CN111788193B - PD-1/PD-L1 small molecule inhibitor and application thereof in medicines - Google Patents
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Abstract
Description
Translated fromChinese相关申请的交叉引用：CROSS-REFERENCE TO RELATED APPLICATIONS:
本申请要求引用申请号为201810203812.4的中国专利的优先权，在先申请在中国国家知识产权局的申请日为2018.03.13，其全部内容通过引用并入本文。This application claims the priority of Chinese patent application number 201810203812.4, the application date of which was filed with the State Intellectual Property Office of China on March 13, 2018, and all the contents of which are incorporated herein by reference.
发明领域Field of the Invention
本发明公开了一类用作PD-1/PD-L1蛋白相互作用的抑制剂的小分子化合物及其制备方法和药物组合物与用途，属于药物领域。The present invention discloses a class of small molecule compounds used as inhibitors of PD-1/PD-L1 protein interaction, a preparation method thereof, a pharmaceutical composition and uses thereof, and belongs to the field of medicine.
发明背景Background of the Invention
随着社会经济的不断发展、人民生活水平逐渐提高、居民饮食结构改变加之人口老龄化、城市化、环境不断恶化等因素影响，我国的疾病谱和死亡谱发生明显的变化，恶性肿瘤的发病率呈现不断上升趋势。恶性肿瘤已成为危害人类生命健康、制约社会经济发展的头号杀手。随着医疗技术水平的提高，尽管人类对抗肿瘤的方法不断创新，目前临床运用的手术、化疗、放疗及新近出现的分子靶向药物治疗使大部分肿瘤患者得到缓解甚至治愈，但仍然有部分患者对上述治疗手段敏感性差，预后欠佳。相比其他类型的肿瘤疗法，免疫疗法能够提供持久的疗效，并已由最初的非特异性免疫治疗逐渐向特异性的免疫靶向治疗方向转化。近十多年，免疫检查点抑制剂与嵌合抗原受体T细胞疗法里程碑式的成功，推动肿瘤免疫成为继手术、放疗、化疗及靶向治疗后又一有效的癌症治疗手段。With the continuous development of social economy, the gradual improvement of people's living standards, the change of residents' dietary structure, the aging of the population, urbanization, and the deteriorating environment, the disease spectrum and death spectrum in my country have changed significantly, and the incidence of malignant tumors has shown a rising trend. Malignant tumors have become the number one killer that endangers human life and health and restricts social and economic development. With the improvement of medical technology, although human methods of fighting tumors are constantly innovating, the current clinical use of surgery, chemotherapy, radiotherapy and the newly emerging molecular targeted drug therapy have relieved or even cured most tumor patients, but there are still some patients who are not sensitive to the above treatment methods and have poor prognosis. Compared with other types of tumor therapies, immunotherapy can provide lasting therapeutic effects and has gradually transformed from the initial non-specific immunotherapy to specific immune targeted therapy. In the past decade, the milestone success of immune checkpoint inhibitors and chimeric antigen receptor T cell therapy has promoted tumor immunity to become another effective cancer treatment after surgery, radiotherapy, chemotherapy and targeted therapy.
而免疫治疗的机制是活化特异性T细胞，靶向攻击清除肿瘤细胞，激活患者体内抗肿瘤免疫系统应答。T细胞活化主要是指“双信号”介入，即第一信号由抗原肽-主要组织相容性复合体与T细胞抗原受体复合体提供，CD28与B7等协同刺激分子提供T细胞活化的第二信使。当缺乏协同刺激分子刺激时易引发T细胞应答失衡，使肿瘤逃逸机体免疫监控。作为T细胞活化的第二信号，程序性死亡受体1(programmed death receptor-1，PD-1)和其对应的配体(programmed death-ligand 1，PD-L1)信号通路的激活可抑制机体抗肿瘤免疫应答，从而通过药物阻断该通路能显著抑制肿瘤的生长。The mechanism of immunotherapy is to activate specific T cells, target and eliminate tumor cells, and activate the patient's anti-tumor immune system response. T cell activation mainly refers to the intervention of "double signals", that is, the first signal is provided by the antigen peptide-major histocompatibility complex and the T cell antigen receptor complex, and co-stimulatory molecules such as CD28 and B7 provide the second messenger for T cell activation. When there is a lack of co-stimulatory molecule stimulation, it is easy to cause an imbalance in T cell response, allowing the tumor to escape the body's immune surveillance. As the second signal of T cell activation, the activation of the programmed death receptor-1 (PD-1) and its corresponding ligand (PD-L1) signaling pathway can inhibit the body's anti-tumor immune response, so that blocking this pathway with drugs can significantly inhibit tumor growth.
PD-1又称CD279，是通过消减杂交技术在凋亡的T细胞杂交瘤中发现的一种免疫共抑制分子，它是由268个氨基酸组成的I型跨膜蛋白，属于CD28家族成员。PD-1在结构上主要由胞外Ig V样结构域、疏水跨膜区以及胞质区3部分组成，胞质区保留有免疫受体酪氨酸抑制基序(ITIM)及免疫受体酪氨酸转化基序(ITSM)。PD-1不仅表达于活化的T淋巴细胞、B淋巴细胞、自然杀伤(NK)细胞以及单核细胞等免疫细胞中，还可表达于一些肿瘤细胞系或肿瘤细胞表面。PD-L1是PD-1的一个天然配体，生理状况下，PD-1与PD-L1相互作用产生的负向信号是一种“刹车”机制，主要防止过度免疫反应带来的附加损伤。例如，外周自体反应T细胞的PD-1与组织内非造血细胞表面的PD-L1相互作用，能够抑制该T细胞群的增殖及细胞因子分泌，从而达到免疫耐受效果。肿瘤免疫过程主要发生在外周，这时的T细胞已经在初级淋巴系统接受过抗原呈递细胞的激动并成熟，表现PD-1高表达。而肿瘤细胞因受到胞外较高水平细胞因子的刺激或是某些通路的持续激活从而上调PD-L1的表达。一旦肿瘤被外周T细胞浸润，大量PD-1与PD-L1结合产生了过度的负向调节信号，使原本活跃的T细胞受体(Tcell receptor，TCR)下游信号受到抑制，T细胞逐渐失能甚至凋亡，肿瘤从而实现了免疫逃逸。PD-1, also known as CD279, is an immune co-inhibitory molecule discovered in apoptotic T cell hybridomas through subtractive hybridization. It is a type I transmembrane protein composed of 268 amino acids and belongs to the CD28 family. PD-1 is mainly composed of three parts in structure: the extracellular Ig V-like domain, the hydrophobic transmembrane region, and the cytoplasmic region. The cytoplasmic region retains the immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based conversion motif (ITSM). PD-1 is not only expressed in immune cells such as activated T lymphocytes, B lymphocytes, natural killer (NK) cells, and monocytes, but also expressed on some tumor cell lines or tumor cell surfaces. PD-L1 is a natural ligand of PD-1. Under physiological conditions, the negative signal generated by the interaction between PD-1 and PD-L1 is a "brake" mechanism that mainly prevents additional damage caused by excessive immune response. For example, the PD-1 of peripheral autoreactive T cells interacts with PD-L1 on the surface of non-hematopoietic cells in the tissue, which can inhibit the proliferation and cytokine secretion of the T cell group, thereby achieving immune tolerance. The tumor immune process mainly occurs in the periphery. At this time, the T cells have been stimulated and matured by antigen-presenting cells in the primary lymphoid system, showing high expression of PD-1. Tumor cells upregulate the expression of PD-L1 due to stimulation by high levels of extracellular cytokines or continuous activation of certain pathways. Once the tumor is infiltrated by peripheral T cells, a large number of PD-1 and PD-L1 combine to produce excessive negative regulatory signals, which inhibit the originally active T cell receptor (TCR) downstream signals, and T cells gradually become disabled or even apoptotic, so that the tumor achieves immune escape.
靶向于PD-1的单抗药物于2014年问世，分别是默克(Merck)的派姆单抗(Pembrolizumab)和百时美施贵宝(Bristol-Myers Squibb，BMS)的纳武单抗(Nivolumab)，用于治疗转移性黑色素瘤。2016年3月，罗氏旗下基因泰克(Genentech)研发的PD-L1单抗阿特珠单抗(Atezolizumab)被美国FDA批准治疗膀胱癌，同年11月获批用于治疗肺癌。与抗体药物市场的如火如荼不同，小分子免疫检查点阻断剂的研发并没有呈现出井喷的模式。现有报道的小分子抑制剂包括哈佛Sharpe课题组的苯磺酰胺类化合物，百时美施贵宝公开的2，6-二取代甲苯型免疫调节剂以及Curis/Aurigene合作开发的拟肽类分子，其中只有Curis/Aurigene合作开发的拟肽类小分子2016年6月获得美国FDA的IND申请，目前处于临床阶段。Monoclonal antibody drugs targeting PD-1 were introduced in 2014, namely, Pembrolizumab from Merck and Nivolumab from Bristol-Myers Squibb (BMS), for the treatment of metastatic melanoma. In March 2016, Atezolizumab, a PD-L1 monoclonal antibody developed by Genentech under Roche, was approved by the US FDA for the treatment of bladder cancer, and in November of the same year, it was approved for the treatment of lung cancer. Unlike the booming antibody drug market, the development of small molecule immune checkpoint blockers has not shown a blowout pattern. The small molecule inhibitors reported so far include the benzenesulfonamide compounds of Harvard Sharpe's research group, the 2,6-disubstituted toluene-type immunomodulator disclosed by Bristol-Myers Squibb, and the peptidomimetic molecules jointly developed by Curis/Aurigene. Among them, only the peptidomimetic small molecule jointly developed by Curis/Aurigene obtained the IND application from the US FDA in June 2016 and is currently in the clinical stage.
相对于抗体药物，小分子抑制剂具有可控的药动学行为，且花费相对较低，很好地弥补了大分子药物的临床缺陷。因而，针对PD-1/PD-L1设计合成具有阻断作用的小分子抑制剂时具有实际意义。Compared with antibody drugs, small molecule inhibitors have controllable pharmacokinetic behavior and are relatively inexpensive, which makes up for the clinical deficiencies of large molecule drugs. Therefore, it is of practical significance to design and synthesize small molecule inhibitors with blocking effects against PD-1/PD-L1.
发明概述SUMMARY OF THE INVENTION
本发明解决的技术问题是提供一种具有抑制PD-1/PD-L1相互作用的小分子抑制剂，其为如式(I)所示的化合物，或式(I)所示的化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，以及提供式(I)所示化合物的制备方法、药物组合物和其在制备预防或治疗与PD-1/PD-L1信号通路有关疾病药物中的用途。The technical problem solved by the present invention is to provide a small molecule inhibitor having the ability to inhibit the PD-1/PD-L1 interaction, which is a compound as shown in formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug of the compound as shown in formula (I), as well as a preparation method and a pharmaceutical composition of the compound as shown in formula (I) and its use in the preparation of a drug for preventing or treating diseases related to the PD-1/PD-L1 signaling pathway.
发明详述DETAILED DESCRIPTION OF THE INVENTION
为解决本发明的技术问题，本发明提供如下技术方案：In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:
本发明技术方案的第一方面是提供一类PD-1/PD-L1类小分子抑制剂的化合物，其为如式(I)所示的结构或如式(I)所示结构的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，The first aspect of the technical solution of the present invention is to provide a class of PD-1/PD-L1 small molecule inhibitor compounds, which are structures as shown in formula (I) or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs of the structure as shown in formula (I),
式中，In the formula,
R1为-(CH2)nAr，其中，Ar为C6-12芳基或C5-12杂芳基；所述Ar任选地被1、2、3或4个取代基所取代，所述取代基各自独立地为H、D、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基或C1-6烷氧基；n为1、2、3或4；R1 is -(CH2 )n Ar, wherein Ar is C6-12 aryl or C5-12 heteroaryl; Ar is optionally substituted by 1, 2, 3 or 4 substituents, each of which is independently H, D, cyano, halogen, amino, methylsulfonyl, acetamido, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy or C1-6 alkoxy; n is 1, 2, 3 or 4;
A为-CH2O-、-OCH2-、-CH2-CH2-、-C(O)NH-或-NHC(O)-；A is-CH2O- ,-OCH2- , -CH2-CH2- , -C(O)NH- or -NHC(O)-;
R2为
其中，R5和R6各自独立地为H、卤素、C1-6烷基、C1-6卤代烷基或C1-6烷氧基；Z为CH或N；wherein R5 and R6 are each independently H, halogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy; Z is CH or N;
R7为
Rv为
R3为C1-8烷氨基或C3-9杂环基，其中，所述的C3-9杂环基中至少含有一个N原子；所述的C1-8烷氨基或C3-9杂环基任选地被0、1、2、3或4个取代基所取代，所述取代基为氢、羟基、卤素、羧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基、氨基、氨基C1-6烷基、乙酰氨基、氰基、磺酰胺基或氧代(＝O)；R3 isC1-8 alkylamino orC3-9 heterocyclic group, wherein theC3-9 heterocyclic group contains at least one nitrogen atom; theC1-8 alkylamino orC3-9 heterocyclic group is optionally substituted by 0, 1, 2, 3 or 4 substituents, wherein the substituents are hydrogen, hydroxyl, halogen, carboxyl,C1-6 alkyl,C1-6 haloalkyl,C1-6 haloalkoxy,C1-6 alkoxy, amino,aminoC1-6 alkyl, acetamido, cyano, sulfonamido or oxo (=O);
P为0、1、2或3；P is 0, 1, 2, or 3;
X和Y各自独立地为H、D、C1-6烷基、C1-6烷氧基、卤素或者氰基。X and Y are each independently H, D, C1-6 alkyl, C1-6 alkoxy, halogen or cyano.
在一些实施方案中，本发明所述的Ar为苯基、吡啶基、嘧啶基、吲哚基或喹啉基；所述Ar任选地被1、2、3或4个取代基取代，所述取代基各自独立地为H、D、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基或C1-6烷氧基。In some embodiments, Ar described in the present invention is phenyl, pyridyl, pyrimidinyl, indolyl or quinolyl; Ar is optionally substituted by 1, 2, 3 or 4 substituents, each of which is independently H, D, cyano, halogen, amino, mesyl, acetamido,C1-6 alkyl,C1-6 haloalkyl,C1-6 haloalkoxy orC1-6 alkoxy.
在一些实施方案中，本发明所述的Rv为以下结构式形成的基团之一：In some embodiments,Rv of the present invention is one of the groups formed by the following structural formulas:
所述W1、W3和W5各自独立地为CH2、S、O、S(O)2或NH，W2和W4各自独立地为CH或N；Rv任选地被0、1、2或3个取代基取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基或氨基C1-6烷基。SaidW1 ,W3 andW5 are each independently CH2, S, O, S(O)2 or NH,W2 andW4 are each independently CH or N;Rv is optionally substituted by 0, 1, 2 or 3 substituents, and said substituents are hydroxyl, cyano, amino, oxo (=O),C1-6 alkyl,C1-6 haloalkyl,C1-6 haloalkoxy,C1-6 alkoxy oraminoC1-6 alkyl.
在另一些实施方案中，本发明所述的Rv为以下结构式形成的基团之一：In other embodiments,Rv of the present invention is one of the groups formed by the following structural formulas:
其中，所述的Rv任选地被0、1、2或3个取代基取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基或氨基C1-6烷基。Wherein, the Rv is optionally substituted by 0, 1, 2 or 3 substituents, and the substituents are hydroxyl, cyano, amino, oxo (=O), C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy or aminoC1-6 alkyl.
在一些实施方案中，本发明所述的R5和R6各自独立地为H、D、氟、氯、溴、甲基、乙基、正丙基、异丙基、叔丁基、异丁基、正丁基、三氟甲基、二氟甲基、一氟甲基、甲氧基或乙氧基。In some embodiments, R5 and R6 described in the present invention are each independently H, D, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, n-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy.
在一些实施方案中，本发明所述的R3为如下结构形成的基团之一：In some embodiments,R3 of the present invention is one of the groups formed by the following structures:
一些实施方案中，本发明提供的一种具有抑制PD-1/PD-L1相互作用的小分子抑制剂，其为如式(II)所示的化合物，或其立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，In some embodiments, the present invention provides a small molecule inhibitor having the ability to inhibit PD-1/PD-L1 interaction, which is a compound as shown in formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof,
式中，In the formula,
R1为-(CH2)nAr，其中，Ar为苯基、吡啶基、嘧啶基、吲哚基或喹啉基；所述Ar任选地被1、2、3或4个取代基取代，所述取代基各自独立地为H、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C1-6烷基或C1-6烷氧基；n为1、2、3或4；R1 is -(CH2 )n Ar, wherein Ar is phenyl, pyridyl, pyrimidinyl, indolyl or quinolyl; the Ar is optionally substituted by 1, 2, 3 or 4 substituents, each of which is independently H, cyano, halogen, amino, methylsulfonyl, acetylamino, C1-6 alkyl or C1-6 alkoxy; n is 1, 2, 3 or 4;
R2、R3、R5、R6、Rv、X、Y、Z和p具有本发明所述的含义。R2 , R3 , R5 , R6 , Rv , X, Y, Z and p have the meanings described herein.
一方面，本发明涉及药物组合物，该药物组合物，包含本发明式(I)或式(II)所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，及其药学上可接受的辅料或它们的组合。On the one hand, the present invention relates to a pharmaceutical composition, which comprises a compound of formula (I) or (II) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient or a combination thereof.
一方面，本发明涉及式(I)或(II)所述的化合物或其药物组合物在制备用于防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病的药物的用途。On the one hand, the present invention relates to the use of a compound described in formula (I) or (II) or a pharmaceutical composition thereof in the preparation of a drug for protecting, treating, curing or alleviating a patient's disease related to the PD-1/PD-L1 signaling pathway.
在一些实施方案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease related to the PD-1/PD-L1 signaling pathway described in the present invention is cancer, infectious disease or autoimmune disease.
在一些实施方案中，本发明所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或系统性自身免疫病。In some embodiments, the cancer described in the present invention is a disease in which cells in an organ or body tissue proliferate indefinitely; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; and the autoimmune disease is an organ-specific autoimmune disease or a systemic autoimmune disease.
在一些实施方案中，本发明所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the disease of immortalized cell proliferation in the organ or body tissue described in the present invention is bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia. , childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancers or a combination of the above diseases; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
在一些实施方案中，本发明所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、乳头瘤病毒感染和流感。In some embodiments, the viral infectious diseases described in the present invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection and influenza.
在一些实施方案中，本发明所述的器官特异性免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的系统性自身免疫病为类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病和自身免疫性溶血性贫血。另一方面，本发明提供一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，其包括向受治疗者使用治疗有效量本发明的化合物，从而调节受治疗者中的免疫应答。In some embodiments, the organ-specific immune disease described in the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, primary biliary cirrhosis, multiple encephalosclerosis and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia. On the other hand, the present invention provides a method for regulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, thereby regulating the immune response in the subject.
在一些实施方案中，本发明描述了一种防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病的方法，所述方法包含给予患者有效治疗剂量的本发明所述的化合物或药物组合物。In some embodiments, the present invention describes a method for protecting, treating, curing or alleviating a disease associated with the PD-1/PD-L1 signaling pathway in a patient, the method comprising administering to the patient an effective therapeutic dose of a compound or pharmaceutical composition described herein.
在一些实施方案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease related to the PD-1/PD-L1 signaling pathway described in the present invention is cancer, infectious disease or autoimmune disease.
在一些实施方案中，本发明所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或系统性自身免疫病。In some embodiments, the cancer described in the present invention is a disease in which cells in an organ or body tissue proliferate indefinitely; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; and the autoimmune disease is an organ-specific autoimmune disease or a systemic autoimmune disease.
在一些实施方案中，本发明所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the disease of immortalized cell proliferation in the organ or body tissue described in the present invention is bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia. , childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancers or a combination of the above diseases; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
在一些实施方案中，本发明所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、乳头瘤病毒感染和流感。In some embodiments, the viral infectious diseases described in the present invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection and influenza.
在一些实施方案中，本发明所述的器官特异性免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的系统性自身免疫病为类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病和自身免疫性溶血性贫血。另一方面，本发明提供一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，其包括向受治疗者使用治疗有效量本发明的化合物，从而调节受治疗者中的免疫应答。In some embodiments, the organ-specific immune disease described in the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, primary biliary cirrhosis, multiple encephalosclerosis and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia. On the other hand, the present invention provides a method for regulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, thereby regulating the immune response in the subject.
在一些实施方案中，将本发明所描述的化合物或药物组合物用于防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病。In some embodiments, the compounds or pharmaceutical compositions described herein are used to protect, treat, cure or alleviate diseases related to the PD-1/PD-L1 signaling pathway in patients.
在一些实施方案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease related to the PD-1/PD-L1 signaling pathway described in the present invention is cancer, infectious disease or autoimmune disease.
在一些实施方案中，本发明所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或系统性自身免疫病。In some embodiments, the cancer described in the present invention is a disease in which cells in an organ or body tissue proliferate indefinitely; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; and the autoimmune disease is an organ-specific autoimmune disease or a systemic autoimmune disease.
在一些实施方案中，本发明所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the disease of immortalized cell proliferation in the organ or body tissue described in the present invention is bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia. , solid tumors of childhood, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancer or a combination of the above diseases; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
在一些实施方案中，本发明所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、乳头瘤病毒感染和流感。In some embodiments, the viral infectious diseases described in the present invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection and influenza.
在一些实施方案中，本发明所述的器官特异性免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的系统性自身免疫病为类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病和自身免疫性溶血性贫血。In some embodiments, the organ-specific immune disease described in the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia.
另一方面，本发明提供一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，其包括向受治疗者使用治疗有效量本发明的化合物，从而调节受治疗者中的免疫应答。In another aspect, the present invention provides a method of modulating an immune response mediated by the PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, thereby modulating the immune response in the subject.
另一方面，本发明涉及式(I)或(II)所包含的化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I) or (II).
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。其他的方面的内容将在下面作更加具体完整的描述。The foregoing content only summarizes certain aspects of the present invention, but is not limited to these aspects. The content of other aspects will be described in more detail and complete below.
本发明详细说明书Detailed description of the invention
定义和一般术语Definitions and general terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It should be further appreciated that certain features of the invention, which for clarity are described in the context of multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考″Organic Chemistry″，Thomas Sorrell，University Science Books，Sausalito：1999，和″March′s Advanced Organic Chemistry”by Michael B.Smith and Jerry March，JohnWiley&Sons，NewYork：2007中的描述，其全部内容通过引用并入本文。Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。"Stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。"Chiral" refers to a molecule that is non-superimposable on its mirror image; "achiral" refers to a molecule that is superimposable on its mirror image.
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。"Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。"Diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；andEliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50∶50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R，S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R, S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。Depending on the choice of starting materials and process, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, such as a racemate and a diastereomeric mixture (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques，et al.，Enantiomers，Racematesand Resolutions(Wiley Interscience，New York，1981)；Principles of AsymmetricSynthesis(2ndEd.Robert E.Gawley，Jeffrey Aubé，Elsevier，Oxford，UK，2012)；Eliel，E.L.Stereochemistry of Carbon Compounds(McGraw-Hill，NY，1962)；Wilen，S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel，Ed.，Univ.of NotreDame Press，Notre Dame，IN 1972)；Chiral Separation Techniques：A PracticalApproach(Subramanian，G.Ed.，Wiley-VCH Verlag GmbH&Co.KGaA，Weinheim，Germany，2007)。Any racemate of the final product or intermediate obtained can be separated into optical antipodes by known methods by methods familiar to those skilled in the art, such as by separation of the diastereoisomeric salts obtained thereof. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2，4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions carried out by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions carried out by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现，即，该描述包括其中所述事件或情形出现的情况以及不出现的情况。例如，“任选地被1、2、3或4个...所取代”包括该基团被1个、或2个、或3个、或4个所述的取代基所取代的情况，以及该基团不被所述取代基取代的情况。进一步地，当该基团被1个以上所述取代基取代时，所述取代基之间是相互独立，即，所述的1个以上的取代基可以是互不相同的，也可以是相同的。The term "optionally" or "optionally" means that the event or situation described subsequently may but does not necessarily occur, that is, the description includes the case where the event or situation described therein occurs and the case where it does not occur. For example, "optionally substituted by 1, 2, 3 or 4..." includes the case where the group is substituted by 1, or 2, or 3, or 4 of the substituents, and the case where the group is not substituted by the substituents. Furthermore, when the group is substituted by more than one of the substituents, the substituents are independent of each other, that is, the more than one substituents described may be different from each other or the same.
像本发明所描述的，本发明的化合物可以独立任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。术语“独立任选地”与术语“任选独立地”可以交换使用，一般而言，术语“独立任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子可以被具体取代基1所取代或未取代。除非其他方面表明，一个任选的取代基团可以有一个取代基1在基团的各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基1所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基1可以是，但并不限于：氢，氧代(＝O)，氟，氯，溴，碘，羟基，氨基，羧基，烷基，烷基-S(＝O)t-，卤代烷基，羟基烷基，氨基烷基，醛基，氨基酰基，烷氧基，烷氨基，烷硫基，卤代烷氧基，氰基，芳基，杂芳基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基烷氧基，烷基-(C＝O)-，苄基，环丙基，苯基，烷氨基-C(＝O)-，CN-烷基-C(＝O)-，烷基-O-C(＝O)-烷基，酯基，羟基烷基酰基，或烷氧基烷基等。在合理的情况下，取代基1能进一步独立任选地被取代基2单取代或相同或不同的多取代。其中所述的取代基2可以是，但不限于：氢，氧代(＝O)，氟，氯，溴，碘，羟基，氨基，羧基，烷基，烷基-S(＝O)t-，卤代烷基，羟基烷基，氨基烷基，醛基，氨基酰基，烷氧基，烷氨基，烷硫基，卤代烷氧基，氰基，芳基，杂芳基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基烷氧基，烷基-(C＝O)-，苄基，环丙基，苯基，烷氨基-C(＝O)-，CN-烷基-C(＝O)-，烷基-O-C(＝O)-烷基，酯基，羟基烷基酰基，或烷氧基烷基等。其中，t为0，1，或2。As described herein, the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". The term "independently optionally" is used interchangeably with the term "optionally independently". In general, the term "independently optionally" whether or not preceded by the term "substituted" indicates that one or more hydrogen atoms in a given structure may be substituted or unsubstituted with a specific substituent 1. Unless otherwise indicated, an optional substituted group may have a substituent 1 substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted with one or more substituents 1 selected from a specific group, the substituents may be substituted the same or differently at each position. The substituent 1 can be, but is not limited to, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t -, haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde, aminoacyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, alkylamino-C (=O)-, CN-alkyl-C (=O)-, alkyl-OC (=O)-alkyl, ester, hydroxyalkylacyl, or alkoxyalkyl, etc. Where appropriate, the substituent 1 can be further independently and optionally substituted by substituents 2, monosubstituted or polysubstituted by the same or different substituents. The substituent 2 can be, but is not limited to, hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)t -, haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde, aminoacyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl-(C=O)-, benzyl, cyclopropyl, phenyl, alkylamino-C (=O)-, CN-alkyl-C (=O)-, alkyl-OC (=O)-alkyl, ester, hydroxyalkylacyl, or alkoxyalkyl, etc., wherein t is 0, 1, or 2.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent secondary combination of the individual members of these group types and ranges. For example, the term "C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is connected.
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-10个碳原子；另外一些实施例是，烷基基团含有1-8个碳原子；另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子；另外一些实施例是，烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH3)，乙基(Et，-CH2CH3)，正丙基(n-Pr，-CH2CH2CH3)，异丙基(i-Pr，-CH(CH3)2)，正丁基(n-Bu，-CH2CH2CH2CH3)，2-甲基丙基或异丁基(i-Bu，-CH2CH(CH3)2)，1-甲基丙基或仲丁基(s-Bu，-CH(CH3)CH2CH3)，叔丁基(t-Bu，-C(CH3)3)，正戊基(-CH2CH2CH2CH2CH3)，2-戊基(-CH(CH3)CH2CH2CH3)，3-戊基(-CH(CH2CH3)2)，2-甲基-2-丁基(-C(CH3)2CH2CH3)，3-甲基-2-丁基(-CH(CH3)CH(CH3)2)，3-甲基-1-丁基(-CH2CH2CH(CH3)2)，2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)，正己基(-CH2CH2CH2CH2CH2CH3)，2-己基(-CH(CH3)CH2CH2CH2CH3)，3-己基(-CH(CH2CH3)(CH2CH2CH3))，2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)，3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)，4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)，3-甲基-3-戊基(-C(CH3)(CH2CH3)2)，2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)，2，3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)，3，3-二甲基-2-丁基(-CH(CH3)C(CH3)3)，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。烷基可以被本发明所述的取代基所取代。The term "alkyl" used in the present invention includes saturated straight or branched monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1 to 10 carbon atoms; in other embodiments, the alkyl group contains 1 to 8 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 1 to 4 carbon atoms; in other embodiments, the alkyl group contains 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2 CH3 ), n-propyl (n-Pr, -CH2 CH2 CH3 ), isopropyl (i-Pr, -CH(CH3 )2 ), n-butyl (n-Bu, -CH2 CH2 CH2 CH3 ), 2-methylpropyl or isobutyl (i-Bu, -CH2 CH(CH3 )2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3 )CH2 CH3 ), tert-butyl (t-Bu, -C(CH3 )3 ), n-pentyl (-CH2 CH2 CH2 CH2 CH 3 ), 2-pentyl (-CH(CH3 )CH 2 CH 2 CH3 ), 3-pentyl (-CH(CH 3 )CH2 CH2 CH3 ),2 CH3 )2 ), 2-methyl-2-butyl (-C(CH3 )2 CH2 CH3 ), 3-methyl-2-butyl (-CH(CH3 )CH(CH3 )2 ), 3-methyl-1-butyl (-CH2 CH2 CH(CH3 )2 ), 2-methyl-1-butyl (-CH2 CH(CH3 )CH2 CH3 ), n-hexyl (-CH2 CH2 CH2 CH2 CH2 CH3 ), 2-hexyl (-CH(CH3 )CH2 CH2 CH2 CH3 ), 3-hexyl (-CH(CH2 CH3 )(CH2 CH2 CH3 )), 2-methyl-2-pentyl (-C(CH3 )2 CH2 CH2 CH3 ), 3-methyl-2-pentyl (-CH(CH3 )CH(CH3 )CH2 CH3 ), 4-methyl-2-pentyl (-CH(CH3 )CH2 CH(CH3 )2 ), 3-methyl-3-pentyl (-C(CH3 )(CH2 CH3 )2 ), 2-methyl-3-pentyl (-CH(CH2 CH3 )CH(CH3 )2 ), 2,3-dimethyl-2-butyl (-C(CH3 )2 CH(CH3 )2 ), 3,3-dimethyl-2-butyl (-CH(CH3 )C(CH3 )3 ), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains. The alkyl group may be substituted with the substituents described herein.
术语“卤代烷基”表示烷基可以被一个或多个相同或不同卤素原子所取代的情况。其中烷基基团具有如本发明所述的含义，这样的实例包括，但并不限于三氟甲基，二氟甲基，一氟甲基，2，2-二氟乙基，3，3，3-三氟丙基等。卤代烷基可以被本发明所述的取代基所取代。The term "haloalkyl" refers to an alkyl group that may be substituted with one or more halogen atoms that are the same or different. The alkyl group has the meaning as described herein, and such examples include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 3,3,3-trifluoropropyl, etc. The haloalkyl group may be substituted with a substituent as described herein.
术语“氨基”是指具有式-NH2的基团。The term "amino" refers to a group having the formula-NH2 .
术语“羧基”，无论是单独使用还是和其他术语连用，表示-CO2H；术语“羰基”，无论是单独使用还是和其他术语连用，表示-(C＝O)-。The term "carboxy", whether used alone or in combination with other terms, refers to -CO2 H; the term "carbonyl", whether used alone or in combination with other terms, refers to -(C=O)-.
术语“烷氨基”或者“烷基氨基”是指“N-烷基氨基”或“N，N-烷基氨基”，其中氨基基团的氢原子被一个或两个独立的烷基基团所取代，其中烷基基团具有如本发明所述的含义。其中一些实施例是，烷基氨基是一个C1-8烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是，烷基氨基是C1-3的较低级的烷基氨基基团。实例包括，但并不限于，N-甲氨基，N-乙氨基，N，N-二甲基氨基等等。“烷氨基”或者“烷基氨基”可以被本发明所述的取代基所取代。术语“C1-8烷氨基”指烷氨基中每一个独立的烷基含碳原子数为1-8个，烷氨基具有如上所述的定义。The term "alkylamino" or "alkylamino" refers to "N-alkylamino" or "N,N-alkylamino", wherein the hydrogen atom of the amino group is replaced by one or two independent alkyl groups, wherein the alkyl group has the meaning as described in the present invention. In some embodiments, the alkylamino group is a lower alkylamino group in which a C1-8 alkyl group is attached to a nitrogen atom. In other embodiments, the alkylamino group is a lower alkylamino group of C1-3 . Examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, and the like. "Alkylamino" or "alkylamino" may be substituted by the substituents described in the present invention. The term "C1-8 alkylamino" means that each independent alkyl group in the alkylamino group contains 1 to 8 carbon atoms, and the alkylamino group has the definition as described above.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中，烷基基团具有如本发明所述的含义。术语“G1-6烷氧基”是指含碳原子数为1-6的烷基通过氧原子与分子其他部分相连。在一些实施方案中，烷氧基基团含有1-6个碳原子；在另一些实施方案中，烷氧基基团含有1-4个碳原子；在又一些实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明所描述的取代基所取代。烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH3)，乙氧基(EtO、-OCH2CH3)，1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3)，等等。The term "alkoxy" refers to an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. The term "G1-6 alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms attached to the rest of the molecule via an oxygen atom. In some embodiments, the alkoxy group contains 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in yet other embodiments, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3 ), ethoxy (EtO, -OCH2 CH3 ), 1-propoxy (n-PrO, n-propoxy, -OCH2 CH2 CH3 ), and the like.
术语“烷酰基”或“烷基酰基”表示烷基基团通过羰基(-C(＝O)-)与分子其余部分相连，其中，烷基基团具有如本发明所述的含义。所述烷酰基基团可以任选地被一个或多个本发明所描述的取代基所取代。烷酰基基团的实例包括，但并不限于，乙酰基(-C(＝O)CH3)，丙酰基(-C(＝O)CH2CH3)，丁酰基(-C(＝O)CH2CH2CH3)等等。The term "alkanoyl" or "alkylacyl" means an alkyl group attached to the rest of the molecule through a carbonyl group (-C(=O)-), wherein the alkyl group has the meaning as described herein. The alkanoyl group may be optionally substituted with one or more substituents as described herein. Examples of alkanoyl groups include, but are not limited to, acetyl (-C(=O)CH3 ), propionyl (-C(=O)CH2 CH3 ), butyryl (-C(=O)CH2 CH2 CH3 ), and the like.
术语“烷酰氨基”或“烷酰基氨基”表示烷酰基通过基团(-NH-)与分子的其他部分相连，其中烷酰基具有如本发明所述的含义。所述烷酰氨基基团可以任选地被一个或多个本发明所描述的取代基所取代。烷酰氨基基团的实例包括，但并不限于，乙酰氨基(CH3-C(＝O)-NH-)，丙酰氨基(CH3CH2-C(＝O)-NH-)等等。The term "alkanoylamino" or "alkanoylamino" means that an alkanoyl group is attached to the rest of the molecule through a (-NH-) group, wherein alkanoyl has the meaning as described herein. The alkanoylamino group may be optionally substituted with one or more substituents as described herein. Examples of alkanoylamino groups include, but are not limited to, acetylamino (CH3 -C(=O)-NH-), propionylamino (CH3 CH2 -C(=O)-NH-), and the like.
术语“烷氧基酰基”、“烷氨基酰基”、“氨基酰基”表示烷氧基、烷氨基或氨基(-NH2)基团通过羰基(-C(＝O)-)与分子其余部分相连，其中，烷氧基和烷氨基基团具有如本发明所述的含义。所述烷氧基酰基、烷氨基酰基、氨基酰基基团可以任选地被一个或多个本发明所描述的取代基所取代。烷氧基酰基、烷氨基酰基的实例包括，但并不限于，甲氧基酰基(-C(＝O)OCH3)，乙氧基酰基(-C(＝O)OCH2CH3)，甲氨基酰基(-C(＝O)NHCH3)，二甲氨基酰基(-C(＝O)N(CH3)2)等等。The terms "alkoxyacyl", "alkylaminoacyl" and "aminoacyl" refer to an alkoxy, alkylamino or amino (-NH2 ) group attached to the rest of the molecule via a carbonyl (-C(=O)-) group, wherein the alkoxy and alkylamino groups have the meanings as described herein. The alkoxyacyl, alkylaminoacyl and aminoacyl groups may be optionally substituted with one or more substituents as described herein. Examples of alkoxyacyl and alkylaminoacyl groups include, but are not limited to, methoxyacyl (-C(=O)OCH3 ), ethoxyacyl (-C(=O)OCH2 CH3 ), methylaminoacyl (-C(=O)NHCH3 ), dimethylaminoacyl (-C(=O)N(CH3 )2 ) and the like.
术语“烷基磺酰基”、“烷氧基磺酰基”、“烷氨基磺酰基”、“氨基磺酰基”表示烷基、烷氧基、烷氨基或氨基(-NH2)基团通过磺酰基(-SO2-)与分子其余部分相连，其中，烷基、烷氧基、烷氨基基团具有如本发明所述的含义。所述烷基磺酰基、烷氧基磺酰基、烷氨基磺酰基、氨基磺酰基基团可以任选地被一个或多个本发明所描述的取代基所取代。烷基磺酰基基团的实例包括，但并不限于，甲磺酰基(-SO2CH3)，乙基磺酰基(-SO2CH2CH3)，等等。The terms "alkylsulfonyl", "alkoxysulfonyl", "alkylaminosulfonyl" and "aminosulfonyl" refer to an alkyl, alkoxy, alkylamino or amino (-NH2 ) group connected to the rest of the molecule through a sulfonyl (-SO2 -) group, wherein alkyl, alkoxy and alkylamino groups have the meanings as described herein. The alkylsulfonyl, alkoxysulfonyl, alkylaminosulfonyl and aminosulfonyl groups may be optionally substituted with one or more substituents as described herein. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl (-SO2 CH3 ), ethylsulfonyl (-SO2 CH2 CH3 ), and the like.
术语“芳基”可以是单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子，且只有一个连接点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用，如芳香环可以包括苯基，萘基和蒽。芳基可以被本发明所述的取代基所取代。术语“C6-12芳基”指芳基中碳原子数为6-12个，芳基具有如上定义。The term "aryl" can be a monocyclic, bicyclic, and tricyclic carbon ring system, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 atoms, and has only one connection point to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring", such as aromatic rings can include phenyl, naphthyl and anthracene. The aryl group can be substituted with the substituents described in the present invention. The term "C6-12 aryl" refers to an aryl group having 6-12 carbon atoms, and the aryl group has the above definition.
术语“杂芳基”，“杂芳环”在此处可交换使用，都是指单环，双环，三环或者四环体系，其中，双环杂芳环，三环杂芳环或者四环杂芳环体系以稠合的形式成环。其中，杂芳环体系整体是芳香性的，环上一个或多个原子独立独立任选地被杂原子所取代(杂原子选自N、O、P、S、在此S或P独立任选地被一个或多个氧原子所取代得到像SO、SO2、PO、PO2的基团)。杂芳体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。杂芳体系基团可以是3-7个原子组成的单环，或7-10个原子组成的双环，或10-15个原子组成的三环。具有7-10个原子的双环可以是二环[4，5]，[5，5]，[5，6]或[6，6]体系，具有10-15个原子的三环可以是三环[5，5，6]、[5，7，6]或[6，5，6]体系。术语“C5-12杂芳基”指杂芳基中含碳原子数为5-12个，杂芳基具有如上定义。The terms "heteroaryl" and "heteroaromatic ring" are used interchangeably herein and refer to monocyclic, bicyclic, tricyclic or tetracyclic ring systems, wherein the bicyclic heteroaromatic ring, tricyclic heteroaromatic ring or tetracyclic heteroaromatic ring system is fused to form a ring. The heteroaromatic ring system is aromatic as a whole, and one or more atoms in the ring are independently and optionally substituted by heteroatoms (heteroatoms are selected from N, O, P, S, where S or P is independently and optionally substituted by one or more oxygen atoms to obtain groups such as SO,SO2 , PO,PO2 ). The heteroaromatic system can be attached to the main structure at any heteroatom or carbon atom to form a stable compound. The heteroaromatic system group can be a monocyclic ring composed of 3-7 atoms, a bicyclic ring composed of 7-10 atoms, or a tricyclic ring composed of 10-15 atoms. The bicyclic ring with 7-10 atoms may be a bicyclic [4,5], [5,5], [5,6] or [6,6] system, and the tricyclic ring with 10-15 atoms may be a tricyclic [5,5,6], [5,7,6] or [6,5,6] system. The term "C5-12 heteroaryl" refers to a heteroaryl group having 5 to 12 carbon atoms, and the heteroaryl group has the above definition.
另外一些实施例是，杂芳体系(包含杂芳基，杂芳环)包括以下例子，但并不限于这些例子：呋喃-2-基，呋喃-3-基，N-咪唑基，咪唑-2-基，咪唑-4-基，咪唑-5-基，异噁唑-3-基，异噁唑-4-基，异噁唑-5-基，噁唑-2-基，噁唑-4-基，噁唑-5-基，4-甲基异噁唑-5-基，N-吡咯基，吡咯-2-基，吡咯-3-基，吡啶-2-基，吡啶-3-基，吡啶-4-基，嘧啶-2-基，嘧啶-4-基，嘧啶-5-基，哒嗪基(如哒嗪-3-基)，噻唑-2-基，噻唑-4-基，噻唑-5-基，四唑基(如四唑-5-基)，三唑基(如三唑-2-基和三唑-5-基)，噻吩-2-基，噻吩-3-基，吡唑基(如吡唑-2-基)，异噻唑基，1，2，3-噁二唑基，1，2，5-噁二唑基，1，2，4-噁二唑基，1，2，3-三唑基，1，2，3-硫代二唑基，1，3，4-硫代二唑基，1，2，5-硫代二唑基，1，3，4-噻二唑-2-基，吡嗪基，吡嗪-2-基，1，3，5-三嗪基，苯并[d]噻唑-2-基，咪唑并[1，5-a]吡啶-6-基，苯并咪唑基，苯并恶唑基，喹喔啉基，1，8-二氮杂萘基，苯并噻吩基，苯并噻唑基，吲哚基(如吲哚-2-基)，嘌呤基，喹啉基(如喹啉-2-基，喹啉-3-基，喹啉-4-基)，异喹啉基(如异喹啉-1-基，异喹啉-3-基或异喹啉-4-基)，苯并吡唑基，吖啶基，苯并咪唑基，苯并吲哚基，苯并异噁嗪基，苯并[4，6]咪唑并[1，2-a]吡啶基，苯并[d]咪唑[2，1-b]噻唑基，苯并噻二唑基，苯并噻唑基，苯并硫代苯基，苯并三唑基，苯并硫代吡喃基，苯并噁嗪基，苯并噁唑基，苯并噻唑基，β-咔啉基，咔唑基，邻二氮杂萘基，二苯并呋喃基，咪唑并吡啶基，咪唑并噻唑基，吲唑基，吲哚嗪基，吲哚基，异苯并噻嗯基，异喹啉基，异噻唑烷基，异噻唑基，萘啶基，噁唑烷二酮基，噁唑烷基，噁唑并吡啶基，噁唑基，茶嵌二氮苯基，菲啶基，菲绕啉基，吩砒嗪基，吩嗪基，吩噻嗪基，吩噁嗪基，酞嗪基，蝶啶基，吡啶并吡啶基，喹唑啉基，喹噁啉基，硫代苯基，三嗪基，2H-吡咯并[3，4-c]吡啶基，吡唑并[2’，1’：2，3]恶唑并[4，5-c]吡啶基，咪唑并[2’，1’：2，3]噻唑并[4，5-c]吡啶基，咪唑并[2’，1’：2，3]噻唑并[4，5-b]吡啶基，咪唑并[2’，1’：2，3]噻唑并[5，4-b]吡啶基，吡唑并[2’，1’：2，3]噻唑并[4，5-b]吡嗪基，1H-苯并[4，5]噻吩并[2，3-d]咪唑基，苯并[4，5]噻吩并[2，3-d]咪唑基，咪唑并[2′，1′：2，3]噻唑并[4，5-b]吡嗪基，咪唑并[2′，1′：2，3]噻唑并[5，4-b]吡啶基，咪唑并[2′，1′：2，3]噻唑并[4，5-c]吡啶基，1H-苯并[f]咪唑并[4，5-b][1，4]硫氮杂卓基等。杂芳基可以被本发明所述的取代基所取代。In some other embodiments, the heteroaromatic system (including heteroaromatic groups and heteroaromatic rings) includes the following examples, but is not limited to these examples: furan-2-yl, furan-3-yl, N-imidazolyl, imidazolyl, imidazolyl, imidazolyl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 4-methylisoxazol-5-yl, N-pyrrolyl, pyrrol-2-yl, pyrrol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazinyl (such as pyridazin-3-yl), thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, tetrazolyl (such as tetrazol-5-yl), triazolyl (such as triazol-2-yl and triazol-5-yl), thiophene-2-yl, thiophene-3-yl, pyrazolyl (such as pyrazol- 2-yl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl, benzo[d]thiazol-2-yl, imidazo[1,5-a ] pyridin-6-yl, benzimidazolyl, benzoxazolyl, quinoxalinyl, 1,8-naphthyridinyl, benzothiophenyl, benzothiazolyl, indolyl (such as indol-2-yl), purinyl, quinolyl (such as quinol-2-yl, quinol-3-yl, quinol-4-yl), isoquinolyl (such as isoquinol-1-yl, isoquinol-3-yl or isoquinol-4-yl), benzopyrazolyl, acridinyl, benzimidazolyl, benzindolyl, benzo isoxazinyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzo[d]imidazo[2,1-b]thiazolyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, o-naphthyridinyl, dibenzofuranyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolizinyl, indole phenyl, isobenzothienyl, isoquinolyl, isothiazolidinyl, isothiazolyl, naphthyridinyl, oxazolidinyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, theazolyl, phenanthridinyl, phenanthrolinyl, phenanthrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridinyl, quinazolinyl, quinoxalinyl, thiophenyl, triazinyl, 2H-pyrrolo[3,4-c]pyridinyl, pyrazolo[2',1 ': 2,3]oxazolo[4,5-c]pyridinyl, imidazo[2',1': 2,3]thiazo[4,5-c]pyridinyl, imidazo[2',1': 2,3]thiazo[4,5-b]pyridinyl, imidazo[2',1': 2,3]thiazo[5,4-b]pyridinyl, pyrazolo[2',1': 2,3]thiazo[4,5-b]pyrazinyl, 1H-benzo[4,5]thieno[ [2,3-d] imidazolyl, benzo[4,5]thieno[2,3-d] imidazolyl, imidazo[2',1':2,3]thiazo[4,5-b]pyrazinyl, imidazo[2',1':2,3]thiazo[5,4-b]pyridinyl, imidazo[2',1':2,3]thiazo[4,5-c]pyridinyl, 1H-benzo[f]imidazo[4,5-b][1,4]thiazepinyl, etc. The heteroaryl group may be substituted by the substituents described in the present invention.
术语“杂环基”，“杂环”，“杂脂环族”或“杂环基”在此处可交换使用，都是指单环，双环，三环或者四环体系，其中环上一个或多个原子独立任选地被杂原子所取代，环可以是完全饱和的或包含一个或多个不饱和度，但绝不是芳香族类，杂环体系整体不具有芳香性。例如一些实施例中，双环的杂环基，其中一个环具有芳香性，另一个环整体不具有芳香性。杂环体系可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。一个或多个环上的氢原子独立地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，“杂环基”，“杂环”，“杂脂环族”或“杂环的”基团是指4-12元单环或多环(3-9个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P独立任选地被一个或多个氧原子所取代得到像SO，SO2，PO，PO2的基团，同时，-CH2-基团可以独立任选地被-C(＝O)-替代；当所述的环为三元环时，其中只有一个杂原子，当所述环为多环时，可任选地为桥环，螺环或稠环)。术语“C3-9杂环基”指杂环基中含碳原子数为3-9个，其中杂环基具有如上定义。The terms "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic group" are used interchangeably herein and refer to a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein one or more atoms in the ring are independently optionally substituted with heteroatoms, the ring may be fully saturated or contain one or more unsaturations, but is never aromatic, and the heterocyclic ring system as a whole is not aromatic. For example, in some embodiments, a bicyclic heterocyclic group, one ring is aromatic and the other ring is not aromatic as a whole. The heterocyclic ring system can be attached to the main structure at any heteroatom or carbon atom to form a stable compound. One or more hydrogen atoms on the ring are independently substituted with one or more substituents described herein. Some of the embodiments are, "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic" groups refer to 4-12 membered monocyclic or polycyclic rings (3-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein S or P is independently optionally substituted by one or more oxygen atoms to obtain groups such as SO,SO2 , PO,PO2 , and the-CH2- group can be independently optionally replaced by -C(=O)-; when the ring is a three-membered ring, there is only one heteroatom, and when the ring is a polycyclic ring, it can be optionally a bridged ring, a spiro ring or a fused ring). The term "C3-9heterocyclyl " refers to a heterocyclyl group containing 3-9 carbon atoms, wherein the heterocyclyl group has the above definition.
“杂环基”可以是碳原子基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，噻噁烷基，氮杂环丁基，氧杂环丁基，硫杂环丁基，哌啶基，高哌啶基，环氧丙基，氮杂环庚基，氧杂环庚基，硫杂环庚基，N-吗啉基，2-吗啉基，3-吗啉基，硫代吗啉基，N-哌嗪基，2-哌嗪基，3-哌嗪基，高哌嗪基，1，2，3，6-四氢吡啶-1-基，氧氮杂卓基，二氮杂卓基，硫氮杂卓基，吡咯啉-1-基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2-吲哚啉基，2H-吡喃基，4H-吡喃基，二氧杂环己基，1，3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氢噻吩基，咪唑烷基，1，2，3，4-四氢异喹啉基，1，2，6-噻二嗪烷1，1-二氧-2-基，六氢-2H-[1，4]二氧芑[2，3-c]吡咯基，喹嗪基，1，1-二氧化硫代吗啉基，2，3，3a，7a-四氢-1H-异吲哚基，异吲哚啉基，1，2，3，4-四氢喹啉基，二苯并呋喃基，二氢苯并异噻嗪基，二氢苯并异噁嗪基，二氧戊环基，二氢吡嗪基，二氢吡啶基，二氢吡唑基，二氢嘧啶基，二氢吡咯基，1，4-二噻烷基，呋喃酮基，呋喃基，咪唑烷基，咪唑啉基，咪唑基，咪唑并吡啶基，咪唑并噻唑基，吲唑基，二氢吲哚基，吲哚嗪基，异苯并四氢呋喃基，异苯并四氢噻嗯基，异苯并噻嗯基，异苯并二氢吡喃基，异香豆素基，异二氢吲哚基，异噻唑烷基，异噁唑烷基，吗啉基，十氢吲哚基，十氢异吲哚基，噁二唑基，噁唑烷二酮基，噁唑烷基，噁唑并吡啶基，环氧乙烷基，哌嗪基，哌啶基，4-哌啶酮基，吡咯基，喹宁环基，四氢异喹啉基，四氢噻嗯基，硫吗啉基，噻唑烷基，1，3，5-三噻烷基，2-氧代吡咯烷基，氧代-1，3-噻唑烷基，2-哌啶酮基，3，5-二氧代哌啶基，1，2，3，4-四氢异喹啉基，1，3-苯并二噁茂基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，4-氧代吗啉基和嘧啶二酮基。"Heterocyclic group" can be a carbon atom group or a heteroatom group. "Heterocyclic group" also includes groups formed by the combination of a heterocyclic group with a saturated or partially unsaturated ring or a heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, thioxanyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, glycidyl, azepanyl, oxetanyl, thietanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepinyl, diazepinyl, thiazepinyl, pyrroline -1-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolinyl, 2-indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolane, pyrazolyl, dithianyl, dithiolanyl, dihydrothienyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinane 1,1-dioxol-2-yl, hexahydro-2H-[1,4]dioxin[2,3-c]pyrrolyl, quinolizinyl, 1,1-dioxidothiomorpholinyl, 2,3,3a,7a-tetrahydro-1H-isoindolyl, isoindolinyl, 1,2,3 , 4-tetrahydroquinolinyl, dibenzofuranyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dioxolanyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, 1,4-dithianyl, furanonyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, dihydroindolyl, indolizinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothian ... , decahydroisoindolyl, oxadiazolyl, oxazolidinedione, oxazolidinyl, oxazolopyridinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrrolyl, quinuclidinyl, tetrahydroisoquinolyl, tetrahydrothianthianthyl, thiomorpholinyl, thiazolidinyl, 1,3,5-trithianyl, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxolyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 4-oxomorpholinyl and pyrimidinedione.
一些实施例中，杂环基为4-12个原子组成的杂环基，是指包含4-12个环原子的饱和或部分不饱和的单环或多环，其中至少一个环原子选自氮、硫和氧原子。4-12个原子组成的杂环基的实例包括，但不限于，氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1，3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3，4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。The term "heteroatom" refers to O, S, N, P and Si, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl).
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(1)。The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
术语“螺环基”，“螺环”，“螺双环基”，“螺双环”表示一个环起源于另一个环上特殊的环状碳。例如，像下面所描述的，一个饱和的桥环体系(环D和B′)被称为“稠合双环”，反之环A’和环D在两个饱和的环体系中共享一个碳原子，则被称为“螺环”。螺环里面的每一个环要么是碳环要么是杂环。这样的实例包括，但并不限于，4-氮杂螺[2.4]庚烷-5-基，4-氧杂螺[2.4]庚烷-5-基，5-氮杂螺[2.4]庚烷-5-基，螺[2.4]庚烷基，螺[4.4]壬烷基，7-羟基-5-氮杂螺[2.4]庚烷-5-基等。The terms "spirocyclyl", "spirocycle", "spirobicyclyl", and "spirobicyclic" mean that one ring originates from a specific annular carbon of another ring. For example, as described below, a saturated bridged ring system (rings D and B') is called a "fused bicyclic", whereas rings A' and D share a carbon atom in both saturated ring systems and are called "spirocycles". Each ring in a spirocycle is either a carbocyclic or a heterocyclic ring. Such examples include, but are not limited to, 4-azaspiro[2.4]heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, spiro[2.4]heptan-5-yl, spiro[4.4]nonanyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-yl, and the like.
术语“螺杂双环基”表示一个环起源于另一个环上特殊的环状碳。例如，像上面所描述的，一个饱和的桥环体系(环D和B′)被称为“稠合双环”，反之环A’和环D在两个饱和的环体系中共享一个碳原子，则被称为“螺环”。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7个原子，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此N，S或P独立任选地被一个或多个氧原子所取代得到像NO，NO2，SO，SO2，PO，PO2的基团，-CH2-基团可以独立任选地被-C(＝O)-替代；这样的实例包括，但并不限于4-氮杂螺[2.4]庚烷基，4-氧杂螺[2.4]庚烷基，5-氮杂螺[2.4]庚烷基，2-氮杂螺[4.5]癸烷基，2-氮杂螺[3.3]庚烷基，2-氮杂螺[4.4]壬烷基，3-氮杂螺[5.4]癸烷基，2-氧-6-氮杂螺[3.3]庚烷基，2，6-二氮杂螺[3.3]庚烷基，2-硫-6-氮杂螺[3.3]庚烷基2-一氧化物，2-硫-6-氮杂螺[3.3]庚烷基2，2-二氧化物，2，8-二氮杂螺[4.5]癸烷基，2，7-二氮杂螺[4.4]辛烷基，2，7-二氮杂螺[4.5]癸烷基，2，6-二氮杂螺[4.5]癸烷基，2，8-二氮杂螺[4.5]癸烷-3-酮-基，1，8-二氮杂螺[4.5]癸烷基，1，7-二氮杂螺[4.4]壬烷基，1，7-二氮杂螺[4.4]壬烷-6-酮-基，2，9-二氮杂螺[5.5]十一烷-1-酮-基，1-氧-3，8-二氮杂螺[4.5]癸烷-2-酮-基，1-氧-3，7-二氮杂螺[4.5]癸烷-2-酮-基，2，6-二氮杂螺[3.4]辛烷基，2，5-二氮杂螺[3.5]壬烷基，2，6-二氮杂螺[3.3]庚烷基，2-氧-7-氮杂螺[3.5]壬烷基，2-氧-6-氮杂螺[3.4]辛烷基等。螺杂环基可以被本发明所述的取代基所取代。The term "spiro heterobicyclic group" means that one ring originates from a specific cyclic carbon of another ring. For example, as described above, a saturated bridged ring system (ring D and B') is called a "fused bicyclic ring", whereas ring A' and ring D share one carbon atom in two saturated ring systems, which is called a "spirocyclic ring". And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 atoms, i.e., 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein N, S or P is independently optionally substituted with one or more oxygen atoms to give groups such as NO,NO2 , SO,SO2 , PO,PO2 ,-CH2 -groups may be independently optionally replaced by -C(=O)-; examples include, but are not limited to, 4-azaspiro[2.4]heptyl, 4-oxaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, 2-azaspiro[4.5]decyl, 2-azaspiro[3.3]heptyl, 2-azaspiro[4.4]nonyl, 3-azaspiro[5.4]decyl, 2-oxo-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2-thio-6-azaspiro[3.3]heptyl 2-monoxide, 2-thio-6-azaspiro[3.3]heptyl 2,2-dioxide, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]octyl, 2,7-diazaspiro[4.5 ]decyl, 2,6-diazaspiro[4.5]decyl, 2,8-diazaspiro[4.5]decane-3-one-yl, 1,8-diazaspiro[4.5]decyl, 1,7-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[4.4]nonan-6-one-yl, 2,9-diazaspiro[5.5]undecane-1-one-yl, 1-oxo-3,8- Diazaspiro[4.5]decane-2-one-yl, 1-oxo-3,7-diazaspiro[4.5]decane-2-one-yl, 2,6-diazaspiro[3.4]octanyl, 2,5-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 2-oxo-7-azaspiro[3.5]nonanyl, 2-oxo-6-azaspiro[3.4]octanyl, etc. The spiroheterocyclic group may be substituted by the substituents described in the present invention.
术语“稠合双环”，“稠环”，“稠合双环基”或“稠环基”表示饱和或不饱和的稠环体系，涉及到非芳香族的双环体系，至少有一个环是非芳香性的。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。稠合双环中的每一个环要么是碳环要么是杂脂环族，这样的实例包括，但并不限于，六氢-呋喃[3，2-b]呋喃基，2，3，3a，4，7，7a-六氢-1H-茚基，7-氮杂双环[2.2.1]庚烷基，稠合双环[3.3.0]辛烷基，稠合双环[3.1.0]己烷基，1，2，3，4，4a，5，8，8a-八氢萘基，这些都包含在稠合双环的体系之内。The terms "fused bicyclic ring", "fused ring", "fused bicyclic radical" or "fused cyclic radical" refer to saturated or unsaturated fused ring systems, and to non-aromatic bicyclic ring systems, at least one of the rings is non-aromatic. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic rings may be substituted thereon). Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic, and such examples include, but are not limited to, hexahydro-furan[3,2-b]furanyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 7-azabicyclo[2.2.1]heptanyl, fused bicyclo[3.3.0]octanyl, fused bicyclo[3.1.0]hexanyl, 1,2,3,4,4a,5,8,8a-octahydronaphthyl, all of which are included in the fused bicyclic ring system.
术语“稠合杂双环基”表示饱和或不饱和的稠环体系，涉及到非芳香族的双环体系，至少有一个环是非芳香性的。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7个原子组成的环，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此N，S或P独立任选地被一个或多个氧原子所取代得到像NO，NO2，SO，SO2，PO，PO2的基团，-CH2-基团可以独立任选地被-C(＝O)-替代，这样的实例包括，但并不限于，六氢-2H-[1，4]二氧芑[2，3-c])吡咯基，3-氮杂双环[3.3.0]辛烷基，8-氮杂双环[4.3.0]壬烷基，8-氮杂双环[4.3.0]壬烷3-基，3-氮杂双环[4.3.0]壬烷-3-基，1，5-二氧-8-氮杂双环[4.3.0]壬烷基，(1R，6S)-2，5-二氧-8-氮杂双环[4.3.0]壬烷基，(1R，6R)-2，5-二氧-8-氮杂双环[4.3.0]壬烷基，异吲哚啉基，1，2，3，4-四氢喹啉基，(1S，5S)-1-羟基-3-氮杂双环[3.1.0]己烷基，(1R，5S)-1-羟基-3-氮杂双环[3.1.0]己烷基，3-氮-7-氧杂双环[3.3.0]辛烷基，3，7-二氮杂双环[3.3.0]辛烷基，2，6-二氮杂双环[3.3.0]辛烷基，2，7-二氮杂双环[3.3.0]辛烷基，2，7-二氮杂双环[3.3.0]辛烷基，2，8-二氮杂双环[4.3.0]壬烷基，3，8-二氮杂双环[4.3.0]壬烷基，3-氧-8-氮杂双环[4.3.0]壬烷基，2-氧-8-氮杂双环[4.3.0]壬烷基，2，8-二氮-5-氧杂双环[4.3.0]壬烷基，4，9-二氮杂双环[4.3.0]壬烷基，2，9-二氮杂双环[4.3.0]壬烷基，2-氧代-3-氧-8-氮杂双环[4.3.0]壬烷基，3-氧代-2，4，8-三氮杂双环[4.3.0]壬烷基，3-氧代-4-氧-2，8-二氮杂双环[4.3.0]壬烷基，3-氧代-2，8-二氮杂双环[4.3.0]壬烷基，3，8-二氮杂双环[4.3.0]壬烷基，3，7-二氮杂双环[4.3.0]壬烷基，3，9-二氮杂双环[4.3.0]壬烷基，3-氧-8-氮杂双环[4.3.0]壬烷基，3-硫-8-氮杂双环[4.3.0]壬烷基，5，6-二氢-4H-吡咯并[3，4-c]异恶唑基，[1，2，4]三氮唑[4，3-a]并哌啶基，异恶唑并[4，3-c]哌啶基，4，5，6，7-四氢异恶唑并[3，4-c]吡啶基，[1，2，4]三氮唑并[4，3-a]哌嗪基，2-氧代-3-氧-8-氮杂双环[4.3.0]壬烷基，2-氧-7-氮杂双环[4.4.0]癸烷基，1，5-二氧-9-氮杂双环[4.4.0]癸烷基，3-氮杂双环[4.4.0]癸烷基，2，7-二氮杂十氢萘基，2-氧-8-氮杂双环[4.4.0]癸烷基，六氢吡咯并[1，2-a]吡嗪-1(2H)-酮-基，十氢-1H-吡啶并[1，2-a]吡嗪-1-酮-基，3-氮杂双环[3，1，0]己烷-1-氨基-基等。稠合杂双环基可以被本发明所述的取代基所取代。The term "fused heterobicyclic group" means a saturated or unsaturated fused ring system, which refers to a non-aromatic bicyclic ring system, at least one of which is non-aromatic. Such a system may contain independent or conjugated unsaturated states, but its core structure does not contain aromatic rings or aromatic heterocycles (but aromatics can be substituents thereon). At least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 3-7 atoms, that is, 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, wherein N, S or P is independently optionally substituted by one or more oxygen atoms to obtain groups such asNO ,NO2 , SO,SO2 , PO, PO2,-CH2 -groups may be independently optionally replaced by -C(=O)-, examples of which include, but are not limited to, hexahydro-2H-[1,4]dioxin[2,3-c])pyrrolyl, 3-azabicyclo[3.3.0]octanyl, 8-azabicyclo[4.3.0]nonanyl, 8-azabicyclo[4.3.0]nonan-3-yl, 3-azabicyclo[4.3.0]nonan-3-yl, 1,5-dioxo-8-azabicyclo[4.3.0]nonyl, (1R,6S)-2,5-dioxo-8-azabicyclo[4.3.0]nonyl, (1R,6R)-2,5-dioxo-8-azabicyclo[4.3.0]nonyl, isoindolyl, 1,2,3,4-tetrahydroquinolyl, (1S,5S)-1-hydroxy-3-azabicyclo[3.1 .0]hexyl, (1R,5S)-1-hydroxy-3-azabicyclo[3.1.0]hexyl, 3-aza-7-oxabicyclo[3.3.0]octyl, 3,7-diazabicyclo[3.3.0]octyl, 2,6-diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl, 2,7-diazabicyclo[3.3.0]octyl, ] octyl, 2,8-diazabicyclo[4.3.0]nonyl, 3,8-diazabicyclo[4.3.0]nonyl, 3-oxo-8-azabicyclo[4.3.0]nonyl, 2-oxo-8-azabicyclo[4.3.0]nonyl, 2,8-diaza-5-oxabicyclo[4.3.0]nonyl, 4,9-diazabicyclo[4.3.0]nonyl, 2, 9-diazabicyclo[4.3.0]nonyl, 2-oxo-3-oxo-8-azabicyclo[4.3.0]nonyl, 3-oxo-2,4,8-triazabicyclo[4.3.0]nonyl, 3-oxo-4-oxo-2,8-diazabicyclo[4.3.0]nonyl, 3-oxo-2,8-diazabicyclo[4.3.0]nonyl, 3,8-diazabicyclo[4.3.0]nonyl Bicyclo[4.3.0]nonyl, 3,7-diazabicyclo[4.3.0]nonyl, 3,9-diazabicyclo[4.3.0]nonyl, 3-oxo-8-azabicyclo[4.3.0]nonyl, 3-thio-8-azabicyclo[4.3.0]nonyl, 5,6-dihydro-4H-pyrrolo[3,4-c]isoxazolyl, [1,2,4]triazole[4, 3-a]piperidinyl, isoxazolo[4,3-c]piperidinyl, 4,5,6,7-tetrahydroisoxazolo[3,4-c]pyridinyl, [1,2,4]triazolo[4,3-a]piperazinyl, 2-oxo-3-oxo-8-azabicyclo[4.3.0]nonyl, 2-oxo-7-azabicyclo[4.4.0]decyl, 1,5-dioxo-9-azabicyclo[4 .4.0]decyl, 3-azabicyclo[4.4.0]decyl, 2,7-diazadecahydronaphthyl, 2-oxo-8-azabicyclo[4.4.0]decyl, hexahydropyrrolo[1,2-a]pyrazine-1(2H)-one-yl, decahydro-1H-pyrido[1,2-a]pyrazine-1-one-yl, 3-azabicyclo[3,1,0]hexane-1-amino-yl, etc. The fused heterobicyclic group may be substituted by the substituents described in the present invention.
像本发明所描述的，取代基画一个键连接到环上形成的环体系代表取代基在该环上任何可取代的位置都可以取代。例如，式(a)代表p个取代基R可以在吡啶环上任何可能被取代的位置上取代。As described in the present invention, a substituent is connected to a ring by a bond to form a ring system, which means that the substituent can be substituted at any substitutable position on the ring. For example, formula (a) represents that p substituents R can be substituted at any substitutable position on the pyridine ring.
像本发明所描述的，一个连接键连接到环上形成的环体系(如式b所示)代表连接键可以在环体系上任何可连接的位置与分子其余部分相连。式b代表八氢环戊烯并吡咯环上任何可能连接的位置均可与分子其余部分相连。As described in the present invention, a linker bonded to a ring to form a ring system (as shown in formula b) represents that the linker bond can be connected to the rest of the molecule at any connectable position on the ring system. Formula b represents that any possible connectable position on the octahydrocyclopenta-pyrrole ring can be connected to the rest of the molecule.
像本发明所描述的，环C上有两个连接点可与分子其余部分相连，例如，如式c所示，除非以其他方式明确指出，否则表示式c中既可以是E端也可以是E’端与分子的其余部分相连，即两端的连接方式可以互换。As described in the present invention, there are two connection points on ring C that can be connected to the rest of the molecule. For example, as shown in formula c, unless otherwise clearly indicated, it means that in formula c, either the E end or the E' end can be connected to the rest of the molecule, that is, the connection methods of the two ends can be interchangeable.
如本发明所描述，连接点可以在环上任何可连接的位置与分子其余部分连接，同时连接的两端可以互换。例如，式d代表环上任何可能被连接的位置均可作为连接的点，同时连接点的两端可以互换。As described in the present invention, the connection point can be connected to the rest of the molecule at any connectable position on the ring, and the two ends of the connection can be interchanged. For example, formula d represents that any position on the ring that may be connected can be used as the connection point, and the two ends of the connection point can be interchanged.
另外，需要说明的是，除非以其他方式明确指出，在本文中通篇采用的描述方式“各...和...独立地为”、“...和...各自独立地为”和“...和...分别独立地为”可以互换，应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。例如，
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reactions, such as gastrointestinal upset, dizziness, etc., when administered to humans. Preferably, the term "pharmaceutically acceptable" as used herein refers to approved by federal regulatory agencies or state governments or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, more particularly in humans.
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体，例如水和油类，包括石油、动物、植物或合成来源的，例如花生油、大豆油、矿物油、芝麻油等。水和水性溶液盐水溶液和水性葡萄糖与甘油溶液优选用作载体、特别是可注射溶液。适宜的药物载体描述于E.W.Martin的“Remington′s PharmaceuticalSciences”中。The term "carrier" refers to a diluent, adjuvant, excipient or matrix with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water and aqueous saline solutions and aqueous glucose and glycerol solutions are preferably used as carriers, particularly injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W.Martin.
本发明的“水合物”是指本发明所提供的化合物或其盐，其还包括化学量或非化学当量通过非共价分子间力结合的水，也可说是溶剂分子是水所形成的缔合物。The "hydrate" of the present invention refers to the compound or salt thereof provided by the present invention, which further includes chemically or non-chemically equivalent water bound by non-covalent intermolecular forces, and can also be said to be an association formed by water as the solvent molecule.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，MeOH，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, MeOH, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
本发明的“酯”是指含有羟基的式(I)-式(II)所示化合物可形成体内可水解的酯。这样的酯是例如在人或动物体内水解产生母体醇的药学上可接受的酯。含有羟基的式(I)-式(II)所示化合物体内可水解的酯的基团包括，但不限于，磷酸基，乙酰氧基甲氧基，2，2-二甲基丙酰氧基甲氧基，烷酰基，苯甲酰基，苯甲乙酰基，烷氧基羰基，二烷基氨基甲酰基和N-(二烷基氨基乙基)-N-烷基氨基甲酰基等。The "ester" of the present invention refers to an ester that can be hydrolyzed in vivo by the compound shown in formula (I)-formula (II) containing a hydroxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce a parent alcohol. The groups of the ester that can be hydrolyzed in vivo by the compound shown in formula (I)-formula (II) containing a hydroxyl group include, but are not limited to, a phosphate group, an acetoxymethoxy group, a 2,2-dimethylpropionyloxymethoxy group, an alkanoyl group, a benzoyl group, a benzoyl group, an alkoxycarbonyl group, a dialkylaminoformyl group, and a N-(dialkylaminoethyl)-N-alkylaminoformyl group.
本发明的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry，Wiley Interscience，第4版，Jerry March，pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977，7，509-514)，其中例如在惰性溶剂例如DCM中，使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。"Nitrogen oxide" of the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidants such as hydrogen peroxide or peracids (e.g. peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as DCM, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).
化合物可存在多种不同几何异构体和互变异构体，所述式(I)-式(II)化合物包括所有此类形式。为避免疑惑，当化合物以几种几何异构体或互变异构体之一存在并且只具体描述或显示一种时，显然所有其它形式包括在式(I)-式(II)中。Compounds can exist in a variety of different geometrical isomers and tautomers, and the compounds of formula (I)-formula (II) include all such forms. To avoid doubt, when a compound exists in one of several geometrical isomers or tautomers and only one is specifically described or shown, it is obvious that all other forms are included in formula (I)-formula (II).
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)-式(II)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella，Pro-drugs as Novel DeliverySystems，Vol.14 of the A.C.S.Symposium Series，Edward B.Roche，ed.，BioreversibleCarriers in Drug Design，American Pharmaceutical Association and PergamonPress，1987，J.Rautio et al，Prodrugs：Design and Clinical Applications，NatureReview Drug Discovery，2008，7，255-270，and S.J.Hecker et al，Prodrugs ofPhosphates and Phosphonates，Journal of Medicinal Chemistry，2008，51，2328-2345。The term "prodrug" used in the present invention refers to a compound that is converted into a compound represented by formula (I)-formula (II) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, the esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, see the following: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention.
另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。本发明包括同位素标记的化合物，它们等同于式(I)-式(II)所述的化合物，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如3H和14C)的那些可用于药物和/或底物组织分布测定。同位素标记的本发明式(I)-式(II)所示化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。In addition, unless otherwise indicated, the structural formula of the compounds described in the present invention includes enriched isotopes of one or more different atoms. The present invention includes isotope-labeled compounds, which are equivalent to the compounds described in formula (I)-formula (II), but one or more atoms are replaced by atoms whose atomic mass or mass number is different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2 H,3 H,13 C,11 C,14 C,15 N,18 O,17 O,31 P,32 P,35 S,18 F and36 Cl, respectively. Compounds of the present invention containing the above-mentioned isotopes and/or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or the prodrugs all belong to the scope of the present invention. Certain isotopically labeled compounds of the invention, such as those into which radioactive isotopes (e.g.,3 H and14 C) are introduced, are useful in drug and/or substrate tissue distribution assays. Isotopically labeled compounds of formula (I) to (II) of the invention and their prodrugs can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents when carrying out the processes disclosed in the following schemes and/or the Examples and Preparations.
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.
本发明化合物的各种药学上可接受的盐形式都是有用的。术语“药学上可接受的盐”是指那些盐形式对于制药化学家而言是显而易见的，即它们基本上无毒并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄。其他因素，在性质上更加实用，对于选择也很重要，这些是：原材料的成本、结晶的容易、产率、稳定性、吸湿性和结果原料药的流动性。简单地讲，药物组合物可以通过有效成分与药学上可接受的载体制备得到。Various pharmaceutically acceptable salt forms of the compounds of the invention are useful. The term "pharmaceutically acceptable salt" refers to those salt forms that are obvious to the pharmaceutical chemist, i.e., they are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, are also important for selection, and these are: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting drug substance. In brief, a pharmaceutical composition can be prepared by combining the active ingredient with a pharmaceutically acceptable carrier.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M. Berge et al.，describepharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences，66：1-19，1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，硝酸盐等，和有机酸盐如乙酸盐，丙酸盐，乙醇酸盐，草酸盐，马来酸盐，丙二酸盐，琥珀酸盐，富马酸盐，酒石酸盐，枸橼酸盐，苯甲酸盐，扁桃酸盐，甲磺酸盐，乙磺酸盐，甲苯磺酸盐，磺基水杨酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。The "pharmaceutically acceptable salt" used in the present invention refers to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M. Berge et al., describepharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, nitrates, etc., and organic acid salts such as acetates, propionates, glycolates, oxalates, maleates, malonates, succinates, fumarates, tartrates, citrates, benzoates, mandelates, methanesulfonates, ethanesulfonates, toluenesulfonates, sulfosalicylate, etc., or these salts are obtained by other methods described in books and literature, such as ion exchange methods.
其他药学上可接受的盐包括己二酸盐、苹果酸盐、2-羟基丙酸、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐、等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N+(C1-4烷基)4的盐。Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionic acid, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C1-4 alkyl)4 salts.
本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。胺盐，例如但不限于N，N’-二苄基乙二胺，氯普鲁卡因，胆碱，氨，二乙醇胺和其它羟烷基胺，乙二胺，N-甲基还原葡糖胺，普鲁卡因，N-苄基苯乙胺，1-对-氯苄基-2-吡咯烷-1’-基甲基-苯并咪唑，二乙胺和其它烷基胺，哌嗪和三(羟甲基)氨基甲烷；碱土金属盐，例如但不限于钡，钙和镁；过渡金属盐，例如但不限于锌。The present invention also contemplates quaternary ammonium salts formed by compounds of any N-containing group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates and aromatic sulfonates. Amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucosamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkaline earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc.
术语“保护基团”或“Pg”是指一个取代基与别的官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC)，苄氧羰基(CBZ)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH2CH2SO2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene，Protective Groups in Organic Synthesis，John Wiley&Sons，New York，1991；and P.J.Kocienski，Protecting Groups，Thieme，Stuttgart，2005.The term "protecting group" or "Pg" refers to a substituent that is used to block or protect a specific functionality when reacting with another functional group. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent of a carboxyl group used to block or protect the functionality of the carboxyl group. Typical carboxyl protecting groups include -CH2 CH2 SO2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, and the like. For a general description of protecting groups, please refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P J Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
本发明中“室温”指的是温度由10℃到40℃。在一些实施例中，“室温”指的是温度由20℃到30℃；在另一些实施例中，“室温”指的是25℃。In the present invention, "room temperature" refers to a temperature from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature from 20°C to 30°C; in other embodiments, "room temperature" refers to 25°C.
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。In this specification, if there is any discrepancy between a chemical name and a chemical structure, the structure prevails.
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、公认的缩写为准，或参照IUPAC-IUB Commission on BiochemicalNomenclature(参见Biochem.1972，11：942-944)。Any abbreviations for protecting groups, amino acids and other compounds used in the present invention are based on their commonly used and recognized abbreviations, or refer to IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11: 942-944), unless otherwise specified.
本发明化合物的描述Description of the compounds of the present invention
本发明提供一种化合物或其药物组合物，其可作为PD-1/PD-L1的抑制剂。本发明进一步涉及所述化合物或其药物组合物用于制备药剂的用途，该药剂通过用所述化合物抑制PD-1活性来治疗疾病和/或病症。本发明又进一步描述了合成所述化合物的方法。本发明的化合物显示出改善的生物活性及药代动力学性质。The present invention provides a compound or a pharmaceutical composition thereof, which can be used as an inhibitor of PD-1/PD-L1. The present invention further relates to the use of the compound or a pharmaceutical composition thereof for preparing a medicament, which treats a disease and/or a condition by inhibiting PD-1 activity with the compound. The present invention further describes a method for synthesizing the compound. The compounds of the present invention show improved biological activity and pharmacokinetic properties.
本发明一方面提供一种PD-1/PD-L1类小分子抑制剂的化合物，其为如式(I)所示的结构或如式(I)所示结构的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，On the one hand, the present invention provides a compound of a PD-1/PD-L1 small molecule inhibitor, which has a structure as shown in formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug of the structure as shown in formula (I).
其中，A、X、R1、R2、R3和p具有本发明所述的含义。A, X, R1 , R2 , R3 and p have the meanings as defined in the present invention.
在一些实施方案中，本发明所述的R1为-(CH2)nAr，其中，Ar为C6-12芳基或C5-12杂芳基；所述Ar任选地被1、2、3或4个取代基取代，所述取代基各自独立地为H、D、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基或C1-6烷氧基；n为1、2、3或4。In some embodiments, R1 described in the present invention is -(CH2 )n Ar, wherein Ar is C6-12 aryl or C5-12 heteroaryl; the Ar is optionally substituted by 1, 2, 3 or 4 substituents, each of which is independently H, D, cyano, halogen, amino, methylsulfonyl, acetamido, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy or C1-6 alkoxy; n is 1, 2, 3 or 4.
在一些实施方案中，本发明所述的R1为-(CH2)nAr，其中，所述Ar为苯基、吡啶基、嘧啶基、吲哚基或喹啉基；Ar任选地被1、2、3或4个取代基取代，所述取代基各自独立地为H、氰基、卤素、氨基、甲磺酰基、乙酰氨基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基或C1-6烷氧基；n为1。In some embodiments, R1 described in the present invention is -(CH2 )n Ar, wherein Ar is phenyl, pyridyl, pyrimidinyl, indolyl or quinolyl; Ar is optionally substituted by 1, 2, 3 or 4 substituents, each of which is independently H, cyano, halogen, amino, methylsulfonyl, acetamido, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy or C1-6 alkoxy; n is 1.
在一些实施方案中，本发明所述的A为-CH2O-、-OCH2-、-CH2-CH2-、-C(O)NH-或-NHC(O)-。In some embodiments, A described in the present invention is -CH2 O-, -OCH2 -, -CH2 -CH2 -, -C(O)NH-, or -NHC(O)-.
在一些实施方案中，本发明所述的A为-CH2O-。In some embodiments, A described herein is -CH2 O-.
在一些实施方案中，本发明所述的R2为
其中，R5和R6各自独立地为H、卤素、C1-6烷基、C1-6卤代烷基或C1-6烷氧基；Z为CH或N；wherein R5 and R6 are each independently H, halogen, C1-6 alkyl, C1-6 haloalkyl or C1-6 alkoxy; Z is CH or N;
R7为
Rv为
X和Y为H、C1-6烷基、C1-6烷氧基、卤素或者氰基。X and Y are H, C1-6 alkyl, C1-6 alkoxy, halogen or cyano.
在一些实施方案中，本发明所述的R5或R6各自独立的为H、D、氟、氯、溴、甲基、乙基、正丙基、异丙基、叔丁基、异丁基、正丁基、三氟甲基、二氟甲基、一氟甲基、甲氧基或乙氧基。In some embodiments, R5 or R6 described in the present invention are each independently H, D, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, n-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, methoxy or ethoxy.
在一些实施方案中，本发明所述的R7为
在一些实施方案中，本发明所述的Rv为
在一些实施方案中，本发明所述的Rv为以下结构式形成的基团之一：In some embodiments,Rv of the present invention is one of the groups formed by the following structural formulas:
其中，所述W1、W3和W5各自独立地为CH2、S、O、S(O)2或者NH，W2和W4各自独立地为CH或CH或N；m1、m2、m3、m4、m5、m6、m7和m8各自独立地为0、1、2或3；Wherein, W1 , W3 and W5 are each independently CH2 , S, O, S(O)2 or NH, W2 and W4 are each independently CH or CH or N; m1, m2, m3, m4, m5, m6, m7 and m8 are each independently 0, 1, 2 or 3;
所述Rv任选地被0、1、2或3个取代基取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基或氨基C1-6烷基。The Rv is optionally substituted by 0, 1, 2 or 3 substituents, and the substituents are hydroxy, cyano, amino, oxo (=O), C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy or aminoC1-6 alkyl.
在另一些实施方案中，本发明所述的Rv为以下结构式形成的基团之一：In other embodiments,Rv of the present invention is one of the groups formed by the following structural formulas:
其中，所述Rv任选地被0、1、2或3个取代基取代，所述取代基为羟基、氰基、氨基、氧代(＝O)、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基或氨基C1-6烷基。Wherein, the Rv is optionally substituted by 0, 1, 2 or 3 substituents, and the substituents are hydroxyl, cyano, amino, oxo (=O), C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy or aminoC1-6 alkyl.
在一些实施方案中，本发明所述的Y为甲基、乙基、异丙基、正丙基、正丁基、叔丁基或异丁基；优选的，Y为甲基。In some embodiments, Y described in the present invention is methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl or isobutyl; preferably, Y is methyl.
在一些实施方案中，本发明所述的R3为C1-8烷氨基或C3-9杂环基，其中，所述的C3-9杂环基中至少含有一个N原子；所述的C1-8烷氨基或C3-9杂环基任选地被0、1、2、3或4个取代基所取代，所述取代基为氢、羟基、卤素、羧基、C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6烷氧基、氨基、氨基C1-6烷基、乙酰氨基、氰基、磺酰胺基或氧代(＝O)。In some embodiments, R3 described in the present inventionisC1-8 alkylamino orC3-9 heterocyclic group, wherein theC3-9 heterocyclic group contains at least one N atom; theC1-8 alkylamino orC3-9 heterocyclic group is optionally substituted by 0, 1, 2, 3 or 4 substituents, and the substituents are hydrogen, hydroxyl, halogen, carboxyl,C1-6 alkyl,C1-6 haloalkyl,C1-6 haloalkoxy,C1-6 alkoxy, amino,aminoC1-6 alkyl, acetamido, cyano, sulfonamido or oxo (=O).
在一些实施方案中，本发明所述的R3为如下结构形成的基团之一：In some embodiments, R3 of the present invention is one of the groups formed by the following structures:
在一些实施方案中，本发明所述的p为0、1、2或3。In some embodiments, p described herein is 0, 1, 2 or 3.
在一些实施方案中，本发明所述的X为H、C1-6烷基、C1-6烷氧基、卤素或者氰基；优选的，X为氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。In some embodiments, X of the present invention is H, C1-6 alkyl, C1-6 alkoxy, halogen or cyano; preferably, X is fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
在一些试试方案中，本发明所述的化合物为如式(II)所示的结构或如式(II)所示结构的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或前药，In some embodiments, the compound of the present invention is a structure as shown in formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug of the structure as shown in formula (II).
其中，R1、R2、R3、R5、R6、Rv、X、Y、Z和p具有本发明所述的含义。Herein, R1 , R2 , R3 , R5 , R6 , Rv , X, Y, Z and p have the meanings as defined in the present invention.
在一些实施方案中，本发明包含以下其中之一的化合物或以下其中之一的化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐或前药：In some embodiments, the present invention comprises a compound of one of the following or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of one of the following compounds:
一方面，本发明涉及药物组合物，该药物组合物，包含本发明式(I)或式(II)所述的化合物，或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，及其药学上可接受的辅料或它们的组合。On the one hand, the present invention relates to a pharmaceutical composition, which comprises a compound of formula (I) or (II) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient or a combination thereof.
一方面，本发明涉及式(I)或(II)所述的化合物或其药物组合物在制备用于防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病的药物的用途。On the one hand, the present invention relates to the use of a compound described in formula (I) or (II) or a pharmaceutical composition thereof in the preparation of a drug for protecting, treating, curing or alleviating a patient's disease related to the PD-1/PD-L1 signaling pathway.
在一些实施案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease related to the PD-1/PD-L1 signaling pathway described in the present invention is cancer, infectious disease or autoimmune disease.
在另一些实施案中，本发明所述的癌症选自器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或系统性自身免疫病。In other embodiments, the cancer described in the present invention is selected from diseases in which cells in an organ or body tissue proliferate indefinitely; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; and the autoimmune disease is an organ-specific autoimmune disease or a systemic autoimmune disease.
在一些实施案中，本发明所述的器官或体组织中细胞无限增殖的疾病是为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the disease of immortalized cell proliferation in an organ or body tissue described in the present invention is bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia , childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancers or a combination of the above diseases; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
在一些实施案中，本发明所述病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、乳头瘤病毒感染和流感。In some embodiments, the viral infectious diseases described in the present invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection and influenza.
在一些实施案中，本发明所述的所述的器官特异性自身免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的系统性自身免疫病为类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病和自身免疫性溶血性贫血。In some embodiments, the organ-specific autoimmune disease described in the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia.
在一些实施方案中，本发明描述了一种防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病的方法，所述方法包含给予患者有效治疗剂量的本发明所述的化合物或药物组合物。In some embodiments, the present invention describes a method for protecting, treating, curing or alleviating a disease associated with the PD-1/PD-L1 signaling pathway in a patient, the method comprising administering to the patient an effective therapeutic dose of a compound or pharmaceutical composition described herein.
在一些实施方案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease related to the PD-1/PD-L1 signaling pathway described in the present invention is cancer, infectious disease or autoimmune disease.
在一些实施方案中，本发明所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或系统性自身免疫病。In some embodiments, the cancer described in the present invention is a disease in which cells in an organ or body tissue proliferate indefinitely; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; and the autoimmune disease is an organ-specific autoimmune disease or a systemic autoimmune disease.
在一些实施方案中，本发明所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the disease of immortalized cell proliferation in the organ or body tissue described in the present invention is bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia. , childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancers or a combination of the above diseases; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
在一些实施方案中，本发明所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、乳头瘤病毒感染和流感。In some embodiments, the viral infectious diseases described in the present invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection and influenza.
在一些实施方案中，本发明所述的器官特异性免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的系统性自身免疫病为类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病和自身免疫性溶血性贫血。另一方面，本发明提供一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，其包括向受治疗者使用治疗有效量本发明的化合物，从而调节受治疗者中的免疫应答。In some embodiments, the organ-specific immune disease described in the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, primary biliary cirrhosis, multiple encephalosclerosis and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia. On the other hand, the present invention provides a method for regulating an immune response mediated by a PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, thereby regulating the immune response in the subject.
在一些实施方案中，将本发明所描述的化合物或药物组合物用于防护、处理、治疗或减轻患者与PD-1/PD-L1信号通路有关疾病。In some embodiments, the compounds or pharmaceutical compositions described herein are used to protect, treat, cure or alleviate diseases related to the PD-1/PD-L1 signaling pathway in patients.
在一些实施方案中，本发明所述的PD-1/PD-L1信号通路有关的疾病为癌症、感染性疾病或自身免疫性疾病。In some embodiments, the disease related to the PD-1/PD-L1 signaling pathway described in the present invention is cancer, infectious disease or autoimmune disease.
在一些实施方案中，本发明所述的癌症为器官或体组织中存在细胞无限增殖的疾病；所述感染性疾病为细菌感染性疾病、病毒感染性疾病或真菌感染性疾病；所述自身免疫性疾病为器官特异性自身免疫病或系统性自身免疫病。In some embodiments, the cancer described in the present invention is a disease in which cells in an organ or body tissue proliferate indefinitely; the infectious disease is a bacterial infectious disease, a viral infectious disease, or a fungal infectious disease; and the autoimmune disease is an organ-specific autoimmune disease or a systemic autoimmune disease.
在一些实施方案中，本发明所述的器官或体组织中细胞无限增殖的疾病为骨癌、头颈癌、胰腺癌、皮肤癌、恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、肛门区域癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、非霍奇金淋巴瘤、食道癌、小肠癌、内分泌系统癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、儿童实体瘤、淋巴细胞淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、肿瘤血管生成、脊柱肿瘤、脑干胶质瘤、垂体腺瘤、卡波济氏肉瘤、表皮样癌、鳞状上皮细胞癌、T细胞淋巴瘤或环境诱发的癌症或以上所述疾病的组合；其中所述慢性或急性白血病包含急性髓细胞白血病、慢性髓细胞白血病、急性淋巴细胞白血病和慢性淋巴细胞白血病。In some embodiments, the disease of immortalized cell proliferation in the organ or body tissue described in the present invention is bone cancer, head and neck cancer, pancreatic cancer, skin cancer, malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia. , childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma or environmentally induced cancers or a combination of the above diseases; wherein the chronic or acute leukemia comprises acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
在一些实施方案中，本发明所述的病毒感染性疾病为艾滋病、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒感染、乳头瘤病毒感染和流感。In some embodiments, the viral infectious diseases described in the present invention are AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus infection, papillomavirus infection and influenza.
在一些实施方案中，本发明所述的器官特异性免疫病为慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖性糖尿病、重症肌无力、溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、肺出血肾炎综合征、原发性胆汁性肝硬化、多发性脑脊髓硬化症和急性特发性多神经炎；所述的系统性自身免疫病为类风湿关节炎、系统性红斑狼疮、系统性血管炎、硬皮病、天疱疮、皮肌炎、混合性结缔组织病和自身免疫性溶血性贫血。In some embodiments, the organ-specific immune disease described in the present invention is chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, Goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis and acute idiopathic polyneuritis; the systemic autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia.
另一方面，本发明提供一种调节受治疗者中由PD-1信号传导通路介导的免疫应答的方法，其包括向受治疗者使用治疗有效量本发明的化合物，从而调节受治疗者中的免疫应答。In another aspect, the present invention provides a method of modulating an immune response mediated by the PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, thereby modulating the immune response in the subject.
另一方面，本发明涉及式(I)或(II)所包含的化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I) or (II).
本发明的化合物的组合物Compositions of compounds of the present invention
像本发明所描述的，本发明药物组合物包含任何一种本发明的式(I)或(II)所示化合物，进一步包含药学上可接受的辅料，这些辅料，例如像本发明所应用的，包括任何溶剂、固体赋形剂、稀释剂、粘合剂、崩解剂、或其他液体赋形剂、分散剂、矫味剂或悬浮剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington：The Science and Practice of Pharmacy，21st edition，2005，ed.D.B.Troy，Lippincott Williams&Wilkins，Philadelphia，andEncyclopedia of Pharmaceutical Technology，eds.J.Swarbrick and J.C.Boylan，1988-1999.Marcel Dekker，New York，综合此处文献的内容，表明不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。As described in the present invention, the pharmaceutical composition of the present invention comprises any one of the compounds of formula (I) or (II) of the present invention, and further comprises a pharmaceutically acceptable excipient, such as any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999. Marcel Dekker, New York, the contents of the documents herein indicate that different excipients can be applied to the preparation of pharmaceutically acceptable compositions and their known preparation methods. Except insofar as any conventional excipients are incompatible with the compounds of the present invention, for example by producing any undesirable biological effect or interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, their use is contemplated by the present invention.
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。当本发明的化合物以药物的形式施用于哺乳动物例如人时，其可以以化合物本身的形式被给予或者可以以含有例如0.1至99.5％(更优选0.5至90％)活性成分以及药学可接受的载体的药物组合物的形式被给予。Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavoring agents; spices; preservatives and antioxidants. When the compound of the present invention is administered to mammals such as humans in the form of a drug, it can be administered in the form of the compound itself or can be administered in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of active ingredients and a pharmaceutically acceptable carrier.
“治疗有效量”或“有效量”是指本发明的一种或多种化合物治疗或预防特定疾病、病症或综合征减轻、改善或消除特定疾病、病症或综合征的一个或多个症状或阻止或延迟本文所述的特定疾病、病症或综合征的一个或多个症状的开始的足够量。在癌症的情况下，治疗有效量的药物可以减少癌细胞的数量；降低癌尺寸；抑制(即，减慢到一定程度或备选地终止)癌细胞浸润入周围器官；压制(即，减慢到一定程度或备选地终止)肿瘤转移；一定程度上一直肿瘤生长；和/或一定程度上缓解与癌症相关的一个或多个症状。在感染性疾病状态的情况下，治疗有效量是足以降低或缓解感染性疾病(由细菌、病毒和真菌引起的感染症状)的量。本领域普通技术人员将能研究本文所包含的因素和在不进行过度实验的情况下确定本发明的化合物的有效量。"Therapeutically effective amount" or "effective amount" refers to a sufficient amount of one or more compounds of the present invention to treat or prevent a specific disease, condition or syndrome to reduce, improve or eliminate one or more symptoms of a specific disease, condition or syndrome or to prevent or delay the onset of one or more symptoms of a specific disease, condition or syndrome described herein. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce cancer size; inhibit (i.e., slow to a certain extent or alternatively terminate) cancer cell infiltration into surrounding organs; suppress (i.e., slow to a certain extent or alternatively terminate) tumor metastasis; to a certain extent tumor growth; and/or alleviate one or more symptoms associated with cancer to a certain extent. In the case of infectious disease states, a therapeutically effective amount is an amount sufficient to reduce or alleviate infectious diseases (infection symptoms caused by bacteria, viruses and fungi). One of ordinary skill in the art will be able to study the factors contained herein and determine the effective amount of the compounds of the present invention without undue experimentation.
施用方案可影响有效量的构成。本发明的化合物可在与PD-1/PD-L1信号通路有关的病症发作之前或之后被施用于个体。此外，可以每天或相继施用多个分剂量以及错开的剂量，或者可以连续输注给药，或者可以推注给药。此外，本发明的化合物的剂量可以根据治疗或预防的情形的紧迫性按比例酌情增加或减少。The administration regimen may affect the composition of the effective amount. The compounds of the present invention may be administered to an individual before or after the onset of a condition associated with the PD-1/PD-L1 signaling pathway. In addition, multiple divided doses and staggered doses may be administered daily or sequentially, or may be administered by continuous infusion, or may be administered by push injection. In addition, the dosage of the compounds of the present invention may be increased or decreased as appropriate in proportion to the urgency of the situation for treatment or prevention.
本发明的化合物可用于治疗本文所述的状态、病症或疾病，或用于制备治疗这些疾病的药物组合物。本发明的化合物在这些疾病治疗中的使用方法或用于治疗这些疾病的含有本发明的化合物的药物制剂。The compounds of the invention can be used to treat the conditions, disorders or diseases described herein, or to prepare pharmaceutical compositions for treating these diseases. The compounds of the invention can be used in methods of treating these diseases or pharmaceutical preparations containing the compounds of the invention for treating these diseases.
“药学可接受的载体”在本领域中是公认的，包括适于将本发明的化合物施用于哺乳动物的药学可接受的材料、组合物或载体。所述载体包括参与携带主题物质或将其从一个器官或机体的一部分转移到另一个器官或机体的另一部分的液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。各载体在与制剂中的其它成分相容和对患者无害的意义上必须是“可接受的”。可用作药学可接受的载体的材料的一些实例包括：糖类，如乳糖、葡萄糖和蔗糖；淀粉类，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；粉状西黄蓍胶；麦芽；明胶；滑石粉；赋形剂，如可可脂和栓剂蜡类；油类，如花生油、棉子油、红花油、芝麻油、橄榄油、玉米油和豆油；二醇类，如丙二醇；多元醇类，如甘油、山梨醇、甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等张盐水；林格氏溶液；乙醇；磷酸盐缓冲液；和药物制剂中所用的其它无毒的可相容的物质。"Pharmaceutically acceptable carriers" are recognized in the art and include pharmaceutically acceptable materials, compositions or vehicles suitable for administering the compounds of the present invention to mammals. The carriers include liquid or solid fillers, diluents, excipients, solvents or encapsulating materials that participate in carrying the subject substance or transferring it from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic, compatible substances used in pharmaceutical formulations.
在组合物中也可以存在润湿剂、乳化剂和润滑剂如十二烷基硫酸钠和硬脂酸镁，以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂。Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
药学可接受的抗氧化剂的实例包括：水溶性抗氧化剂，如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等；油溶性抗氧化剂，如棕榈酸抗坏血酸酯、丁基化羟基苯甲醚(BHA)、丁化羟基甲苯(BHT)、卵磷脂、棓酸丙酯、α-生育酚等；和金属螯合剂，如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.
本发明的制剂包括适于口服、鼻、局部、口含、舌下、直肠、阴道和/或胃肠外施用的那些。制剂可以方便地以单位剂型形式存在并且可以通过药学领域公知的任何方法来制备。可以与载体物质组合来制备单剂量形式的活性成分的量一般是产生治疗作用的化合物的量。一般而言，以百分之一为单位，该量为约1％至约99％活性成分，优选约5％至约70％，最优选约10至约30％。The preparations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration. The preparations can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to prepare a single dose form is generally the amount of the compound that produces the therapeutic effect. Generally speaking, in units of one percent, the amount is about 1% to about 99% active ingredient, preferably about 5% to about 70%, and most preferably about 10 to about 30%.
制备这些制剂或组合物的方法包括使本发明的化合物与载体、独立任选地和一种或多种辅助成分结合的步骤。一般而言，制剂是通过将本发明的化合物与液体载体或很细的固体载体或这二者均匀且紧密地结合在一起、然后如果需要的话，将该产物成型来制备的。The method for preparing these preparations or compositions comprises the step of combining the compound of the present invention with a carrier, independently and optionally with one or more auxiliary components. In general, the preparation is prepared by uniformly and intimately combining the compound of the present invention with a liquid carrier or a very fine solid carrier or both, and then, if necessary, shaping the product.
适于口服施用的本发明的制剂可以是胶囊剂、扁囊剂、丸剂、片剂、锭剂(使用矫味的基质，通常为蔗糖和阿拉伯胶或西黄蓍胶)、散剂、颗粒剂、或者在水性或非水性液体中的溶液剂或混悬剂、或者水包油或油包水型液体乳剂、或者酏剂或糖浆剂、或者软锭剂(使用惰性基质，如明胶和甘油、或蔗糖和阿拉伯胶)和/或漱口剂等的形式，其各自含有既定量的本发明的化合物作为活性成分。本发明的化合物还可以以大丸剂、药糖剂或糊剂的形式施用。Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, or elixirs or syrups, or pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia) and/or mouthwashes, etc., each containing a predetermined amount of a compound of the invention as the active ingredient. The compound of the invention may also be administered in the form of a bolus, electuary or paste.
在用于口服施用的本发明的固体剂型(胶囊剂、片剂、丸剂、糖衣丸、散剂、颗粒剂等)中，将活性成分与一种或多种药学可接受的载体如柠檬酸钠或磷酸二钙和/或任何下列物质混合：填充剂或增量剂，如淀粉类、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸；粘合剂，例如，羧甲基纤维素、藻酸盐类、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶；保湿剂，如甘油；崩解剂，如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、海藻酸、某些硅酸和碳酸钠；溶液阻滞剂(solution retarding agent)，如石蜡；吸收促进剂，如季铵化合物；润湿剂，例如，鲸蜡醇和甘油单硬脂酸酯；吸附剂，如高岭土和皂土；润滑剂，如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，以及其混合物；和着色剂。在胶囊剂、片剂和丸剂的情况下，药物组合物还可包含缓冲剂。类似类型的固体组合物还可在使用赋形剂如乳糖或奶糖以及高分子量聚乙二醇等的软和硬填充明胶胶囊中用作填充物。In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicic acids and sodium carbonate; solution retarding agents, such as paraffin; absorption promoters, such as quaternary ammonium compounds; wetting agents, for example, cetyl alcohol and glyceryl monostearate; adsorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents.Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
片剂可以通过压制或模制来制备，可任选地使用一种或多种辅助成分。压制片可以用粘合剂(例如，明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如，羟乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备。模制片可以通过将用惰性液体稀释剂润湿的粉状化合物的混合物在合适的机器中进行模制来制备。Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared with a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant. Molded tablets can be prepared by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine.
片剂和本发明的药物组合物的其它固体剂型如糖衣丸、胶囊剂、丸剂和颗粒剂可任选地被刻痕或用包衣和壳如肠溶衣和制药领域公知的其它包衣来制备。也可以将它们用例如提供所需释放性质的各种比例的羟丙基甲基纤维素、其它聚合物基质、脂质体和/或微球进行配制以便提供其中的活性成分的缓慢释放或控制释放。可将它们例如通过用截留细菌的滤器过滤或通过在使用前即刻掺入可溶解于无菌水或一些其它可注射无菌溶媒中的无菌固体组合物形式的灭菌剂来进行灭菌。这些组合物还可任选地含有遮光剂并且可以是仅在或优先在胃肠道的某个部分中释放活性成分、任选以延迟方式释放活性成分的组合物。可使用的包埋组合物的实例包括聚合物物质和蜡类。活性成分也可以是微囊化的形式，如果适宜的话，使用一种或多种上述赋形剂。Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells such as enteric coatings and other coatings known in the pharmaceutical field. They may also be formulated with various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes and/or microspheres, for example, to provide the desired release properties, so as to provide slow release or controlled release of the active ingredient therein. They may be sterilized, for example, by filtering with a filter that retains bacteria or by immediately incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other injectable sterile solvent before use. These compositions may also optionally contain an opacifier and may be a composition that releases the active ingredient only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, using one or more of the above-mentioned excipients.
用于口服施用的本发明的化合物的液体剂型包括药学可接受的乳剂、微乳、溶液、混悬液、糖浆剂和酏剂。除活性成分以外，液体剂型还可含有本领域中常用的惰性稀释剂例如水或其它溶剂、增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1，3-丁二醇、油类(特别是棉子油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇醇、聚乙二醇和失水山梨醇的脂肪酸酯以及其混合物。Liquid dosage forms of the compounds of the present invention for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may also contain inert diluents commonly used in the art such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.
除惰性稀释剂以外，口服组合物还可包含辅剂(adjuvant)如润湿剂、乳化剂和助悬剂、甜味剂、矫味剂、着色剂、芳香剂和防腐剂。Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
除活性化合物以外，混悬剂还可包含助混剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨醇和失水山梨醇酯、微晶纤维素、偏氢氧化铝(aluminummetahydroxide)、皂土、琼脂和西黄蓍胶以及其混合物。Suspensions, in addition to the active compounds, may contain adjuvants such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
用于直肠或阴道施用的本发明的药物组合物的制剂可以以栓剂的形式存在，其可以通过将一种或多种本发明的化合物与一种或多种合适的无刺激的赋形剂或载体(包括例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯)混合来制备，并且其在室温下是固体，但是在体温下是液体，因此将在直肠或阴道腔中熔化并释放出活性化合物。Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be in the form of suppositories, which may be prepared by mixing one or more of the compounds of the invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylates, and which are solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.
适于阴道施用的本发明的制剂还包括含有本领域中已知适宜的载体的阴道栓、卫生栓、乳膏剂、凝胶剂、糊剂、泡沫剂或喷雾制剂。Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
本发明的化合物的用于局部或透皮施用的剂型包括散剂、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液剂、贴剂和吸入剂。可以将活性成分在无菌条件下与药学可接受的载体和可能需要的任何防腐剂、缓冲剂或抛射剂混合。Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that may be required.
除本发明的活性化合物以外，软膏剂、糊剂、乳膏剂和凝胶剂还可包含赋形剂，如动物和植物脂肪、油类、蜡类、石蜡类、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇类、硅氧烷类、皂土类、硅酸、滑石粉和氧化锌、或其混合物。Ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
除本发明的化合物以外，散剂和喷雾剂还可包含赋形剂如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。喷雾剂还可包含常规抛射剂如氯氟烃类和挥发性的未被取代的烃类，如丁烷和丙烷。In addition to the compounds of this invention, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
透皮贴剂具有为机体提供本发明的化合物的控制传递的另外的优点。该类剂型可以通过将化合物溶解或分散于合适的溶媒中来制备。还可以使用吸收促进剂来增加通过皮肤的化合物通量。可以通过提供控速膜或将活性化合物分散于聚合物基质或凝胶中来控制该类流动的速度。Transdermal patches have the additional advantage of providing the body with controlled delivery of the compound of the present invention. Such dosage forms can be prepared by dissolving or being dispersed in a suitable solvent. Absorption enhancers can also be used to increase the flux of the compound through the skin. The speed of such flow can be controlled by providing a rate-controlled membrane or by the active compound being dispersed in a polymer matrix or a gel.
在本发明的范围内还包括眼用制剂、眼用软膏剂、散剂、溶液剂等。Also included within the scope of this invention are ophthalmic formulations, eye ointments, powders, solutions, and the like.
适于胃肠外施用的本发明的药物组合物包含一种或多种本发明的化合物以及一种或多种药学可接受的无菌的等张的水性或非水性溶液、分散物、混悬剂或乳剂、或者可在使用前即刻被重组到无菌的可注射溶液或分散物中的无菌粉末，其可包含抗氧化剂、缓冲剂、抑菌剂、使得制剂与接受者的血液等张的溶质或助悬剂或增稠剂。Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the recipient, or suspending or thickening agents.
可用于本发明的药物组合物中的合适的水性和非水性载体的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)以及其合适的混合物、植物油类如橄榄油和可注射的有机酯类如油酸乙酯。可以例如通过使用包衣材料如卵磷脂、在分散物的情况下通过维持所需的粒度、和通过使用表面活性剂来维持合适的流动性。Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.
这些组合物还可包含辅剂如防腐剂、润湿剂、乳化剂和分散剂。可以通过包含各种抗细菌剂和抗真菌剂例如尼泊金酯、三氯叔丁醇、苯酚、山梨酸等来确保预防微生物的作用。还可能需要在组合物中包含等张剂如糖类、氯化钠等。此外，可以通过包含延迟吸收的物质如单硬脂酸铝和明胶来造成可注射药物形式的延长吸收。These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be necessary to include isotonic agents such as sugars, sodium chloride, etc. in the composition. In addition, extended absorption of injectable drug forms may be caused by including substances that delay absorption such as aluminum monostearate and gelatin.
在一些情况中，为了延长药物的作用，需要减慢得自皮下或肌内注射的药物吸收。这可以通过使用水溶性差的结晶性或无定形物质的液体混悬液来实现。这样，药物的吸收速率将取决于其溶出速率，溶出速率又可能取决于晶体大小和晶形。或者，通过将药物溶解或混悬于油性基质中来实现胃肠外施用的药物形式的延长吸收。In some cases, in order to prolong the effect of the drug, it is necessary to slow down the absorption of the drug obtained from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. Like this, the absorption rate of the drug will depend on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, the extended absorption of the drug form for parenteral administration can be achieved by dissolving or suspending the drug in an oily base.
可注射的储库形式是通过在可生物降解的聚合物如聚丙交酯-聚乙交酯中形成主题化合物的微囊基质来制备的。根据药物与聚合物的比例以及所用的具体化合物的性质，可以控制药物释放速率。其它可生物降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。可注射的储库制剂也可以通过将药物包在与机体组织相容的脂质体或微乳中来制备。Injectable reservoir forms are prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer such as polylactide-polyglycolide. According to the ratio of the drug to the polymer and the properties of the specific compound used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable reservoir preparations can also be prepared by encapsulating the drug in a liposome or microemulsion compatible with body tissues.
本发明的制剂可以被口服、胃肠外、局部或直肠施用。它们当然是以适合于各施用途径的形式被给予。例如，它们以片剂或胶囊剂的形式被施用，通过注射剂、吸入剂、眼用洗剂、软膏剂、栓剂等被施用，通过注射、输注或吸入被施用；通过洗剂或软膏剂被局部施用；通过栓剂被直肠施用。优选的是口服和/或静脉内施用。The preparations of the present invention can be administered orally, parenterally, topically or rectally. They are of course administered in a form suitable for each route of administration. For example, they are administered in the form of tablets or capsules, administered by injection, inhalation, eye lotion, ointment, suppository, etc., administered by injection, infusion or inhalation; topically administered by lotion or ointment; rectally administered by suppository. Oral and/or intravenous administration is preferred.
本文所用的措辞“胃肠外施用”意指除肠内和局部施用以外的施用方式，通常是通过注射施用，非限制性地包括静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和胸骨内注射和输注。The expression "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
本文所用的措辞“全身施用”和“外周施用”意指化合物、药物或其它材料的除直接施用于中枢神经系统以外的施用，从而使得其进入患者的系统中并因此进行代谢和其它相似过程，例如皮下施用。As used herein, the expressions "systemic administration" and "peripheral administration" refer to administration of a compound, drug or other material other than directly into the central nervous system so that it enters the patient's system and thereby undergoes metabolism and other similar processes, such as subcutaneous administration.
这些化合物可通过任何合适的施用途径被施用于人和其它动物来进行治疗，包括口服、鼻(例如以喷雾剂形式)、直肠、阴道内、胃肠外、脑池内和局部(以散剂、软膏剂或滴剂形式)施用，所述局部施用包括口含和舌下施用。These compounds can be administered to humans and other animals for therapeutic purposes by any suitable route of administration, including oral, nasal (e.g., as a spray), rectal, intravaginal, parenteral, intracisternal, and topical (as powders, ointments or drops), including buccal and sublingual.
不管所选择的施用途径如何，用本领域技术人员已知的常规方法将可以以合适的水合形式使用的本发明的化合物和/或本发明的药物组合物配制成药学可接受的剂型。Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms using conventional methods known to those skilled in the art.
可以改变本发明的药物组合物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可有效实现所需治疗响应、对患者无毒的活性成分的量。Actual dosage levels of the active ingredients in the pharmaceutical compositions of the invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
所选择的剂量水平将取决于多种因素，包括所用的具体的本发明的化合物或其酯、盐或酰胺的活性、施用途径、施用时间、所用的具体化合物的排泄速率、治疗的持续时间、与所用的具体化合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、情况、一般健康状况和既往医学史以及医学领域中公知的类似因素。The selected dosage level will depend upon a variety of factors including the activity of the specific compound of the present invention employed, or its ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the specific compound employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the specific compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
具有本领域普通技能的医师或兽医可容易地确定和开具出所需的药物组合物的有效量。例如，医师或兽医可以以低于获得所需治疗作用所需要的剂量的水平开始药物组合物中所用的本发明的化合物的剂量并逐渐增加其剂量直至实现所需的作用。A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the compound of the present invention used in the pharmaceutical composition at a level lower than the dosage required to obtain the desired therapeutic effect and gradually increase its dosage until the desired effect is achieved.
一般而言，本发明的化合物的合适的日剂量将是有效产生治疗作用的最低剂量的化合物量。该类有效剂量一般将取决于上述因素。一般而言，当用于所示的镇痛作用时，本发明的化合物用于患者的静脉内和皮下剂量为约0.0001至约100mg/kg体重/天，更优选约0.01至约50mg/kg/天，还更优选为约1.0至约100mg/kg/天。有效量是治疗与蛋白激酶有关的病症的量。In general, a suitable daily dose of a compound of the invention will be the amount of the compound at the lowest dose effective to produce a therapeutic effect. Such effective doses will generally depend on the factors described above. In general, when used for the analgesic effect shown, the intravenous and subcutaneous doses of the compounds of the invention for patients are about 0.0001 to about 100 mg/kg body weight/day, more preferably about 0.01 to about 50 mg/kg/day, and even more preferably about 1.0 to about 100 mg/kg/day. An effective amount is an amount for treating a disorder associated with a protein kinase.
如果需要的话，活性化合物的有效日剂量可以在一天中以分开施用的二、三、四、五、六或更多个亚剂量以适宜的时间间隔施用，任选地，所述亚剂量是单位剂型。If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day and, optionally, in unit dosage form.
对于约50-70kg的个体，本发明的药物组合物或组合可以为约1-1000mg活性成分的单位剂量，或者约1-500mg或者约1-250mg或者约1-150mg或者约0.5-100mg或者约1-50mg的活性成分。化合物、其药物组合物或组合的治疗有效剂量取决于个体的种类、体重、年龄和个体条件、治疗的障碍或疾病或其严重程度。具有普通技术的医师、临床医师或兽医能够容易地确定预防、治疗或抑制障碍或疾病的进程所需的每种活性成分的有效量。For an individual of about 50-70kg, the pharmaceutical composition of the present invention or combination can be a unit dose of about 1-1000mg active ingredient, or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active ingredient. The therapeutically effective dose of the compound, its pharmaceutical composition or combination depends on the type, body weight, age and individual condition of the individual, the disorder or disease or its severity for treatment. A physician, clinician or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient required for the prevention, treatment or inhibition of the process of the disorder or disease.
上述剂量性质在体外和体内试验中应用有利的哺乳动物，例如小鼠、大鼠、狗、猴或其相关器官、组织或制备物可进行说明。本发明化合物可以在体外以溶液剂例如水溶液剂的形式应用，并且可以在体内以肠内、非肠道、有利地以静脉内例如作为混悬剂或水溶液剂应用。体外剂量范围可以是约10-3摩尔至10-9摩尔浓度之间。体内治疗有效量范围可以取决于施用途径，为约0.1-500mg/kg或约1-100mg/kg之间。The above dosage properties are described in vitro and in vivo tests using advantageous mammals, such as mice, rats, dogs, monkeys or their related organs, tissues or preparations. The compounds of the present invention can be used in vitro in the form of solutions such as aqueous solutions, and can be used in vivo in the form of enteral, non-intestinal, intravenous, such as as suspensions or aqueous solutions. The in vitro dosage range can be between about 10-3 molar to 10-9 molar concentrations. The therapeutically effective amount range in vivo can depend on the route of administration, and is between about 0.1-500 mg/kg or about 1-100 mg/kg.
本文所用的术语“个体”意指动物。通常，动物是哺乳动物。个体还意指例如灵长类(例如人，男性或女性)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施例中，个体是灵长类。在其它实施例中，个体是人。As used herein, the term "subject" means an animal. Typically, an animal is a mammal. A subject also means, for example, a primate (e.g., a human, male or female), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
虽然本发明的化合物可以单独施用，但是优选以药物组合物的形式施用所述化合物。While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition.
药物联合Drug combination
使用本发明所提供的一种或多种化合物或组合物，或其药学上可接受的衍生物与其它的药物活化剂联合来组合治疗，用于治疗本文所述的疾病和病症。Combination therapy using one or more compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, in combination with other pharmaceutically active agents is useful for treating the diseases and conditions described herein.
将配制用于口服、全身性传递包括肠道外或静脉内传递或用于局部或表面施用的有效量的化合物或包含治疗有效浓度的化合物的组合物给予表现出疾病或病症症状而需要治疗的个体。所述量有效地治疗、控制或缓解了该疾病或病症的一种或多种症状。An effective amount of a compound or a composition comprising a therapeutically effective concentration of a compound formulated for oral, systemic delivery, including parenteral or intravenous delivery, or for topical or topical administration is administered to an individual exhibiting symptoms of a disease or condition in need of treatment. The amount is effective to treat, control or alleviate one or more symptoms of the disease or condition.
本领域普通技术人员能够理解本发明所提供的化合物、异构体、前体药物和药学上可接受的衍生物，包括药物组合物和包含这些化合物的制剂，可广泛应用于联合治疗以治疗本发明所述的不适和疾病。因此，本发明预期将本发明所提供的化合物、异构体、前体药物和药学上可接受的衍生物与其它活性药物联合使用，以用于治疗本发明所述的疾病/不适。Those of ordinary skill in the art will appreciate that the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided by the present invention, including pharmaceutical compositions and preparations containing these compounds, can be widely used in combined therapy to treat the discomfort and diseases described in the present invention. Therefore, the present invention contemplates the use of the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided by the present invention in combination with other active drugs to treat the diseases/discomforts described in the present invention.
一般合成方法General Synthesis Methods
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)-(II)所示化合物。下面的反应方案和实施例用于进一步举例说明本发明的内容。Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as for the compounds of formula (I)-(II). The following reaction schemes and examples are provided to further illustrate the present invention.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare many other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.
下面所描述的实施例，除非其他方面表明所有的温度定为℃。试剂购买于商品供应商如Aldrich Chemical Company，Arco Chemical Company and Alfa ChemicalCompany，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。In the examples described below, all temperatures are set at °C unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水DCM和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正已烷，N，N-二甲基乙酰胺和N，N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal. Anhydrous DCM and chloroform were obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振光谱以CDC13，d6-DMSO，CD3OD或d6-丙酮为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)，d(doublet，双峰)，t(triplet，三重峰)，m(multiplet，多重峰)，br(broadened，宽峰)，dd(doublet ofdoublets，四重峰)，dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The NMR spectra were measured using CDC13 , d6 -DMSO, CD3 OD or d6 -acetone as solvents (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks appear, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.
低分辨率质谱(MS)数据通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data were determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示：Both spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL/min; the HPLC peak was recorded and read at UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water solution (phase B). The gradient elution conditions are shown in Table 1:
表1Table 1
化合物纯化是通过Agilent 1100系列高效液相色谱(HPLC)来评价的，其中UV检测在210nm和254nm处，Zorbax SB-C18柱，规格为2.1×30mm，4μm，10分钟，流速为0.6mL/min，5-95％的(0.1％甲酸乙腈溶液)的(0.1％甲酸水溶液)，柱温保持在40℃。Compound purification was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm, a Zorbax SB-C18 column, 2.1×30 mm, 4 μm, 10 min, a flow rate of 0.6 mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), and the column temperature was maintained at 40°C.
下面简写词的使用贯穿本发明：The following abbreviations are used throughout this invention:
BOC，Boc 叔丁氧基羰基BOC, Boc tert-butoxycarbonyl
(pin)2B2 联硼酸频那醇酯(pin)2 B2 -Bis(2-Pinacol)boric acid ester
CHCl3 氯仿CHCl3Chloroform
CDCl3 氘代氯仿CDCl3- deuterated chloroform
DCM 二氯甲烷DCM Dichloromethane
DMF N，N-二甲基甲酰胺DMF N,N-Dimethylformamide
DMSO 二甲基亚砜DMSO Dimethyl sulfoxide
d6-DMSO 氘代二甲基亚砜d6 -DMSO Deuterated dimethyl sulfoxide
DIAD 偶氮二甲酸二异丙酯DIAD Diisopropyl azodicarboxylate
EDC，EDCI 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HATU 2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
H2 氢气H2 Hydrogen
MeOH，CH3OH 甲醇MeOH, CH3 OH Methanol
mL，ml 毫升mL, ml milliliter
N2 氮气N2 Nitrogen
Pd/C 钯/碳Pd/C Palladium/Carbon
Pd(OAc)2 醋酸钯Pd(OAc)2- palladium acetate
Pd2(dba)3 三(二亚苄基丙酮)二钯Pd2 (dba)3- tris(dibenzylideneacetone)dipalladium
PdCl2(dppf) 1，1′-双二苯基膦二茂铁二氯化钯PdCl2 (dppf) 1,1′-bis(diphenylphosphinoferrocene)palladium dichloride
AcOK 乙酸钾AcOK Potassium Acetate
EA 乙酸乙酯EA Ethyl acetate
XPhos-Pd-G2 氯(2-二环己基膦基-2′，4′，6′-三异丙基-1，1′-联苯基)[2-(2′-氨基-1，1′-联苯)]钯(II)XPhos-Pd-G2 Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)
PPh3 三苯基膦PPh3 triphenylphosphine
PE 石油醚PE Petroleum Ether
HEX 正己烷HEX Hexane
RT rt 室温RT rt Room temperature
Rt 保留时间Rt retention time
TFA 三氟乙酸TFA Trifluoroacetic acid
NBS N-溴丁二酰亚胺NBS N-Bromosuccinimide
Cs2CO3 碳酸铯Cs2 CO3 Cesium carbonate
Xantphos 9，9-二甲基-4，5-双二苯基膦氧杂蒽Xantphos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene
合成方案Synthesis scheme
下面的实施例可以对本发明做进一步的描述，然而，这些实施例不应作为对本发明的范围的限制。The present invention is further described in the following examples; however, these examples should not be construed as limiting the scope of the present invention.
合成中间体方案1Synthetic intermediate Scheme 1
本发明化合物中间体(3a)可以通过合成中间体方案1的合成方法得到：化合物(1a)与化合物(2a)在碱性条件下，加热反应生成化合物(3a)。其中Z、q和R6具有如本发明所述的含义。The intermediate compound (3a) of the present invention can be obtained by the synthesis method of the intermediate synthesis scheme 1: Compound (1a) and compound (2a) are heated under alkaline conditions to generate compound (3a), wherein Z, q and R6 have the meanings as described in the present invention.
合成中间体方案2Synthetic intermediate Scheme 2
本发明化合物中间体(3b)可以通过中间体方案2的合成方法得到：化合物(1b)与(pin)2B2在碱的条件下，反应生成化合物(2b)；化合物(2b)在碱性条件下与化合物(3a)反应得到化合物(3b)。其中Y、Z、q和R6具有如本发明所述的含义。The intermediate compound (3b) of the present invention can be obtained by the synthesis method of intermediate scheme 2: compound (1b) reacts with (pin)2 B2 under alkaline conditions to generate compound (2b); compound (2b) reacts with compound (3a) under alkaline conditions to obtain compound (3b). wherein Y, Z, q and R6 have the meanings as described in the present invention.
合成中间体方案3Synthetic intermediate Scheme 3
本发明化合物中间体(3c)可以通过合成中间体方案3的合成方法得到：化合物(3b)与化合物(1c)加热反应生成化合物(3c)。其中X、Y、Z、q和R6具有如本发明所述的含义。The intermediate compound (3c) of the present invention can be obtained by the synthesis method of the intermediate synthesis scheme 3: Compound (3b) and compound (1c) are heated to react to generate compound (3c), wherein X, Y, Z, q and R6 have the meanings as described in the present invention.
合成中间体方案4Synthetic intermediate Scheme 4
本发明化合物中间体(3d)可以通过中间体方案4的合成方法得到：化合物(3c)与化合物(1d)在碱性条件下，反应生成化合物(2d)；化合物(2d)在碱性条件下与(2da)反应得到化合物(3d)。其中X、Y、Z、q、R1、Rv和R6具有如本发明所述的含义。The intermediate compound (3d) of the present invention can be obtained by the synthesis method of intermediate scheme 4: compound (3c) reacts with compound (1d) under alkaline conditions to generate compound (2d); compound (2d) reacts with (2da) under alkaline conditions to obtain compound (3d). wherein X, Y, Z, q, R1 , Rv and R6 have the meanings as described in the present invention.
合成方案Synthesis scheme
本发明化合物可以通过合成方案的合成方法得到：化合物(3d)与化合物(1e)在合适的溶剂中发生还原反应，得到目标产物。其中X、Y、Z、q、R1、R3、Rv和R6具有如本发明所述的含义。The compound of the present invention can be obtained by the synthesis method of the synthesis scheme: Compound (3d) and compound (1e) undergo reduction reaction in a suitable solvent to obtain the target product, wherein X, Y, Z, q,R1 ,R3 ,Rv andR6 have the meanings as described in the present invention.
下面的实施例可以对本发明做进一步的描述，然而，这些实施例不应作为对本发明的范围的限制。The present invention is further described in the following examples; however, these examples should not be construed as limiting the scope of the present invention.
实施例Example
实施例1 (S)-1-(5-氯-4-((3′-(3-(2-氰基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物1)Example 1 (S)-1-(5-chloro-4-((3′-(3-(2-cyano-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 1)
步骤1)[2-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)苯基]甲醇Step 1) [2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol
将PdCl2(dppf)(7.28g，9.95mmol)、AcOK(29.3g，299mmol)和联硼酸频那醇酯(37.9g，149mmol)溶于1，4-二氧六环(200.1mL)中，再加入(3-溴-2-甲基-苯基)甲醇(20.1g，100mmol)。反应混合物升温至90℃反应10h。反应混合物停止搅拌，并冷却至室温，然后减压浓缩。所得残留物经硅胶柱层析分离纯化(HEX/EA＝10/1，v/v)得标题化合物为淡绿色固体23.9g，产率为96％；PdCl2 (dppf) (7.28 g, 9.95 mmol), AcOK (29.3 g, 299 mmol) and biboronic acid pinacol ester (37.9 g, 149 mmol) were dissolved in 1,4-dioxane (200.1 mL), and (3-bromo-2-methyl-phenyl) methanol (20.1 g, 100 mmol) was added. The reaction mixture was heated to 90°C for 10 h. The reaction mixture was stopped from stirring, cooled to room temperature, and then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (HEX/EA=10/1, v/v) to obtain the title compound as a light green solid (23.9 g), with a yield of 96%;
LC-MS：(pos.ion)m/z：231.1[M-18+1]+；LC-MS: (pos.ion)m/z: 231.1[M-18+1]+ ;
1H NMR(400MHz，d6-DMSO)δ7.50(d，J＝7.3Hz，1H)，7.45(d，J＝7.4Hz，1H)，7.14(t，J＝7.5Hz，1H)，5.05(t，J＝5.4Hz，1H)，4.48(d，J＝5.3Hz，2H)，2.39(s，3H)，1.29(s，12H).1 H NMR (400MHz, d6 -DMSO) δ7.50 (d, J=7.3Hz, 1H), 7.45 (d, J=7.4Hz, 1H), 7.14 (t, J=7.5Hz, 1H), 5.05 (t, J=5.4Hz, 1H), 4.48 (d, J=5.3Hz, 2H), 2.39 (s, 3H), 1.29 (s, 12H).
步骤2)1-溴-3-(3-溴丙氧基)-2-甲基苯Step 2) 1-Bromo-3-(3-bromopropoxy)-2-methylbenzene
将3-溴-2-甲基苯酚(15.1g，80.7mmol)溶于丙酮(180.1mL)，加入碳酸钾(33.3g，241mmol)，然后加入1，3-二溴丙烷(20.4mL，201mmol)，氮气保护，反应混合物升温回流反应12h。停止搅拌，冷却至室温，抽滤，并用DCM冲洗滤饼，然后减压滤液浓缩。所得浓缩残留物经硅胶柱层析(正己烷)分离纯化，得标题化合物为无色油状物24.1g，产率为97％；Dissolve 3-bromo-2-methylphenol (15.1 g, 80.7 mmol) in acetone (180.1 mL), add potassium carbonate (33.3 g, 241 mmol), then add 1,3-dibromopropane (20.4 mL, 201 mmol), protect with nitrogen, and heat the reaction mixture to reflux for 12 h. Stop stirring, cool to room temperature, filter, rinse the filter cake with DCM, and then concentrate the filtrate under reduced pressure. The concentrated residue is separated and purified by silica gel column chromatography (n-hexane) to obtain the title compound as a colorless oil 24.1 g, with a yield of 97%;
1H NMR(400MHz，CDCl3)δ7.20(d，J＝8.0Hz，1H)，7.03(t，J＝8.1Hz，1H)，6.82(d，J＝8.2Hz，1H)，4.12(t，J＝5.7Hz，2H)，3.65(t，J＝6.4Hz，2H)，2.40-2.36(m，2H)，2.35(s，3H).1 H NMR (400MHz, CDCl3 ) δ7.20 (d, J=8.0Hz, 1H), 7.03 (t, J=8.1Hz, 1H), 6.82 (d, J=8.2Hz, 1H), 4.12 (t , J=5.7Hz, 2H), 3.65 (t, J=6.4Hz, 2H), 2.40-2.36 (m, 2H), 2.35 (s, 3H).
步骤3)(3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲醇Step 3) (3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methanol
将[2-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)苯基]甲醇(20.0g，80.6mmol)和1-溴-3-(3-溴丙氧基)-2-甲基苯(26.1g，84.7mmol)溶于THF(400.1mL)，再加入磷酸钾溶液(400.1mL，200mmol)。反应混合物于氮气保护及室温下搅拌20min，然后加入XPhos-Pd-G2(1.27g，1.62mmol)，并于氮气保护下，继续室温搅拌10h。反应结束后，加水稀释(300mL)，再用乙酸乙酯萃取(150mL×3)，合并有机相。合并的有机相用无水硫酸钠干燥，然后减压浓缩，所得残留物经硅胶柱层析分离纯化(PE/EA＝3/1，v/v)分离纯化，得标题化合物为橙红色粘稠油15.9g，产率为57％；Dissolve [2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (20.0 g, 80.6 mmol) and 1-bromo-3-(3-bromopropoxy)-2-methylbenzene (26.1 g, 84.7 mmol) in THF (400.1 mL), and then add potassium phosphate solution (400.1 mL, 200 mmol). The reaction mixture was stirred at room temperature under nitrogen protection for 20 min, and then XPhos-Pd-G2 (1.27 g, 1.62 mmol) was added, and stirring was continued at room temperature under nitrogen protection for 10 h. After the reaction was completed, dilute with water (300 mL), and then extract with ethyl acetate (150 mL×3), and combine the organic phases. The combined organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (PE/EA=3/1, v/v) to obtain 15.9 g of the title compound as an orange-red viscous oil with a yield of 57%.
LC-MS：(pos.ion)m/z：332.0[M-18+1]+；LC-MS: (pos.ion)m/z: 332.0[M-18+1]+ ;
1H NMR(400MHz，CDCl3)δ7.41(d，J＝7.5Hz，1H)，7.27(t，J＝7.3Hz，1H)，7.21(t，J＝7.9Hz，1H)，7.11(d，J＝7.4Hz，1H)，6.90(d，J＝8.1Hz，1H)，6.78(d，J＝7.5Hz，1H)，4.78(s，2H)，4.27-4.09(m，2H)，3.68(t，J＝6.5Hz，2H)，2.45-2.36(m，2H)，2.08(s，3H)，1.95(s，3H).1 H NMR (400MHz, CDCl3 ) δ7.41 (d, J=7.5Hz, 1H), 7.27 (t, J=7.3Hz, 1H), 7.21 (t, J=7.9Hz, 1H), 7.11 (d , J=7.4Hz, 1H), 6.90 (d, J=8.1Hz, 1H), 6.78 (d, J=7.5Hz, 1H), 4.78 (s, 2H), 4.27-4.09 (m, 2H), 3.68 (t, J=6.5Hz, 2H), 2.45-2.36 (m, 2H), 2.08 (s, 3H), 1.95 (s, 3H).
步骤4)4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 4) 4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
0℃下将(3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲醇(15.9g，45.5mmol)，5-氯-2，4-二羟基-苯甲醛(8.64g，50.1mmol)溶于THF(242.1mL)，加入PPh3(17.9g，68.2mmol)，氮气保护，缓慢注入DIAD(13.4mL，68.1mmol)，室温条件下搅拌5h。反应结束后停止搅拌，加水(100mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(PE/EA＝8/1，v/v)分离得黄色固体5.3g，产率为23％；At 0°C, (3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methanol (15.9 g, 45.5 mmol) and 5-chloro-2,4-dihydroxy-benzaldehyde (8.64 g, 50.1 mmol) were dissolved in THF (242.1 mL), PPh3 (17.9 g, 68.2 mmol) was added, nitrogen was protected, DIAD (13.4 mL, 68.1 mmol) was slowly injected, and stirred at room temperature for 5 h. After the reaction was completed, stirring was stopped, water (100 mL) was added to dilute, and ethyl acetate was extracted (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Silica gel column chromatography was used for separation and purification (PE/EA=8/1, v/v) to obtain 5.3 g of a yellow solid with a yield of 23%;
LC-MS：(pos.ion)m/z：504.2[M+1]+；LC-MS: (pos.ion)m/z: 504.2[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ11.16(s，1H)，10.03(s，1H)，7.71(s，1H)，7.50(d，J＝7.4Hz，1H)，7.29(t，J＝7.6Hz，1H)，7.22(t，J＝7.9Hz，1H)，7.09(d，J＝7.4Hz，1H)，6.98(d，J＝8.2Hz，1H)，6.87(s，1H)，6.70(d，J＝7.5Hz，1H)，5.31(s，2H)，4.18-4.04(m，2H)，3.71(t，J＝6.5Hz，2H)，2.29(dd，J＝12.3，6.1Hz，2H)，2.01(s，3H)，1.84(s，3H).1 H NMR (400MHz, d6 -DMSO) δ 11.16 (s, 1H), 10.03 (s, 1H), 7.71 (s, 1H), 7.50 (d, J=7.4Hz, 1H), 7.29 (t, J=7.6Hz, 1H), 7.22 (t, J=7.9Hz, 1H), 7.09 (d, J=7.4Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.87 (s, 1H), 6.70 (d, J=7.5Hz, 1H), 5.31 (s, 2H), 4.18-4.04 (m, 2H), 3.71 (t, J=6.5Hz, 2H ), 2.29 (dd, J=12.3, 6.1Hz, 2H), 2.01 (s, 3H), 1.84 (s, 3H).
步骤5)7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-7-氮杂螺[3.5]壬烷-2-腈Step 5) 7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-azaspiro[3.5]nonane-2-carbonitrile
将4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(1g，1.98mmol)和7-氮杂螺[3.5]壬烷-2-腈(0.357g，2.37mmol)溶于DMF(15mL)，加入碳酸钾(0.685g，4.96mmol)，加入Nal(0.357g，2.38mmol)，氮气保护，升温至75℃搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到淡黄色固体0.71g，产率为62.4％；4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (1 g, 1.98 mmol) and 7-azaspiro[3.5]nonane-2-carbonitrile (0.357 g, 2.37 mmol) were dissolved in DMF (15 mL), potassium carbonate (0.685 g, 4.96 mmol) and Nal (0.357 g, 2.38 mmol) were added, and the mixture was heated to 75° C. and stirred for 13 h under nitrogen protection. Stirring was stopped, the mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Silica gel column chromatography was used for separation and purification (DCM/MeOH=10/1, v/v) to obtain 0.71 g of a light yellow solid with a yield of 62.4%;
LC-MS：(pos.ion)m/z：573.2[M+1]+。LC-MS: (pos.ion)m/z: 573.2[M+1]+ .
步骤6)7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬烷-2-腈Step 6) 7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]nonane-2-carbonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.295g，1.48mmol)溶于DMF(12mL)，加入碳酸铯(1g，3.1mmol)，室温搅拌10min。加入7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)内基)-7-氮杂螺[3.5]壬烷-2-腈(0.71g，1.24mmol)和NaI(18mg，0.124mmol)，氮气保护，升温至75℃搅拌4h。随后停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得黄色固体160mg，产率为18.74％；5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.295 g, 1.48 mmol) was dissolved in DMF (12 mL), cesium carbonate (1 g, 3.1 mmol) was added, and the mixture was stirred at room temperature for 10 min. 7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)inyl)-7-azaspiro[3.5]nonane-2-carbonitrile (0.71 g, 1.24 mmol) and NaI (18 mg, 0.124 mmol) were added, nitrogen was protected, the temperature was raised to 75°C and stirred for 4 h. Then the stirring was stopped, the mixture was cooled to room temperature, water (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 160 mg of a yellow solid with a yield of 18.74%;
LC-MS：(pos.ion)m/z：689.2[M+1]+。LC-MS: (pos.ion)m/z: 689.2[M+1]+ .
步骤7)(S)-1-(5-氯-4-((3′-(3-(2-氰基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 7) (S)-1-(5-chloro-4-((3′-(3-(2-cyano-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬烷-2-腈(160mg，0.23mmol)和D-哌啶酸(0.044g，0.34mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，随后冷却至室温，缓慢加入氰基硼氢化钠(0.072g，1.15mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，分离得黄色固体47mg，产率为25.23％；7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]nonane-2-carbonitrile (160 mg, 0.23 mmol) and D-piperidinic acid (0.044 g, 0.34 mmol) were dissolved in DMF (15.0 mL), acetic acid was added to adjust the pH to about 5, heated to 60° C. and stirred for 1 h, then cooled to room temperature, sodium cyanoborohydride (0.072 g, 1.15 mmol) was slowly added, nitrogen was protected, and stirred at room temperature for 12 h. Stirring was stopped, cooled to room temperature, saturated carbonic acid solution (30 mL) was added, and stirred at room temperature for 30 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 47 mg of a yellow solid with a yield of 25.23%.
LC-MS：(pos.ion)m/z：802.3[M+1]+；LC-MS: (pos.ion)m/z: 802.3[M+1]+ ;
1H NMR(600MHz，d6-DMSO)δ9.00(d，J＝10.7Hz，2H)，8.46(s，1H)，7.48(d，J＝7.4Hz，1H)，7.41(s，1H)，7.26(t，J＝7.5Hz，1H)，7.20(t，J＝7.8Hz，1H)，7.11(s，1H)，7.06(d，J＝7.5Hz，1H)，6.94(d，J＝8.2Hz，1H)，6.67(d，J＝7.4Hz，1H)，5.36-5.29(m，2H)，5.29-5.23(m，2H)，4.02(dt，J＝22.1，7.6Hz，2H)，3.77(d，J＝13.8Hz，1H)，3.60(d，J＝13.6Hz，1H)，3.51(s，1H)，3.31(dt，J＝17.1，8.6Hz，2H)，3.13(s，1H)，2.88(d，J＝6.7Hz，1H)，2.38(s，2H)，2.28(d，J＝5.7Hz，2H)，2.16(t，J＝10.2Hz，2H)，2.02(s，3H)，2.00(d，J＝11.7Hz，2H)，1.92(d，J＝6.2Hz，2H)，1.91(s，1H)，1.81(s，3H)，1.79-1.76(m，1H)，1.72(d，J＝8.9Hz，1H)，1.62(s，2H)，1.58(s，2H)，1.48(s，3H)，1.37(s，1H).1 H NMR (600MHz, d6 -DMSO) δ9.00 (d, J=10.7Hz, 2H), 8.46 (s, 1H), 7.48 (d, J=7.4Hz, 1H), 7.41 (s, 1H) , 7.26 (t, J=7.5Hz, 1H), 7.20 (t, J=7.8Hz, 1H), 7.11 (s, 1H), 7.06 (d, J=7.5Hz, 1H ), 6.94 (d, J=8.2Hz, 1H), 6.67 (d, J=7.4Hz, 1H), 5.36-5.29 (m, 2H), 5.29-5.23 (m, 2H), 4.02 (dt, J= 22.1, 7.6Hz, 2H), 3.77 (d, J＝13.8Hz, 1H), 3.60 (d, J＝13.6Hz, 1H ), 3.51 (s, 1H), 3.31 (dt, J=17.1, 8.6Hz, 2H), 3.13 (s, 1H), 2.88 (d, J=6.7Hz, 1H), 2.38 (s, 2H), 2.28 (d, J=5.7Hz, 2H), 2.16 (t, J=10.2Hz, 2H), 2.02 (s, 3H), 2.00 ( d, J=11.7Hz, 2H), 1.92 (d, J=6.2Hz, 2H), 1.91 (s, 1H), 1.81 (s, 3H), 1.79-1.76 (m, 1H), 1.72 (d, J =8.9Hz, 1H), 1.62(s, 2H), 1.58(s, 2H), 1.48(s, 3H), 1.37(s, 1H).
实施例2 (S)-1-(4-((3′-(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物2)Example 2 (S)-1-(4-((3′-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 2)
步骤1)4-((3′-(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)-甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-methoxy)-5-chloro-2-hydroxybenzaldehyde
将4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯基]-3-基)-甲氧基)-5-氯-2-羟基-苯甲醛(0.65g，1.29mmol)和9-氧杂-3-氮杂螺[5.5]十一烷(0.24g，1.54mmol)溶于DMF(15mL)，加入碳酸钾(0.445g，3.22mmol)，加入NaI(0.23g，1.55mmol)，氮气保护，升温至75℃搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)得到淡黄色固体0.51g，产率为68.3％；4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)-methoxy)-5-chloro-2-hydroxy-benzaldehyde (0.65 g, 1.29 mmol) and 9-oxa-3-azaspiro[5.5]undecane (0.24 g, 1.54 mmol) were dissolved in DMF (15 mL), potassium carbonate (0.445 g, 3.22 mmol) and NaI (0.23 g, 1.55 mmol) were added, and the mixture was heated to 75° C. and stirred for 13 h under nitrogen protection. Stirring was stopped, the mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Silica gel column chromatography was used for separation and purification (DCM/MeOH=8/1, v/v) to obtain 0.51 g of a light yellow solid with a yield of 68.3%;
LC-MS：(pos.ion)m/z：578.2[M+1]+。LC-MS: (pos.ion)m/z: 578.2[M+1]+ .
步骤2)5-((5-((3′-(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.161g，1.05mmol)溶于DMF(12mL)，加入碳酸铯(0.574g，1.76mmol)，室温搅拌10min。加入4-((3′-(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(0.51g，0.88mmol)和NaI(13mg，0.088mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得黄色固体175mg，产率为28.5％；Dissolve 5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.161 g, 1.05 mmol) in DMF (12 mL), add cesium carbonate (0.574 g, 1.76 mmol), and stir at room temperature for 10 min. Add 4-((3′-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (0.51 g, 0.88 mmol) and NaI (13 mg, 0.088 mmol), protect with nitrogen, heat to 75°C and stir for 4 h. Stop stirring, cool to room temperature, dilute with water (30 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 175 mg of a yellow solid with a yield of 28.5%;
LC-MS：(pos.ion)m/z：694.3[M+1]+。LC-MS: (pos.ion)m/z: 694.3[M+1]+ .
步骤3)(S)-1-(4-((3′-(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将5-((5-((3′-(3-(3-氧杂-9-氮杂螺[5.5]十一碳-9-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(0.17g，0.244mmol)和D-哌啶酸(0.063g，0.487mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.076g，1.21mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，分离得棕黄色固体38mg，产率为19.2％；5-((5-((3′-(3-(3-oxa-9-azaspiro[5.5]undec-9-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (0.17 g, 0.244 mmol) and D-piperidinic acid (0.063 g, 0.487 mmol) were dissolved in DMF (15.0 mL), acetic acid was added to adjust the pH to about 5, heated to 60° C. and stirred for 1 h, cooled to room temperature, sodium cyanoborohydride (0.076 g, 1.21 mmol) was slowly added, nitrogen was protected, and stirred at room temperature for 12 h. Stirring was stopped, cooled to room temperature, saturated carbonic acid solution (30 mL) was added, and stirred at room temperature for 30 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Silica gel column chromatography (DCM/MeOH=8/1, v/v) was used to separate and purify the product to obtain 38 mg of a brown-yellow solid with a yield of 19.2%.
LC-MS：(pos.ion)m/z：807.4[M+1]+；LC-MS: (pos.ion)m/z: 807.4[M+1]+ ;
1H NMR(600MHz，d6-DMSO)δ9.00(d，J＝9.3Hz，2H)，8.46(s，1H)，7.49(d，J＝7.3Hz，1H)，7.41(s，1H)，7.26(t，J＝7.4Hz，1H)，7.20(t，J＝7.7Hz，1H)，7.11(s，1H)，7.06(d，J＝7.4Hz，1H)，6.95(d，J＝8.1Hz，1H)，6.68(d，J＝7.4Hz，1H)，5.34(d，J＝13.5Hz，2H)，5.27(d，J＝12.7Hz，2H)，4.08-3.99(m，2H)，3.77(d，J＝13.7Hz，1H)，3.61(d，J＝13.7Hz，1H)，3.52(d，J＝7.6Hz，6H)，3.14(s，1H)，2.89(s，1H)，2.67(s，2H)，2.58(s，3H)，2.28(s，1H)，2.02(s，3H)，1.99(s，2H)，1.81(s，3H)，1.80-1.76(m，1H)，1.72(s，1H)，1.55(s，3H)，1.48(s，3H)，1.40(s，5H).1 H NMR (600MHz, d6 -DMSO) δ9.00 (d, J=9.3Hz, 2H), 8.46 (s, 1H), 7.49 (d, J=7.3Hz, 1H), 7.41 (s, 1H) , 7.26 (t, J=7.4Hz, 1H), 7.20 (t, J=7.7Hz, 1H), 7.11 (s, 1H), 7.06 (d, J=7.4Hz, 1H), 6.95 (d, J= 8.1Hz, 1H), 6.68 (d, J=7.4Hz, 1H), 5.34 (d, J=13.5Hz, 2H), 5.27 (d, J=12.7Hz, 2H), 4.08- 3.99 (m, 2H), 3.77 (d, J = 13.7Hz, 1H), 3.61 (d, J = 13.7Hz, 1H), 3.52 (d, J = 7.6Hz, 6H), 3.14 (s, 1H), 2.89(s,1H),2.67(s,2H),2.58(s,3H),2.28(s,1H),2.02(s,3H),1.99(s,2H),1.81(s,3H),1.80 -1.76(m, 1H), 1.72(s, 1H), 1.55(s, 3H), 1.48(s, 3H), 1.40(s, 5H).
实施例3(S)-1-(4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物3)Example 3 (S)-1-(4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 3)
步骤1)2-氧杂-8-氮杂螺[4.5]癸烷Step 1) 2-Oxa-8-azaspiro[4.5]decane
在氮气保护下，将2-氧杂-8-氮杂螺[4.5]癸烷-8-羧酸叔丁酯溶于三氟乙酸(4mL)和DCM(25mL)中，室温反应23h，将反应液浓缩，得到棕褐色油状液体585.2mg，产率51％；Under nitrogen protection, tert-butyl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate was dissolved in trifluoroacetic acid (4 mL) and DCM (25 mL), reacted at room temperature for 23 h, and the reaction solution was concentrated to obtain 585.2 mg of a brown oily liquid with a yield of 51%;
LC-MS：(pos.ion)m/z：142.1[M+1]+。LC-MS: (pos.ion)m/z: 142.1[M+1]+ .
步骤2)4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 2) 4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
将2-氧杂-8-氮杂螺[4.5]癸烷(300mg，2.1245mmol)和4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1.04g，2.06mmol)溶于DMF(15mL)中，依次加入K2CO3(600mg，4.34mmol)和NaI(300mg，2.00mmol)，加热至75℃，反应17h。用乙酸乙酯萃取(30mL×3)，水洗(50mL)，用无水硫酸钠干燥，过滤，浓缩。用硅胶柱层析(DCM/MeOH＝10/1，v/v)分离纯化，得到橙红色固体350mg，产率30％；2-Oxa-8-azaspiro[4.5]decane (300 mg, 2.1245 mmol) and 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (1.04 g, 2.06 mmol) were dissolved in DMF (15 mL), K2 CO3 (600 mg, 4.34 mmol) and NaI (300 mg, 2.00 mmol) were added in sequence, heated to 75°C, and reacted for 17 h. The mixture was extracted with ethyl acetate (30 mL×3), washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 350 mg of an orange-red solid with a yield of 30%;
LC-MS：(pos.ion)m/z：564.1[M+1]+。LC-MS: (pos.ion)m/z: 564.1[M+1]+ .
步骤3)4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-甲氧基)苯甲醛Step 3) 4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridine-3-methoxy)benzaldehyde
4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯(350mg，0.62mmol)和5-(氯甲基)吡啶-3-甲腈盐酸盐(123mg，0.80mmol)溶于N，N-二甲基甲酰胺(20mL)中，加入碳酸铯(404mg，1.23mmol)和碘化钠(9.3mg，0.06mmol)，加热至75℃，反应3h。将反应冷却到室温，用乙酸乙酯萃取(30mL×3)，加水洗(50mL)，用无水硫酸钠干燥，过滤。浓缩后的粗产物，用硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色固体342mg，产率81％；4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzene (350 mg, 0.62 mmol) and 5-(chloromethyl)pyridine-3-carbonitrile hydrochloride (123 mg, 0.80 mmol) were dissolved in N,N-dimethylformamide (20 mL), cesium carbonate (404 mg, 1.23 mmol) and sodium iodide (9.3 mg, 0.06 mmol) were added, heated to 75° C., and reacted for 3 h. The reaction was cooled to room temperature, extracted with ethyl acetate (30 mL×3), washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered. The concentrated crude product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 342 mg of a yellow solid with a yield of 81%;
LC-MS：(pos.ion)m/z：681.4[M+1]+。LC-MS: (pos.ion)m/z: 681.4[M+1]+ .
步骤4)(S)-1-(4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 4) (S)-1-(4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-甲氧基)苯甲醛(342mg，0.50mmol)和(2S)-哌啶-2-甲酸(130mg，1.00mmol)溶于N，N-二甲基甲酰胺(10mL)中，加入乙酸(0.1mL，2.0mmol)，加热至60℃，反应1.5小时。冷却至室温，缓慢加入氰基硼氢化钠(158mg，2.51mmol)，室温反应16小时。随后加热至80℃，反应5小时。将反应冷却至室温，加入饱和碳酸钾溶液(30mL)，室温搅拌30min。停止反应，用乙酸乙酯萃取(30mL×3)，加水洗(50mL)，用无水硫酸钠干燥，过滤。浓缩后的粗产物，用硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到淡黄色固体60mg，产率15％；4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridine-3-methoxy)benzaldehyde (342 mg, 0.50 mmol) and (2S)-piperidine-2-carboxylic acid (130 mg, 1.00 mmol) were dissolved in N,N-dimethylformamide (10 mL), acetic acid (0.1 mL, 2.0 mmol) was added, heated to 60°C, and reacted for 1.5 hours. After cooling to room temperature, sodium cyanoborohydride (158 mg, 2.51 mmol) was slowly added, and the reaction was allowed to react at room temperature for 16 hours. Subsequently, the reaction was heated to 80°C and reacted for 5 hours. The reaction was cooled to room temperature, saturated potassium carbonate solution (30 mL) was added, and stirred at room temperature for 30 minutes. Stop the reaction, extract with ethyl acetate (30 mL × 3), wash with water (50 mL), dry with anhydrous sodium sulfate, and filter. The concentrated crude product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 60 mg of a light yellow solid with a yield of 15%;
LC-MS：(pos.ion)m/z：794.2[M+1]+；LC-MS: (pos.ion)m/z: 794.2[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.00(d，J＝5.2Hz，2H)，8.46(s，1H)，7.49(d，J＝7.3Hz，1H)，7.41(s，1H)，7.27(t，J＝7.6Hz，1H)，7.21(d，J＝7.7Hz，1H)，7.12(s，1H)，7.06(d，J＝7.5Hz，1H)，6.97(d，J＝8.3Hz，1H)，6.70(d，J＝7.4Hz，1H)，5.33(s，2H)，5.27(s，2H)，4.08(d，J＝7.0Hz，2H)，3.74(t，J＝7.1Hz，3H)，3.62(d，J＝13.5Hz，2H)，3.51(s，2H)，3.15(s，2H)，2.95(s，3H)，2.89(s，3H)，2.29(s，1H)，2.13(s，2H)，2.03(s，3H)，1.83(s，3H)，1.78(s，1H)，1.71(d，J＝7.2Hz，6H)，1.48(s，3H)，1.38(s，1H).1 H NMR (400MHz, d6 -DMSO) δ9.00 (d, J=5.2Hz, 2H), 8.46 (s, 1H), 7.49 (d, J=7.3Hz, 1H), 7.41 (s, 1H) , 7.27 (t, J=7.6Hz, 1H), 7.21 (d, J=7.7Hz, 1H), 7.12 (s, 1H), 7.06 (d, J=7.5Hz, 1H), 6.97 (d, J= 8.3Hz, 1H), 6.70 (d, J=7.4Hz, 1H), 5.33 (s, 2H), 5.27 (s, 2H), 4 .08 (d, J=7.0Hz, 2H), 3.74 (t, J=7.1Hz, 3H), 3.62 (d, J=13.5Hz, 2H), 3.51 (s, 2H), 3.15 (s, 2H) , 2.95(s, 3H), 2.89(s, 3H), 2.29(s, 1H), 2.13(s, 2H), 2.03(s, 3H), 1.83(s, 3H), 1.78(s, 1H), 1.71(d, J=7.2Hz, 6H), 1.48(s, 3H), 1.38(s, 1H).
实施例4(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2，2′-二甲基-3′-(3-(2-氧代-1，7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物4)Example 4 (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2′-dimethyl-3′-(3-(2-oxo-1,7-diazaspiro[4.4]non-7-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 4)
步骤1)5-氯-4-((2，2′-二甲基-3′-(3-(2-氧代-1，7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-chloro-4-((2,2′-dimethyl-3′-(3-(2-oxo-1,7-diazaspiro[4.4]nonan-7-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1.5g，3.0mmol)和4，8-二氮杂螺[4.4]壬-3-酮(500mg，3.56mmol)溶于N，N-二甲基甲酰胺(25mL)中，依次加入K2CO3(1g，7.23mmol)和NaI(540mg，3.60mmol)，加热至75℃，反应23h。将反应冷却到室温，用乙酸乙酯萃取(30mL×3)，水洗，饱和食盐洗，用无水硫酸钠干燥，过滤。浓缩后的粗产物，用硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)。得到橙红色固体粉末365mg，产率22％；4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (1.5 g, 3.0 mmol) and 4,8-diazaspiro[4.4]nonan-3-one (500 mg, 3.56 mmol) were dissolved in N,N-dimethylformamide (25 mL), K2 CO3 (1 g, 7.23 mmol) and NaI (540 mg, 3.60 mmol) were added in sequence, heated to 75°C, and reacted for 23 h. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (30 mL×3), washed with water, washed with saturated salt, dried over anhydrous sodium sulfate, and filtered. The concentrated crude product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v). 365 mg of orange-red solid powder was obtained with a yield of 22%;
LC-MS：(pos.ion)m/z：564.4[M+1]+。LC-MS: (pos.ion)m/z: 564.4[M+1]+ .
步骤2)5-((4-氯-5-((2，2′-二甲基-3′-(3-(2-氧代-1，7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((4-chloro-5-((2,2′-dimethyl-3′-(3-(2-oxo-1,7-diazaspiro[4.4]nonan-7-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
将5-氯-4-((2，2′-二甲基-3′-(3-(2-氧代-1，7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-羟基苯甲醛(365mg，0.64mmol)和5-(氯甲基)吡啶-3-甲腈盐酸盐(160mg，0.84mmol)溶于N，N-二甲基甲酰胺(25mL)中，加入碳酸铯(634mg，1.94mmol)和碘化钠(9.7mg，0.065mmol)，加热至75℃，反应3小时。待反应冷却到室温，用乙酸乙酯萃取(30mL×3)，水洗(50mL)，用无水硫酸钠干燥，过滤。浓缩后的粗产物，用硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色固体100mg，产率81％；5-Chloro-4-((2,2′-dimethyl-3′-(3-(2-oxo-1,7-diazaspiro[4.4]non-7-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (365 mg, 0.64 mmol) and 5-(chloromethyl)pyridine-3-carbonitrile hydrochloride (160 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (25 mL), cesium carbonate (634 mg, 1.94 mmol) and sodium iodide (9.7 mg, 0.065 mmol) were added, heated to 75° C., and reacted for 3 hours. After the reaction was cooled to room temperature, it was extracted with ethyl acetate (30 mL×3), washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered. The concentrated crude product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 100 mg of a yellow solid with a yield of 81%;
LC-MS：(pos.ion)m/z：601.1[M+1]+。LC-MS: (pos.ion)m/z: 601.1[M+1]+ .
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2，2′-二甲基-3′-(3-(2-氧代-1，7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2′-dimethyl-3′-(3-(2-oxo-1,7-diazaspiro[4.4]non-7-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将5-((4-氯-5-((2，2′-二甲基-3′-(3-(2-氧代-1，7-二氮杂螺[4.4]壬-7-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈(100mg，0.15mmol)和(2S)-哌啶-2-甲酸(38mg，0.29mmol)溶于N，N-二甲基甲酰胺(10mL)中，加入乙酸(0.1mL)，加热至60℃，搅拌1.5h。停止加热，冷却至室温，加入氰基硼氢化钠(46.3mg，0.74mmol)，室温反应14h。将反应加热至80℃，反应5h。将反应冷却至室温，加入饱和碳酸钾溶液(30mL)，搅拌30分钟。停止反应，用乙酸乙酯萃取(30mL×3)，加水洗(50mL)，用无水硫酸钠干燥，过滤。浓缩后的粗产物，用硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到淡红色固体28mg，产率24％；5-((4-chloro-5-((2,2′-dimethyl-3′-(3-(2-oxo-1,7-diazaspiro[4.4]non-7-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (100 mg, 0.15 mmol) and (2S)-piperidine-2-carboxylic acid (38 mg, 0.29 mmol) were dissolved in N,N-dimethylformamide (10 mL), acetic acid (0.1 mL) was added, heated to 60° C., and stirred for 1.5 h. Heating was stopped, cooled to room temperature, sodium cyanoborohydride (46.3 mg, 0.74 mmol) was added, and the reaction was allowed to react at room temperature for 14 h. The reaction was heated to 80° C. and reacted for 5 h. The reaction was cooled to room temperature, saturated potassium carbonate solution (30 mL) was added, and stirred for 30 minutes. Stop the reaction, extract with ethyl acetate (30 mL × 3), wash with water (50 mL), dry with anhydrous sodium sulfate, and filter. The concentrated crude product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 28 mg of a light red solid with a yield of 24%;
LC-MS：(pos.ion)m/z：793.5[M+1]+；LC-MS: (pos.ion)m/z: 793.5[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(s，2H)，8.47(s，1H)，7.93(s，1H)，7.49(d，J＝7.4Hz，1H)，7.43(s，1H)，7.27(t，J＝7.7Hz，1H)，7.21(t，J＝7.9Hz，1H)，7.14(s，1H)，7.07(d，J＝7.3Hz，1H)，6.96(d，J＝8.2Hz，1H)，6.68(d，J＝7.4Hz，1H)，5.31(d，J＝30.5Hz，4H)，4.07(d，J＝5.9Hz，2H)，3.80(d，J＝14.0Hz，1H)，3.64(d，J＝13.6Hz，2H)，3.48(d，J＝5.2Hz，1H)，3.42(d，J＝4.6Hz，1H)，3.17(s，2H)，2.88(s，1H)，2.67(s，4H)，2.31(s，1H)，2.17(dd，J＝15.5，7.3Hz，2H)，2.03(s，3H)，1.96(s，2H)，1.91(s，2H)，1.82(s，3H)，1.81-1.76(m，1H)，1.73(s，1H)，1.49(s，3H)，1.37(s，1H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (s, 2H), 8.47 (s, 1H), 7.93 (s, 1H), 7.49 (d, J=7.4Hz, 1H), 7.43 (s, 1H), 7.27 (t, J=7.7Hz, 1H), 7.21 (t, J=7.9Hz, 1H), 7.14 (s, 1H), 7.07 (d, J=7.3Hz, 1H), 6.96 (d, J=8.2Hz, 1H), 6.68 (d, J=7.4Hz, 1H), 5.31 (d, J=30.5Hz, 4H), 4.07 (d, J=5.9Hz, 2H), 3.80 (d, J= 14. 0Hz, 1H), 3.64 (d, J=13.6Hz, 2H), 3.48 (d, J=5.2Hz, 1H), 3.42 (d, J=4.6Hz, 1H), 3.17 (s, 2H), 2.88 ( s, 1H), 2.67 (s, 4H), 2.31 (s, 1H), 2.17 (dd, J=15.5, 7.3Hz, 2H), 2.03 (s, 3H), 1.96 (s, 2H), 1.91 (s , 2H), 1.82(s, 3H), 1.81-1.76(m, 1H), 1.73(s, 1H), 1.49(s, 3H), 1.37(s, 1H).
实施例5(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(6-羟基-2-氮杂螺[3.4]辛-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物5)Example 5 (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(6-hydroxy-2-azaspiro[3.4]octan-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 5)
步骤1)5-氯-2-羟基-4-((3′-(3-(6-羟基-2-氮杂螺[3.4]辛-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯甲醛Step 1) 5-chloro-2-hydroxy-4-((3′-(3-(6-hydroxy-2-azaspiro[3.4]oct-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(0.8g，1.58mmol)和2-氮杂-螺[3.4]辛-7-醇(0.242g，1.58mmol)溶于DMF(15mL)，加入碳酸钾(0.658g，4.76mmol)，加入NaI(0.285g，1.90mmol)，氮气保护，升温至75℃条件下搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到淡黄色粘稠物0.37g，产率为42.3％；4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (0.8 g, 1.58 mmol) and 2-aza-spiro[3.4]octan-7-ol (0.242 g, 1.58 mmol) were dissolved in DMF (15 mL), potassium carbonate (0.658 g, 4.76 mmol) and NaI (0.285 g, 1.90 mmol) were added, and the mixture was heated to 75 ° C and stirred for 13 h under nitrogen protection. Stirring was stopped, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Silica gel column chromatography was used for separation and purification (DCM/MeOH=10/1, v/v) to obtain 0.37 g of a light yellow viscous product with a yield of 42.3%;
LC-MS：(pos.ion)m/z：550.2[M+1]+。LC-MS: (pos.ion)m/z: 550.2[M+1]+ .
步骤2)5-((4-氯-2-甲酰基-5-((3′-(3-(6-羟基-2-氮杂螺[3.4]辛-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-chloro-2-formyl-5-((3′-(3-(6-hydroxy-2-azaspiro[3.4]octan-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.17g，0.85mmol)溶于DMF(12mL)，加入碳酸铯(0.533g，1.64mmol)，室温搅拌10min。加入5-氯-2-羟基-4-((3′-(3-(6-羟基-2-氮杂螺[3.4]辛-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯甲醛(360mg，0.65mmol)和NaI(9mg，0.065mmol)，氮气保护，体系于75℃条件下搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得黄色固体0.135g，产率为30.96％；Dissolve 5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.17 g, 0.85 mmol) in DMF (12 mL), add cesium carbonate (0.533 g, 1.64 mmol), and stir at room temperature for 10 min. Add 5-chloro-2-hydroxy-4-((3′-(3-(6-hydroxy-2-azaspiro[3.4]octan-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde (360 mg, 0.65 mmol) and NaI (9 mg, 0.065 mmol), protect with nitrogen, and stir the system at 75°C for 4 h. Stop stirring, cool to room temperature, dilute with water (30 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.135 g of a yellow solid with a yield of 30.96%.
LC-MS：(pos.ion)m/z：666.2[M+1]+。LC-MS: (pos.ion)m/z: 666.2[M+1]+ .
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(6-羟基-2-氮杂螺[3.4]辛-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(6-hydroxy-2-azaspiro[3.4]octan-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将5-((4-氯-2-甲酰基-5-((3′-(3-(6-羟基-2-氮杂-螺[3.4]辛-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(134mg，0.2011mmol)和D-哌啶酸(0.038g，0.29mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.063g，1.00mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，分离得黄色固体0.025g，产率为15.9％；5-((4-chloro-2-formyl-5-((3′-(3-(6-hydroxy-2-aza-spiro[3.4]octan-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (134 mg, 0.2011 mmol) and D-piperidinic acid (0.038 g, 0.29 mmol) were dissolved in DMF (15.0 mL), acetic acid was added to adjust the pH to about 5, heated to 60° C. and stirred for 1 h, cooled to room temperature, sodium cyanoborohydride (0.063 g, 1.00 mmol) was slowly added, nitrogen was protected, and stirred at room temperature for 12 h. Stirring was stopped, cooled to room temperature, saturated carbonic acid solution (30 mL) was added, and stirred at room temperature for 30 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 0.025 g of a yellow solid with a yield of 15.9%.
LC-MS：(pos.ion)m/z：779.3[M+1]+；LC-MS: (pos.ion)m/z: 779.3[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.00(d，J＝2.8Hz，2H)，8.46(s，1H)，7.49(d，J＝7.5Hz，1H)，7.42(s，1H)，7.27(t，J＝7.5Hz，1H)，7.21(t，J＝7.8Hz，1H)，7.13(s，1H)，7.06(d，J＝7.5Hz，1H)，6.96(d，J＝8.2Hz，1H)，6.70(d，J＝7.5Hz，1H)，5.34(s，2H)，5.27(s，2H)，4.08(s，2H)，3.79(d，J＝13.4Hz，2H)，3.63(d，J＝14.0Hz，2H)，3.51(s，2H)，3.16(s，2H)，2.89(s，2H)，2.30(s，2H)，2.03(s，4H)，1.96(s，2H)，1.89(d，J＝4.4Hz，1H)，1.83(d，J＝1.8Hz，3H)，1.79(s，1H)，1.76-1.66(m，3H)，1.48(s，5H)，1.37(s，2H).1 H NMR (400MHz, d6 -DMSO) δ9.00 (d, J=2.8Hz, 2H), 8.46 (s, 1H), 7.49 (d, J=7.5Hz, 1H), 7.42 (s, 1H) , 7.27 (t, J=7.5Hz, 1H), 7.21 (t, J=7.8Hz, 1H), 7.13 (s, 1H), 7.06 (d, J=7.5Hz, 1H), 6.96 (d, J= 8.2Hz, 1H), 6.70 (d, J=7.5Hz, 1H), 5.34 (s, 2H), 5.27 (s, 2H), 4.08 (s, 2H), 3.79 (d, J=13.4Hz, 2H), 3.63 (d, J=14.0Hz, 2H), 3.51 (s, 2H), 3.16 (s, 2H), 2.89 (s, 2H) , 2.30 (s, 2H), 2.03 (s, 4H), 1.96 (s, 2H), 1.89 (d, J = 4.4Hz, 1H), 1.83 (d, J = 1.8Hz, 3H), 1.79 (s, 1H), 1.76-1.66(m, 3H), 1.48(s, 5H), 1.37(s, 2H).
实施例159(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(六氢-2H-吡喃并[3，2-c]吡啶-6(7H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物159)Example 159 (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(hexahydro-2H-pyrano[3,2-c]pyridin-6(7H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 159)
步骤1)5-氯-4-((3′-(3-(六氢-2H-吡喃并[3，2-c]吡啶-6(7H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-chloro-4-((3′-(3-(hexahydro-2H-pyrano[3,2-c]pyridin-6(7H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基苯甲醛(0.6g，1.19mmol)和反-3，4，4a，5，6，7，8，8a-八氢-2H-吡喃并[3，2-c]吡啶(0.2g，1.42mmol)溶于DMF(15mL)，加入碳酸钾(0.197g，1.42mmol)，加入NaI(0.214g，1.42mmol)，氮气保护，体系于75℃条件下搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到淡黄色粘稠物0.38g，产率为56.65％；Dissolve 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxybenzaldehyde (0.6 g, 1.19 mmol) and trans-3,4,4a,5,6,7,8,8a-octahydro-2H-pyrano[3,2-c]pyridine (0.2 g, 1.42 mmol) in DMF (15 mL), add potassium carbonate (0.197 g, 1.42 mmol), add NaI (0.214 g, 1.42 mmol), protect with nitrogen, and stir the system at 75°C for 13 h. Stop stirring, cool to room temperature, dilute with water (50 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Separate and purify by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.38 g of a light yellow viscous product with a yield of 56.65%;
LC-MS：(pos.ion)m/z：564.2[M+1]+。LC-MS: (pos.ion)m/z: 564.2[M+1]+ .
步骤2)5-((4-氯-2-甲酰基-5-((3′-(3-(六氢-2H-吡喃并[3，2-c]吡啶-6(7H)-基)丙氧基)-2，2-二甲基-[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-chloro-2-formyl-5-((3′-(3-(hexahydro-2H-pyrano[3,2-c]pyridin-6(7H)-yl)propoxy)-2,2-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.175g，0.879mmol)溶于DMF(12mL)，加入碳酸铯(0.548g，1.68mmol)，室温搅拌10min。加入5-氯-4-((3′-(3-(六氢-2H-吡喃并[3，2-c]吡啶-6(7H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯基]-3-基)甲氧基)-2-羟基苯甲醛(0.38mg，0.67mmol)和NaI(10mg，0.067mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得黄色固体0.128g，产率为27.9％；Dissolve 5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.175 g, 0.879 mmol) in DMF (12 mL), add cesium carbonate (0.548 g, 1.68 mmol), and stir at room temperature for 10 min. Add 5-chloro-4-((3′-(3-(hexahydro-2H-pyrano[3,2-c]pyridin-6(7H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (0.38 mg, 0.67 mmol) and NaI (10 mg, 0.067 mmol), protect with nitrogen, heat to 75°C and stir for 4 h. Stop stirring, cool to room temperature, dilute with water (30 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.128 g of a yellow solid with a yield of 27.9%;
LC-MS：(pos.ion)m/z：680.3[M+1]+。LC-MS: (pos.ion)m/z: 680.3[M+1]+ .
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(六氢-2H-吡喃并[3，2-c]吡啶-6(7H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(hexahydro-2H-pyrano[3,2-c]pyridin-6(7H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将5-((4-氯-2-甲酰基-5-((3′-(3-(六氢-2H-吡喃并[3，2-c]吡啶-6(7H)-基)丙氧基)-2，2-二甲基-[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(0.123g，0.180mmol)和D-哌啶酸(0.035g，0.27mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.056g，0.89mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)，室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，分离得淡黄色固体0.02g，产率为13.9％。5-((4-chloro-2-formyl-5-((3′-(3-(hexahydro-2H-pyrano[3,2-c]pyridin-6(7H)-yl)propoxy)-2,2-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (0.123 g, 0.180 mmol) and D-piperidinic acid (0.035 g, 0.27 mmol) were dissolved in DMF (15.0 mL), acetic acid was added to adjust the pH to about 5, heated to 60° C. and stirred for 1 h, cooled to room temperature, sodium cyanoborohydride (0.056 g, 0.89 mmol) was slowly added, nitrogen was protected, and stirred at room temperature for 12 h. Stirring was stopped, cooled to room temperature, saturated carbonic acid solution (30 mL) was added, stirred at room temperature for 30 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 0.02 g of a light yellow solid with a yield of 13.9%.
LC-MS：(pos.ion)m/z：793.3[M+1]+；LC-MS: (pos.ion)m/z: 793.3[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(d，J＝2.0Hz，2H)，8.47(s，1H)，7.49(d，J＝7.5Hz，1H)，7.42(s，1H)，7.27(t，J＝7.5Hz，1H)，7.22(t，J＝7.9Hz，1H)，7.13(s，1H)，7.07(d，J＝7.5Hz，1H)，6.97(d，J＝8.2Hz，1H)，6.70(d，J＝7.5Hz，1H)，5.38-5.30(m，2H)，5.29(d，J＝13.7Hz，2H)，4.09(d，J＝6.2Hz，2H)，3.90(d，J＝10.2Hz，1H)，3.82-3.75(m，2H)，3.66(s，1H)，3.62(s，1H)，3.58(s，2H)，3.41(s，2H)，3.16(s，2H)，2.89(s，1H)，2.31(d，J＝13.1Hz，1H)，2.24(s，2H)，2.16(s，1H)，2.03(s，4H)，1.84(s，4H)，1.79(s，1H)，1.74(d，J＝4.8Hz，2H)，1.60(d，J＝12.1Hz，2H)，1.49(s，3H)，1.38(s，1H)，1.29(d，J＝8.7Hz，2H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (d, J=2.0Hz, 2H), 8.47 (s, 1H), 7.49 (d, J=7.5Hz, 1H), 7.42 (s, 1H) , 7.27 (t, J=7.5Hz, 1H), 7.22 (t, J=7.9Hz, 1H), 7.13 (s, 1H), 7.07 (d, J=7.5Hz, 1H), 6.97 (d, J= 8.2Hz, 1H), 6.70 (d, J=7.5Hz, 1H), 5.38-5.30 (m, 2H), 5.29 (d, J=13.7Hz, 2H), 4.09 (d, J=6.2Hz, 2H) ,3.90(d,J=10.2H z, 1H), 3.82-3.75 (m, 2H), 3.66 (s, 1H), 3.62 (s, 1H), 3.58 (s, 2H), 3.41 (s, 2H), 3.16 (s, 2H), 2.89 (s, 1H), 2.31 (d, J=13.1Hz, 1H), 2.24 (s, 2H), 2.16 (s, 1H), 2.03 (s, 4H), 1.84 (s, 4H), 1.79 (s, 1H), 1.74 (d, J=4.8Hz, 2H), 1.60 (d, J=12.1Hz, 2H), 1.49 (s, 3H), 1.38 (s, 1H), 1.29 (d, J=8.7Hz, 2H).
实施例7(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(六氢呋喃并[3，4-c]吡啶-5(3H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物7)Example 7 (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 7)
步骤1)5-氯-4-((3′-(3-(六氢呋喃并[3，4-c]吡啶-5(3H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-chloro-4-((3′-(3-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(0.6g，1.19mmol)和1，3，3a，4，5，6，7，7a-八氢呋喃并[3，4-c]吡啶盐酸盐(0.233mg，1.42mmol)溶于DMF(15mL)，加入碳酸钾(0.411g，2.97mmol)，加入NaI(0.214g，1.43mmol)，氮气保护，升温至75℃搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到淡黄色固体0.4g，产率为61.06％。Dissolve 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (0.6 g, 1.19 mmol) and 1,3,3a,4,5,6,7,7a-octahydrofuro[3,4-c]pyridine hydrochloride (0.233 mg, 1.42 mmol) in DMF (15 mL), add potassium carbonate (0.411 g, 2.97 mmol), add NaI (0.214 g, 1.43 mmol), protect with nitrogen, heat to 75°C and stir for 13 h. Stop stirring, cool to room temperature, dilute with water (50 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.4 g of a light yellow solid with a yield of 61.06%.
LC-MS：(pos.ion)m/z：550.2[M+1]+；LC-MS: (pos.ion)m/z: 550.2[M+1]+ ;
步骤2)5-((4-氯-2-甲酰基-5-((3′-(3-(六氢呋喃并[3，4-c]吡啶-5(3H)-基)丙氧基)-2，2′-二甲基[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-chloro-2-formyl-5-((3′-(3-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)propoxy)-2,2′-dimethyl[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.188g，0.94mmol)溶于DMF(12mL)，加入碳酸铯(0.592g，1.82mmol)，室温搅拌10min。加入5-氯-4-((3′-(3-(六氢呋喃并[3，4-c]吡啶-5(3H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-2-羟基苯甲醛(400mg，0.73mmol)和NaI(10mg，0.073mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)得黄色固体400mg，产率为82.57％。Dissolve 5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.188 g, 0.94 mmol) in DMF (12 mL), add cesium carbonate (0.592 g, 1.82 mmol), and stir at room temperature for 10 min. Add 5-chloro-4-((3′-(3-(hexahydrofurano[3,4-c]pyridin-5(3H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (400 mg, 0.73 mmol) and NaI (10 mg, 0.073 mmol), protect with nitrogen, heat to 75°C and stir for 4 h. Stop stirring, cool to room temperature, dilute with water (30 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The residue was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 400 mg of a yellow solid with a yield of 82.57%.
LC-MS：(pos.ion)m/z：666.2[M+1]+；LC-MS: (pos.ion)m/z: 666.2[M+1]+ ;
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(六氢呋喃并[3，4-c]吡啶-5(3H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将5-((4-氯-2-甲酰基-5-((3′-(3-(六氢呋喃并[3，4-c]吡啶-5(3H)-基)丙氧基)-2，2′-二甲基[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(0.4mg，0.60mmol)和D-哌啶酸(0.118g，0.91mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.192g，3.05mmol)，氮气保护，室温搅拌12小时。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，分离得淡黄色固体70mg，产率为14.96％。5-((4-chloro-2-formyl-5-((3′-(3-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)propoxy)-2,2′-dimethyl[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (0.4 mg, 0.60 mmol) and D-piperidinic acid (0.118 g, 0.91 mmol) were dissolved in DMF (15.0 mL), acetic acid was added to adjust the pH to about 5, heated to 60° C. and stirred for 1 h, cooled to room temperature, sodium cyanoborohydride (0.192 g, 3.05 mmol) was slowly added, nitrogen was protected, and stirred at room temperature for 12 hours. Stirring was stopped, cooled to room temperature, saturated carbonic acid solution (30 mL) was added, and stirred at room temperature for 30 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 70 mg of a light yellow solid with a yield of 14.96%.
LC-MS：(pos.ion)m/z：779.5[M+1]+；LC-MS: (pos.ion)m/z: 779.5[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(s，2H)，8.46(s，1H)，7.49(d，J＝7.4Hz，1H)，7.42(s，1H)，7.26(t，J＝7.5Hz，1H)，7.21(t，J＝7.9Hz，1H)，7.13(s，1H)，7.06(d，J＝7.5Hz，1H)，6.96(d，J＝8.2Hz，1H)，6.69(d，J＝7.5Hz，1H)，5.38-5.30(m，2H)，5.27(s，2H)，4.07(d，J＝6.4Hz，2H)，3.82(d，J＝5.7Hz，1H)，3.77(s，1H)，3.72(dd，J＝16.6，7.9Hz，3H)，3.65(s，1H)，3.60(d，J＝16.9Hz，3H)，3.16-3.13(m，1H)，2.88(s，2H)，2.30(s，2H)，2.11(s，2H)，2.03(s，4H)，1.83(s，5H)，1.72(d，J＝9.7Hz，3H)，1.49(s，3H)，1.37(s，2H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (s, 2H), 8.46 (s, 1H), 7.49 (d, J=7.4Hz, 1H), 7.42 (s, 1H), 7.26 (t, J=7.5Hz, 1H), 7.21 (t, J=7.9Hz, 1H), 7.13 (s, 1H), 7.06 (d, J=7.5Hz, 1H), 6.96 (d, J=8.2Hz, 1H) , 6.69 (d, J=7.5Hz, 1H), 5.38-5.30 (m, 2H), 5.27 (s, 2H), 4.07 (d, J=6.4 Hz, 2H), 3.82 (d, J=5.7Hz, 1H), 3.77 (s, 1H), 3.72 (dd, J=16.6, 7.9Hz, 3H), 3.65 (s, 1H), 3.60 (d, J =16.9Hz, 3H), 3.16-3.13(m, 1H), 2.88(s, 2H), 2.30(s, 2H), 2.11(s, 2H), 2.03(s, 4H), 1.83(s, 5H) , 1.72 (d, J=9.7Hz, 3H), 1.49 (s, 3H), 1.37 (s, 2H).
实施例8(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(六氢-1H-吡咯并[3，4-c]吡啶-5(6H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物8)Example 8 (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(hexahydro-1H-pyrrolo[3,4-c]pyridin-5(6H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 8)
步骤1)5-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)六氢-1H-吡咯并[3，4-c]吡啶-2(3H)-羧酸叔丁酯Step 1) tert-butyl 5-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1g，1.98mmol)和1，3，3a，4，5，6，7，7a-八氢吡咯并[3，4-c]吡啶-2-甲酸叔丁酯盐酸盐(0.625g，2.37mmol)溶于DMF(15mL)，加入碳酸钾(0.685g，4.96mmol)，加入NaI(0.357g，2.38mmol)，氮气保护，升温至75℃搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到淡黄色粘稠物1.03g，产率为79.9％。Dissolve 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (1 g, 1.98 mmol) and 1,3,3a,4,5,6,7,7a-octahydropyrrolo[3,4-c]pyridine-2-carboxylic acid tert-butyl ester hydrochloride (0.625 g, 2.37 mmol) in DMF (15 mL), add potassium carbonate (0.685 g, 4.96 mmol), add NaI (0.357 g, 2.38 mmol), protect with nitrogen, heat to 75°C and stir for 13 h. Stop stirring, cool to room temperature, dilute with water (50 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The residue was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 1.03 g of a light yellow viscous substance with a yield of 79.9%.
LC-MS：(pos.ion)m/z：649.3[M+1]+；LC-MS: (pos.ion)m/z: 649.3[M+1]+ ;
步骤2)5-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)六氢-1H-吡咯并[3，4-c]吡啶-2(3H)-羧酸叔丁酯Step 2) tert-butyl 5-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.44g，2.21mmol)溶于DMF(12mL)，加入碳酸铯(1.4g，4.2mmol)，室温搅拌10min。加入5-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)六氢-1H-吡咯并[3，4-c]吡啶-2(3H)-羧酸叔丁酯(1.1g，1.7mmol)和NaI(0.025g，0.17mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得黄色固体0.482g，产率为37％。Dissolve 5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.44 g, 2.21 mmol) in DMF (12 mL), add cesium carbonate (1.4 g, 4.2 mmol), and stir at room temperature for 10 min. Add 5-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylic acid tert-butyl ester (1.1 g, 1.7 mmol) and NaI (0.025 g, 0.17 mmol), protect with nitrogen, heat to 75°C and stir for 4 h. Stop stirring, cool to room temperature, dilute with water (30 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.482 g of a yellow solid. The yield was 37%.
LC-MS：(pos.ion)m/z：765.3[M+1]+；LC-MS: (pos.ion)m/z: 765.3[M+1]+ ;
步骤3)(2S)-1-(4-((3′-(3-(2-(叔丁氧基羰基)六氢-1H-吡咯并[3，4-c]吡啶-5(6H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3′-(3-(2-(tert-butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-c]pyridin-5(6H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将5-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)六氢-1H-吡咯并[3，4-c]吡啶-2(3H)-羧酸叔丁酯(0.482g，0.63mmol)和D-哌啶酸(0.122g，0.94mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.197g，3.13mmol)，氮气保护，室温搅拌12小时。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，分离得黄色固体0.183g，产率为33.07％。5-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylic acid tert-butyl ester (0.482 g, 0.63 mmol) and D-piperidinic acid (0.122 g, 0.94 mmol) were dissolved in DMF (15.0 mL), acetic acid was added to adjust the pH to about 5, the mixture was heated to 60°C and stirred for 1 h, cooled to room temperature, sodium cyanoborohydride (0.197 g, 3.13 mmol) was slowly added, and the mixture was stirred at room temperature for 12 hours under nitrogen protection. Stop stirring, cool to room temperature, add saturated carbonic acid solution (30 mL), stir at room temperature for 30 min, extract with ethyl acetate (100 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Separate and purify by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 0.183 g of a yellow solid with a yield of 33.07%.
LC-MS：(pos.ion)m/z：878.4[M+1]+；LC-MS: (pos.ion)m/z: 878.4[M+1]+ ;
步骤4)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(六氢-1H-吡咯并[3，4-c]吡啶-5(6H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 4) (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(hexahydro-1H-pyrrolo[3,4-c]pyridin-5(6H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将(2S)-1-(4-(3′-(3-(2-(叔丁氧基羰基)六氢-1H-吡咯并[3，4-c]吡啶-5(6H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.183g，0.20mmol)溶于DCM(20mL)，加入TFA(2mL)，室温搅拌反应5小时。停止搅拌，浓缩溶剂，加入饱和碳酸钾溶液(40mL)，室温搅拌反应15min，乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩。薄层析分离纯化(DCM/MeOH＝6/1)，得到白色固体0.043g，产率26.5％。(2S)-1-(4-(3′-(3-(2-(tert-butoxycarbonyl)hexahydro-1H-pyrrolo[3,4-c]pyridin-5(6H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (0.183 g, 0.20 mmol) was dissolved in DCM (20 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 5 hours. The stirring was stopped, the solvent was concentrated, saturated potassium carbonate solution (40 mL) was added, the mixture was stirred at room temperature for 15 min, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated and purified by thin layer chromatography (DCM/MeOH=6/1) to obtain 0.043 g of a white solid with a yield of 26.5%.
LC-MS：(pos.ion)m/z：778.3[M+1]+；LC-MS: (pos.ion)m/z: 778.3[M+1]+ ;
1H NMR(600MHz，d6-DMSO)δ9.62(s，1H)，9.04-8.99(m，2H)，8.48(s，1H)，7.50(d，J＝7.5Hz，1H)，7.43(s，1H)，7.27(t，J＝7.5Hz，1H)，7.21(t，J＝7.9Hz，1H)，7.15(s，1H)，7.07(d，J＝7.3Hz，1H)，6.96(d，J＝8.3Hz，1H)，6.68(d，J＝7.5Hz，1H)，5.40-5.32(m，2H)，5.31-5.24(m，2H)，4.04(dd，J＝11.9，6.2Hz，2H)，3.81(d，J＝13.6Hz，1H)，3.66(d，J＝13.6Hz，1H)，3.51(s，1H)，3.21-3.12(m，5H)，2.98(d，J＝8.7Hz，1H)，2.91(s，1H)，2.62(s，2H)，2.33(s，3H)，2.22(s，1H)，2.10(s，1H)，2.03(s，3H)，1.92(s，2H)，1.82(d，J＝2.1Hz，4H)，1.72(d，J＝9.6Hz，1H)，1.63(s，1H)，1.57(s，1H)，1.50(s，3H)，1.42-1.32(m，2H).1 H NMR (600 MHz, d6 -DMSO) δ9.62 (s, 1H), 9.04-8.99 (m, 2H), 8.48 (s, 1H), 7.50 (d, J = 7.5Hz, 1H), 7.43 (s, 1H), 7.27 (t, J = 7.5Hz, 1H), 7.21 (t, J = 7.9Hz, 1H), 7.15 (s, 1H), 7.07 (d, J=7.3Hz, 1H), 6.96 (d, J=8.3Hz, 1H), 6.68 (d, J=7.5Hz, 1H), 5.40-5.32 (m, 2H), 5.31-5.24 (m, 2H), 4.04 (dd, J=11.9, 6.2Hz, 2H), 3.81 (d , J=13.6Hz, 1H), 3.66 (d, J=13.6Hz, 1H), 3.51 (s, 1H), 3.21-3.12 (m, 5H), 2.98 (d, J=8.7Hz, 1H), 2.91 (s, 1H), 2.62 (s, 2H), 2.33 (s, 3H), 2.22 (s, 1H), 2 .10 (s, 1H), 2.03 (s, 3H), 1.92 (s, 2H), 1.82 (d, J = 2.1Hz, 4H), 1.72 (d, J = 9.6Hz, 1H), 1.63 (s, 1H), 1.57 (s, 1H), 1.50 (s, 3H), 1.42-1.32 (m, 2H).
实施例9(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物9)Example 9 (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 9)
步骤1)5-氯-4-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯基]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-chloro-4-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(0.9g，1.78mmol)，3，3a，4，5，6，6a-六氢-1H-呋喃并[3，4-c]吡咯盐酸盐(0.32g，2.14mmol)溶于DMF(15mL)，加入碳酸钾(0.62g，4.46mmol)，加入NaI(0.32g，2.14mmol)，氮气保护，升温至75℃搅拌13小时。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)得到淡黄色固体0.62g，产率为64.7％。4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (0.9 g, 1.78 mmol), 3,3a,4,5,6,6a-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (0.32 g, 2.14 mmol) were dissolved in DMF (15 mL), potassium carbonate (0.62 g, 4.46 mmol) and NaI (0.32 g, 2.14 mmol) were added, and the mixture was heated to 75° C. and stirred for 13 hours under nitrogen protection. Stirring was stopped, the mixture was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 0.62 g of a light yellow solid with a yield of 64.7%.
LC-MS：(pos.ion)m/z：536.2[M+1]+；LC-MS: (pos.ion)m/z: 536.2[M+1]+ ;
步骤2)5-((4-氯-5-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((4-chloro-5-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.273g，1.38mmol)溶于DMF(12mL)，加入碳酸铯(0.753g，2.31mmol)，室温搅拌10min。加入5-氯-4-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯基]-3-基)甲氧基)-2-羟基苯甲醛(0.62g，1.15mmol)和NaI(17mg，0.115mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得黄色固体112mg，产率为14.85％。Dissolve 5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.273 g, 1.38 mmol) in DMF (12 mL), add cesium carbonate (0.753 g, 2.31 mmol), and stir at room temperature for 10 min. Add 5-chloro-4-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (0.62 g, 1.15 mmol) and NaI (17 mg, 0.115 mmol), protect with nitrogen, heat to 75°C and stir for 4 h. Stop stirring, cool to room temperature, dilute with water (30 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 112 mg of a yellow solid with a yield of 14.85%.
LC-MS：(pos.ion)m/z：652.2[M+1]+；LC-MS: (pos.ion)m/z: 652.2[M+1]+ ;
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将5-((4-氯-5-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈(0.112g，0.17mmol)和D-哌啶酸(0.033g，0.255mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.053g，0.84mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，分离得黄色固体22mg，产率为16.7％。5-((4-chloro-5-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furano[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (0.112 g, 0.17 mmol) and D-piperidinic acid (0.033 g, 0.255 mmol) were dissolved in DMF (15.0 mL), acetic acid was added to adjust the pH to about 5, heated to 60° C. and stirred for 1 h, cooled to room temperature, sodium cyanoborohydride (0.053 g, 0.84 mmol) was slowly added, and stirred at room temperature for 12 h under nitrogen protection. Stirring was stopped, cooled to room temperature, saturated carbonic acid solution (30 mL) was added, and stirred at room temperature for 30 min, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 22 mg of a yellow solid with a yield of 16.7%.
LC-MS：(pos.ion)m/z：765.3[M+1]+；LC-MS: (pos.ion)m/z: 765.3[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(s，2H)，8.46(s，1H)，7.49(d，J＝7.5Hz，1H)，7.42(s，1H)，7.26(t，J＝7.5Hz，1H)，7.21(t，J＝7.9Hz，1H)，7.12(s，1H)，7.07(d，J＝7.3Hz，1H)，6.95(d，J＝8.3Hz，1H)，6.68(d，J＝7.5Hz，1H)，5.33(s，2H)，5.26(s，2H)，4.06(d，J＝6.2Hz，2H)，3.79(d，J＝13.6Hz，1H)，3.65(s，3H)，3.15(s，2H)，2.89(s，3H)，2.80(s，4H)，2.31(d，J＝6.8Hz，2H)，2.03(s，6H)，1.82(s，4H)，1.73(s，1H)，1.49(s，3H)，1.35(d，J＝15.1Hz，2H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (s, 2H), 8.46 (s, 1H), 7.49 (d, J=7.5Hz, 1H), 7.42 (s, 1H), 7.26 (t, J=7.5Hz, 1H), 7.21 (t, J=7.9Hz, 1H), 7.12 (s, 1H), 7.07 (d, J=7.3Hz, 1H), 6.95 (d, J=8.3Hz, 1H) , 6.68 (d, J=7.5Hz, 1H), 5.33 (s, 2H), 5.26 (s, 2H), 4.06 (d, J=6.2Hz, 2H), 3.79 (d, J=13.6Hz, 1H), 3.65 (s, 3H), 3.15 (s, 2H), 2.89 (s, 3H ), 2.80 (s, 4H), 2.31 (d, J=6.8Hz, 2H), 2.03 (s, 6H), 1.82 (s, 4H), 1.73 (s, 1H), 1.49 (s, 3H), 1.35 (d, J=15.1Hz, 2H).
实施例10(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物10)Example 10 (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(5-hydroxyhexadihydrocyclopenta[c]pyrrole-2(1H)-propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 10)
步骤1)5-氯-2-羟基-4-((3′-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯基]-3-基)甲氧基)苯甲醛Step 1) 5-chloro-2-hydroxy-4-((3′-(3-(5-hydroxyhexadihydrocyclopenta[c]pyrrol-2(1H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(0.8g，1.59mmol)和1，2，3，4，5，6，6a-八氢环戊[c]吡咯-5-醇(0.242g，1.90mmol)溶于DMF(15mL)，加入碳酸钾(0.658g，4.76mmol)，加入NaI(0.285g，1.90mmol)，氮气保护，升温至75℃搅拌13h。停止搅拌，冷却至室温，加水(50mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到淡黄色粘稠物0.7g，产率为80.14％。Dissolve 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (0.8 g, 1.59 mmol) and 1,2,3,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-ol (0.242 g, 1.90 mmol) in DMF (15 mL), add potassium carbonate (0.658 g, 4.76 mmol), add NaI (0.285 g, 1.90 mmol), protect with nitrogen, heat to 75°C and stir for 13 h. Stop stirring, cool to room temperature, dilute with water (50 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The residue was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.7 g of a light yellow viscous product with a yield of 80.14%.
LC-MS：(pos.ion)m/z：550.2[M+1]+；LC-MS: (pos.ion)m/z: 550.2[M+1]+ ;
步骤2)5-((4-氯-2-甲酰基-((3′-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-chloro-2-formyl-((3′-(3-(5-hydroxyhexadihydrocyclopenta[c]pyrrol-2(1H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
将5-(氯甲基)吡啶-3-甲腈盐酸盐(0.33g，1.65mmol)溶于DMF(12mL)，加入碳酸铯(1.03g，3.18mmol)，室温搅拌10min。加入5-氯-2-羟基-4-((3′-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯基]-3-基)甲氧基)苯甲醛(0.71g，1.24mmol)和NaI(19mg，0.13mmol)，氮气保护，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(30mL)稀释，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)得黄色固体460mg，产率为54.26％。Dissolve 5-(Chloromethyl)pyridine-3-carbonitrile hydrochloride (0.33 g, 1.65 mmol) in DMF (12 mL), add cesium carbonate (1.03 g, 3.18 mmol), and stir at room temperature for 10 min. Add 5-chloro-2-hydroxy-4-((3′-(3-(5-hydroxyhexadihydrocyclopenta[c]pyrrole-2(1H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde (0.71 g, 1.24 mmol) and NaI (19 mg, 0.13 mmol), protect with nitrogen, heat to 75°C and stir for 4 h. Stop stirring, cool to room temperature, dilute with water (30 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 460 mg of a yellow solid. The yield was 54.26%.
LC-MS：(pos.ion)m/z：666.2[M+1]+；LC-MS: (pos.ion)m/z: 666.2[M+1]+ ;
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(5-hydroxyhexadihydrocyclopenta[c]pyrrole-2(1H)-propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将((4-氯-2-甲酰基-5-((3′-(3-(5-羟基己二氢环戊二烯并[c]吡咯-2(1H)-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(460mg，0.69mmol)和D-哌啶酸(0.033g，1.03mmol)溶于DMF(15.0mL)，加入乙酸调节pH至5左右，加热至60℃搅拌1h，冷却至室温，缓慢加入氰基硼氢化钠(0.216g，3.44mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，分离得黄色固体80mg，产率为14.87％。Dissolve ((4-chloro-2-formyl-5-((3′-(3-(5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (460 mg, 0.69 mmol) and D-piperidinic acid (0.033 g, 1.03 mmol) in DMF (15.0 mL), add acetic acid to adjust the pH to about 5, heat to 60° C. and stir for 1 h, cool to room temperature, slowly add sodium cyanoborohydride (0.216 g, 3.44 mmol), protect with nitrogen, and stir at room temperature for 12 h. Stop stirring, cool to room temperature, add saturated carbonic acid solution (30 mL), stir at room temperature for 30 min, extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The product was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 80 mg of a yellow solid with a yield of 14.87%.
LC-MS：(pos.ion)m/z：779.3[M+1]+；LC-MS: (pos.ion)m/z: 779.3[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(s，2H)，8.46(s，1H)，7.49(d，J＝7.3Hz，1H)，7.42(s，1H)，7.24(dt，J＝15.8，7.7Hz，2H)，7.13(s，1H)，7.06(d，J＝7.5Hz，1H)，6.95(d，J＝8.1Hz，1H)，6.69(d，J＝7.4Hz，1H)，5.30(d，J＝28.4Hz，4H)，4.07(d，J＝6.3Hz，3H)，3.79(d，J＝13.6Hz，2H)，3.63(d，J＝13.6Hz，2H)，3.51(s，1H)，3.16-3.12(m，1H)，3.02(s，4H)，2.89(s，1H)，2.73(s，2H)，2.30(s，1H)，2.09(s，2H)，2.03(s，3H)，1.83(s，6H)，1.73(s，1H)，1.58-1.44(m，5H)，1.37(s，1H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (s, 2H), 8.46 (s, 1H), 7.49 (d, J=7.3Hz, 1H), 7.42 (s, 1H), 7.24 (dt, J=15.8, 7.7Hz, 2H), 7.13 (s, 1H), 7.06 (d, J=7.5Hz, 1H), 6.95 (d, J=8.1Hz, 1H), 6.69 (d, J=7.4Hz, 1H), 5.30 (d, J=28.4Hz, 4H), 4.07 (d, J=6.3Hz , 3H), 3.79 (d, J=13.6Hz, 2H), 3.63 (d, J=13.6Hz, 2H), 3.51 (s, 1H), 3.16-3.12 (m, 1H), 3.02 (s, 4H) , 2.89(s, 1H), 2.73(s, 2H), 2.30(s, 1H), 2.09(s, 2H), 2.03(s, 3H), 1.83(s, 6H), 1.73(s, 1H), 1.58-1.44(m, 5H), 1.37(s, 1H).
实施例11(S)-1-(4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)哌啶-2-甲酸(化合物11)Example 11 (S)-1-(4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)piperidine-2-carboxylic acid (Compound 11)
步骤1)4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(2.8g，5.6mmol)和3-氧杂-8-氮杂螺[4.5]癸烷(940mg，6.65mmol)溶于DMF(12mL)，依次加入K2CO3(1.9g，14mmol)和NaI(1g，6.67mmol)加热至75℃，反应12.5h。停止加热，冷却至室温，加水稀释(80mL)，乙酸乙酯萃取(50mL×3)，收集有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，得到棕褐色粘稠物600mg，产率19％。4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (2.8 g, 5.6 mmol) and 3-oxa-8-azaspiro[4.5]decane (940 mg, 6.65 mmol) were dissolved in DMF (12 mL), K2 CO3 (1.9 g, 14 mmol) and NaI (1 g, 6.67 mmol) were added in sequence, heated to 75°C, and reacted for 12.5 h. The heating was stopped, the mixture was cooled to room temperature, diluted with water (80 mL), extracted with ethyl acetate (50 mL×3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 600 mg of a brown viscous product with a yield of 19%.
LC-MS：(pos.ion)m/z：564.1[M+1]+；LC-MS: (pos.ion)m/z: 564.1[M+1]+ ;
步骤2)4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
将4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(550mg，0.97mmol)和3-(溴甲基)吡啶氢溴酸盐(320mg，1.26mmol)溶于DMF(15mL)，加入Cs2CO3(794mg，2.43mmol)，和NaI(14mg，0.10mmol)，加热至75℃反应3.5h。停止反应，冷却至室温，加水稀释(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色固体380mg，产率59.48％。4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (550 mg, 0.97 mmol) and 3-(bromomethyl)pyridine hydrobromide (320 mg, 1.26 mmol) were dissolved in DMF (15 mL), Cs2 CO3 (794 mg, 2.43 mmol) and NaI (14 mg, 0.10 mmol) were added, and the mixture was heated to 75° C. for 3.5 h. The reaction was stopped, cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 380 mg of a yellow solid. The yield was 59.48%.
LC-MS：(pos.ion)m/z：655.1[M+1]+；LC-MS: (pos.ion)m/z: 655.1[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)piperidine-2-carboxylic acid
将4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛(120mg，0.18mmol)和D-哌啶酸(35mg，0.27mmol)溶于DMF(8mL)，加入乙酸调节溶液pH至5左右，加热至60℃搅拌反应1h，冷却至室温，缓慢加入氰基硼氢化钠(57mg，0.90mmol)，室温搅拌反应15h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，分离得白色固体30mg，产率为21.32％。4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde (120 mg, 0.18 mmol) and D-piperidinic acid (35 mg, 0.27 mmol) were dissolved in DMF (8 mL), acetic acid was added to adjust the pH of the solution to about 5, the reaction was heated to 60°C and stirred for 1 h, cooled to room temperature, sodium cyanoborohydride (57 mg, 0.90 mmol) was slowly added, and the reaction was stirred at room temperature for 15 h. Stop stirring, cool to room temperature, add saturated carbonic acid solution (30 mL) and stir at room temperature for 30 min, extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, separate and purify by silica gel column chromatography (DCM/MeOH=8/1, v/v), and separate 30 mg of a white solid with a yield of 21.32%.
LC-MS：(pos.ion)m/z：768.2[M+1]+；LC-MS: (pos.ion)m/z: 768.2[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ8.70(s，1H)，8.56(d，J＝4.3Hz，1H)，7.90(d，J＝7.7Hz，1H)，7.49(d，J＝7.5Hz，1H)，7.43(s，2H)，7.27(t，J＝7.4Hz，1H)，7.21(t，J＝7.9Hz，1H)，7.14(s，1H)，7.07(d，J＝7.4Hz，1H)，6.96(d，J＝8.1Hz，1H)，6.69(d，J＝7.4Hz，1H)，5.26(d，J＝6.6Hz，4H)，4.06(d，J＝6.3Hz，2H)，3.75-3.69(m，3H)，3.62(d，J＝13.9Hz，2H)，3.51(s，1H)，3.44(s，2H)，3.15(s，1H)，2.89(s，2H)，2.73(s，4H)，2.29(s，1H)，2.03(s，5H)，1.83(s，3H)，1.80-1.76(m，1H)，1.69(s，3H)，1.64(s，3H)，1.47(s，3H)，1.36(s，1H).1 H NMR (400MHz, d6 -DMSO) δ 8.70 (s, 1H), 8.56 (d, J = 4.3Hz, 1H), 7.90 (d, J = 7.7Hz, 1H), 7.49 (d, J = 7.5Hz, 1H), 7.43 (s, 2H), 7.27 (t, J＝7.4Hz, 1H), 7.21 (t, J＝7.9Hz, 1H), 7.14 (s, 1H), 7.07 (d, J＝ 7.4Hz, 1H), 6.96 (d, J=8.1Hz, 1H), 6.69 (d, J=7.4Hz, 1H), 5.26 (d, J=6.6Hz, 4H), 4.06 (d, J=6.3Hz, 2H), 3.75-3.69 (m, 3H), 3.62 (d, J=13.9Hz, 2H), 3.51 (s, 1H), 3.44 (s, 2H), 3.15(s, 1H), 2.89(s, 2H), 2.73(s, 4H), 2.29(s, 1H), 2.03(s, 5H), 1.83(s, 3H), 1.80-1.76(m, 1H) , 1.69(s, 3H), 1.64(s, 3H), 1.47(s, 3H), 1.36(s, 1H).
实施例12 8-(3-((3′-((2-氯-4-(吗啉代甲基)-5-(吡啶-3-基甲氧基)苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2-氧杂-8-氮杂-螺[4.5]癸烷(化合物12)Example 12 8-(3-((3′-((2-chloro-4-(morpholinomethyl)-5-(pyridin-3-ylmethoxy)phenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2-oxa-8-aza-spiro[4.5]decane (Compound 12)
步骤1)4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(2.8g，5.6mmol)和3-氧杂-8-氮杂螺[4.5]癸烷(940mg，6.65mmol)溶于DMF(12mL)，依次加入K2CO3(1.9g，14mmol)和NaI(1g，6.67mmol)。随后加热至75℃，反应12.5h。停止加热，冷却至室温，加水稀释(80mL)，乙酸乙酯萃取(50mL×3)，收集有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，得到棕褐色粘稠物600mg，产率19％。4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (2.8 g, 5.6 mmol) and 3-oxa-8-azaspiro[4.5]decane (940 mg, 6.65 mmol) were dissolved in DMF (12 mL), and K2 CO3 (1.9 g, 14 mmol) and NaI (1 g, 6.67 mmol) were added in sequence. The mixture was then heated to 75°C and reacted for 12.5 h. The mixture was stopped, cooled to room temperature, diluted with water (80 mL), extracted with ethyl acetate (50 mL×3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 600 mg of a brown viscous product with a yield of 19%.
LC-MS：(pos.ion)m/z：564.1[M+1]+；LC-MS: (pos.ion)m/z: 564.1[M+1]+ ;
步骤2)4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
将4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(550mg，0.97mmol)和3-(溴甲基)吡啶氢溴酸盐(320mg，1.26mmol)溶于DMF(15mL)，加入Cs2CO3(794mg，2.43mmol)，和NaI(14mg，0.10mmol)，加热至75℃反应3.5h。停止反应，冷却至室温，加水稀释(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色固体380mg，产率59.48％。4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (550 mg, 0.97 mmol) and 3-(bromomethyl)pyridine hydrobromide (320 mg, 1.26 mmol) were dissolved in DMF (15 mL), Cs2 CO3 (794 mg, 2.43 mmol) and NaI (14 mg, 0.10 mmol) were added, and the mixture was heated to 75° C. for 3.5 h. The reaction was stopped, cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 380 mg of a yellow solid. The yield was 59.48%.
LC-MS：(pos.ion)m/z：655.1[M+1]+；LC-MS: (pos.ion)m/z: 655.1[M+1]+ ;
步骤3)8-(3-((3′-((2-氯-4-(吗啉代甲基)-5-(吡啶-3-基甲氧基)苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2-氧杂-8-氮杂-螺[4.5]癸烷Step 3) 8-(3-((3′-((2-chloro-4-(morpholinomethyl)-5-(pyridin-3-ylmethoxy)phenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2-oxa-8-aza-spiro[4.5]decane
将4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛(130mg，0.20mmol)和吗啉(24mg，0.27mmol)溶于DMF(8mL)，加入乙酸调节溶液pH至5左右，加热至60℃搅拌反应1h，冷却至室温，缓慢加入氰基硼氢化钠(62mg，0.98mmol)，室温搅拌反应15h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)，分离得白色固体40mg，产率为27.76％。4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde (130 mg, 0.20 mmol) and morpholine (24 mg, 0.27 mmol) were dissolved in DMF (8 mL), acetic acid was added to adjust the pH of the solution to about 5, the reaction was heated to 60°C and stirred for 1 h, cooled to room temperature, sodium cyanoborohydride (62 mg, 0.98 mmol) was slowly added, and the reaction was stirred at room temperature for 15 h. Stop stirring, cool to room temperature, add saturated carbonic acid solution (30 mL) and stir at room temperature for 30 min, extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, separate and purify by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 40 mg of a white solid with a yield of 27.76%.
LC-MS：(pos.ion)m/z：726.2[M+1]+；LC-MS: (pos.ion)m/z: 726.2[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ8.72(s，1H)，8.55(d，J＝3.4Hz，1H)，7.90(d，J＝7.4Hz，1H)，7.49(d，J＝7.4Hz，1H)，7.47-7.40(m，1H)，7.31(s，1H)，7.26(d，J＝7.4Hz，1H)，7.21(t，J＝7.7Hz，1H)，7.14(s，1H)，7.07(d，J＝7.3Hz，1H)，6.96(d，J＝8.1Hz，1H)，6.69(d，J＝7.3Hz，1H)，5.25(s，4H)，4.06(d，J＝5.7Hz，2H)，3.72(t，J＝6.5Hz，2H)，3.55(s，3H)，3.42(d，J＝13.5Hz，4H)，3.34(s，6H)，2.73(s，3H)，2.33(s，4H)，2.03(s，4H)，1.83(s，3H)，1.67(d，J＝22.4Hz，5H).1 H NMR (400MHz, d6 -DMSO) δ 8.72 (s, 1H), 8.55 (d, J = 3.4Hz, 1H), 7.90 (d, J = 7.4Hz, 1H), 7.49 (d, J = 7.4Hz, 1H), 7.47-7.40 (m, 1H), 7.31 (s, 1H), 7.26 (d, J=7.4Hz, 1H), 7.21 (t, J=7.7Hz, 1H), 7.14 (s, 1H), 7.07 (d, J=7.3Hz, 1H), 6.96 (d, J=8. 1Hz, 1H), 6.69 (d, J=7.3Hz, 1H), 5.25 (s, 4H), 4.06 (d, J=5.7Hz, 2H), 3.72 (t, J=6.5Hz, 2H), 3.55 ( s, 3H), 3.42 (d, J=13.5Hz, 4H), 3.34 (s, 6H), 2.73 (s, 3H), 2.33 (s, 4H), 2.03 (s, 4H), 1.83 (s, 3H) ), 1.67 (d, J=22.4Hz, 5H).
实施例13(R)-2-((4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)氨基)丙酸(化合物13)Example 13 (R)-2-((4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)amino)propanoic acid (Compound 13)
步骤1)4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
将4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(2.8g，5.6mmol)和3-氧杂-8-氮杂螺[4.5]癸烷(940mg，6.65mmol)溶于DMF(12mL)，依次加入K2CO3(1.9g，14mmol)和NaI(1g，6.67mmol)。随后加热至75℃，反应12.5h。停止加热，冷却至室温，加水稀释(80mL)，乙酸乙酯萃取(50mL×3)，收集有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，得到棕褐色粘稠物600mg，产率19％。4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (2.8 g, 5.6 mmol) and 3-oxa-8-azaspiro[4.5]decane (940 mg, 6.65 mmol) were dissolved in DMF (12 mL), and K2 CO3 (1.9 g, 14 mmol) and NaI (1 g, 6.67 mmol) were added in sequence. The mixture was then heated to 75°C and reacted for 12.5 h. The mixture was stopped, cooled to room temperature, diluted with water (80 mL), extracted with ethyl acetate (50 mL×3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was separated and purified by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 600 mg of a brown viscous product with a yield of 19%.
LC-MS：(pos.ion)m/z：564.1[M+1]+；LC-MS: (pos.ion)m/z: 564.1[M+1]+ ;
步骤2)4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
将4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(550mg，0.97mmol)和3-(溴甲基)吡啶氢溴酸盐(320mg，1.26mmol)溶于DMF(15mL)，加入Cs2CO3(794mg，2.43mmol)和NaI(14mg，0.097mmol)，随后加热至75℃反应3.5h。停止反应，冷却至室温，加水稀释(30mL)，乙酸乙酯萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，浓缩。硅胶柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色固体380mg，产率59.48％。4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (550 mg, 0.97 mmol) and 3-(bromomethyl)pyridine hydrobromide (320 mg, 1.26 mmol) were dissolved in DMF (15 mL), Cs2 CO3 (794 mg, 2.43 mmol) and NaI (14 mg, 0.097 mmol) were added, and then heated to 75° C. for 3.5 h. The reaction was stopped, cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was separated and purified by silica gel column chromatography (DCM/MeOH=10/1, v/v) to obtain 380 mg of a yellow solid. The yield was 59.48%.
LC-MS：(pos.ion)m/z：655.1[M+1]+；LC-MS: (pos.ion)m/z: 655.1[M+1]+ ;
步骤3)(R)-2-((4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)氨基)丙酸Step 3) (R)-2-((4-((3′-(3-(2-oxa-8-azaspiro[4.5]decan-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)amino)propanoic acid
将4-((3′-(3-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛(120mg，0.183mmol)和(2R)-2-氨基丙酸(24mg，0.26mmol)溶于DMF(8mL)，加入乙酸调节溶液pH至5左右，加热至60℃搅拌反应1h，冷却至室温，缓慢加入氰基硼氢化钠(57mg，0.90mmol)，室温搅拌反应15h。停止搅拌，冷却至室温，加入饱和碳酸溶液(30mL)室温搅拌30min，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，硅胶柱层析分离纯化(DCM/MeOH＝8/1，v/v)，分离得白色固体15mg，产率为11.25％。4-((3′-(3-(2-oxa-8-azaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde (120 mg, 0.183 mmol) and (2R)-2-aminopropionic acid (24 mg, 0.26 mmol) were dissolved in DMF (8 mL), acetic acid was added to adjust the pH of the solution to about 5, the reaction was heated to 60°C and stirred for 1 h, cooled to room temperature, sodium cyanoborohydride (57 mg, 0.90 mmol) was slowly added, and the reaction was stirred at room temperature for 15 h. Stop stirring, cool to room temperature, add saturated carbonic acid solution (30 mL) and stir at room temperature for 30 min, extract with ethyl acetate (100 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, separate and purify by silica gel column chromatography (DCM/MeOH=8/1, v/v), and separate 15 mg of a white solid with a yield of 11.25%.
LC-MS：(pos.ion)m/z：728.2[M+1]+；LC-MS: (pos.ion)m/z: 728.2[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ8.74(s，1H)，8.57(d，J＝4.1Hz，1H)，7.97(s，1H)，7.54(s，1H)，7.49(d，J＝7.0Hz，1H)，7.44(dd，J＝7.8，4.9Hz，1H)，7.27(t，J＝7.5Hz，1H)，7.21(t，J＝7.9Hz，1H)，7.20-7.13(m，1H)，7.07(d，J＝7.5Hz，1H)，6.96(d，J＝8.4Hz，1H)，6.69(d，J＝7.6Hz，1H)，5.39-5.19(m，4H)，4.07(d，J＝6.9Hz，2H)，3.94-3.85(m，2H)，3.73(t，J＝7.0Hz，2H)，3.51(s，2H)，3.45(s，3H)，3.19-3.14(m，2H)，2.89(s，6H)，2.10(s，2H)，2.03(s，3H)，1.82(d，J＝8.0Hz，3H)，1.70(d，J＝7.0Hz，6H).1 H NMR (400MHz, d6 -DMSO) δ 8.74 (s, 1H), 8.57 (d, J=4.1Hz, 1H), 7.97 (s, 1H), 7.54 (s, 1H), 7.49 (d, J=7.0Hz, 1H), 7.44 (dd, J=7.8, 4.9Hz, 1H), 7.27 (t, J=7.5Hz, 1H), 7.21 (t, J=7.9Hz, 1H), 7.20-7.13 ( m, 1H), 7.07 (d, J=7.5Hz, 1H), 6.96 (d, J=8.4Hz, 1H), 6. 69 (d, J=7.6Hz, 1H), 5.39-5.19 (m, 4H), 4.07 (d, J=6.9Hz, 2H), 3.94-3.85 (m, 2H), 3.73 (t, J=7.0Hz , 2H), 3.51(s, 2H), 3.45(s, 3H), 3.19-3.14(m, 2H), 2.89(s, 6H), 2.10(s, 2H), 2.03(s, 3H), 1.82( d, J=8.0Hz, 3H), 1.70 (d, J=7.0Hz, 6H).
实施例14 (S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物14)Example 14 (S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 14)
步骤1)5-氯-2-羟基-4-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯甲醛Step 1) 5-chloro-2-hydroxy-4-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(700mg，1.39mmol)和2-羟基-2，7-二氮杂螺环[3.5]壬烷盐酸盐(370.3mg，2.08mmol)的DMF(20mL)溶液中，依次加入碳酸钾(576.1mg，4.17mmol)和碘化钠(312.4mg，2.08mmol)，随后加热至70℃，反应16h。停止搅拌，冷却至室温，原料反应完全。加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色固体685mg，产率87.4％。Under nitrogen protection, potassium carbonate (576.1 mg, 4.17 mmol) and sodium iodide (312.4 mg, 2.08 mmol) were added to a DMF (20 mL) solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (700 mg, 1.39 mmol) and 2-hydroxy-2,7-diazaspiro[3.5]nonane hydrochloride (370.3 mg, 2.08 mmol) in sequence, and then heated to 70°C and reacted for 16 h. Stirring was stopped and cooled to room temperature, and the raw materials were completely reacted. Dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 685 mg of a yellow solid. Yield: 87.4%.
LC-MS：(pos.ion)m/z：564.0[M+1]+；LC-MS: (pos.ion)m/z: 564.0[M+1]+ ;
步骤2)5-((4-氯-2-甲酰基-5-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-chloro-2-formyl-5-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
向5-氯-2-羟基-4-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯甲醛(680mg，1.21mmol)和5-氯甲基-3-氰基吡啶盐酸盐(273.5mg，1.45mmol)的DMF溶液(20mL)中，依次加入碳酸铯(981.9mg，3.01mmol)和碘化钠(36.14mg，0.24mmol)，N2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到黄色固体476mg，产率58.05％。To a DMF solution (20 mL) of 5-chloro-2-hydroxy-4-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde (680 mg, 1.21 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (273.5 mg, 1.45 mmol) was added cesium carbonate (981.9 mg, 3.01 mmol) and sodium iodide (36.14 mg, 0.24 mmol) in sequence, underN2 protection, and reacted at 75°C for 4 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 476 mg of a yellow solid with a yield of 58.05%.
LC-MS：(pos.ion)m/z：680.2[M+1]+；LC-MS: (pos.ion)m/z: 680.2[M+1]+ ;
步骤3)(S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((4-氯-2-甲酰基-5-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(250mg，0.37mmol)和D-哌啶酸(94.94mg，0.74mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼氰化钠(115.5mg，1.84mmol)，室温反应3h后，80℃反应16h。停止搅拌，随后加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1，v/v)，得到淡黄色固体70mg，产率24.01％。Acetic acid was added to a DMF (10 mL) solution of 5-((4-chloro-2-formyl-5-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (250 mg, 0.37 mmol) and D-piperidinic acid (94.94 mg, 0.74 mmol), the pH was adjusted to about 5, the mixture was reacted at 60°C for 1 h, cooled to room temperature, sodium borocyanide (115.5 mg, 1.84 mmol) was added to the reaction system, the mixture was reacted at room temperature for 3 h, and then reacted at 80°C for 16 h. Stirring was stopped, and a saturated potassium carbonate solution was then added, and the mixture was stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=4/1, v/v) to obtain 70 mg of a light yellow solid. The yield is 24.01%.
LC-MS：(pos.ion)m/z：793.2[M+1]+；LC-MS: (pos.ion)m/z: 793.2[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(s，1H)，8.99(s，1H)，8.45(s，1H)，7.49(d，J＝7.4Hz，1H)，7.41(s，1H)，7.26(t，J＝7.5Hz，1H)，7.20(t，J＝7.9Hz，1H)，7.11(s，1H)，7.06(d，J＝7.4Hz，1H)，6.94(d，J＝8.1Hz，1H)，6.67(d，J＝7.4Hz，1H)，5.32(s，2H)，5.26(s，2H)，4.05(dd，J＝16.0，7.0Hz，4H)，3.76(d，J＝13.9Hz，2H)，3.60(d，J＝13.9Hz，3H)，3.51(s，2H)，3.14(d，J＝6.9Hz，2H)，2.11-2.04(m，2H)，2.02(s，3H)，1.92(s，2H)，1.81(s，4H)，1.51(dd，J＝14.6，7.9Hz，9H)，1.36(s，1H)，1.23(s，3H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (s, 1H), 8.99 (s, 1H), 8.45 (s, 1H), 7.49 (d, J=7.4Hz, 1H), 7.41 (s, 1H), 7.26 (t, J=7.5Hz, 1H), 7.20 (t, J=7.9Hz, 1H), 7.11 (s, 1H), 7.06 (d, J=7.4Hz, 1H), 6.94 (d, J＝8.1Hz, 1H), 6.67(d, J＝7.4Hz, 1H), 5.32(s, 2H), 5.26(s, 2H), 4.05 (dd, J=16.0, 7.0Hz, 4H), 3.76 (d, J=13.9Hz, 2H), 3.60 (d, J=13.9Hz, 3H), 3.51 (s, 2H), 3.14( d, J=6.9Hz, 2H), 2.11-2.04 (m, 2H), 2.02 (s, 3H), 1.92 (s, 2H), 1.81 (s, 4H), 1.51 (dd, J=14.6, 7.9Hz , 9H), 1.36 (s, 1H), 1.23 (s, 3H).
实施例15 (S)-1-(4-((3′-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物15)Example 15 (S)-1-(4-((3′-(3-(2-oxa-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 15)
步骤1)4-((3′-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(2-oxa-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(500mg，0.99mmol)和2-氧-7-氮杂螺环[3.5]壬烷草酸盐(323.4mg，1.49mmol)的DMF(20mL)溶液中，依次加入碳酸钾(617.3mg，4.47mmol)和NaI(223.1mg，1.49mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，原料反应完全。加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色固体307mg，产率56.23％。Under nitrogen protection, potassium carbonate (617.3 mg, 4.47 mmol) and NaI (223.1 mg, 1.49 mmol) were added to a DMF (20 mL) solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (500 mg, 0.99 mmol) and 2-oxo-7-azaspiro[3.5]nonane oxalate (323.4 mg, 1.49 mmol) in sequence, and the mixture was heated to 70°C and reacted for 16 h. Stirring was stopped and the mixture was cooled to room temperature. The reaction of the raw materials was complete. Dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 307 mg of a yellow solid. Yield: 56.23%.
LC-MS：(pos.ion)m/z：550.1[M+1]+；LC-MS: (pos.ion)m/z: 550.1[M+1]+ ;
步骤2)5-((5-((3′-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(2-oxa-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3′-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(300mg，0.55mmol)和5-氯甲基-3-氰基吡啶盐酸盐(1546mg，0.82mmol)的DMF溶液(20mL)中，依次加入碳酸铯(309.9mg，1.2mmol)和碘化钠(16.35mg，0.11mmol)，N2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1)得到黄色油状液体73mg，产率20.09％。To a DMF solution (20 mL) of 4-((3′-(3-(2-oxa-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (300 mg, 0.55 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (1546 mg, 0.82 mmol) were added cesium carbonate (309.9 mg, 1.2 mmol) and sodium iodide (16.35 mg, 0.11 mmol) in sequence, the mixture was protectedby N2 and reacted at 75°C for 4 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1) to obtain 73 mg of a yellow oily liquid with a yield of 20.09%.
LC-MS：(pos.ion)m/z：666.4[M+1]+；LC-MS: (pos.ion)m/z: 666.4[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(2-oxa-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(2-氧杂-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(70mg，0.11mmol)和D-哌啶酸(27.14mg，0.21mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼氰化钠(33.01mg，0.53mmol)，室温反应3h后，升温至80℃反应16h。随后停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1，v/v)，得到淡黄色固体15mg，产率18.32％。Acetic acid was added to a DMF (10 mL) solution of 5-((5-((3′-(3-(2-oxa-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (70 mg, 0.11 mmol) and D-piperidinic acid (27.14 mg, 0.21 mmol), the pH was adjusted to about 5, the reaction was carried out at 60° C. for 1 h, the reaction was cooled to room temperature, sodium borocyanide (33.01 mg, 0.53 mmol) was added to the reaction system, the reaction was carried out at room temperature for 3 h, the temperature was raised to 80° C. for 16 h. Then the stirring was stopped, a saturated potassium carbonate solution was added, and the mixture was stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=4/1, v/v) to obtain 15 mg of a light yellow solid. The yield is 18.32%.
LC-MS：(pos.ion)m/z：779.5[M+1]+；LC-MS: (pos.ion)m/z: 779.5[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(d，J＝7.7Hz，2H)，8.46(s，1H)，7.49(d，J＝7.5Hz，1H)，7.42(s，1H)，7.32-7.16(m，2H)，7.12(s，1H)，7.07(d，J＝7.4Hz，1H)，6.96(d，J＝8.2Hz，1H)，6.69(d，J＝7.5Hz，1H)，5.32(d，J＝14.0Hz，2H)，5.27(s，2H)，4.29(s，3H)，4.05(d，J＝6.4Hz，2H)，3.77(d，J＝13.5Hz，2H)，3.61(d，J＝13.6Hz，1H)，3.52(s，6H)，2.03(s，3H)，1.82(s，4H)，1.49(s，3H)，1.24(s，9H)，0.85(d，J＝7.0Hz，2H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (d, J=7.7Hz, 2H), 8.46 (s, 1H), 7.49 (d, J=7.5Hz, 1H), 7.42 (s, 1H) , 7.32-7.16 (m, 2H), 7.12 (s, 1H), 7.07 (d, J = 7.4Hz, 1H), 6.96 (d, J = 8.2Hz, 1H), 6.69 (d, J = 7.5Hz, 1H), 5.32 (d, J=14. 0Hz, 2H), 5.27 (s, 2H), 4.29 (s, 3H), 4.05 (d, J=6.4Hz, 2H), 3.77 (d, J=13.5Hz, 2H), 3.61 (d, J=13.6 Hz, 1H), 3.52 (s, 6H), 2.03 (s, 3H), 1.82 (s, 4H), 1.49 (s, 3H), 1.24 (s, 9H), 0.85 (d, J=7.0Hz, 2H ).
实施例16 (S)-1-(4-((3′-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物16)Example 16 (S)-1-(4-((3′-(3-(2-oxa-6-azaspiro[3.5]non-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 16)
步骤1)4-((3′-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(2-oxa-6-azaspiro[3.5]non-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(600mg，1.19mmol)和2-氧-6-氮杂螺环[3.5]壬烷草酸盐(388mg，1.79mmol)的DMF(20mL)溶液中，依次加入碳酸钾(740.7mg，5.36mmol)和NaI(267.8mg，1.79mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到红色油状液体427mg，产率65.18％。Under nitrogen protection, potassium carbonate (740.7 mg, 5.36 mmol) and NaI (267.8 mg, 1.79 mmol) were added successively to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (600 mg, 1.19 mmol) and 2-oxo-6-azaspiro[3.5]nonane oxalate (388 mg, 1.79 mmol) in DMF (20 mL), and the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 427 mg of a red oily liquid with a yield of 65.18%.
LC-MS：(pos.ion)m/z：550.1[M+1]+；LC-MS: (pos.ion)m/z: 550.1[M+1]+ ;
步骤2)5-((5-((3′-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(2-oxa-6-azaspiro[3.5]non-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3′-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(420mg，0.76mmol)和5-氯甲基-3-氰基吡啶盐酸盐(173.2mg，0.92mmol)的DMF溶液(20mL)中，依次加入碳酸铯(621.9mg，1.91mmol)和碘化钠(22.89mg，0.15mmol)，N2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到红色油状液体342mg，产率67.24％。To a DMF solution (20 mL) of 4-((3′-(3-(2-oxa-6-azaspiro[3.5]nonan-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (420 mg, 0.76 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (173.2 mg, 0.92 mmol) were added cesium carbonate (621.9 mg, 1.91 mmol) and sodium iodide (22.89 mg, 0.15 mmol) in sequence, underN2 protection, and reacted at 75°C for 4 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 342 mg of a red oily liquid with a yield of 67.24%.
LC-MS：(pos.ion)m/z：666.5[M+1]+；LC-MS: (pos.ion)m/z: 666.5[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(2-oxa-6-azaspiro[3.5]nonan-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(2-氧杂-6-氮杂螺[3.5]壬-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(340mg，0.51mmol)和D-哌啶酸(131.8mg，1.02mmol)的DMF(20mL)溶液中加入乙酸调节pH至5左右，随后升温至60℃反应1h，再冷却至室温，向反应体系中加入硼氰化钠(160.4mg，2.55mmol)，室温搅拌反应3h后，再升温至80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝6/1，v/v)，得到淡红色固体52mg，产率13.07％。Acetic acid was added to a DMF (20 mL) solution of 5-((5-((3′-(3-(2-oxa-6-azaspiro[3.5]non-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (340 mg, 0.51 mmol) and D-piperidinic acid (131.8 mg, 1.02 mmol) to adjust the pH to about 5, then the temperature was raised to 60°C for reaction for 1 h, and then cooled to room temperature. Sodium borocyanide (160.4 mg, 2.55 mmol) was added to the reaction system, and the reaction was stirred at room temperature for 3 h, and then the temperature was raised to 80°C for reaction for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=6/1, v/v) to obtain 52 mg of a light red solid. The yield is 13.07%.
LC-MS：(pos.ion)m/z：779.6[M+1]+；LC-MS: (pos.ion)m/z: 779.6[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(s，2H)，8.48(s，1H)，7.46(d，J＝18.6Hz，2H)，7.23(d，J＝23.1Hz，2H)，7.15(s，1H)，7.07(s，1H)，6.97(s，1H)，6.69(s，1H)，5.31(d，J＝31.0Hz，4H)，4.26(d，J＝31.9Hz，5H)，4.05(s，4H)，3.81(s，6H)，2.00(d，J＝18.4Hz，6H)，1.83(s，4H)，1.75(s，3H)，1.50(s，5H)，1.37(s，1H)，1.17(s，1H).1 H NMR (400 MHz, d6 -DMSO) δ9.01 (s, 2H), 8.48 (s, 1H), 7.46 (d, J = 18.6Hz, 2H), 7.23 (d, J = 23.1Hz, 2H), 7.15 (s, 1H), 7.07 (s, 1H), 6.97 (s, 1H), 6.69 (s, 1H), 5.31 (d, J = 31.0 Hz, 4H), 4.26 (d, J=31.9Hz, 5H), 4.05 (s, 4H), 3.81 (s, 6H), 2.00 (d, J=18.4Hz, 6H), 1.83 (s, 4H), 1.75 (s, 3H), 1.50 (s, 5H), 1.37 (s, 1H), 1.17 (s, 1H).
实施例17 (2S)-1-(4-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物17)Example 17 (2S)-1-(4-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 17)
步骤1)4-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(600mg，1.191mmol)和2-氧-7-氮杂螺环[4.5]癸烷盐酸盐(317.4mg，1.79mmol)的DMF(20mL)溶液中，依次加入碳酸钾(411.5mg，2.98mmol)和NaI(267.8mg，1.79mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温。随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到棕红色油状液体200mg，产率29.77％。Under nitrogen protection, potassium carbonate (411.5 mg, 2.98 mmol) and NaI (267.8 mg, 1.79 mmol) were added to a DMF (20 mL) solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (600 mg, 1.191 mmol) and 2-oxo-7-azaspiro[4.5]decane hydrochloride (317.4 mg, 1.79 mmol) in sequence, and the mixture was heated to 70° C. and reacted for 16 h. Stirring was stopped and the mixture was cooled to room temperature. The mixture was then diluted with water (20 mL), extracted with ethyl acetate (50 mL×3), and the organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/MeOH=10/1, v/v) to obtain 200 mg of a brown-red oily liquid with a yield of 29.77%.
LC-MS：(pos.ion)m/z：564.4[M+1]+；LC-MS: (pos.ion)m/z: 564.4[M+1]+ ;
步骤2)5-((5-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(450mg，0.80mmol)和5-氯甲基-3-氰基吡啶盐酸盐(181mg，0.96mmol)的DMF溶液(20mL)中，依次加入碳酸铯(649.8mg，1.99mmol)和碘化钠(23.92mg，0.16mmol)，N2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到红色油状液体520mg，产率95.83％。To a DMF solution (20 mL) of 4-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (450 mg, 0.80 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (181 mg, 0.96 mmol) were added cesium carbonate (649.8 mg, 1.99 mmol) and sodium iodide (23.92 mg, 0.16 mmol) in sequence, underN2 protection, and reacted at 75°C for 4 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 520 mg of a red oily liquid with a yield of 95.83%.
LC-MS：(pos.ion)m/z：680.5[M+1]+；LC-MS: (pos.ion)m/z: 680.5[M+1]+ ;
步骤3)(2S)-1-(4-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-吡啶-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(520mg，0.76mmol)和D-哌啶酸(197.5mg，1.53mmol)的DMF(20mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼氰化钠(240.2mg，3.82mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1，v/v)，得到淡红色固体112mg，产率18.47％。To a DMF (20 mL) solution of 5-((5-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-pyridin-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (520 mg, 0.76 mmol) and D-piperidinic acid (197.5 mg, 1.53 mmol) was added acetic acid, the pH was adjusted to about 5, the mixture was reacted at 60° C. for 1 h, cooled to room temperature, sodium borocyanide (240.2 mg, 3.82 mmol) was added to the reaction system, the mixture was reacted at room temperature for 3 h, and then reacted at 80° C. for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and the mixture was stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=4/1, v/v) to obtain 112 mg of a light red solid. The yield is 18.47%.
LC-MS：(pos.ion)m/z：793.3[M+1]+；LC-MS: (pos.ion)m/z: 793.3[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(d，J＝1.3Hz，2H)，8.47(s，1H)，7.49(d，J＝7.5Hz，1H)，7.43(s，1H)，7.26(t，J＝7.6Hz，1H)，7.20(t，J＝7.9Hz，1H)，7.15(s，1H)，7.06(d，J＝7.5Hz，1H)，6.96(d，J＝8.2Hz，1H)，6.68(d，J＝7.5Hz，1H)，5.35(s，2H)，5.27(s，2H)，4.06(d，J＝6.2Hz，3H)，3.84(s，3H)，3.66(d，J＝13.9Hz，9H)，2.03(s，4H)，1.82(s，5H)，1.71(d，J＝9.7Hz，2H)，1.50(t，J＝48.5Hz，9H)，1.23(s，2H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (d, J=1.3Hz, 2H), 8.47 (s, 1H), 7.49 (d, J=7.5Hz, 1H), 7.43 (s, 1H) , 7.26 (t, J=7.6Hz, 1H), 7.20 (t, J=7.9Hz, 1H), 7.15 (s, 1H), 7.06 (d, J=7.5Hz, 1H), 6.96 (d, J= 8.2Hz, 1H), 6.68 (d, J=7.5Hz, 1H), 5.35 (s, 2H), 5.27 (s, 2H), 4.06 (d, J=6.2Hz, 3H), 3.84 (s, 3H), 3.66 (d, J= 13.9Hz, 9H), 2.03 (s, 4H), 1.82 (s, 5H), 1.71 (d, J=9.7Hz, 2H), 1.50 (t, J=48.5Hz, 9H), 1.23 (s, 2H) .
实施例18 (S)-1-(4-((3′-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物18)Example 18 (S)-1-(4-((3′-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 18)
步骤1)4-((3′-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(800mg，1.59mmol)和9-氧-2-氮杂螺环[5.5]十一烷(369.8mg，2.38mmol)的DMF(20mL)溶液中，依次加入碳酸钾(329.2mg，2.38mmol)和NaI(357mg，2.38mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到棕红色油状液体566mg，产率61.66％。Under nitrogen protection, potassium carbonate (329.2 mg, 2.38 mmol) and NaI (357 mg, 2.38 mmol) were added successively to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (800 mg, 1.59 mmol) and 9-oxo-2-azaspiro[5.5]undecane (369.8 mg, 2.38 mmol) in DMF (20 mL), and the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, then dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 566 mg of a brown-red oily liquid with a yield of 61.66%.
LC-MS：(pos.ion)m/z：578.4[M+1]+；LC-MS: (pos.ion)m/z: 578.4[M+1]+ ;
步骤2)5-((5-((3′-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3′-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(560mg，0.97mmol)和5-氯甲基-3-氰基吡啶盐酸盐(219.7mg，1.16mmol)的DMF溶液(20mL)中，依次加入碳酸铯(789mg，2.42mmol)和碘化钠(29.04mg，0.19mmol)，N2保护，75℃反应4h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝20/1，v/v)得到红色油状液体408mg，产率60.66％。To a DMF solution (20 mL) of 4-((3′-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (560 mg, 0.97 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (219.7 mg, 1.16 mmol) were added cesium carbonate (789 mg, 2.42 mmol) and sodium iodide (29.04 mg, 0.19 mmol) in sequence, the mixture was protectedby N2 and reacted at 75°C for 4 h. Stop stirring, cool to room temperature, then dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=20/1, v/v) to obtain 408 mg of a red oily liquid with a yield of 60.66%.
LC-MS：(pos.ion)m/z：694.5[M+1]+；LC-MS: (pos.ion)m/z: 694.5[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(9-oxa-2-azaspiro[5.5]undec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(9-氧杂-2-氮杂螺[5.5]十一烷-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(300mg，0.43mmol)和D-哌啶酸(111.6mg，0.86mmol)的DMF(20mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼氰化钠(135.8mg，2.16mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到淡红色固体18mg，产率5.16％。To a DMF (20 mL) solution of 5-((5-((3′-(3-(9-oxa-2-azaspiro[5.5]undecane-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (300 mg, 0.43 mmol) and D-piperidinic acid (111.6 mg, 0.86 mmol) was added acetic acid, the pH was adjusted to about 5, the mixture was reacted at 60° C. for 1 h, cooled to room temperature, sodium borocyanide (135.8 mg, 2.16 mmol) was added to the reaction system, the mixture was reacted at room temperature for 3 h, and then reacted at 80° C. for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and the mixture was stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 18 mg of a light red solid. The yield is 5.16%.
LC-MS：(pos.ion)m/z：807.6[M+1]+；LC-MS: (pos.ion)m/z: 807.6[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.00(d，J＝6.1Hz，2H)，8.46(s，1H)，7.49(d，J＝7.3Hz，1H)，7.42(s，1H)，7.25(dt，J＝15.9，7.7Hz，2H)，7.12(d，J＝2.7Hz，1H)，7.06(d，J＝7.4Hz，1H)，6.97(d，J＝8.3Hz，1H)，6.70(d，J＝7.5Hz，1H)，5.33(s，2H)，5.27(s，2H)，4.13-4.03(m，2H)，3.81(d，J＝13.6Hz，2H)，3.65(d，J＝14.0Hz，3H)，3.52(d，J＝12.6Hz，6H)，2.06-1.95(m，5H)，1.84(d，J＝3.7Hz，4H)，1.71(s，4H)，1.48(d，J＝9.4Hz，4H)，1.39(s，2H)，1.23(s，6H)，0.85(s，1H).1 H NMR (400MHz, d6 -DMSO) δ9.00 (d, J=6.1Hz, 2H), 8.46 (s, 1H), 7.49 (d, J=7.3Hz, 1H), 7.42 (s, 1H) , 7.25 (dt, J=15.9, 7.7Hz, 2H), 7.12 (d, J=2.7Hz, 1H), 7.06 (d, J=7.4Hz, 1H), 6.97 (d, J=8.3Hz, 1H) , 6.70 (d, J=7.5Hz, 1H), 5.33 (s, 2H), 5.2 7 (s, 2H), 4.13-4.03 (m, 2H), 3.81 (d, J = 13.6Hz, 2H), 3.65 (d, J = 14.0Hz, 3H), 3.52 (d, J = 12.6Hz, 6H ), 2.06-1.95 (m, 5H), 1.84 (d, J = 3.7Hz, 4H), 1.71 (s, 4H), 1.48 (d, J = 9.4Hz, 4H), 1.39 (s, 2H), 1.23 (s, 6H), 0.85 (s, 1H).
实施例19 (S)-1-(4-((3′-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物19)Example 19 (S)-1-(4-((3′-(3-(8-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 19)
步骤1)4-((3′-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(8-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(800mg，1.59mmol)和8-氧杂-2-氮杂螺[4.5]癸烷(336.3mg，2.38mmol)的DMF(20mL)溶液中，依次加入碳酸钾(329.2mg，2.38mmol)和NaI(357mg，2.38mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到棕红色油状液体640mg，产率71.45％。Under nitrogen protection, to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (800 mg, 1.59 mmol) and 8-oxa-2-azaspiro[4.5]decane (336.3 mg, 2.38 mmol) in DMF (20 mL) were added potassium carbonate (329.2 mg, 2.38 mmol) and NaI (357 mg, 2.38 mmol) in sequence, the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, then dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 640 mg of a brown-red oily liquid with a yield of 71.45%.
LC-MS：(pos.ion)m/z：564.2[M+1]+LC-MS: (pos.ion)m/z: 564.2[M+1]+
步骤2)5-((5-((3′-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(8-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3′-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(640mg，1.14mmol)和5-氯甲基-3-氰基吡啶盐酸盐(257.4mg，1.36mmol)的DMF溶液(20mL)中，依次加入碳酸铯(924.1mg，2.83mmol)和碘化钠(34.01mg，0.23mmol)，N2保护，75℃反应4h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到红色油状液体190mg，产率24.62％。To a DMF solution (20 mL) of 4-((3′-(3-(8-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (640 mg, 1.14 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (257.4 mg, 1.36 mmol) was added cesium carbonate (924.1 mg, 2.83 mmol) and sodium iodide (34.01 mg, 0.23 mmol) in sequence, the mixture was protectedby N2 and reacted at 75°C for 4 h. Stop stirring, cool to room temperature, then dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 190 mg of a red oily liquid with a yield of 24.62%.
LC-MS：(pos.ion)m/z：680.1[M+1]+；LC-MS: (pos.ion)m/z: 680.1[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(8-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(8-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(190mg，0.28mmol)和D-哌啶酸(72.16mg，0.56mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反应1h，再冷却至室温，向反应体系中加入硼氰化钠(87.77mg，1.40mmol)，室温搅拌3h后，升温至80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1，v/v)，得到淡黄色固体35mg，产率15.79％。Acetic acid was added to a DMF (10 mL) solution of 5-((5-((3′-(3-(8-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (190 mg, 0.28 mmol) and D-piperidinic acid (72.16 mg, 0.56 mmol), and the pH was adjusted to about 5. The mixture was then heated to 60° C. for reaction for 1 h, cooled to room temperature, and sodium borocyanide (87.77 mg, 1.40 mmol) was added to the reaction system. After stirring at room temperature for 3 h, the mixture was heated to 80° C. for reaction for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=4/1, v/v) to obtain 35 mg of a light yellow solid. The yield is 15.79%.
LC-MS：(pos.ion)m/z：793.3[M+1]+；LC-MS: (pos.ion)m/z: 793.3[M+1]+ ;
1H NMR(40)0MHz，d6-DMSO)δ9.04-8.96(m，2H)，8.46(s，1H)，7.49(d，J＝7.4Hz，1H)，7.42(s，1H)，7.26(t，J＝7.5Hz，1H)，7.18(d，J＝7.8Hz，1H)，7.12(s，1H)，7.06(d，J＝7.5Hz，1H)，6.95(d，J＝8.2Hz，1H)，6.68(d，J＝7.5Hz，1H)，5.32(d，J＝11.3Hz，2H)，5.25(d，J＝12.6Hz，2H)，3.83-3.75(m，3H)，3.64(s，1H)，3.60(s，1H)，3.50(t，J＝10.8Hz，6H)，3.15(dd，J＝11.3，4.3Hz，1H)，2.89(s，3H)，2.62(s，2H)，2.02(s，3H)，1.82(s，5H)，1.68(t，J＝6.7Hz，3H)，1.49(t，J＝13.0Hz，7H)，1.36(s，1H)，1.22(s，1H).1 H NMR (40) 0MHz, d6 -DMSO) δ 9.04-8.96 (m, 2H), 8.46 (s, 1H), 7.49 (d, J=7.4Hz, 1H), 7.42 (s, 1H), 7.26 (t, J=7.5Hz, 1H), 7.18 (d, J=7.8Hz, 1H), 7.12 (s, 1H), 7.06 (d, J=7.5Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.68 (d, J=7.5Hz, 1H), 5.32 (d, J=11.3Hz, 2H), 5.25 (d, J= 12.6Hz, 2H), 3.83-3.75 (m, 3H), 3.64 (s, 1H), 3.60 (s, 1H), 3.50 (t, J=10.8Hz, 6H), 3.15 (dd, J=11.3, 4.3 Hz, 1H), 2.89 (s, 3H), 2.62 (s, 2H), 2.02 (s, 3H), 1.82 (s, 5H), 1.68 (t, J=6.7Hz, 3H), 1.49 (t, J =13.0Hz, 7H), 1.36(s, 1H), 1.22(s, 1H).
实施例20 (2S)-1-(4-((3′-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物20)Example 20 (2S)-1-(4-((3′-(3-(7-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 20)
步骤1)4-((3′-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(7-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基苯甲醛(800mg，1.59mmol)和7-氧杂-2-氮杂螺[4.5]癸烷半草酸盐(414.1mg，1.11mmol)的DMF(20mL)溶液中，依次加入碳酸钾(548.7mg，3.97mmol)和NaI(357mg，2.38mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1)，得到棕红色油状液体548mg，产率61.18％。Under nitrogen protection, potassium carbonate (548.7 mg, 3.97 mmol) and NaI (357 mg, 2.38 mmol) were added successively to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxybenzaldehyde (800 mg, 1.59 mmol) and 7-oxa-2-azaspiro[4.5]decane hemioxalate (414.1 mg, 1.11 mmol) in DMF (20 mL), the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, then dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=10/1) to obtain 548 mg of a brown-red oily liquid with a yield of 61.18%.
LC-MS：(pos.ion)m/z：564.4[M+1]+LC-MS: (pos.ion)m/z: 564.4[M+1]+
步骤2)5-((5-((3′-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(7-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3′-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(540mg，0.96mmol)和5-氯甲基-3-氰基吡啶盐酸盐(221.2mg，1.17mmol)的DMF溶液(20mL)中，依次加入碳酸铯(794.2mg，2.44mmol)和碘化钠(29.23mg，0.19mmol)，N2保护，75℃反应4h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝20/1，v/v)得到黄色油状液体616mg，产率94.6％。To a DMF solution (20 mL) of 4-((3′-(3-(7-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (540 mg, 0.96 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (221.2 mg, 1.17 mmol) were added cesium carbonate (794.2 mg, 2.44 mmol) and sodium iodide (29.23 mg, 0.19 mmol) in sequence, the mixture was protectedby N2 and reacted at 75°C for 4 h. Stop stirring, cool to room temperature, then dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=20/1, v/v) to obtain 616 mg of a yellow oily liquid with a yield of 94.6%.
LC-MS：(pos.ion)m/z：680.2[M+1]+；LC-MS: (pos.ion)m/z: 680.2[M+1]+ ;
步骤3)(2S)-1-(4-((3′-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3′-(3-(7-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(7-氧杂-2-氮杂螺[4.5]癸-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(300mg，0.44mmol)和D-哌啶酸(113.9mg，0.88mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼氰化钠(138.6mg，2.21mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。随后加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到淡红色固体48mg，产率13.72％。To a DMF (10 mL) solution of 5-((5-((3′-(3-(7-oxa-2-azaspiro[4.5]dec-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (300 mg, 0.44 mmol) and D-piperidinic acid (113.9 mg, 0.88 mmol) was added acetic acid, the pH was adjusted to about 5, the mixture was reacted at 60° C. for 1 h, cooled to room temperature, sodium borocyanide (138.6 mg, 2.21 mmol) was added to the reaction system, the mixture was reacted at room temperature for 3 h, and then reacted at 80° C. for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and the mixture was stirred for 30 min. Subsequently, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/MeOH=10/1, v/v) to obtain 48 mg of a light red solid with a yield of 13.72%.
LC-MS：(pos.ion)m/z：793.3[M+1]+；LC-MS: (pos.ion)m/z: 793.3[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.03-8.97(m，2H)，8.46(s，1H)，7.49(d，J＝7.4Hz，1H)，7.42(s，1H)，7.27(t，J＝7.5Hz，1H)，7.21(t，J＝7.9Hz，1H)，7.12(s，1H)，7.07(d，J＝7.3Hz，1H)，6.96(d，J＝8.1Hz，1H)，6.69(d，J＝7.5Hz，1H)，5.33(s，2H)，5.27(s，2H)，4.07(d，J＝6.5Hz，3H)，3.78(d，J＝13.9Hz，2H)，3.64(s，4H)，3.51(s，4H)，2.03(s，5H)，1.83(s，4H)，1.64(s，2H)，1.52(d，J＝25.4Hz，9H)，1.38(d，J＝7.0Hz，1H)，1.24(s，3H).1 H NMR (400MHz, d6 -DMSO) δ9.03-8.97 (m, 2H), 8.46 (s, 1H), 7.49 (d, J=7.4Hz, 1H), 7.42 (s, 1H), 7.27 ( t, J=7.5Hz, 1H), 7.21 (t, J=7.9Hz, 1H), 7.12 (s, 1H), 7.07 (d, J=7.3Hz, 1H), 6.96 (d, J=8.1Hz, 1H), 6.69 (d, J=7.5Hz, 1H ), 5.33 (s, 2H), 5.27 (s, 2H), 4.07 (d, J = 6.5Hz, 3H), 3.78 (d, J = 13.9Hz, 2H), 3.64 (s, 4H), 3.51 (s , 4H), 2.03 (s, 5H), 1.83 (s, 4H), 1.64 (s, 2H), 1.52 (d, J=25.4Hz, 9H), 1.38 (d, J=7.0Hz, 1H), 1.24 (s, 3H).
实施例160 (2S)-1-(4-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物160)Example 160 (2S)-1-(4-((3′-(3-(2-oxa-7-azaspiro[4.4]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 160)
步骤1)4-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(2-oxa-7-azaspiro[4.4]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(600mg，1.91mmol)和2-氧杂-7-氮杂螺[4.4]壬烷(227.2mg，1.79mmol)的DMF(20mL)溶液中，依次加入碳酸钾(246.9mg，1.79mmol)和NaI(267.8mg，1.79mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到棕红色油状液体200mg，产率30.53％。Under nitrogen protection, to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (600 mg, 1.91 mmol) and 2-oxa-7-azaspiro[4.4]nonane (227.2 mg, 1.79 mmol) in DMF (20 mL) were added potassium carbonate (246.9 mg, 1.79 mmol) and NaI (267.8 mg, 1.79 mmol) in sequence, the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 200 mg of a brown-red oily liquid with a yield of 30.53%.
LC-MS：(pos.ion)m/z：550.4[M+1]+LC-MS: (pos.ion)m/z: 550.4[M+1]+
步骤2)5-((5-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(2-oxa-7-azaspiro[4.4]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(550mg，0.99mmol)和5-氯甲基-3-氰基吡啶盐酸盐(226.8mg，1.2mmol)的DMF溶液(20mL)中，依次加入碳酸铯(814.4mg，2.5mmol)和碘化钠(29.97mg，0.2mmol)，N2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到黄色固体274mg，产率41.14％。To a DMF solution (20 mL) of 4-((3′-(3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (550 mg, 0.99 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (226.8 mg, 1.2 mmol), cesium carbonate (814.4 mg, 2.5 mmol) and sodium iodide (29.97 mg, 0.2 mmol) were added in sequence, the mixture was protectedby N2 , and the reaction was carried out at 75°C for 4 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 274 mg of a yellow solid with a yield of 41.14%.
LC-MS：(pos.ion)m/z：666.2[M+1]+；LC-MS: (pos.ion)m/z: 666.2[M+1]+ ;
步骤3)(2S)-1-(4-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3′-(3-(2-oxa-7-azaspiro[4.4]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(270mg，0.40mmol)和D-哌啶酸(104.7mg，0.81mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反应1h，再冷却至室温，向反应体系中加入硼氰化钠(127.3mg，2.02mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1，v/v)，得到淡黄色固体53mg，产率16.78％。To a DMF (10 mL) solution of 5-((5-((3′-(3-(2-oxa-7-azaspiro[4.4]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (270 mg, 0.40 mmol) and D-piperidinic acid (104.7 mg, 0.81 mmol) was added acetic acid, the pH was adjusted to about 5, then the temperature was raised to 60°C for reaction for 1 h, and then cooled to room temperature, sodium borocyanide (127.3 mg, 2.02 mmol) was added to the reaction system, and the reaction was continued at room temperature for 3 h, and then at 80°C for reaction for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and the mixture was stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=4/1, v/v) to obtain 53 mg of a light yellow solid. The yield is 16.78%.
LC-MS：(pos.ion)m/z：779.3[M+1]+；LC-MS: (pos.ion)m/z: 779.3[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.00(d，J＝2.8Hz，2H)，8.45(s，1H)，7.49(d，J＝7.4Hz，1H)，7.42(s，1H)，7.26(t，J＝7.6Hz，1H)，7.20(t，J＝7.9Hz，1H)，7.11(s，1H)，7.06(d，J＝7.4Hz，1H)，6.95(d，J＝8.2Hz，1H)，6.68(d，J＝7.4Hz，1H)，5.33(s，2H)，5.26(s，2H)，4.05(dt，J＝12.9，6.5Hz，3H)，3.79(d，J＝13.7Hz，2H)，3.73-3.68(m，3H)，3.62(d，J＝13.7Hz，1H)，3.55(s，1H)，3.51(s，1H)，3.44(d，J＝8.1Hz，1H)，3.17(s，1H)，2.03(s，3H)，1.99-1.93(m，3H)，1.89(d，J＝7.1Hz，1H)，1.87-1.75(m，9H)，1.73(s，1H)，1.48(s，3H)，1.36(s，1H)，1.23(s，1H).1 H NMR (400MHz, d6 -DMSO) δ9.00 (d, J=2.8Hz, 2H), 8.45 (s, 1H), 7.49 (d, J=7.4Hz, 1H), 7.42 (s, 1H) , 7.26 (t, J=7.6Hz, 1H), 7.20 (t, J=7.9Hz, 1H), 7.11 (s, 1H), 7.06 (d, J=7.4Hz, 1H), 6.95 (d, J= 8.2Hz, 1H), 6.68 (d, J=7.4Hz, 1H), 5.33 (s, 2H), 5.26 (s, 2H), 4.05 (dt, J=12.9, 6.5Hz, 3 H), 3.79 (d, J = 13.7Hz, 2H), 3.73-3.68 (m, 3H), 3.62 (d, J = 13.7Hz, 1H), 3.55 (s, 1H), 3.51 (s, 1H), 3.44 (d, J=8.1Hz, 1H), 3.17 (s, 1H), 2.03 (s, 3H), 1.99-1.93 (m, 3H), 1.89 (d, J=7.1Hz, 1H), 1.87-1.75 (m, 9H), 1.73 (s, 1H), 1.48 (s, 3H), 1.36 (s, 1H), 1.23 (s, 1H).
实施例22 (S)-1-(4-((3′-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物22)Example 22 (S)-1-(4-((3′-(3-(2-oxa-6-azaspiro[3.4]octan-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 22)
步骤1)4-((3′-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(2-oxa-6-azaspiro[3.4]octan-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(600mg，1.19mmol)和2-氧杂-6-氮杂螺[3.4]辛烷(263.8mg，0.83mmol)的DMF(20mL)溶液中，依次加入碳酸钾(411.5mg，2.97mmol)和NaI(267.8mg，1.78mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到红色油状液体260mg，产率40.72％。Under nitrogen protection, potassium carbonate (411.5 mg, 2.97 mmol) and NaI (267.8 mg, 1.78 mmol) were added successively to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (600 mg, 1.19 mmol) and 2-oxa-6-azaspiro[3.4]octane (263.8 mg, 0.83 mmol) in DMF (20 mL), and the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, then dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 260 mg of a red oily liquid with a yield of 40.72%.
LC-MS：(pos.ion)m/z：536.2[M+1]+；LC-MS: (pos.ion)m/z: 536.2[M+1]+ ;
步骤2)5-((5-((3′-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(2-oxa-6-azaspiro[3.4]octan-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3′-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(260mg，0.48mmol)和5-氯甲基-3-氰基吡啶盐酸盐(110mg，0.58mmol)的DMF溶液(20mL)中，依次加入碳酸铯(395mg，1.21mmol)和碘化钠(14.54mg，0.10mmol)，N2保护，升温至75℃反应4h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到红色油状液体240mg，产率75.88％。To a DMF solution (20 mL) of 4-((3′-(3-(2-oxa-6-azaspiro[3.4]octan-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (260 mg, 0.48 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (110 mg, 0.58 mmol) was added cesium carbonate (395 mg, 1.21 mmol) and sodium iodide (14.54 mg, 0.10 mmol) in sequence, underN2 protection, and the temperature was raised to 75°C for reaction for 4 h. Stop stirring, cool to room temperature, then dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 240 mg of a red oily liquid with a yield of 75.88%.
LC-MS：(pos.ion)m/z：652.5[M+1]+；LC-MS: (pos.ion)m/z: 652.5[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(2-oxa-6-azaspiro[3.4]octan-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(2-氧杂-6-氮杂螺[3.4]辛-6-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(240mg，0.37mmol)和D-哌啶酸(95.06mg，0.74mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反应1h，再冷却至室温，向反应体系中加入硼氰化钠(115.6mg，1.84mmol)，室温搅拌3h后，再升温至80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1，v/v)，得到白色固体31mg，产率11.01％。Acetic acid was added to a DMF (10 mL) solution of 5-((5-((3′-(3-(2-oxa-6-azaspiro[3.4]octan-6-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (240 mg, 0.37 mmol) and D-piperidinic acid (95.06 mg, 0.74 mmol), and the pH was adjusted to about 5. The mixture was then heated to 60° C. for 1 h, cooled to room temperature, and sodium borocyanide (115.6 mg, 1.84 mmol) was added to the reaction system. After stirring at room temperature for 3 h, the mixture was heated to 80° C. for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=4/1, v/v) to obtain 31 mg of a white solid. The yield is 11.01%.
LC-MS：(pos.ion)m/z：765.5[M+1]+；LC-MS: (pos.ion)m/z: 765.5[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(s，2H)，8.48(s，1H)，7.49(d，J＝7.6Hz，1H)，7.44(s，1H)，7.30-7.14(m，3H)，7.06(d，J＝7.3Hz，1H)，6.95(d，J＝8.1Hz，1H)，6.67(d，J＝7.4Hz，1H)，5.36(s，2H)，5.28(s，2H)，4.49(dd，J＝19.7，5.6Hz，4H)，4.04(dd，J＝14.1，6.8Hz，3H)，3.83(d，J＝13.7Hz，2H)，3.67(d，J＝13.6Hz，4H)，2.72(s，2H)，2.13(s，2H)，2.00(d，J＝17.2Hz，6H)，1.81(s，4H)，1.72(s，1H)，1.50(s，3H)，1.36(s，1H)，1.22(s，1H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (s, 2H), 8.48 (s, 1H), 7.49 (d, J=7.6Hz, 1H), 7.44 (s, 1H), 7.30-7.14 ( m, 3H), 7.06 (d, J=7.3Hz, 1H), 6.95 (d, J=8.1Hz, 1H), 6.67 (d, J=7.4Hz, 1H), 5.36 (s, 2H), 5.28 ( s, 2H), 4.49 (dd, J=19.7, 5 .6Hz, 4H), 4.04 (dd, J=14.1, 6.8Hz, 3H), 3.83 (d, J=13.7Hz, 2H), 3.67 (d, J=13.6Hz, 4H), 2.72 (s, 2H) , 2.13(s, 2H), 2.00(d, J=17.2Hz, 6H), 1.81(s, 4H), 1.72(s, 1H), 1.50(s, 3H), 1.36(s, 1H), 1.22( s, 1H).
实施例23 (S)-1-(4-((3′-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物23)Example 23 (S)-1-(4-((3′-(3-(7-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 23)
步骤1)4-((3′-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(7-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1000mg，1.98mmol)和7-氧-2-氮杂螺环[3.5]壬烷半草酸盐(478.5mg，1.39mmol)的DMF(20mL)溶液中，依次加入碳酸钾(685.8mg，4.96mmol)和NaI(446.3mg，2.98mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到棕红色油状液体553mg，产率50.65％。Under nitrogen protection, potassium carbonate (685.8 mg, 4.96 mmol) and NaI (446.3 mg, 2.98 mmol) were added successively to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (1000 mg, 1.98 mmol) and 7-oxo-2-azaspiro[3.5]nonane hemioxalate (478.5 mg, 1.39 mmol) in DMF (20 mL), and the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, then dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 553 mg of a brown-red oily liquid with a yield of 50.65%.
LC-MS：(pos.ion)m/z：550.4[M+1]+；LC-MS: (pos.ion)m/z: 550.4[M+1]+ ;
步骤2)5-((5-((3′-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(7-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3′-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(550mg，0.10mmol)和5-氯甲基-3-氰基吡啶盐酸盐(226.8mg，1.2mmol)的DMF溶液(20mL)中，依次加入碳酸铯(814.4mg，2.5mmol)和碘化钠(29.97mg，0.20mmol)，N2保护，升温至75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到红色油状液体220mg，产率33.03％。To a DMF solution (20 mL) of 4-((3′-(3-(7-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (550 mg, 0.10 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (226.8 mg, 1.2 mmol) were added cesium carbonate (814.4 mg, 2.5 mmol) and sodium iodide (29.97 mg, 0.20 mmol) in sequence, underN2 protection, and the temperature was raised to 75°C for reaction for 4 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 220 mg of a red oily liquid with a yield of 33.03%.
LC-MS：(pos.ion)m/z：666.2[M+1]+；LC-MS: (pos.ion)m/z: 666.2[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(7-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(220mg，0.33mmol)和D-哌啶酸(85.31mg，0.66mmol)的DMF(20mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反1h，再冷却至室温，向反应体系中加入硼氰化钠(103.8mg，1.652mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1，v/v)，得到淡黄色固体20mg，产率7.77％。To a DMF (20 mL) solution of 5-((5-((3′-(3-(7-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (220 mg, 0.33 mmol) and D-piperidinic acid (85.31 mg, 0.66 mmol) was added acetic acid, the pH was adjusted to about 5, then the temperature was raised to 60°C for 1 h, and then cooled to room temperature, sodium borocyanide (103.8 mg, 1.652 mmol) was added to the reaction system, and the reaction was carried out at room temperature for 3 h, and then at 80°C for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=4/1, v/v) to obtain 20 mg of a light yellow solid. The yield is 7.77%.
LC-MS：(pos.ion)m/z：779.3[M+1]+；LC-MS: (pos.ion)m/z: 779.3[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(s，2H)，8.47(s，1H)，7.49(d，J＝7.2Hz，1H)，7.42(s，1H)，7.26(t，J＝7.5Hz，1H)，7.21(t，J＝7.9Hz，1H)，7.14(s，1H)，7.06(d，J＝7.5Hz，1H)，6.96(d，J＝8.2Hz，1H)，6.69(d，J＝7.5Hz，1H)，5.35(s，2H)，5.27(s，2H)，4.07(d，J＝6.0Hz，3H)，3.81(s，1H)，3.77(d，J＝5.0Hz，1H)，3.68-3.58(m，5H)，2.02(d，J＝6.3Hz，3H)，1.99-1.88(m，3H)，1.82(s，4H)，1.75(s，6H)，1.49(s，4H)，1.36(s，1H)，1.23(s，4H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (s, 2H), 8.47 (s, 1H), 7.49 (d, J=7.2Hz, 1H), 7.42 (s, 1H), 7.26 (t, J=7.5Hz, 1H), 7.21 (t, J=7.9Hz, 1H), 7.14 (s, 1H), 7.06 (d, J=7.5Hz, 1H), 6.96 (d, J=8.2Hz, 1H) , 6.69(d, J=7.5Hz, 1H), 5.35(s , 2H), 5.27 (s, 2H), 4.07 (d, J=6.0Hz, 3H), 3.81 (s, 1H), 3.77 (d, J=5.0Hz, 1H), 3.68-3.58 (m, 5H) , 2.02(d, J=6.3Hz, 3H), 1.99-1.88(m, 3H), 1.82(s, 4H), 1.75(s, 6H), 1.49(s, 4H), 1.36(s, 1H), 1.23(s,4H).
实施例24 (S)-1-(4-((3′-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物24)Example 24 (S)-1-(4-((3′-(3-(6-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 24)
步骤1)4-((3′-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(6-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1000mg，1.98mmol)和6-氧-2-氮杂螺环[3.5]壬烷半草酸盐(478.5mg，1.39mmol)的DMF(20mL)溶液中，依次加入碳酸钾(685.8mg，4.96mmol)和NaI(446.3mg，2.97mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到红色油状液体356mg，产率32.60％。Under nitrogen protection, potassium carbonate (685.8 mg, 4.96 mmol) and NaI (446.3 mg, 2.97 mmol) were added successively to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (1000 mg, 1.98 mmol) and 6-oxo-2-azaspiro[3.5]nonane hemioxalate (478.5 mg, 1.39 mmol) in DMF (20 mL), and the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 356 mg of a red oily liquid with a yield of 32.60%.
LC-MS：(pos.ion)m/z：550.4[M+1]+；LC-MS: (pos.ion)m/z: 550.4[M+1]+ ;
步骤2)5-((5-((3′-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(6-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
向4-((3′-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(350mg，0.64mmol)和5-氯甲基-3-氰基吡啶盐酸盐(144.3mg，0.76mmol)的DMF溶液(20mL)中，依次加入碳酸铯(518.3mg，1.59mmol)和碘化钠(19.07mg，0.13mmol)，N2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到红色油状液体168mg，产率39.63％。To a DMF solution (20 mL) of 4-((3′-(3-(6-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (350 mg, 0.64 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (144.3 mg, 0.76 mmol) were added cesium carbonate (518.3 mg, 1.59 mmol) and sodium iodide (19.07 mg, 0.13 mmol) in sequence, the mixture was protected withN2 and reacted at 75°C for 4 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 168 mg of a red oily liquid with a yield of 39.63%.
LC-MS：(pos.ion)m/z：666.2[M+1]+；LC-MS: (pos.ion)m/z: 666.2[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(6-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(6-氧杂-2-氮杂螺[3.5]壬-2-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(160mg，0.24mmol)和D-哌啶酸(62.04mg，0.66mmol)的DMF(20mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反应1h，再冷却至室温，向反应体系中加入硼氰化钠(62.04mg，0.98mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝7/1，v/v)，得到白色固体33mg，产率17.63％。Acetic acid was added to a DMF (20 mL) solution of 5-((5-((3′-(3-(6-oxa-2-azaspiro[3.5]non-2-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (160 mg, 0.24 mmol) and D-piperidinic acid (62.04 mg, 0.66 mmol), and the pH was adjusted to about 5. The mixture was then heated to 60° C. for 1 h, cooled to room temperature, and sodium borocyanide (62.04 mg, 0.98 mmol) was added to the reaction system. The mixture was reacted at room temperature for 3 h, and then reacted at 80° C. for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and the mixture was stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=7/1, v/v) to obtain 33 mg of a white solid. The yield is 17.63%.
LC-MS：(pos.ion)m/z：779.4[M+1]+；LC-MS: (pos.ion)m/z: 779.4[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.00(d，J＝5.9Hz，2H)，8.45(s，1H)，7.48(d，J＝7.3Hz，1H)，7.41(s，1H)，7.26(t，J＝7.5Hz，1H)，7.19(t，J＝7.9Hz，1H)，7.10(s，1H)，7.06(d，J＝7.6Hz，1H)，6.93(d，J＝8.2Hz，1H)，6.67(d，J＝7.5Hz，1H)，5.29(d，J＝24.5Hz，4H)，4.04-3.96(m，3H)，3.77(d，J＝13.8Hz，2H)，3.61(s，3H)，3.03(d，J＝6.9Hz，2H)，2.59(t，J＝6.8Hz，2H)，2.26(s，1H)，2.00(d，J＝13.8Hz，5H)，1.80(s，4H)，1.74(d，J＝6.7Hz，3H)，1.69-1.63(m，2H)，1.48(s，3H)，1.43(d，J＝5.5Hz，3H)，1.23(s，2H).1 H NMR (400MHz, d6 -DMSO) δ9.00 (d, J=5.9Hz, 2H), 8.45 (s, 1H), 7.48 (d, J=7.3Hz, 1H), 7.41 (s, 1H) , 7.26 (t, J=7.5Hz, 1H), 7.19 (t, J=7.9Hz, 1H), 7.10 (s, 1H), 7.06 (d, J=7.6Hz, 1H), 6.93 (d, J= 8.2Hz, 1H), 6.67 (d, J=7.5Hz, 1H), 5.29 (d, J=24.5Hz, 4H), 4.04- 3.96 (m, 3H), 3.77 (d, J = 13.8Hz, 2H), 3.61 (s, 3H), 3.03 (d, J = 6.9Hz, 2H), 2.59 (t, J = 6.8Hz, 2H), 2.26 (s, 1H), 2.00 (d, J = 13.8Hz, 5H), 1.80 (s, 4H), 1.74 (d, J = 6.7Hz, 3H), 1.69-1.63 (m, 2H), 1.48 (s , 3H), 1.43 (d, J=5.5Hz, 3H), 1.23 (s, 2H).
实施例25 (S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2，2′-二甲基-3′-(3-(2-氧代-1，9-二氮杂螺[5.5]十一烷-9-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物25)Example 25 (S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2′-dimethyl-3′-(3-(2-oxo-1,9-diazaspiro[5.5]undec-9-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 25)
步骤1)5-氯-4-((2，2′-二甲基-3′-(3-(2-氧代-1，9-二氮杂螺[5.5]十一碳-9-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-chloro-4-((2,2′-dimethyl-3′-(3-(2-oxo-1,9-diazaspiro[5.5]undec-9-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1000mg，1.09mmol)和5，9-二氮杂螺环[5.5]十一烷盐酸盐(609.5mg，2.978mmol)的DMF(20mL)溶液中，依次加入碳酸钾(435.2mg，5.95mmol)和NaI(446.3mg，2.98mmol)，随后加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色固体422mg，产率54.29％。Under nitrogen protection, to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (1000 mg, 1.09 mmol) and 5,9-diazaspiro[5.5]undecane hydrochloride (609.5 mg, 2.978 mmol) in DMF (20 mL) were added potassium carbonate (435.2 mg, 5.95 mmol) and NaI (446.3 mg, 2.98 mmol) in sequence, and then the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 422 mg of a yellow solid. The yield is 54.29%.
LC-MS：(pos.ion)m/z：591.4[M+1]+LC-MS: (pos.ion)m/z: 591.4[M+1]+
步骤2)5-((4-氯-5-((2，2′-二甲基-3′-(3-(2-氧代-1，9-二氮杂螺[5.5]十一碳-9-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((4-chloro-5-((2,2′-dimethyl-3′-(3-(2-oxo-1,9-diazaspiro[5.5]undeca-9-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile
向5-氯-4-((2，2′-二甲基-3′-(3-(2-氧代-1，9-二氮杂螺[5.5]十一碳-9-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-羟基苯甲醛(630mg，1.07mmol)和5-氯甲基-3-氰基吡啶盐酸盐(241.8mg，1.28mmol)的DMF溶液(20mL)中，依次加入碳酸铯(868.2mg，2.66mmol)和碘化钠(31.95mg，0.21mmol)，N2保护，升温至75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到红色固体422mg，产率55.98％。To a DMF solution (20 mL) of 5-chloro-4-((2,2′-dimethyl-3′-(3-(2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (630 mg, 1.07 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (241.8 mg, 1.28 mmol) were added cesium carbonate (868.2 mg, 2.66 mmol) and sodium iodide (31.95 mg, 0.21 mmol) in sequence, underN2 protection, and the temperature was raised to 75°C for reaction for 4 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 422 mg of a red solid with a yield of 55.98%.
LC-MS：(pos.ion)m/z：707.2[M+1]+；LC-MS: (pos.ion)m/z: 707.2[M+1]+ ;
步骤3)(S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((2，2′-二甲基-3′-(3-(2-氧代-1，9-二氮杂螺[5.5]十一烷-9-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((2,2′-dimethyl-3′-(3-(2-oxo-1,9-diazaspiro[5.5]undec-9-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((4-氯-5-((2，2′-二甲基-3′-(3-(2-氧代-1，9-二氮杂螺[5.5]十一碳-9-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-甲酰基苯氧基)甲基)烟腈(200mg，0.28mmol)和D-哌啶酸(73.04mg，0.56mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，随后升温至60℃反应1h，冷却至室温，再向反应体系中加入硼氰化钠(88.84mg，0.14mmol)，室温搅拌3h后，升温至80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1，v/v)，得到白色固体22mg，产率9.48％。Acetic acid was added to a DMF (10 mL) solution of 5-((4-chloro-5-((2,2′-dimethyl-3′-(3-(2-oxo-1,9-diazaspiro[5.5]undec-9-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile (200 mg, 0.28 mmol) and D-piperidinic acid (73.04 mg, 0.56 mmol), and the pH was adjusted to about 5. The mixture was then heated to 60° C. for reaction for 1 h, cooled to room temperature, and sodium borocyanide (88.84 mg, 0.14 mmol) was added to the reaction system. After stirring at room temperature for 3 h, the mixture was heated to 80° C. for reaction for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=4/1, v/v) to obtain 22 mg of a white solid. Yield: 9.48%.
LC-MS：(pos.ion)m/z：820.6[M+1]+；LC-MS: (pos.ion)m/z: 820.6[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.00(dd，J＝7.1，1.7Hz，2H)，8.46(s，1H)，7.49(d，J＝7.5Hz，1H)，7.41(s，1H)，7.27(t，J＝7.7Hz，1H)，7.21(t，J＝7.9Hz，1H)，7.11(s，1H)，7.07(d，J＝7.2Hz，1H)，6.95(d，J＝8.2Hz，1H)，6.68(d，J＝7.5Hz，1H)，5.33(s，2H)，5.26(s，2H)，4.05(d，J＝7.2Hz，2H)，3.77(d，J＝13.8Hz，2H)，3.61(d，J＝13.7Hz，3H)，3.51(s，5H)，3.43-3.39(m，3H)，2.09(s，2H)，2.03(s，3H)，1.82(s，4H)，1.63(s，6H)，1.48(s，3H)，1.37(s，1H)，1.23(s，3H).1 H NMR (400MHz, d6 -DMSO) δ9.00 (dd, J=7.1, 1.7Hz, 2H), 8.46 (s, 1H), 7.49 (d, J=7.5Hz, 1H), 7.41 (s, 1H), 7.27 (t, J=7.7Hz, 1H), 7.21 (t, J=7.9Hz, 1H), 7.11 (s, 1H), 7.07 (d, J=7.2Hz, 1H), 6.95 (d, J=8.2Hz, 1H), 6.68 (d, J=7.5Hz, 1H), 5.3 3 (s, 2H), 5.26 (s, 2H), 4.05 (d, J = 7.2Hz, 2H), 3.77 (d, J = 13.8Hz, 2H), 3.61 (d, J = 13.7Hz, 3H), 3.51 (s, 5H), 3.43-3.39 (m, 3H), 2.09 (s, 2H), 2.03 (s, 3H), 1.82 (s, 4H), 1.63 (s, 6H), 1.48 (s, 3H) ,1.37(s,1H),1.23(s,3H).
实施例26(2S)-1-(4-((3′-(3-(2，7-二氮杂螺[4.4]壬-2-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物26)Example 26 (2S)-1-(4-((3′-(3-(2,7-diazaspiro[4.4]non-2-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 26)
步骤1)叔丁基-7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[4.4]壬烷-2-羧酸甲酯Step 1) tert-butyl-7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid methyl ester
氮气保护下，向4-((3′-(3-溴丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(1000mg，2.04mmol)和2，7-二氮杂螺[4.4]壬烷-2-甲酸叔丁酯(693.1mg，3.06mmol)的DMF(20mL)溶液中，依次加入碳酸钾(425mg，3.07mmol)，碘化钠(460mg，3.06mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，随后加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到红色油状液体920mg，产率70.94％。Under nitrogen protection, potassium carbonate (425 mg, 3.07 mmol) and sodium iodide (460 mg, 3.06 mmol) were added successively to a solution of 4-((3′-(3-bromopropoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (1000 mg, 2.04 mmol) and tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (693.1 mg, 3.06 mmol) in DMF (20 mL), the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, then dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 920 mg of a red oily liquid with a yield of 70.94%.
LC-MS：(pos.ion)m/z：635.3[M-1]+；LC-MS: (pos.ion)m/z: 635.3[M-1]+ ;
步骤2)叔丁基-7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[4.4]壬烷-2-羧酸甲酯Step 2) tert-butyl-7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid methyl ester
向叔丁基-7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[4.4]壬烷-2-羧酸甲酯(920mg，1.44mmol)和5-氯甲基-3-氰基吡啶盐酸盐(328.6mg，1.73mmol)的DMF溶液(20mL)中，依次加入碳酸铯(1.18g，3.62mmol)和碘化钠(43.42mg，0.28mmol)，N2保护，升温至75℃反应4h。停止搅拌，冷却至室温。加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到红色油状液体840mg，产率77.19％。To a DMF solution (20 mL) of tert-butyl-7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid methyl ester (920 mg, 1.44 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (328.6 mg, 1.73 mmol), cesium carbonate (1.18 g, 3.62 mmol) and sodium iodide (43.42 mg, 0.28 mmol) were added in sequence,N2 was protected, and the temperature was raised to 75°C for reaction for 4 h. Stirring was stopped and the mixture was cooled to room temperature. Dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 840 mg of a red oily liquid with a yield of 77.19%.
LC-MS：(pos.ion)m/z：751.3[M+1]+；LC-MS: (pos.ion)m/z: 751.3[M+1]+ ;
步骤3)(2S)-1-(4-((3′-(3-(7-(叔丁氧基羰基)-2，7-二氮杂螺[4.4]壬-2-基)丙氧基)-2-甲基-[1，1′联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3′-(3-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)propoxy)-2-methyl-[1,1′biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向叔丁基-7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[4.4]壬烷-2-羧酸甲酯(840mg，1.11mmol)和D-哌啶酸(288.8mg，2.23mmol)的DMF(20mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼氰化钠(351.3mg，5.59mmol)，室温反应3h后，随后升温至80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30mm。随后加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1，v/v)，得到淡红色固体240mg，产率24.83％。To a DMF (20 mL) solution of tert-butyl-7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid methyl ester (840 mg, 1.11 mmol) and D-piperidinic acid (288.8 mg, 2.23 mmol), acetic acid was added, the pH was adjusted to about 5, the mixture was reacted at 60° C. for 1 h, cooled to room temperature, sodium borocyanide (351.3 mg, 5.59 mmol) was added to the reaction system, the mixture was reacted at room temperature for 3 h, and then the mixture was heated to 80° C. for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and the mixture was stirred at 30 mm. The mixture was then diluted with water (20 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/MeOH=4/1, v/v) to obtain 240 mg of a light red solid with a yield of 24.83%.
LC-MS：(pos.ion)m/z：864.4[M+1]+；LC-MS: (pos.ion)m/z: 864.4[M+1]+ ;
步骤4)(2S)-1-(4-((3′-(3-(2，7-二氮杂螺[4.4]壬-2-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 4) (2S)-1-(4-((3′-(3-(2,7-diazaspiro[4.4]non-2-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向(2S)-1-(4-((3′-(3-(7-(叔丁氧基羰基)-2，7-二氮杂螺[4.4]壬-2-基)丙氧基)-2-甲基-[1，1′联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(240mg，0.31mmol)的DCM(25mL)溶液中，加入三氟乙酸(1mL)，室温反应3h。停止搅拌，TLC检测。浓缩溶剂，制备分离纯化得到淡黄色固体产物45mg，产率18.85％。To a solution of (2S)-1-(4-((3′-(3-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]non-2-yl)propoxy)-2-methyl-[1,1′biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (240 mg, 0.31 mmol) in DCM (25 mL) was added trifluoroacetic acid (1 mL) and reacted at room temperature for 3 h. Stirring was stopped and the product was tested by TLC. The solvent was concentrated and the product was isolated and purified to obtain 45 mg of a light yellow solid product with a yield of 18.85%.
LC-MS：(pos.ion)m/z：764.5[M+1]+；LC-MS: (pos.ion)m/z: 764.5[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.00(s，1H)，8.97(s，1H)，8.43(s，1H)，7.46(d，J＝10.0Hz，2H)，7.34(t，J＝7.9Hz，1H)，7.25(t，J＝7.4Hz，1H)，7.20(d，J＝7.3Hz，1H)，7.08(s，1H)，6.91(d，J＝8.2Hz，1H)，6.85(d，J＝7.5Hz，1H)，6.78(s，1H)，5.30(s，2H)，5.27(s，2H)，4.03(t，J＝6.2Hz，2H)，3.72(d，J＝13.8Hz，2H)，3.50(d，J＝13.3Hz，2H)，3.07(s，2H)，2.96(s，1H)，2.23(s，3H)，2.14(s，1H)，1.99(s，1H)，1.88-1.79(m，3H)，1.73(dd，J＝13.5，7.0Hz，6H)，1.44(s，3H)，1.24(s，7H).1 H NMR (400MHz, d6 -DMSO) δ9.00 (s, 1H), 8.97 (s, 1H), 8.43 (s, 1H), 7.46 (d, J=10.0Hz, 2H), 7.34 (t, J=7.9Hz, 1H), 7.25 (t, J=7.4Hz, 1H), 7.20 (d, J=7.3Hz, 1H), 7.08 (s, 1H), 6.91 (d, J=8.2Hz, 1H) , 6.85 (d, J=7.5Hz, 1H), 6.78 (s, 1H), 5.30 (s, 2H), 5.27 (s, 2H), 4.03 (t, J = 6.2Hz, 2H), 3.72 (d, J = 13.8Hz, 2H), 3.50 (d, J = 13.3Hz, 2H), 3.07 (s, 2H), 2.96 (s, 1H), 2.23 (s, 3H), 2.14 (s, 1H), 1.99 (s, 1H), 1.88-1.79 (m, 3H), 1.73 (dd, J=13.5, 7.0Hz, 6H) ,1.44(s,3H),1.24(s,7H).
实施例27 N-(2-((5-氯-4-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺(化合物27)Example 27 N-(2-((5-chloro-4-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide (Compound 27)
步骤1)5-氯-2-羟基-4-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯甲醛Step 1) 5-chloro-2-hydroxy-4-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(800mg，1.588mmol)和2-羟基-2，7-二氮杂螺环[3.5]壬烷盐酸盐(423.2mg，2.38mmol)的DMF(20mL)溶液中，依次加入碳酸钾(658.4mg，4.76mmol)，碘化钠(357mg，2.38mmol)，随后加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色固体437mg，产率48.79％。Under nitrogen protection, to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (800 mg, 1.588 mmol) and 2-hydroxy-2,7-diazaspiro[3.5]nonane hydrochloride (423.2 mg, 2.38 mmol) in DMF (20 mL) were added potassium carbonate (658.4 mg, 4.76 mmol) and sodium iodide (357 mg, 2.38 mmol) in sequence, and then the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, dilute with water (50 mL), extract with ethyl acetate (80 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 437 mg of a yellow solid with a yield of 48.79%.
LC-MS：(pos.ion)m/z：564.2[M+1]+；LC-MS: (pos.ion)m/z: 564.2[M+1]+ ;
步骤2)5-氯-4-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-吡啶-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 5-Chloro-4-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]pyridin-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzaldehyde
向5-氯-2-羟基-4-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯甲醛(330mg，0.58mmol)和3-溴甲基吡啶溴酸盐(221.9mg，0.87mmol)的DMF溶液(20mL)中，依次加入碳酸铯(571.8mg，1.75mmol)和碘化钠(17.54mg，0.11mmol)，N2保护，升温至75℃反应4h。停止搅拌，冷却至室温，加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到红色油状液体240mg，产率62.62％。To a DMF solution (20 mL) of 5-chloro-2-hydroxy-4-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde (330 mg, 0.58 mmol) and 3-bromomethylpyridinium bromide (221.9 mg, 0.87 mmol) were added cesium carbonate (571.8 mg, 1.75 mmol) and sodium iodide (17.54 mg, 0.11 mmol) in sequence, underN2 protection, and the temperature was raised to 75°C for reaction for 4 h. Stop stirring, cool to room temperature, dilute with water (50 mL), extract with ethyl acetate (80 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 240 mg of a red oily liquid with a yield of 62.62%.
LC-MS：(pos.ion)m/z：655.1[M+1]+；LC-MS: (pos.ion)m/z: 655.1[M+1]+ ;
步骤3)N-(2-((5-氯-4-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺Step 3) N-(2-((5-chloro-4-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide
向5-氯-4-((3′-(3-(2-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-吡啶-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苯甲醛(150mg，0.22mmol)和N-(2-氨基乙基)乙酰胺(35.08mg，0.34mmol)的CH3OH(10mL)溶液中加入乙酸，调节pH至5左右，室温反应15min，再向反应体系中加入硼氰化钠(71.93mg，1.14mmol)，室温反应2h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到白色固体50mg，产率29.46％。Acetic acid was added to a CH 3 OH (10 mL) solution of 5-chloro-4-((3′-(3-(2-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′ -biphenyl]-pyridin-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzaldehyde (150 mg, 0.22 mmol) and N-(2-aminoethyl)acetamide (35.08 mg, 0.34 mmol), and the pH was adjusted to about 5. The reaction was carried out at room temperature for 15 min, and sodium borocyanide (71.93 mg, 1.14 mmol) was added to the reaction system, and the reaction was carried out at room temperature for 2 h. Stirring was stopped, and a saturated potassium carbonate solution was added, and the mixture was stirred for 30 min. Dilute with water (50 mL), extract with ethyl acetate (80 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 50 mg of a white solid. The yield is 29.46%.
LC-MS：(pos.ion)m/z：741.4[M+1]+；LC-MS: (pos.ion)m/z: 741.4[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ8.70(s，1H)，8.55(s，1H)，7.89(d，J＝7.6Hz，1H)，7.80(s，1H)，7.45(dd，J＝17.6，6.3Hz，2H)，7.37(s，1H)，7.26(t，J＝7.3Hz，1H)，7.19(t，J＝7.6Hz，1H)，7.12(s，1H)，7.06(d，J＝7.3Hz，1H)，6.94(d，J＝8.0Hz，1H)，6.67(d，J＝7.5Hz，1H)，5.24(s，4H)，4.04(dd，J＝16.7，6.9Hz，3H)，3.63(s，2H)，3.11(d，J＝5.9Hz，2H)，2.42(s，2H)，2.27(d，J＝14.2Hz，4H)，2.09-1.96(m，6H)，1.87(d，J＝15.6Hz，3H)，1.82(s，3H)，1.77(s，3H)，1.53-1.42(m，6H).1 H NMR (400MHz, d6 -DMSO) δ 8.70 (s, 1H), 8.55 (s, 1H), 7.89 (d, J = 7.6Hz, 1H), 7.80 (s, 1H), 7.45 (dd, J=17.6, 6.3Hz, 2H), 7.37 (s, 1H), 7.26 (t, J=7.3Hz, 1H), 7.19 (t, J=7.6Hz, 1H), 7.12 (s, 1H), 7.06 ( d, J＝7.3Hz, 1H), 6.94 (d, J＝8.0Hz, 1H), 6.67 (d, J=7.5Hz, 1H), 5.24 (s, 4H), 4.04 (dd, J=16.7, 6.9Hz, 3H), 3.63 (s, 2H), 3.11 (d, J=5.9Hz, 2H) , 2.42 (s, 2H), 2.27 (d, J = 14.2Hz, 4H), 2.09-1.96 (m, 6H), 1.87 (d, J = 15.6Hz, 3H), 1.82 (s, 3H), 1.77 ( s, 3H), 1.53-1.42 (m, 6H).
实施例121 N-(2-((4-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺(化合物121)Example 121 N-(2-((4-((3′-(3-(2-oxa-7-azaspiro[4.4]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide (Compound 121)
步骤1)4-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(2-oxa-7-azaspiro[4.4]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(1000mg，1.95mmol)和2-氧杂-7-氮杂螺[4.4]壬烷(378.7mg，2.97mmol)的DMF(20mL)溶液中，依次加入碳酸钾(411.5mg，2.97mmol)，碘化钠(446.3mg，2.97mmol)，随后加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(50mL)，再用乙酸乙酯萃取(100mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到棕红色固体680mg，产率62.28％。Under nitrogen protection, to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (1000 mg, 1.95 mmol) and 2-oxa-7-azaspiro[4.4]nonane (378.7 mg, 2.97 mmol) in DMF (20 mL) were added potassium carbonate (411.5 mg, 2.97 mmol) and sodium iodide (446.3 mg, 2.97 mmol) in sequence, and then heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, dilute with water (50 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 680 mg of a brown-red solid with a yield of 62.28%.
LC-MS：(pos.ion)m/z：550.1[M+1]-；LC-MS: (pos.ion)m/z: 550.1[M+1]- ;
步骤2)4-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 4-((3′-(3-(2-oxa-7-azaspiro[4.4]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde
向4-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(420mg，0.76mmol)和3-溴甲基吡啶溴酸盐(231.7mg，0.91mmol)的DMF溶液(20mL)中，依次加入碳酸铯(621.9mg，1.9mmol)和碘化钠(22.89mg，0.15mmol)，N2保护，升温至75℃反应4h。停止搅拌，冷却至室温，加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到黄色固体250mg，产率51.07％。To a DMF solution (20 mL) of 4-((3′-(3-(2-oxa-7-azaspiro[4.4]nonan-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (420 mg, 0.76 mmol) and 3-bromomethylpyridinium bromide (231.7 mg, 0.91 mmol), cesium carbonate (621.9 mg, 1.9 mmol) and sodium iodide (22.89 mg, 0.15 mmol) were added in sequence, underN2 protection, and the temperature was raised to 75°C for reaction for 4 h. Stop stirring, cool to room temperature, dilute with water (50 mL), extract with ethyl acetate (80 mL×3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 250 mg of a yellow solid with a yield of 51.07%.
LC-MS：(pos.ion)m/z：641.1[M+1]+；LC-MS: (pos.ion)m/z: 641.1[M+1]+ ;
步骤3)N-(2-((4-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺Step 3) N-(2-((4-((3′-(3-(2-oxa-7-azaspiro[4.4]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide
向4-((3′-(3-(2-氧杂-7-氮杂螺[4.4]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-(吡啶-3-基甲氧基)苯甲醛(150mg，0.22mmol)和N-(2-氨基乙基)乙酰胺(35.08mg，0.34mmol)的CH3OH(10mL)溶液中加入乙酸，调节pH至5，室温反应15min，再向反应体系中加入硼氰化钠(71.93mg，1.14mmol)，室温反应2h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。随后加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到白色固体50mg，产率29.46％。Acetic acid was added to a solution of 4-((3′-(3-(2-oxa-7-azaspiro[4.4]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-(pyridin-3-ylmethoxy)benzaldehyde (150 mg, 0.22 mmol) and N-(2-aminoethyl)acetamide (35.08 mg, 0.34 mmol) in CH3 OH (10 mL), the pH was adjusted to 5, the reaction was carried out at room temperature for 15 min, sodium borocyanide (71.93 mg, 1.14 mmol) was added to the reaction system, and the reaction was carried out at room temperature for 2 h. Stirring was stopped, saturated potassium carbonate solution was added, and the mixture was stirred for 30 min. Subsequently, the mixture was diluted with water (50 mL), extracted with ethyl acetate (80 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/MeOH=10/1, v/v) to obtain 50 mg of a white solid with a yield of 29.46%.
LC-MS：(pos.ion)m/z：727.2[M+1]+；LC-MS: (pos.ion)m/z: 727.2[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ8.70(s，1H)，8.55(s，1H)，7.89(d，J＝7.1Hz，1H)，7.80(s，1H)，7.51-7.41(m，2H)，7.37(s，1H)，7.26(t，J＝7.3Hz，1H)，7.19(t，J＝7.6Hz，1H)，7.12(s，1H)，7.06(d，J＝7.1Hz，1H)，6.95(d，J＝7.9Hz，1H)，6.67(d，J＝7.3Hz，1H)，5.24(s，4H)，4.04(d，J＝5.5Hz，2H)，3.69(s，2H)，3.63(s，2H)，3.55-3.49(m，2H)，3.41(d，J＝7.8Hz，2H)，3.11(d，J＝5.7Hz，2H)，2.56(s，2H)，2.37(d，J＝8.4Hz，1H)，2.04(s，3H)，1.90(s，3H)，1.82(s，5H)，1.77(s，4H)，1.74(d，J＝7.2Hz，3H).1 H NMR (400MHz, d6 -DMSO) δ 8.70 (s, 1H), 8.55 (s, 1H), 7.89 (d, J = 7.1Hz, 1H), 7.80 (s, 1H), 7.51-7.41 ( m, 2H), 7.37 (s, 1H), 7.26 (t, J=7.3Hz, 1H), 7.19 (t, J=7.6Hz, 1H), 7.12 (s, 1H), 7.06 (d, J=7.1 Hz, 1H), 6.95 (d, J=7.9Hz, 1H), 6.67 (d, J=7.3Hz, 1H), 5.2 4 (s, 4H), 4.04 (d, J = 5.5Hz, 2H), 3.69 (s, 2H), 3.63 (s, 2H), 3.55-3.49 (m, 2H), 3.41 (d, J = 7.8Hz , 2H), 3.11 (d, J=5.7Hz, 2H), 2.56 (s, 2H), 2.37 (d, J=8.4Hz, 1H), 2.04 (s, 3H), 1.90 (s, 3H), 1.82 (s, 5H), 1.77 (s, 4H), 1.74 (d, J=7.2Hz, 3H).
实施例29 N-(2-((5-氯-4-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺(化合物29)Example 29 N-(2-((5-chloro-4-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide (Compound 29)
步骤1)5-氯-4-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯基]-3-基)甲氧基)-2-羟基苯甲醛Step 1) 5-chloro-4-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde
氮气保护下，向4-[[3-[3-(3-溴丙氧基)-2-甲基-苯基]-2-甲基-苯基]甲氧基]-5-氯-2-羟基-苯甲醛(800mg，1.58mmol)和六氢-1H-呋喃并[3，4-C]吡咯盐酸盐(356.4mg，2.38mmol)的DMF(20mL)溶液中，依次加入碳酸钾(658.4mg，4.76mmol)，碘化钠(357mg，2.38mmol)，随后加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(50mL)，乙酸乙酯萃取(100mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色油状液体400mg，产率62.28％。Under nitrogen protection, to a solution of 4-[[3-[3-(3-bromopropoxy)-2-methyl-phenyl]-2-methyl-phenyl]methoxy]-5-chloro-2-hydroxy-benzaldehyde (800 mg, 1.58 mmol) and hexahydro-1H-furo[3,4-C]pyrrole hydrochloride (356.4 mg, 2.38 mmol) in DMF (20 mL) were added potassium carbonate (658.4 mg, 4.76 mmol) and sodium iodide (357 mg, 2.38 mmol) in sequence, and then the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, dilute with water (50 mL), extract with ethyl acetate (100 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 400 mg of a yellow oily liquid with a yield of 62.28%.
LC-MS：(pos.ion)m/z：536.3[M+1]-；LC-MS: (pos.ion)m/z: 536.3[M+1]- ;
步骤2)5-氯-4-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯基]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苯甲醛Step 2) 5-chloro-4-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzaldehyde
向5-氯-4-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯基]-3-基)甲氧基)-2-羟基苯甲醛(400mg，0.74mmol)和3-溴甲基吡啶溴酸盐(226.5mg，0.89mmol)的DMF溶液(20mL)中，依次加入碳酸铯(607.8mg，1.86mmol)和碘化钠(22.37mg，0.14mmol)，N2保护，升温至75℃反应4h。停止搅拌，冷却至室温，随后加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到红色油状液体300mg，产率51.07％。To a DMF solution (20 mL) of 5-chloro-4-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-hydroxybenzaldehyde (400 mg, 0.74 mmol) and 3-bromomethylpyridinium bromide (226.5 mg, 0.89 mmol) were added cesium carbonate (607.8 mg, 1.86 mmol) and sodium iodide (22.37 mg, 0.14 mmol) in sequence, underN2 protection, and the temperature was raised to 75°C for reaction for 4 h. Stop stirring, cool to room temperature, then dilute with water (50 mL), extract with ethyl acetate (80 mL×3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 300 mg of a red oily liquid with a yield of 51.07%.
LC-MS：(pos.ion)m/z：627.1[M+1]+；LC-MS: (pos.ion)m/z: 627.1[M+1]+ ;
步骤3)N-(2-((5-氯-4-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苄基)氨基)乙基)乙酰胺Step 3) N-(2-((5-chloro-4-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzyl)amino)ethyl)acetamide
向5-氯-4-((2，2′-二甲基-3′-(3-(四氢-1H-呋喃并[3，4-c]吡咯-5(3H)-基)丙氧基)-[1，1′-联苯基]-3-基)甲氧基)-2-(吡啶-3-基甲氧基)苯甲醛(300mg，0.4783mmol)和N-(2-氨基乙基)乙酰胺(73.28mg，0.71mmol)的CH3OH(10mL)溶液中加入乙酸，调节pH至5左右，室温反应15min，再向反应体系中加入硼氰化钠(150.3mg，2.39mmol)，室温继续反应2h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(50mL)，乙酸乙酯萃取(80mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝15/1，v/v)，得到淡黄色色固体110mg，产率32.24％。Acetic acid was added to a solution of 5-chloro-4-((2,2′-dimethyl-3′-(3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)propoxy)-[1,1′-biphenyl]-3-yl)methoxy)-2-(pyridin-3-ylmethoxy)benzaldehyde (300 mg, 0.4783 mmol) and N-(2-aminoethyl)acetamide (73.28 mg, 0.71 mmol) in CH3 OH (10 mL), the pH was adjusted to about 5, the reaction was carried out at room temperature for 15 min, sodium borocyanide (150.3 mg, 2.39 mmol) was added to the reaction system, and the reaction was continued at room temperature for 2 h. Stirring was stopped, saturated potassium carbonate solution was added, and stirring was continued for 30 min. The mixture was diluted with water (50 mL), extracted with ethyl acetate (80 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/MeOH=15/1, v/v) to obtain 110 mg of a light yellow solid with a yield of 32.24%.
LC-MS：(pos.ion)m/z：713.3[M+1]+；LC-MS: (pos.ion)m/z: 713.3[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ8.71(s，1H)，8.56(s，1H)，7.94-7.83(m，2H)，7.52-7.36(m，3H)，7.25(d，J＝6.9Hz，1H)，7.18(d，J＝7.3Hz，1H)，7.14(s，1H)，7.06(d，J＝6.8Hz，1H)，6.94(d，J＝7.8Hz，1H)，6.67(d，J＝7.0Hz，1H)，5.26(s，4H)，4.04(d，J＝5.1Hz，2H)，3.71(s，6H)，3.50(s，1H)，3.37(d，J＝5.8Hz，2H)，3.14(d，J＝5.0Hz，2H)，2.68(s，2H)，2.59(s，2H)，2.34(d，J＝7.5Hz，2H)，2.03(s，3H)，1.89(s，3H)，1.82(s，3H)，1.78(s，3H).1 H NMR (400MHz, d6 -DMSO) δ8.71 (s, 1H), 8.56 (s, 1H), 7.94-7.83 (m, 2H), 7.52-7.36 (m, 3H), 7.25 (d, J =6.9Hz, 1H), 7.18 (d, J = 7.3Hz, 1H), 7.14 (s, 1H), 7.06 (d, J = 6.8Hz, 1H), 6.94 (d, J = 7.8Hz, 1H), 6.67 (d, J=7.0Hz, 1H), 5.26 (s, 4H), 4.04 (d, J = 5.1Hz, 2H), 3.71 (s, 6H), 3.50 (s, 1H), 3.37 (d, J = 5.8Hz, 2H), 3.14 (d, J = 5.0Hz, 2H), 2.68 (s, 2H), 2.59 (s, 2H), 2.34 (d, J=7.5Hz, 2H), 2.03 (s, 3H), 1.89 (s, 3H), 1.82 (s, 3H), 1.78(s, 3H).
实施例30(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物30)Example 30 (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(1-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 30)
步骤1)5-氯-2-羟基-4-((3′-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯甲醛Step 1) 5-chloro-2-hydroxy-4-((3′-(3-(1-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde
将7-氮杂螺[3.5]壬-1-醇盐酸盐(0.4g，2mmol)溶于DMF(10.1mL)，加入碳酸钾(1.0g，7.2mmol)，室温搅拌10min。加入4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(0.5g，1mmol)，NaI(0.2g，1mmol)，升温至75℃条件下搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1，v/v)得黄色固体0.42g，产率为80％。7-Azaspiro[3.5]nonan-1-ol hydrochloride (0.4 g, 2 mmol) was dissolved in DMF (10.1 mL), potassium carbonate (1.0 g, 7.2 mmol) was added, and the mixture was stirred at room temperature for 10 min. 4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (0.5 g, 1 mmol) and NaI (0.2 g, 1 mmol) were added, and the mixture was heated to 75°C and stirred for 12 h. Stirring was stopped, the mixture was cooled to room temperature, diluted with water (30 mL), extracted with EA (20 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, washed, concentrated under reduced pressure, and separated by column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.42 g of a yellow solid with a yield of 80%.
LC-MS：(pos.ion)m/z：565.2[M+1]+；LC-MS: (pos.ion)m/z: 565.2[M+1]+ ;
步骤2)5-((4-氯-2-甲酰基-5-((3′-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈Step 2) 5-((4-chloro-2-formyl-5-((3′-(3-(1-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile
将5-(氯甲基)烟腈盐酸盐(0.17g，0.90mmol)溶于DMF(15.0mL)，加入碳酸铯(1.5g，4.6mmol)，室温搅拌10min。加入5-氯-2-羟基-4-((3′-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯甲醛(0.42g，0.74mmol)和NaI(22.0mg，0.147mmol)，升温至75℃条件下搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝5/1，v/v)得黄色固体0.37g，产率为73％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.17 g, 0.90 mmol) was dissolved in DMF (15.0 mL), cesium carbonate (1.5 g, 4.6 mmol) was added, and the mixture was stirred at room temperature for 10 min. 5-Chloro-2-hydroxy-4-((3′-(3-(1-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzaldehyde (0.42 g, 0.74 mmol) and NaI (22.0 mg, 0.147 mmol) were added, and the mixture was heated to 75° C. and stirred for 4 h. Stop stirring, cool to room temperature, add water (15 mL) to dilute, extract with EA (15 mL×5), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=5/1, v/v) to obtain 0.37 g of a yellow solid with a yield of 73%.
LC-MS：(pos.ion)m/z：681.1[M+1]+；LC-MS: (pos.ion)m/z: 681.1[M+1]+ ;
步骤3)(2S)-1-(5-氯-2-((5-氰基吡啶-3-基)甲氧基)-4-((3′-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(5-chloro-2-((5-cyanopyridin-3-yl)methoxy)-4-((3′-(3-(1-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将5-((4-氯-2-甲酰基-5-((3′-(3-(1-羟基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)苯氧基)甲基)烟腈(0.37g，0.54mmol)和D-哌啶酸(0.14g，1.1mmol)溶于DMF(15.1mL)，加入乙酸(0.2mL，3mmol)，随后加热至60℃搅拌1.5h，冷却至室温，缓慢加入氰基硼氢化钠(0.17g，2.7mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝3/1，v/v)分离得淡黄色固体22.5mg，产率为5％。5-((4-chloro-2-formyl-5-((3′-(3-(1-hydroxy-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile (0.37 g, 0.54 mmol) and D-piperidinic acid (0.14 g, 1.1 mmol) were dissolved in DMF (15.1 mL), acetic acid (0.2 mL, 3 mmol) was added, and then heated to 60°C and stirred for 1.5 h. The mixture was cooled to room temperature, and sodium cyanoborohydride (0.17 g, 2.7 mmol) was slowly added. The mixture was protected by nitrogen and stirred at room temperature for 12 h. Stop stirring, cool to room temperature, add saturated sodium bicarbonate solution (25 mL), stir at room temperature for 30 min, extract with EA (25 mL×3), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, separate by column chromatography (DCM/MeOH=3/1, v/v) to obtain 22.5 mg of light yellow solid, with a yield of 5%.
LC-MS：(pos.ion)m/z：794.2[M+1]+；LC-MS: (pos.ion)m/z: 794.2[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.01(d，J＝6.9Hz，2H)，8.46(s，1H)，7.49(d，J＝7.4Hz，1H)，7.43(s，1H)，7.29-7.21(m，2H)，7.12(d，J＝3.5Hz，1H)，7.07(d，J＝7.4Hz，1H)，6.98(d，J＝8.2Hz，1H)，6.71(d，J＝7.7Hz，1H)，5.34(s，2H)，5.27(s，2H)，4.14-4.04(m，2H)，3.81(d，J＝14.2Hz，2H)，3.65(d，J＝13.3Hz，2H)，3.51(s，1H)，3.19-3.13(m，4H)，2.95-2.87(m，2H)，2.38-2.27(m，2H)，2.22-2.16(m，3H)，2.12-2.07(m，1H)，2.03(s，3H)，1.84-1.71(m，9H)，1.55-1.43(m，4H)，1.43-1.33(m，2H).1 H NMR (400MHz, d6 -DMSO) δ9.01 (d, J=6.9Hz, 2H), 8.46 (s, 1H), 7.49 (d, J=7.4Hz, 1H), 7.43 (s, 1H) , 7.29-7.21 (m, 2H), 7.12 (d, J=3.5Hz, 1H), 7.07 (d, J=7.4Hz, 1H), 6.98 (d, J=8.2Hz, 1H), 6.71 (d, J＝7.7Hz, 1H), 5.34(s, 2H), 5.27(s, 2H), 4.14-4.04(m, 2H), 3.81 (d, J=14.2Hz, 2H), 3.65 (d, J=13.3Hz, 2H), 3.51 (s, 1H), 3.19-3.13 (m, 4H), 2.95-2.87 (m, 2H ), 2.38-2.27(m, 2H), 2.22-2.16(m, 3H), 2.12-2.07(m, 1H), 2.03(s, 3H), 1.84-1.71(m, 9H), 1.55-1.43(m , 4H), 1.43-1.33(m, 2H).
实施例31(S)-1-(4-((3′-(3-(2-氨基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物31)Example 31 (S)-1-(4-((3′-(3-(2-amino-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate (Compound 31)
步骤1)(7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-7-氮杂螺[3.5]壬-2-基)胺基甲酸叔丁酯Step 1) tert-Butyl (7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-azaspiro[3.5]nonan-2-yl)carbamate
将4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯代-2-羟基苯甲醛(0.5g，1mmol)，7-氮杂螺[3.5]壬-2-基胺基甲酸叔丁酯(0.3g，1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g，6mmol)，加入NaI(0.2g，1mmol)，升温至75℃反应12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1，v/v)得红色油0.6g，产率为90％。4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (0.5 g, 1 mmol), tert-butyl 7-azaspiro[3.5]non-2-ylcarbamate (0.3 g, 1 mmol) were dissolved in DMF (10.1 mL), potassium carbonate (0.8 g, 6 mmol) and NaI (0.2 g, 1 mmol) were added, and the temperature was raised to 75°C for reaction for 12 h. Stirring was stopped, the mixture was cooled to room temperature, diluted with water (30 mL), extracted with EA (20 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, washed, concentrated under reduced pressure, and separated by column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.6 g of red oil with a yield of 90%.
LC-MS：(pos.ion)m/z：664.2[M+1]+；LC-MS: (pos.ion)m/z: 664.2[M+1]+ ;
步骤2)(7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-7-氮杂螺[3.5]壬-2-基)胺基甲酸叔丁酯Step 2) tert-butyl (7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-azaspiro[3.5]nonan-2-yl)carbamate
将5-(氯甲基)烟腈盐酸盐(0.2g，1mmol)溶于DMF(20.1mL)，加入碳酸铯(2.0g，6.1mmol)，室温搅拌10min。加入(7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3基)氧基)丙基)-7-氮杂-螺[3.5]壬-2-基)胺基甲酸叔丁酯(0.6g，0.9mmol)和NaI(30.0mg，0.200mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1，v/v)得红色固体0.6g，产率为90％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.2 g, 1 mmol) was dissolved in DMF (20.1 mL), cesium carbonate (2.0 g, 6.1 mmol) was added, and the mixture was stirred at room temperature for 10 min. Tert-butyl (7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]non-2-yl)carbamate (0.6 g, 0.9 mmol) and NaI (30.0 mg, 0.200 mmol) were added, and the mixture was heated to 75° C. and stirred for 4 h. Stop stirring, cool to room temperature, add water (15 mL) to dilute, extract with EA (15 mL×5), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.6 g of a red solid with a yield of 90%.
LC-MS：(pos.ion)m/z：780.1[M+1]+；LC-MS: (pos.ion)m/z: 780.1[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(2-((叔丁氧基羰基)胺基)-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(2-((tert-butoxycarbonyl)amino)-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将(7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬-2-基)胺基甲酸叔丁酯(0.6g，0.8mmol)和D-哌啶酸(0.2g，2mmol)溶于DMF(15.0mL)，加入乙酸(0.2mL，3mmol)，加热至60℃搅拌1.0h，冷却至室温，缓慢加入氰基硼氢化钠(0.2g，3.0mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝3/1，v/v)分离得黄色固体0.13g，产率为20％。Dissolve tert-butyl (7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]non-2-yl)carbamate (0.6 g, 0.8 mmol) and D-piperidinic acid (0.2 g, 2 mmol) in DMF (15.0 mL), add acetic acid (0.2 mL, 3 mmol), heat to 60°C and stir for 1.0 h, cool to room temperature, slowly add sodium cyanoborohydride (0.2 g, 3.0 mmol), protect with nitrogen, and stir at room temperature for 12 h. Stop stirring, cool to room temperature, add saturated sodium bicarbonate solution (25 mL), stir at room temperature for 30 min, extract with EA (25 mL×3), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=3/1, v/v) to obtain 0.13 g of a yellow solid with a yield of 20%.
LC-MS：(pos.ion)m/z：446.70[0.5(M+1)]+；LC-MS: (pos.ion)m/z: 446.70[0.5(M+1)]+ ;
步骤4)(S)-1-(4-((3′-(3-(2-氨基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 4) (S)-1-(4-((3′-(3-(2-amino-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate
将(S)-1-(4-((3′-(3-(2-((叔丁氧基羰基)胺基)-7-氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.13g，0.15mmol)溶于DCM(25.1mL)，加入TFA(2.0mL)，室温搅拌4h。减压浓缩体系，送制备分离得淡黄色固体32.7mg，产率为25％。(S)-1-(4-((3′-(3-(2-((tert-butoxycarbonyl)amino)-7-azaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (0.13 g, 0.15 mmol) was dissolved in DCM (25.1 mL), TFA (2.0 mL) was added, and the mixture was stirred at room temperature for 4 h. The system was concentrated under reduced pressure and sent for preparative separation to obtain 32.7 mg of a light yellow solid with a yield of 25%.
LC-MS：(pos.ion)m/z：396.7[0.5(M+1)]+；LC-MS: (pos.ion)m/z: 396.7[0.5(M+1)]+ ;
1H NMR(600MHz，d6-DMSO)δ9.66(s，1H)，9.04(d，J＝14.6Hz，2H)，8.48(s，1H)，8.10(s，2H)，7.53(s，1H)，7.52-7.48(m，1H)，7.30-7.28(m，1H)，7.26-7.22(m，2H)，7.08(d，J＝7.5Hz，1H)，6.98(d，J＝8.3Hz，1H)，6.71(d，J＝7.5Hz，1H)，5.45-5.36(m，2H)，5.36-5.30(m，2H)，4.31-4.26(m，2H)，4.15-4.05(m，2H)，3.75-3.67(m，2H)，3.25(s，4H)，3.03-2.92(m，2H)，2.89-2.82(m，2H)，2.37-2.28(m，1H)，2.24-2.16(m，2H)，2.12-2.08(m，2H)，2.04(s，3H)，2.01-1.93(m，2H)，1.92-1.82(m，4H)，1.82-1.59(m，6H)，1.49(s，2H).1 H NMR (600MHz, d6 -DMSO) δ9.66 (s, 1H), 9.04 (d, J=14.6Hz, 2H), 8.48 (s, 1H), 8.10 (s, 2H), 7.53 (s, 1H), 7.52-7.48(m, 1H), 7.30-7.28(m, 1H), 7.26-7.22(m, 2H), 7.08(d, J=7.5Hz, 1H), 6.98(d, J=8.3Hz , 1H), 6.71 (d, J=7.5Hz, 1H), 5.45-5.36 (m, 2H), 5.36-5.30 (m, 2H), 4.31-4.26(m, 2H), 4.15-4.05(m, 2H), 3.75-3.67(m, 2H), 3.25(s, 4H), 3.03-2.92(m, 2H), 2.89-2.82(m, 2H ), 2.37-2.28(m, 1H), 2.24-2.16(m, 2H), 2.12-2.08(m, 2H), 2.04(s, 3H), 2.01-1.93(m, 2H), 1.92-1.82(m , 4H), 1.82-1.59 (m, 6H), 1.49 (s, 2H).
实施例32(S)-1-(4-((3′-(3-(2，7-二氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物32)Example 32 (S)-1-(4-((3′-(3-(2,7-diazaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate (Compound 32)
步骤1)7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯Step 1) tert-Butyl 7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
将4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]3-基)甲氧基)-5-氯代-2-羟基苯甲醛(0.5g，1mmol)，2，7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.3g，1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g，6mmol)，加入NaI(0.2g，1mmol)，升温至75℃搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝100/1，v/v)得红色固体0.533g，产率为80％。4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (0.5 g, 1 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (0.3 g, 1 mmol) were dissolved in DMF (10.1 mL), potassium carbonate (0.8 g, 6 mmol) and NaI (0.2 g, 1 mmol) were added, and the temperature was raised to 75° C. and stirred for 12 h. Stirring was stopped, the mixture was cooled to room temperature, diluted with water (30 mL), extracted with EA (20 mL×3), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, washed, concentrated under reduced pressure, and separated by column chromatography (DCM/MeOH=100/1, v/v) to obtain 0.533 g of a red solid with a yield of 80%.
LC-MS：(pos.ion)m/z：650.2[M+1]+；LC-MS: (pos.ion)m/z: 650.2[M+1]+ ;
步骤2)7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯Step 2) tert-Butyl 7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
将5-(氯甲基)烟腈盐酸盐(0.186g，0.984mmol)溶于DMF(10.1mL)，加入碳酸铯(1.61g，4.94mmol)，室温搅拌10min。加入7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.533g，0.821mmol)和NaI(24.6mg，0.164mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1，v/v)得黄色固体0.6g，产率为95％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.186 g, 0.984 mmol) was dissolved in DMF (10.1 mL), cesium carbonate (1.61 g, 4.94 mmol) was added, and the mixture was stirred at room temperature for 10 min. 7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (0.533 g, 0.821 mmol) and NaI (24.6 mg, 0.164 mmol) were added, and the mixture was heated to 75° C. and stirred for 4 h. Stop stirring, cool to room temperature, add water (15 mL) to dilute, extract with EA (15 mL×5), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.6 g of a yellow solid with a yield of 95%.
LC-MS：(pos.ion)m/z：766.3[M+1]+；LC-MS: (pos.ion)m/z: 766.3[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(2-(叔丁氧基羰基)-2，7-二氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.6g，0.8mmol)和D-哌啶酸(0.2g，2mmol)溶于DMF(15.0mL)，加入乙酸(0.2mL，3mmol)，加热至60℃搅拌1.5h，随后冷却至室温，缓慢加入氰基硼氢化钠(0.25g，4.0mmol)，氮气保护，室温搅拌12h。停止搅拌，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝3/1，v/v)分离得黄色固体0.44g，产率为60％。7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (0.6 g, 0.8 mmol) and D-piperidinic acid (0.2 g, 2 mmol) were dissolved in DMF (15.0 mL), acetic acid (0.2 mL, 3 mmol) was added, heated to 60°C and stirred for 1.5 h, then cooled to room temperature, sodium cyanoborohydride (0.25 g, 4.0 mmol) was slowly added, nitrogen protection was used, and the mixture was stirred at room temperature for 12 h. Stop stirring, add saturated sodium bicarbonate solution (25 mL) and stir at room temperature for 30 min, extract with EA (25 mL×3), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=3/1, v/v) to obtain 0.44 g of a yellow solid with a yield of 60%.
LC-MS：(pos.ion)m/z：879.3[M+1]+；LC-MS: (pos.ion)m/z: 879.3[M+1]+ ;
步骤4)(S)-1-(4-((3′-(3-(2，7-二氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 4) (S)-1-(4-((3′-(3-(2,7-diazaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate
将(S)-1-(4-((3′-(3-(2-(叔丁氧基羰基)-2，7-二氮杂螺[3.5]壬-7-基)丙氧基)-2，2′-二甲基[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.44g，0.50mmol)溶于DCM(25.1mL)，加入TFA(2.5mL)，室温搅拌4h。浓缩溶剂，送制备分离得黄色固体66.0mg，产率为15％。(S)-1-(4-((3′-(3-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-7-yl)propoxy)-2,2′-dimethyl[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (0.44 g, 0.50 mmol) was dissolved in DCM (25.1 mL), TFA (2.5 mL) was added, and the mixture was stirred at room temperature for 4 h. The solvent was concentrated and sent for preparative separation to obtain 66.0 mg of a yellow solid with a yield of 15%.
LC-MS：(pos.ion)m/z：779.2[M+1]+；LC-MS: (pos.ion)m/z: 779.2[M+1]+ ;
1H NMR(600MHz，d6-DMSO)δ10.14(s，1H)，9.19(s，2H)，9.04(s，2H)，8.49(s，1H)，7.52(d，J＝29.4Hz，2H)，7.32-7.26(m，1H)，7.26-7.17(m，2H)，7.08(d，J＝6.4Hz，1H)，6.97(d，J＝7.4Hz，1H)，6.71(d，J＝6.8Hz，1H)，5.44-5.38(m，2H)，5.37-5.28(m，2H)，4.40-4.32(m，2H)，4.31-4.23(m，2H)，3.91-3.82(m，4H)，3.79-3.72(m，2H)，3.55-3.50(m，2H)，3.29-3.19(m，2H)，3.11-2.81(m，4H)，2.80-2.67(m，1H)，2.23-2.14(m，4H)，2.04(s，3H)，1.96-1.88(m，2H)，1.85(s，3H)，1.78-1.58(m，4H).1 H NMR (600MHz, d6 -DMSO) δ 10.14 (s, 1H), 9.19 (s, 2H), 9.04 (s, 2H), 8.49 (s, 1H), 7.52 (d, J=29.4Hz, 2H), 7.32-7.26 (m, 1H), 7.26-7.17 (m, 2H), 7.08 (d, J=6.4Hz, 1H), 6.97 (d, J=7.4Hz, 1H), 6.71 (d, J =6.8Hz, 1H), 5.44-5.38(m, 2H), 5.37-5.28(m, 2H), 4. 40-4.32(m, 2H), 4.31-4.23(m, 2H), 3.91-3.82(m, 4H), 3.79-3.72(m, 2H), 3.55-3.50(m, 2H), 3.29-3.19(m , 2H), 3.11-2.81(m, 4H), 2.80-2.67(m, 1H), 2.23-2.14(m, 4H), 2.04(s, 3H), 1.96-1.88(m, 2H), 1.85(s ,3H),1.78-1.58(m,4H).
实施例33(S)-1-(4-((3′-(3-(2，8-二氮杂螺[4.5]癸-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物33)Example 33 (S)-1-(4-((3′-(3-(2,8-diazaspiro[4.5]dec-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 33)
步骤1)8-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，8-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯Step 1) 8-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester
将2，7-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯盐酸盐(0.3g，1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g，6mmol)，室温搅拌10min，加入4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛(0.5g，1mmol)，NaI(0.2g，1mmol)，升温至75℃搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，硅胶柱层析分离(DCM/MeOH＝8/1，v/v)得粉红色固体0.43g，产率为70％。Dissolve tert-butyl 2,7-diazaspiro[4.5]decane-2-carboxylate hydrochloride (0.3 g, 1 mmol) in DMF (10.1 mL), add potassium carbonate (0.8 g, 6 mmol), stir at room temperature for 10 min, add 4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy]-5-chloro-2-hydroxybenzaldehyde (0.5 g, 1 mmol), NaI (0.2 g, 1 mmol), heat to 75°C and stir for 12 h. Stop stirring, cool to room temperature, dilute with water (30 mL), extract with EA (20 mL×3), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, separate by silica gel column chromatography (DCM/MeOH=8/1, v/v) to obtain 0.43 g of pink solid with a yield of 70%.
LC-MS：(pos.ion)m/z：664.5[M+1]+；LC-MS: (pos.ion)m/z: 664.5[M+1]+ ;
步骤2)8-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，8-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯Step 2) 8-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester
将5-(氯甲基)烟腈盐酸盐(0.15g，0.79mmol)溶于DMF(10.1mL)，加入碳酸铯(1.3g，4.0mmol)，室温搅拌10min。加入8-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，8-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯(0.43g，0.65mmol)和NaI(19.0mg，0.127mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，硅胶柱层析分离(DCM/MeOH＝5/1，v/v)得棕色固体0.47g，产率为93％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.15 g, 0.79 mmol) was dissolved in DMF (10.1 mL), cesium carbonate (1.3 g, 4.0 mmol) was added, and the mixture was stirred at room temperature for 10 min. 8-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (0.43 g, 0.65 mmol) and NaI (19.0 mg, 0.127 mmol) were added, and the mixture was heated to 75° C. and stirred for 4 h. Stop stirring, cool to room temperature, add water (15 mL) to dilute, extract with EA (15 mL×5), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by silica gel column chromatography (DCM/MeOH=5/1, v/v) to obtain 0.47 g of brown solid. The yield is 93%.
LC-MS：(pos.ion)m/z：780.3[M+1]+；LC-MS: (pos.ion)m/z: 780.3[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(2-(叔丁氧基羰基)-2，8-二氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将8-(3-((3-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，8-二氮杂螺[4.5]癸烷-2-羧酸叔丁酯(0.47g，0.60mmol)和D-哌啶酸(0.16g，1.2mmol)溶于DMF(15.1mL)，加入AcOH(0.2mL，3mmol)，加热至60℃搅拌1.5h，冷却至室温，缓慢加入NaBH3CN(0.2g，3.0mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液室温搅拌30min，EA(25mL×3)萃取，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝5/1，v/v)分离得红色固体0.16g，产率为30％。tert-Butyl 8-(3-((3-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.47 g, 0.60 mmol) and D-piperidinic acid (0.16 g, 1.2 mmol) were dissolved in DMF (15.1 mL), AcOH (0.2 mL, 3 mmol) was added, the mixture was heated to 60°C and stirred for 1.5 h, cooled to room temperature, NaBH3 CN (0.2 g, 3.0 mmol) was slowly added, nitrogen protection was used, and the mixture was stirred at room temperature for 12 h. Stop stirring, cool to room temperature, add saturated sodium bicarbonate solution and stir at room temperature for 30 min, extract with EA (25 mL×3), wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=5/1, v/v) to obtain 0.16 g of red solid with a yield of 30%.
LC-MS：(pos.ion)m/z：446.8[0.5(M+1)]+；LC-MS: (pos.ion)m/z: 446.8[0.5(M+1)]+ ;
步骤4)(S)-1-(4-((3′-(3-(2，8-二氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 4) (S)-1-(4-((3′-(3-(2,8-diazaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将(S)-1-(4-((3′-(3-(2-(叔丁氧基羰基)-2，8-二氮杂螺[4.5]癸烷-8-基)丙氧基)-2，2′-二甲基[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.16g，0.18mmol)溶于DCM(25.0mL)，加入TFA(2.0mL)，室温搅拌4h。浓缩溶剂，送制备分离后浓缩有机溶剂，水溶液用饱和碳酸钠将pH调至7-8，依次用DCM(10mL×3)和EA(10mL×1)萃取，有机相用水(20mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，浓缩有机相得黄色固体22.8mg，产率为16％。(S)-1-(4-((3′-(3-(2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-8-yl)propoxy)-2,2′-dimethyl[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (0.16 g, 0.18 mmol) was dissolved in DCM (25.0 mL), TFA (2.0 mL) was added, and the mixture was stirred at room temperature for 4 h. The solvent was concentrated, and the organic solvent was concentrated after preparative separation. The pH of the aqueous solution was adjusted to 7-8 with saturated sodium carbonate, and extracted with DCM (10 mL×3) and EA (10 mL×1) in sequence. The organic phase was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, washed, and the organic phase was concentrated to obtain 22.8 mg of a yellow solid with a yield of 16%.
LC-MS：(pos.ion)m/z：397.3[0.5(M+1)]+；LC-MS: (pos.ion)m/z: 397.3[0.5(M+1)]+ ;
1H NMR(400MHz，d6-DMSO)δ8.98(d，J＝10.8Hz，2H)，8.43(s，1H)，7.53-7.41(m，2H)，7.26-7.21(m，1H)，7.19-7.15(m，1H)，7.07-7.03(m，2H)，6.98-6.87(m，1H)，6.67(d，J＝7.3Hz，1H)，5.35-5.19(m，4H)，4.81-4.74(m，1H)，4.03-3.98(m，2H)，3.51(s，1H)，3.08-3.03(m，2H)，2.86-2.79(m，4H)，2.43-2.36(m，2H)，2.34-2.29(m，2H)，2.25-2.21(m，2H)，2.11-1.92(m，5H)，1.86-1.73(m，5H)，1.70-1.65(m，2H)，1.63-1.55(m，2H)，1.55-1.34(m，8H).1 H NMR (400MHz, d6 -DMSO) δ8.98 (d, J=10.8Hz, 2H), 8.43 (s, 1H), 7.53-7.41 (m, 2H), 7.26-7.21 (m, 1H), 7.19-7.15 (m, 1H), 7.07-7.03 (m, 2H), 6.98-6.87 (m, 1H), 6.67 (d, J=7.3Hz, 1H), 5.35-5.19 (m, 4H), 4.81- 4.74(m,1H),4.03-3.98 (m, 2H), 3.51 (s, 1H), 3.08-3.03 (m, 2H), 2.86-2.79 (m, 4H), 2.43-2.36 (m, 2H), 2.34-2.29 (m, 2H), 2.25 -2.21(m, 2H), 2.11-1.92(m, 5H), 1.86-1.73(m, 5H), 1.70-1.65(m, 2H), 1.63-1.55(m, 2H), 1.55-1.34(m, 8H).
实施例34(S)-1-(4-((3′-(3-(3，9-二氮杂螺[5.5]十一烷-3-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物34)Example 34 (S)-1-(4-((3′-(3-(3,9-diazaspiro[5.5]undec-3-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate (Compound 34)
步骤1)9-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-3，9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯Step 1) tert-Butyl 9-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
将3，9-二氮杂螺[5.5]十一烷-9-甲酸叔丁酯盐酸盐(0.3g，1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g，6mmol)，室温搅拌10min。加入4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛(0.5g，1mmol)，NaI(0.2g，1mmol)，升温至75℃条件下搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝8/1，v/v)得黄色粘稠油0.63g，产率为90％。Dissolve tert-butyl 3,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (0.3 g, 1 mmol) in DMF (10.1 mL), add potassium carbonate (0.8 g, 6 mmol), and stir at room temperature for 10 min. Add 4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy]-5-chloro-2-hydroxybenzaldehyde (0.5 g, 1 mmol) and NaI (0.2 g, 1 mmol), and stir at 75°C for 12 h. Stop stirring, cool to room temperature, dilute with water (30 mL), extract with EA (20 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=8/1, v/v) to obtain 0.63 g of yellow viscous oil with a yield of 90%.
LC-MS：(pos.ion)m/z：678.0[M+1]+；LC-MS: (pos.ion)m/z: 678.0[M+1]+ ;
步骤2)9-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-3，9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯Step 2) tert-butyl 9-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
将5-(氯甲基)烟腈盐酸盐(0.21g，1.1mmol)溶于DMF(15.1mL)，加入碳酸铯(1.8g，5.5mmol)，室温搅拌10min。加入9-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-3，9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(0.63g，0.93mmol)和NaI(28.0mg，0.19mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝5/1，v/v)得红色固体0.63g，产率为85％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.21 g, 1.1 mmol) was dissolved in DMF (15.1 mL), cesium carbonate (1.8 g, 5.5 mmol) was added, and the mixture was stirred at room temperature for 10 min. 9-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (0.63 g, 0.93 mmol) and NaI (28.0 mg, 0.19 mmol) were added, and the mixture was heated to 75° C. and stirred for 4 h. Stop stirring, cool to room temperature, add water (15 mL) to dilute, extract with EA (15 mL×5), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=5/1, v/v) to obtain 0.63 g of a red solid with a yield of 85%.
LC-MS：(pos.ion)m/z：397.2[0.5(M+1)]+；LC-MS: (pos.ion)m/z: 397.2[0.5(M+1)]+ ;
步骤3)(S)-1-(4-((3′-(3-(9-(叔丁氧基羰基)-3，9-二氮杂螺[5.5]十一烷-3-基)丙氧基)-2，2′-二甲基[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(9-(tert-butoxycarbonyl)-3,9-diazaspiro[5.5]undec-3-yl)propoxy)-2,2′-dimethyl[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将9-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-3，9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯(0.63g，0.79mmol)和D-哌啶酸(0.21g，1.6mmol)溶于DMF(15.1mL)，加入乙酸(0.2mL，3mmol)，加热至60℃搅拌1.0h，冷却至室温，缓慢加入氰基硼氢化钠(0.25g，4.0mmol)，氮气保护，室温搅拌12h。升温至80℃，搅拌3.0h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝5/1，v/v)分离得黄色固体0.13g，产率为18％。Dissolve tert-butyl 9-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.63 g, 0.79 mmol) and D-piperidinic acid (0.21 g, 1.6 mmol) in DMF (15.1 mL), add acetic acid (0.2 mL, 3 mmol), heat to 60° C. and stir for 1.0 h, cool to room temperature, slowly add sodium cyanoborohydride (0.25 g, 4.0 mmol), protect with nitrogen, and stir at room temperature for 12 h. Heat to 80° C. and stir for 3.0 h. Stop stirring, cool to room temperature, add saturated sodium bicarbonate solution (25 mL), stir at room temperature for 30 min, extract with EA (25 mL×3), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=5/1, v/v) to obtain 0.13 g of yellow solid with a yield of 18%.
LC-MS：(pos.ion)m/z：454.0[0.5(M+1)]+；LC-MS: (pos.ion)m/z: 454.0[0.5(M+1)]+ ;
步骤4)(S)-1-(4-((3′-(3-(3，9-二氮杂螺[5.5]十一烷-3-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 4) (S)-1-(4-((3′-(3-(3,9-diazaspiro[5.5]undec-3-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate
将(S)-1-(4-((3′-(3-(9-(叔丁氧基羰基)-3，9-二氮杂螺[5.5]十一烷-3-基)丙氧基)-2，2′-二甲基[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.13g，0.14mmol)溶于DCM(25.0mL)，加入TFA(2.0mL)，室温搅拌4h。减压浓缩体系，送制备分离得淡黄色固体32.9mg，产率为25％。(S)-1-(4-((3′-(3-(9-(tert-butoxycarbonyl)-3,9-diazaspiro[5.5]undec-3-yl)propoxy)-2,2′-dimethyl[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (0.13 g, 0.14 mmol) was dissolved in DCM (25.0 mL), TFA (2.0 mL) was added, and the mixture was stirred at room temperature for 4 h. The system was concentrated under reduced pressure and sent for preparative separation to obtain 32.9 mg of a light yellow solid with a yield of 25%.
LC-MS：(pos.ion)m/z：404.4[0.5(M+1)]+；LC-MS: (pos.ion)m/z: 404.4[0.5(M+1)]+ ;
1H NMR(600MHz，d6-DMSO)δ9.44(s，1H)，9.03(d，J＝15.5Hz，2H)，8.53(s，2H)，8.47(s，1H)，7.54-7.43(m，2H)，7.32-7.26(m，1H)，7.25-7.21(m，1H)，7.16(d，J＝4.4Hz，1H)，7.08-7.06(m，1H)，6.98(d，J＝8.4Hz，1H)，6.72(d，J＝7.5Hz，1H)，5.39-5.34(m，2H)，5.33-5.27(m，2H)，4.13-4.07(m，2H)，3.63-3.50(m，6H)，3.22-3.16(m，4H)，3.13-3.00(m，6H)，2.21-2.16(m，2H)，2.04(s，3H)，1.90-1.84(m，4H)，1.79-1.76(m，2H)，1.74-1.64(m，2H)，1.60-1.50(m，6H)，1.45-1.34(m，2H).1 H NMR (600MHz, d6 -DMSO) δ9.44 (s, 1H), 9.03 (d, J=15.5Hz, 2H), 8.53 (s, 2H), 8.47 (s, 1H), 7.54-7.43 ( m, 2H), 7.32-7.26 (m, 1H), 7.25-7.21 (m, 1H), 7.16 (d, J＝4.4Hz, 1H), 7.08-7.06 (m, 1H), 6.98 (d, J＝ 8.4Hz, 1H), 6.72(d, J=7.5Hz, 1H), 5.39-5.34(m , 2H), 5.33-5.27(m, 2H), 4.13-4.07(m, 2H), 3.63-3.50(m, 6H), 3.22-3.16(m, 4H), 3.13-3.00(m, 6H), 2.21 -2.16(m, 2H), 2.04(s, 3H), 1.90-1.84(m, 4H), 1.79-1.76(m, 2H), 1.74-1.64(m, 2H), 1.60-1.50(m, 6H) ,1.45-1.34(m,2H).
实施例35(S)-1-(4-((3′-(3-(2，9-二氮杂螺[5.5]十一烷-9-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物35)Example 35 (S)-1-(4-((3′-(3-(2,9-diazaspiro[5.5]undec-9-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate (Compound 35)
步骤1)9-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，9-二氮杂螺[5.5]十一烷-2-羧酸叔丁酯Step 1) tert-butyl 9-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate
将4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛(0.75g，1.5mmol)，2，9-二氮杂螺[5.5]十一烷-4-羧酸叔丁酯(0.45g，1.8mmol)溶于DMF(10.1mL)，加入碳酸钾(1.2g，8.7mmol)，加入NaI(0.27g，1.8mmol)，升温至75℃搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM)得红色油0.8g，产率为80％。4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy]-5-chloro-2-hydroxybenzaldehyde (0.75 g, 1.5 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-4-carboxylate (0.45 g, 1.8 mmol) were dissolved in DMF (10.1 mL), potassium carbonate (1.2 g, 8.7 mmol) and NaI (0.27 g, 1.8 mmol) were added, and the temperature was raised to 75° C. and stirred for 12 h. Stirring was stopped, the mixture was cooled to room temperature, diluted with water (30 mL), extracted with EA (20 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, washed, concentrated under reduced pressure, and separated by column chromatography (DCM) to obtain 0.8 g of red oil with a yield of 80%.
LC-MS：(pos.ion)m/z：678.2[M+1]+；LC-MS: (pos.ion)m/z: 678.2[M+1]+ ;
步骤2)9-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，9-二氮杂螺[5.5]十一烷-2-羧酸叔丁酯Step 2) tert-butyl 9-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate
将5-(氯甲基)烟腈盐酸盐(0.3g，2mmol)溶于DMF(20.1mL)，加入碳酸铯(2.0g，6.1mmol)，室温搅拌10min。加入9-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，9-二氮杂螺[5.5]十一烷-2-羧酸叔丁酯(0.8g，1mmol)和NaI(40.0mg，0.267mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1，v/v)得淡红色固体0.6g，产率为60％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.3 g, 2 mmol) was dissolved in DMF (20.1 mL), cesium carbonate (2.0 g, 6.1 mmol) was added, and the mixture was stirred at room temperature for 10 min. 9-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,9-diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester (0.8 g, 1 mmol) and NaI (40.0 mg, 0.267 mmol) were added, and the mixture was heated to 75° C. and stirred for 4 h. Stop stirring, cool to room temperature, add water (15 mL) to dilute, extract with EA (15 mL×5), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.6 g of light red solid with a yield of 60%.
LC-MS：(pos.ion)m/z：794.2[M+1]+；LC-MS: (pos.ion)m/z: 794.2[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(2-(叔丁氧基羰基)-2，9-二氮杂螺[5.5]十一烷-9-基)丙氧基)-2，2′-二甲基[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(2-(tert-butoxycarbonyl)-2,9-diazaspiro[5.5]undec-9-yl)propoxy)-2,2′-dimethyl[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将9-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2，2′-二甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，9-二氮杂螺[5.5]十一烷-2-羧酸叔丁酯(0.6g，0.8mmol)和D-哌啶酸(0.2g，2mmol)溶于DMF(15.0mL)，加入乙酸(0.2mL，3mmol)，加热至60℃搅拌1.5h，冷却至室温，缓慢加入氰基硼氢化钠(0.2g，3mmol)，氮气保护，室温搅拌12h，升温至80℃搅拌5h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝4/1，v/v)分离黄色固体0.38g，产率为60％。9-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,9-diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester (0.6 g, 0.8 mmol) and D-piperidinic acid (0.2 g, 2 mmol) were dissolved in DMF (15.0 mL), acetic acid (0.2 mL, 3 mmol) was added, heated to 60°C and stirred for 1.5 h, cooled to room temperature, sodium cyanoborohydride (0.2 g, 3 mmol) was slowly added, nitrogen protection was used, the mixture was stirred at room temperature for 12 h, and the temperature was raised to 80°C and stirred for 5 h. Stop stirring, cool to room temperature, add saturated sodium bicarbonate solution (25 mL), stir at room temperature for 30 min, extract with EA (25 mL×3), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, separate 0.38 g of yellow solid by column chromatography (DCM/MeOH=4/1, v/v), and the yield is 60%.
LC-MS：(pos.ion)m/z：907.3[M+1]+；LC-MS: (pos.ion)m/z: 907.3[M+1]+ ;
步骤4)(S)-1-(4-((3′-(3-(2，9-二氮杂螺[5.5]十一碳-9-基)丙氧基)-2，2′-二甲基-[1，1′-联苯]甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 4) (S)-1-(4-((3′-(3-(2,9-diazaspiro[5.5]undec-9-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate
将(S)-1-(4-((3′-(3-(2-(叔丁氧基羰基)-2，9-二氮杂螺[5.5]十一烷-9-基)丙氧基)-2，2′-二甲基[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.38g，0.42mmol)溶于DCM(25.1mL)，加入TFA(2.5mL)，室温搅拌4h。减压浓缩体系，送制备分离得黄色固体47.6mg，产率为12％。(S)-1-(4-((3′-(3-(2-(tert-butoxycarbonyl)-2,9-diazaspiro[5.5]undec-9-yl)propoxy)-2,2′-dimethyl[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (0.38 g, 0.42 mmol) was dissolved in DCM (25.1 mL), TFA (2.5 mL) was added, and the mixture was stirred at room temperature for 4 h. The system was concentrated under reduced pressure and sent for preparative separation to obtain 47.6 mg of a yellow solid with a yield of 12%.
LC-MS：(pos.ion)m/z：807.3[M+1]+；LC-MS: (pos.ion)m/z: 807.3[M+1]+ ;
1H NMR(600MHz，d6-DMSO)δ9.88(s，1H)，9.03(d，J＝7.7Hz，2H)，8.94(s，1H)，8.83(s，1H)，8.48(s，1H)，7.54(s，1H)，7.52-7.46(m，1H)，7.29(t，J＝6.6Hz，1H)，7.26-7.18(m，2H)，7.08(d，J＝7.4Hz，1H)，6.98(d，J＝8.1Hz，1H)，6.71(d，J＝7.4Hz，1H)，5.44-5.37(m，2H)，5.36-5.27(m，2H)，4.37-4.33(m，1H)，4.28-4.24(m，1H)，4.12-4.07(m，2H)，4.05-3.98(m，2H)，3.45-3.38(m，4H)，3.35-3.26(m，4H)，3.25-3.17(m，2H)，3.11(d，J＝4.0Hz，2H)，3.00(s，2H)，2.90-2.83(m，1H)，2.25-2.20(m，2H)，2.16-2.08(m，1H)，2.04(s，3H)，1.86(s，3H)，1.75-1.68(m，6H)，1.64-1.57(m，2H)，1.45(s，1H).1 H NMR (600MHz, d6 -DMSO) δ9.88 (s, 1H), 9.03 (d, J=7.7Hz, 2H), 8.94 (s, 1H), 8.83 (s, 1H), 8.48 (s, 1H), 7.54 (s, 1H), 7.52-7.46 (m, 1H), 7.29 (t, J=6.6Hz, 1H), 7.26-7.18 (m, 2H), 7.08 (d, J=7.4Hz, 1H ), 6.98 (d, J = 8.1Hz, 1H), 6.71 (d, J = 7.4Hz, 1H), 5.44-5.37 (m, 2H), 5.36-5.27 (m, 2H), 4.37-4.33 (m, 1H), 4 .28-4.24(m, 1H), 4.12-4.07(m, 2H), 4.05-3.98(m, 2H), 3.45-3.38(m, 4H), 3.35-3.26(m, 4H), 3.25-3.17( m, 2H), 3.11 (d, J=4.0Hz, 2H), 3.00 (s, 2H), 2.90-2.83 (m, 1H), 2.25-2.20 (m, 2H), 2.16-2.08 (m, 1H) , 2.04(s, 3H), 1.86(s, 3H), 1.75-1.68(m, 6H), 1.64-1.57(m, 2H), 1.45(s, 1H).
实施例36(S)-1-(4-((3′-(3-(2-胺基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1，1′-联苯]-甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物36)Example 36 (S)-1-(4-((3′-(3-(2-amino-7-azaspiro[3.5]non-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate (Compound 36)
步骤1)[2-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)苯基]甲醇Step 1) [2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol
将PdCl2(dppf)(7.28g，9.95mmol)，乙酸钾(29.3g，299mmol)，联硼酸频哪醇酯(37.9g，149mmol)溶于1，4-二氧六环(200.1mL)，加入(3-溴-2-甲基-苯基)甲醇(20.1g，100mmol)，升温至90℃条件下搅拌12h。停止搅拌，冷却至室温，直接柱层析分离(Hexane/EA＝5/1，v/v)得淡绿色固体23.9g，产率为96％。PdCl2 (dppf) (7.28 g, 9.95 mmol), potassium acetate (29.3 g, 299 mmol), and biboronic acid pinacol ester (37.9 g, 149 mmol) were dissolved in 1,4-dioxane (200.1 mL), and (3-bromo-2-methyl-phenyl)methanol (20.1 g, 100 mmol) was added, and the mixture was heated to 90° C. and stirred for 12 h. Stirring was stopped, and the mixture was cooled to room temperature, and directly separated by column chromatography (Hexane/EA=5/1, v/v) to obtain 23.9 g of a light green solid with a yield of 96%.
LC-MS：(pos.ion)m/z：231.1[M-18+1]+；LC-MS: (pos.ion)m/z: 231.1[M-18+1]+ ;
步骤2)1-溴-3-(3-溴丙氧基)苯Step 2) 1-Bromo-3-(3-bromopropoxy)benzene
将3-溴苯酚(5.1g，29mmol)溶于丙酮(60.0mL)，加入碳酸钾(12.0g，86.8mmol)，然后加入1，3-二溴丙烷(7.3mL，72mmol)，氮气保护，升温至60℃回流12h。停止搅拌，冷却室温，抽滤除去碳酸钾并用DCM洗涤，减压浓缩直接柱层析(Hexane)分离得淡黄色油8.3g，产率为96％。3-Bromophenol (5.1 g, 29 mmol) was dissolved in acetone (60.0 mL), potassium carbonate (12.0 g, 86.8 mmol) was added, and then 1,3-dibromopropane (7.3 mL, 72 mmol) was added, and the mixture was heated to 60°C and refluxed for 12 h under nitrogen protection. Stirring was stopped, and the mixture was cooled to room temperature, and potassium carbonate was removed by suction filtration and washed with DCM. After concentration under reduced pressure, 8.3 g of light yellow oil was obtained by direct column chromatography (Hexane), and the yield was 96%.
步骤3)(3′-(3-溴丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲醇Step 3) (3′-(3-bromopropoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methanol
将[2-甲基-3-(4，4，5，5-四甲基-1，3，2-二氧硼杂环戊烷-2-基)苯基]甲醇(4.4g，18mmol)，1-溴-3-(3-溴丙氧基)苯(5.0g，17mmol)溶于THF(160.2mL)和H2O(40.3mL)的混合溶剂，加入磷酸钾(9.0g，42mmol)，氮气保护，室温搅拌20min，加入Pd(dppf)Cl2(0.62g，0.85mmol)，氮气保护，升温回流12h。停止搅拌，加水(60mL)稀释，EA(100mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(PE/EA＝5/1，v/v)分离得褐色油3.6g，产率为63％。[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (4.4 g, 18 mmol), 1-bromo-3-(3-bromopropoxy)benzene (5.0 g, 17 mmol) were dissolved in a mixed solvent of THF (160.2 mL) and H2 O (40.3 mL), potassium phosphate (9.0 g, 42 mmol) was added, nitrogen was protected, and the mixture was stirred at room temperature for 20 min, Pd(dppf)Cl2 (0.62 g, 0.85 mmol) was added, nitrogen was protected, and the temperature was raised to reflux for 12 h. Stirring was stopped, water (60 mL) was added for dilution, and EA (100 mL×3) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, washed, concentrated under reduced pressure, and separated by column chromatography (PE/EA=5/1, v/v) to obtain 3.6 g of brown oil with a yield of 63%.
LC-MS：(pos.ion)m/z：318.2[M-18+1]+；LC-MS: (pos.ion)m/z: 318.2[M-18+1]+ ;
步骤4)4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛Step 4) 4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy]-5-chloro-2-hydroxybenzaldehyde
0℃将(3′-(3-溴丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲醇(2.0g，6.0mmol)和5-氯-2，4-二羟基苯甲醛(1.1g，6.4mmol)溶于THF(30.1mL)，加入三苯基膦(2.3g，8.8mmol)，氮气保护，缓慢注入DIAD(1.8mL，9.1mmol)，室温条件下搅拌24h。停止搅拌，加水(30mL)稀释，EA(30mL×3)萃取，合并有机相并用无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(PE/EA＝10/1，v/v)分离得黄色固体1.9g，产率为65％。Dissolve (3′-(3-bromopropoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methanol (2.0 g, 6.0 mmol) and 5-chloro-2,4-dihydroxybenzaldehyde (1.1 g, 6.4 mmol) in THF (30.1 mL) at 0°C, add triphenylphosphine (2.3 g, 8.8 mmol), protect with nitrogen, slowly inject DIAD (1.8 mL, 9.1 mmol), and stir at room temperature for 24 h. Stop stirring, dilute with water (30 mL), extract with EA (30 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (PE/EA=10/1, v/v) to obtain 1.9 g of yellow solid, with a yield of 65%.
步骤5)(7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-7-氮杂螺[3.5]壬-2-基)氨基甲酸叔丁酯Step 5) tert-butyl (7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-azaspiro[3.5]nonan-2-yl)carbamate
将4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛(0.5g，1mmol)，7-氮杂螺[3.5]壬-2-基氨基甲酸叔丁酯(0.3g，1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g，6mmol)，加入NaI(0.2g，1mmol)，升温至75℃搅拌10h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(Hexane/EA＝1/3，v/v)得红色固体0.33g，产率为50％。4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy]-5-chloro-2-hydroxybenzaldehyde (0.5 g, 1 mmol) and tert-butyl 7-azaspiro[3.5]non-2-ylcarbamate (0.3 g, 1 mmol) were dissolved in DMF (10.1 mL), potassium carbonate (0.8 g, 6 mmol) and NaI (0.2 g, 1 mmol) were added, and the temperature was raised to 75° C. and stirred for 10 h. Stirring was stopped, the mixture was cooled to room temperature, diluted with water (30 mL), extracted with EA (20 mL×3), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, washed, concentrated under reduced pressure, and separated by column chromatography (Hexane/EA=1/3, v/v) to obtain 0.33 g of a red solid with a yield of 50%.
LC-MS：(pos.ion)m/z：650.2[M+1]+；LC-MS: (pos.ion)m/z: 650.2[M+1]+ ;
步骤6)(7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬-2-基)氨基甲酸叔丁酯Step 6) Tert-butyl (7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]nonan-2-yl)carbamate
将5-(氯甲基)烟腈盐酸盐(0.12g，0.63mmol)溶于DMF(10.1mL)，加入碳酸铯(0.99g，3.0mmol)，室温搅拌10min。加入(7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬-2-基)氨基甲酸叔丁酯(0.33g，0.51mmol)和NaI(15.0mg，0.10mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝90/1，v/v)得黄色固体0.3g，产率为80％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.12 g, 0.63 mmol) was dissolved in DMF (10.1 mL), cesium carbonate (0.99 g, 3.0 mmol) was added, and the mixture was stirred at room temperature for 10 min. Tert-butyl (7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]non-2-yl)carbamate (0.33 g, 0.51 mmol) and NaI (15.0 mg, 0.10 mmol) were added, and the mixture was heated to 75° C. and stirred for 4 h. Stop stirring, cool to room temperature, add water (15 mL) to dilute, extract with EA (15 mL×5), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=90/1, v/v) to obtain 0.3 g of a yellow solid with a yield of 80%.
LC-MS：(pos.ion)m/z：766.2[M+1]+；LC-MS: (pos.ion)m/z: 766.2[M+1]+ ;
步骤7)(S)-1-(4-((3′-(3-(2-((叔丁氧基羰基)胺基)-7-氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 7) (S)-1-(4-((3′-(3-(2-((tert-butoxycarbonyl)amino)-7-azaspiro[3.5]non-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将(7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-7-氮杂-螺[3.5]壬-2-基)氨基甲酸叔丁酯(0.3g，0.4mmol)和D-哌啶酸(0.1g，0.8mmol)溶于DMF(15.0mL)，加入乙酸(0.2mL，3mmol)，加热至60℃搅拌1.5h，冷却至室温，缓慢加入氰基硼氢化钠(0.12g，1.9mmol)，氮气保护，室温搅拌12h，停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝3/1，v/v)分离得黄色固体0.1g，产率为30％。Tert-butyl (7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-7-aza-spiro[3.5]nonan-2-yl)carbamate (0.3 g, 0.4 mmol) and D-piperidinic acid (0.1 g, 0.8 mmol) were dissolved in DMF (15.0 mL), acetic acid (0.2 mL, 3 mmol) was added, and the mixture was heated to 60° C. and stirred for 1. 5h, cooled to room temperature, slowly added sodium cyanoborohydride (0.12g, 1.9mmol), protected by nitrogen, stirred at room temperature for 12h, stopped stirring, cooled to room temperature, added saturated sodium bicarbonate solution (25mL) and stirred at room temperature for 30min, extracted with EA (25mL×3), combined organic phases and washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, washed, concentrated under reduced pressure, separated by column chromatography (DCM/MeOH=3/1, v/v) to obtain 0.1g of yellow solid with a yield of 30%.
LC-MS：(pos.ion)m/z：440.3[0.5(M+1)]+；LC-MS: (pos.ion)m/z: 440.3[0.5(M+1)]+ ;
步骤8)(S)-1-(4-((3′-(3-(2-胺基-7-氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1，1′-联苯]-甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 8) (S)-1-(4-((3′-(3-(2-amino-7-azaspiro[3.5]non-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate
将(S)-1-(4-((3′-(3-(2-((叔丁氧基羰基)胺基)-7-氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(0.1g，0.1mmol)溶于DCM(25.1mL)，加入TFA(2.0mL)，室温搅拌4h。减压浓缩体系，送制备分离得白色粘稠固体41.3mg，产率为40％。(S)-1-(4-((3′-(3-(2-((tert-butoxycarbonyl)amino)-7-azaspiro[3.5]non-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (0.1 g, 0.1 mmol) was dissolved in DCM (25.1 mL), TFA (2.0 mL) was added, and the mixture was stirred at room temperature for 4 h. The system was concentrated under reduced pressure and sent for preparative separation to obtain 41.3 mg of a white viscous solid with a yield of 40%.
LC-MS：(pos.ion)m/z：779.2[M+1]+；LC-MS: (pos.ion)m/z: 779.2[M+1]+ ;
1H NMR(600MHz，d6-DMSO)δ9.59(s，1H)，9.04(d，J＝12.3Hz，2H)，8.47(s，1H)，8.10(s，2H)，7.54(s，1H)，7.50(d，J＝6.2Hz，1H)，7.43-7.35(m，1H)，7.34-7.27(m，1H)，7.23(d，J＝7.1Hz，2H)，6.97(d，J＝6.6Hz，1H)，6.90(d，J＝6.4Hz，1H)，6.86(s，1H)，5.44-5.38(m，2H)，5.36-5.25(m，2H)，4.38-4.32(m，1H)，4.31-4.20(m，1H)，4.13-4.07(s，2H)，3.47-3.41(m，4H)，3.25-3.19(m，2H)，3.02-2.92(m，2H)，2.91-2.80(m，2H)，2.35-2.28(m，1H)，2.25(s，3H)，2.18-2.06(m，4H)，2.03-1.93(m，2H)，1.89-1.85(m，1H)，1.85-1.60(m，6H)，1.60-1.38(m，2H).1 H NMR (600MHz, d6 -DMSO) δ9.59 (s, 1H), 9.04 (d, J=12.3Hz, 2H), 8.47 (s, 1H), 8.10 (s, 2H), 7.54 (s, 1H), 7.50 (d, J=6.2Hz, 1H), 7.43-7.35 (m, 1H), 7.34-7.27 (m, 1H), 7.23 (d, J=7.1Hz, 2H), 6.97 (d, J =6.6Hz, 1H), 6.90 (d, J = 6.4Hz, 1H), 6.86 (s, 1H), 5.44-5.38 (m, 2H), 5.36-5.25 (m, 2H ), 4.38-4.32(m, 1H), 4.31-4.20(m, 1H), 4.13-4.07(s, 2H), 3.47-3.41(m, 4H), 3.25-3.19(m, 2H), 3.02-2.92 (m, 2H), 2.91-2.80 (m, 2H), 2.35-2.28 (m, 1H), 2.25 (s, 3H), 2.18-2.06 (m, 4H), 2.03-1.93 (m, 2H), 1.89 -1.85(m, 1H), 1.85-1.60(m, 6H), 1.60-1.38(m, 2H).
实施例37(S)-1-(4-((3′-(3-(2，7-二氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐(化合物37)Example 37 (S)-1-(4-((3′-(3-(2,7-diazaspiro[3.5]non-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate (Compound 37)
步骤1)7-(3-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[3.5]壬-2-羧酸叔丁酯Step 1) tert-butyl 7-(3-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
将4-((3′-(3-溴丙氧基)-2，2′-二甲基-[1，1′-联苯]-3-基)甲氧基]-5-氯-2-羟基苯甲醛(0.5g，1mmol)，2，7-二氮杂螺[3.5]壬-2-羧酸叔丁酯(0.3g，1mmol)溶于DMF(10.1mL)，加入碳酸钾(0.8g，6mmol)，加入NaI(0.2g，1mmol)，升温至75℃搅拌12h。停止搅拌，冷却至室温，加水(30mL)稀释，EA(20mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(Hexane/EA＝1/3，v/v)得红色固体0.4g，产率为60％。4-((3′-(3-bromopropoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy]-5-chloro-2-hydroxybenzaldehyde (0.5 g, 1 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (0.3 g, 1 mmol) were dissolved in DMF (10.1 mL), potassium carbonate (0.8 g, 6 mmol) and NaI (0.2 g, 1 mmol) were added, and the temperature was raised to 75° C. and stirred for 12 h. Stirring was stopped, the mixture was cooled to room temperature, diluted with water (30 mL), extracted with EA (20 mL×3), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, washed, concentrated under reduced pressure, and separated by column chromatography (Hexane/EA=1/3, v/v) to obtain 0.4 g of a red solid with a yield of 60%.
LC-MS：(pos.ion)m/z：636.2[M+1]+；LC-MS: (pos.ion)m/z: 636.2[M+1]+ ;
步骤2)7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[3.5]壬-2-羧酸叔丁酯Step 2) tert-Butyl 7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate
将5-(氯甲基)烟腈盐酸盐(0.14g，0.74mmol)溶于DMF(10.1mL)，加入碳酸铯(1.2g，3.7mmol)，室温搅拌10min。加入7-(3-((3′-((2-氯-4-甲酰基-5-羟基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[3.5]壬-2-羧酸叔丁酯(0.4g，0.6mmol)和NaI(19.0mg，0.13mmol)，升温至75℃搅拌4h。停止搅拌，冷却至室温，加水(15mL)稀释，EA(15mL×5)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析分离(DCM/MeOH＝10/1，v/v)得黄色固体0.36g，产率为80％。5-(Chloromethyl)nicotinonitrile hydrochloride (0.14 g, 0.74 mmol) was dissolved in DMF (10.1 mL), cesium carbonate (1.2 g, 3.7 mmol) was added, and the mixture was stirred at room temperature for 10 min. 7-(3-((3′-((2-chloro-4-formyl-5-hydroxyphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (0.4 g, 0.6 mmol) and NaI (19.0 mg, 0.13 mmol) were added, and the mixture was heated to 75° C. and stirred for 4 h. Stop stirring, cool to room temperature, add water (15 mL) to dilute, extract with EA (15 mL×5), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, and separate by column chromatography (DCM/MeOH=10/1, v/v) to obtain 0.36 g of a yellow solid with a yield of 80%.
LC-MS：(pos.ion)m/z：752.2[M+1]+；LC-MS: (pos.ion)m/z: 752.2[M+1]+ ;
步骤3)(S)-1-(4-((3′-(3-(2-(叔丁氧基羰基)-2，7-二氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (S)-1-(4-((3′-(3-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
将7-(3-((3′-((2-氯-5-((5-氰基吡啶-3-基)甲氧基)-4-甲酰基苯氧基)甲基)-2′-甲基-[1，1′-联苯]-3-基)氧基)丙基)-2，7-二氮杂螺[3.5]壬烷-2-羧酸叔丁酯(0.36g，0.48mmol)和D-哌啶酸(0.12g，0.93mmol)溶于DMF(15.0mL)，加入乙酸(0.2mL，3mmol)，加热至60℃搅拌1.5h，冷却至室温，缓慢加入氰基硼氢化钠(0.15g，2.4mmol)，氮气保护，室温搅拌12h。停止搅拌，冷却至室温，加入饱和碳酸氢钠溶液(25mL)室温搅拌30min，EA(25mL×3)萃取，合并有机相并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，抽滤，洗涤，减压浓缩，柱层析(DCM/MeOH＝3/1，v/v)分离得黄色固体94.2mg，产率为23％。Dissolve tert-butyl 7-(3-((3′-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2′-methyl-[1,1′-biphenyl]-3-yl)oxy)propyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.36 g, 0.48 mmol) and D-piperidinic acid (0.12 g, 0.93 mmol) in DMF (15.0 mL), add acetic acid (0.2 mL, 3 mmol), heat to 60°C and stir for 1.5 h, cool to room temperature, slowly add sodium cyanoborohydride (0.15 g, 2.4 mmol), protect with nitrogen, and stir at room temperature for 12 h. Stop stirring, cool to room temperature, add saturated sodium bicarbonate solution (25 mL), stir at room temperature for 30 min, extract with EA (25 mL×3), combine the organic phases and wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, wash, concentrate under reduced pressure, separate by column chromatography (DCM/MeOH=3/1, v/v) to obtain 94.2 mg of a yellow solid with a yield of 23%.
LC-MS：(pos.ion)m/z：432.8[0.5(M+1)]+；LC-MS: (pos.ion)m/z: 432.8[0.5(M+1)]+ ;
步骤4)(S)-1-(4-((3′-(3-(2，7-二氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸三氟乙酸盐Step 4) (S)-1-(4-((3′-(3-(2,7-diazaspiro[3.5]non-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid trifluoroacetate
将(S)-1-(4-((3′-(3-(2-(叔丁氧基羰基)-2，7-二氮杂螺[3.5]壬-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(94.2mg，0.109mmol)溶于DCM(25.1mL)，加入TFA(2.0mL)，室温搅拌4h。减压浓缩体系，送制备分离得黄色粘稠固体34.4mg，产率为36％。(S)-1-(4-((3′-(3-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]non-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (94.2 mg, 0.109 mmol) was dissolved in DCM (25.1 mL), TFA (2.0 mL) was added, and the mixture was stirred at room temperature for 4 h. The system was concentrated under reduced pressure and sent for preparative separation to obtain 34.4 mg of a yellow viscous solid with a yield of 36%.
LC-MS：(pos.ion)m/z：765.2[M+1]+；LC-MS: (pos.ion)m/z: 765.2[M+1]+ ;
1H NMR(600MHz，d6-DMSO)δ9.93(s，1H)，9.19-8.88(m，4H)，8.48(s，1H)，7.59-7.46(m，2H)，7.42-7.35(m，1H)，7.34-7.26(m，1H)，7.26-7.16(m，2H)，6.96(d，J＝6.9Hz，1H)，6.90(d，J＝6.3Hz，1H)，6.85(s，1H)，5.44-5.38(m，2H)，5.36-5.25(m，2H)，4.40-4.30(m，1H)，4.30-4.19(m，1H)，4.10(s，2H)，3.85(s，2H)，3.76(s，2H)，3.44-3.40(m，2H)，3.21(s，2H)，3.04-2.83(m，4H)，2.25(s，3H)，2.20(d，J＝13.6Hz，2H)，2.15(s，3H)，1.95-1.84(m，2H)，1.80-1.57(m，4H)，1.57-1.38(m，2H).1 H NMR (600MHz, d6 -DMSO) δ9.93 (s, 1H), 9.19-8.88 (m, 4H), 8.48 (s, 1H), 7.59-7.46 (m, 2H), 7.42-7.35 (m , 1H), 7.34-7.26 (m, 1H), 7.26-7.16 (m, 2H), 6.96 (d, J=6.9Hz, 1H), 6.90 (d, J=6.3Hz, 1H), 6.85 (s, 1H), 5.44-5.38(m, 2H), 5.36-5.25(m, 2H), 4.40 -4.30(m,1H),4.30-4.19(m,1H),4.10(s,2H),3.85(s,2H),3.76(s,2H),3.44-3.40(m,2H),3.21(s , 2H), 3.04-2.83 (m, 4H), 2.25 (s, 3H), 2.20 (d, J=13.6Hz, 2H), 2.15 (s, 3H), 1.95-1.84 (m, 2H), 1.80- 1.57(m, 4H), 1.57-1.38(m, 2H).
实施例67(2S)-1-(4-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸(化合物67)Example 67 (2S)-1-(4-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (Compound 67)
步骤1)4-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛Step 1) 4-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde
氮气保护下，向4-((3′-(3-溴丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(740mg，1.51mmol)和2-氧杂-7-氮杂螺[4.5]癸烷盐酸盐(402.6mg，2.27mmol)的DMF(20mL)溶液中，依次加入碳酸钾(522mg，3.77mmol)和NaI(339.7mg，2.26mmol)，加热至70℃，反应16h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(50mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)，得到黄色油状液体370mg，产率44.52％。Under nitrogen protection, potassium carbonate (522 mg, 3.77 mmol) and NaI (339.7 mg, 2.26 mmol) were added successively to a solution of 4-((3′-(3-bromopropoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (740 mg, 1.51 mmol) and 2-oxa-7-azaspiro[4.5]decane hydrochloride (402.6 mg, 2.27 mmol) in DMF (20 mL), the mixture was heated to 70°C and reacted for 16 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (50 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 370 mg of a yellow oily liquid with a yield of 44.52%.
LC-MS：(pos.ion)m/z：550.1[M+1]+；LC-MS: (pos.ion)m/z: 550.1[M+1]+ ;
步骤2)5-((5-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈Step 2) 5-((5-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile
将4-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-羟基苯甲醛(370mg，067mmol)和5-氯甲基-3-氰基吡啶盐酸盐(148.8mg，0.81mmol)的DMF溶液(20mL)中，依次加入碳酸铯(534.3mg，1.68mmol)和碘化钠(19.66mg，0.13mmol)，N2保护，75℃反应4h。停止搅拌，冷却至室温，加水稀释(20mL)，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝10/1，v/v)得到黄色油状液体400mg，产率89.27％。To a DMF solution (20 mL) of 4-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-hydroxybenzaldehyde (370 mg, 067 mmol) and 5-chloromethyl-3-cyanopyridine hydrochloride (148.8 mg, 0.81 mmol) was added cesium carbonate (534.3 mg, 1.68 mmol) and sodium iodide (19.66 mg, 0.13 mmol) in sequence, underN2 protection, and reacted at 75°C for 4 h. Stop stirring, cool to room temperature, dilute with water (20 mL), extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography (DCM/MeOH=10/1, v/v) to obtain 400 mg of a yellow oily liquid with a yield of 89.27%.
LC-MS：(pos.ion)m/z：666.2[M+1]+；LC-MS: (pos.ion)m/z: 666.2[M+1]+ ;
步骤3)(2S)-1-(4-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-5-氯-2-((5-氰基吡啶-3-基)甲氧基)苄基)哌啶-2-甲酸Step 3) (2S)-1-(4-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-chloro-2-((5-cyanopyridin-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid
向5-((5-((3′-(3-(2-氧杂-7-氮杂螺[4.5]癸-7-基)丙氧基)-2-甲基-[1，1′-联苯]-3-基)甲氧基)-4-氯-2-甲酰基苯氧基)甲基)烟腈(400mg，0.6mmol)和D-哌啶酸(155.1mg，1.2mmol)的DMF(10mL)溶液中加入乙酸，调节pH至5左右，60℃反应1h，冷却至室温，再向反应体系中加入硼氰化钠(188.7mg，3mmol)，室温反应3h后，80℃反应16h。停止搅拌，加入饱和碳酸钾溶液，搅拌30min。加水稀释(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和食盐水(20mL)洗涤，并用无水硫酸钠干燥，过滤，浓缩，柱层析分离纯化(DCM/MeOH＝4/1，v/v)，得到淡黄色固体92mg，产率19.66％。To a DMF (10 mL) solution of 5-((5-((3′-(3-(2-oxa-7-azaspiro[4.5]dec-7-yl)propoxy)-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile (400 mg, 0.6 mmol) and D-piperidinic acid (155.1 mg, 1.2 mmol) was added acetic acid, the pH was adjusted to about 5, the mixture was reacted at 60° C. for 1 h, cooled to room temperature, sodium borocyanide (188.7 mg, 3 mmol) was added to the reaction system, the mixture was reacted at room temperature for 3 h, and then reacted at 80° C. for 16 h. Stirring was stopped, saturated potassium carbonate solution was added, and the mixture was stirred for 30 min. Dilute with water (20 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), and dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (DCM/MeOH=4/1, v/v) to obtain 92 mg of a light yellow solid. The yield is 19.66%.
LC-MS：(pos.ion)m/z：779.2[M+1]+；LC-MS: (pos.ion)m/z: 779.2[M+1]+ ;
1H NMR(400MHz，d6-DMSO)δ9.04-8.97(m，2H)，8.45(s，1H)，7.49(d，J＝7.2Hz，1H)，7.42(s，1H)，7.35(t，J＝7.9Hz，1H)，7.28(t，J＝7.5Hz，1H)，7.21(d，J＝7.2Hz，1H)，7.12(s，1H)，6.93(d，J＝8.3Hz，1H)，6.88-6.81(m，2H)，5.34(s，2H)，5.26(s，2H)，4.05(t，J＝6.2Hz，2H)，3.79(d，J＝13.9Hz，1H)，3.66(dd，J＝18.6，11.5Hz，4H)，3.55(d，J＝8.1Hz，1H)，3.51(s，1H)，3.32(d，J＝8.5Hz，2H)，3.15(d，J＝4.3Hz，1H)，2.34-2.26(m，2H)，2.24(s，4H)，1.90(d，J＝5.6Hz，2H)，1.79(s，1H)，1.75-1.67(m，2H)，1.56-1.31(m，10H)，1.23(s，1H).1 H NMR (400MHz, d6 -DMSO) δ9.04-8.97 (m, 2H), 8.45 (s, 1H), 7.49 (d, J=7.2Hz, 1H), 7.42 (s, 1H), 7.35 ( t, J=7.9Hz, 1H), 7.28 (t, J=7.5Hz, 1H), 7.21 (d, J=7.2Hz, 1H), 7.12 (s, 1H), 6.93 (d, J=8.3Hz, 1H), 6.88-6.81 (m, 2H), 5.34 (s, 2H), 5.26 (s, 2H), 4.05 (t, J=6.2Hz, 2H), 3.7 9 (d, J=13.9Hz, 1H), 3.66 (dd, J=18.6, 11.5Hz, 4H), 3.55 (d, J=8.1Hz, 1H), 3.51 (s, 1H), 3.32 (d, J =8.5Hz, 2H), 3.15 (d, J = 4.3Hz, 1H), 2.34-2.26 (m, 2H), 2.24 (s, 4H), 1.90 (d, J = 5.6Hz, 2H), 1.79 (s , 1H), 1.75-1.67(m, 2H), 1.56-1.31(m, 10H), 1.23(s, 1H).
本发明化合物的体外抗肿瘤活性测定In vitro antitumor activity assay of the compounds of the present invention
体外酶学水平的检测方法采用Cisbio公司PD-1/PD-L1 binding assay kit检测试剂盒The in vitro enzymatic level detection method uses the PD-1/PD-L1 binding assay kit of Cisbio.
1.实验原理：1. Experimental principle:
PD-1蛋白带HIS标签，PD-1的配体PD-L1带hFc标签，分别用Eu标记的anti-hFc抗体和XL665标记的anti-HIS抗体与两个标签蛋白结合。激光激发后，能量能够从供体Eu上转移到受体XL665，使得XL665发光。而加入抑制剂后，阻断了PD-1与配体PD-L1的结合，使得Eu和XL665距离较远，能量不能转移，XL665不发光。The PD-1 protein has a HIS tag, and the PD-1 ligand PD-L1 has an hFc tag. The two tag proteins are bound to anti-hFc antibodies labeled with Eu and anti-HIS antibodies labeled with XL665. After laser excitation, energy can be transferred from the donor Eu to the acceptor XL665, causing XL665 to emit light. After the addition of the inhibitor, the binding of PD-1 to the ligand PD-L1 is blocked, making Eu and XL665 far apart, energy cannot be transferred, and XL665 does not emit light.
2.实验方法：2. Experimental methods:
使用Cisbio Bioassays的HTRF测定试剂盒(目录号64ICP01PEG)进行PD1/PD-L1结合测定，具体操作方法参照试剂盒说明进行。简单叙述如下，使用384孔白色酶标板，将化合物溶于DMSO溶液中，浓度为10mM。首先将化合物储备溶液用稀释剂稀释40倍，然后使用含有2.5％DMSO的试剂盒稀释缓冲液稀释5倍。在每个孔中加入4ul的稀释液或稀释液稀释的目标化合物，最终的DMSO浓度为0.5％。PD1和PD-L1溶液分别以每孔3ul加入，化合物与PD1和PD-L1预孵育10分钟后，将按照产品说明书制备的10ul检测抗体加入到每个孔中。在室温下孵育平板过夜后，通过在PHERAstar FS酶标仪(BMG，德国)中读取平板获得数据。HTRF信号计算为10000×(665/620比率)。将各化合物的计算信号拟合成具有可变斜率的S形剂量-反应曲线，并且通过曲线拟合(GraphPad Prism 7)获得IC50值。The PD1/PD-L1 binding assay was performed using the HTRF assay kit (Catalog No. 64ICP01PEG) from Cisbio Bioassays. The specific operation method was carried out according to the instructions of the kit. Briefly described as follows, using a 384-well white ELISA plate, the compounds were dissolved in DMSO solution at a concentration of 10mM. The compound stock solution was first diluted 40 times with diluent and then diluted 5 times with the kit dilution buffer containing 2.5% DMSO. 4ul of diluent or target compound diluted with diluent was added to each well, and the final DMSO concentration was 0.5%. PD1 and PD-L1 solutions were added at 3ul per well, respectively. After the compounds were pre-incubated with PD1 and PD-L1 for 10 minutes, 10ul of detection antibody prepared according to the product instructions was added to each well. After incubating the plate overnight at room temperature, the data were obtained by reading the plate in a PHERAstar FS microplate reader (BMG, Germany). The HTRF signal was calculated as 10000×(665/620 ratio). The calculated signal for each compound was fitted to a sigmoidal dose-response curve with a variable slope, and theIC50 value was obtained by curve fitting (GraphPad Prism 7).
实验结果如下：The experimental results are as follows:
表2 本发明化合物在分子水平对PD-1/PD-L1相互作用的抑制活性评价Table 2 Evaluation of the inhibitory activity of the compounds of the present invention on PD-1/PD-L1 interaction at the molecular level
实验结论：Experimental conclusion:
从表中可见，本发明化合物在分子水平可显著抑制PD-1与PD-L1的相互作用，因此可用于治疗与PD-1/PD-L1的相互作用相关的疾病。As can be seen from the table, the compounds of the present invention can significantly inhibit the interaction between PD-1 and PD-L1 at the molecular level, and can therefore be used to treat diseases related to the interaction between PD-1/PD-L1.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.
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