CN101993415B - Compound as Hedgehog path inhibitor, medicine composition containing same and application thereof - Google Patents
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- CN101993415B CN101993415BCN2010102818562ACN201010281856ACN101993415BCN 101993415 BCN101993415 BCN 101993415BCN 2010102818562 ACN2010102818562 ACN 2010102818562ACN 201010281856 ACN201010281856 ACN 201010281856ACN 101993415 BCN101993415 BCN 101993415B
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Abstract
Description
Translated fromChinese技术领域technical field
本发明涉及一种化合物，尤其涉及一种作为抑制剂的化合物以及包含该化合物的组合物(C07D 521/00)。 The present invention relates to a compound, in particular to a compound as an inhibitor and a composition (C07D 521/00) comprising the compound. the
背景技术Background technique
1980年在果蝇中发现的hedgehog信号通路在动物胚胎形成时期对细胞的增殖、分化以及决定细胞命运等进程中起重要的调节作用。功能正常的Hedgehog信号通路是形成脑、四肢、肺、皮肤、前列腺等重要器官所必须的条件(Ingham PW & McMahon AP(2001)Genes & Development 15，3059-3087)。尽管Hedgehog信号通路在成人体内的水平远低于胚胎时期，该通路在成人组织的增殖与更新过程中依然起着至关重要的作用。干细胞是一类具有自我更新能力的多潜能细胞，即干细胞保持未定向分化状态和具有增殖能力，在合适的条件或给予合适的信号，它可以分化成多种功能细胞或组织器官。Hedgehog通路是干细胞活性的重要调节器，它可以刺激多种组织中干细胞的自我更新与增殖(Beachy PA，Karhadkar SS，& Berman DM(2004)Nature 432，324-331)。 The hedgehog signaling pathway discovered in Drosophila in 1980 plays an important regulatory role in the process of cell proliferation, differentiation and determination of cell fate during animal embryogenesis. A properly functioning Hedgehog signaling pathway is necessary for the formation of vital organs such as the brain, limbs, lungs, skin, and prostate (Ingham PW & McMahon AP (2001) Genes & Development 15, 3059-3087). Although the level of the Hedgehog signaling pathway in adults is much lower than that in embryos, this pathway still plays a vital role in the proliferation and renewal of adult tissues. Stem cells are a kind of pluripotent cells with self-renewal ability, that is, stem cells maintain an undifferentiated state and have the ability to proliferate. Under appropriate conditions or given appropriate signals, they can differentiate into various functional cells or tissues and organs. The Hedgehog pathway is an important regulator of stem cell activity, which can stimulate the self-renewal and proliferation of stem cells in various tissues (Beachy PA, Karhadkar SS, & Berman DM (2004) Nature 432, 324-331). the
在脊椎动物包括哺乳动物中存在三种Hedgehog蛋白：Sonic hedgehog(Shh)，Desert hedgehog(Dhh)和Indian hedgehog(Ihh).由于在多种组织中都有表达，Shh蛋白得到了最多的关注。这些分泌的配体通过与12次跨膜蛋白Ptch1结合来激活Hedgehog信号通路。当未与配体例如Shh蛋白结合时，Ptch1抑制另一种跨膜蛋白(7次跨膜蛋白)Smoothend(Smo)的活性，但当与配体结合时，Ptch1蛋白被激活而释放其对Smo的抑制，从而导致Smo移动到细胞膜，引发一系列的细胞内信号传导(Varjosalo M & Taipale J(2007)Journal of Cell Science 120，3-6)。由激活的Smo引发的信号传导级联导致Gli转录因子的活化，Gli转录因子易位进入细胞核中，在那里它们控制靶基因的转录。在 脊椎动物中，有三种锌指蛋白家族的Gli转录因子，分别是Gli1、Gli2和Gli3。其中Gli1与Gli2主要作为转录的激活因子而Gli3则主要作为阻抑因子。由于Gli2基因的持续过表达，它通常被认定为Smo蛋白激活后的主要靶点。Gli1的表达与Hedgehog通路的激活高度相关，因此它经常被用作读数来指示Hedgehog通路的激活状态。Gli转录因子的激活可以引发Gli1、Ptch1、Myc、Bcl-2等Hedgehog靶基因的转录(Ferretti E，De Smaele E，Di Marcotullio L，ScrepantiI，& Gulino A(2005)Trends in Molecular Medicine 11，537-545)。 There are three Hedgehog proteins in vertebrates including mammals: Sonic hedgehog (Shh), Desert hedgehog (Dhh) and Indian hedgehog (Ihh). Shh protein has received the most attention due to its expression in various tissues. These secreted ligands activate the Hedgehog signaling pathway by binding to the 12-transmembrane protein Ptch1. When not bound to a ligand such as Shh protein, Ptch1 inhibits the activity of another transmembrane protein (seven transmembrane protein) Smoothend (Smo), but when bound to a ligand, Ptch1 protein is activated to release its effect on Smo The inhibition of Smo leads to the movement of Smo to the cell membrane, triggering a series of intracellular signal transduction (Varjosalo M & Taipale J (2007) Journal of Cell Science 120, 3-6). The signaling cascade initiated by activated Smo leads to the activation of Gli transcription factors, which translocate into the nucleus where they control the transcription of target genes. In vertebrates, there are three Gli transcription factors of the zinc finger protein family, Gli1, Gli2, and Gli3. Among them, Gli1 and Gli2 mainly act as activators of transcription, while Gli3 mainly acts as a repressor. Due to the persistent overexpression of the Gli2 gene, it is generally identified as the main target of Smo protein activation. The expression of Gli1 is highly correlated with the activation of the Hedgehog pathway, so it is often used as a readout to indicate the activation status of the Hedgehog pathway. The activation of Gli transcription factors can trigger the transcription of Hedgehog target genes such as Gli1, Ptch1, Myc, Bcl-2 (Ferretti E, De Smaele E, Di Marcotullio L, ScrepantiI, & Gulino A (2005) Trends in Molecular Medicine 11, 537- 545). the
近期的研究表明，癌症与Hedgehog通路的异常激活密切相关。在大多数偶发性基底细胞癌中，研究人员发现Ptch1和Smo的变异导致了不依赖配体的Hedgehog通路激活(Gailani MR，StahleBackdahl M，Leffell DJ，Glynn M，Zaphiropoulos PG，Pressman C，Unden AB，Dean M，Brash DE，Bale AE，et al.(1996)Nature Genetics 14，78-81；Xie JW，Murone M，Luoh SM，Ryan A，Gu QM，Zhang CH，Bonifas JM，Lam CW，Hynes M，Goddard A，et al.(1998)Nature 391，90-92)，而Ptch1和Sufu的变异所引发的Hedgehog通路的激活也被发现与成神经管细胞瘤与横纹肌瘤密切相关(Rubin LL & de Sauvage FJ(2006)Nature Reviews Drug Discovery 5，1026-1033；Tostar U，Malm CJ，Meis-Kindblom JM，Kindblom LG，Toftgard R，& Unden AB(2006)Journal of Pathology 208，17-25)。Hedgehog通路的激活与其他的器官的癌症也有关联。这些癌症包括但不限于前列腺癌(Karhadkar SS，Bova GS，Abdallah N，Dhara S，Gardner D，Maitra A，Isaacs JT，Berman DM，& Beachy PA(2004)Nature 431，707-712；Sanchez P，Hernandez AM，Stecca B，Kahler AJ，DeGueme AM，Barrett A，Beyna M，Datta MW，Datta S，& Altaba ARI(2004)Proceedings of the National Academy of Sciences of the United States ofAmerica 101，12561-12566)；乳腺癌(Kubo M，Nakamura M，Tasaki A，Yamanaka N，Nakashima H，Nomura M，Kuroki S，& Katano M(2004)Cancer Research 64，6071-6074)；胰腺癌(Thayer SP，di Magliano MP，Heiser PW，Nielsen CM，Roberts DJ，Lauwers GY，Qi YP，Gysin S，Fernandez-del Castillo CF，Yajnik V，et al.(2003)Nature 425，851-856)；消化道肿瘤(Berman DM，Karhadkar SS，Maitra A，de Oca RM，Gerstenblith MR，Briggs K，Parker AR，Shimada Y，Eshleman JR，Watkins DN，et al.(2003)Nature425，846-851)；小细胞肺癌(Watkins DN，Berman DM，Burkholder SG，Wang BL， Beachy PA，& Baylin SB(2003)Nature 422，313-317)；非小细胞肺癌(Yuan Z，Goetz JA，Singh S，Ogden SK，Petty WJ，Black CC，Memoli VA，Dmitrovsky E，&Robbins DJ(2007)Oncogene 26，1046-1055)等。 Recent studies have shown that cancer is closely related to abnormal activation of the Hedgehog pathway. In most sporadic basal cell carcinomas, mutations in Ptch1 and Smo lead to ligand-independent activation of the Hedgehog pathway (Gailani MR, StahleBackdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, et al. (1996) Nature Genetics 14, 78-81; Xie JW, Murone M, Luoh SM, Ryan A, Gu QM, Zhang CH, Bonifas JM, Lam CW, Hynes M, Goddard A, et al. (1998) Nature 391, 90-92), and the activation of the Hedgehog pathway triggered by the mutation of Ptch1 and Sufu was also found to be closely related to medulloblastoma and rhabdomyoma (Rubin LL & de Sauvage FJ (2006) Nature Reviews Drug Discovery 5, 1026-1033; Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgard R, & Unden AB (2006) Journal of Pathology 208, 17-25). Activation of the Hedgehog pathway has also been linked to cancers in other organs. These cancers include but are not limited to prostate cancer (Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, & Beachy PA (2004) Nature 431, 707-712; Sanchez P, Hernandez AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S, & Altaba ARI (2004) Proceedings of the National Academy of Sciences of the United States of America 101, 12561-12566); breast cancer (Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S, & Katano M (2004) Cancer Research 64, 6071-6074); Pancreatic cancer (Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez-del Castillo CF, Yajnik V, et al. (2003) Nature 425, 851-856); Gastrointestinal neoplasms (Berman DM, Karhadkar SS, Maitra A , de Oca RM, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, et al. (2003) Nature 425, 846-851); small cell lung cancer (Watkins DN, Berman DM, Burkholder SG, Wang BL, Beachy PA, & Baylin SB (2003) Nature 422, 313-317); non-small cell lung cancer (Yuan Z, Goetz JA, Singh S, Ogden SK, Petty WJ, Black CC, Memoli VA, Dmitrovsky E, & Robbins DJ (2007) Oncogene 26, 1046-1055) et al. the
越来越多的证据表明Hedgehog通路可能与肿瘤干细胞紧密关联(Parisi MJ & Lin H(1998)Cell Res 8，15-21；Peacock CD，Wang QJ，Gesell GS，Corcoran-Schwartz IM，Jones E，Kim J，Devereux WL，Rhodes JT，Huff CA，Beachy PA，et al.(2007)Proceedings of the National Academy of Sciences of the United States of America 104，4048-4053)。肿瘤干细胞可能对肿瘤的生长以及增殖起到至关重要的作用。有研究发现，在白血病以及一些实体瘤例如在脑和胰腺中，有一小部分癌细胞有能力大量增殖而在体内成为新的肿瘤(Clarke MF，Dick JE，Dirks PB，Eaves CJ，Jamieson CH，Jones DL，Visvader J，Weissman IL，Wahl GM(2006)Cancer Res 66，9339-9344)。肿瘤干细胞存在的假说将会对抗肿瘤药物设计有重大的影响，因为彻底根除肿瘤需要靶向性地消灭所有的肿瘤干细胞。 More and more evidence shows that the Hedgehog pathway may be closely related to tumor stem cells (Parisi MJ & Lin H (1998) Cell Res 8, 15-21; Peacock CD, Wang QJ, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, et al. (2007) Proceedings of the National Academy of Sciences of the United States of America 104, 4048-4053). Cancer stem cells may play a vital role in tumor growth and proliferation. Studies have found that in leukemia and some solid tumors such as brain and pancreas, a small number of cancer cells have the ability to proliferate in large numbers and become new tumors in vivo (Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM (2006) Cancer Res 66, 9339-9344). The hypothesis of the existence of cancer stem cells will have a major impact on the design of anticancer drugs, because complete eradication of tumors requires the targeted elimination of all cancer stem cells. the
一部分胰腺癌细胞具有肿瘤干细胞的特点，具备自我更新以及分化的性质(Li CW，Heidt DG，Dalerba P，Burant CF，Zhang LJ，Adsay V，Wicha M，Clarke MF，Simeone DM(2007)Cancer Research 67，1030-1037)。Feldmann等人利用动物模型证明，Hedgehog抑制剂与吉西他滨联用可以抑制胰腺癌的生长，而吉西他滨和hedgehog抑制剂单独的治疗效果都不明显。该研究表明抑制Hedgehog通路可能抑制肿瘤干细胞的自我更新与增殖(Feldmann G，Fendrich V，McGovern K，Bedja D，Bisht S，Alvarez H，Koorstra JBM，Habbe N，Karikari C，Mullendore M，et al.(2008)Molecular Cancer Therapeutics 7，2725-2735)。在该研究中，Feldmann等人还发现，抑制Hedgehog通路可以有效地防止癌细胞转移。 Some pancreatic cancer cells have the characteristics of tumor stem cells, with the properties of self-renewal and differentiation (Li CW, Heidt DG, Dalerba P, Burant CF, Zhang LJ, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Cancer Research 67 , 1030-1037). Feldmann et al. used animal models to prove that the combination of Hedgehog inhibitors and gemcitabine can inhibit the growth of pancreatic cancer, while the treatment effect of gemcitabine and hedgehog inhibitors alone is not obvious. This study shows that inhibition of the Hedgehog pathway may inhibit the self-renewal and proliferation of cancer stem cells (Feldmann G, Fendrich V, McGovern K, Bedja D, Bisht S, Alvarez H, Koorstra JBM, Habbe N, Karikari C, Mullendore M, et al. ( 2008) Molecular Cancer Therapeutics 7, 2725-2735). In this study, Feldmann et al. also found that inhibiting the Hedgehog pathway can effectively prevent cancer cell metastasis. the
除了调节肿瘤细胞的分化，增殖和转移，Hedgehog通路正向调节药物转运蛋白的表达，导致癌细胞对细胞毒抗癌药物的抗药性(Sims-Mourtada J，Izzo JG，Ajani J，Chao KSC(2007)Oncogene 26，5674-5679)。Hedgehog通路还能够调节肿瘤的血管生成(Klagsbrun M(1991)Annual Review of Physiology 53，217-239；Cherrington JM，Strawn LM，Shawver LK(2000)Advances in Cancer Research，79，1-38)。综上所述，抑制Hedgehog信号通路的化合物以及其药 用组合物将会有非常好的抗癌临床应用前景。 In addition to regulating the differentiation, proliferation and metastasis of tumor cells, the Hedgehog pathway positively regulates the expression of drug transporters, leading to the resistance of cancer cells to cytotoxic anticancer drugs (Sims-Mourtada J, Izzo JG, Ajani J, Chao KSC (2007 ) Oncogene 26, 5674-5679). The Hedgehog pathway can also regulate tumor angiogenesis (Klagsbrun M (1991) Annual Review of Physiology 53, 217-239; Cherrington JM, Strawn LM, Shawver LK (2000) Advances in Cancer Research, 79, 1-38). In summary, compounds that inhibit the Hedgehog signaling pathway and their pharmaceutical compositions will have very good anticancer clinical application prospects. the
发明内容Contents of the invention
本发明的目的在于提供一种作为抑制剂的化合物，其用于抑制Hedgehog信号通路，可为临床有效抗癌提供新的药物。 The object of the present invention is to provide a compound as an inhibitor, which is used for inhibiting the Hedgehog signaling pathway, and can provide a new drug for clinically effective anticancer. the
本发明的另一个目的在于提供作为抑制剂的药物组合物，其包含作为有效成分的所述化合物I，可用于抑制Hedgehog信号通路以抗癌。 Another object of the present invention is to provide a pharmaceutical composition as an inhibitor, which contains the compound I as an active ingredient, which can be used to inhibit Hedgehog signaling pathway to fight cancer. the
本发明的一个目的在于提供所述化合物在制备用于抑制Hedgehog信号通路的药物中的应用。 One object of the present invention is to provide the application of the compound in the preparation of drugs for inhibiting Hedgehog signaling pathway. the
本发明的另一个目的在于提供所述化合物的制备方法。 Another object of the present invention is to provide a preparation method of the compound. the
根据本发明的一个方面，本发明提供了式I化合物或其药学上可接受的盐或溶剂化物： According to one aspect of the present invention, the present invention provides formula I compound or its pharmaceutically acceptable salt or solvate:
式I Formula I
其中： in:
A代表： A stands for:
X代表S、S＝O、S(O)2、O、CHR11或者NR12； X represents S, S=O, S(O)2 , O, CHR11 or NR12 ;
R11代表氢、氰基、卤素、C1-6烷基、C1-6烷氧基、-C(O)2R14或者-NR13aR13b，其中烷基或烷氧基未被取代或者被一个或多个卤素或羟基取代； R11 represents hydrogen, cyano, halogen, C1-6 alkyl, C1-6 alkoxy, -C(O)2 R14 or -NR13 aR13 b, wherein the alkyl or alkoxy is not replaced by substituted or substituted by one or more halogen or hydroxy;
R12代表氢、C1-6烷基、C3-8杂环烷基-C1-6烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、C6-10芳基-C1-6烷基、C5-10杂芳基-C1-6烷基、-C(O)2R14、-C(O)R14或者-S(O)2R14； R12 represents hydrogen, C1-6 alkyl, C3-8 heterocycloalkyl-C1-6 alkyl, C3-8 heterocycloalkyl, C6-10 aryl, C5-10 heteroaryl radical, C6-10 aryl-C1-6 alkyl, C5-10 heteroaryl-C1-6 alkyl, -C(O)2 R14 , -C(O)R14 or -S (O)2 R14 ;
R13a和R13b独立地代表氢、未被取代或被一个或多个卤素取代的C1-6烷基、C1-6烷氧基-C1-6烷基、-C(O)2R14、-S(O)2R14、C6-10芳基-C1-6烷基或者C5-10杂芳 基-C1-6烷基； R13a and R13b independently represent hydrogen, C1-6 alkyl unsubstituted or substituted by one or more halogens, C1-6 alkoxy-C1-6 alkyl, -C(O)2 R14 , -S(O)2 R14 , C6-10 aryl-C1-6 alkyl or C5-10 heteroaryl-C1-6 alkyl;
R14代表未被取代或被一个或多个卤素取代的C1-6烷基； R14 represents C1-6 alkyl that is unsubstituted or substituted by one or more halogens;
m和1独立地代表1或者2；n代表0、1或者2； m and 1 independently represent 1 or 2; n represents 0, 1 or 2;
R1和R2独立地代表氢或者C1-6烷基；其中烷基未被取代或者被一个或多个卤素或羟基取代； R1 and R2 independently represent hydrogen or C1-6 alkyl; wherein the alkyl is unsubstituted or substituted by one or more halogen or hydroxyl;
Y、Z和U独立地代表氮或者CR11； Y, Z and U independently represent nitrogen or CR11 ;
W和V独立地代表氮或者CR15； W and V independently represent nitrogen or CR15 ;
R15代表氢、C1-6烷基或者C1-6烷氧基，其中烷基或烷氧基未被取代或者被一个或多个卤素取代； R15 represents hydrogen, C1-6 alkyl or C1-6 alkoxy, wherein the alkyl or alkoxy is unsubstituted or substituted by one or more halogens;
R3代表氢、卤素、氰基、C1-6烷基或者C1-6烷氧基，其中烷基或者烷氧基未被取代或被一个或多个卤素取代； R represents hydrogen, halogen, cyano, C1-6 alkyl or C1-6 alkoxy, wherein the alkyl or alkoxy is unsubstituted or substituted by one or more halogens;
R4和R5独立地代表氢、卤素、C1-6烷基或者C1-6烷氧基，其中烷基或者烷氧基未被取代或被一个或多个卤素取代，并且R4和R5不同时为氢； R4 and R5 independently represent hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, wherein the alkyl or alkoxy is unsubstituted or substituted by one or more halogens, and R4 andR is not simultaneously hydrogen;
R6和R7独立地代表氢、卤素、C1-6烷基或者C1-6烷氧基，其中烷基或者烷氧基未被取代或被一个或多个卤素取代； R6 and R7 independently represent hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, wherein the alkyl or alkoxy is unsubstituted or substituted by one or more halogens;
R8和R9独立地代表氢、卤素、C1-6烷基或者C1-6烷氧基，其中烷基或者烷氧基未被取代或被一个或多个卤素取代；， R8 and R9 independently represent hydrogen, halogen, C1-6 alkyl or C1-6 alkoxy, wherein the alkyl or alkoxy is unsubstituted or substituted by one or more halogens;
R10代表氢、卤素、氰基、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基、C3-8杂环烷基、-C(O)R14、-C(O)2R14、-SR14、-S(O)2R14或者-NR13aR13b，其中烷基或烷氧基未被取代或被一个或多个卤素取代，并且其中C3-8杂环烷基未被取代或者被1或2个C1-6烷基取代。 R10 represents hydrogen, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C6-10 aryl, C5-10 heteroaryl, C3-8 cycloalkyl, C3 -8 heterocycloalkyl, -C(O)R14 , -C(O)2 R14 , -SR14 , -S(O)2 R14 or -NR13a R13b , wherein alkyl or alkoxy Unsubstituted or substituted by one or more halogens, and wherein the C3-8 heterocycloalkyl is unsubstituted or substituted by 1 or 2 C1-6 alkyl groups.
根据本发明的另一方面，本发明提供了一种药物组合物，其包含治疗有效量的式I化合物或者其药学上可接受的盐或溶剂物以及适量的可药用载体。 According to another aspect of the present invention, the present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof and an appropriate amount of a pharmaceutically acceptable carrier. the
根据本发明的另一方面，本发明提供了式I化合物在制备用于抑制Hedgehog通路的药物中的应用。 According to another aspect of the present invention, the present invention provides the use of the compound of formula I in the preparation of a medicament for inhibiting Hedgehog pathway. the
本发明还提供了式I化合物在制备用于治疗与Hedgehog通路异常激活有关的癌症的药物中的应用，其中癌症选自于基底细胞癌、髓母细胞瘤、横纹肌肉瘤、胰腺癌、乳腺癌、脊膜瘤、恶性胶质瘤、黑色素瘤、胃癌、食道癌、胆管癌、前列腺癌、结肠癌、小细胞肺癌、非小细胞肺癌、神经胶质细胞癌、多发性骨髓瘤以及白血病。 The present invention also provides the application of the compound of formula I in the preparation of a drug for treating cancers related to abnormal activation of the Hedgehog pathway, wherein the cancer is selected from basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, pancreatic cancer, breast cancer, Meningioma, malignant glioma, melanoma, gastric cancer, esophageal cancer, cholangiocarcinoma, prostate cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, glial cell carcinoma, multiple myeloma, and leukemia. the
根据本发明的另一个方面，本发明提供了所述化合物的制备方法，其中，反应路线为： According to another aspect of the present invention, the present invention provides the preparation method of described compound, wherein, reaction scheme is:
其中，所述方法包括以下步骤： Wherein, described method comprises the following steps:
1)通过式1d的化合物与式1c的化合物进行Suzuki偶联反应来制备得到式1b的化合物； 1) The compound of formula 1b is prepared by Suzuki coupling reaction between the compound of formula 1d and the compound of formula 1c;
2)通过式1b的化合物与取代杂环羧酸进行缩合反应来制备得到式1a的化合物；以及 2) A compound of formula 1a is prepared by condensation reaction of a compound of formula 1b with a substituted heterocyclic carboxylic acid; and
3)从式1a的化合物制备得到式I的化合物。 3) Prepare the compound of formula I from the compound of formula 1a. the
或者反应路线为： Or the reaction route is:
其中，所述方法包括以下步骤： Wherein, described method comprises the following steps:
1)通过式1c的化合物与取代杂环羧酸进行缩合反应来制备得到式1b的化合物；以及 1) A compound of formula 1b is prepared by condensation reaction of a compound of formula 1c with a substituted heterocyclic carboxylic acid; and
2)通过式1b的化合物与亲核试剂(A)反应制备得到式1a的化合物； 2) prepare the compound of formula 1a by reacting the compound of formula 1b with nucleophile (A);
3)式1a的化合物与取代的苯硼酸进行Suzuki偶联反应来制备得到式I的化合物。 3) The compound of formula 1a is prepared by Suzuki coupling reaction with substituted phenylboronic acid to obtain the compound of formula I. the
本发明中的方法以及化合物可以用来抑制激活的Hedgehog信号通路，也就是说可以抑制由于Hedgehog异常激活所导致的异常生长状态。应用本发明所描述的方法，足够量的式I化合物或者式I化合物与药用载体所形成的药物组合物与细胞接触，可以抑制异常激活的Hedgehog通路从而控制或逆转异常的生长状态，从而可在临床上有效地治疗与异常激活的Hedgehog通路有关的癌症。 The methods and compounds of the present invention can be used to inhibit the activated Hedgehog signaling pathway, that is to say, it can inhibit the abnormal growth state caused by the abnormal activation of Hedgehog. Applying the method described in the present invention, a sufficient amount of the compound of formula I or the pharmaceutical composition formed by the compound of formula I and a pharmaceutical carrier is contacted with the cells, which can inhibit the abnormally activated Hedgehog pathway so as to control or reverse the abnormal growth state, so that Clinically effective in treating cancers associated with aberrantly activated Hedgehog pathway. the
具体实施方式Detailed ways
对本发明中所涉及的部分术语定义如下： Some terms involved in the present invention are defined as follows:
“烷基”作为基团或是其他基团的一部分，例如卤素取代的烷基、羟基取代的烷基，可以是直链的或是支链的。例如，C1-6烷基表示1到6个碳的烷基，包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基； "Alkyl" as a group or part of another group, such as halogen substituted alkyl, hydroxy substituted alkyl, can be straight chain or branched. For example, C1-6 alkyl means an alkyl group of 1 to 6 carbons, including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , n-pentyl, n-hexyl;
“烷氧基”是指烷基与氧原子连结后的生成基团，包括但不限于甲氧基、乙氧基、异丙氧基、环丙氧基等。 "Alkoxy" refers to a group formed after an alkyl group is linked to an oxygen atom, including but not limited to methoxy, ethoxy, isopropoxy, cyclopropoxy and the like. the
“芳基”是指包含六到十个碳原子的单环或稠合的芳环。特定的芳基包括苯基和萘基，其中优选苯基。 "Aryl" means a single or fused aromatic ring containing six to ten carbon atoms. Specific aryl groups include phenyl and naphthyl, with phenyl being preferred. the
“杂芳基”是指任何稠合或非稠合的芳环系统，其中至少一个环是含有1-4个选自氮、氧和硫的杂原子的五到八元环，优选至少一个杂原子选自氮。杂芳基包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、恶唑基、异恶唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基等。 "Heteroaryl" means any fused or non-fused aromatic ring system in which at least one ring is a five to eight membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, preferably at least one heteroatom Atoms are selected from nitrogen. Heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzo Pyrazolyl, indolyl, etc. the
“环烷基”是指包含指定数目的碳原子的饱和的或部分不饱和的单环、稠环或桥环。例如，C3-8环烷基是指三到八个碳的环烷基，包括环丙基、环丁基、环戊基、环己基等。 "Cycloalkyl" means a saturated or partially unsaturated monocyclic, fused or bridged ring containing the indicated number of carbon atoms. For example, C3-8 cycloalkyl refers to a cycloalkyl group of three to eight carbons, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
“杂环烷基”是指本发明中所定义的环烷基，其中一个或多个环上的碳原子被氧、氮、-NR-、硫、羰基、-S(O)-或-S(O)2等基团取代；杂环烷基包括但不限于吗啉基、哌嗪基、哌啶基、硫代吗啉基等。 "Heterocycloalkyl" refers to a cycloalkyl group as defined in the present invention, wherein one or more ring carbon atoms are replaced by oxygen, nitrogen, -NR-, sulfur, carbonyl, -S(O)- or -S (O)2 and other groups are substituted; heterocycloalkyl groups include but are not limited to morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl and the like.
“药学上可接受的盐”在本发明中是指酸加成盐。“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其他副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、丙酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、对甲苯磺酸盐和水杨酸盐等。 "Pharmaceutically acceptable salt" refers to an acid addition salt in the present invention. "Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, phosphate, etc.; organic acid salts include but not limited to formate, acetate, propionate, glycolate, gluconate , Lactate, Oxalate, Maleate, Succinate, Fumarate, Tartrate, Citrate, Glutamate, Aspartate, Benzoate, Methanesulfonate , p-toluenesulfonate and salicylate, etc. the
本发明中提及的“溶剂化物”是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，一个与水形成的配合物称为“水合物”。式I化合物的溶剂化物属于本发明范围之内。 The "solvate" mentioned in the present invention refers to the complex formed by the compound of the present invention and a solvent. They are either reacted in the solvent or precipitated or crystallized from the solvent. For example, a complex formed with water is called a "hydrate". Solvates of the compounds of formula I are within the scope of the present invention. the
在本发明的优选实施方式中，在式I的化合物中， In a preferred embodiment of the present invention, in the compound of formula I,
X代表S、O、S＝O、S(O)2或者NR12； X represents S, O, S=O, S(O)2 or NR12 ;
Y、Z和U为独立地代表氮或者CR11，其中R11代表氢、氟、氯、溴、甲基、三氟甲基、甲氧基或者三氟甲氧基； Y, Z and U independently represent nitrogen or CR11 , wherein R11 represents hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
W和V为独立地代表氮或者CH； W and V independently represent nitrogen or CH;
R3代表氢、氟、氯、溴、氰基、甲基、三氟甲基、甲氧基、乙氧基或者三氟甲氧基； R represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy;
R4和R5独立地代表氢、氟、氯、溴、甲基、三氟甲基、甲氧基、乙氧基或者三氟甲氧基，其中R4或者R5不同时为氢。 R4 and R5 independently represent hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy, wherein R4 or R5 are not simultaneously hydrogen.
其中： in:
R6、R7、R8或者R9独立地代表氢、氟、氯、溴、甲基、三氟甲基、甲氧基或者三氟甲氧基； R6 , R7 , R8 or R9 independently represent hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy or trifluoromethoxy;
R10代表氟、氯、氰基、甲基、乙基、异丙基、三氟甲基、甲氧基、异丙氧基、二氟甲氧基，三氟甲氧基、环丙基、甲磺酰基、二甲胺基、NHS(O)2Me、吗啉基或者哌嗪基，其中吗啉基或者哌嗪基未被取代或者被1或2个甲基取代。 R10 represents fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl, Methanesulfonyl, dimethylamino, NHS(O)2 Me, morpholinyl or piperazinyl, wherein the morpholinyl or piperazinyl is unsubstituted or substituted with 1 or 2 methyl groups.
其中： in:
R1或者R2独立地代表氢、甲基或者羟基取代的甲基。 R1 or R2 independently represent hydrogen, methyl or hydroxy-substituted methyl.
其中： in:
R4和R5独立地代表氢、氯或者甲基，其中R4和R5不同时为氢。 R4 and R5 independently represent hydrogen, chlorine or methyl, wherein R4 and R5 are not hydrogen at the same time.
其中： in:
X代表S、O、S＝O、S(O)2或者NR12，其中R12代表甲基、乙基、乙酰基、甲磺酰基、苄基、吡啶甲基或者噻唑甲基； X represents S, O, S=O, S(O)2 or NR12 , wherein R12 represents methyl, ethyl, acetyl, methanesulfonyl, benzyl, picolyl or thiazolylmethyl;
Y、Z和U独立地代表氮、CH或者CHF。 Y, Z and U independently represent nitrogen, CH or CHF. the
其中： in:
m和1代表1；当n代表0或2时，R1和R2同时为氢； m and 1 represent 1; when n represents 0 or 2,R1 andR2 are hydrogen at the same time;
R6和R7独立地代表氢或者氯； R6 and R7 independently represent hydrogen or chlorine;
R8和R9独立地选自氢、甲基、氟或者氯； RandR are independently selected from hydrogen, methyl, fluorine or chlorine;
R10代表甲氧基、三氟甲氧基、三氟甲基、二氟甲氧基或者氰基。 R10 represents methoxy, trifluoromethoxy, trifluoromethyl, difluoromethoxy or cyano.
根据本发明，更优选的式I化合物的实例为： According to the present invention, the example of more preferred formula I compound is:
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-(哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-(piperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-(4-甲基哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-(4-methylpiperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-(4-乙基哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-(4-ethylpiperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[(3S)-3-甲基哌嗪-1-基]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(3S)-3-methylpiperazin-1-yl]nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-(4-乙酰基哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-(4-acetylpiperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-(4-苄基哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-(4-benzylpiperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-硫代吗啉烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-thiomorpholine nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[(3R，5S)-3，5-二甲基哌嗪-1-基]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(3R,5S)-3,5-dimethylpiperazin-1-yl ]Nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-吗啉烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-morpholine nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-吗啉烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-morpholine nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-[(2R，6S)-2，6-二甲基吗啉基]烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-[(2R,6S)-2,6-dimethylmorpholinyl]nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-吗啉烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-morpholine nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-(哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-(piperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-(3，5-二甲基哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-(3,5-dimethylpiperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-[(2R，6S)-2，6-二甲基吗啉基]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-[(2R,6S)-2,6-dimethylmorpholinyl]nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-硫代吗啉烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-thiomorpholine nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-{[(3R)-3-N，N-二甲基氨基]四氢吡咯-1-基}烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-{[(3R)-3-N,N-dimethylamino]tetrahydropyrrole- 1-yl} nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-{[(3S)-3-N，N-二甲基氨基]四氢吡咯-1-基}烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-{[(3S)-3-N,N-dimethylamino]tetrahydropyrrole- 1-yl} nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-(4-甲基-1，4-二氮杂 
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-[(3R)-3-甲基哌嗪-1-基]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-[(3R)-3-methylpiperazin-1-yl]nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-[(3S)-3-甲基哌嗪-1-基]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-[(3S)-3-methylpiperazin-1-yl]nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-(3，4-甲基哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-(3,4-methylpiperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-(4-苄基哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-(4-benzylpiperazin-1-yl)nicotinamide;
5-{5-{2-甲基-3-[4’-(三氟甲基)苯基]苯基-氨基甲酰基}-吡啶-2-基}-(1S，4S)-2，5-二氮杂 
5-{5-{2-甲基-[4’-(三氟甲基)苯基]苯基-氨基甲酰基}-吡啶-2-基}-1，4-二氮杂 
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-(1，1-二氧代-硫代吗啉)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-(1,1-dioxo-thiomorpholine)nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-[4-(甲磺酰基)哌嗪-1基]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-[4-(methylsulfonyl)piperazin-1 base]nicotinamide;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-[4-(乙酰基)哌嗪-1基]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-[4-(acetyl)piperazin-1 base]nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-(4-甲基-1，4-二氮杂 
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-{[(3R)-3-N，N-二甲基氨基]四氢吡咯-1-基}烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-{[(3R)-3-N,N-dimethylamino]tetrahydropyrrole -1-yl}nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-{[(3S)-3-N，N-二甲基氨基]四氢吡咯-1-基}烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-{[(3S)-3-N,N-dimethylamino]tetrahydropyrrole -1-yl}nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-(1，1-二氧代-硫代吗啉)烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-(1,1-dioxo-thiomorpholine)nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-(1，4-二氮杂 
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-(2，5-二氮杂 
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[(3R)-3-甲基哌嗪-1-基]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(3R)-3-methylpiperazin-1-yl]nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[4-(甲磺酰基)哌嗪-1-基]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[4-(methylsulfonyl)piperazin-1-yl]nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-(4-甲基-1，4-二氮杂 
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-{[(3S)-3-N，N-二甲基氨基]四氢吡咯-1-基}烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-{[(3S)-3-N,N-dimethylamino]tetrahydropyrrole-1- Base} Nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-{[(3R)-3-N，N-二甲基氨基]四氢吡咯-1-基}烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-{[(3R)-3-N,N-dimethylamino]tetrahydropyrrole-1- Base} Nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-[(3S)-3-甲基哌嗪-1-基]烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-[(3S)-3-methylpiperazin-1-yl]nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-[(3R)-3-甲基哌嗪-1-基]烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-[(3R)-3-methylpiperazin-1-yl]nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-(1，1-二氧代-硫代吗啉)烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-(1,1-dioxo-thiomorpholine)nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-(4-苄基哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-(4-benzylpiperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-(3，5-二甲基哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-(3,5-dimethylpiperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-硫代吗啉烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-thiomorpholine nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-(3，4-二甲基哌嗪-1-基)烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-(3,4-dimethylpiperazin-1-yl)nicotinamide;
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-(2，5-二氮杂 
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-(1，4-二氮杂 
N-{2-甲基-3-[4’-(氰基)苯基]}苯基-6-[4-(甲磺酰基)哌嗪-1-基]烟酰胺； N-{2-methyl-3-[4'-(cyano)phenyl]}phenyl-6-[4-(methylsulfonyl)piperazin-1-yl]nicotinamide;
N-{2-甲基-3-[4’-(二氟甲氧基)苯基]}苯基-6-[(2R，6S)-2，6-二甲基吗啉]烟酰胺； N-{2-methyl-3-[4'-(difluoromethoxy)phenyl]}phenyl-6-[(2R,6S)-2,6-dimethylmorpholine]nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[(2R，6S)-2，6-二甲基吗啉]哒嗪-3酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(2R,6S)-2,6-dimethylmorpholine]pyridazine- 3 amides;
N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-[4-(苯基)哌嗪-1基]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-[4-(phenyl)piperazin-1 base]nicotinamide;
N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[(2R，6S)-2，6-二甲基吗啉]烟酰胺； N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(2R,6S)-2,6-dimethylmorpholine]nicotinamide;
N-{2-甲基-3-[4’-(二氟甲氧基)苯基]}苯基-6-(1，1-二氧代-硫代吗啉)烟酰胺； N-{2-methyl-3-[4'-(difluoromethoxy)phenyl]}phenyl-6-(1,1-dioxo-thiomorpholine)nicotinamide;
N-{4-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[(2R，6S)-2，6-二甲基吗啉]烟酰胺； N-{4-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(2R,6S)-2,6-dimethylmorpholine]nicotinamide;
本发明的通式I化合物合成方法可按照下列反应路线I或II所示的步骤进行制备： The synthesis method of the compound of general formula I of the present invention can be prepared according to the steps shown in the following reaction scheme I or II:
反应路线I Reaction Scheme I
反应路线I中的化合物I的合成通法，在反应路线I的路线图中详细描述。 The general synthesis of compound I in Reaction Scheme I is described in detail in the scheme of Reaction Scheme I. the
步骤1：式1d的多取代或单取代的苯硼酸起始原料与式1c的取代的溴代苯胺通过Suzuki偶联反应制备式1b的中间体。 Step 1: The polysubstituted or monosubstituted phenylboronic acid starting material of formula 1d and the substituted bromoaniline of formula 1c are prepared by Suzuki coupling reaction to prepare the intermediate of formula 1b. the
其中，Suzuki偶联反应的方法可以参考文献(Kotha，S.；Lahiri，K and Kashinath，D.Tetrahedron 2002，48，9633-9695)中的方法；使用的钯催化剂可以选自于双三苯基磷二氯化钯(Pd(PPh3)2Cl2)、四(三苯基膦)钯(Pd(PPh3)4)、乙酸钯(Pd(OAc)2)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)以及氯化钯(PdCl2)；反应温度在80℃至160℃；反应溶剂可以选自于1，4-二氧六环、甲苯、乙醇以及水；无机碱可以选择碳酸钠、碳酸钾等。 Wherein, the method of Suzuki coupling reaction can refer to the method in the literature (Kotha, S.; Lahiri, K and Kashinath, D.Tetrahedron 2002,48,9633-9695); The palladium catalyst used can be selected from bistriphenyl Phosphorous palladium dichloride (Pd(PPh3 )2 Cl2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh3 )4 ), palladium acetate (Pd(OAc)2 ), [1,1′-bis (Diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2 ) and palladium chloride (PdCl2 ); the reaction temperature is from 80°C to 160°C; the reaction solvent can be selected from 1,4 -Dioxane, toluene, ethanol and water; sodium carbonate, potassium carbonate and the like can be selected for the inorganic base.
例如，苯硼酸与2-氨基溴苯在催化剂为四(三苯基膦)钯(Pd(PPh3)4)，无机碱为碳酸钠，反应溶剂为甲苯、乙醇以及水的混合溶液中，加热到100℃-130℃，反应12小时得到相对应的产物。 For example, phenylboronic acid and 2-aminobromobenzene are heated in a mixed solution in which the catalyst is tetrakis(triphenylphosphine) palladium (Pd(PPh3 )4 ), the inorganic base is sodium carbonate, and the reaction solvent is toluene, ethanol and water. To 100°C-130°C, react for 12 hours to obtain the corresponding product.
步骤2：取代杂环羧酸特别是取代烟酸与式1b的中间体缩合制备相应的式1a的酰胺化合物。 Step 2: Condensation of substituted heterocyclic carboxylic acid, especially substituted nicotinic acid, with the intermediate of formula 1b to prepare the corresponding amide compound of formula 1a. the
其中，制备酰胺的反应可选择将取代烟酸与氯化亚砜或者草酰氯反应的方法制备相应的取代烟酰氯，随后与式1b的化合物缩合制备得到相应的式1a的化合物；也可选择DCC(二环己基碳二亚胺)、EDC(1-乙基-3-(3-三甲氨丙基)碳二亚胺)、HATU(2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯)、 TBTU(O-苯并三氮唑-N，N，N′，N′-四甲基脲四氟硼酸酯)、DIC(N，N′-二异丙基碳二亚胺)等缩合剂制备相应的式1a的酰胺；也可选择将取代烟酸与CDI(N，N′-羰基二咪唑)等一些试剂反应制备相应的活泼酰胺，然后制备对应的式1a酰胺。 Among them, the reaction of preparing amide can be selected by reacting substituted nicotinic acid with thionyl chloride or oxalyl chloride to prepare the corresponding substituted nicotinyl chloride, and then condensing with the compound of formula 1b to prepare the corresponding compound of formula 1a; DCC can also be selected (Dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-trimethylaminopropyl) carbodiimide), HATU (2-(7-azobenzotriazole)-N , N, N', N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N, N, N', N'-tetramethyluronium tetrafluoroborate), Condensing agents such as DIC (N, N'-diisopropylcarbodiimide) to prepare the corresponding amides of formula 1a; you can also choose to react substituted nicotinic acid with some reagents such as CDI (N, N'-carbonyldiimidazole) The corresponding active amide is prepared, followed by the corresponding amide of formula la. the
其中，所选用的碱可以选自于三乙胺、二异丙基乙胺(DIPEA)、吡啶、二甲氨基吡啶(DMAP)等；反应溶剂可选自于二氯甲烷、四氢呋喃、1，4-二氧六环、N，N-二甲基甲酰胺(DMF)等溶剂；反应温度可选择0℃至室温。 Wherein, the selected base can be selected from triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) etc.; the reaction solvent can be selected from dichloromethane, tetrahydrofuran, 1,4 -Solvents such as dioxane, N,N-dimethylformamide (DMF); the reaction temperature can be selected from 0°C to room temperature. the
步骤3：可选择相对应的式1a化合物与对应的胺或其它具有亲核取代活性的试剂进行反应来生成式I化合物。 Step 3: The corresponding compound of formula 1a can be selected to react with the corresponding amine or other reagents with nucleophilic substitution activity to generate the compound of formula I. the
其中，反应溶剂可选自于二甲基亚砜(DMSO)、N，N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮、乙醇以及异丙醇等溶剂；在选自于三乙胺、二异丙基乙基胺(DIPEA)、碳酸钾、碳酸铯或碳酸钠等碱的作用下，反应温度在80℃-240℃，与相应的式1a化合物反应制备对应的式I化合物。 Wherein, the reaction solvent can be selected from solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N-methylpyrrolidone, ethanol and isopropanol; Under the action of bases such as amine, diisopropylethylamine (DIPEA), potassium carbonate, cesium carbonate or sodium carbonate, react with the corresponding compound of formula 1a at a reaction temperature of 80°C to 240°C to prepare the corresponding compound of formula I. the
反应路线II Reaction Scheme II
反应路线II中的化合物I的合成通法，在反应路线II的路线图中详细描述。 The general synthesis of compound I in Reaction Scheme II is described in detail in the scheme of Reaction Scheme II. the
步骤1：取代杂环羧酸特别是取代烟酸与式1c化合物缩合制备相应的式1b的酰胺化合物。 Step 1: Condensation of substituted heterocyclic carboxylic acid, especially substituted nicotinic acid, with the compound of formula 1c to prepare the corresponding amide compound of formula 1b. the
其中，制备酰胺的反应可选择将取代烟酸与氯化亚砜或者草酰氯反应的方 法制备相应的取代烟酰氯，随后与式1c的化合物缩合制备得到相应的式1b的化合物；也可选择DCC(二环己基碳二亚胺)、EDC(1-乙基-3-(3-三甲氨丙基)碳二亚胺)、HATU(2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯)、TBTU(O-苯并三氮唑-N，N，N′，N′-四甲基脲四氟硼酸酯)、DIC(N，N′-二异丙基碳二亚胺)等缩合剂制备相应的式1b的酰胺；也可选择将取代烟酸与CDI(N，N′-羰基二咪唑)等一些试剂反应制备相应的活泼酰胺，然后制备对应的式1b酰胺。 Among them, the reaction of preparing amides can be selected to react substituted nicotinic acid with thionyl chloride or oxalyl chloride to prepare the corresponding substituted nicotinyl chloride, and then condense with the compound of formula 1c to obtain the corresponding compound of formula 1b; DCC (dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-trimethylaminopropyl) carbodiimide), HATU (2-(7-azobenzotriazole)- N, N, N', N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N, N, N', N'-tetramethyluronium tetrafluoroborate) , DIC (N, N'-diisopropylcarbodiimide) and other condensing agents to prepare the corresponding amides of formula 1b; it is also possible to choose some reagents such as substituted nicotinic acid and CDI (N, N'-carbonyldiimidazole) The reaction produces the corresponding reactive amide, which then produces the corresponding amide of formula 1b. the
其中，所选用的碱可以选自于三乙胺、二异丙基乙胺(DIPEA)、吡啶、二甲氨基吡啶(DMAP)等；反应溶剂可选自于二氯甲烷、四氢呋喃、1，4-二氧六环、N，N-二甲基甲酰胺(DMF)等溶剂；反应温度可选择0℃至室温。 Wherein, the selected base can be selected from triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) etc.; the reaction solvent can be selected from dichloromethane, tetrahydrofuran, 1,4 -Solvents such as dioxane, N,N-dimethylformamide (DMF); the reaction temperature can be selected from 0°C to room temperature. the
步骤2：可选择相对应的式1b化合物与对应的胺或其它具有亲核取代活性的试剂(A)进行反应来生成式1a化合物。 Step 2: The corresponding compound of formula 1b can be selected to react with the corresponding amine or other reagent (A) having nucleophilic substitution activity to generate the compound of formula 1a. the
其中，反应溶剂可选自于二甲基亚砜(DMSO)、N，N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮、乙醇以及异丙醇等溶剂；在选自于三乙胺、二异丙基乙基胺(DIPEA)、碳酸钾、碳酸铯以及碳酸钠等的碱的作用下，反应温度在80℃-240℃，与相应的式1b化合物反应制备对应的式1a化合物。 Wherein, the reaction solvent can be selected from solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N-methylpyrrolidone, ethanol and isopropanol; Under the action of bases such as amine, diisopropylethylamine (DIPEA), potassium carbonate, cesium carbonate, and sodium carbonate, the reaction temperature is 80°C-240°C, and the corresponding compound of formula 1b is reacted to prepare the corresponding compound of formula 1a . the
步骤3：多取代或单取代的苯硼酸与式1a的中间体通过Suzuki偶联反应制备式I化合物。 Step 3: The compound of formula I is prepared by Suzuki coupling reaction between polysubstituted or monosubstituted phenylboronic acid and the intermediate of formula 1a. the
其中，Suzuki偶联反应的方法可以参考文献(Kotha，S.；Lahiri，K and Kashinath，D.Tetrahedron 2002，48，9633-9695)中的方法；使用的钯催化剂可以选自于双三苯基磷二氯化钯(Pd(PPh3)2Cl2)、四(三苯基膦)钯(Pd(PPh3)4)、乙酸钯(Pd(OAc)2)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)以及氯化钯(PdCl2)；反应温度在80℃-160℃；反应溶剂可以选自于1，4-二氧六环、甲苯、乙醇以及水；无机碱可以选择碳酸钠、碳酸钾等。 Wherein, the method of Suzuki coupling reaction can refer to the method in the literature (Kotha, S.; Lahiri, K and Kashinath, D.Tetrahedron 2002,48,9633-9695); The palladium catalyst used can be selected from bistriphenyl Phosphorous palladium dichloride (Pd(PPh3)2 Cl2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh3 )4 ), palladium acetate (Pd(OAc)2 ), [1,1′-bis( Diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2 ) and palladium chloride (PdCl2 ); the reaction temperature is 80°C-160°C; the reaction solvent can be selected from 1,4- Dioxane, toluene, ethanol, and water; sodium carbonate, potassium carbonate, etc. can be selected as the inorganic base.
例如，苯硼酸与2-氨基溴苯在催化剂为四(三苯基膦)钯(Pd(pph3)4)，无机碱为碳酸钠，反应溶剂为甲苯、乙醇以及水的混合溶液中，加热到100℃-130℃，反应12小时得到相对应的产物。 For example, phenylboronic acid and 2-aminobromobenzene are heated in a mixed solution in which the catalyst is tetrakis(triphenylphosphine) palladium (Pd(pph3 )4 ), the inorganic base is sodium carbonate, and the reaction solvent is toluene, ethanol and water. To 100°C-130°C, react for 12 hours to obtain the corresponding product.
本发明的化合物可能含一个或多个手性碳原子，因此，化合物可以作为对映异构体、非对映异构体或它们的混合物存在。上述化合物可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。非对映化合物可由结晶或色谱 法分离。对映异构体也可经由结晶、手性色谱或其他已知方法分离。每个不对称碳原子可以是R或S构型，两种构型都在本发明范围之内。 The compounds of the present invention may contain one or more chiral carbon atoms and thus the compounds may exist as enantiomers, diastereomers or mixtures thereof. The above compounds can be selected from racemates, diastereomers or enantiomers as starting materials or intermediates. Diastereomeric compounds can be separated by crystallization or chromatography. Enantiomers may also be separated via crystallization, chiral chromatography or other known methods. Each asymmetric carbon atom can be in the R or S configuration, both configurations are within the scope of this invention. the
本发明包括上述化合物的前药。前药包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到母体化合物；本发明的前药特指与氨基形成的前药，通常由本发明化合物中的活泼氮原子与活化的酰基化合物反应制备而得。具体的前药制备方法可参照(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.Chem Lett.1994，4，1985-1990.Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。 The present invention includes prodrugs of the above compounds. Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed or released via enzymatic reactions to obtain parent compounds under physiological conditions; prodrugs of the present invention specifically refer to prodrugs formed with amino groups, usually by active Prepared by reacting nitrogen atoms with activated acyl compounds. Concrete prodrug preparation method can refer to (Saulnier, M.G.; Frennesson, D.B.; Deshpande, M.S.; Hansel, S.B and Vysa, D.M.Bioorg.Med.Chem Lett.1994,4,1985-1990.Greenwald, R.B.; Choe, Y.H. ; Conover, C.D.; Shum, K.; Wu, D.; Royzen, M.J. Med. Chem. 2000, 43, 475.). the
通常，本发明化合物可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括但不限于水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。 In general, the compounds of the present invention can be administered in suitable dosage forms with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, buccal and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, syrups and the like. The compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions and the like. The above-mentioned dosage forms can be made from the active compound and one or more carriers or excipients through common pharmaceutical methods. The aforementioned carriers need to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include, but are not limited to, water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like. The active compounds can form solutions or suspensions with the above-mentioned carriers. the
具体的给药方式和剂型取决于化合物本身的理化性质以及所应用疾病的严重程度等。 The specific administration method and dosage form depend on the physical and chemical properties of the compound itself and the severity of the applied disease. the
一方面，本发明的化合物或剂型适用于热血动物；在另一方面，本发明的化合物和剂型适用于哺乳动物，比如人类。 In one aspect, the compounds or dosage forms of the invention are suitable for use in warm-blooded animals; in another aspect, the compounds and dosage forms of the invention are suitable for use in mammals, such as humans. the
本发明的化合物可抑制hedgehog信号转导，因此用于治疗当ptch1不能或不能充分抑制Smo(Ptch1失功能表型)时和/或当Smo在Ptch1抑制的情况下依然具有活性(Smo获功能表型)时异常的Hedgehog通路有关的癌症。 The compounds of the present invention inhibit hedgehog signaling and are therefore useful in the treatment of Smo when ptch1 is unable or insufficient to inhibit Smo (Ptch1 loss-of-function phenotype) and/or when Smo is active in the presence of Ptch1 inhibition (Smo gain-of-function phenotype). type) in cancers associated with abnormal Hedgehog pathway. the
本发明化合物可以单独应用于基底细胞癌和髓母细胞瘤等肿瘤，也可以与其他药物组合施用于(但不限于)胰腺癌、乳腺癌、脊膜瘤、恶性胶质瘤、黑色素瘤、胃癌、食道癌、胆管癌、前列腺癌、结肠癌、小细胞肺癌、非小细胞肺癌、神经胶质细胞癌以及多发性骨髓瘤等。 The compound of the present invention can be applied to tumors such as basal cell carcinoma and medulloblastoma alone, and can also be administered in combination with other drugs (but not limited to) pancreatic cancer, breast cancer, meningioma, malignant glioma, melanoma, gastric cancer , Esophageal cancer, bile duct cancer, prostate cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, glial cell carcinoma, and multiple myeloma. the
可以与本化合物联用的药物包括但不限于吉西他滨、顺铂、卡铂、格列卫、替莫唑胺、阿霉素、达卡巴嗪、特罗凯、依托泊苷、柔红霉素以及阿糖胞苷等。 Drugs that can be used in combination with this compound include, but are not limited to, gemcitabine, cisplatin, carboplatin, Gleevec, temozolomide, doxorubicin, dacarbazine, tarceva, etoposide, daunorubicin, and arabinosin Glycosides etc. the
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。通常，一般经胃肠道外给药的剂量是1-200mg/kg。口服给药的剂型可以含有1-1000mg/kg本发明的化合物。 The compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice. The "effective amount" of a compound to be administered is determined by factors such as the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration. Usually, the general dosage for parenteral administration is 1-200 mg/kg. Dosage forms for oral administration may contain 1-1000 mg/kg of the compound of the invention. the
实施例 Example
下文所描述的实验、合成方法以及所涉及的中间体是对本发明的阐明，并不限制本发明的范围。 The experiments, synthesis methods and intermediates described below are illustrative of the present invention and do not limit the scope of the present invention. the
本发明中实验所使用的起始原料或购买自试剂供应商或经由标准方法由已知原料制备。除非另有说明，本文的实施例应用下述条件： The starting materials used in the experiments in the present invention were either purchased from reagent suppliers or prepared from known materials by standard methods. Unless otherwise stated, the examples herein apply the following conditions:
1)温度的单位是摄氏度(℃)；室温的定义是18-25℃； 1) The unit of temperature is Celsius (°C); the definition of room temperature is 18-25°C;
2)有机溶剂使用无水硫酸镁或无水硫酸钠干燥；使用旋转蒸发仪在减压升温条件下旋干(例如：15mmHg，30℃)； 2) Dry the organic solvent with anhydrous magnesium sulfate or anhydrous sodium sulfate; use a rotary evaporator to spin dry under reduced pressure and elevated temperature (for example: 15mmHg, 30°C);
3)柱层析分离时使用硅胶作为载体，TLC表示硅胶薄层板； 3) Silica gel is used as a carrier during column chromatography separation, and TLC indicates a silica gel thin-layer plate;
4)通常情况下，反应的进度通过TLC或LC-MS监测； 4) Usually, the progress of the reaction is monitored by TLC or LC-MS;
5)最终产品的鉴定由核磁共振(Bruker AVANCE 300，300MHz)和LC-MS(Bruker esquine 6000，Agilent 1200series)完成。 5) The identification of the final product was completed by nuclear magnetic resonance (Bruker AVANCE 300, 300MHz) and LC-MS (Bruker esquine 6000, Agilent 1200series). the
制备实施例1：N-{2-甲基-3-[4’-(三氟甲基)苯基]}苯基-6-吗啉烟酰胺的合成 Preparation Example 1: Synthesis ofN-{2-methyl-3-[4'-(trifluoromethyl)phenyl]}phenyl-6-morpholine nicotinamide
1)制备式3的3-氨基-2-甲基-4’-三氟甲基联苯：1) 3-amino-2-methyl-4'-trifluoromethylbiphenyl of preparation formula 3:
称取3-溴-2-甲基苯胺(1.0g，5.4mmol，式1化合物)、4-三氟甲基苯硼酸(1.3g，6.8mmol，式2化合物)、双三苯基磷二氯化钯(0.4g，0.54mmol)以及碳酸钠(1.7g，16.0mmol)置于微波合成反应管中，氮气保护，微波加热至120℃反应30min。反应完毕后过滤除去不溶物，滤液用水稀释，乙酸乙酯萃取，有机相用盐水洗涤，无水硫酸钠干燥。减压除去溶剂，粗品经柱层析纯化(正己烷∶乙酸乙酯8∶1)，得黄色固体(1.3g，90.0％，式3化合物)。 Weigh 3-bromo-2-methylaniline (1.0g, 5.4mmol, compound of formula 1), 4-trifluoromethylphenylboronic acid (1.3g, 6.8mmol, compound of formula 2), bistriphenylphosphine dichloride Palladium chloride (0.4 g, 0.54 mmol) and sodium carbonate (1.7 g, 16.0 mmol) were placed in a microwave synthesis reaction tube under nitrogen protection, and heated to 120° C. for 30 min by microwave. After the reaction was completed, the insoluble matter was removed by filtration, the filtrate was diluted with water, extracted with ethyl acetate, the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (n-hexane:ethyl acetate 8:1) to obtain a yellow solid (1.3 g, 90.0%, compound of formula 3). the
1H-NMR(300MHz，DMSO-d6)δ：7.65(d，2H，J＝8.1Hz)，7.42(d，2H，J＝8.1Hz)，7.09(t，1H，J＝7.8Hz)，6.75(d，1H，J＝7.8Hz)，6.67(d，1H，J＝7.5Hz)，3.86(br，2H)，2.04(s，3H). 1 H-NMR (300MHz, DMSO-d6 ) δ: 7.65 (d, 2H, J=8.1Hz), 7.42 (d, 2H, J=8.1Hz), 7.09 (t, 1H, J=7.8Hz), 6.75(d, 1H, J=7.8Hz), 6.67(d, 1H, J=7.5Hz), 3.86(br, 2H), 2.04(s, 3H).
MS(ESI，m/z)：[M+H]+251.9 MS (ESI, m/z): [M+H]+ 251.9
2)制备式5的6-氯-N-(2-甲基-4′-三氟甲基联苯基)烟酰胺：2) Preparation of 6-chloro-N-(2-methyl-4′-trifluoromethylbiphenyl)nicotinamide of formula 5:
将3-氨基-2-甲基-4’-三氟甲基联苯(1.3g，5.2mmol，式3化合物)、6-氯代烟酸(1.06g，6.73mmol，式4化合物)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI，1.5g，7.83mmol)混合溶于15mL吡啶中，于室温搅拌反应20h。TLC检测反应，反应完毕后，除去溶剂，油状物溶于乙酸乙酯，依次用水、饱和食盐水洗涤，无水硫酸钠干燥。除去溶剂的粗品，经硅胶柱层析纯化(正己烷∶乙酸乙酯10∶1～3∶1)，得白色固体(1.4g，69.2％，式5化合物)。 3-amino-2-methyl-4'-trifluoromethylbiphenyl (1.3g, 5.2mmol, compound of formula 3), 6-chloronicotinic acid (1.06g, 6.73mmol, compound of formula 4) and 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.5 g, 7.83 mmol) was mixed and dissolved in 15 mL of pyridine, and stirred at room temperature for 20 h. The reaction was detected by TLC. After the reaction was completed, the solvent was removed, and the oil was dissolved in ethyl acetate, washed with water and saturated brine in turn, and dried over anhydrous sodium sulfate. The crude product from which the solvent was removed was purified by silica gel column chromatography (n-hexane: ethyl acetate 10:1-3:1) to obtain a white solid (1.4 g, 69.2%, compound of formula 5). the
1H-NMR(300MHz，DMSO-d6)δ：8.90(d，1H，J＝2.1Hz)，8.21(dd，1H，J＝2.1Hz，J＝8.1Hz)，7.82(d，1H，J＝7.8Hz)，7.69(d，3H，J＝8.1Hz)，7.50(d，1H，J＝8.4Hz)，7.43(d，2H，J＝8.1Hz)，7.35(t，1H，J＝7.8Hz)，7.15(d，1H，J＝7.5Hz)，2.20(s，3H). 1 H-NMR (300MHz, DMSO-d6 ) δ: 8.90(d, 1H, J=2.1Hz), 8.21(dd, 1H, J=2.1Hz, J=8.1Hz), 7.82(d, 1H, J =7.8Hz), 7.69(d, 3H, J=8.1Hz), 7.50(d, 1H, J=8.4Hz), 7.43(d, 2H, J=8.1Hz), 7.35(t, 1H, J=7.8 Hz), 7.15(d, 1H, J=7.5Hz), 2.20(s, 3H).
MS(ESI，m/z)：[M+H]+391.1 MS (ESI, m/z): [M+H]+ 391.1
3)制备式7的N-[(2-甲基-4′-三氟甲基联苯基)]烟酰胺基吗啉：3) N-[(2-methyl-4'-trifluoromethylbiphenyl)]nicotinamidomorpholine of formula 7:
称取6-氯-N-(2-甲基-4′-三氟甲基联苯基)烟酰胺(50mg，0.13mmol，式5的化合物)、吗啡啉(55mg，0.64mmol)及碳酸钾(37mg，0.27mmol)置于微波合成反应管中，加入1～2mL的DMSO，微波加热至180℃反应30min。反应完毕后将反应物滴加至10mL水中，收集析出的固体，用水、正己烷洗涤，干燥，得粗品。经薄层色谱硅胶制备板纯化，得类白色固体(37mg，64.5％，式7化合物)。 Weigh 6-chloro-N-(2-methyl-4'-trifluoromethylbiphenyl)nicotinamide (50mg, 0.13mmol, compound of formula 5), morpholine (55mg, 0.64mmol) and potassium carbonate (37 mg, 0.27 mmol) was placed in a microwave synthesis reaction tube, 1-2 mL of DMSO was added, and heated to 180° C. for 30 min by microwave. After the reaction was completed, the reactant was added dropwise to 10 mL of water, and the precipitated solid was collected, washed with water and n-hexane, and dried to obtain a crude product. Purification by thin-layer chromatography on silica gel preparative plate afforded an off-white solid (37 mg, 64.5%, compound of formula 7). the
1H-NMR(300MHz，DMSO-d6)δ：9.81(s，1H)，8.78(d，1H，J＝2.4Hz)，8.11 (dd，1H，J＝2.1Hz，J＝9.0Hz)，7.83(d，2H，J＝8.1Hz)，7.56(d，2H，J＝8.1Hz)，7.40(d，1H，J＝6.9Hz)，7.32(t，1H，J＝7.5Hz)，7.16(dd，1H，J＝7.5Hz)，6.93(d，1H，J＝9.0Hz)，3.71(t，4H，J＝4.2Hz)，3.59(t，4H，J＝5.1Hz)，2.09(s，3H). 1 H-NMR (300MHz, DMSO-d6 ) δ: 9.81 (s, 1H), 8.78 (d, 1H, J=2.4Hz), 8.11 (dd, 1H, J=2.1Hz, J=9.0Hz), 7.83(d, 2H, J=8.1Hz), 7.56(d, 2H, J=8.1Hz), 7.40(d, 1H, J=6.9Hz), 7.32(t, 1H, J=7.5Hz), 7.16( dd, 1H, J=7.5Hz), 6.93(d, 1H, J=9.0Hz), 3.71(t, 4H, J=4.2Hz), 3.59(t, 4H, J=5.1Hz), 2.09(s, 3H).
MS(ESI，m/z)：[M+H]+442.2 MS (ESI, m/z): [M+H]+ 442.2
制备实施例2：N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[(2R，6S)-2，6-二甲基吗啉]哒嗪-3-酰胺的合成 Preparation Example 2: N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(2R,6S)-2,6-dimethylmorph Synthesis of pheno]pyridazine-3-amides
1)制备式3的N-(3-溴-2-甲基苯基)-6-氯哒嗪-3-酰胺：1) N-(3-bromo-2-methylphenyl)-6-chloropyridazine-3-amide of formula 3:
冰浴下，将3-溴-2-甲基苯胺(372.1mg，2.0mmol，式1化合物)、6-氯哒嗪-3-酸(317.1mg，2.0mmol，式2化合物)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI，766.8mg，4.0mmol)混合溶于10mL吡啶中，室温搅拌过夜，减压除去吡啶，残渣用乙酸乙酯溶解，有机相用水洗(3×5mL)，用无水硫酸钠干燥。过滤，浓缩，硅胶柱层析纯化(正己烷∶乙酸乙酯5∶1)，得白色固体(265.0mg，40.6％，式3化合物)。 Under ice bath, 3-bromo-2-methylaniline (372.1 mg, 2.0 mmol, compound of formula 1), 6-chloropyridazine-3-acid (317.1 mg, 2.0 mmol, compound of formula 2), 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 766.8 mg, 4.0 mmol) was mixed and dissolved in 10 mL of pyridine, stirred at room temperature overnight, pyridine was removed under reduced pressure, and the residue was washed with ethyl acetate Dissolved, the organic phase was washed with water (3×5 mL), and dried over anhydrous sodium sulfate. It was filtered, concentrated, and purified by silica gel column chromatography (n-hexane:ethyl acetate 5:1) to obtain a white solid (265.0 mg, 40.6%, compound of formula 3). the
1H-NMR(300MHz，CDCl3)δ：9.95(s，1H)，8.48(d，1H，J＝8.7Hz)，8.05(d，1H，J＝8.1Hz)，7.77(d，1H，J＝8.7Hz)，7.47(d，1H，J＝8.1Hz)，7.16(t，1H，J＝8.1Hz)，2.51(s，3H). 1 H-NMR (300MHz, CDCl3 ) δ: 9.95(s, 1H), 8.48(d, 1H, J=8.7Hz), 8.05(d, 1H, J=8.1Hz), 7.77(d, 1H, J =8.7Hz), 7.47(d, 1H, J=8.1Hz), 7.16(t, 1H, J=8.1Hz), 2.51(s, 3H).
MS(ESI，m/z)：[M+H]+327.9 MS (ESI, m/z): [M+H]+ 327.9
2)制备式5的N-(3-溴-2-甲基苯基)-6-[(2R，6S)-2，6-二甲基吗啉]哒嗪-3-酰胺：2) Preparation of N-(3-bromo-2-methylphenyl)-6-[(2R,6S)-2,6-dimethylmorpholine]pyridazine-3-amide of formula 5:
将N-(3-溴-2-甲基苯基)-6-氯哒嗪-3-酰胺(100mg，0.31mmol，式3化合物)、(2R，6S)-2，6-二甲基吗啉(0.19mL，1.5mmol，式4化合物)和碳酸钾(126.7mg，0.92mmol)混合溶于4mL N，N-二甲基甲酰胺中，在微波合成仪130℃反应10min，冷却，反应液倒入冰水中，析出白色固体，抽滤，干燥，得白色固体(122mg，98.4％，式5化合物)。 N-(3-bromo-2-methylphenyl)-6-chloropyridazine-3-amide (100mg, 0.31mmol, compound of formula 3), (2R,6S)-2,6-dimethylmorpha Phenyl (0.19mL, 1.5mmol, compound of formula 4) and potassium carbonate (126.7mg, 0.92mmol) were mixed and dissolved in 4mL N,N-dimethylformamide, reacted in a microwave synthesizer at 130°C for 10min, cooled, and the reaction solution Pour it into ice water to precipitate a white solid, filter it with suction, and dry it to obtain a white solid (122mg, 98.4%, compound of formula 5). the
1H-NMR(300MHz，CDCl3)δ：9.81(s，1H)，8.12(t，2H，J＝3.3Hz)，7.41(d，1H，J＝8.1Hz)，7.12(t，1H，J＝8.1Hz)，7.02(d，1H，J＝9.6Hz)，4.30(d，2H，J＝13.2Hz)，3.75(m，2H)，2.77(dd，2H，J＝10.8Hz，J＝12.9Hz)，2.50(s，3H)，1.30(d，6H，J＝6.3Hz). 1 H-NMR (300MHz, CDCl3 ) δ: 9.81(s, 1H), 8.12(t, 2H, J=3.3Hz), 7.41(d, 1H, J=8.1Hz), 7.12(t, 1H, J =8.1Hz), 7.02(d, 1H, J=9.6Hz), 4.30(d, 2H, J=13.2Hz), 3.75(m, 2H), 2.77(dd, 2H, J=10.8Hz, J=12.9 Hz), 2.50(s, 3H), 1.30(d, 6H, J=6.3Hz).
MS(ESI，m/z)：[M+H]+405.2 MS (ESI, m/z): [M+H]+ 405.2
3)制备式7的N-{2-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[(2R，6S)-2，6-二甲基吗啉]哒嗪-3-酰胺：3) N-{2-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(2R, 6S)-2,6-dimethyl of the preparation formula 7 Morpholine]pyridazine-3-amide:
在氮气保护下，将N-(3-溴-2-甲基苯基)-6-[(2R，6S)-2，6-二甲基吗啉]哒嗪-3-酰胺(100mg，0.20mmol，式5化合物)、4-三氟甲氧基苯硼酸(61.4mg，0.30mmol，式6化合物)、双三苯基磷二氯化钯(27.9mg，0.04mmol)和碳酸钠(63.3mg，0.60mmol)加入到4mL 1，4-二氧六环和水(3∶1)的混合溶剂中，在微波合成仪130℃反应60min，抽滤，硅胶柱层析(正己烷∶乙酸乙酯1∶4)，得白色固体(50.0mg，51.6％，式7化合物)。 Under nitrogen protection, N-(3-bromo-2-methylphenyl)-6-[(2R,6S)-2,6-dimethylmorpholine]pyridazine-3-amide (100mg, 0.20 mmol, compound of formula 5), 4-trifluoromethoxyphenylboronic acid (61.4 mg, 0.30 mmol, compound of formula 6), bistriphenylphosphine palladium dichloride (27.9 mg, 0.04 mmol) and sodium carbonate (63.3 mg , 0.60mmol) was added to 4mL of 1,4-dioxane and water (3:1) mixed solvent, reacted in a microwave synthesizer at 130°C for 60min, suction filtered, silica gel column chromatography (n-hexane: ethyl acetate 1:4), a white solid (50.0 mg, 51.6%, compound of formula 7) was obtained. the
1H-NMR(300MHz，CDCl3)δ：9.85(s，1H)，8.23(m，2H)，7.30(m，5H)，7.06(m，2H)，4.30(d，2H，J＝12.3Hz)，3.76(br，2H)，2.78(t，2H，J＝11.4Hz)，2.25(s，3H)，1.30(m，6H). 1 H-NMR (300MHz, CDCl3 ) δ: 9.85(s, 1H), 8.23(m, 2H), 7.30(m, 5H), 7.06(m, 2H), 4.30(d, 2H, J=12.3Hz ), 3.76(br, 2H), 2.78(t, 2H, J=11.4Hz), 2.25(s, 3H), 1.30(m, 6H).
MS(ESI，m/z)：[M+H]+487.3 MS (ESI, m/z): [M+H]+ 487.3
制备实施例3：N-{4-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[(2R，6S)-2，6-二甲基吗啉]烟酰胺的合成Preparation Example 3: N-{4-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(2R,6S)-2,6-dimethylmorph Synthesis of pheno]nicotinamide
1)制备式3的N-(3-溴-4-甲基苯基)-6-氯-烟酰胺：1) N-(3-bromo-4-methylphenyl)-6-chloro-nicotinamide of formula 3:
将3-溴-4甲基苯胺(169mg，1.07mmol，式1化合物)，6-氯代烟酸化合物(200mg，1.07mmol，式2化合物)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)混合溶于15mL吡啶，于室温搅拌反应20h。TLC检测反应，反应完毕后，除去溶剂，油状物溶于乙酸乙酯，依次用水、饱和食盐水洗涤，无水硫酸钠干燥。除去溶剂得黄色固体(300mg，85.8％，式3化合物)。 3-Bromo-4 methylaniline (169mg, 1.07mmol, compound of formula 1), 6-chloronicotinic acid compound (200mg, 1.07mmol, compound of formula 2) and 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (EDCI) was mixed and dissolved in 15 mL of pyridine, and stirred at room temperature for 20 h. The reaction was detected by TLC. After the reaction was completed, the solvent was removed, and the oil was dissolved in ethyl acetate, washed with water and saturated brine in turn, and dried over anhydrous sodium sulfate. The solvent was removed to give a yellow solid (300 mg, 85.8%, compound of formula 3). the
1H-NMR(300MHz，CDCl3)δ：8.96(s，1H)，8.49(s，1H)，8.31(d，1H，J＝8.1Hz)，8.21(dd，1H，J＝2.1Hz，J＝8.4Hz)，7.50(d，1H J＝8.4Hz)，7.30(d，3H，J＝7.8Hz)，7.09(d，1H，J＝7.5Hz)，2.46(s，3H). 1 H-NMR (300MHz, CDCl3 ) δ: 8.96(s, 1H), 8.49(s, 1H), 8.31(d, 1H, J=8.1Hz), 8.21(dd, 1H, J=2.1Hz, J =8.4Hz), 7.50(d, 1H J=8.4Hz), 7.30(d, 3H, J=7.8Hz), 7.09(d, 1H, J=7.5Hz), 2.46(s, 3H).
LC-MS(m/z)：[M+H]+326.9 LC-MS (m/z): [M+H]+ 326.9
2)制备式5的N-(3-溴-4-甲基苯基)-6-[(2R，6S)-2，6-二甲基吗啉]烟酰胺：2) N-(3-bromo-4-methylphenyl)-6-[(2R,6S)-2,6-dimethylmorpholine]nicotinamide of formula 5:
称取N-(3-溴-4-甲基苯基)-6-氯-烟酰胺(100mg，0.31mmol，式3化合物)，(2R，6S)-2，6-二甲基吗啉(180mg，1.54mmol，式4化合物)及碳酸钾(85mg，0.61mmol)置于微波管中，加入1～2mL的DMF，微波加热至150℃反应30min。反应完毕后将反应物滴加至10mL水中，收集析出的固体，用水、正己烷洗涤，干燥，得粗品。经薄层色谱硅胶预制备板纯化，得黄色固体(67mg，53.5％，式5化合物)，无需纯化，直接用于下一步。 Weigh N-(3-bromo-4-methylphenyl)-6-chloro-nicotinamide (100mg, 0.31mmol, compound of formula 3), (2R,6S)-2,6-dimethylmorpholine ( 180mg, 1.54mmol, compound of formula 4) and potassium carbonate (85mg, 0.61mmol) were placed in a microwave tube, 1-2mL of DMF was added, and heated to 150°C for 30min by microwave. After the reaction was completed, the reactant was added dropwise to 10 mL of water, and the precipitated solid was collected, washed with water and n-hexane, and dried to obtain a crude product. Purified by thin-layer chromatography silica gel pre-preparation plate to obtain a yellow solid (67 mg, 53.5%, compound of formula 5), which was directly used in the next step without further purification. the
LC-MS(m/z)：[M+H]+406.0 LC-MS (m/z): [M+H]+ 406.0
3)制备式7的N-{4-甲基-3-[4’-(三氟甲氧基)苯基]}苯基-6-[(2R，6S)-2，6-二甲基吗啉]烟酰胺：3) N-{4-methyl-3-[4'-(trifluoromethoxy)phenyl]}phenyl-6-[(2R, 6S)-2,6-dimethyl of the preparation formula 7 Morpholine] Niacinamide:
称取N-(3-溴-4-甲基苯基)-6-[(2R，6S)-2，6-二甲基吗啉]烟酰胺(67mg，0.16mmol，式5化合物)，4-三氟甲氧基苯硼酸(51mg，0.25mmol，式6化合物)，双三苯基磷二氯化钯(11mg，0.016mmol)和碳酸钠(53mg，0.5mmol)置于微波合成管中，加入4mL 1，4-二氧六环和水(3∶1)的混合溶剂，加入氮气保护，在微波合成仪中加热至120℃反应30min。反应完毕后过滤除去不溶物，滤液用水稀释，乙酸乙酯萃取，有机相用盐水洗涤，无水硫酸钠干燥。减压除去溶剂，粗品经柱层析纯化(正己烷∶乙酸乙酯＝8∶1)，得白色固体(15mg，19.3％，式7化合物)。 Weigh N-(3-bromo-4-methylphenyl)-6-[(2R,6S)-2,6-dimethylmorpholine]nicotinamide (67mg, 0.16mmol, compound of formula 5), 4 -trifluoromethoxyphenylboronic acid (51mg, 0.25mmol, compound of formula 6), bistriphenylphosphine palladium dichloride (11mg, 0.016mmol) and sodium carbonate (53mg, 0.5mmol) were placed in a microwave synthesis tube, Add 4 mL of a mixed solvent of 1,4-dioxane and water (3:1), add nitrogen protection, and heat to 120 ° C in a microwave synthesizer for 30 min. After the reaction was completed, the insoluble matter was removed by filtration, the filtrate was diluted with water, extracted with ethyl acetate, the organic phase was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (n-hexane:ethyl acetate=8:1) to obtain a white solid (15 mg, 19.3%, compound of formula 7). the
1H-NMR(300MHz，CDCl3)δ：8.31(d，1H，J＝8.1Hz)，8.20(d，1H，J＝2.4Hz，)，7.57(dd，1H，J＝2.1Hz，J＝9.0Hz)，7.37(m，5H)，7.08(d，1H，J＝7.8Hz)，6.51(d，1H，J＝9.3Hz)，4.13(m，2H)，3.66(m，2H)，2.58(t，2H，J＝10.8Hz)，2.07(s，3H)，1.23(s，6H). 1 H-NMR (300MHz, CDCl3 ) δ: 8.31 (d, 1H, J=8.1Hz), 8.20 (d, 1H, J=2.4Hz,), 7.57 (dd, 1H, J=2.1Hz, J= 9.0Hz), 7.37(m, 5H), 7.08(d, 1H, J=7.8Hz), 6.51(d, 1H, J=9.3Hz), 4.13(m, 2H), 3.66(m, 2H), 2.58 (t, 2H, J=10.8Hz), 2.07(s, 3H), 1.23(s, 6H).
LC-MS(m/z)：[M+H]+486.3 LC-MS (m/z): [M+H]+ 486.3
实施例化合物： Embodiment compound:
下列化合物(表一)利用类似起始原料通过类似于上述方法而制备： The following compounds (Table 1) were prepared using similar starting materials by methods analogous to those described above:
表一Table I
实验实施例1 Experimental Example 1
以下，对本发明的化合物进行试验以评价其对于Hedgehog信号传导途径的抑制能力。 Next, the compounds of the present invention were tested to evaluate their ability to inhibit Hedgehog signaling pathway. the
1.生物活性筛选试验：(Hedghog信号传导通路Gli-luciferrase报道基因试验)1.Biological activity screening test: (Hedghog signaling pathway Gli-luciferrase reporter gene test)
Gli双荧光素酶报告基因检测实验材料和方法 Gli dual luciferase reporter gene detection experimental materials and methods
1.材料 1. Materials
1.1细胞株：shhLightII，(ATCC：CRL-2795) 1.1 Cell line: shhLightII, (ATCC: CRL-2795)
1.296孔板：Corning，Cat#3610 1. 296-well plate: Corning, Cat#3610
1.3细胞生长培养基：DMEM(Gibco，11995)，加10％NCS(Gibco)，加0.4mG/mL G418(invitrogen，10031035)，加0.15mg/mL zeocin(invitrogen，R25001) 1.3 Cell growth medium: DMEM (Gibco, 11995), plus 10% NCS (Gibco), plus 0.4mG/mL G418 (invitrogen, 10031035), plus 0.15mg/mL zeocin (invitrogen, R25001)
1.4细胞诱导培养基：DMEM(Gibco，11995)，加0.5％NCS，加5mMHEPES，pH 7.4 1.4 Cell induction medium: DMEM (Gibco, 11995), plus 0.5% NCS, plus 5mM HEPES, pH 7.4
1.5诱导剂：A：20a-hydroxycholesterol(sigma，Cat.H6378)，S：22(s)-hydroxycholesterol(Sigma，Cat.H5884)；诱导条件：A∶S＝1∶1混合，使其终浓度分别为5uM. 1.5 Inducer: A: 20a-hydroxycholesterol (sigma, Cat.H6378), S: 22(s)-hydroxycholesterol (Sigma, Cat.H5884); induction conditions: A: S = 1: 1 mixed, so that the final concentration is 5uM.
1.6双报告基因试剂盒：Dual-Glo luciferase assay kit：promega(E2920) 1.6 Dual reporter kit: Dual-Glo luciferase assay kit: promega (E2920)
1.7多道移液器 1.7 multichannel pipette
1.8微孔板振荡器 1.8 microplate shaker
1.9酶标仪：Tecan IF200 1.9 Microplate reader: Tecan IF200
2.方法 2. Method
2.1细胞接种：取对数生长期的ShhlightII细胞，接种于96孔板，30,000cells/孔/100uL，37℃，5％CO2生长两天，使细胞达到最大生长密度 2.1 Cell inoculation: Take ShhlightII cells in the logarithmic growth phase, inoculate in 96-well plate, 30,000cells/well/100uL, grow for two days at 37°C, 5% CO2 to make the cells reach the maximum growth density
2.2细胞诱导与给药：将于96孔板生长两天的细胞从培养箱取出。吸去旧的培养基，加入含诱导剂(A∶S＝1∶1，各10uM，2倍终浓度)的细胞诱导培养基，100uL/孔。然后，加入含有不同浓度待测样品的细胞诱导培养基(2倍待测终浓度)，100uL/孔。将给药完毕的96孔板置于37℃，含5％CO2的培养箱，孵育40h。 2.2 Cell induction and administration: the cells grown in the 96-well plate for two days were taken out of the incubator. The old medium was sucked off, and cell induction medium containing inducer (A:S=1:1, each 10uM, 2 times final concentration) was added, 100uL/well. Then, cell induction medium (2 times the final concentration to be tested) containing different concentrations of the samples to be tested was added, 100 uL/well. The 96-well plate after administration was placed in an incubator containing 5% CO2 at 37° C. for 40 h.
2.3报告基因检测：实验开始前，将96孔板，及试剂盒平衡至室温。吸去含诱导剂及待测药物的培养基，加入室温平衡的细胞诱导培养基50ul/孔。然后按照说明书，加入 
2.4根据试剂盒说明书计算抑制率，origin8软件对数拟合得到待测化合物的IC50值。IC50越低，表示待测化合物活性越高。 2.4 The inhibition rate was calculated according to the kit instructions, and the IC50 value of the test compound was obtained by logarithmic fitting with origin8 software. The lower the IC50 , the higher the activity of the test compound.
表一中的化合物对于Hedgehog信号传导途径的抑制能力参照表二下(Gli双荧光素酶报告基因检测)： For the inhibitory ability of the compounds inTable 1 to the Hedgehog signaling pathway, refer toTable 2 (Gli dual luciferase reporter gene detection):
*表示IC50＝0.1nM-10nM *Indicates IC50 ＝0.1nM-10nM
**表示IC50＝10nM-100nM **Indicates IC50 =10nM-100nM
***表示IC50＝100nM-1000nM *** means IC50 ＝100nM-1000nM
****表示IC50＝1000nM-10000nM **** means IC50 ＝1000nM-10000nM
表二Table II
从表二中可以看出，本发明的化合物对于Hedgehog信号传导途径可表现出非常好的体外抑制能力，从而可用于与Hedgehog信号传导途径异常激活有关的癌症的治疗。 It can be seen from Table 2 that the compounds of the present invention can exhibit very good inhibitory ability to the Hedgehog signal transduction pathway in vitro, and thus can be used for the treatment of cancers related to the abnormal activation of the Hedgehog signal transduction pathway. the
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