,1'H-3,4'-bipyrazol-5-amine (Intermediate P114, 159 mg, 0.897 mmol) in EtOAc (4 mL) was cooled to 0 ° C. NaOH (987 μL, 1.97 mmol) and phenyl chloroformate (135 μL, 1.08 mmol) were added sequentially and the mixture was stirred for 5 minutes. The mixture was allowed to reach ambient temperature and stirred for 24 hours. The mixture was washed with H2 O (2X) and saturated NaCl. The solution was dried over MgSO4 /activated carbon and eluted through a SiO2 plug with EtOAc. The filtrate was concentrated and the residue was washed with hexanes (3X) and dried in vacuo to give the title compound (232 mg, 87%) as a colorless wax. MS (apci) m/z = 298.1 (M+H).
步骤B：1-(4-溴-1,1'-二甲基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：将1,1'-二甲基-1H,1'H-3,4'-联吡唑-5-基氨基甲酸苯酯(44.6mg，0.150mmol)在干燥CH2Cl2(1.0mL)中的溶液冷却至0℃并且一次性添加N-溴代琥珀酰亚胺(28.0mg，0.157mmol)。在0℃下搅拌混合物5分钟，允许其达到环境温度并且搅拌直至通过TLC分析观测到起始物质完全耗尽(16小时)为止。向混合物中添加(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备F，59.3mg，0.180mmol)，接着添加DIEA(78.4μL，0.450mmol)并且在环境温度下搅拌混合物3小时。用CH2Cl2(3mL)稀释混合物并且用H2O(3X)洗涤。经Na2SO4干燥CH2Cl2溶液并且通过短SiO2柱用CH2Cl2、EtOAc和10％(9:1MeOH/NH4OH)/EtOAc进行洗脱来洗脱干燥的溶液。合并产物汇集物并且浓缩，得到无色玻璃状物。将玻璃状物溶解于EtOAc中并且通过填充的过滤混浊溶液。浓缩滤液并且用Et2O洗涤残余白色固体，并且在真空中干燥，得到标题化合物(57mg，71％)。MS(apci)m/z＝538.2(M+H)。[0266] Step B:1-(4-Bromo-1,1'-dimethyl-1H,1'H-[3,4'-bipyrazol]-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : A solution of phenyl 1,1'-dimethyl-1H,1'H-3,4'-bipyrazol-5-ylcarbamate (44.6 mg, 0.150 mmol) in dryCH2Cl2 (1.0mL ) was cooled to 0°C and N-bromosuccinimide (28.0 mg, 0.157 mmol) was added in one portion. The mixture was stirred at 0°C for 5 minutes, allowed to reach ambient temperature and stirred until complete consumption of the starting material was observed by TLC analysis (16 hours). To the mixture was added (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation F, 59.3 mg, 0.180 mmol), followed by DIEA (78.4 μL, 0.450 mmol) and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with CH2 Cl2 (3 mL) and washed with H2 O (3×). The CH2 Cl2 solution was dried over Na2 SO4 and the dried solution was eluted through a short SiO2 column with CH2 Cl2 , EtOAc, and 10% (9:1 MeOH/NH4 OH)/EtOAc. The product pools were combined and concentrated to give a colorless glass. The glass was dissolved in EtOAc and the cloudy solution was filtered through a plug of Celite®. The filtrate was concentrated and the residual white solid was washed withEt2O and dried in vacuo to give the title compound (57 mg, 71%). MS (apci) m/z = 538.2 (M+H).
实例567Example 567
1-(4-氯-1,1'-二甲基-1H,1'H-[3,4'-联吡唑]-5-基)-3-((3S,4R)-4-(3,4-二氟1-(4-chloro-1,1'-dimethyl-1H,1'H-[3,4'-bipyrazole]-5-yl)-3-((3S,4R)-4-(3,4-difluoro苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲phenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
使用对于实例566所述的程序，在步骤B中用N-氯代琥珀酰亚胺替代N-溴代琥珀酰亚胺来制备标题化合物。分离呈白色固体状的化合物(51mg，69％)。MS(apci)m/z＝494.1(M+H)。The title compound was prepared using the procedure described for Example 566, substituting N-chlorosuccinimide for N-bromosuccinimide in Step B. The compound was isolated as a white solid (51 mg, 69%). MS (apci) m/z = 494.1 (M+H).
实例568Example 568
1-(4-氯-1-苯基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-1-(4-chloro-1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
一次性用N-氯代琥珀酰亚胺(37.5mg，0.275mmol)处理1-苯基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基氨基甲酸苯酯(90.9mg，0.250mmol)在干燥CH2Cl2(1.0mL)中的溶液并且在环境温度下搅拌混合物直到完成(通过TLC分析测定)为止(72小时)。向混合物中添加(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备F，98.8mg，0.300mmol)，接着添加DIEA(131μL，0.750mmol)并且在环境温度下搅拌混合物5小时。用CH2Cl2(3mL)稀释混合物并且用H2O(2X)、1M NaOH(2X)和H2O洗涤。经Na2SO4/活性碳干燥CH2Cl2溶液并且通过填充的过滤干燥的溶液并且浓缩。在SiO2柱上使用分步梯度洗脱：50％EtOAc-己烷，EtOAc，并且然后5％MeOH/EtOAc来纯化残余物。浓缩合并的产物汇集物，得到无色糖浆状物。用50％Et2O-己烷处理糖浆状物并且超声直到颗粒白色悬浮液形成为止。倾析溶剂，用50％Et2O-己烷(2X)洗涤固体并且在真空中干燥，得到呈白色固体状的标题化合物(106mg，76％)。MS(apci)m/z＝560.3(M+H)。A solution of phenyl 1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-ylcarbamate (90.9 mg, 0.250 mmol) in dry CH2 Cl2 (1.0 mL) was treated in one portion with N-chlorosuccinimide (37.5 mg, 0.275 mmol) and the mixture was stirred at ambient temperature until complete (as determined by TLC analysis) (72 hours). To the mixture was added (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation F, 98.8 mg, 0.300 mmol), followed by DIEA (131 μL, 0.750 mmol) and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with CH2 Cl2 (3 mL) and washed with H2 O (2×), 1 M NaOH (2×), and H2 O.TheCH2Cl2 solution was dried overNa2SO4 /activated carbon and the dried solution was filtered through a packof 4% MeOH and concentrated. The residue was purified ona SiO2 column using a step gradient elution: 50% EtOAc-hexane, EtOAc, and then 5% MeOH/EtOAc. The combined product pool was concentrated to give a colorless syrup. The syrup was treated with 50%Et2O -hexane and sonicated until a white suspension of particles formed. The solvent was decanted, and the solid was washed with 50% Et2O-hexane (2X) and dried in vacuo to give the title compound (106 mg, 76%) as a white solid. MS (apci) m/z = 560.3 (M+H).
根据实例568的方法使用适当的氨基甲酸苯酯和氨基吡咯烷中间体来制备下表中的化合物。The compounds in the following table were prepared according to the method of Example 568 using the appropriate phenyl carbamate and aminopyrrolidine intermediates.
实例574Example 574
1-(4-溴-1-苯基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-1-(4-Bromo-1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
一次性用N-溴代琥珀酰亚胺(53.4mg，0.300mmol)处理1-苯基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基氨基甲酸苯酯(90.9mg，0.250mmol)在干燥CH2Cl2(1.0mL)中的溶液并且在环境温度下搅拌混合物直到完成(通过TLC分析测定)为止(4小时)。向混合物中添加(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备F，98.8mg，0.300mmol)，接着添加DIEA(131μL，0.750mmol)，并且在环境温度下搅拌混合物3小时。用CH2Cl2(3mL)稀释混合物并且用H2O(2X)、1M NaOH(2X)和H2O洗涤。经Na2SO4/活性碳干燥CH2Cl2溶液并且通过填充的过滤干燥的溶液并且浓缩。在SiO2柱上，用以下分步梯度洗脱来纯化残余物：50％EtOAc-己烷，EtOAc，然后5％MeOH/EtOAc。浓缩合并的产物汇集物，得到无色玻璃状物。将玻璃状物溶解于Et2O中并且用己烷处理直到悬浮液形成为止。浓缩悬浮液，得到呈白色固体状的标题化合物，将其在真空中干燥(142mg，94％)。MS(apci)m/z＝604.2(M+H)。A solution of phenyl 1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-ylcarbamate (90.9 mg, 0.250 mmol) in dry CH2 Cl2 (1.0 mL) was treated in one portion with N-bromosuccinimide (53.4 mg, 0.300 mmol) and the mixture was stirred at ambient temperature until complete (as determined by TLC analysis) (4 hours). To the mixture was added (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation F, 98.8 mg, 0.300 mmol) followed by DIEA (131 μL, 0.750 mmol) and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with CH2 Cl2 (3 mL) and washed with H2 O (2×), 1 M NaOH (2×), and H2 O.TheCH2Cl2 solution was dried overNa2SO4 /activated carbon and the dried solution was filtered through a pack ofCelite® and concentrated. The residue was purified on aSiO2 column using a step gradient elution: 50% EtOAc-hexanes, EtOAc, then 5% MeOH/EtOAc. The combined product pool was concentrated to give a colorless glass. The glass was dissolved inEt2O and treated with hexanes until a suspension formed. The suspension was concentrated to give the title compound as a white solid, which was dried in vacuo (142 mg, 94%). MS (apci) m/z = 604.2 (M+H).
根据实例574的方法使用适当的氨基甲酸苯酯和氨基吡咯烷中间体来制备下表中的化合物。The compounds in the following table were prepared according to the method of Example 574 using the appropriate phenyl carbamate and aminopyrrolidine intermediates.
实例580Example 580
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-苯基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(哌啶-4-基)-1H-吡唑-5-基)脲二盐酸盐(Piperidin-4-yl)-1H-pyrazol-5-yl)urea dihydrochloride
向4-(5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯基-1H-吡唑-3-基)哌啶-1-甲酸叔丁酯(根据实例569的方法来制备；73mg，0.12mmol)在2:1EtOAc/MeOH(4mL)中的溶液中添加4M HCl的二噁烷溶液(3mL)并且在环境温度下搅拌反应物直到完成(通过HPLC分析测定)为止(2小时)。浓缩混合物，并且用50％EtOAc-己烷处理残余物。超声混合物直到精细颗粒悬浮液形成为止。收集固体，用50％EtOAc-己烷洗涤并且在真空中干燥，得到呈白色固体状的标题化合物(70mg，100％)。MS(apci)m/z＝525.8(M+H)。To a solution of tert-butyl 4-(5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)piperidine-1-carboxylate (prepared according to the method of Example 569; 73 mg, 0.12 mmol) in 2:1 EtOAc/MeOH (4 mL) was added 4M HCl in dioxane (3 mL) and the reaction was stirred at ambient temperature until completion (as determined by HPLC analysis) (2 hours). The mixture was concentrated, and the residue was treated with 50% EtOAc-hexanes. The mixture was sonicated until a fine particle suspension was formed. The solid was collected, washed with 50% EtOAc-hexanes and dried in vacuo to give the title compound (70 mg, 100%) as a white solid. MS (apci) m/z=525.8 (M+H).
根据实例580的方法使用适当的N-Boc中间体来制备下表中的化合物。The compounds in the following table were prepared according to the method of Example 580 using the appropriate N-Boc intermediate.
实例592Example 592
1-(4-溴-3-(1-(甲磺酰基)哌啶-4-基)-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-1-(4-Bromo-3-(1-(methylsulfonyl)piperidin-4-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(3,4-Difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
用DIEA(72.1μL，0.414mmol)处理1-(4-溴-1-苯基-3-(哌啶-4-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲二盐酸盐(实例582，70mg，0.103mmol)在干燥CH2Cl2(1mL)中的悬浮液并且在环境温度下搅拌混合物5分钟。将所得到的均质溶液冷却至0℃并且添加MsCl(8.41μL，0.109mmol)。搅拌混合物2小时，期间温度逐渐升高至环境温度。用CH2Cl2(3mL)稀释混合物并且用H2O(2X)洗涤。经Na2SO4干燥CH2Cl2溶液，过滤并且浓缩。在SiO2上，用50％EtOAc-己烷，然后5％MeOH/EtOAc洗脱来纯化残余物。浓缩合并的产物汇集物并且在50％Et2O-己烷下超声残余无色玻璃状物直到颗粒悬浮液形成为止。倾析溶剂并且在真空中干燥固体，得到呈淡粉红色固体状的标题化合物(54mg，77％)。MS(apci)m/z＝681.2(M+H)。A suspension of 1-(4-bromo-1-phenyl-3-(piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea dihydrochloride (Example 582, 70 mg, 0.103 mmol) in dry CH2 Cl2 (1 mL) was treated with DIEA (72.1 μL, 0.414 mmol) and the mixture was stirred at ambient temperature for 5 minutes. The resulting homogeneous solution was cooled to 0° C. and MsCl (8.41 μL, 0.109 mmol) was added. The mixture was stirred for 2 hours, during which the temperature was gradually increased to ambient temperature. The mixture was diluted with CH2 Cl2 (3 mL) and washed with H2 O (2×). The CH2 Cl2 solution was dried over Na2 SO4 , filtered and concentrated. The residue was purified on SiO2 eluting with 50% EtOAc-hexanes followed by 5% MeOH/EtOAc. The combined product pools were concentrated and the remaining colorless glass was sonicated under 50% Et2 O-hexanes until a particle suspension formed. The solvent was decanted and the solid was dried in vacuo to afford the title compound (54 mg, 77%) as a pale pink solid. MS (apci) m/z = 681.2 (M+H).
实例593Example 593
1-(3-(1-乙酰基哌啶-4-基)-4-溴-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-1-(3-(1-acetylpiperidin-4-yl)-4-bromo-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
用DIEA(73.3μL，0.420mmol)处理1-(4-溴-1-苯基-3-(哌啶-4-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲二盐酸盐(实例582，71mg，0.105mmol)在干燥CH2Cl2(1mL)中的悬浮液并且在环境温度下搅拌混合物5分钟。将所得到的均质溶液冷却至0℃并且添加Ac2O(10.4μL，0.110mmol)。搅拌混合物1小时，期间温度逐渐达到10℃。用CH2Cl2(3mL)稀释混合物并且用H2O(2X)洗涤。经Na2SO4干燥溶液，过滤并且浓缩。在SiO2上，用以下分步梯度洗脱来纯化残余物：EtOAc(5％)，然后10％MeOH/EtOAc。浓缩合并的产物汇集物并且将残余无色玻璃状物溶解于50％CH2Cl2/己烷中。浓缩溶液，得到呈奶白色固体状的标题化合物，将其在真空中干燥(50mg，74％)。MS(apci)m/z＝645.2(M+H)。A suspension of 1-(4-bromo-1-phenyl-3-(piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea dihydrochloride (Example 582, 71 mg, 0.105 mmol) in dry CH2 Cl2 (1 mL) was treated with DIEA (73.3 μL, 0.420 mmol) and the mixture was stirred at ambient temperature for 5 minutes. The resulting homogeneous solution was cooled to 0° C. and Ac2 O (10.4 μL, 0.110 mmol) was added. The mixture was stirred for 1 hour, during which the temperature gradually reached 10° C. The mixture was diluted with CH2 Cl2 (3 mL) and washed with H2 O (2×). The solution was dried over Na2 SO4 , filtered and concentrated. The residue was purified onSiO2 using a step gradient elution of 5% EtOAc followed by 10% MeOH/EtOAc. The combined product pools were concentrated and the remaining colorless glass was dissolved in 50%CH2Cl2 /hexanes . The solution was concentrated to afford the title compound as a cream-colored solid, which was dried in vacuo (50 mg, 74%). MS (apci) m/z = 645.2 (M+H).
实例594Example 594
1-(4-氯-1-苯基-3-(1-(三氟甲磺酰基)哌啶-4-基)-1H-吡唑-5-基)-3-((3S,1-(4-chloro-1-phenyl-3-(1-(trifluoromethanesulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲盐酸盐4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea hydrochloride
用DIEA(66.3μL，0.380mmol)处理1-(4-氯-1-苯基-3-(哌啶-4-基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲二盐酸盐(实例581，60mg，0.0949mmol)在干燥CH2Cl2(1.5mL)中的悬浮液并且在环境温度下搅拌混合物5分钟。将所得到的均质溶液冷却至-40℃(干冰、CH3CN浴)并且添加三氟甲磺酸酐(17.3μL，0.103mmol)。搅拌混合物1小时，期间温度达到-5℃。浓缩反应混合物，并且用H2O(3×，在超声下)洗涤残余物并且用50％EtOAc-己烷处理。超声混合物，用MgSO4处理并且搅拌30分钟。通过盖有MgSO4层的填充的过滤混合物，使用50％EtOAc-己烷进行冲洗和洗脱。浓缩滤液，得到无色泡沫状物。将泡沫状物溶解于EtOAc(3mL)中并且用2M HCl的Et2O溶液(300μL)处理。搅拌所得到的混浊白色混合物5分钟并且通过填充的过滤(EtOAc冲洗)。浓缩滤液，得到呈奶白色固体状的标题化合物，将其在真空中干燥(32mg，46％)。MS(apci)m/z＝691.2(M+H)。A suspension of 1-(4-chloro-1-phenyl-3-(piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea dihydrochloride (Example 581, 60 mg, 0.0949 mmol) in dry CH2 Cl2 (1.5 mL) was treated with DIEA (66.3 μL, 0.380 mmol) and the mixture was stirred at ambient temperature for 5 minutes. The resulting homogeneous solution was cooled to -40°C (dry ice, CH3 CN bath) and trifluoromethanesulfonic anhydride (17.3 μL, 0.103 mmol) was added. The mixture was stirred for 1 hour, during which the temperature reached -5°C. The reaction mixture was concentrated, and the residue was washed with H2 O (3× under ultrasound) and treated with 50% EtOAc-hexanes. The mixture was ultrasonicated, treated withMgSO4 and stirred for 30 minutes. The mixture was filtered through a filter covered witha layer of MgSO4 and rinsed and eluted with 50% EtOAc-hexane. The filtrate was concentrated to give a colorless foam. The foam was dissolved in EtOAc (3 mL) and treated with a2M HCl solution in Et2O (300 μL). The resulting turbid white mixture was stirred for 5 minutes and filtered through a filter (EtOAc rinse) filled with MgSO4. The filtrate was concentrated to give the title compound as a milky white solid, which was dried in vacuo (32 mg, 46%). MS (apci) m/z=691.2 (M+H).
实例595Example 595
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((R)-1-(甲磺酰基)吡咯烷-2-基)-1-苯基-1H-吡唑-5-基)脲((R)-1-(Methylsulfonyl)pyrrolidin-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea
根据对于实例592所述的程序，使用1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-3-((R)-吡咯烷-2-基)-1H-吡唑-5-基)脲二盐酸盐(实例583)来制备，得到呈白色固体状的标题化合物(84mg，83％)。MS(apci)m/z＝603.3(M+H)。Prepared according to the procedure described for Example 592 using 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((R)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)urea dihydrochloride (Example 583) to give the title compound as a white solid (84 mg, 83%). MS (apci) m/z = 603.3 (M+H).
实例596Example 596
1-(3-((R)-1-乙酰基吡咯烷-2-基)-4-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,1-(3-((R)-1-acetylpyrrolidin-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据对于实例593所述的程序，使用1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-3-((R)-吡咯烷-2-基)-1H-吡唑-5-基)脲二盐酸盐(实例583)来制备，得到呈奶白色固体状的标题化合物(89mg，94％)。MS(apci)m/z＝567.3(M+H)。Prepared according to the procedure described for Example 593 using 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((R)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)urea dihydrochloride (Example 583) to give the title compound as a cream-colored solid (89 mg, 94%). MS (apci) m/z = 567.3 (M+H).
实例597Example 597
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((R)-1-甲基吡咯烷-2-基)-1-苯基-1H-吡唑-5-基)脲二盐酸盐((R)-1-Methylpyrrolidin-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea dihydrochloride
将1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-3-((R)-吡咯烷-2-基)-1H-吡唑-5-基)脲二盐酸盐(实例583，80mg，0.134mmol)和DIEA(93.5μL，0.536mmol)在干燥CH2Cl2(2mL)中的溶液冷却至0℃并且添加碘代甲烷(9.26μL，0.147mmol)。搅拌混合物3小时，期间温度逐渐达到环境温度。用CH2Cl2(2mL)和H2O(3mL)稀释混合物并且添加1M NaOH至pH＝11。去除水层并且用H2O(2X)洗涤CH2Cl2部分，经Na2SO4干燥，过滤并且浓缩。通过SiO2色谱法，使用分步梯度洗脱(EtOAc，10％MeOH/EtOAc和10％(9:1MeOH/NH4OH)/EtOAc)纯化残余物。浓缩合并的产物汇集物，得到呈无色蜡状的游离碱产物，将其在真空中干燥。将产物的游离碱溶解于EtOAc(3mL)中并且用2M HCl的Et2O溶液(0.4mL)处理。搅拌所得到的悬浮液10分钟并且浓缩，得到呈淡棕褐色固体状的标题化合物，将其在真空中干燥(25mg，31％)。MS(apci)m/z＝539.3(M+H)。A solution of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((R)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)urea dihydrochloride (Example 583, 80 mg, 0.134 mmol) and DIEA (93.5 μL, 0.536 mmol) in dry CH2 Cl2 (2 mL) was cooled to 0° C. and iodomethane (9.26 μL, 0.147 mmol) was added. The mixture was stirred for 3 hours, during which the temperature gradually reached ambient temperature. The mixture was diluted with CH2 Cl2 (2 mL) and H2 O (3 mL) and 1 M NaOH was added to pH=11. The aqueous layer was removed and the CH2 Cl2 portion was washed with H2 O (2×), dried over Na2 SO4 , filtered and concentrated. The residue was purified bySiO2 chromatography using a step gradient elution (EtOAc, 10% MeOH/EtOAc and 10% (9:1 MeOH/NH4OH )/EtOAc). The combined product pool was concentrated to give the free base product as a colorless wax, which was dried in vacuo. The free base of the product was dissolved in EtOAc (3 mL) and treated with 2M HCl inEt2O (0.4 mL). The resulting suspension was stirred for 10 minutes and concentrated to give the title compound as a light tan solid, which was dried in vacuo (25 mg, 31%). MS (apci) m/z = 539.3 (M+H).
实例598Example 598
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((S)-1-甲基吡咯烷-2-基)-1-苯基-1H-吡唑-5-基)脲二盐酸盐((S)-1-Methylpyrrolidin-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea dihydrochloride
根据对于实例597所述的程序，使用1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-3-((S)-吡咯烷-2-基)-1H-吡唑-5-基)脲二盐酸盐(实例586)来制备，得到呈奶白色固体状的标题化合物(31mg，39％)。MS(apci)m/z＝539.3(M+H)。Prepared according to the procedure described for Example 597 using 1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((S)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)urea dihydrochloride (Example 586) to give the title compound as a cream-colored solid (31 mg, 39%). MS (apci) m/z = 539.3 (M+H).
实例599Example 599
1-(4-溴-3-((1-(甲磺酰基)哌啶-4-基氧基)甲基)-1-苯基-1H-吡唑-5-基)-3-1-(4-Bromo-3-((1-(methylsulfonyl)piperidin-4-yloxy)methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲((3S,4R)-4-(3,4-Difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
在对于合成实例592所述的程序中使用1-(4-溴-1-苯基-3-((哌啶-4-基氧基)甲基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲二盐酸盐(实例591)，得到呈白色固体状的标题化合物(23mg，88％)。MS(apci)m/z＝711.2(M+H)。1-(4-Bromo-1-phenyl-3-((piperidin-4-yloxy)methyl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea dihydrochloride (Example 591) was used in the procedure described for the synthesis of Example 592 to give the title compound (23 mg, 88%) as a white solid. MS (apci) m/z = 711.2 (M+H).
实例600Instance 600
1-(3-((1-乙酰基哌啶-4-基氧基)甲基)-4-溴-1-苯基-1H-吡唑-5-基)-3-((3S,1-(3-((1-acetylpiperidin-4-yloxy)methyl)-4-bromo-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea
根据对于实例593所述的程序，使用1-(4-溴-1-苯基-3-((哌啶-4-基氧基)甲基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲二盐酸盐(实例591)来制备，得到呈白色固体状的标题化合物(24mg，96％)。MS(apci)m/z＝675.2(M+H)。Prepared according to the procedure described for Example 593 using 1-(4-bromo-1-phenyl-3-((piperidin-4-yloxy)methyl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea dihydrochloride (Example 591) to give the title compound as a white solid (24 mg, 96%). MS (apci) m/z = 675.2 (M+H).
实例601Example 601
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(4-异丙1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-isopropyl)-基-5-氧代基-4,5-二氢-1,3,4-噁二唑-2-基)-4-甲基-1-苯基-1H-吡唑-5-基)脲(5-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：5-氨基-N'-异丙基-4-甲基-1-苯基-1H-吡唑-3-甲酰肼：向5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酸(中间体171，146mg，0.672mmol)和DIEA(468μL，2.69mmol)在干燥CH2Cl2(3.0mL)中的溶液中添加氯甲酸异丁酯(98.1μL，0.739mmol)。在环境温度下搅拌混合物1小时并且冷却至0℃。一次性添加异丙基肼盐酸盐(149mg，1.34mmol)并且在环境温度下搅拌混合物48小时。用H2O(2X)洗涤混合物并且经Na2SO4干燥。通过SiO2塞，用50％EtOAc-己烷进行洗脱来洗脱干燥的溶液。将洗脱液浓缩成糖浆状物。用己烷洗涤糖浆状物并且溶解于Et2O中。浓缩溶液，得到呈油性白色固体状的粗标题化合物(148mg，54％)。MS(apci)m/z＝274.1(M+H)。粗产物含有30％的不希望的区位异构体(5-氨基-N-异丙基-4-甲基-1-苯基-1H-吡唑-3-甲酰肼)并且直接用于下一步骤。Step A:5-amino-N'-isopropyl-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid hydrazide : To a solution of 5-amino-4-methyl-1-phenyl-1H-pyrazole-3 -carboxylic acid (Intermediate 171, 146 mg, 0.672 mmol) and DIEA (468 μL, 2.69 mmol) in dryCH2Cl2 (3.0 mL) was added isobutyl chloroformate (98.1 μL, 0.739 mmol). The mixture was stirred at ambient temperature for 1 hour and cooled to 0°C. Isopropylhydrazine hydrochloride (149 mg, 1.34 mmol) was added in one portion and the mixture was stirred at ambient temperature for 48 hours. The mixture was washed withH2O (2X) anddried overNa2SO4 . The dried solution was eluted through aSiO2 plug with 50% EtOAc-hexane. The eluate was concentrated to a syrup. The syrup was washed with hexanes and dissolved inEt2O . The solution was concentrated to give the crude title compound (148 mg, 54%) as an oily white solid. MS (apci) m/z = 274.1 (M+H). The crude product contained 30% of the undesired regioisomer (5-amino-N-isopropyl-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid hydrazide) and was used directly in the next step.
步骤B：5-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)-3-异丙基-1,3,4-噁二唑-2(3H)-酮：向粗5-氨基-N'-异丙基-4-甲基-1-苯基-1H-吡唑-3-甲酰肼(148mg，0.379mmol)在干燥CH2Cl2(3mL)中的溶液中一次性添加三光气(57.4mg，0.190mmol)并且在环境温度下搅拌所得到的白色悬浮液17小时。缓慢添加DIEA(264μL，1.52mmol)并且在环境温度下搅拌所得到的均质溶液4小时。用H2O(3X)洗涤混合物，经Na2SO4干燥，过滤并且浓缩。在SiO2柱上，使用25％EtOAc-己烷进行洗脱来纯化残余物。得到呈白色泡沫状的产物，将其在真空中干燥(35mg，31％)。MS(apci)m/z＝300.1(M+H)。Step B:5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-3-isopropyl-1,3,4-oxadiazol-2(3H)-one : To a solution of crude 5-amino-N'-isopropyl-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid hydrazide (148 mg, 0.379 mmol) in dryCH2Cl2 (3mL ) was added triphosgene (57.4 mg, 0.190 mmol) in one portion and the resulting white suspension was stirred at ambient temperature for 17 hours. DIEA (264 μL, 1.52 mmol) was slowly added and the resulting homogeneous solution was stirred at ambient temperature for 4 hours. The mixture was washed withH2O (3X), driedoverNa2SO4 , filtered and concentrated. The residue was purified on aSiO2 column eluting with 25% EtOAc-hexane. The product was obtained as a white foam which was dried in vacuo (35 mg, 31%). MS (apci) m/z = 300.1 (M+H).
步骤C：3-(4-异丙基-5-氧代基-4,5-二氢-1,3,4-噁二唑-2-基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯：将5-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)-3-异丙基-1,3,4-噁二唑-2(3H)-酮(30mg，0.100mmol)在EtOAc(1mL)中的溶液冷却至0℃。依序添加NaOH(251μL，0.501mmol)和氯甲酸苯酯(37.7μL，0.301mmol)并且搅拌混合物5分钟。去除冰浴，并且在环境温度下搅拌混合物16小时。用H2O(2X)、1M HCl、H2O和饱和NaCl洗涤混合物。用1等体积的己烷稀释有机层并且经MgSO4干燥。通过SiO2塞，用50％EtOAc-己烷进行洗脱来洗脱溶液。浓缩洗脱液并且用己烷(3×，在超声下)洗涤残余白色固体，并且在真空中干燥，得到标题化合物(28mg，67％)。MS(apci)m/z＝420.1(M+H)。Step C:Phenyl 3-(4-isopropyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate : A solution of 5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-3-isopropyl-1,3,4-oxadiazol-2(3H)-one (30 mg, 0.100 mmol) in EtOAc (1 mL) was cooled to 0°C. NaOH (251 μL, 0.501 mmol) and phenyl chloroformate (37.7 μL, 0.301 mmol) were added sequentially and the mixture was stirred for 5 minutes. The ice bath was removed and the mixture was stirred at ambient temperature for 16 hours. The mixture was washed withH2O (2X), 1M HCl,H2O , and saturated NaCl. The organic layer was diluted with 1 equal volume of hexanes and dried over MgSO4. The solution was eluted through a SiO2 plug using 50% EtOAc-hexanes. The eluent was concentrated and the residual white solid was washed with hexanes (3× under ultrasound) and dried in vacuo to give the title compound (28 mg, 67%). MS (apci) m/z=420.1 (M+H).
步骤D：1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-(4-异丙基-5-氧代基-4,5-二氢-1,3,4-噁二唑-2-基)-4-甲基-1-苯基-1H-吡唑-5-基)脲：向3-(4-异丙基-5-氧代基-4,5-二氢-1,3,4-噁二唑-2-基)-4-甲基-1-苯基-1H-吡唑-5-基氨基甲酸苯酯(26mg，0.0620mmol)和(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(制备F，26.5mg，0.0806mmol)在CH2Cl2(1mL)中的混合物中添加DIEA(54.1μL，0.310mmol)。在环境温度下搅拌所得到的均质溶液3小时。用CH2Cl2(2mL)稀释混合物并且用H2O(2X)、1M NaOH(2X)和H2O洗涤。经Na2SO4干燥CH2Cl2溶液，过滤并且浓缩。在SiO2柱上，用分步梯度洗脱：50％EtOAc/己烷，EtOAc，然后5％MeOH/EtOAc来纯化残余物。浓缩合并的产物汇集物，得到无色玻璃状物。将玻璃状物溶解于1:1CH2Cl2/己烷中，并且浓缩，得到呈白色固体状的标题化合物，将其在真空中干燥(20mg，56％)。MS(apci)m/z＝582.2(M+H)。Step D:1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-isopropyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea : To phenyl 3-(4-isopropyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-ylcarbamate (26 mg, 0.0620 mmol) and (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation F, 26.5 mg, 0.0806 mmol) inCH2Cl2 was added. To the mixture in 4% paraffin wax (1 mL) was added DIEA (54.1 μL, 0.310 mmol). The resulting homogeneous solution was stirred at ambient temperature for 3 hours. The mixture was diluted with CH2 Cl2 (2 mL) and washed with H2 O (2×), 1 M NaOH (2×) and H2 O. The CH2 Cl2 solution was dried over Na2 SO4 , filtered and concentrated. The residue was purified on a SiO2 column using a step gradient elution: 50% EtOAc/hexane, EtOAc, then 5% MeOH/EtOAc. The combined product pool was concentrated to give a colorless glass. The glass was dissolved in 1:1 CH2 Cl2 /hexane and concentrated to give the title compound as a white solid, which was dried in vacuo (20 mg, 56%). MS (apci) m/z=582.2 (M+H).
实例602Example 602
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(4-甲基-5-氧代基-4,5-二氢-1,3,4-噁二唑-2-基)-1-苯基-1H-吡唑-5-基)脲(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea
步骤A：2-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-羰基)-1-甲肼甲酸叔丁酯：向5-氨基-4-甲基-1-苯基-1H-吡唑-3-甲酸(中间体171，0.434g，2.00mmol)在干燥CH2Cl2(5mL)中的精细悬浮液中添加DIEA(0.766mL，4.40mmol)并且在环境温度下搅拌混合物5分钟。用氯甲酸异丁酯(0.292mL，2.20mmol)处理所得到的溶液并且搅拌混合物2小时。添加1-甲肼甲酸叔丁酯(0.308mL，2.00mmol)并且在环境温度下搅拌混合物23小时。用H2O(2X)洗涤混合物，经Na2SO4干燥，并且通过SiO2塞(50％EtOAc-己烷进行洗脱)洗脱干燥的CH2Cl2溶液。将洗脱液浓缩成无色蜡状固体。用50％Et2O-己烷处理固体并且搅拌直到颗粒白色悬浮液形成为止。倾析溶剂，用50％Et2O-己烷洗涤残余固体并且在真空中干燥，得到呈白色粉末状的标题化合物(550mg，80％)。MS(apci)m/z＝346.2(M+H)。Step A:tert-Butyl 2-(5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbonyl)-1-methylhydrazinecarboxylate : To a fine suspension of 5-amino-4-methyl-1-phenyl-1H -pyrazole-3-carboxylic acid (Intermediate 171, 0.434 g, 2.00 mmol) in dryCH2Cl2 (5 mL) was added DIEA (0.766 mL, 4.40 mmol) and the mixture was stirred at ambient temperature for 5 minutes. The resulting solution was treated with isobutyl chloroformate (0.292 mL, 2.20 mmol) and the mixture was stirred for 2 hours. tert-Butyl 1-methylhydrazinecarboxylate (0.308 mL, 2.00 mmol) was added and the mixture was stirred at ambient temperature for 23 hours. The mixture was washed withH2O (2X ), dried overNa2SO4 , and the driedCH2Cl2 solution was eluted through aSiO2 plug (50% EtOAc-hexanes ). The eluent was concentrated to a colorless waxy solid. The solid was treated with 50%Et2O -hexane and stirred until a white suspension of particles formed. The solvent was decanted, and the residual solid was washed with 50%Et2O -hexane and dried in vacuo to give the title compound (550 mg, 80%) as a white powder. MS (apci) m/z = 346.2 (M+H).
步骤B：5-氨基-N',4-二甲基-1-苯基-1H-吡唑-3-甲酰肼二盐酸盐：向2-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-羰基)-1-甲肼甲酸叔丁酯(540mg，1.56mmol)在EtOAc(10mL)中的溶液中添加4M HCl的二噁烷溶液(7.82mL，31.3mmol)并且在环境温度下搅拌混合物17小时。浓缩所得到的白色悬浮液并且在真空中干燥残余白色固体，得到标题化合物(490mg，99％)。MS(apci)m/z＝246.1(M+H)。1H NMR(DMSO d6)δ11.6(br s,2H),11.3(s,1H),7.63(d,2H),7.54(t,2H),7.44(t,1H),2.82(s,3H),2.13(s,3H)。Step B:5-Amino-N',4-dimethyl-1-phenyl-1H-pyrazole-3-carboxylic acid hydrazide dihydrochloride : To a solution of tert-butyl 2-(5-amino-4-methyl-1-phenyl-1H-pyrazole-3-carbonyl)-1-methylhydrazinecarboxylate (540 mg, 1.56 mmol) in EtOAc (10 mL) was added 4M HCl in dioxane (7.82 mL, 31.3 mmol) and the mixture was stirred at ambient temperature for 17 hours. The resulting white suspension was concentrated and the residual white solid was dried in vacuo to give the title compound (490 mg, 99%). MS (apci) m/z = 246.1 (M+H).1 H NMR(DMSO d6 )δ11.6(br s,2H),11.3(s,1H),7.63(d,2H),7.54(t,2H),7.44(t,1H),2.82(s,3H),2.13(s,3H).
步骤C：5-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)-3-甲基-1,3,4-噁二唑-2(3H)-酮：将5-氨基-N',4-二甲基-1-苯基-1H-吡唑-3-甲酰肼二盐酸盐(484mg，1.52mmol)和DIEA(1.32mL，7.61mmol)在干燥CH2Cl2(10mL)中的溶液冷却至0℃并且一次性添加三光气(230mg，0.761mmol)。搅拌混合物17小时，期间温度在2小时后达到环境温度。再添加DIEA(0.40mL)并且搅拌混合物5小时。用H2O(3X)洗涤混合物，经Na2SO4干燥，并且通过短SiO2柱用25％EtOAc-己烷进行洗脱来洗脱干燥的溶液。浓缩洗脱液并且用50％Et2O-己烷处理残余蜡状固体并且搅拌直到精细颗粒悬浮液形成为止。倾析溶剂并且用50％Et2O-己烷(2X)洗涤残余固体并且在真空中干燥，得到呈奶白色固体状的标题化合物(197mg，48％)。MS(apci)m/z＝272.1(M+H)。Step C:5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one : A solution of 5-amino-N',4-dimethyl-1-phenyl-1H-pyrazole-3-carboxylic acid hydrazide dihydrochloride (484 mg, 1.52 mmol) and DIEA (1.32 mL, 7.61 mmol) in dryCH2Cl2 (10 mL) was cooled to 0°C and triphosgene (230 mg, 0.761 mmol) was added inone portion. The mixture was stirred for 17 hours, during which the temperature reached ambient temperature after 2 hours. Additional DIEA (0.40 mL) was added and the mixture was stirred for 5 hours. The mixture was washed withH2O (3X), dried overNa2SO4 , and the dried solution was eluted through a shortSiO2 column eluting with 25% EtOAc-hexanes. The eluent was concentrated and the residual waxy solid was treated with 50%Et2O -hexanes and stirred until a fine particle suspension formed. The solvent was decanted and the residual solid was washed with 50%Et2O -hexanes (2X) and dried in vacuo to give the title compound as a cream solid (197 mg, 48%). MS (apci) m/z = 272.1 (M+H).
步骤D：4-甲基-3-(4-甲基-5-氧代基-4,5-二氢-1,3,4-噁二唑-2-基)-1-苯基-1H-吡唑-5-基氨基甲酸苯酯：在对于制备实例601(步骤C)所述的程序中使用5-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)-3-甲基-1,3,4-噁二唑-2(3H)-酮，得到呈白色固体状的标题化合物(80mg，59％)。MS(apci)m/z＝272.1(氨基吡唑片段M+H)。Step D:Phenyl 4-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate : Using 5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one in the procedure described for Preparation Example 601 (Step C), the title compound was obtained as a white solid (80 mg, 59%). MS (apci) m/z = 272.1 (aminopyrazole fragment M+H).
步骤E：1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-(4-甲基-5-氧代基-4,5-二氢-1,3,4-噁二唑-2-基)-1-苯基-1H-吡唑-5-基)脲：根据实例601步骤D的方法，使用4-甲基-3-(4-甲基-5-氧代基-4,5-二氢-1,3,4-噁二唑-2-基)-1-苯基-1H-吡唑-5-基氨基甲酸苯酯来制备。分离呈白色固体状的标题化合物(50mg，60％)。MS(apci)m/z＝554.2(M+H)。Step E:1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea : Prepared according to the method of Example 601, Step D using phenyl 4-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate. The title compound was isolated as a white solid (50 mg, 60%). MS (apci) m/z = 554.2 (M+H).
实例603Example 603
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl)基-3-(吡嗪-2-基氧基)-1H-吡唑-5-基)脲3-(pyrazin-2-yloxy)-1H-pyrazol-5-yl)urea
步骤A：4-甲基-1-苯基-3-(吡嗪-2-基氧基)-1H-吡唑-5-胺：在密封管中合并5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮(制备P135步骤A，300mg，1.59mmol)、2-氯吡嗪(185mg，1.59mmol)、CuCN(14.2mg，0.159mmol)、碳酸铯(620mg，1.90mmol)与干燥的DMF(3.2mL)。添加乙二胺(23.3μL，0.349mmol)并且用N2吹拂容器并且密封。在110℃下搅拌混合物18小时并且冷却至环境温度。将混合物添加至冰H2O(30mL)中并且搅拌10分钟。用EtOAc(3X)萃取混合物，并且用饱和NaCl(2X)洗涤合并的有机部分，经MgSO4干燥，通过填充的过滤。浓缩滤液并且在SiO2柱上用40％EtOAc-己烷洗脱来纯化残余糖浆状物，得到呈白色固体状的标题化合物(310mg，73％)。MS(apci)m/z＝268.0(M+H)。1H NMR(CDCl3)δ8.54(s,1H),8.28(s,1H),8.16(s,1H),7.58(d,2H),7.44(t,2H),7.31(t,1H),3.74(br s,2H),1.81(s,3H)。[0266] Step A:4-Methyl-1-phenyl-3-(pyrazin-2-yloxy)-1H-pyrazol-5-amine : 5-amino-4-methyl-1-phenyl-1H-pyrazol-3(2H)-one (Preparation P135, Step A, 300 mg, 1.59 mmol), 2-chloropyrazine (185 mg, 1.59 mmol), CuCN (14.2 mg, 0.159 mmol), cesium carbonate (620 mg, 1.90 mmol) and dry DMF (3.2 mL) were combined in a sealed tube. Ethylenediamine (23.3 μL, 0.349 mmol) was added and the vessel was purged withN and sealed. The mixture was stirred at 110°C for 18 hours and cooled to ambient temperature. The mixture was added to icyH2O (30 mL) and stirred for 10 minutes. The mixture was extracted with EtOAc (3×), and the combined organic fractions were washed with saturated NaCl (2×), dried over MgSO4 , and filtered through a plug of Celite®. The filtrate was concentrated and the residual syrup was purified on a SiO2 column eluting with 40% EtOAc-hexanes to give the title compound (310 mg, 73%) as a white solid. MS (apci) m/z = 268.0 (M+H).1 H NMR (CDCl3 ) δ 8.54 (s, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.58 (d, 2H), 7.44 (t, 2H), 7.31 (t, 1H), 3.74 (br s, 2H), 1.81 (s, 3H).
步骤B：1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-苯基-3-(吡嗪-2-基氧基)-1H-吡唑-5-基)脲：向4-甲基-1-苯基-3-(吡嗪-2-基氧基)-1H-吡唑-5-胺(50.0mg，0.187mmol)在干燥DMF(1.0mL)中的溶液中添加CDI(36.4mg，0.224mmol)和DIEA(49.0μL，0.281mmol)。在环境温度下搅拌混合物16小时。再添加CDI(31mg)并且搅拌混合物24小时。向混合物中添加(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺(制备L1，98.1mg，0.412mmol)并且在环境温度下搅拌混合物5小时。用冷却的H2O(4mL)稀释混合物并且用2M HCl处理所得到的乳状悬浮液至pH＝7(起始pH＝11)。用EtOAc(3X)萃取混合物并且用饱和NaCl(3X)洗涤合并的EtOAc部分。经MgSO4干燥EtOAc溶液，通过填充的过滤并且浓缩。在SiO2柱上，用分步梯度洗脱(EtOAc，5％MeOH/EtOAc，10％(9:1CH3OH/NH4OH)/EtOAc)纯化残余无色玻璃状物。使所得到的白色泡沫状物从50％EtOAc-己烷中重结晶，得到呈白色球状的标题化合物，将其压碎并且在真空中干燥(44mg，44％)。MS(apci)m/z＝532.2(M+H)。Step B:1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyrazin-2-yloxy)-1H-pyrazol-5-yl)urea : To a solution of 4-methyl-1-phenyl-3-(pyrazin-2-yloxy)-1H-pyrazol-5-amine (50.0 mg, 0.187 mmol) in dry DMF (1.0 mL) was added CDI (36.4 mg, 0.224 mmol) and DIEA (49.0 μL, 0.281 mmol). The mixture was stirred at ambient temperature for 16 hours. Additional CDI (31 mg) was added and the mixture was stirred for 24 hours. To the mixture was added (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine (Preparation L1, 98.1 mg, 0.412 mmol) and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with cooledH2O (4 mL) and the resulting milky suspension was treated with 2M HCl to pH = 7 (initial pH = 11). The mixture was extracted with EtOAc (3X) and the combined EtOAc portions were washed with saturated NaCl (3X). The EtOAc solution was dried overMgSO4 , filtered through a pack of Celite® and concentrated. The residual colorless glass was purified on aSiO2 column using a step gradient elution (EtOAc, 5% MeOH/EtOAc, 10% (9:1 CH3OH/NH4OH )/EtOAc). The resulting white foam was recrystallized from 50% EtOAc-hexanes to afford the title compound as white spheres which were crushed and dried in vacuo (44 mg, 44%). MS (apci) m/z = 532.2 (M+H).
实例604Example 604
1-((3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-基)-3-(4-甲基-1-((3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-甲基-6-氧代基-1,6-二氢吡啶-3-基)-1-苯基-1H-吡唑-5-基)脲3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea
将三光气(23.1mg，0.074mmol)在干燥CH3CN(1mL)中的溶液冷却至0℃并且经45分钟添加(3S,4R)-1-(2-甲氧基乙基)-4-(3,4,5-三氟苯基)吡咯烷-3-胺二盐酸盐(制备M，76.4mg，0.220mmol)和DIEA(115μL，0.660mmol)在干燥CH3CN(0.5mL)中的溶液。搅拌混合物1小时，期间温度达到15℃。一次性添加5-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)-1-甲基吡啶-2(1H)-酮(56.1mg，0.200mmol)并且在环境温度下搅拌混合物7小时，接着在40℃下搅拌17小时。将混合物冷却至环境温度并且用冷却H2O(4mL)稀释。用2M NaOH处理冷混合物(pH＝5)至pH＝10。用EtOAc(3X)萃取混合物并且用H2O和饱和NaCl(2X)洗涤合并的萃取物。经MgSO4干燥EtOAc溶液并且通过短SiO2柱用EtOAc，10％MeOH/EtOAc，然后用10％(9:1/CH3OH-NH4OH)/EtOAc进行洗脱来洗脱。浓缩合并的产物汇集物。用Et2O处理残余物并且搅动直到白色悬浮液形成为止。倾析溶剂并且用Et2O(2X)洗涤残余固体并且在真空中干燥，得到呈白色固体状的标题化合物(34mg，29％)。MS(apci)m/z＝581.2(M+H)。A solution of triphosgene (23.1 mg, 0.074 mmol) in dry CH3 CN (1 mL) was cooled to 0° C. and a solution of (3S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-amine dihydrochloride (Preparation M, 76.4 mg, 0.220 mmol) and DIEA (115 μL, 0.660 mmol) in dry CH3 CN (0.5 mL) was added over 45 minutes. The mixture was stirred for 1 hour, during which the temperature reached 15° C. 5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one (56.1 mg, 0.200 mmol) was added in one portion and the mixture was stirred at ambient temperature for 7 hours, then at 40° C. for 17 hours. The mixture was cooled to ambient temperature and diluted with cold H2 O (4 mL). The cold mixture (pH=5) was treated with 2M NaOH to pH=10. The mixture was extracted with EtOAc (3X) and the combined extracts were washed with H2 O and saturated NaCl (2X). The EtOAc solution was dried over MgSO4 and eluted through a short SiO2 column with EtOAc, 10% MeOH/EtOAc, and then eluted with 10% (9:1/CH3 OH-NH4 OH)/EtOAc. The combined product pool was concentrated. The residue was treated with Et2 O and stirred until a white suspension formed. The solvent was decanted and the residual solid was washed with Et2 O (2X) and dried in vacuo to give the title compound (34 mg, 29%) as a white solid. MS (apci) m/z=581.2 (M+H).
实例605Example 605
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-甲氧基-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-苯基-4-(三氟甲基)-1H-吡唑-5-基)脲1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea
步骤A：制备5-氟-3-甲氧基-1-苯基-4-(三氟甲基)-1H-吡唑：将NEt3(0.657mL，4.72mmol)和苯肼(0.561g，5.19mmol)在EtOH(2mL)中的混合物逐滴添加至1,3,3,3-四氟-1-甲氧基-2-(三氟甲基)丙-1-烯(1.00g，4.72mmol)在EtOH(3mL)中的溶液中。添加完成后，在环境温度下搅拌反应物过夜，浓缩并且通过硅胶柱色谱法用0％至10％EtOAc/己烷洗脱来纯化，得到标题化合物(372mg，1.43mmol，30.3％产率)。MS(apci)m/z＝261.1(M+H)。Step A:Preparation of 5-fluoro-3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazole : A mixture ofNEt3 (0.657 mL, 4.72 mmol) and phenylhydrazine (0.561 g, 5.19 mmol) in EtOH (2 mL) was added dropwise to a solution of 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)prop-1-ene (1.00 g, 4.72 mmol) in EtOH (3 mL). After the addition was complete, the reaction was stirred at ambient temperature overnight, concentrated, and purified by silica gel column chromatography eluting with 0% to 10% EtOAc/hexanes to afford the title compound (372 mg, 1.43 mmol, 30.3% yield). MS (apci) m/z = 261.1 (M+H).
步骤B：制备3-甲氧基-1-苯基-4-(三氟甲基)-1H-吡唑-5-胺：在密封容器中将5-氟-3-甲氧基-1-苯基-4-(三氟甲基)-1H-吡唑(400mg，1.54mmol)、肼(148mg，4.61mmol)与NEt3(643μL，4.61mmol)合并在DME(3mL)中并且在90℃砂浴中加热3小时。冷却反应物并且添加雷尼镍(132mg，1.54mmol)。在环境温度下搅拌反应物3小时，通过过滤，浓缩并且通过反相柱色谱法用0％至80％乙腈/水洗脱来纯化，得到标题化合物(322mg，1.25mmol，81.4％产率)。MS(apci)m/z＝258.1(M+H)。[0146] Step B:Preparation of 3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-amine : 5-Fluoro-3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazole (400 mg, 1.54 mmol), hydrazine (148 mg, 4.61 mmol) andNEt3 (643 μL, 4.61 mmol) were combined in DME (3 mL) in a sealed vessel and heated in a 90°C sand bath for 3 hours. The reaction was cooled and Raney nickel (132 mg, 1.54 mmol) was added. The reaction was stirred at ambient temperature for 3 hours, filtered, concentrated and purified by reverse phase column chromatography eluting with 0% to 80% acetonitrile/water to give the title compound (322 mg, 1.25 mmol, 81.4% yield). MS (apci) m/z = 258.1 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-甲氧基-1-苯基-4-(三氟甲基)-1H-吡唑-5-基)脲：将3-甲氧基-1-苯基-4-(三氟甲基)-1H-吡唑-5-胺(77mg，0.2994mmol)、CDI(50.97mg，0.3143mmol)与DIEA(521.4μL，2.994mmol)合并在0.8mL DMF中并且在环境温度下搅拌过夜。然后将0.6mL所得到的溶液添加至(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(60mg，0.18mmol)中并且在环境温度下搅拌混合物2小时，将其加载至加样装置上并且通过反相柱色谱法用5％至80％乙腈/水洗脱来纯化，得到标题化合物(40mg，0.074mmol，52％产率)。(MS(apci)m/z＝540.2(M+H))。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea : 3-Methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-amine (77 mg, 0.2994 mmol), CDI (50.97 mg, 0.3143 mmol) and DIEA (521.4 μL, 2.994 mmol) were combined in 0.8 mL of DMF and stirred at ambient temperature overnight. 0.6 mL of the resulting solution was then added to (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (60 mg, 0.18 mmol) and the mixture was stirred at ambient temperature for 2 hours, loaded onto an injection device, and purified by reverse phase column chromatography eluting with 5% to 80% acetonitrile/water to give the title compound (40 mg, 0.074 mmol, 52% yield). (MS (apci) m/z=540.2 (M+H)).
实例606Example 606
1-((3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-甲氧基-1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-苯基-4-(三氟甲基)-1H-吡唑-5-基)脲1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea
通过如实例605步骤C中所述的方法，使用(3S,4R)-4-(3,5-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备。通过反相柱色谱法，使用5％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(11mg，0.021mmol，30％产率)。MS(apci)m/z＝540.2(M+H)。Prepared by the method described in Example 605, Step C, using (3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride instead of (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride. The material was purified by reverse phase column chromatography using 5% to 80% acetonitrile/H2O as eluent to give the title compound (11 mg, 0.021 mmol, 30% yield). MS (apci) m/z = 540.2 (M+H).
实例607Example 607
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-甲氧基-1-苯1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl)基-4-(三氟甲基)-1H-吡唑-5-基)脲4-(trifluoromethyl)-1H-pyrazol-5-yl)urea
通过如实例605步骤C中所述的方法，使用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备。通过反相柱色谱法，使用5％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(22mg，0.042mmol，60％产率)。MS(apci)m/z＝522.2(M+H)。Prepared by the method described in Example 605, Step C, using (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride instead of (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride. The material was purified by reverse phase column chromatography using 5% to 80% acetonitrile/H2O as eluent to give the title compound (22 mg, 0.042 mmol, 60% yield). MS (apci) m/z = 522.2 (M+H).
实例608Example 608
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-甲氧基-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-苯基-4-(三氟甲基)-1H-吡唑-5-基)脲1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea
步骤A：制备2-甲基-3-(1-甲基-1H-咪唑-4-基)-3-氧代丙腈：在-78℃下将丙腈(0.893g，16.2mmol)逐滴添加至1M LHMDS的THF溶液(13.0mL，13.0mmol)中。搅拌混合物30分钟并且逐滴添加1-甲基-1H-咪唑-4-甲酸乙酯(1.00g，6.49mmol)在THF(20mL，加热以溶解起始物质)中的溶液。使反应物升温至环境温度，搅拌过夜，倒入冰水(50mL)中并且用EtOAc(100mL)萃取。使用2N HCl将pH调节至6.5并且用EtOAc(100mL)萃取混合物。然后使用2N HCl将pH调节至6并且用EtOAc(2×100mL)萃取混合物。干燥(MgSO4)来自pH 6.5和pH 6萃取的合并的萃取物，过滤并且浓缩，得到标题化合物(1.02g，6.25mmol，96.4％产率)。MS(apci)m/z＝164.2(M+H)。Step A:preparation of 2-methyl-3-(1-methyl-1H-imidazole-4-yl)-3-oxopropionitrile : at -78 ° C, propionitrile (0.893 g, 16.2 mmol) was added dropwise to a THF solution (13.0 mL, 13.0 mmol) of 1M LHMDS. The mixture was stirred for 30 minutes and a solution of 1-methyl-1H-imidazole-4-ethyl formate (1.00 g, 6.49 mmol) in THF (20 mL, heated to dissolve the starting material) was added dropwise. The reactant was allowed to warm to ambient temperature, stirred overnight, poured into ice water (50 mL) and extracted with EtOAc (100 mL). 2N HCl was used to adjust the pH to 6.5 and the mixture was extracted with EtOAc (100 mL). 2N HCl was then used to adjust the pH to 6 and the mixture was extracted with EtOAc (2 × 100 mL). The combined extracts from the pH 6.5 and pH 6 extractions were dried (MgSO4 ), filtered and concentrated to give the title compound (1.02 g, 6.25 mmol, 96.4% yield).MS (apci) m/z = 164.2 (M+H).
步骤B：制备4-甲基-3-(1-甲基-1H-咪唑-4-基)-1-苯基-1H-吡唑-5-胺盐酸盐：向压力容器中装入2-甲基-3-(1-甲基-1H-咪唑-4-基)-3-氧代丙腈(1.00g，6.13mmol)、绝对EtOH(12.3mL，6.13mmol)和苯肼盐酸盐(0.975g，6.74mmol)。密封反应物，在80℃下加热过夜并且浓缩，得到标题化合物(1.70g，5.87mmol，95.7％产率)。MS(apci)m/z＝254.1(M+H)。Step B:Preparation of 4-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-amine hydrochloride : A pressure vessel was charged with 2-methyl-3-(1-methyl-1H-imidazol-4-yl)-3-oxopropionitrile (1.00 g, 6.13 mmol), absolute EtOH (12.3 mL, 6.13 mmol) and phenylhydrazine hydrochloride (0.975 g, 6.74 mmol). The reaction was sealed, heated at 80° C. overnight and concentrated to give the title compound (1.70 g, 5.87 mmol, 95.7% yield). MS (apci) m/z = 254.1 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-(1-甲基-1H-咪唑-4-基)-1-苯基-1H-吡唑-5-基)脲：将4-甲基-3-(1-甲基-1H-咪唑-4-基)-1-苯基-1H-吡唑-5-胺(20mg，0.07896mmol)溶解于2mL EtOAc中并且添加NaOH(789.6μL，0.7896mmol)，接着添加氯甲酸苯酯(29.72μL，0.2369mmol)。在环境温度下搅拌反应物过夜，添加10mL EtOAc并且用盐水洗涤有机层，干燥(MgSO4)，浓缩并且溶解于CH2Cl2(1mL)中。添加(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(20mg，0.061mmol)和DIEA(88μL，0.51mmol)并且在环境温度下搅拌反应物过夜，浓缩并且通过反相柱色谱法用0％至70％乙腈/水洗脱来纯化，得到标题化合物(2.4mg，0.0045mmol，8.9％产率)。(MS(apci)m/z＝536.2(M+H))。[0266] Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea : 4-Methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-amine (20 mg, 0.07896 mmol) was dissolved in 2 mL of EtOAc and NaOH (789.6 μL, 0.7896 mmol) was added followed by phenyl chloroformate (29.72 μL, 0.2369 mmol). The reaction was stirred at ambient temperature overnight, 10 mL of EtOAc was added and the organic layer was washed with brine, dried (MgSO4 ), concentrated and dissolved inCH2Cl2 (1mL ). (3S,4R)-4-(3,4-Difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (20 mg, 0.061 mmol) and DIEA (88 μL, 0.51 mmol) were added and the reaction was stirred at ambient temperature overnight, concentrated and purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/water to give the title compound (2.4 mg, 0.0045 mmol, 8.9% yield). (MS (apci) m/z = 536.2 (M+H)).
实例609Example 609
1-((反式)-4-(4-氯-3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-5-1-((trans)-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5-氧代基-2-苯基-2,5-二氢-1H-吡唑-3-基)脲Oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea
将CDI(360mg，2.22mmol)、5-氨基-4-甲基-1-苯基-1H-吡唑-3(2H)-酮(350mg，1.85mmol)与DIEA(805μL，4.62mmol)合并在3mL DMF中并且在环境温度下搅拌过夜。再添加CDI(360mg，2.22mmol)并且在环境温度下搅拌反应物24小时。将0.2mL所得到的溶液添加至(反式)-4-(4-氯-3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(67.5mg，0.195mmol)和DIEA(80.9μl，0.465mmol)在DMF(2mL)中的溶液中并且在环境温度下搅拌3小时。将反应物加载至加样装置上并且通过反相柱色谱法用0％至70％乙腈/水洗脱来纯化，得到标题化合物(39mg，0.0799mmol，86.0％产率)。(MS(apci)m/z＝488.1(M+H))。CDI (360 mg, 2.22 mmol), 5-amino-4-methyl-1-phenyl-1H-pyrazole-3 (2H) -one (350 mg, 1.85 mmol) and DIEA (805 μ L, 4.62 mmol) are merged in 3 mL DMF and stirred at ambient temperature overnight. CDI (360 mg, 2.22 mmol) is added again and the reactant is stirred at ambient temperature for 24 hours. 0.2 mL of the resulting solution is added to a solution of (trans) -4- (4-chloro-3-fluorophenyl) -1- (2-methoxyethyl) pyrrolidin-3-amine dihydrochloride (67.5 mg, 0.195 mmol) and DIEA (80.9 μ l, 0.465 mmol) in DMF (2 mL) and stirred at ambient temperature for 3 hours. The reaction was loaded onto an injection device and purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/water to give the title compound (39 mg, 0.0799 mmol, 86.0% yield) (MS (apci) m/z = 488.1 (M+H)).
根据实例609的方法，用适当的吡咯烷中间体替代(3S,4R)-4-(4-氯-3-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备下列化合物。The following compounds were prepared according to the method of Example 609, substituting the appropriate pyrrolidine intermediate for (3S,4R)-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride.
实例615Example 615
1-(4-氰基-3-甲氧基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(4-cyano-3-methoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
步骤A：制备5-氨基-3-甲氧基-1-苯基-1H-吡唑-4-甲腈：在压力管中向苯肼(0.783g，7.24mmol)在乙醇(5mL)中的溶液中添加2-(二甲氧基亚甲基)丙二腈(1.0g，7.24mmol)。将混合物加热至100℃，持续18小时。蒸发溶剂并且通过硅胶柱色谱法用5％至35％丙酮/己烷洗脱来纯化粗产物，得到标题化合物(708mg，45.6％产率)。MS(apci)m/z＝215.1(M+H)。Step A:Preparation of 5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile : To a solution of phenylhydrazine (0.783 g, 7.24 mmol) in ethanol (5 mL) was added 2-(dimethoxymethylene)malononitrile (1.0 g, 7.24 mmol) in a pressure tube. The mixture was heated to 100° C. for 18 hours. The solvent was evaporated and the crude product was purified by silica gel column chromatography eluting with 5% to 35% acetone/hexanes to give the title compound (708 mg, 45.6% yield). MS (apci) m/z=215.1 (M+H).
步骤B：制备1-(4-氰基-3-甲氧基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲：将5-氨基-3-甲氧基-1-苯基-1H-吡唑-4-甲腈(160mg，0.747mmol)、CDI(133mg，0.822mmol)与DIEA(650μL，3.73mmol)合并在5mL DMF中并且在环境温度下搅拌3天。添加(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(295mg，0.896mmol)并且在环境温度下搅拌反应物1小时，将其加载至加样装置上并且通过反相柱色谱法用0％至70％乙腈/水洗脱来纯化，得到标题化合物(328mg，0.661mmol，88.4％产率)。MS(apci)m/z＝497.2(M+H)。Step B:Preparation of 1-(4-cyano-3-methoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea : 5-Amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile (160 mg, 0.747 mmol), CDI (133 mg, 0.822 mmol) and DIEA (650 μL, 3.73 mmol) were combined in 5 mL of DMF and stirred at ambient temperature for 3 days. (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (295 mg, 0.896 mmol) was added and the reaction was stirred at ambient temperature for 1 hour, loaded onto an injection device and purified by reverse phase column chromatography eluting with 0% to 70% acetonitrile/water to give the title compound (328 mg, 0.661 mmol, 88.4% yield). MS (apci) m/z = 497.2 (M+H).
实例616Example 616
1-((3S,4R)-4-(3-氯-5-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-1-((3S,4R)-4-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5-氧代基-2-苯基-2,5-二氢-1H-吡唑-3-基)脲5-Oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea
如实例615步骤B中所述，用5-氨基-3-乙基-1-苯基-1H-吡唑-4-甲腈替代5-氨基-3-甲氧基-1-苯基-1H-吡唑-4-甲腈来制备。通过反相柱色谱法，使用0％至70％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(890mg，1.80mmol，76.4％产率)。MS(apci)m/z＝495.2(M+H)。Prepared as described in Example 615, Step B, substituting 5-amino-3-ethyl-1-phenyl-1H-pyrazole-4-carbonitrile for 5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile. The material was purified by reverse phase column chromatography using 0% to 70% acetonitrile/H2O as eluent to give the title compound (890 mg, 1.80 mmol, 76.4% yield). MS (apci) m/z = 495.2 (M+H).
实例617Example 617
1-(4-氰基-1-苯基-3-(三氟甲基)-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯1-(4-cyano-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲1-(2-methoxyethyl)pyrrolidin-3-yl)urea
如实例615步骤B中所述，用5-氨基-1-苯基-3-(三氟甲基)-1H-吡唑-4-甲腈替代5-氨基-3-甲氧基-1-苯基-1H-吡唑-4-甲腈来制备。通过反相柱色谱法，使用0％至70％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(0.81g，1.52mmol，76.4％产率)。MS(apci)m/z＝535.2(M+H)。Prepared as described in Example 615, Step B, substituting 5-amino-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonitrile for 5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile. The material was purified by reverse phase column chromatography using 0% to 70% acetonitrile/H2O as eluent to give the title compound (0.81 g, 1.52 mmol, 76.4% yield). MS (apci) m/z = 535.2 (M+H).
实例618Example 618
1-(4-氰基-5-氧代基-2-苯基-2,5-二氢-1H-吡唑-3-基)-3-((3S,4R)-4-(3,4-二1-(4-cyano-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)-3-((3S,4R)-4-(3,4-dihydro-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(2-(2-(2-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea)
将1-(4-氰基-3-甲氧基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲(30mg，0.06042mmol，如实例615中所述制备)溶解于HCl(61.20mg，0.6042mmol)中并且在环境温度下搅拌两天。将反应物倒入2N NaOH(5mL)中并且用EtOAc(2×25mL)萃取。干燥(MgSO4)合并的有机萃取物，浓缩并且通过反相柱色谱法使用0％至70％乙腈/H2O作为洗脱剂纯化。分离峰1，得到标题化合物(11mg，0.02280mmol，37.73％产率)。MS(apci)m/z＝483.2(M+H)。1-(4-Cyano-3-methoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea (30 mg, 0.06042 mmol, prepared as described in Example 615) was dissolved in HCl (61.20 mg, 0.6042 mmol) and stirred at ambient temperature for two days. The reaction was poured into 2N NaOH (5 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (MgSO4 ), concentrated, and purified by reverse phase column chromatography using 0% to 70% acetonitrile/HO as eluent. Peak 1 was isolated to give the title compound (11 mg, 0.02280 mmol, 37.73% yield). MS (apci) m/z = 483.2 (M+H).
实例619Example 619
5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-3-甲5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-methyl氧基-1-苯基-1H-吡唑-4-甲酰胺Oxy-1-phenyl-1H-pyrazole-4-carboxamide
如实例618中所述，分离峰2而非峰1来制备，得到标题化合物(1.9mg，0.0037mmol，6.1％产率)。MS(apci)m/z＝515.2(M+H)。Prepared as described in Example 618, isolating Peak 2 instead of Peak 1 to give the title compound (1.9 mg, 0.0037 mmol, 6.1% yield).MS (apci) m/z = 515.2 (M+H).
根据实例618的方法，用适当的甲腈替代5-氨基-3-甲氧基-1-苯基-1H-吡唑-4-甲腈并且对于实例623至626，也用适当的吡咯烷中间体替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备下列化合物。The following compounds were prepared according to the method of Example 618, substituting the appropriate carbonitrile for 5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile and, for Examples 623 to 626, also substituting the appropriate pyrrolidine intermediate for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride.
实例627Example 627
5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl基-1H-吡唑-4-甲酰胺1H-pyrazole-4-carboxamide
步骤A：活化5-氨基-1-苯基-1H-吡唑-4-甲酰胺：将5-氨基-1-苯基-1H-吡唑-4-甲酰胺(500mg，2.47mmol)溶解于2mL CHCl3中并且添加吡啶(600μL，7.42mmol)，接着添加氯甲酸苯酯(682μL，5.44mmol)。在环境温度下搅拌反应物2小时并且用2mL 2N NaOH淬灭。在相分离过滤器板中用数份CH2Cl2萃取反应物并且浓缩合并的有机萃取物。通过硅胶柱色谱法，用5％至40％丙酮/己烷洗脱来纯化粗物质，得到双-氨基甲酸苯酯加合物(191mg，0.432mmol，17.5％产率)。MS(apci)m/z＝443.1(M+H)。Step A:Activation of 5-amino-1-phenyl-1H-pyrazole-4-carboxamide : 5-amino-1-phenyl-1H-pyrazole-4-carboxamide (500 mg, 2.47 mmol) was dissolved in2 mL of CHCl and pyridine (600 μL, 7.42 mmol) was added, followed by phenyl chloroformate (682 μL, 5.44 mmol). The reaction was stirred at ambient temperature for 2 hours and quenched with 2 mL of 2N NaOH. The reaction was extracted with several portionsofCH₂Cl₂ on a phase separation filter plate and the combined organic extracts were concentrated. The crude material was purified by silica gel column chromatography eluting with 5% to 40% acetone/hexanes to give the bis-phenyl carbamate adduct (191 mg, 0.432 mmol, 17.5% yield). MS (apci) m/z = 443.1 (M+H).
步骤B：制备5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯基-1H-吡唑-4-甲酰胺：将(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(33mg，0.099mmol)、步骤A的产物(20mg，0.045mmol)与DIEA(39μL，0.23mmol)合并在0.2mL DMF中并且在环境温度下搅拌过夜。将混合物加载至加样装置上并且通过反相柱色谱法使用0％至70％乙腈/H2O作为洗脱剂来纯化，得到标题化合物(17mg，0.035mmol，78％产率)。MS(apci)m/z＝485.2(M+H)。[0266] Step B:Preparation of 5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carboxamide : (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (33 mg, 0.099 mmol), the product of Step A (20 mg, 0.045 mmol) and DIEA (39 μL, 0.23 mmol) were combined in 0.2 mL of DMF and stirred overnight at ambient temperature. The mixture was loaded onto an apparatus and purified by reverse phase column chromatography using 0% to 70% acetonitrile/HO as eluent to give the title compound (17 mg, 0.035 mmol, 78% yield). MS (apci) m/z = 485.2 (M+H).
实例628Example 628
5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl基-1H-吡唑-4-甲酰胺1H-pyrazole-4-carboxamide
步骤A：制备2-(2,2-二氟-1-羟基亚乙基)丙二腈：向丙二腈(4g，61mmol)在甲醇中的溶液中装入甲醇钠(14g，67mmol)，接着装入2,2-二氟乙酸甲酯(8.0g，73mmol)。将反应物加热至60℃，持续4小时并且在真空中浓缩，得到标题化合物(8.7g，60mmol，100％产率)。1HNMR(400MHz,CDCl3)δppm 6.13(t,J＝54Hz,1H)。Step A:Preparation of 2-(2,2-difluoro-1-hydroxyethylidene)malononitrile : To a solution of malononitrile (4 g, 61 mmol) in methanol was charged sodium methoxide (14 g, 67 mmol) followed by methyl 2,2-difluoroacetate (8.0 g, 73 mmol). The reaction was heated to 60° C. for 4 hours and concentrated in vacuo to afford the title compound (8.7 g, 60 mmol, 100% yield).1 H NMR (400 MHz, CDCl3 ) δ ppm 6.13 (t, J=54 Hz, 1H).
步骤B：制备2-(1-氯-2,2-二氟亚乙基)丙二腈：向2-(2,2-二氟-1-羟基亚乙基)丙二腈(1.9g，13mmol)在CH2Cl2中的浆料中添加PCl5(2.7g，13mmol)并且在环境温度下搅拌反应物16小时。用CH2Cl2稀释反应物，用水和盐水洗涤，经MgSO4干燥并且浓缩，得到标题化合物(2.3g，14mmol，107％产率)。Step B:Preparation of 2-(1-chloro-2,2-difluoroethylidene)malononitrile : To a slurry of 2-(2,2-difluoro-1-hydroxyethylidene)malononitrile (1.9 g, 13 mmol) in CH2 Cl2 was added PCl5 (2.7 g, 13 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was diluted with CH2 Cl2 , washed with water and brine, dried over MgSO 4 and concentrated to give the title compound (2.3 g, 14 mmol, 107% yield).
步骤C：制备5-氨基-3-(二氟甲基)-1-苯基-1H-吡唑-4-甲腈：向2-(1-氯-2,2-二氟亚乙基)丙二腈的乙醇溶液中添加苯肼盐酸盐(2.3g，16mmol)并且将反应物加热至70℃持续4小时。在真空中浓缩反应物并且将物质分配于EtOAc与水之间。分离各层并且用盐水洗涤有机层，干燥(MgSO4)并且在真空中浓缩。通过硅胶柱色谱法，使用5％EtOAc/CH2Cl2作为洗脱剂来纯化粗物质，得到标题化合物(0.25g，1.1mmol，7.5％产率)。MS(apci)m/z＝233.1(M-H)。Step C:Preparation of 5-amino-3-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carbonitrile : To a solution of 2-(1-chloro-2,2-difluoroethylidene)malononitrile in ethanol was added phenylhydrazine hydrochloride (2.3 g, 16 mmol) and the reaction was heated to 70°C for 4 hours. The reaction was concentrated in vacuo and the material was partitioned between EtOAc and water. The layers were separated and the organic layer was washed with brine, dried (MgSO4 ) and concentrated in vacuo. The crude material was purified bysilica gel column chromatography using 5% EtOAc/CH2Cl2 as eluent to give the title compound (0.25 g, 1.1 mmol, 7.5% yield). MS (apci) m/z = 233.1 (MH).
步骤D：制备3-(二氟甲基)-5-(3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)脲基)-1-苯基-1H-吡唑-4-甲酰胺：如实例618中对于5-氨基-3-甲氧基-1-苯基-1H-吡唑-4-甲腈所述制备5-氨基-3-(二氟甲基)-1-苯基-1H-吡唑-4-甲腈。通过反相柱色谱法，使用5％至80％乙腈/H2O作为洗脱剂来纯化物质，接着通过Gilson制备型HPLC使用Chiral Technologies OD-H柱并且使用己烷/EtOH(9:1)作为洗脱剂来纯化，得到标题化合物(1.7mg，0.0032mmol，0.30％产率(两个步骤))。MS(apci)m/z＝533.2(M-H)。[0266] Step D:Preparation of 3-(difluoromethyl)-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl )pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carboxamide: 5-Amino-3-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carbonitrile was prepared as described for 5-amino-3-methoxy-1-phenyl-1H-pyrazole-4-carbonitrile in Example 618. The material was purified by reverse phase column chromatography using 5% to 80% acetonitrile/H2O as eluent followed by Gilson preparative HPLC using a Chiral Technologies OD-H column and hexanes/EtOH (9:1) as eluent to give the title compound (1.7 mg, 0.0032 mmol, 0.30% yield over two steps). MS (apci) m/z = 533.2 (MH).
实例629Example 629
1-(4-溴-3-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-1-(4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-甲氧基乙基)吡咯烷-3-基)胍二盐酸盐(methoxyethyl)pyrrolidin-3-yl)guanidine dihydrochloride
将1-(4-溴-3-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)硫脲(40mg，0.07267mmol，通过实例630中所述的方法来制备)与AgOTf(46.68mg，0.1817mmol)合并在5mL CH2Cl2中并且在冰MeOH浴中冷却。使氨气鼓泡通过溶液1分钟并且允许反应物升温至环境温度。添加HCl(5N IPA溶液，60.7μL，0.303mmol)和MeOH(2mL)并且通过过滤反应物。用数份MeOH洗涤固体并且浓缩合并的滤液并且通过反相柱色谱法使用0％至70％乙腈/0.1N HCl水溶液作为洗脱剂来纯化，得到标题化合物(11mg，0.01814mmol，24.97％产率)。MS(apci)m/z＝535.1(M+H)。1-(4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)thiourea (40 mg, 0.07267 mmol, prepared by the method described in Example 630) was combined with AgOTf (46.68 mg, 0.1817 mmol) in 5 mL of CH2 Cl2 and cooled in an ice-MeOH bath. Ammonia gas was bubbled through the solution for 1 minute and the reaction was allowed to warm to ambient temperature. HCl (5N IPA solution, 60.7 μL, 0.303 mmol) and MeOH (2 mL) were added and the reaction was filtered through Celite®. The solid was washed with several portions of MeOH and the combined filtrates were concentrated and purified by reverse phase column chromatography using 0% to 70% acetonitrile/0.1 N aqueous HCl as eluent to give the title compound (11 mg, 0.01814 mmol, 24.97% yield). MS (apci) m/z=535.1 (M+H).
实例630Example 630
1-(4-溴-3-甲基-1-苯基-1H-吡唑-5-基)-3-((3S,4R)-4-(3,4-二氟苯基)-1-(2-1-(4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-甲氧基乙基)吡咯烷-3-基)硫脲(methoxyethyl)pyrrolidin-3-yl)thiourea
将4-溴-3-甲基-1-苯基-1H-吡唑-5-胺(250mg，0.992mmol)、DIEA(864μL，4.96mmol)与二(1H-咪唑-1-基)甲硫酮(177mg，0.992mmol)合并在1mL DMF中并且在环境温度下搅拌3天并且然后在70℃下搅拌过夜。添加(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(326mg，0.992mmol)并且在环境温度下搅拌反应物24小时。将混合物加载至加样装置上并且通过反相柱色谱法使用5％至80％乙腈/H2O作为洗脱剂来纯化，得到标题化合物(364mg，0.661mmol，66.7％产率)。MS(apci)m/z＝550.1(M+H)。4-Bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine (250 mg, 0.992 mmol), DIEA (864 μL, 4.96 mmol) and bis(1H-imidazol-1-yl)methanthione (177 mg, 0.992 mmol) were combined in 1 mL of DMF and stirred at ambient temperature for 3 days and then at 70° C. overnight. (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (326 mg, 0.992 mmol) was added and the reaction was stirred at ambient temperature for 24 hours. The mixture was loaded onto a sample loading device and purified by reverse phase column chromatography using 5% to 80% acetonitrile/H2 O as eluent to give the title compound (364 mg, 0.661 mmol, 66.7% yield). MS (apci) m/z=550.1 (M+H).
实例631Example 631
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(4-甲基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-甲基-6-氧代基-1,6-二氢吡啶-3-基)-1-苯基-1H-吡唑-5-基)硫脲(1-Methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)thiourea
如对于实例630所述，用5-(5-氨基-4-甲基-1-苯基-1H-吡唑-3-基)-1-甲基吡啶-2(1H)-酮替代4-溴-3-甲基-1-苯基-1H-吡唑-5-胺来制备。通过反相柱色谱法，使用5％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(4.5mg，0.00778mmol，12.5％产率)。MS(apci)m/z＝579.2(M+H)。Prepared as described for Example 630, substituting 5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one for 4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine. The material was purified by reverse phase column chromatography using 5% to 80% acetonitrile/H2O as eluent to give the title compound (4.5 mg, 0.00778 mmol, 12.5% yield). MS (apci) m/z = 579.2 (M+H).
实例632Example 632
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1',4-二甲1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1',4-dimethyl基-1-苯基-1H,1'H-3,4'-联吡唑-5-基)硫脲1-phenyl-1H,1'H-3,4'-bipyrazol-5-yl)thiourea
如对于实例630所述，用1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-胺替代4-溴-3-甲基-1-苯基-1H-吡唑-5-胺来制备。通过反相柱色谱法，使用5％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(71mg，0.129mmol，75.8％产率)。MS(apci)m/z＝552.2(M+H)。Prepared as described for Example 630, substituting 1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-amine for 4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine. The material was purified by reverse phase column chromatography using 5% to 80% acetonitrile/H2O as eluent to give the title compound (71 mg, 0.129 mmol, 75.8% yield). MS (apci) m/z = 552.2 (M+H).
实例633Example 633
1-((3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1',4-二甲基-1-((3S,4R)-4-(4-Fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1',4-dimethyl-1-苯基-1H,1'H-3,4'-联吡唑-5-基)硫脲1-Phenyl-1H,1'H-3,4'-bipyrazol-5-yl)thiourea
如对于实例630所述，用1',4-二甲基-1-苯基-1H,1'H-3,4'-联吡唑-5-胺替代4-溴-3-甲基-1-苯基-1H-吡唑-5-胺并且用(3S,4R)-4-(4-氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐替代(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐来制备。通过反相柱色谱法，使用5％至80％乙腈/H2O作为洗脱剂来纯化物质，得到标题化合物(50mg，0.0937mmol，69.0％产率)。MS(apci)m/z＝534.2(M+H)。Prepared as described for Example 630, substituting 1',4-dimethyl-1-phenyl-1H,1'H-3,4'-bipyrazol-5-amine for 4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-amine and (3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride for (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride. The material was purified by reverse phase column chromatography using 5% to 80% acetonitrile/H2O as eluent to give the title compound (50 mg, 0.0937 mmol, 69.0% yield). MS (apci) m/z = 534.2 (M+H).
根据实例52的方法，使用适当的起始物质在适合溶剂(如CH2Cl2、DMF、DMA或CH3CN)中来制备以下化合物。The following compounds were prepared according to the method of Example 52 using appropriate starting materials ina suitable solvent such asCH2Cl2 , DMF, DMA orCH3CN .
根据实例1的方法，使用适当的起始物质在适合溶剂(如CH2Cl2、DMF、DMA或CH3CN)中来制备下列化合物。The following compounds were prepared according to the method of Example 1 using appropriate starting materials ina suitable solvent such asCH2Cl2 , DMF, DMA orCH3CN .
实例648Example 648
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(3-甲基-1-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methyl-1-苯基-1H-吡唑-4-基)脲Phenyl-1H-pyrazol-4-yl)urea
步骤A：制备3-甲基-1-苯基-1H-吡唑-4-甲酸乙酯：在环境温度下搅拌3-甲基-1H-吡唑-4-甲酸乙酯(0.600g，3.89mmol)、苯基硼酸(0.498g，4.09mmol)、Cu(OAc)2(0.530g，2.92mmol)、吡啶(0.630mL，7.78mmol)在干燥DMF(39mL)中的混合物3天。将反应混合物分配于EtOAc与水之间并且去除有机层。用EtOAc(2X)萃取水层并且用水和饱和NaCl洗涤合并的有机层。经MgSO4干燥EtOAc溶液，过滤并且浓缩。通过硅胶快速色谱法(4:1己烷/EtOAc)纯化残余物，得到标题化合物(0.428g，48％)。MS(apci)m/z＝231.1(M+H)。Step A:Preparation of ethyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate : A mixture of ethyl 3-methyl-1H-pyrazole-4-carboxylate (0.600 g, 3.89 mmol), phenylboronic acid (0.498 g, 4.09 mmol), Cu(OAc)2 (0.530 g, 2.92 mmol), and pyridine (0.630 mL, 7.78 mmol) in dry DMF (39 mL) was stirred at ambient temperature for 3 days. The reaction mixture was partitioned between EtOAc and water, and the organic layer was removed. The aqueous layer was extracted with EtOAc (2X), and the combined organic layers were washed with water and saturated NaCl. The EtOAc solution was dried overMgSO4 , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (4:1 hexanes/EtOAc) to give the title compound (0.428 g, 48%). MS (apci) m/z = 231.1 (M+H).
步骤B：制备3-甲基-1-苯基-1H-吡唑-4-甲酸：向3-甲基-1-苯基-1H-吡唑-4-甲酸乙酯(0.428g，1.86mmol)在1:1MeOH/THF(8.0mL)中的溶液中添加1M LiOH(3.72mL，3.72mmol)并且在环境温度下搅拌混合物16小时。在真空中去除溶剂，用水稀释残余物并且用Et2O(2X)萃取。用1M HCl处理水层至pH为4至5并且用EtOAc(3X)萃取。用水和饱和NaCl洗涤合并的有机部分。经MgSO4干燥EtOAc溶液，过滤并且浓缩，得到粗产物(0.280g，75％)，其未经进一步纯化即用于下一步骤中。MS(apci)m/z＝203.1(M+H)。Step B:Preparation of 3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid : To a solution of ethyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (0.428 g, 1.86 mmol) in 1:1 MeOH/THF (8.0 mL) was added 1 M LiOH (3.72 mL, 3.72 mmol) and the mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo, and the residue was diluted with water and extracted withEt2O (2X). The aqueous layer was treated with 1 M HCl to a pH of 4 to 5 and extracted with EtOAc (3X). The combined organic fractions were washed with water and saturated NaCl. The EtOAc solution was dried over MgSO4, filtered, and concentrated to give the crude product (0.280 g, 75%), which was used in the next step without further purification. MS (apci) m/z = 203.1 (M+H).
步骤C：制备1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基-乙基)吡咯烷-3-基)-3-(3-甲基-1-苯基-1H-吡唑-4-基)脲：向3-甲基-1-苯基-1H-吡唑-4-甲酸(50mg，0.25mmol)和Et3N(0.039mL，0.30mmol)在甲苯(2mL)中的溶液中添加叠氮基磷酸二苯酯(0.064mL，0.30mmol)。在回流下加热溶液1小时并且冷却至环境温度。用THF(1mL)稀释混合物并且添加(3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-胺二盐酸盐(98mg，0.30mmol)，接着添加Et3N(0.108mL，0.90mmol)。在环境温度下搅拌反应混合物16小时。将混合物分配于EtOAc与饱和NaHCO3水溶液之间。去除有机层并且用EtOAc(2X)萃取水层。用饱和NaCl洗涤合并的有机层，经MgSO4干燥，过滤并且浓缩。通过硅胶快速色谱法(5％MeOH/DCM)纯化残余物，得到标题化合物(66mg，59％)。MS(apci)m/z＝456.2(M+H)。Step C:Preparation of 1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxy-ethyl)pyrrolidin-3-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)urea : To a solution of 3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (50 mg, 0.25 mmol) andEt3N (0.039 mL, 0.30 mmol) in toluene (2 mL) was added diphenylphosphoryl azide (0.064 mL, 0.30 mmol). The solution was heated at reflux for 1 hour and cooled to ambient temperature. The mixture was diluted with THF (1 mL) and (3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (98 mg, 0.30 mmol) was added, followed byEt3N (0.108 mL, 0.90 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between EtOAc and saturated aqueousNaHCO3 . The organic layer was removed and the aqueous layer was extracted with EtOAc (2X). The combined organic layers were washed with saturated NaCl, dried overMgSO4 , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (5% MeOH/DCM) to give the title compound (66 mg, 59%). MS (apci) m/z = 456.2 (M+H).
实例649Example 649
1-((3S,4R)-4-(3,4-二氟苯基)-1-(2-甲氧基乙基)吡咯烷-3-基)-3-(1-苯基-3-1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(三氟甲基)-1H-吡唑-4-基)脲(Trifluoromethyl)-1H-pyrazol-4-yl)urea
根据对于实例648步骤C所述的程序，使用1-苯基-3-(三氟甲基)-1H-吡唑-4-甲酸作为3-甲基-1-苯基-1H-吡唑-4-甲酸的替代物来制备。MS(apci)m/z＝510.2(M+H)。Prepared according to the procedure described for Example 648, Step C, using 1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid as a substitute for 3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid. MS (apci) m/z = 510.2 (M+H).
本申请涉及如下方面：This application involves the following aspects:
1.一种式I化合物：1. A compound of formula I:
或其立体异构体、互变异构体或药学上可接受的盐、溶剂合物或前药，其中：or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
所述Y-B部分和所述NH-C(＝X)-NH部分呈反式构型；The Y-B portion and the NH-C(=X)-NH portion are in a trans configuration;
Ra、Rb、Rc和Rd独立地选自H和(1-3C)烷基；Ra ,Rb ,Rc andRd are independently selected from H and (1-3C)alkyl;
X是O、S或NH；X is O, S or NH;
R1是(1-3C烷氧基)(1-6C)烷基、(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、氨基羰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-6C)烷基、(1-3C烷基氨基)(1-3C)烷基、(1-4C烷氧基羰基)(1-6C)烷基、氨基(1-6C)烷基、羟基(1-3C烷氧基)(1-6C)烷基、二(1-3C烷氧基)(1-6C)烷基、(1-3C烷氧基)三氟(1-6C)烷基、羟基三氟(1-6C)烷基、(1-4C烷氧基羰基)(1-3C烷氧基)(1-6C)烷基、羟基羰基(1-3C烷氧基)(1-6C)烷基、hetAr5(CH2)0-1或Ar5(CH2)0-1；R1 is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3C alkyl) alkyl), (1-4C alkoxycarbonyl)(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3C alkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3C alkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4C alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl, hydroxycarbonyl(1-3C alkoxy)(1-6C)alkyl, hetAr5 (CH2 )0-1 or Ar5 (CH2 )0-1 ;
R2是H、F或OH；R2 is H, F or OH;
Y是键、-O-或-OCH2-；Y is a bond, -O- or -OCH2 -;
B是Ar1、hetAr1、1-6C烷基或(1-6C)烷氧基；B is Ar1 , hetAr1 , 1-6C alkyl or (1-6C)alkoxy;
Ar1是苯基，其任选被一个或多个独立地选自以下的取代基取代：卤素、CF3、CF3O-、(1-4C)烷氧基、羟基(1-4C)烷基、(1-6C)烷基以及CN；Ar1 is phenyl, optionally substituted with one or more substituents independently selected from halogen, CF3 , CF3 O—, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl, and CN;
hetAr1是5至6元杂芳基，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、卤素、OH、CF3、NH2以及羟基(1-2C)烷基；hetAr1 is a 5- to 6-membered heteroaryl group having 1 to 3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, halogen, OH, CF3 , NH2 and hydroxy(1-2C)alkyl;
环C是式C-1、C-2或C-3Ring C is of formula C-1, C-2 or C-3
R3是H、(1-6C)烷基、羟基(1-6C)烷基、Ar2、hetCyc1、(3-7C)环烷基或hetAr2；R3 is H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar2 , hetCyc1 , (3-7C)cycloalkyl, or hetAr2 ;
Ar2是苯基，其任选被一个或多个独立地选自以下的基团取代：卤素、(1-6C)烷基和羟甲基；Ar2 is phenyl, optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and hydroxymethyl;
hetCyc1是5至6元饱和的或部分不饱和的杂环，其具有1至2个独立地选自N和O的环杂原子；hetCyc1 is a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O;
hetAr2是5至6元杂芳基环，其具有1至3个独立地选自N、O和S的环杂原子，并且任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基和卤素；hetAr2 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S, and optionally substituted with one or more groups independently selected from: (1-6C)alkyl and halogen;
R4是H、OH、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-3C烷氧基)(1-6C)烷基、氨基(1-6C)烷基、氨基-羰基(1-6C)烷基、(1-3C)烷基磺酰胺基(1-6C)烷基、磺酰胺基(1-6C)烷基、羟基-羰基(1-6C)烷基、hetAr3(1-6C)烷基、Ar3(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、二氟(1-6C)烷氧基、三氟(1-6C)烷氧基、四氟(2-6C)烷氧基、五氟(2-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、氨基(2-6C)烷氧基、氨基羰基(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、hetCyc2(1-6C)烷氧基、hetAr3(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基[任选被F、OH、(1-6C烷基)、(1-6C)烷氧基或(1-3C烷氧基)(1-6C)烷基取代]、hetAr4、Ar4、hetCyc2(O)CH2-、(1-4C烷氧基羰基)(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、氨基羰基(1-6C)烷氧基、hetCyc2C(＝O)(1-6C)烷氧基、羟基(1-3C烷氧基)(1-6C)烷氧基、羟基三氟(1-6C)烷氧基、(1-3C)烷基磺酰胺基(1-6C)烷氧基、(1-3C)烷基酰胺基(1-6C)烷氧基、二(1-3C烷基)氨基羧基、hetCyc2C(＝O)O-、羟基二氟(1-6C)烷基、(1-4C烷基羧基)(1-6C)烷基、(1-6C)烷氧基羰基、羟基羰基、氨基羰基、(1-3C烷氧基)氨基-羰基、hetCyc3、卤素、CN、三氟甲磺酰基、N-(1-3C烷基)吡啶酮基、N-(1-3C三氟烷基)吡啶酮基、(1-4C烷基硅烷氧基)(1-6C)烷氧基、异吲哚啉-1,3-二酮基(1-6C)烷氧基或N-(1-3C烷基)噁二唑酮基；R4 is H, OH, (1-6C) alkyl, monofluoro(1-6C) alkyl, difluoro(1-6C) alkyl, trifluoro(1-6C) alkyl, tetrafluoro(2-6C) alkyl, pentafluoro(2-6C) alkyl, cyano(1-6C) alkyl, hydroxy(1-6C) alkyl, dihydroxy(2-6C) alkyl, (1-3C alkoxy)(1-6C) alkyl, amino(1-6C) alkyl, amino-carbonyl(1-6C) alkyl, (1-3C) alkylsulfonamido(1-6C) alkyl, sulfonamido(1-6C) alkyl, hydroxy-carbonyl(1-6C) alkyl, hetAr3 (1-6C) alkyl, Ar3 (1-6C) alkyl, (1-6C) alkoxy, monofluoro(1-6C) alkoxy, difluoro(1-6C) alkoxy, trifluoro(1-6C) alkoxy, tetrafluoro(2-6C) alkoxy, pentafluoro(2-6C) alkoxy, cyano(1-6C) alkoxy, hydroxy(1-6C) alkoxy, dihydroxy(2-6C) alkoxy, amino(2-6C) alkoxy, aminocarbonyl(1-6C) alkoxy, hydroxycarbonyl(1-6C) alkoxy, hetCyc2 (1-6C) alkoxy, hetAr3 (1-6C) alkoxy, Ar3 (1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6Calkyl), (1-6C)alkoxy or (1-3Calkoxy)(1-6C)alkyl], hetAr4 , Ar4 , hetCyc2 (O)CH2 -, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc2 C(=O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy, di(1-3Calkyl)aminocarboxyl, hetCyc2 C(=O)O-, hydroxydifluoro(1-6C)alkyl, (1-4Calkylcarboxyl)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, (1-3Calkoxy)amino-carbonyl, hetCyc3 , halogen, CN, trifluoromethanesulfonyl, N-(1-3C alkyl)pyridonyl, N-(1-3C trifluoroalkyl)pyridonyl, (1-4C alkylsilyloxy)(1-6C)alkoxy, isoindoline-1,3-dione(1-6C)alkoxy or N-(1-3C alkyl)oxadiazolone;
hetCyc2是4至6元杂环，其具有1至2个独立地选自N和O的环杂原子，并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、(1-4C烷基羧基)(1-6C)烷基和(1-6C)酰基；hetCyc2 is a 4- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O, and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxyl)(1-6C)alkyl, and (1-6C)acyl;
hetCyc3是4至7元杂环，其具有1至2个独立地选自N和O的环杂原子，并且任选被一个或多个独立地选自以下的取代基取代：F、CN、CF3、(1-6C)烷基、羟基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)酰基-、(1-6C)烷基磺酰基、三氟甲磺酰基以及(1-4C烷氧基)羰基；hetCyc3 is a 4- to 7-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O, and optionally substituted with one or more substituents independently selected from F, CN, CF3 , (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethanesulfonyl, and (1-4C alkoxy)carbonyl;
hetAr3是5元杂芳基环，其具有1至3个独立地选自N、O和S的环原子并且任选被(1-6C)烷基取代；hetAr3 is a 5-membered heteroaryl ring having 1 to 3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;
Ar3是苯基，其任选被(1-4C)烷氧基取代；Ar3 is phenyl, which is optionally substituted with (1-4C)alkoxy;
hetAr4是5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的取代基取代：(1-6C)烷基、卤素、CN、羟基(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、(3-6C环烷基)CH2-、(3-6C环烷基)C(＝O)-、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、(1-6C)烷基磺酰基、NH2、(1-6C烷基)氨基、二(1-6C烷基)氨基、(1-3C三氟烷氧基)、(1-3C)三氟烷基以及甲氧基苯甲基；或是9至10元双环杂芳基，其具有1至3个环氮原子；hetAr4 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S, and O, and optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH2 -, (3-6Ccycloalkyl)C(═O)-, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH2 , (1-6Calkyl)amino, di(1-6Calkyl)amino, (1-3Ctrifluoroalkoxy), (1-3C)trifluoroalkyl, and methoxybenzyl; or a 9- to 10-membered bicyclic heteroaryl having 1 to 3 ring nitrogen atoms;
Ar4是苯基，其任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基、卤素、CN、CF3、CF3O-、(1-6C)烷氧基、(1-6C烷基)OC(＝O)-、氨基羰基、(1-6C)烷基硫基、羟基(1-6C)烷基、(1-6C烷基)SO2-、HOC(＝O)-以及(1-3C烷氧基)(1-3C烷基)OC(＝O)-；Ar4 is phenyl, which is optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF3 , CF3 O-, (1-6C)alkoxy, (1-6C alkyl)OC(═O)-, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO2 -, HOC(═O)-, and (1-3C alkoxy)(1-3C alkyl)OC(═O)-;
R5是H、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、卤素、CN、(1-4C)烷氧基、羟基(1-4C)烷基、(1-3C烷氧基)(1-4C)烷基、(1-4C烷基)OC(＝O)-、(1-6C)烷基硫基、苯基[任选被一个或多个独立地选自以下的基团取代：卤素、(1-6C)烷基和(1-6C)烷氧基]、(3-4C)环烷基、氨基、氨基羰基或三氟(1-3C烷基)酰胺基；或Ris H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3Calkoxy)(1-4C)alkyl, (1-4Calkyl)OC(═O)—, (1-6C)alkylthio, phenyl [optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy], (3-4C)cycloalkyl, amino, aminocarbonyl or trifluoro(1-3Calkyl)amido; or
R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和的或不饱和的碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代，或R4 andR5 together with the atoms to which they are attached form a 5- to 6-membered saturated, partially unsaturated or unsaturated carbocyclic ring, which is optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or
R4和R5连同其所连接的原子一起形成5至6元饱和的、部分不饱和的或不饱和的杂环，其具有选自N、O或S的环杂原子，其中所述杂环任选被一个或两个独立地选自以下的取代基取代：(1-6C烷基)C(＝O)O-、(1-6)酰基、(1-6C)烷基和氧代基，并且所述硫环原子任选被氧化成S(＝O)或SO2；R4 andR5 , together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or unsaturated heterocyclic ring having ring heteroatoms selected from N, O or S, wherein the heterocyclic ring is optionally substituted with one or two substituents independently selected from (1-6C alkyl)C(═O)O—, (1-6)acyl, (1-6C)alkyl and oxo, and the sulfur ring atom is optionally oxidized to S(═O) orSO2 ;
hetAr5是5至6元杂芳基环，其具有1至3个独立地选自N、O或S的环杂原子，其中所述环任选被一个或多个独立地选自以下的取代基取代：卤素、(1-6C)烷基、(1-6C)烷氧基和CF3；hetAr5 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, or S, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, and CF3 ;
Ar5是苯基，其任选被一个或多个独立地选自以下的基团取代：卤素、(1-6C)烷基、(1-6C)烷氧基、CF3O-、(1-4C)烷氧羰基和氨基羰基；Ar5 is phenyl, optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CF3 O—, (1-4C)alkoxycarbonyl, and aminocarbonyl;
R3a是氢、卤素、(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、任选被一个或多个独立地选自卤素、(1-6C)烷基和羟甲基的取代基取代的苯基，或具有1至3个独立地选自N、O和S的环杂原子并且任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代的5至6元杂芳基环；R3a is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C)alkyl and hydroxymethyl, or a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S and optionally substituted by one or more groups independently selected from (1-6C)alkyl and halogen;
R3b是氢、(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、任选被一个或多个独立地选自卤素、(1-6C)烷基和羟甲基的取代基取代的苯基，或具有1至3个独立地选自N、O和S的环杂原子并且任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代的5至6元杂芳基环；R3b is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C)alkyl and hydroxymethyl, or a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S and optionally substituted by one or more groups independently selected from (1-6C)alkyl and halogen;
R4a是氢、(1-6C)烷基、三氟(1-6C)烷基、苯基[任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基、卤素、CN、CF3、CF3O-、(1-6C)烷氧基、(1-6C烷基)OC(＝O)-、氨基羰基、(1-6C)烷基硫基、羟基(1-6C)烷基、(1-6C烷基)SO2-、HOC(＝O)-以及(1-3C烷氧基)(1-3C烷基)OC(＝O)-]，或5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子并且任选被1至2个独立地选自以下的取代基取代：(1-6C)烷基、羟基(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、(3-6C环烷基)CH2-、(3-6C环烷基)C(＝O)-、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、(1-6C)烷基磺酰基、NH2、(1-6C烷基)氨基、二(1-6C烷基)氨基、(1-3C三氟烷氧基)(1-3C)三氟烷基以及甲氧基苯甲基；并且R4a is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionally substituted by one or more groups independently selected from the group consisting of (1-6C)alkyl, halogen, CN, CF3 , CF3 O-, (1-6C)alkoxy, (1-6C alkyl)OC(═O)-, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO2 -, HOC(═O)-, and (1-3C alkoxy)(1-3C alkyl)OC(═O)-], or a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S, and O and optionally substituted by 1 to 2 substituents independently selected from the group consisting of (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH2 -, (3-6C cycloalkyl)C(=O)-, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH2 , (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl, and methoxybenzyl; and
R5a是氢、卤素、(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、任选被一个或多个独立地选自卤素、(1-6C)烷基和羟甲基的取代基取代的苯基，或具有1至3个独立地选自N、O和S的环杂原子并且任选被一个或多个独立地选自(1-6C)烷基和卤素的基团取代的5至6元杂芳基环。R5a is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substituted by one or more substituents independently selected from halogen, (1-6C)alkyl and hydroxymethyl, or a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S and optionally substituted by one or more groups independently selected from (1-6C)alkyl and halogen.
2.根据1所述的化合物，其中：2. The compound according to 1, wherein:
B和所述NH-C(＝X)-NH部分呈反式构型；B and the NH-C(=X)-NH moiety are in a trans configuration;
Ra、Rb、Rc和Rd独立地选自H和(1-3C)烷基；Ra ,Rb ,Rc andRd are independently selected from H and (1-3C)alkyl;
X是O或S；X is O or S;
R1是(1-3C烷氧基)(1-6C)烷基、(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、氨基羰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-6C)烷基或(1-3C烷基氨基)(1-3C)烷基；Ris (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C)alkyl, or (1-3C alkylamino)(1-3C)alkyl;
R2是H、F或OH；R2 is H, F or OH;
B是Ar1或hetAr1；B is Ar1 or hetAr1 ;
Ar1是苯基，其任选被一个或多个独立地选自以下的取代基取代：卤素、CF3、CF3O-、(1-4C)烷氧基、羟基(1-4C)烷基以及(1-6C)烷基；Ar1 is phenyl, optionally substituted with one or more substituents independently selected from halogen, CF3 , CF3 O—, (1-4C)alkoxy, hydroxy(1-4C)alkyl, and (1-6C)alkyl;
hetAr1是5至6元杂芳基，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、卤素、OH、CF3、NH2以及羟基(1-2C)烷基；hetAr1 is a 5- to 6-membered heteroaryl group having 1 to 3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, halogen, OH, CF3 , NH2 and hydroxy(1-2C)alkyl;
环C是Ring C is
R3是H、(1-6C)烷基、羟基(1-6C)烷基、Ar2、hetCyc1、(3-7C)环烷基或hetAr2；R3 is H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar2 , hetCyc1 , (3-7C)cycloalkyl, or hetAr2 ;
Ar2是苯基，其任选被一个或多个独立地选自以下的基团取代：卤素、(1-6C)烷基和羟甲基；Ar2 is phenyl, optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and hydroxymethyl;
hetCyc1是5至6元饱和的或部分不饱和的杂环，其具有1至2个独立地选自N和O的环杂原子；hetCyc1 is a 5- to 6-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O;
hetAr2是5至6元杂芳基环，其具有1至3个独立地选自N、O和S的环杂原子并且任选被(1-6C)烷基取代；hetAr2 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;
R4是H、OH、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-3C烷氧基)(1-6C)烷基、氨基(1-6C)烷基、氨基-羰基(1-6C)烷基、(1-3C)烷基磺酰胺基(1-6C)烷基、磺酰胺基(1-6C)烷基、羟基-羰基(1-6C)烷基、hetAr3(1-6C)烷基、Ar3(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、二氟(1-6C)烷氧基、三氟(1-6C)烷氧基、四氟(2-6C)烷氧基、五氟(2-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、氨基(2-6C)烷氧基、氨基羰基(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、hetCyc2(1-6C)烷氧基、hetAr3(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；R4 is H, OH, (1-6C) alkyl, monofluoro(1-6C) alkyl, difluoro(1-6C) alkyl, trifluoro(1-6C) alkyl, tetrafluoro(2-6C) alkyl, pentafluoro(2-6C) alkyl, cyano(1-6C) alkyl, hydroxy(1-6C) alkyl, dihydroxy(2-6C) alkyl, (1-3C alkoxy)(1-6C) alkyl, amino(1-6C) alkyl, amino-carbonyl(1-6C) alkyl, (1-3C) alkylsulfonamido(1-6C) alkyl, sulfonamido(1-6C) alkyl, hydroxy-carbonyl(1-6C) alkyl, hetAr3 (1-6C) alkyl, Ar3 (1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc2 (1-6C)alkoxy, hetAr3 (1-6C)alkoxy, Ar3 (1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 or Ar4 ;
hetCyc2是4至6元杂环，其具有1至2个独立地选自N和O的环杂原子并且任选被1至2个独立地选自(1-6C)烷基的基团取代；hetCyc2 is a 4- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl;
hetAr3是5元杂芳基环，其具有1至3个独立地选自N、O和S的环原子并且任选被(1-6C)烷基取代；hetAr3 is a 5-membered heteroaryl ring having 1 to 3 ring atoms independently selected from N, O and S and optionally substituted with (1-6C)alkyl;
Ar3是苯基，其任选被(1-4C)烷氧基取代；Ar3 is phenyl, which is optionally substituted with (1-4C)alkoxy;
hetAr4是5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子并且任选被1至2个独立地选自(1-6C)烷基的取代基取代，或是9至10元双环杂芳基，其具有1至3个环氮原子；hetAr4 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl, or a 9- to 10-membered bicyclic heteroaryl having 1 to 3 ring nitrogen atoms;
Ar4是苯基，其任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基、卤素、CN、CF3、CF3O-、(1-6C)烷氧基、(1-6C烷基)OC(＝O)-、氨基-羰基、(1-6C)烷基硫基、羟基(1-6C)烷基、(1-6C烷基)SO2-、HOC(＝O)-以及(1-3C烷氧基)(1-3C烷基)OC(＝O)-；Ar4 is phenyl, which is optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF3 , CF3 O-, (1-6C)alkoxy, (1-6C alkyl)OC(═O)-, amino-carbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO2 -, HOC(═O)-, and (1-3C alkoxy)(1-3C alkyl)OC(═O)-;
R5是H、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、卤素、CN、(1-4C)烷氧基、羟基(1-4C)烷基、(1-3C烷氧基)(1-4C)烷基、(1-4C烷基)OC(＝O)-、(1-6C)烷基硫基，或任选被一个或多个独立地选自以下的基团取代的苯基：卤素、(1-6C)烷基和(1-6C)烷氧基；或Ris H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3Calkoxy)(1-4C)alkyl, (1-4Calkyl)OC(═O)—, (1-6C)alkylthio, or phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; or
R4和R5连同其所连接的原子一起形成5至6元饱和碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代，或R4 andR5 together with the atoms to which they are attached form a 5- to 6-membered saturated carbocyclic ring, which is optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or
R4和R5连同其所连接的原子一起形成5至6元饱和杂环，其具有选自N、O或S的环杂原子，其中所述环氮原子任选被(1-6C烷基)C(＝O)O-或(1-6)酰基取代，并且所述硫环原子任选被氧化成S(＝O)或SO2。R4 andR5 together with the atoms to which they are attached form a 5- to 6-membered saturated heterocyclic ring having ring heteroatoms selected from N, O or S, wherein the ring nitrogen atom is optionally substituted with (1-6Calkyl)C(=O)O- or (1-6)acyl, and the sulfur ring atom is optionally oxidized to S(=O) orSO2 .
3.根据1或2所述的化合物，其中X是O。3. The compound according to 1 or 2, wherein X is O.
4.根据1或2所述的化合物，其中X是S。4. The compound according to 1 or 2, wherein X is S.
5.根据1至4中任一项所述的化合物，其中R1选自(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基和三氟(1-6C)烷基。5. The compound according to any one of 1 to 4, wherein R1 is selected from (1-3C alkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl and trifluoro(1-6C)alkyl.
6.根据5所述的化合物，其中R1是(1-3C烷氧基)(1-6C)烷基。6. The compound according to 5, wherein R1 is (1-3C alkoxy)(1-6C)alkyl.
7.根据1至6中任一项所述的化合物，其中B是Ar1。7. The compound according to any one of 1 to 6, wherein B is Ar1 .
8.根据7所述的化合物，其中Ar1是任选被一个或多个卤素取代的苯基。8. The compound according to 7, wherein Ar1 is phenyl optionally substituted by one or more halogens.
9.根据1至6中任一项所述的化合物，其中环B是hetAr1。9. The compound according to any one of 1 to 6, wherein Ring B is hetAr1 .
10.根据9所述的化合物，其中环B是任选被1至2个独立地选自(1-6C)烷基或卤素的基团取代的吡啶基。10. The compound according to 9, wherein Ring B is pyridyl optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl or halogen.
11.根据1至10中任一项所述的化合物，其中环C是式C-1。11. The compound according to any one of 1 to 10, wherein ring C is of formula C-1.
12.根据11所述的化合物，其中：12. The compound according to 11, wherein:
R4是H、OH、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、氰基(1-6C)烷基、羟基(1-6C)烷基、二羟基(2-6C)烷基、(1-3C烷氧基)(1-6C)烷基、氨基(1-6C)烷基、氨基-羰基(1-6C)烷基、(1-3C)烷基磺酰胺基(1-6C)烷基、磺酰胺基(1-6C)烷基、羟基-羰基(1-6C)烷基、hetAr3(1-6C)烷基、Ar3(1-6C)烷基、(1-6C)烷氧基、单氟(1-6C)烷氧基、二氟(1-6C)烷氧基、三氟(1-6C)烷氧基、四氟(2-6C)烷氧基、五氟(2-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、二羟基(2-6C)烷氧基、氨基(2-6C)烷氧基、氨基羰基(1-6C)烷氧基、羟基羰基(1-6C)烷氧基、hetCyc2(1-6C)烷氧基、hetAr3(1-6C)烷氧基、Ar3(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(1-3C烷基磺酰基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4或Ar4；并且R4 is H, OH, (1-6C) alkyl, monofluoro(1-6C) alkyl, difluoro(1-6C) alkyl, trifluoro(1-6C) alkyl, tetrafluoro(2-6C) alkyl, pentafluoro(2-6C) alkyl, cyano(1-6C) alkyl, hydroxy(1-6C) alkyl, dihydroxy(2-6C) alkyl, (1-3C alkoxy)(1-6C) alkyl, amino(1-6C) alkyl, amino-carbonyl(1-6C) alkyl, (1-3C) alkylsulfonamido(1-6C) alkyl, sulfonamido(1-6C) alkyl, hydroxy-carbonyl(1-6C) alkyl, hetAr3 (1-6C) alkyl, Ar3 (1-6C)alkyl, (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc2 (1-6C)alkoxy, hetAr3 (1-6C)alkoxy, Ar3 (1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 or Ar4 ; and
R5是H、(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基、五氟(2-6C)烷基、卤素、CN、(1-4C)烷氧基、羟基(1-4C)烷基、(1-3C烷氧基)(1-4C)烷基、(1-4C烷基)OC(＝O)-、(1-6C)烷基硫基，或任选被一个或多个独立地选自以下的基团取代的苯基：卤素、(1-6C)烷基和(1-6C)烷氧基。R5 is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)OC(=O)-, (1-6C)alkylthio, or phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy.
13.根据12所述的化合物，其中R4选自H、(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基、(1-4C烷氧基)(1-6C)烷氧基、(3-6C)环烷基、hetAr4以及Ar4。13. The compound according to 12, wherein R4 is selected from H, (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 and Ar4 .
14.根据13所述的化合物，其中R4选自(1-6C)烷基、三氟(1-6C)烷基、氰基(1-6C)烷基、(1-3C烷氧基)(1-6C)烷基以及(3-6C)环烷基。14. The compound according to 13, wherein R4 is selected from (1-6C)alkyl, trifluoro(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl and (3-6C)cycloalkyl.
15.根据13所述的化合物，其中R4选自(1-6C)烷氧基、氰基(1-6C)烷氧基、羟基(1-6C)烷氧基以及(1-4C烷氧基)(1-6C)烷氧基。15. The compound according to 13, wherein R4 is selected from (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy and (1-4Calkoxy)(1-6C)alkoxy.
16.根据15所述的化合物，其中R4选自hetAr4和Ar4。16. The compound according to 15, wherein R4 is selected from hetAr4 and Ar4 .
17.根据16所述的化合物，其中R4为Ar4。17. The compound according to 16, wherein R4 is Ar4 .
18.根据1至17中任一项所述的化合物，其中R5选自H、卤素、CN、(1-6C)烷基、(1-4C)烷氧基、羟基(1-4C)烷基、(1-6C)烷基硫基，或任选被一个或多个独立地选自以下的基团取代的苯基：卤素、(1-6C)烷基和(1-6C)烷氧基。18. A compound according to any one of 1 to 17, wherein R5 is selected from H, halogen, CN, (1-6C)alkyl, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkylthio, or phenyl optionally substituted by one or more groups independently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy.
19.根据18所述的化合物，其中R5选自H、卤素和(1-6C)烷基。19. The compound according to 18, wherein R5 is selected from H, halogen and (1-6C)alkyl.
20.根据19所述的化合物，其中R5是(1-6C)烷基。20. The compound according to 19, wherein R5 is (1-6C)alkyl.
21.根据1至11中任一项所述的化合物，其中：21. The compound according to any one of 1 to 11, wherein:
R4和R5连同其所连接的原子一起形成5至6元饱和碳环，其任选被一个或多个独立地选自(1-6C)烷基的取代基取代，或R4 andR5 together with the atoms to which they are attached form a 5- to 6-membered saturated carbocyclic ring, which is optionally substituted with one or more substituents independently selected from (1-6C)alkyl, or
R4和R5连同其所连接的原子一起形成5至6元饱和杂环，其具有选自N、O或S的环杂原子，其中所述环氮原子任选被(1-6C烷基)C(＝O)O-或(1-6)酰基取代，并且所述硫环原子任选被氧化成S(＝O)或SO2。R4 andR5 together with the atoms to which they are attached form a 5- to 6-membered saturated heterocyclic ring having ring heteroatoms selected from N, O or S, wherein the ring nitrogen atom is optionally substituted with (1-6Calkyl)C(=O)O- or (1-6)acyl, and the sulfur ring atom is optionally oxidized to S(=O) orSO2 .
22.根据1至21中任一项所述的化合物，其中R3选自H、Ar2、hetAr2和(1-6C)烷基。22. The compound according to any one of 1 to 21, wherein R3 is selected from H, Ar2 , hetAr2 and (1-6C)alkyl.
23.根据1至22中任一项所述的化合物，其中R3选自Ar2和(1-6C)烷基。23. A compound according to any one of 1 to 22, wherein R3 is selected from Ar2 and (1-6C)alkyl.
24.根据23所述的化合物，其中R3是Ar2。24. The compound according to 23, wherein R3 is Ar2 .
25.根据1至24中任一项所述的化合物，其中R2是H。25. A compound according to any one of 1 to 24, wherein R2 is H.
26.根据1至25中任一项所述的化合物，其中Ra、Rb、Rc和Rd是H。26. The compound according to any one of 1 to 25, whereinRa ,Rb ,Rc andRd are H.
27.根据1至26中任一项所述的化合物，其中式I的所述Y-B部分和所述-NH-C(＝X)-NH-部分的绝对构型为式C所示的反式构型：27. The compound according to any one of 1 to 26, wherein the absolute configuration of the Y-B portion and the -NH-C(=X)-NH- portion of Formula I is the trans configuration shown in Formula C:
28.根据1至26中任一项所述的化合物，其中式I的环B和所述-NH-C(＝X)-NH-部分的绝对构型为式D所示的反式构型：28. The compound according to any one of 1 to 26, wherein the absolute configuration of Ring B of Formula I and the -NH-C(=X)-NH- moiety is the trans configuration shown in Formula D:
29.根据1至27中任一项所述的化合物，其中Y是键。29. The compound of any one of 1 to 27, wherein Y is a bond.
30.如1所述的化合物，其选自实例1至649的化合物。30. The compound of 1, which is selected from the compounds of Examples 1 to 649.
31.一种药物组合物，其包含如在1至30中任一项所定义的式I化合物或其药学上可接受的盐以及药学上可接受的稀释剂或载体。31. A pharmaceutical composition comprising a compound of formula I as defined in any one of 1 to 30 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
32.一种用于在哺乳动物中治疗疾病或病症的方法，所述疾病或病症选自疼痛、癌症、炎症、神经变性疾病或克氏锥虫(Trypanosoma cruzi)感染，所述方法包括给所述哺乳动物施用治疗有效量的如在1至30中任一项所定义的式I化合物或其药学上可接受的盐。32. A method for treating a disease or condition in a mammal selected from pain, cancer, inflammation, a neurodegenerative disease or Trypanosoma cruzi infection, comprising administering to the mammal a therapeutically effective amount of a compound of formula I as defined in any one of 1 to 30, or a pharmaceutically acceptable salt thereof.
33.如32所述的方法，其中所述疾病或病症是疼痛。33. The method of 32, wherein the disease or condition is pain.
34.一种如在1至30中任一项所定义的式I化合物或其药学上可接受的盐，其用于治疗疼痛、癌症、炎症、神经变性疾病或克氏锥虫感染。34. A compound of formula I as defined in any one of 1 to 30, or a pharmaceutically acceptable salt thereof, for use in treating pain, cancer, inflammation, neurodegenerative diseases or Trypanosoma cruzi infection.
35.一种如在1至30中任一项所定义的式I化合物或其药学上可接受的盐在制备用于治疗疼痛、癌症、炎症、神经变性疾病或克氏锥虫感染的药剂中的用途。35. Use of a compound of formula I as defined in any one of 1 to 30 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pain, cancer, inflammation, neurodegenerative diseases or Trypanosoma cruzi infection.
36.一种用于制备如1所述的化合物的方法，所述方法包括：36. A method for preparing the compound according to 1, comprising:
(a)对于X是O的式I化合物，使具有式II的相应化合物(a) For a compound of formula I wherein X is O, the corresponding compound of formula II
与具有式III的相应化合物With the corresponding compound of formula III
在羰基二咪唑和碱存在下偶联；或Coupling in the presence of carbonyldiimidazole and a base; or
(b)对于X是S的式I化合物，使具有式II的相应化合物(b) For compounds of formula I where X is S, the corresponding compound of formula II
与具有式III的相应化合物With the corresponding compound of formula III
在二(1H-咪唑-2-基)甲烷硫酮和碱存在下偶联；或Coupling in the presence of bis(1H-imidazol-2-yl)methanethione and a base; or
(c)对于X是O的式I化合物，使具有式II的相应化合物(c) For compounds of formula I where X is O, the corresponding compound of formula II
与具有式IV的相应化合物and the corresponding compound of formula IV
在碱存在下偶联，其中L1是离去基团；或Coupling in the presence of a base, wherein L1 is a leaving group; or
(d)对于X是O的式I化合物，使具有式V的相应化合物(d) For compounds of formula I where X is O, the corresponding compound of formula V
其中L2是离去基团，与具有式III的相应化合物WhereinL2 is a leaving group, and the corresponding compound having formula III
在碱存在下偶联；或Coupling in the presence of a base; or
(e)对于X是O的式I化合物，使用二苯基磷酰基叠氮化物使具有式VI的相应化合物活化(e) For compounds of formula I where X is O, activating the corresponding compound of formula VI with diphenylphosphoryl azide
接着使所述活化的中间物与具有式III的相应化合物The activated intermediate is then reacted with the corresponding compound of formula III
在碱存在下偶联；或Coupling in the presence of a base; or
(f)对于X是O的式I化合物，使具有式II的相应化合物(f) For compounds of formula I where X is O, the corresponding compound of formula II
与具有式VII的相应化合物With the corresponding compound of formula VII
在碱存在下偶联；或Coupling in the presence of a base; or
(g)对于R1是(三氟甲氧基)(1-6C)烷基、(1-3C硫烷基)(1-6C)烷基、单氟(1-6C)烷基、二氟(1-6C)烷基、三氟(1-6C)烷基、四氟(2-6C)烷基或五氟(2-6C)烷基的式I化合物，使具有式VIII的相应化合物(g) For compounds of formula I wherein R1 is (trifluoromethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl or pentafluoro(2-6C)alkyl, the corresponding compound of formula VIII is
与具有所述(三氟甲氧基)(1-6C)烷基-L3、(1-3C硫烷基)(1-6C)烷基-L3、单氟(1-6C)烷基-L3、二氟(1-6C)烷基-L3、三氟(1-6C)烷基-L3、四氟(2-6C)烷基-L3或五氟(2-6C)烷基-L3的相应化合物，其中L3是离去原子或离去基团，在碱存在下反应；或with a corresponding compound having said (trifluoromethoxy)(1-6C)alkyl-L3 , (1-3Csulfanyl)(1-6C)alkyl-L3 , monofluoro(1-6C)alkyl-L3 , difluoro(1-6C)alkyl-L3 , trifluoro(1-6C)alkyl-L3 , tetrafluoro(2-6C)alkyl-L3 or pentafluoro(2-6C)alkyl-L3 , wherein L3 is a leaving atom or a leaving group, in the presence of a base; or
(h)对于X是O，R4是CH3OCH2-并且R5是OHCH2-的式I化合物，用无机酸处理具有通式IX的相应化合物；并且(h) for compounds of formula I wherein X is O, R4 is CH3 OCH2 - and R5 is OHCH2 -, treating the corresponding compound of formula IX with a mineral acid; and
任选去除保护基团并且任选制备其药学上可接受的盐。The protecting groups are optionally removed and a pharmaceutically acceptable salt thereof is optionally prepared.
37.一种用于制备II-A的对映异构体1的方法，所述方法包括：37. A method for preparing enantiomer 1 of II-A, the method comprising:
制备外消旋反式II-APreparation of racemic trans II-A
其中环B和NH2基团呈反式构型；wherein ring B and the NH2 group are in a trans configuration;
环B是Ar1或hetAr1；Ring B is Ar1 or hetAr1 ;
Ar1是苯基，其任选被一个或多个独立地选自以下的取代基取代：卤素、CF3、CF3O-、(1-4C)烷氧基、羟基(1-4C)烷基、(1-6C)烷基以及CN；并且Ar1 is phenyl, optionally substituted with one or more substituents independently selected from halogen, CF3 , CF3 O—, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl, and CN; and
hetAr1是5至6元杂芳基，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的基团取代：(1-6C)烷基、卤素、OH、CF3、NH2以及羟基(1-2C)烷基；hetAr1 is a 5- to 6-membered heteroaryl group having 1 to 3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1 to 2 groups independently selected from (1-6C)alkyl, halogen, OH, CF3 , NH2 and hydroxy(1-2C)alkyl;
所述方法包括：The method comprises:
用二-对甲苯甲酰基-D-酒石酸处理外消旋反式II-A，得到外消旋反式II-A的二-对甲苯甲酰基-D-酒石酸盐；Treating racemic trans-II-A with di-p-toluoyl-D-tartaric acid yields di-p-toluoyl-D-tartaric acid salt of racemic trans-II-A;
使反式II-A的二-对甲苯甲酰基-D-酒石酸盐重结晶，得到反式II-A的对映异构体1的二-对甲苯甲酰基-D-酒石酸盐；以及recrystallizing the di-p-toluoyl-D-tartrate salt of trans-II-A to obtain the di-p-toluoyl-D-tartrate salt of enantiomer 1 of trans-II-A; and
用无机碱处理反式II-A的对映异构体1的二-对甲苯甲酰基-D-酒石酸盐，得到具有如所说明的绝对构型的反式II-A的对映异构体1的游离碱：Treatment of the di-p-toluoyl-D-tartrate salt of enantiomer 1 of trans II-A with an inorganic base affords the free base of enantiomer 1 of trans II-A having the absolute configuration as illustrated:
进一步，本发明涉及如下方面：Furthermore, the present invention relates to the following aspects:
1.具有下式的化合物：1. A compound having the formula:
或其立体异构体、互变异构体或药学上可接受的盐，or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,
其中:in:
所述Y-B部分和所述NH-C(＝X)-NH部分呈反式构型；The Y-B portion and the NH-C(=X)-NH portion are in a trans configuration;
X是O；X is O;
B是Ar1,B is Ar1 ,
Y是键；Y is a bond;
环C是Ring C is
Ra、Rb、Rc和Rd是氢；Ra ,Rb ,Rc andRd are hydrogen;
R1是(1-3C烷氧基)(1-6C)烷基、二氟(1-6C)烷基或三氟(1-6C)烷基；R1 is (1-3C alkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl or trifluoro(1-6C)alkyl;
R2式氢；R2 is hydrogen;
R3是Ar2、hetAr2或(1-6C)烷基；R3 is Ar2 , hetAr2 or (1-6C)alkyl;
R4是hetAr4或Ar4；R4 is hetAr4 or Ar4 ;
R5是H、卤素或(1-6C)烷基；R5 is H, halogen or (1-6C)alkyl;
Ar1是苯基，其任选被一个或多个独立地选自以下的取代基取代：卤素、CF3、CF3O-、(1-4C)烷氧基、羟基(1-4C)烷基、(1-6C)烷基以及CN；Ar1 is phenyl, optionally substituted with one or more substituents independently selected from halogen, CF3 , CF3 O—, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl, and CN;
Ar2是苯基，其任选被一个或多个独立地选自以下的基团取代：卤素、(1-6C)烷基和羟甲基；Ar2 is phenyl, optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl, and hydroxymethyl;
hetAr2是5至6元杂芳基环，其具有1至3个独立地选自N、O和S的环杂原子，并且任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基和卤素；hetAr2 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O and S, and optionally substituted with one or more groups independently selected from: (1-6C)alkyl and halogen;
hetAr4是5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子，并且任选被1至2个独立地选自以下的取代基取代：(1-6C)烷基、卤素、CN、羟基(1-6C)烷基、三氟(1-6C)烷基、(3-6C)环烷基、(3-6C环烷基)CH2-(3-6C环烷基)C(＝O)-、(1-3C烷氧基)(1-6C)烷基、(1-6C)烷氧基、(1-6C)烷基磺酰基、NH2、(1-6C烷基)氨基、二(1-6C烷基)氨基、(1-3C三氟烷氧基)、(1-3C)三氟烷基和甲氧基苯甲基；或是9至10元双环杂芳基，其具有1至3个环氮原子；和hetAr4 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S, and O, and optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH2- (3-6Ccycloalkyl)C(=O)-, (1-3Calkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl,NH2 , (1-6Calkyl)amino, di(1-6Calkyl)amino, (1-3Ctrifluoroalkoxy), (1-3C)trifluoroalkyl, and methoxybenzyl; or is a 9- to 10-membered bicyclic heteroaryl having 1 to 3 ring nitrogen atoms; and
Ar4是苯基，其任选被一个或多个独立地选自以下的基团取代：(1-6C)烷基、卤素、CN、CF3、CF3O-、(1-6C)烷氧基、(1-6C烷基)OC(＝O)-、氨基羰基、(1-6C)烷基硫基、羟基(1-6C)烷基、(1-6C烷基)SO2-、HOC(＝O)-和(1-3C烷氧基)(1-3C烷基)OC(＝O)-。Ar4 is phenyl, which is optionally substituted with one or more groups independently selected from (1-6C)alkyl, halogen, CN, CF3 , CF3 O-, (1-6C)alkoxy, (1-6C alkyl)OC(═O)-, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO2 -, HOC(═O)- and (1-3C alkoxy)(1-3C alkyl)OC(═O)-.
2.根据1所述的化合物，其中:2. The compound according to 1, wherein:
R1是(1-3C烷氧基)(1-6C)烷基；R1 is (1-3C alkoxy)(1-6C)alkyl;
R3是Ar2；R3 is Ar2 ;
R4是hetAr4；和R4 is hetAr4 ; and
R5是(1-6C)烷基。R5 is (1-6C)alkyl.
3.根据2所述的化合物，其中Ar1是苯基，其任选被一个或多个卤素取代。3. The compound according to 2, wherein Ar1 is phenyl, which is optionally substituted with one or more halogens.
4.根据3的化合物，其中hetAr4是5至6元杂芳基环，其具有1至3个独立地选自N、S和O的环杂原子并且任选被1至2个独立地选自(1-6C)烷基的取代基取代。4. The compound according to 3, wherein hetAr4 is a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1 to 2 substituents independently selected from (1-6C)alkyl.
5.根据4所述的化合物，其选自：5. The compound according to 4, which is selected from:
或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.
6.根据5所述的化合物，其选自：6. The compound according to 5, which is selected from:
或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.
7.一种药物组合物，其包含如在1至6中任一项所定义的化合物或其药学上可接受的盐以及药学上可接受的稀释剂或载体。7. A pharmaceutical composition comprising a compound as defined in any one of 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
8.1至6中任一项所定义的化合物或其药学上可接受的盐在制备用于治疗疼痛、癌症、炎症、神经变性疾病或克氏锥虫感染的药物中的用途。8. Use of a compound as defined in any one of 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection.
9.根据8所述的用途，其中所述药物用于治疗疼痛。9. The method according to 8, wherein the drug is used to treat pain.
10.根据9所述的用途，其中所述疼痛为慢性疼痛。10. The use according to 9, wherein the pain is chronic pain.
11.根据9所述的用途，其中所述疼痛为急性疼痛。11. The use according to 9, wherein the pain is acute pain.
12.根据9所述的用途，其中所述疼痛为炎症性疼痛。12. The use according to 9, wherein the pain is inflammatory pain.
13.根据9所述的用途，其中所述疼痛为神经病性疼痛。13. The use according to 9, wherein the pain is neuropathic pain.
14.根据9所述的用途，其中所述疼痛与癌症相关。14. The use according to 9, wherein the pain is associated with cancer.
15.根据9所述的用途，其中所述疼痛与手术相关。15. The use according to 9, wherein the pain is associated with surgery.
16.根据9所述的用途，其中所述疼痛与骨折相关。16. The use according to 9, wherein the pain is associated with a bone fracture.
17.化合物，其为反式-4-苯基吡咯烷-3-基氨基甲酸叔丁酯，17. A compound which is tert-butyl trans-4-phenylpyrrolidin-3-ylcarbamate,
18.一种制备反式-4-苯基吡咯烷-3-基氨基甲酸叔丁酯的方法，包括以下步骤:18. A method for preparing trans-4-phenylpyrrolidin-3-ylcarbamic acid tert-butyl ester, comprising the following steps:
步骤A:制备反式-1-苯甲基-3-硝基-4-苯基吡咯烷，包括用TFA处理(E)-(2-硝基乙烯基)苯并冷却至–15℃，然后添加N-甲氧基甲基-N-(三甲基硅烷基甲基)苯甲胺；Step A: Preparation of trans-1-benzyl-3-nitro-4-phenylpyrrolidine by treating (E)-(2-nitrovinyl)benzene with TFA and cooling to –15°C, followed by the addition of N-methoxymethyl-N-(trimethylsilylmethyl)benzylamine;
步骤B:制备反式-1-苯甲基-4-苯基吡咯烷-3-胺，包括向于EtOH中的所述反式-1-苯甲基-3-硝基-4-苯基-吡咯烷中添加浓HCl，然后添加锌粉；Step B: Preparation of trans-1-benzyl-4-phenylpyrrolidin-3-amine comprising adding concentrated HCl to the trans-1-benzyl-3-nitro-4-phenyl-pyrrolidine in EtOH followed by zinc powder;
步骤C:制备反式-(1-苯甲基-4-苯基-吡咯烷-3-基)-氨基甲酸叔丁酯，包括向所述反式-1-苯甲基-4-苯基吡咯烷-3-胺于THF和三乙胺中的混合物中加入(Boc)2O；和Step C: preparing trans-(1-benzyl-4-phenyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester, comprising adding (Boc)2 O to a mixture of said trans-1-benzyl-4-phenylpyrrolidin-3-amine in THF and triethylamine; and
步骤D:制备反式-4-苯基吡咯烷-3-基氨基甲酸叔丁酯，包括用10％Pd/C于EtOH中处理所述反式-(1-苯甲基-4-苯基-吡咯烷-3-基)-氨基甲酸叔丁酯。Step D: Preparation of trans-tert-butyl 4-phenylpyrrolidin-3-ylcarbamate by treating the trans-(1-benzyl-4-phenyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester with 10% Pd/C in EtOH.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/485,858 | 2011-05-13 |
| Publication Number | Publication Date |
|---|---|
| HK1258894A1true HK1258894A1 (en) | 2019-11-22 |
| HK1258894B HK1258894B (en) | 2021-12-17 |
| Publication | Publication Date | Title |
|---|---|---|
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