Intermediates and processes for bicyclic compounds as CDK inhibitors

Abstract

Disclosed herein are bicyclic compound derivatives useful as cyclin-dependent kinase inhibitors, methods of preparation and uses thereof.

Description

Technical Field

[0001] Disclosed herein are bicyclic compound derivatives useful as cyclin-dependent kinase inhibitors, and preparation methods and uses thereof. Background Art

[0002] Cyclin-dependent kinase (CDK) is a family of Ser / Thr protein kinases that have the function of driving the cell cycle (Norbury, C. and Nurse, P., Annu Rev Biochem, 61, 441-470). During the cell cycle, CDK4 and CDK6 initiate phosphorylation of retinoblastoma (Rb) by binding to cyclin D and partially release transcription factor E2F. CDK2 then forms a complex with cyclin E to fully phosphorylate Rb, fully release E2F and initiate the S phase (Harbour, JW et al., Cell, 98 (6), 859-869). Then in the S phase, CDK2 forms a complex with cyclin A (Echalier, A. et al., Biochim Biophys Acta, 1804 (3), 511-519). Interestingly, in normal cells, CDK2 is mostly dispensable for the cell cycle, whereas in some cancer cells, CDK2 kinase activity plays a critical role in abnormal growth processes (Caruso, JA et al., Cancer Res, 78(19), 5481-5491).

[0003] Cancer cells with CCNE gene amplification or cyclin E overexpression overactivate CDK2, causing dysregulation of Rb phosphorylation and leading to cancer cell proliferation (Wood, DJ et al., Cell Chem Biol, 26(1), 121-130). Abnormal CCNE has been shown to be a disease driver in multiple cancer types such as ovarian cancer, esophageal cancer, bladder cancer, pancreatic cancer, etc., which are associated with poor disease outcomes (Au-Yeung, G. et al., Clin Cancer Res, 23(7), 1862-1874; DeLair, DF et al., J Pathol, 243(2), 230-241; Fu, YP et al., Cancer Res, 74(20), 5808-5818; Huber, AR et al., BMC Gastroenterol, 15, 80; Miller, CT et al., Clin Cancer Res, 9(13), 4819-4825). In addition, in ER+HER2- breast cancer patients, one of the clinical resistance mechanisms of CDK4 / 6i (such as palbociclib, ribociclib and abemaciclib) is the overexpression of CCNE and the activation of CDK2 (Knudsen, ES et al., Cell Rep, 38 (9), 110448). Knockdown of CDK2 siRNA in palbociclib-resistant breast cancer cell lines and mouse models showed that CDK2 inhibition can overcome CDK4 / 6 inhibitor resistance (Pandey, K. et al., Cancers (Basel), 12 (12)). Another potential use of CDK2 inhibitors is based on the trastuzumab resistance mechanism. In HER2+ BC patients, the incidence of trastuzumab resistance with cyclin E amplification or overexpression is about 35%, which is associated with worse clinical benefit, while trastuzumab-resistant cells are sensitive to CDK2 inhibition (Scaltriti, M. et al., Proc Natl Acad Sci USA, 108(9), 3761-3766). In a wide range of cancer types, CCNE1 amplification predicts response to CDK2 inhibition, indicating that CDK2 is a potentially influential therapeutic target.

[0004] The low toxicity of targeting CDK2 has also been confirmed in animal models. Except for germ cell abnormalities, CDK2 knockout mice survive and develop normally (Berthet, C. et al., Curr Biol, 13 (20), 1775-1785). However, mice with single knockout of CDK1 or double knockout of CDK4 and CDK6 are embryonic lethal (Satyanarayana, A. and Kaldis, P., Oncogene, 28 (33), 2925-2939).

[0005] The crystal structure of CDK2, especially its kinase domain, is highly similar to CDK1, and most of the commercially available CDK2 inhibitors have poor CDK1 selectivity (Wells, CI et al., Nat Commun, 11(1), 2743). It is desirable to obtain a cancer-specific drug to obtain a highly selective CDK2 inhibitor, thereby retaining CDK family members to limit off-target CDK-driven toxicity, especially CDK1 / CDK4 / CDK6. Summary of the invention

[0006] The inventors of the present invention unexpectedly discovered that a straight-chain alkyl group attached to the rightmost nitrogen atom (at least compared to counterparts with branched alkyl groups such as isopropyl) exhibits lower toxicity and that the compounds of the present invention may cause fewer side effects when acting on the human body.

[0007] In one embodiment, disclosed herein are bicyclic compound derivatives of formula (I). This embodiment includes the following aspects:

[0008] Aspect 1. A method for synthesizing compound (I):

[0009]

[0010] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, wherein the method comprises:

[0011]

[0012] n1 is 0, 1 or 2;

[0013] n2 is 1, 2 or 3;

[0014] n3 is 0, 1 or 2;

[0015] n4 is 0, 1, 2, 3 or 4;

[0016] n5 and n6 are each independently 0, 1 or 2, provided that n5 and n6 are not simultaneously 0;

[0017] n7 is 0, 1, 2, 3 or 4;

[0018] n8 is 1, 2, 3 or 4;

[0019] R 1 is selected from hydrogen, halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3-membered to 8-membered heterocyclic group, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (═O), or —CN, wherein the —C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R 1a replace;

[0020] R 1a is selected from halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3-membered to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -NO2, OH or -CN;

[0021] R X Each is independently selected from hydrogen, halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3-membered to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xa R Xb 、-OR Xa 、-SR Xa 、-SO2R Xa 、-SO2NR Xa R Xb 、-C(O)R Xa 、-CO2R Xa 、-C(O)NR Xa R Xb 、-NR Xa COR Xb 、-NR Xa CO2R Xb 、-NR Xa S02R Xb or -CN, wherein the -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R Xc replace; or

[0022] Two R's X Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0 to 3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members; the ring is optionally substituted with at least one substituent R Xc replace;

[0023] R Xa and R Xb Each is independently selected from hydrogen, deuterium, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl, wherein the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R Xd replace;

[0024] R Xc and R Xd Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xe R Xf 、-OR Xe 、-SR Xe 、-SO2R Xe 、-SO2NR Xe R Xf 、-C(O)R Xe 、-CO2R Xe 、-C(O)NR Xe R Xf 、-NR Xe COR Xf 、-NR Xe CO2R Xf 、-NR Xe S02R Xf or -CN;

[0025] R Xe and R Xf Each is independently selected from -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl;

[0026] Y 1 , Y 2 and Y 3 are each independently selected from O, C or N;

[0027] Q is selected from O or NR Q ;

[0028] R 3 and R Q Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl or 5- to 12-membered heteroaryl, wherein the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 3a replace;

[0029] R 3a independently selected from hydrogen, halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 3c 、-CN、-SO2R 3c 、-SO2NR 3c R 3d 、-C(O)R 3c 、-CO2R 3c 、-C(O)NR 3c R 3d 、-NR 3c R 3d 、-NR 3c COR 3d 、-NR 3c CO2R 3d or -NR 3c S02R 3d , wherein -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 3e 、-SO2R 3e 、-SO2NR 3e R 3f 、-C(O)R 3e 、-CO2R 3f 、-C(O)NR 3e R 3f 、-NR 3e R 3f 、-NR 3e COR 3f 、-NR 3e CO2R 3f or -NR 3e S02R 3f replace;

[0030] R 3c , R 3d , R 3e and R3f Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl;

[0031] R 4 is selected from hydrogen, halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 4a 、-CN、-SO2R 4a 、-SO2NR 4a R 4b 、-C(O)R 4a or -CO2R 4a ;

[0032] R 4a and R 4b Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 wherein the -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 The aryl or 5- to 12-membered heteroaryl group is optionally substituted with -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl, 5- to 12-membered heteroaryl, -NO2, OH or -CN;

[0033] R 5 independently selected from hydrogen, halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy or -C3-C8 cycloalkyl;

[0034] Z 1 , Z 2 and Z 3 Each independently selected from -CR Z or N;

[0035] R Z is independently selected at each occurrence from hydrogen, halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -NR Za R Zb 、-OR Za 、-SR Za 、-SO2RZa 、-SO2NR Za R Zb 、-C(O)R Za 、-CO2R Za 、-C(O)NR Za R Zb 、-NR Za COR Zb 、-NR Za CO2R Zb 、-NR Za S02R Zb or -CN, wherein the -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R Zc replace;

[0036] R Za and R Zb Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 The -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R Zd replace;

[0037] R Zc and R Zd Each is independently selected from halogen, hydroxyl, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Ze R Zf 、-OR Ze 、-SR Ze 、-SO2R Ze 、-SO2NR Ze R Zf 、-C(O)R Ze 、-CO2R Ze 、-C(O)NR Ze R Zf 、-NR Ze COR Zf 、-NR Ze CO2R Zf 、-NR Ze S02RZf or -CN;

[0038] R Ze and R Zf Each is independently selected from -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl.

[0039] Aspect 2. The method according to aspect 1, wherein R 1 is selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic radical, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (═O), or —CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R 1a replace;

[0040] R 1a is selected from halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic radical, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -NO2, OH or -CN;

[0041] Preferably, R 1 is selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 3- to 8-membered heterocyclic radical, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (═O), or —CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R 1a replace;

[0042] R 1a is selected from halogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -NO2, OH or -CN;

[0043] More preferably, R 1is phenyl; wherein the phenyl is substituted by -NO2.

[0044] Aspect 3. The method according to any one of the preceding aspects, wherein the compound is selected from (IIa) and (IIb):

[0045]

[0046] Preferably, the compound is (IIIa):

[0047]

[0048] Preferably, the compound is selected from (IVa) and (IVb):

[0049]

[0050] Aspect 4. The method according to any one of the preceding aspects, wherein R 3 and R Q each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, wherein each of the methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R 3a replace;

[0051] R 3a independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -OR 3c 、-CN、-SO2R 3c 、-SO2NR 3c R 3d 、-C(O)R 3c 、-CO2R 3c 、-C(O)NR 3c R 3d 、-NR 3c R 3d 、-NR3c COR 3d 、-NR 3c CO2R 3d or -NR 3c S02R 3d wherein the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, 5- to 12-membered heteroaryl, Each of the above is optionally replaced by -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 3e 、-SO2R 3e 、-SO2NR 3e R 3f 、-C(O)R 3e 、-CO2R 3f 、-C(O)NR 3e R 3f 、-NR 3e R 3f 、-NR 3e COR 3f 、-NR 3e CO2R 3f or -NR 3e S02R 3f replace;

[0052] R 3c , R 3d , R 3e and R 3fEach is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, wherein the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl each of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (═O), —CN, —OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy;

[0053] Preferably, R 3 and R Q Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl;

[0054] More preferably, R 3 and R Q Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl);

[0055] Even more preferably, R 3 and R Q are each independently hydrogen.

[0056] Aspect 5. The method according to any one of the preceding aspects, wherein R 4 is selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 4a 、-CN、-SO2R4a 、-SO2NR 4a R 4b 、-C(O)R 4a or -CO2R 4a ;

[0057] R 4a and R 4b each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic radical, C6-C 12 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic radical, C6-C 12 The aryl or 5- to 12-membered heteroaryl is optionally substituted with methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl, 5- to 12-membered heteroaryl, -NO2, OH or -CN;

[0058] Preferably, R 4 is selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, -C1-C8 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 4a 、-CN、-SO2R 4a 、-SO2NR 4a R 4b 、-C(O)R 4a or -CO2R 4a ;

[0059] R 4a and R 4b Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, 3- to 8-membered heterocyclic group, C6-C 12 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic radical, C6-C 12 The aryl or 5- to 12-membered heteroaryl is optionally substituted with methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl, 5- to 12-membered heteroaryl, -NO2, OH or -CN;

[0060] More preferably, R 4 Selected from hydrogen, -C(O)R 4a or -CO2R 4a ;

[0061] R 4a is phenyl, wherein the phenyl group is optionally substituted with -NO2.

[0062] Aspect 6. A method as described in any of the preceding aspects, wherein Partially selected

[0063] Preferably, the Partially selected

[0065] More preferably, the Partially selected

[0066] Even more preferably, the Partially selected

[0067]

[0068] Aspect 7. The method according to any one of the preceding aspects, wherein Z 1 , Z 2 and Z 3 At most two of them are N; preferably, Z 1 , Z 2 and Z 3 At most one of them is N;

[0069] More preferably, Z 1 , Z 2 and Z 3 Independently for -CR Z .

[0070] Aspect 8. The method according to any one of the preceding aspects, wherein R Z is independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -NR Za RZb 、-OR Za 、-SR Za 、-SO2R Za 、-SO2NR Za R Zb 、-C(O)R Za 、-CO2R Za 、-C(O)NR Za R Zb 、-NR Za COR Zb 、-NR Za CO2R Zb 、-NR Za S02R Zb or -CN, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally replaced by at least one R Zc replace;

[0071] R Za and R Zb each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, wherein each of the methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Zd replace;

[0072] R Zc and R Zd each independently selected from -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -NR Ze R Zf 、-ORZe 、-SR Ze 、-SO2R Ze 、-SO2NR Ze R Zf 、-C(O)R Ze 、-CO2R Ze 、-C(O)NR Ze R Zf 、-NR Ze COR Zf 、-NR Ze CO2R Zf 、-NR Ze S02R Zf or -CN;

[0073] R Ze and R Zf Each is independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl;

[0074] Preferably, R Z is independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -NR Za R Zb 、-OR Za 、-SR Za 、-SO2R Za 、-SO2NR Za R Zb 、-C(O)R Za 、-CO2R Za 、-C(O)NR Za R Zb 、-NR Za COR Zb 、-NR Za CO2R Zb 、-NR Za S02R Zb or -CN;

[0075] R Za and R ZbEach is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl;

[0076] More preferably, R Z is independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or i-propyl), butyl (n-, sec-, i- or t-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -NH2, -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, or -CN;

[0077] Even more preferably, R Z is independently selected at each occurrence from hydrogen, -F and methyl.

[0078] Aspect 9. A method as described in any of the preceding aspects, wherein Partially selected

[0079] Preferably, the Partially selected

[0080] Aspect 10. The method according to any one of the preceding aspects, wherein R X each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xa R Xb 、-OR Xa 、-SR Xa 、-SO2R Xa 、-SO2NR Xa R Xb 、-C(O)R Xa 、-CO2R Xa 、-C(O)NRXa R Xb 、-NR Xa COR Xb 、-NR Xa CO2R Xb 、-NR Xa S02R Xb or -CN, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally replaced by at least one R Xc replace;

[0081] R Xa and R Xb each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, wherein each of the methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Xd replace;

[0082] R Xc and R Xd each independently selected from -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xe R Xf 、-OR Xe 、-SR Xe 、-SO2R Xe 、-SO2NR Xe R Xf 、-C(O)R Xe 、-CO2R Xe 、-C(O)NR Xe RXf 、-NR Xe COR Xf 、-NR Xe CO2R Xf 、-NR Xe S02R Xf or -CN;

[0083] R Xe and R Xf Each is independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl;

[0084] Preferably, R X independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, oxo (=O), -NR Xa R Xb 、-OR Xa 、-SR Xa 、-SO2R Xa 、-SO2NR Xa R Xb 、-C(O)R Xa 、-CO2R Xa 、-C(O)NR Xa R Xb 、-NR Xa COR Xb 、-NR Xa CO2R Xb 、-NR Xa S02R Xb or -CN;

[0085] R Xa and R Xb Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl;

[0086] More preferably, R X independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, oxo (=O) or -OH; and

[0087] Even more preferably, R X For hydrogen.

[0088] Aspect 11. The method according to any one of the preceding aspects, wherein the two R X Together with the atoms to which they are attached, they form a 3-, 4-, 5-, 6-, 7- or 8-membered ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members; said ring is optionally substituted with at least one substituent R Xc replace;

[0089] R Xc each independently selected from -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xe R Xf 、-OR Xe 、-SR Xe 、-SO2R Xe 、-SO2NR Xe R Xf 、-C(O)R Xe 、-CO2R Xe 、-C(O)NR Xe R Xf 、-NR Xe COR Xf 、-NR Xe CO2R Xf 、-NR Xe S02R Xf or -CN;

[0090] R Xe and R XfEach is independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl;

[0091] Preferably, the two R X Together with the atoms to which they are attached, they form a 3-, 4-, 5- or 6-membered ring; the ring is optionally substituted with at least one substituent R Xc replace;

[0092] R Xc Each is independently selected from -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxo (=O) or -CN;

[0093] More preferably, the two R X Together with the atoms to which they are attached they form a 3-, 4-, 5-, or 6-membered ring.

[0094] Aspect 12. The method according to any one of the preceding aspects, wherein Partially selected

[0095] Aspect 13. The method according to any one of the preceding aspects, wherein the compound is selected from

[0096]

[0097] Aspect 14. A method as described in any of the preceding aspects, wherein

[0098] The reaction reagents of step A include a non-nucleophilic base;

[0099] Preferably, the reaction reagent of step A comprises lithium diisopropylamide (LDA), lithium diethylamide (LDEA), N,N-diisopropylethylamine (DIEA), lithium hexamethyldisilazane (LHDS or LiHMDS), sodium hexamethyldisilazane (NaHMDS), lithium isopropylcyclohexylamide (LICA), lithium dicyclohexylamide (LDCA) or lithium 2,2,6,6-tetramethylpiperidinium (LTMP), or any combination of the non-nucleophilic bases;

[0100] More preferably, the reaction reagent of step A comprises lithium diisopropylamide (LDA), N,N-diisopropylethylamine (DIEA), lithium hexamethyldisilazane (LHDS, LiHMDS) or sodium hexamethyldisilazane (NaHMDS), or any combination of said non-nucleophilic bases;

[0101] Even more preferably, the reactant of step A comprises N,N-diisopropylethylamine (DIEA).

[0102] Aspect 15. A method as described in any of the preceding aspects, wherein

[0103] The reaction temperature of step A is -10°C to 60°C; preferably, the reaction temperature of step A is 0°C to 55°C; more preferably, the reaction temperature of step A is 50°C. DETAILED DESCRIPTION

[0104] The following terms have the indicated meanings throughout the specification:

[0105] As used herein, including the appended aspects, singular forms of words such as "a / an" and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0106] Unless the context clearly dictates otherwise, the term "or" is used to mean, and is used interchangeably with, the term "and / or."

[0107] The term "alkyl" refers to a hydrocarbon group selected from straight and branched saturated hydrocarbon groups containing 1 to 18, such as 1 to 12, further such as 1 to 10, further such as 1 to 8, or 1 to 6 or 1 to 4 carbon atoms. 1-6 Examples of alkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0108] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused, bridged or spiro cycloalkyl groups.

[0109] The term "aryl", used alone or in combination with other terms, refers to a group selected from:

[0110] - 5- and 6-membered carbocyclic aromatic rings, for example, phenyl;

[0111] - bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example, naphthyl and indanyl; and

[0112] - a tricyclic ring system, such as a 10- to 15-membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic, for example, fluorenyl.

[0113] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0114] The term "aryl-alkyl-" refers to an alkyl group as defined above that is further substituted with an aryl group. Examples of aryl-alkyl groups include aryl-C 1-8 Alkyl, such as phenylethyl or phenylmethyl (benzyl).

[0115] The term "heteroaryl" refers to a group selected from:

[0116] - a 5-, 6- or 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from nitrogen (N), sulfur (S) and oxygen (O), for example, 1 to 4 (or in some embodiments, 1 to 3, in some embodiments, 1 to 2) heteroatoms, the remaining ring atoms being carbon;

[0117] - a 7- to 12-membered bicyclic ring comprising at least one heteroatom selected from N, O and S, such as 1 to 4 (or in some embodiments, 1 to 3, or in other embodiments, 1 or 2) heteroatoms, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring; and

[0118] - an 11- to 14-membered tricyclic ring comprising at least one heteroatom selected from N, O and S, e.g., 1 to 4 (or in some embodiments, 1 to 3, or in other embodiments, 1 or 2) heteroatoms, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

[0119] When the total number of S and O atoms in the heteroaryl exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When the heteroaryl contains more than one heteroatom ring member, the heteroatom can be the same or different. The nitrogen atom in one or more rings of the heteroaryl can be oxidized to form an N-oxide. As used herein, the term "C-connected heteroaryl" means that the heteroaryl is connected to the core molecule through a bond from a C-atom of the heteroaryl ring.

[0120] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S) and oxygen (O) and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5 to 6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0121] "Heterocyclyl", "heterocycle" or "heterocyclic" are interchangeable and include non-aromatic heterocyclic groups containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon, including monocyclic, fused, bridged and spirocyclic rings, i.e. containing monocyclic heterocyclic groups, bridged heterocyclic groups, spiro heterocyclic groups and fused heterocyclic groups. The term "optionally oxidized sulfur" as used herein refers to S, SO or SO2.

[0122] "H" and "H" are interchangeable and refer to protium ( 1 H), deuterium ( 2 H) or tritium ( 3 H). A "deuterated analog" refers to a compound in which one or more protium ( 1 H) is replaced by an equal amount of deuterium ( 2 H) Replacement.

[0123] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. In the case where the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a wider class of stereoisomers. It is intended to include all such possible stereoisomers in the form of substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specifically noted, a reference to an isomer is applicable to any possible isomer. As long as the isomer composition is not specified, all possible isomers are included.

[0124] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35%, such as no more than 30%, further such as no more than 25%, even further such as no more than 20% of any other stereoisomer by weight. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10%, such as no more than 5%, such as no more than 1% of any other stereoisomer by weight.

[0125] Unless stated otherwise, when compounds disclosed herein contain olefinic double bonds, such double bonds are intended to include both E and Z geometric isomers.

[0126] When the compounds disclosed herein contain disubstituted cyclohexyl or cyclobutyl, the substituents found on the cyclohexyl or cyclobutyl ring can take cis and trans forms. The cis form means that both substituents are located on the upper side of the 2 substituent positions on the carbon, while the trans form means that they are located on the opposite side.

[0127] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter separated) to the desired degree of homogeneity by techniques commonly used in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods, including, for example: reverse phase and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high pressure, medium pressure, and low pressure liquid chromatography methods and apparatus; small scale analytical chromatography; simulated moving bed ("SMB") chromatography and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

[0128] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of each other. Based on their physicochemical differences, diastereomeric mixtures can be separated into their individual diastereomers by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by reacting the enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), converting the enantiomer mixture into a diastereomeric mixture, separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers into the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0129] Some of the compounds disclosed herein may exist with different points of hydrogen attachment, known as tautomers. For example, a compound comprising a carbonyl -CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both the individual keto and enol forms as well as mixtures thereof are also intended to be included.

[0130] Can undergo tautomerism to form Wherein *A and *B refer to the position where the substituent is attached to the pyrazole.

[0131] "Pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0132] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, an addition salt (such as a pharmaceutically acceptable addition salt) can be prepared by conventional methods for preparing acid addition salts from base compounds, by dissolving the free base in a suitable organic solvent and / or water and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0133] As defined herein, "pharmaceutically acceptable salts thereof" include at least one salt of a compound of formula (I) and salts of stereoisomers of a compound of formula (I), such as enantiomeric salts and / or diastereomeric salts.

[0134] As used herein, the terms "administration," "administering," "treating," and "treatment" refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. Treatment of cells encompasses contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treatment" also refer to in vitro and ex vivo treatment of a cell, for example, by an agent, a diagnostic agent, a binding compound, or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rats, mice, dogs, cats, and rabbits), and most preferably a human.

[0135] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient (such as a compound) that is sufficient to affect the treatment of a disease, disorder or symptom when administered to a subject to treat a disease, or at least one clinical symptom of a disease or condition. The term "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or the symptoms of the disease or condition, the severity of the disease, disorder and / or the symptoms of the disease or condition, the age of the subject to be treated, and / or the weight of the subject to be treated. In any given case, the appropriate amount may be obvious to those skilled in the art, or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof that is effective in "treating" a disease or condition as defined above in a subject. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of a combination object used to effectively treat a disease, disorder or illness.

[0136] The pharmaceutical composition comprising the compounds disclosed herein can be administered to a subject in need thereof via oral, inhalation, rectal, parenteral or topical administration. For oral administration, the pharmaceutical composition can be a conventional solid preparation, such as a tablet, powder, granule, capsule, etc.; a liquid preparation, such as water or oil suspension; or other liquid preparations, such as syrups, solutions, suspensions, etc.; for parenteral administration, the pharmaceutical composition can be a solution, an aqueous solution, an oil suspension concentrate, a lyophilized powder, etc. Preferably, the dosage form of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays or injections, more preferably tablets or capsules. The pharmaceutical composition can be a single unit administration using an accurate dose. In addition, the pharmaceutical composition may also include additional active ingredients.

[0137] All preparations of the pharmaceutical composition disclosed herein can be prepared by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients, and then the desired preparation is prepared. "Pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical preparation, for example: diluents; vehicles, such as water, various organic solvents, etc.; fillers, such as starch, sucrose, etc.; binders, such as cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone (PVP); wetting agents, such as glycerol; disintegrants, such as agar, calcium carbonate and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as hexadecanol; absorption carriers, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition also includes other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners and dyes.

[0138] The term "disease" refers to any illness, ailment, ailment, symptom, or indication, and is interchangeable with the terms "disorder" or "condition."

[0139] In this specification and subsequent aspects, unless the context requires otherwise, the term "comprise" and variations such as "comprises" and "comprising" are intended to specify the presence of the following features, but do not exclude the presence or addition of one or more other features. When used herein, the term "comprises" can be replaced by the terms "contains", "includes" or sometimes "has".

[0140] Throughout this specification and the following aspects, the term "C n-m " denotes a range including endpoints, wherein n and m are integers and represent the number of carbons. Examples include C 1-8 , C 1-6 wait.

[0141] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0142] abbreviation

[0143]

[0144]

[0145]

[0146] Example

[0147] The following examples are intended to be exemplary only and should not be considered to be limited in any way. Efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be considered. Unless otherwise indicated, temperatures are in degrees Celsius. Reagents are purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and are used without further purification unless otherwise indicated. Unless otherwise indicated, the reactions set forth below are carried out in anhydrous solvents under a positive pressure of nitrogen or argon or with a drying tube; the reaction flask is equipped with a rubber septum for introducing substrates and reagents via a syringe; and the glassware is dried and / or heated to dryness.

[0148] Recorded on an Agilent instrument operating at 400 MHz 1 H NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone or (CD3)2CO as solvents and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05) as reference standards. 1 HNMR spectra. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (double of doublets), dt (double of triplets). Coupling constants, when given, are reported in Hertz (Hz).

[0149] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity), detector: MWD (190-400 nm), mass detector: 6120SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120EC-C18, 4.6x50 mm, 2.7 pm, gradient method: flow rate: 1.8 mL / min, time (min) A (%) B (%)

[0150] Time (min) A(％) B(％) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0151] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120EC-C18, 4.6x50 mm, 2.7 pm, gradient method: flow rate: 1.2 mL / min, time (min) A (%) B (%)

[0152]

[0153] LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120EC-C18, 4.6x50 mm, 2.7 pm, gradient method: flow rate: 1.8 mL / min, time (min) A (%) B (%)

[0154]

[0155]

[0156] UPLC-MS: UPLC: Waters Acquity UPLC H-Class, detector: MWD (190-400 nm), mass detector: Waters QDA, mobile phase: A: water containing 0.05% TFA, B: acetonitrile containing 0.05% TFA, column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm, gradient method: flow rate: 0.8 mL / min, time (min) A (%) B (%)

[0157]

[0158] Preparative HPLC was performed on a column (150 x 21.2 mm ID, 5 pm, Gemini NXC 18) with a flow rate of 20 ml / min, an injection volume of 2 ml, at room temperature and UV detection at 214 nm and 254 nm.

[0159] Example 8: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0160] Step 1: 4-Bromo-3-fluorophthalic acid

[0161]

[0162] To a solution of 4-bromo-3-fluorobenzoic acid (30 g, 137.6 mmol) in THF (600 mL) was added LDA (172 mL, 344 mmol) and reacted at -78 ° C under a nitrogen atmosphere for 1 hour. Dry ice (45 g) was added thereto and reacted at -78 ° C for 1 hour. The reaction was quenched with NH4Cl aqueous solution (200 mL). The resulting solution was concentrated in vacuo. The resulting mixture was quenched with MeOH (500 mL). The resulting mixture was stirred at room temperature for 15 minutes. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was a crude product (30 g, 83%). LCMS (ESI) m / z [MH] - =261.2.

[0163] Step 2: (4-bromo-3-fluoro-1,2-phenylene)dimethanol

[0164]

[0165] To a solution of 4-bromo-3-fluorophthalic acid (30 g, 114.5 mmol) in THF (600 mL) was added BH3-THF (343.5 mL, 343.5 mmol) at 0°C. The resulting solution was stirred at 50°C overnight. The reaction was then quenched with MeOH (350 mL) at 0°C. The resulting mixture was concentrated in vacuo. The residue was purified by combi-flash (DCM / MeOH=4:1) to give the product (23 g, 85.8%). LCMS (ESI) m / z [MH] - =233.

[0166] Step 3: 1-Bromo-3,4-bis(chloromethyl)-2-fluorobenzene

[0167]

[0168] At 0°C, (4-bromo-3-fluoro-1,2-phenylene) dimethanol (23 g, 98.2 mmol) was added to SOCl2 (100 mL). The resulting solution was stirred at 80°C for 3 hours. The resulting mixture was concentrated in vacuo. The reaction was then quenched with ice water (150 mL). The mixture was acidified to pH>8 with NaOH solution. The resulting solution was extracted with 3×200 mL of DCM. The resulting mixture was concentrated in vacuo. The residue was a crude product (14 g, 52%).

[0169] Step 4: 5-Bromo-4-fluoro-1,3-dihydrobenzo[c]thiophene

[0170]

[0171] To a solution of 1-bromo-3,4-bis(chloromethyl)-2-fluorobenzene (14 g, 51.8 mmol) in EtOH (100 mL) was added Na2S.9H2O (19.3 g, 80.3 mmol) and H2O (20 mL). The resulting solution was stirred at 80 ° C overnight. The resulting mixture was concentrated in vacuo. The resulting mixture was quenched with H2O (100 mL). The resulting solution was extracted with 3×100 mL of DCM. The organic layer was washed with 3×60 mL of brine. The residue was purified by combi-flash (EtOAc / PE=2%:98%) to give the product (2.9 g, 24.1%).

[0172] Step 5: 5-Bromo-4-fluoro-1,3-dihydrobenzo[c]thiophene 2,2-dioxide

[0173]

[0174] To a solution of 5-bromo-4-fluoro-1,3-dihydrobenzo[c]thiophene (2.9 g, 12.5 mmol) in THF:H2O=4:1 (100 mL) was added NaIO4 (8.1 g, 37.5 mmol), RuCl3 (281 mg, 1.25 mmol) at 0°C. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was extracted with 3×50 mL of EtOAc. The organic layer was concentrated in vacuo. The residue was purified by combi-flash (EtOAc / PE=35:65%) to give the product (2.1 g, 63.6%). 1 H NMR (500 MHz, methanol-d4) δ 7.68 (ddt, J = 7.5, 6.9, 1.0 Hz, 1H), 7.19 (dd, J = 8.0, 1.0 Hz, 1H), 4.52 (s, 2H), 4.48 (d, J = 1.0 Hz, 2H).

[0175] Step 6: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H- Pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0176]

[0177] A mixture of 5-bromo-4-fluoro-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (87 mg, 0.33 mmol), cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentylisopropylcarbamate (65.5 mg, 0.26 mmol), Brettphos Pd G3 (29.9 mg, 0.033 mmol) and K2CO3 (135 mg, 0.98 mmol) in t-BuOH (5 mL) was stirred at 110°C under nitrogen atmosphere for 16 hours. LCMS showed that the reaction was complete. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (0-100%) to give the product in racemic form, which was further separated by chiral preparative HPLC to give:

[0178] Enantiomer 1 (Example 8a, 100% ee); retention time: 4.813 min. 1 H NMR (500MHz, DMSO-d6) δ11.81(s,1H),8.20(s,1H),8.08(t,J=8.5,1H),7.05(d,J=8.5,1H),6.94(d,J=7.5,1H),5.75(s,1H),4.99(m,1H),4.51 (s,2H),4.42(s,2H),3.58(m,1H),3.12–2.95(m,1H),2.45(m,1H),2.05 –1.97(m,1H),1.97–1.85(m,1H),1.70(m,2H),1.58(m,1H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =437.35.

[0179] Enantiomer 2 (Example 8b, 100% ee); retention time: 7.178 min. 1 H NMR (500MHz, DMSO-d6) δ11.81(s,1H),8.20(s,1H),8.08(t,J=8.5,1H),7.05(d,J=8.5,1H),6.94(d,J=7.5,1H),5.75(s,1H),4.99(m,1H),4.51 (s,2H),4.42(s,2H),3.58(m,1H),3.12–2.95(m,1H),2.45(m,1H),2.05 –1.97(m,1H),1.97–1.85(m,1H),1.70(m,2H),1.58(m,1H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =437.35.

[0180] Chiral analysis method: column: CHIRALPAK IE 4.6×250 mm 5 μm; mobile phase: A is MtBE (0.1% 2M NH 3 MeOH) and B is MeOH:DCM=50:50 (v / v); gradient: mobile phase A: mobile phase B=20:80 (v / v); HPLC equipment: HPLC-Agilent; column temperature: 35° C.

[0181] Chiral preparative HPLC conditions: CHIRALPAK IE 20×250 mm 5 μm; mobile phase: A is MtBE and B is MeOH:DCM=50:50 (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B=20:80 (v / v); flow rate: 18 mL / min, wavelength: UV 270 nm and 280 nm, preparative HPLC equipment: Prep-HPLC-Gilson; column temperature: 25°C.

[0182] Example 9: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate

[0183] Step 1: cis-Benzyl (5-(3-hydroxycyclopentyl)-1H-pyrazol-3-yl) carbamate

[0184]

[0185] To a round-bottom flask charged with cis-benzyl(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (5 g, 13.98 mmol) was added 100 mL of formic acid. The resulting mixture was stirred at 75 °C overnight. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel column chromatography eluting with EA / PE (0-75%) to give the product (3.5 g, 70%). LC-MS (ESI): m / z [M+H] + =302.3.

[0186] Step 2: cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentan-1-ol

[0187]

[0188] To a solution of cis-benzyl (5- (3-hydroxycyclopentyl) -1H-pyrazol-3-yl) carbamate (3.5 g, 11.6 mmol) in THF (100 mL) was added Pd / C (10%, wet, 1 g). The suspension was degassed and purged with hydrogen 3 times. The resulting mixture was stirred at room temperature under a hydrogen balloon for 3 hours. The mixture was filtered and the filter cake was washed with EA (50 mL × 3). The filtrate was concentrated under reduced pressure to give a crude product, which was used directly in the next step without further purification. LC-MS (ESI): m / z [M + H] + =168.3.

[0189] Step 3: cis-4-fluoro-5-((5-(3-hydroxycyclopentyl)-1H-pyrazol-3-yl)amino)-1,3-dihydrobenzo [c] Thiophene 2,2-dioxide

[0190]

[0191] A mixture of 5-bromo-4-fluoro-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (1 g, 3.774 mmol), cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentan-1-ol (951 mg, 3.774 mmol), Brettephos Pd G3 (341 mg, 0.377 mmol) and K2CO3 (1.56 g, 11.322 mmol) in t-BuOH (400 mL) was stirred in a sealed tube under N2 atmosphere for 3 hours at 100°C. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:5) to give the product (1.2 g, 90%). LC-MS (ESI): m / z [M+H] + =353.2.

[0192] Step 4: cis-4-nitrophenyl 3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino 4-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazole-1-carboxylate

[0193]

[0194] A mixture of cis-4-fluoro-5-((5-(3-hydroxycyclopentyl)-1H-pyrazol-3-yl)amino)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (1.2 g, 3.399 mmol), DMAP (83 mg, 0.68 mmol), pyridine (1.6 g, 20.394 mmol) and 4-nitrophenyl chloroformate (2.05 g, 10.197 mmol) in DCM (50 mL) was stirred at 45 °C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:3) to give the product (1.2 g, 51%), LC-MS (ESI): m / z [M+H] + =682.4.

[0195] Step 5: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H- Pyrazol-5-yl)cyclopentylpropylcarbamate

[0196]

[0197] A mixture of cis-4-nitrophenyl 3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-5-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazole-1-carboxylate (70 mg, 0.102 mmol), propan-1-amine (18 mg, 0.306 mmol) and DIEA (155 mg, 1.2 mmol) in THF (5 mL) was stirred at 50 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:10) to give the crude product. The crude product was purified by preparative HPLC (Waters SunFire C18: RD-CO-058 column, eluting with a gradient of acetonitrile / water containing 0.1% FA, 10%-60%) to afford the product in racemic form, which was further separated by chiral preparative HPLC to afford:

[0198] Enantiomer 1 (Example 9a, 100% ee); retention time: 5.39 min. 1 H NMR (500MHz, DMSO-d6) δ11.81(s,1H),8.20(s,1H),8.08(t,J=8.2Hz,1H),7.05(d,J= 8.7Hz,2H),5.75(s,1H),5.05-4.95(m,1H),4.51(s,2H),4.42(s,2H),3.10-2.99(m,1 H),2.91(dd,J=13.1,6.6Hz,2H),2.48-2.42(m,1H),2.06-1.97(m,1H),1.95-1.85(m ,1H),1.78-1.66(m,2H),1.64-1.55(m,1H),1.45-1.33(m,2H),0.82(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =437.34.

[0199] Enantiomer 2 (Example 9b, 100% ee); retention time: 8.42 min. 1H NMR (500MHz, DMSO-d6) δ11.81(s,1H),8.20(s,1H),8.08(t,J=8.2Hz,1H),7.05(d,J= 8.7Hz,2H),5.75(s,1H),5.05-4.95(m,1H),4.51(s,2H),4.42(s,2H),3.10-2.99(m,1 H),2.91(dd,J=13.1,6.6Hz,2H),2.48-2.42(m,1H),2.06-1.97(m,1H),1.95-1.85(m ,1H),1.78-1.66(m,2H),1.64-1.55(m,1H),1.45-1.33(m,2H),0.82(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =437.34.

[0200] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A is hexane and B is EtOH (0.1% 2M NH 3 MeOH); gradient: mobile phase A: mobile phase B = 20:80 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[0201] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm×250 mm, 5 μm; mobile phase: A is hexane and B is EtOH (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B = 20:80 (v / v); flow rate: 18 mL / min, wavelength: UV200 nm and 270 nm, preparative HPLC equipment: Prep-HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[0202] Example 10: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl((S)-sec-butyl)carbamate

[0203]

[0204] The title compound was synthesized according to a procedure similar to Example 9. 1H NMR (500MHz, DMSO-d6) δ11.82(s,1H),8.23(s,1H),8.09(t,J=8.5Hz,1H),7.05(d,J=8.5Hz,1H ),6.91(d,J=8.3Hz,1H),5.75(s,1H),5.05-4.95(m,1H),4.52(s,2H),4.43(s,2H),3.45-3.35( m,1H),3.10–2.99(m,1H),2.48-2.42(m,1H),2.08-1.96(m,1H),1.92-1.85(m,1H),1.78-1.65 (m,2H),1.65-1.53(m,1H),1.43-1.30(m,2H),1.05-0.96(m,3H),0.80(dd,J=13.5,7.0Hz,3H). LC-MS(ESI):m / z[M+H] + =451.35.

[0205] Example 11: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thien-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate

[0206]

[0207] The title compound was synthesized according to a procedure similar to Example 9. 1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),8.22(s,1H),8.09(s,1H),7.36(s,1H),7. 05(d,J=8.5Hz,1H),5.74(s,1H),510-4.90(m,1H),4.51(s,2H),4.43(s,2H),3.1 0-2.95(m,1H),2.48-2.41(m,1H),2.08-1.96(m,1H),1.94-1.85(m,1H),1.80-1. 63(m,2H),1.62-1.50(m,1H),1.23(s,3H),0.65-0.55(m,2H),0.50-0.42(m,2H). LC-MS(ESI):m / z[M+H] + =449.33.

[0208] Example 12: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylcyclobutylcarbamate

[0209]

[0210] The title compound was synthesized according to a procedure similar to Example 9. 1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),8.20(s,1H),8.09(t,J=8.6Hz,1H),7.3 6(d,J=7.8Hz,1H),7.05(d,J=8.4Hz,1H),5.75(s,1H),5.08-4.90(m,1H),4.5 1(s,2H),4.42(s,2H),4.05-3.75(m,1H),3.13-2.97(m,1H),2.49-2.41(m,1H ),2.18-1.97(m,3H),1.95-1.81(m,3H),1.80-1.62(m,2H),1.61-1.45(m,3H). LC-MS (ESI): m / z [M+H] + =449.31.

[0211] Example 13: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(3-methyltetrahydrofuran-3-yl)carbamate

[0212]

[0213] The racemic form of the title compound was synthesized following a procedure similar to Example 9, which was further separated by chiral preparative HPLC to give:

[0214] Enantiomer 1 (Example 13a, 100% ee); retention time: 1.09 min. 1 H NMR (500MHz, DMSO-d6) δ11.81(s,1H),8.20(s,1H),8.08(s,1H),7.23(s,1H),7.05(d,J=8. 5Hz,1H),5.75(s,1H),4.99(s,1H),4.51(s,2H),4.42(s,2H),3.82(d,J=7.3Hz,1H),3.80– 3.69(m,2H),3.43(d,J=8.6Hz,1H),3.09–2.97(m,1H),2.48–2.41(m,1H),2.20-2.10(m,1H ),2.05-1.97(m,1H),1.98-1.82(m,1H),1.80-1.67(m,3H),1.65-1.53(m,1H),1.32(s,3H). LC-MS(ESI):m / z[M+H]+ =479.2.

[0215] Enantiomer 2 (Example 13b, 100% ee); retention time: 2.14 min. 1 H NMR (500MHz, DMSO-d6) δ11.81(s,1H),8.20(s,1H),8.08(s,1H),7.23(s,1H),7.05(d,J=8. 5Hz,1H),5.75(s,1H),4.99(s,1H),4.51(s,2H),4.42(s,2H),3.82(d,J=7.3Hz,1H),3.80– 3.69(m,2H),3.43(d,J=8.6Hz,1H),3.09–2.97(m,1H),2.48–2.41(m,1H),2.20-2.10(m,1H ),2.05-1.97(m,1H),1.98-1.82(m,1H),1.80-1.67(m,3H),1.65-1.53(m,1H),1.32(s,3H). LC-MS(ESI):m / z[M+H] + =479.2.

[0216] Enantiomer 3 (Example 13c, 99.97% ee); retention time: 2.78 min. 1 H NMR (500MHz, DMSO-d6) δ11.81(s,1H),8.20(s,1H),8.08(s,1H),7.23(s,1H),7.05(d,J=8. 5Hz,1H),5.75(s,1H),4.99(s,1H),4.51(s,2H),4.42(s,2H),3.82(d,J=7.3Hz,1H),3.80– 3.69(m,2H),3.43(d,J=8.6Hz,1H),3.09–2.97(m,1H),2.48–2.41(m,1H),2.20-2.10(m,1H ),2.05-1.97(m,1H),1.98-1.82(m,1H),1.80-1.67(m,3H),1.65-1.53(m,1H),1.32(s,3H). LC-MS(ESI):m / z[M+H] + =479.2.

[0217] Enantiomer 4 (Example 13d, 100% ee); retention time: 10.56 min. 1H NMR (500MHz, DMSO-d6) δ11.81(s,1H),8.20(s,1H),8.08(s,1H),7.23(s,1H),7.05(d,J=8. 5Hz,1H),5.75(s,1H),4.99(s,1H),4.51(s,2H),4.42(s,2H),3.82(d,J=7.3Hz,1H),3.80– 3.69(m,2H),3.43(d,J=8.6Hz,1H),3.09–2.97(m,1H),2.48–2.41(m,1H),2.20-2.10(m,1H ),2.05-1.97(m,1H),1.98-1.82(m,1H),1.80-1.67(m,3H),1.65-1.53(m,1H),1.32(s,3H). LC-MS(ESI):m / z[M+H] + =479.2.

[0218] Chiral analysis method: column: CHIRALPAK IA 4.6 mm×250 mm, 5 μm; mobile phase: A is MtBE and B is DCM:MeOH; gradient: mobile phase A: mobile phase B = 60:40 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 25° C.

[0219] Chiral preparative HPLC conditions: CHIRALPAK IA 20 mm×250 mm, 5 μm; mobile phase: A is MtBE and B is DCM:MeOH; gradient: mobile phase A:mobile phase B=60:40 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 20° C.

[0220] Example 14: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thien-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methoxy-2-methylpropan-2-yl)carbamate

[0221]

[0222] The title compound was synthesized according to a procedure similar to Example 9. 1H NMR(500MHz,DMSO-d6)δ11.80(s,1H),8.21(s,1H),8.09(t,J=8.6Hz,1H),7.05(d,J =8.5Hz,1H),6.64(s,1H),5.75(d,J=1.9Hz,1H),5.05-4.90(m,1H),4.51(s,2H),4.4 2(s,2H),3.33-3.27(m,2H),3.24(s,3H),3.09-2.99(m,1H),2.48-2.42(m,1H),2.05 -1.97(m,1H),1.95-1.84(m,1H),1.78-1.65(m,2H),1.63-1.53(m,1H),1.16(s,6H). LC-MS(ESI):m / z[M+H] + =481.32.

[0223] Example 15: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate

[0224]

[0225] The racemic form of the title compound was synthesized following a procedure similar to Example 9, which was further separated by chiral preparative HPLC to give:

[0226] Enantiomer 1 (Example 15a, 100% ee); retention time: 4.74 min. 1 H NMR(500MHz,DMSO-d6)δ11.83(s,1H),8.21(s,1H),8.14-8.02(m,1H),7.62(s,1H) ),7.03(d,J=4Hz,1H),5.76(s,1H),5.07-4.97(m,1H),4.61-4.53(m,2H),4.51(s, 2H),4.42(s,2H),4.28-4.19(m,2H),3.11-3.00(m,1H),2.48-2.43(m,1H),2.07-1 .98(m,1H),1.96-1.85(m,1H),1.80-1.66(m,2H),1.65-1.57(m,1H),1.47(s,3H). LC-MS(ESI):m / z[M+H] + =465.2.

[0227] Enantiomer 2 (Example 15b, 100% ee); retention time: 6.54 min.1 H NMR(500MHz,DMSO-d6)δ11.83(s,1H),8.21(s,1H),8.13-8.02(m,1H),7.62(s,1H) ),7.07(d,J=4Hz,1H),5.76(s,1H),5.07-4.98(m,1H),4.61-4.53(m,2H),4.51(s, 2H),4.42(s,2H),4.28-4.20(m,2H),3.11-3.02(m,1H),2.48-2.41(m,1H),2.07-1 .99(m,1H),1.97-1.85(m,1H),1.80-1.65(m,2H),1.65-1.56(m,1H),1.47(s,3H). LC-MS(ESI):m / z[M+H] + =465.2.

[0228] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A is MtBE (0.1% 2M NH 3 MeOH) and B is DCM:MeOH=50:50 (v / v); gradient: mobile phase A: mobile phase B=50:50 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[0229] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm×250 mm, 5 μm; mobile phase: A is MtBE and B is DCM:MeOH=50:50 (v / v) (0.2% 2M NH3MeOH); gradient: mobile phase A: mobile phase B=50:50 (v / v); flow rate: 18 mL / min, wavelength: UV 270 nm and 320 nm, preparative HPLC equipment: Prep-HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[0230] Example 16: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(3,3,3-trifluoropropyl)carbamate

[0231]

[0232] The title compound was synthesized according to a procedure similar to Example 9. 1H NMR (500MHz, DMSO-d6) δ11.83(s,1H),8.20(d,J=2.0Hz,1H),8.06(s,1H),7.26(t,J=5.6Hz,1H),7.05(d,J=8.5Hz,1H),5.75(s,1 H),5.10-4.95(m,1H),4.51(s,2H),4.42(s,2H),3.21(dd,J=13.0,6.7Hz,2H),3.10-2.99(m,1H),2.48–2.34(m,3H),2.08-1.97(m 1H),1.96–1.86(m,1H),1.80-1.65(m,2H),1.65–1.55(m,1H). LC-MS (ESI): m / z [M+H] + =491.25.

[0233] Example 17: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl((1s,4s)-4-hydroxycyclohexyl)carbamate

[0234]

[0235] The title compound was synthesized according to a procedure similar to Example 9. 1 H NMR(500MHz,DMSO-d6)δ11.80(s,1H),8.20(s,1H),8.11(d,J=27.8Hz,1H),7.05(d,J =8.5Hz,1H),6.98(d,J=6.8Hz,1H),5.76(s,1H),5.05-4.93(m,1H),4.51(s,2H),4.4 2(s,2H),4.29(s,1H),3.67(s,1H),3.09-2.98(m,1H),2.47-2.42(m,2H),2.05-1.97 (m,1H),1.96-1.85(m,1H),1.78-1.67(m,2H),1.63-1.52(m,5H),1.47-1.35(m,4H). LC-MS(ESI):m / z[M+H] + =493.3.

[0236] Example 18: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylethylcarbamate

[0237]

[0238] The racemic form of the title compound was synthesized following a procedure similar to Example 9, which was further separated by chiral preparative HPLC to give:

[0239] Enantiomer 1 (Example 18a, 100% ee). 1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),8.20(s,1H),8.08(t,J=8.2Hz,1H),7.17–6 .97(m,2H),5.75(s,1H),5.00(s,1H),4.51(s,2H),4.42(s,2H),3.10–3.01(m,1H) ,2.98(dt,J=13.6,7.0Hz,2H),2.45(dd,J=14.0,7.3Hz,1H),2.05–1.97(m,1H),1. 96–1.85(m,1H),1.79–1.65(m,2H),1.61(d,J=13.8Hz,1H),0.99(t,J=7.2Hz,3H). LC-MS(ESI):m / z[M+H] + =423.1.

[0240] Enantiomer 2 (Example 18b, 100% ee). 1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),8.20(s,1H),8.08(t,J=8.2Hz,1H),7.17–6 .97(m,2H),5.75(s,1H),5.00(s,1H),4.51(s,2H),4.42(s,2H),3.10–3.01(m,1H) ,2.98(dt,J=13.6,7.0Hz,2H),2.45(dd,J=14.0,7.3Hz,1H),2.05–1.97(m,1H),1. 96–1.85(m,1H),1.79–1.65(m,2H),1.61(d,J=13.8Hz,1H),0.99(t,J=7.2Hz,3H). LC-MS(ESI):m / z[M+H] + =423.1.

[0241] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A is MtBE and B is DCM:MeOH=50:50 (v / v) (0.1% 2M NH3MeOH); gradient: mobile phase A: mobile phase B=40:60 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35°C.

[0242] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm×250 mm, 5 μm; mobile phase: A is MtBE and B is DCM:MeOH=50:50 (v / v) (0.2% 2M NH3MeOH); gradient: mobile phase A: mobile phase B=40:60 (v / v); flow rate: 18 mL / min, wavelength: UV 270 nm and 280 nm, preparative HPLC equipment: Prep-HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[0243] Example 19: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-hydroxy-2-methylpropan-2-yl)carbamate

[0244]

[0245] The title compound was synthesized according to a procedure similar to Example 9. 1 H NMR (500MHz, DMSO-d6) δ11.81(s,1H),8.20(d,J=2.0Hz,1H),8.07(s,1H),7.05(d,J=8.5Hz,1H),6.47(s ,1H),5.76(s,1H),5.10-4.90(m,1H),4.70(t,J=5.6Hz,1H),4.51(s,2H),4.42(s,2H),3.33(s,2H),3.08 -2.98(m,1H),2.48-2.41(m,1H),2.05-1.96(m,1H),1.95-1.83(m,1H),1.80-1.64(m,2H),1.64-1.52(m,1H),1.14(s,6H). LC-MS(ESI):m / z[M+H] + =467.3.

[0246] Example 20: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyloxetan-3-ylcarbamate

[0247]

[0248] The title compound was synthesized according to a procedure similar to Example 9. 1H NMR(500MHz,DMSO-d6)δ11.83(s,1H),8.20(s,1H),8.06(s,1H),7.89(d,J=5 .3Hz,1H),7.05(d,J=8.5Hz,1H),5.75(s,1H),5.06-4.95(m,1H),4.64(s,3H) ,4.51(s,2H),4.42(s,4H),3.29(s,1H),3.10-2.99(m,1H),2.48-2.40(m,1H) ,2.05-1.98(m,1H),2.07-1.98(m,1H),1.79-1.66(m,2H),1.65-1.55(m,1H). LC-MS (ESI): m / z [M+H] + =451.3.

[0249] Example 21: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylmethyl(tetrahydrofuran-3-yl)carbamate

[0250]

[0251] The title compound was synthesized according to a procedure similar to Example 9. 1 H NMR (500MHz, DMSO-d6) δ11.84(s,1H),8.21(s,1H),8.08(s,1H),7.05(d,J=8.5Hz, 1H),5.75(s,1H),5.10-4.95(m,1H),4.80-4.58(m,1H),4.51(s,2H),4.42(s,2H), 3.92-3.79(m,1H),3.70-3.59(m,2H),3.58-3.49(m,1H),3.15–3.06(m,1H),2.71( s,3H),2.48-2.38(m,1H),2.12-1.98(m,2H),1.96-1.86(m,1H),1.83-1.67(m,4H). LC-MS(ESI):m / z[M+H] + =479.32.

[0252] Example 22: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(2,2,2-trifluoroethyl)carbamate

[0253]

[0254] The title compound was synthesized according to a procedure similar to Example 9. 1 H NMR(500MHz,DMSO-d6)δ11.82(s,1H),8.20(s,1H),8.08(s,1H),7.87(t,J= 6.3Hz,1H),7.05(d,J=8.5Hz,1H),5.76(s,1H),5.15-4.95(m,1H),4.51(s, 2H),4.42(s,2H),3.83-3.70(m,2H),3.11-3.01(m,1H),2.49-2.45(m,1H), 2.08-1.98(m,1H),1.97-1.86(m,1H),1.81-1.67(m,2H),1.66-1.56(m,1H). LC-MS (ESI): m / z [M+H] + =477.25.

[0255] Example 23: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylcyclopentylcarbamate

[0256]

[0257] The title compound was synthesized according to a procedure similar to Example 9. 1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),8.20(s,1H),8.07(s,1H),7.05(d,J =8.2Hz,2H),5.75(s,1H),5.08-4.90(m,1H),4.51(s,2H),4.42(s,2H),3.8 2-3.70(m,1H),3.11-2.97(m,1H),2.48-2.40(m,1H),2.08-1.96(m,1H),1 .95-1.85(m,1H),1.80-1.65(m,4H),1.65-1.52(m,3H),1.50-1.31(m,4H). LC-MS (ESI): m / z [M+H] + =463.36.

[0258] Example 24: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(tetrahydrofuran-3-yl)carbamate

[0259]

[0260] The racemic form of the title compound was synthesized following a procedure similar to Example 9, which was further separated by chiral preparative HPLC to give:

[0261] Enantiomer 1 (Example 24a, 99.65% ee); retention time: 1.187 min. 1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),8.20(s,1H),8.08(t,J=8.2Hz,1H),7.17–6 .97(m,2H),5.75(s,1H),5.00(s,1H),4.51(s,2H),4.42(s,2H),3.10–3.01(m,1H) ,2.98(dt,J=13.6,7.0Hz,2H),2.45(dd,J=14.0,7.3Hz,1H),2.05–1.97(m,1H),1. 96–1.85(m,1H),1.79–1.65(m,2H),1.61(d,J=13.8Hz,1H),0.99(t,J=7.2Hz,3H). LC-MS(ESI):m / z[M+H] + =465.2.

[0262] Enantiomer 1 (Example 24b, 99.34% ee); retention time: 1.545 min. 1 H NMR(500MHz,DMSO-d6)δ11.81(s,1H),8.20(s,1H),8.08(t,J=8.2Hz,1H),7.17–6 .97(m,2H),5.75(s,1H),5.00(s,1H),4.51(s,2H),4.42(s,2H),3.10–3.01(m,1H) ,2.98(dt,J=13.6,7.0Hz,2H),2.45(dd,J=14.0,7.3Hz,1H),2.05–1.97(m,1H),1. 96–1.85(m,1H),1.79–1.65(m,2H),1.61(d,J=13.8Hz,1H),0.99(t,J=7.2Hz,3H). LC-MS(ESI):m / z[M+H] + =465.2.

[0263] Chiral analysis method: column: CHIRALPAK IA 4.6 mm×250 mm, 5 μm; mobile phase: A is Hex:DCM and B is IPA; gradient: mobile phase A: mobile phase B = 50:60 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[0264] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm×250 mm, 5 μm; mobile phase: A is Hex:DCM and B is IPA; gradient: mobile phase A: mobile phase B=50:50 (v / v); flow rate: 18 mL / min, wavelength: UV 270 nm and 280 nm, preparative HPLC equipment: Prep-HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[0265] Example 25: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl((1s,4s)-4-hydroxy-4-methylcyclohexyl)carbamate

[0266]

[0267] The title compound was synthesized according to a procedure similar to Example 9. 1 H NMR (500MHz, DMSO-d6) δ11.80(s,1H),8.20(s,1H),8.07(d,J=9.0Hz,1H),7.05(d,J=8.5H z,1H),6.87(dd,J=67.2,8.1Hz,1H),5.75(s,1H),5.10-4.90(m,1H),4.51(s,2H),4.42(s ,2H),3.95(s,1H),3.17(s,1H),3.10–2.99(m,1H),2.48-2.38(m,1H),2.05-1.97(m,1H), 1.96-1.84(m,1H),1.78-1.65(m,2H),1.64-1.40(m,7H),1.32-1.20(m,2H),1.07(s,3H). LC-MS(ESI):m / z[M+H] + =507.30.

[0268] Example 26: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl((1r,4r)-4-hydroxycyclohexyl)carbamate

[0269]

[0270] The title compound was synthesized according to a procedure similar to Example 9. 1H NMR(500MHz,DMSO-d6)δ11.81(s,1H),8.20(s,1H),8.08(s,1H),7.05(d,J=8.2 Hz,1H),6.94(s,1H),5.75(s,1H),5.06-4.90(m,1H),4.51(s,3H),4.42(s,2H), 3.19(s,1H),3.03(s,1H),2.58-2.54(m,1H),2.48-2.40(m,1H),2.08-1.97(m,1 H),1.96-1.87(m,1H),1.83-1.66(m,6H),1.63-1.52(m,1H),1.25-1.08(m,4H). LC-MS (ESI): m / z [M+H] + =493.29.

[0271] Example 34: cis-3-(3-((4-fluoro-2,2-dioxo-1,3-dihydrobenzo[c]thiophen-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl((1r,4r)-4-hydroxy-4-methylcyclohexyl)carbamate

[0272]

[0273] The title compound was synthesized according to a procedure similar to Example 9. 1 H NMR (500MHz, DMSO-d6) δ11.80(s,1H),8.19(s,1H),8.07(s,1H),7.05(d,J=8.5Hz,1H),6. 94(d,J=7.6Hz,1H),5.75(s,1H),5.05-4.95(m,1H),4.51(s,2H),4.42(s,2H),4.17(s,1H) ,3.29(s,1H),3.09–2.97(m,1H),2.48–2.42(m,1H),2.05–1.97(m,1H),1.95–1.85(m,1H) ,1.78–1.64(m,4H),1.63-1.56(m,1H),1.55-1.46(m,2H),1.39-1.22(m,4H),1.07(s,3H). LC-MS(ESI):m / z[M+H] + =507.31.

[0274] CDK2 / cyclin E1 and CDK1 / cyclin B1 biochemical assays

[0275] Compounds disclosed herein were tested for inhibition of CDK2 / cyclin E1 or CDK1 / cyclin B1 kinases in an assay based on the time-resolved fluorescence resonance energy transfer (TR-FRET) method. The assay was performed in a 384-well low-volume black plate in a reaction mixture containing CDK2 / cyclin E1 or CDK1 / cyclin B1, 0.060 mM ATP (CDK2 / cyclin E1) or 0.015 mM ATP (CDK1 / cyclin B1), 0.15 μM Rb (Ser780)-biotin substrate and 0 μM-10 μM compound in a buffer containing 50 mM HEPES pH 7.0, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 50 mM MgCl2, 1 mM DTT and 0.005% Tween-20. The kinases were incubated with compounds at room temperature for 60 min, and the reaction was initiated by adding ATP and Rb(Ser780)-biotin substrate. After 120 min of reaction at room temperature, an equal volume of stop / detection solution was added according to the manufacturer's instructions (Cisbio Bioassays). The stop / detection solution contained streptavidin-XL665 and anti-pRb(Ser780)mAb-Eu cryptate in detection buffer (Cisbio Bioassays). The plates were incubated at room temperature for 60 min, and TR-FRET signals (ex337nm, em665nm / 620nm) were recorded on a PHERAstar FSX microplate reader (BMG Labtech). The percentage inhibition of CDK2 / cyclin E1 or CDK1 / cyclin B1 kinase activity in the presence of increasing concentrations of compound was calculated based on the ratio of fluorescence at 665nm to fluorescence at 620nm. The data were fitted to a four-parameter logistic equation by Dotmatics to obtain the IC for each compound. 50 Example Measurement of IC 50 The data are shown in Table 1.

[0276] Table 1

[0277]

[0278] CDK2 / cyclin E1 and CDK1 / cyclin B1 biochemical assays

[0279] The compounds disclosed herein were tested for inhibition of CDK2 / cyclin E1 or CDK1 / cyclin B1 kinases in an assay based on the time-resolved fluorescence resonance energy transfer (TR-FRET) method. The assay was performed in a 384-well low-volume black plate in a reaction mixture containing CDK2 / cyclin E1 or CDK1 / cyclin B1, 1 mM ATP for CDK2 / cyclin E1 and CDK1 / cyclin B1, 0.15 μM Rb (Ser780)-biotin substrate, and 0 μM-10 μM compound in a buffer containing 50 mM HEPES pH 7.0, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 50 mM MgCl2, 1 mM DTT, and 0.005% Tween-20. The kinase was incubated with the compound at room temperature for 60 minutes, and the reaction was initiated by adding ATP and Rb (Ser780)-biotin substrate. After 90 minutes of reaction at room temperature, an equal volume of stop / detection solution was added according to the manufacturer's instructions (Cisbio Bioassays). The stop / detection solution contained streptavidin-XL665 and anti-pRb (Ser780) mAb-Eu cryptate in detection buffer (Cisbio Bioassays). The plate was incubated at room temperature for 60 minutes and the TR-FRET signal (ex337nm, em665nm / 620nm) was recorded on a PHERAstar FSX microplate reader (BMG Labtech). The percentage inhibition of CDK2 / cyclin E1 or CDK1 / cyclin B1 kinase activity in the presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 665nm to fluorescence at 620nm. The data were fitted to a four-parameter logistic equation by Dotmatics to obtain the IC50 for each compound. The IC50 data measured in the embodiment are shown in Table 2.

[0280] Table 2

[0281]

[0282]

[0283] HEK-293 cell treatment

[0284] HEK-293 cells were seeded at 2000 cells / well in a volume of 50 μl / well in a Corning 96-well plate (Cat. No. 3903) in cell culture medium [DMEM, high glucose (Thermo, Cat. No. 11965118), 10% heat-inactivated FBS (Gibco, Cat. No. 10091148), 1% PS (Thermo Cat. No. 15140122)] and then incubated overnight. HEK-293 cells were treated with compounds diluted in 0.4% DMSO according to the following scheme: (1) 250× stock solution was prepared by diluting 4-fold with 10 mM DMSO for a total of 8 doses; (2) 1 μl of 250× stock solution was transferred to 124 μl culture medium to prepare 2× solution in cell culture medium; (3) 50 μl of 2× solution was added to the cells and incubated for 72 hours.

[0285] Cytotoxicity assay

[0286] 25 μl of Reagent [(Promega catalog number G9242)] was added to each well of a 96-well plate. The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. The plate was then allowed to incubate at room temperature for 10 minutes to stabilize the luminescent signal. Luminescence was recorded using the luminescence protocol on a BMG PheraStar.

[0287] IC 50 calculate

[0288] The percent inhibition of the compound was calculated by the following formula: percent inhibition of the compound = 100-100×(signal-low control) / (high control-low control), where signal = each test compound group; low control = medium-only group (no cells), indicating that cell proliferation was completely inhibited; high control = cell group with DMSO added and no compound, indicating cell proliferation without inhibition; Imax is the maximum percent inhibition.

[0289] IC of the compound 50 The value can be obtained by fitting the following formula:

[0290] Y = bottom value + (top value - bottom value) / (1 + ((IC 50 / X)^Hill slope))

[0291] Where X and Y are known values, IC 50 , Hillslope, top value and bottom value are parameters obtained by fitting with software. Y is the inhibition percentage (calculated by the equation), X is the concentration of the compound; IC 50 is the concentration of compound that achieves 50% inhibition. 50 The smaller the value, the stronger the inhibitory ability of the compound.50 The higher the value, the weaker the inhibitory ability of the compound; Hill slope represents the slope of the fitted curve, usually about 1*; Bottom value represents the minimum value of the curve obtained by data fitting, usually 0% ± 20%; Top value represents the maximum value of the curve obtained by data fitting, usually 100% ± 20%. The experimental data were fitted by calculation and analysis using Dotmatics data analysis software. The IC measured in the example 50 The data are shown in Table 3.

[0292] Table 3

[0293]

[0294]

Claims

1. A method for synthesizing compound (I): or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, wherein the method comprises: n1 is 0, 1 or 2; n2 is 1, 2 or 3; n3 is 0, 1 or 2; n4 is 0, 1, 2, 3 or 4; n5 and n6 are each independently 0, 1 or 2, provided that n5 and n6 are not simultaneously 0; n7 is 0, 1, 2, 3 or 4; n8 is 1, 2, 3 or 4; R 1 is selected from hydrogen, halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3-membered to 8-membered heterocyclic group, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (═O), or —CN, wherein the —C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R 1a replace; R 1a is selected from halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3-membered to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -NO2, -OH or -CN; R X Each is independently selected from hydrogen, halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3-membered to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xa R Xb 、-OR Xa 、-SR Xa 、-SO2R Xa 、-SO2NR Xa R Xb 、-C(O)R Xa 、-CO2R Xa 、-C(O)NR Xa R Xb 、-NR Xa COR Xb 、-NR Xa CO2R Xb 、-NR Xa S02R Xb or -CN, wherein the -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R Xc replace; or Two R's X Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0 to 3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members; the ring is optionally substituted with at least one substituent R Xc replace; R Xa and R Xb Each is independently selected from hydrogen, deuterium, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 The -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R Xd replace; R Xc and R Xd Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xe R Xf 、-OR Xe 、-SR Xe 、-SO2R Xe 、-SO2NR Xe R Xf 、-C(O)R Xe 、-CO2R Xe 、-C(O)NR Xe R Xf 、-NR Xe COR Xf 、-NR Xe CO2R Xf 、-NR Xe S02R Xf or -CN; R Xe and R Xf Each is independently selected from -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; Y 1 , Y 2 and Y 3 are each independently selected from O, C or N; Q is selected from O or NR Q ; R 3 and R Q Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 The -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 3a replace; R 3a independently selected from hydrogen, halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 3c 、-CN、-SO2R 3c 、-SO2NR 3c R 3d 、-C(O)R 3c 、-CO2R 3c 、-C(O)NR 3c R 3d 、-NR 3c R 3d 、-NR 3c COR 3d 、-NR 3c CO2R 3d or -NR 3c S02R 3d , wherein -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 3e 、-SO2R 3e 、-SO2NR 3e R 3f 、-C(O)R 3e 、-CO2R 3f 、-C(O)NR 3e R 3f 、-NR 3e R 3f 、-NR 3e COR 3f 、-NR 3e CO2R 3f or -NR 3e S02R 3f replace; R 3c , R 3d , R 3e and R 3f Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; R 4 is selected from hydrogen, halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 4a 、-CN、-SO2R 4a 、-SO2NR 4a R 4b 、-C(O)R 4a or -CO2R 4a ; R 4a and R 4b Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl; wherein the -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 The aryl or 5- to 12-membered heteroaryl is optionally substituted with -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl, 5- to 12-membered heteroaryl, -NO2, -OH or -CN; R 5 is selected from hydrogen, halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy or -C3-C8 cycloalkyl; Z 1 , Z 2 and Z 3 Each independently selected from -CR Z or N; R Z is independently selected at each occurrence from hydrogen, halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -NR Za R Zb 、-OR Za 、-SR Za 、-SO2R Za 、-SO2NR Za R Zb 、-C(O)R Za 、-CO2R Za 、-C(O)NR Za R Zb 、-NR Za COR Zb 、-NR Za CO2R Zb 、-NR Za S02R Zb or -CN, wherein the -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R Zc replace; R Za and R Zb Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 The -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R Zd replace; R Zc and R Zd Each is independently selected from halogen, hydroxyl, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Ze R Zf 、-OR Ze 、-SR Ze 、-SO2R Ze 、-SO2NR Ze R Zf 、-C(O)R Ze 、-CO2R Ze 、-C(O)NR Ze R Zf 、-NR Ze COR Zf 、-NR Ze CO2R Zf 、-NR Ze S02R Zf or -CN; R Ze and R Zf Each is independently selected from -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl.

2. The method of claim 1, wherein R 1 is selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic radical, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (═O), or —CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R 1a replace; R 1a is selected from halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic radical, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -NO2, -OH or -CN; Preferably, R 1 is selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 3- to 8-membered heterocyclic radical, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (═O), or —CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one R 1a replace; R 1a is selected from halogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -NO2, -OH or -CN; More preferably, R 1 is phenyl; wherein the phenyl is substituted by -NO2.

3. The method according to any one of the preceding claims, wherein the compound is selected from (IIa) and (IIb): Preferably, the compound is (IIIa): Preferably, the compound is selected from (IVa) and (IVb):

4. A method as claimed in any one of the preceding claims, wherein R 3 and R Q each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, wherein each of the methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R 3a replace; R 3a independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -OR 3c 、-CN、-SO2R 3c 、-SO2NR 3c R 3d 、-C(O)R 3c 、-CO2R 3c 、-C(O)NR 3c R 3d 、-NR 3c R 3d 、-NR 3c COR 3d 、-NR 3c CO2R 3d or -NR 3c S02R 3d wherein the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, 5- to 12-membered heteroaryl, Each of the above is optionally replaced by -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 3e 、-SO2R 3e 、-SO2NR 3e R 3f 、-C(O)R 3e 、-CO2R 3f 、-C(O)NR 3e R 3f 、-NR 3e R 3f 、-NR 3e COR 3f 、-NR 3e CO2R 3f 、-NR 3e S02R 3f replace; R 3c , R 3d , R 3e and R 3f Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, wherein the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl each of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (═O), —CN, —OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy; Preferably, R 3 and R Q Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; More preferably, R 3 and R Q Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl); Even more preferably, R 3 and R Q are each independently hydrogen.

5. A method as claimed in any one of the preceding claims, wherein R 4 is selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 4a 、-CN、-SO2R 4a 、-SO2NR 4a R 4b 、-C(O)R 4a or -CO2R 4a ; R 4a and R 4b each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic radical, C6-C 12 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic radical, C6-C 12 The aryl or 5- to 12-membered heteroaryl is optionally substituted with methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl, 5- to 12-membered heteroaryl, -NO2, OH or -CN; Preferably, R 4 is selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, -C1-C8 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 4a 、-CN、-SO2R 4a 、-SO2NR 4a R 4b 、-C(O)R 4a or -CO2R 4a ; R 4a and R 4b Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, 3- to 8-membered heterocyclic group, C6-C 12 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic radical, C6-C 12 The aryl or 5- to 12-membered heteroaryl is optionally substituted with methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl, 5- to 12-membered heteroaryl, -NO2, OH or -CN; More preferably, R 4 Selected from hydrogen, -C(O)R 4a or -CO2R 4a ; R 4a is phenyl, wherein the phenyl group is optionally substituted with -NO2.

6. A method as claimed in any one of the preceding claims, wherein Partially selected Preferably, the Partially selected More preferably, the Partially selected Even more preferably, the Partially selected 7. A method as claimed in any one of the preceding claims, wherein Z 1 , Z 2 and Z 3 At most two of them are N; preferably, Z 1 , Z 2 and Z 3 At most one of them is N; More preferably, Z 1 , Z 2 and Z 3 Independently for -CR Z .

8. A method as claimed in any one of the preceding claims, wherein R Z is independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -NR Za R Zb 、-OR Za 、-SR Za 、-SO2R Za 、-SO2NR Za R Zb 、-C(O)R Za 、-CO2R Za 、-C(O)NR Za R Zb 、-NR Za COR Zb 、-NR Za CO2R Zb 、-NR Za S02R Zb or -CN, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally replaced by at least one R Zc replace; R Za and R Zb each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, wherein each of the methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Zd replace; R Zc and R Zd each independently selected from -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -NR Ze R Zf 、-OR Ze 、-SR Ze 、-SO2R Ze 、-SO2NR Ze R Zf 、-C(O)R Ze 、-CO2R Ze 、-C(O)NR Ze R Zf 、-NR Ze COR Zf 、-NR Ze CO2R Zf 、-NR Ze S02R Zf or -CN; R Ze and R Zf Each is independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl; Preferably, R Z is independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -NR Za R Zb 、-OR Za 、-SR Za 、-SO2R Za 、-SO2NR Za R Zb 、-C(O)R Za 、-CO2R Za 、-C(O)NR Za R Zb 、-NR Za COR Zb 、-NR Za CO2R Zb 、-NR Za S02R Zb or -CN; R Za and R Zb Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; More preferably, R Z is independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or i-propyl), butyl (n-, sec-, i- or t-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -NH2, -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, or -CN; Even more preferably, R Z is independently selected at each occurrence from hydrogen, -F and methyl.

9. A method as claimed in any one of the preceding claims, wherein Partially selected Preferably, the Partially selected 10. A method as claimed in any one of the preceding claims, wherein R X each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xa R Xb 、-OR Xa 、-SR Xa 、-SO2R Xa 、-SO2NR Xa R Xb 、-C(O)R Xa 、-CO2R Xa 、-C(O)NR Xa R Xb 、-NR Xa COR Xb 、-NR Xa CO2R Xb 、-NR Xa S02R Xb or -CN, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl is optionally replaced by at least one R Xc replace; R Xa and R Xb each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, wherein each of the methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Xd replace; R Xc and R Xd each independently selected from -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xe R Xf 、-OR Xe 、-SR Xe 、-SO2R Xe 、-SO2NR Xe R Xf 、-C(O)R Xe 、-CO2R Xe 、-C(O)NR Xe R Xf 、-NR Xe COR Xf 、-NR Xe CO2R Xf 、-NR Xe S02R Xf or -CN; R Xe and R Xf Each is independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl; Preferably, R X independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, oxo (=O), -NR Xa R Xb 、-OR Xa 、-SR Xa 、-SO2R Xa 、-SO2NR Xa R Xb 、-C(O)R Xa 、-CO2R Xa 、-C(O)NR Xa R Xb 、-NR Xa COR Xb 、-NR Xa CO2R Xb 、-NR Xa S02R Xb or -CN; R Xa and R Xb Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; More preferably, R X independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, oxo (=O) or -OH; Even more preferably, R X For hydrogen.

11. A method as claimed in any one of the preceding claims, wherein two R X Together with the atoms to which they are attached, they form a 3-, 4-, 5-, 6-, 7- or 8-membered ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the ring optionally substituted with at least one substituent R Xc replace; R Xc each independently selected from -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xe R Xf 、-OR Xe 、-SR Xe 、-SO2R Xe 、-SO2NR Xe R Xf 、-C(O)R Xe 、-CO2R Xe 、-C(O)NR Xe R Xf 、-NR Xe COR Xf 、-NR Xe CO2R Xf 、-NR Xe S02R Xf or -CN; R Xe and R Xf Each is independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl; Preferably, the two R X Together with the atoms to which they are attached, they form a 3-, 4-, 5- or 6-membered ring; the ring is optionally substituted with at least one substituent R Xc replace; R Xc Each is independently selected from -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxo (=O) or -CN; More preferably, the two R X Together with the atoms to which they are attached they form a 3-, 4-, 5-, or 6-membered ring.

12. A method as claimed in any one of the preceding claims, wherein Partially selected 13. The method of any one of the preceding claims, wherein the compound is selected from 14. A method as claimed in any one of the preceding claims, wherein The reaction reagents of step A include a non-nucleophilic base; Preferably, the reaction reagent of step A comprises lithium diisopropylamide (LDA), lithium diethylamide (LDEA), N,N-diisopropylethylamine (DIEA), lithium hexamethyldisilazane (LHDS or LiHMDS), sodium hexamethyldisilazane (NaHMDS), lithium isopropylcyclohexylamide (LICA), lithium dicyclohexylamide (LDCA) or lithium 2,2,6,6-tetramethylpiperidinium (LTMP), or any combination of the non-nucleophilic bases; More preferably, the reaction reagent of step A comprises lithium diisopropylamide (LDA), N,N-diisopropylethylamine (DIEA), lithium hexamethyldisilazane (LHDS, LiHMDS) or sodium hexamethyldisilazane (NaHMDS), or any combination of the non-nucleophilic bases; Even more preferably, the reaction reagent of step A comprises N,N-diisopropylethylamine (DIEA).

15. A method as claimed in any one of the preceding claims, wherein The reaction temperature of step A is -10°C to 60°C; preferably, the reaction temperature of step A is 0°C to 55°C; more preferably, the reaction temperature of step A is 50°C.

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