Bicyclic compounds as CDK inhibitors

Abstract

Disclosed herein are bicyclic compound derivatives useful as inhibitors of cyclin dependent kinases. The use of these inhibitors for inhibiting cyclin-dependent kinases, and the use of such compounds for the treatment of cancer, are disclosed herein.

Description

Technical Field

[0001] Disclosed herein are bicyclic compound derivatives that are useful as inhibitors of cyclin-dependent kinases. Disclosed herein are the use of these inhibitors for inhibiting cyclin-dependent kinases, as well as the use of such compounds for treating cancer. Background Art

[0002] Cyclin-dependent kinases (CDKs) belong to the Ser / Thr protein kinase family and act as driving factors for 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) and partially release the transcription factor E2F by binding to cyclin D. CDK2 then forms a complex with cyclin E, completely phosphorylating Rb, completely releasing E2F and initiating the S phase (Harbour, JW et al., Cell, 98(6), 859-869). During the S phase, CDK2 then 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 key 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, deregulating Rb phosphorylation and leading to cancer cell proliferation (Wood, DJ et al., Cell Chem Biol, 26(1), 121-130). Aberrant CCNE has been shown to be a disease driver in multiple cancer types (e.g., ovarian, esophageal, bladder, pancreatic, etc.) and is 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, one of the mechanisms of clinical drug resistance to CDK4 / 6i (such as palbociclib, ribociclib and abemaciclib) in ER+HER2- breast cancer patients is CCNE overexpression and CDK2 activation (Knudsen, ES et al., Cell Rep, 38(9), 110448). CDK2 siRNA knockdown in breast cancer cell lines and mouse models with palbociclib resistance suggests 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 mechanism of trastuzumab resistance. In HER2+ BC patients, the incidence of trastuzumab resistance with cyclin E amplification or overexpression is approximately 35%, which is associated with poor clinical benefit, while cells with trastuzumab resistance are sensitive to CDK2 inhibition (Scaltriti, M. et al., Proc Natl Acad Sci USA, 108(9), 3761-3766). In multiple cancer types, CCNE1 amplification can predict response to CDK2 inhibition, indicating that CDK2 is a potential effective therapeutic target.

[0004] The low toxicity of targeting CDK2 has also been demonstrated in animal models. Mice with CDK2 knockout survive and develop normally, but their germline cells are abnormal (Berthet, C. et al., Curt Biol [Contemporary Biology], 13(20), 1775-1785). Mice with single knockout of CDK1 or double knockout of CDK4 and CDK6 are embryonic lethal (Satyanarayana, A. and Kaldis, P., Oncogene [Cancer Gene], 28(33), 2925-2939).

[0005] The crystal structure of CDK2 (especially its kinase domain) is highly similar to CDK1, and most commercial 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 derive highly selective CDK2 inhibitors that avoid the involvement of CDK family members and limit CDK-driven off-target toxicity, especially CDK1 / CDK4 / CDK6. Summary of the Invention

[0006] In one embodiment, disclosed herein are bicyclic compound derivatives having formula (I). This embodiment comprises the following aspects:

[0007] Aspect 1. A compound having formula (I):

[0008]

[0009] 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:

[0010] n1 is 0, 1, or 2;

[0011] n2 is 1, 2, or 3;

[0012] n3 is 0, 1, or 2;

[0013] n4 is 0, 1, 2, 3, or 4;

[0014] n5 and n6 are each independently 0 or 1, provided that n5 and n6 are not both 0;

[0015] are each independently a single bond or a double bond, provided that the two double bonds are not directly connected;

[0016] X 1 、X 2 、X 3 and X 4Each independently selected from N, C, S(=O)2 or S(=O), wherein each N is independently replaced by 0 or 1 R Xa and each C is independently substituted with one or two R Xb group substitution;

[0017] R Xa Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 12 membered heterocyclyl, -C6-C 12 aryl or 5 to 12 membered heteroaryl, wherein said -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C8 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R Xaa replace;

[0018] R Xaa Each is independently selected from hydrogen, deuterium, 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 Xab 、-CN、-SO2R Xab 、-SO2NR Xab R Xac 、-C(O)R Xab 、-CO2R Xab 、-C(O)NR Xab R Xac 、-NR Xab R Xac 、-NR Xab COR Xac 、-NR Xab CO2R Xac or -NR Xab SO2R Xac wherein the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -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 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 Xad 、-SO2R Xad 、-SO2NR Xad RXae 、-C(O)R Xad 、-CO2R Xad 、-C(O)NR Xad R Xae 、-NR Xad R Xae 、-NR Xad COR Xae 、-NR Xad CO2R Xae or -NR Xad SO2R Xae replace;

[0019] R Xab 、R Xac 、R Xad and R Xae 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 said -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 is optionally substituted by halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C8 alkyl, 12 substituted with aryl, 5- to 12-membered heteroaryl, oxo (═O), —CN, —OH, or —C1-C8 alkoxy;

[0020] R Xb Each is independently selected from hydrogen, halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xba R Xbb 、-OR Xba 、-SR Xba 、-SO2R Xba 、-SO2NR Xba R Xbb 、-C(O)R Xba 、-CO2R Xba 、-C(O)NR Xba R Xbb 、-NR Xba COR Xbb 、-NR Xba CO2R Xbb or -NR Xba SO2R Xbbor -CN, wherein said -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 by at least one R Xbc replace; or

[0021] Two R's Xb Together with the one or more atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; said ring optionally being substituted with at least one substituent R Xbc replace;

[0022] R Xba and R Xbb 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 said -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally substituted with at least one substituent R Xbd replace;

[0023] R Xbc and R Xbd 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 Xbe R Xbf 、-OR Xbe 、-SR Xbe 、-SO2R Xbe 、-SO2NR Xbe R Xbf 、-C(O)R Xbe 、-CO2R Xbe 、-C(O)NR Xbe R Xbf 、-NR Xbe COR Xbf 、-NR Xbe CO2R Xbf or -NR Xbe SO2R Xbf or -CN;

[0024] R Xbe and R XbfEach 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;

[0025] Y 1 、Y 2 and Y 3 Each is independently selected from O, C or N, wherein C and N are independently replaced by 1 or 2 R 5 group or hydrogen atom substitution;

[0026] Q is selected from O or NR Q ;

[0027] R 1 、R 2 、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 said -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C8 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 1a replace; or

[0028] (R 1 and R 2 )、(R 1 and R Q ) or (R Q and R 2 ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring containing as one or more ring members 0-3 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; said ring optionally substituted with at least one substituent R 1b replace;

[0029] R 1a and R 1b Each is 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 1c 、-CN、-SO2R 1c 、-SO2NR 1c R 1d 、-C(O)R 1c、-CO2R 1c 、-C(O)NR 1c R 1d 、-NR 1c R 1d 、-NR 1c COR 1d 、-NR 1c CO2R 1d or -NR 1c SO2R 1d , wherein -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -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 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 1e 、-SO2R 1e 、-SO2NR 1e R 1f 、-C(O)R 1e 、-CO2R 1f 、-C(O)NR 1e R 1f 、-NR 1e R 1f 、-NR 1e COR 1f 、-NR 1e CO2R 1f or -NR 1e SO2R 1f replace;

[0030] R 1c 、R 1d 、R 1e and R 1f 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 and R 5 Each is independently selected from hydrogen, halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, or -C3-C8 cycloalkyl;

[0032] Z 1 , Z 2 and Z 3Each independently selected from -CR Z , or N;

[0033] R Z 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 or -NR Za SO2R Zb or -CN, wherein said -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 by at least one R Zc replace;

[0034] 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 aryl, or 5 to 12 membered heteroaryl, wherein said -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally substituted with at least one substituent R Zd replace;

[0035] R Zc and R Zd Each 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 、-SO2RZe 、-SO2NR Ze R Zf 、-C(O)R Ze 、-CO2R Ze 、-C(O)NR Ze R Zf 、-NR Ze COR Zf 、-NR Ze CO2R Zf or -NR Ze SO2R Zf or -CN;

[0036] R Ze and R Zf Each 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.

[0037] In some embodiments, X 1 、X 2 、X 3 and X 4 At least one of them is N, X 1 、X 2 、X 3 and X 4 At least one of them is S(=O)2 or S(=O).

[0038] In some embodiments, Y 1 、Y 2 and Y 3 At most one of them is selected from O or N, and Y 1 、Y 2 and Y 3 The other two are both C.

[0039] Aspect 2. The compound according to Aspect 1, wherein the compound is selected from (IIa), (IIb), (IIc) and (IId):

[0040]

[0041] Preferably, the compound is selected from (IIe), (IIf), (IIg), (IIh), (IIi) and (IIj):

[0042]

[0043]

[0044] Aspect 3. The compound according to Aspect 1, wherein the compound is selected from (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg) and (IIIh):

[0045]

[0046] Aspect 4. The compound of Aspect 1, wherein the compound is selected from (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (IVl), (IVm), (IVn), (IVo), (IVp), (IVq), (IVr), (IVs), (IVt), (IVu), (IVv), (IVw) and (IVx):

[0047]

[0048]

[0049]

[0050] Preferably, the compound is selected from (Va) and (VIa):

[0051]

[0052] Preferably, the compound is selected from (Vb), (Vc), (VIb) and (VIc):

[0053]

[0054] More preferably, the compound is selected from (Vd) and (VId)

[0055]

[0056] Even more preferably, the compound is selected from (Ve), (Vf), (VIe) and (VIf):

[0057]

[0058] Aspect 5. The compound according to any one of the preceding aspects, wherein R 1 、R 2 、R 3 and R QR is 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-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, cyclononyl, cyclodecyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl is optionally substituted with at least one substituent R 1a replace;

[0059] R 1a 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, oxo (=O), -OR 1c 、-CN、-SO2R 1c 、-SO2NR 1c R 1d 、-C(O)R 1c 、-CO2R 1c 、-C(O)NR 1c R 1d 、-NR 1c R 1d 、-NR 1c COR 1d 、-NR 1c CO2R 1d or -NR 1c SO2R 1dwherein 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 heterocyclyl, phenyl, 5 to 12 membered heteroaryl Each of the groups 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 1e 、-SO2R 1e 、-SO2NR 1e R 1f 、-C(O)R 1e 、-CO2R 1f 、-C(O)NR 1e R 1f 、-NR 1e R 1f 、-NR 1e COR 1f 、-NR 1e CO2R 1f or -NR 1e SO2R 1f replace;

[0060] R 1c 、R 1d 、R 1e and R 1fEach of the following 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, 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, cyclo each of heptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-, iso-, 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;

[0061] Preferably, R 1 、R 2 、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, cyclononyl, cyclodecyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl;

[0062] More preferably, R 1 、R 2 、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);

[0063] Even more preferably, R 1 and R 2 Each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl Isobutyl or tert-butyl); And R 3 and R Q are each independently hydrogen.

[0064] In another embodiment, R 1 and R 2 is independently a substituted or unsubstituted bridged, spiro or fused ring group, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[2.1.1]hexyl, or bicyclo[1.1.1]pentyl.

[0065] Aspect 6. The compound according to any one of the preceding aspects, wherein R 1 R is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[2.3]hexanyl or tetrahydrofuranyl, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[2.3]hexanyl or tetrahydrofuranyl is optionally substituted with at least one substituent R 1a replace;

[0066] R 1a independently selected from hydrogen, -F, -Cl, -Br, -I, oxo (=O), methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptyl, spiro[2.3]hexanyl, tetrahydrofuranyl, or -OR 1c wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally replaced by OR 1c replace;

[0067] R 1c are independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl; and R 2 It is hydrogen;

[0068] Preferably, R 1independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptyl, spiro[2.3]hexanyl or tetrahydrofuranyl, wherein the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptyl, spiro[2.3]hexanyl or tetrahydrofuranyl. each of cyclobutane, oxetanyl, oxanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[2.3]hexanyl, or tetrahydrofuranyl is optionally substituted with at least one substituent selected from OH, CH2OH, CHOMe, F, Cl, Br, oxo(═O), OMe, OEt, methyl, ethyl, cyclopropyl, cyclopropyl-OH, cyclobutyl, azetidinyl, oxetanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[2.3]hexanyl, or tetrahydrofuranyl; and R 2 It is hydrogen;

[0069] More preferably, R 1 independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl Isobutyl or tert-butyl;

[0070] And R 2 It's hydrogen.

[0071] Aspect 7. The compound according to any one of the preceding aspects, wherein (R 1 and R 2 )、(R 1 and R Q ) or (R Q and R 2 ) together with the atom or atoms to which they are attached form a 3, 4, 5, 6, 7 or 8 membered ring comprising 0, 1, 2 or 3 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; said ring optionally being substituted with at least one substituent R 1b replace;

[0072] R 1bindependently 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 1c 、-CN、-SO2R 1c 、-SO2NR 1c R 1d 、-C(O)R 1c 、-CO2R 1c 、-C(O)NR 1c R 1d 、-NR 1c R 1d 、-NR 1c COR 1d 、-NR 1c CO2R 1d or -NR 1c SO2R 1d 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 heterocyclyl, phenyl, 5 to 12 membered heteroaryl Each of the groups 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 1e 、-SO2R 1e 、-SO2NR 1e R 1f 、-C(O)R 1e 、-CO2R 1f 、-C(O)NR 1e R 1f 、-NR 1e R 1f 、-NR 1e COR 1f 、-NR 1e CO2R 1f or -NR 1e SO2R 1f replace;

[0073] R 1c 、R 1d 、R 1e and R 1f Each of the following 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, 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, cyclo each of heptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-, iso-, 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;

[0074] Preferably, (R 1 and R 2 )、(R 1 and R Q ) or (R Q and R 2 ) together with the atom or atoms to which they are attached form a 4-, 5-, or 6-membered ring; said ring is optionally substituted with at least one substituent R 1b replace;

[0075] R 1b 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 1c 、-CN、-SO2R 1c 、-SO2NR 1c R 1d 、-C(O)R 1c 、-CO2R 1c 、-C(O)NR 1c R 1d 、-NR1c R 1d 、-NR 1c COR 1d 、-NR 1c CO2R 1d or -NR 1c SO2R 1d ;

[0076] R 1c and R 1d Each of the following 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, 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, cyclo each of heptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-, iso-, 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;

[0077] More preferably, (R 1 and R 2 )、(R 1 and R Q ) or (R Q and R 2 ) together with the atom or atoms to which they are attached form a 4-, 5-, or 6-membered ring; said ring is optionally substituted with at least one substituent R 1b replace;

[0078] R 1b independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -CN, or -NH2;

[0079] Even more preferably, R 1 and R2 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered ring; said ring is optionally substituted with at least one substituent R 1b replace;

[0080] R 1b Independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl) or -OH.

[0081] Aspect 8. The compound according to any one of the preceding aspects, wherein the Partially selected

[0082] Aspect 9. The compound according to any one of the preceding aspects, wherein R 4 and R 5 Each is 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, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl;

[0083] Preferably, R 4 and R 5 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0084] Even more preferably, R 4 and R 5 are each independently selected from hydrogen.

[0085] Aspect 10. The compound according to any one of the preceding aspects, wherein the Partially selected

[0086] Preferably, the Partially selected

[0087] More preferably, the Partially selected

[0088] Even more preferably, the Partially selected

[0089] Aspect 11. The compound 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;

[0090] More preferably, Z 1 is N, and Z 2 and Z 3 Yes-CR Z ; or Z 2 is N, and Z 1 and Z 3 Yes-CR Z ; or Z 3 is N, and Z 1 and Z 2 Yes-CR Z .

[0091] Aspect 12. The compound 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 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 or -NR Za SO2R 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;

[0092] R Za and R Zb R is 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-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 is optionally substituted with at least one substituent R Zd replace;

[0093] 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, 3-8 membered heterocyclyl, phenyl, 5-12 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 or -NR Ze SO2R Zf or -CN;

[0094] R Ze and R ZfEach 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;

[0095] 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 or -NR Za SO2R Zb or -CN;

[0096] 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;

[0097] More preferably, R Zis 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;

[0098] Even more preferably, R Z is independently selected at each occurrence 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, -CH2OH, -CH2CHF2, -CH2CF3, -NH2, -OH, -OCHF2, methoxy, ethoxy, propoxy, or butoxy.

[0099] Aspect 13. The compound according to any one of the preceding aspects, wherein the Partially selected

[0100] Preferably, the Partially selected

[0101] Aspect 14. The compound according to any one of the preceding aspects, wherein X 1 、X 2 、X 3 and X 4 Each independently selected from N, NR Xa , CR Xb 、C(R Xb )2、S(=O)2,the condition is X 1 、X 2 、X 3 and X 4 is valence-allowed; preferably, X 1 、X 2 、X 3 and X 4 At most one of them is selected from N or NR Xa , X 1 、X 2 、X 3 and X 4 At most one of them is selected from S(=O)2 or S(=O).

[0102] Aspect 15. The compound according to any one of the preceding aspects, wherein R Xa 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-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 is optionally substituted with at least one substituent R Xaa replace;

[0103] R Xaa 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, oxo (=O), -OR Xab 、-CN、-SO2R Xab 、-SO2NR Xab R Xac 、-C(O)R Xab 、-CO2R Xab 、-C(O)NR Xab R Xac 、-NR Xab R Xac 、-NR Xab COR Xac 、-NR Xab CO2R Xac or -NR Xab SO2R Xacwherein 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 heterocyclyl, phenyl, 5 to 12 membered heteroaryl Each of the groups 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 Xad 、-SO2R Xad 、-SO2NR Xad R Xae 、-C(O)R Xad 、-CO2R Xad 、-C(O)NR Xad R Xae 、-NR Xad R Xae 、-NR Xad COR Xae 、-NR Xad CO2R Xae or -NR Xad SO2R Xae replace;

[0104] R Xab 、R Xac 、R Xad and R XaeEach of the following 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, 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, cyclo each of heptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-, iso-, 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;

[0105] Preferably, R Xa 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 or 3 to 8 membered heterocyclyl 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3 to 8 membered heterocyclyl is optionally substituted with at least one substituent R Xaa replace;

[0106] R Xaa 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, oxo (=O), -OR Xab 、-CN、-C(O)R Xab or -NR Xab R Xacwherein 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 heterocyclyl, phenyl, 5 to 12 membered heteroaryl Each of the groups 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 Xad 、-SO2R Xad 、-C(O)R Xad or -NR Xad R Xae replace;

[0107] R Xab 、R Xac 、R Xad and R Xae Each of the following 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, 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, cyclo each of heptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or isopropyl), butyl (n-, sec-, iso-, 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;

[0108] More preferably, R XaEach of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydrofuranyl, azetidinyl or pyrrolidinyl groups is optionally substituted with at least one substituent R Xaa replace;

[0109] R Xaa independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxo (=O), -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, -CN, benzyl, -NMe2, -NH2, -SO2Me, -COCH3, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, or azetidine is optionally replaced by F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, -OR Xad 、-SO2R Xad 、-C(O)R Xad replace;

[0110] R Xad is selected from hydrogen, methyl, and ethyl;

[0111] Even more preferably, R Xa Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, -C2H4OH, -C2H4OMe, -C3H6OH, -C3H6OMe, -CH2OMe, -C(CH3)2OH, -CD3,

[0112]

[0113] Aspect 16. The compound according to any one of the preceding aspects, wherein R Xbeach 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 Xba R Xbb 、-OR Xba 、-SR Xba 、-SO2R Xba 、-SO2NR Xba R Xbb 、-C(O)R Xba 、-CO2R Xba 、-C(O)NR Xba R Xbb 、-NR Xba COR Xbb 、-NR Xba CO2R Xbb or -NR Xba SO2R Xbb 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 Xbc replace;

[0114] R Xba and R Xbb R is 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-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 is optionally substituted with at least one substituent R Xbd replace;

[0115] R Xbc and R Xbdeach 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 Xbe R Xbf 、-OR Xbe 、-SR Xbe 、-SO2R Xbe 、-SO2NR Xbe R Xbf 、-C(O)R Xbe 、-CO2R Xbe 、-C(O)NR Xbe R Xbf 、-NR Xbe COR Xbf 、-NR Xbe CO2R Xbf or -NR Xbe SO2R Xbf or -CN;

[0116] R Xbe and R Xbf 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;

[0117] Preferably, R Xb 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 Xba R Xbb 、-OR Xba 、-SR Xba 、-SO2R Xba 、-SO2NR Xba R Xbb 、-C(O)R Xba 、-CO2RXba 、-C(O)NR Xba R Xbb 、-NR Xba COR Xbb 、-NR Xba CO2R Xbb or -NR Xba SO2R Xbb or -CN;

[0118] R Xba and R Xbb 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;

[0119] More preferably, R Xb independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, -CD3, 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, -NH2, -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, or -CN;

[0120] Even more preferably, R Xb Independently selected from hydrogen, -F, -Cl, methyl, -CD3, 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.

[0121] Aspect 17. The compound according to any one of the preceding aspects, wherein both R Xb Together with the one or more atoms to which they are attached, they form a 3-, 4-, 5-, 6-, 7- or 8-membered ring comprising, as one or more ring members, 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; said ring optionally being substituted with at least one substituent R Xbc replace;

[0122] R Xbceach 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 Xbe R Xbf 、-OR Xbe 、-SR Xbe 、-SO2R Xbe 、-SO2NR Xbe R Xbf 、-C(O)R Xbe 、-CO2R Xbe 、-C(O)NR Xbe R Xbf 、-NR Xbe COR Xbf 、-NR Xbe CO2R Xbf or -NR Xbe SO2R Xbf or -CN;

[0123] R Xbe and R Xbf 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;

[0124] Preferably, the two R Xb Together with the one or more atoms to which they are attached, they form a 3-, 4-, 5-, or 6-membered ring; said ring is optionally substituted with at least one substituent R Xbc replace;

[0125] R Xbc 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;

[0126] More preferably, both R Xb Together with the atom or atoms to which they are attached they form a 3-, 4-, 5- or 6-membered ring.

[0127] Aspect 18. The compound according to any one of the preceding aspects, wherein the Partially selected

[0128]

[0129]

[0130]

[0131] Aspect 19. The compound according to any one of the preceding aspects, wherein the compound is selected from

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168] Aspect 20. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer, a tautomer thereof, or a prodrug thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0169] Aspect 21. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of Aspects 1-19, or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer, or prodrug thereof. DETAILED DESCRIPTION

[0170] The following terms have the indicated meanings throughout this specification:

[0171] As used herein, including the appended aspects, singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0172] Unless the context clearly indicates otherwise, the term "or" means and is used interchangeably with the term "and / or."

[0173] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing from 1 to 18 (e.g., from 1 to 12, further such as from 1 to 10, further such as from 1 to 8, or from 1 to 6, or from 1 to 4) carbon atoms. 1-6 Examples of alkyl groups 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 groups.

[0174] 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.

[0175] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0176] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0177] - bicyclic ring systems (eg 7- to 12-membered bicyclic ring systems) in which at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0178] - a tricyclic ring system (eg a 10- to 15-membered tricyclic ring system) in which at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0179] 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 5-10Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, and the like. 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.

[0180] 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).

[0181] The term "heteroaryl" refers to a group selected from:

[0182] - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments from 1 to 3, in some embodiments from 1 to 2 heteroatoms) selected from nitrogen (N), sulfur (S), and oxygen (O), wherein the remaining ring atoms are carbon;

[0183] - a 7- to 12-membered bicyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from N, O, and S, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0184] - an 11- to 14-membered tricyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from N, O, and S, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0185] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group 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 group contains more than one heteroatom ring member, these heteroatoms can be the same or different. The nitrogen atom in one or more rings of the heteroaryl group can be oxidized to form an N-oxide. As used herein, the term "C-connected heteroaryl" means that the heteroaryl group is connected to the core molecule through a bond of a C atom of the heteroaryl ring.

[0186] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure herein. In certain embodiments, monocyclic or bicyclic aromatic heterocycles have 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulphur (S) and oxygen (O), and the remaining ring members are carbon. In certain embodiments, monocyclic or bicyclic aromatic heterocycles are monocyclic or bicyclic rings comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulphur (S) and oxygen (O). In certain embodiments, monocyclic or bicyclic aromatic heterocycles are 5 to 6 yuan heteroaryl rings, which are monocyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulphur (S) and oxygen (O). In certain embodiments, monocyclic or bicyclic aromatic heterocycles are 8 to 10 yuan heteroaryl rings, which are bicyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen, sulphur and oxygen.

[0187] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro rings, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups. The term "optionally oxidized sulfur" as used herein refers to S, SO, or SO2.

[0188] "Hydrogen" and "H" are interchangeable and refer to protium ( 1 H), deuterium ( 2 H) or tritium ( 3 H). A "deuterated analogue" refers to a compound in which one or more protium ( 1 H) is replaced by an equal number of deuterium ( 2 H) substitution.

[0189] 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. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. It is intended to include all possible stereoisomers, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically stated, reference to an isomer is applicable to any possible isomer. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0190] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, and even further such as no more than 20% of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, such as no more than 5%, such as no more than 1% of any one or more other stereoisomers.

[0191] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0192] When the compounds disclosed herein contain disubstituted cyclohexyl or cyclobutyl groups, the substituents found on the cyclohexyl or cyclobutyl ring can be formed in cis and trans forms. The cis form means that both substituents are located on the upper side of the carbon 2 substituent positions, while the trans form means that they are located on opposite sides.

[0193] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) to the desired uniformity by common techniques in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reverse phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving bed ("SMB") 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 technology most likely to achieve the desired separation.

[0194] "Diastereoisomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of each other. Diastereoisomer mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art (e.g., by chromatography and / or fractional crystallization). Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chlorid), 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.

[0195] Some of the compounds disclosed herein may have different points of attachment of hydrogen, 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.

[0196] Can undergo tautomerism to form Wherein *A and *B refer to the position of the substituent attached to the pyrazole.

[0197] The term "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.

[0198] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt (e.g., a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and / or water and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. 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.

[0199] As defined herein, "pharmaceutically acceptable salts thereof" include salts of at least one compound of formula (I), and salts of stereoisomers of the compound of formula (I), such as enantiomeric salts and / or diastereomeric salts.

[0200] The terms "administration" and "treating" as used herein, when applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ, or a biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, 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 "administration" and "treatment" also refer to, for example, in vitro and ex vivo treatment of a cell by a reagent, a diagnostic agent, a binding compound, or another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0201] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a compound) that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or disorder, is sufficient to affect the treatment of such disease, disorder, or symptom. The "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, as defined above, that is effective to treat the disease or disorder in the subject. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination of subjects used to effectively treat the disease, disorder, or condition.

[0202] Pharmaceutical compositions comprising the compounds disclosed herein can be administered orally, by inhalation, rectally, parenterally, or topically to a subject in need thereof. For oral administration, the pharmaceutical composition can be a conventional solid formulation, such as a tablet, powder, granule, capsule, etc.; a liquid formulation, such as an aqueous or oily suspension; or other liquid formulations, such as a syrup, solution, suspension, etc.; for parenteral administration, the pharmaceutical composition can be a solution, an aqueous solution, an oily suspension concentrate, a lyophilized powder, etc. Preferably, the formulation 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 with a precise dosage. In addition, the pharmaceutical composition may further comprise another active ingredient.

[0203] All formulations of the pharmaceutical composition disclosed herein can be produced by conventional methods in the pharmaceutical field. For example, active ingredient can be mixed with one or more excipients and then made into required formulations." pharmaceutically acceptable excipient " refers to conventional pharmaceutical carriers suitable for required pharmaceutical formulations, for example: diluent, vehicle (such as water, various organic solvents, etc.), filler (such as starch, sucrose, etc.), adhesive (such as cellulose derivatives, alginate, gelatin and polyvinyl pyrrolidone (PVP)); Wetting agent, such as glycerol; Disintegrant, such as agar, calcium carbonate and sodium bicarbonate; Absorption enhancer, such as quaternary ammonium compound; Surfactant, such as cetyl alcohol; Absorption carrier, such as kaolin and bentonite; Lubricant, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, pharmaceutical composition further comprises other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners and dyes.

[0204] The term "disease" refers to any illness, ailment, condition, symptom, or indication, and is interchangeable with the terms "disorder" or "condition."

[0205] Throughout this specification and the accompanying 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 preclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced with the term "containing" or "including", or sometimes "having".

[0206] Throughout this specification and the accompanying aspects, the term "C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 、C 1-6 wait.

[0207] 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.

[0208] abbreviation

[0209]

[0210]

[0211]

[0212]

[0213] Examples

[0214] The following examples are intended to be purely exemplary and should not be considered as limiting in any way. Although efforts have been made to ensure the accuracy of the numerals (e.g., amounts, temperatures, etc.) used, some experimental errors and deviations should be considered. Unless otherwise indicated, temperatures are expressed 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, reactions described below are carried out under a positive pressure of nitrogen or argon or in anhydrous solvents with a drying tube; Reaction flasks are equipped with rubber septa for introducing substrates and reagents via syringes; and glassware is oven dried and / or heat dried.

[0215] Recorded on an Agilent instrument operating at 400 MHz 1 H NMR spectrum. 1 HNMR

[0216] Spectra were obtained using CDCl, CDCl, CDOD, D2O, d6-DMSO, d6-acetone, or (CD3)2CO as solvents and tetramethylsilane (0.00 ppm) or residual solvent (CDCl: 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. When reporting the number of multiplets, 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, if given, are reported in Hertz (Hz).

[0217] 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, 4.6 x 50 mm, 2.7 μm; gradient method: flow rate: 1.8 mL / min; time (min) A (%) B (%)

[0218] Time (min) A(％) B(％) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0219] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II); detector: MWD (190-400 nm); mass detector: G6125CSQ; mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid; column: Poroshell 120EC-C18, 4.6 x 50 mm, 2.7 μm; gradient method: flow rate: 1.8 mL / min; time (min) A (%) B (%)

[0220] Time (min) A(％) B(％) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0221] 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, 4.6 x 50 mm, 2.7 μm; gradient method: flow rate: 1.2 mL / min; time (min) A (%) B (%)

[0222]

[0223]

[0224] Preparative HPLC was performed on a column (150 x 21.2 mm ID, 5 pm, Gemini NXC 18) at 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.

[0225] Example 1: cis-3-(3-((5-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0226] Step 1: 1,4-dioxaspiro[4.4]nonane-7-carboxylic acid methyl ester

[0227]

[0228] Two parallel reactions were performed. A solution of methyl 3-oxocyclopentanecarboxylate (50.0 g, 351.74 mmol) in toluene (500 mL) was treated with ethylene glycol (43.66 g, 703.47 mmol) and 4-toluenesulfonic acid (6.06 g, 35.17 mmol). The mixture was heated to reflux and stirred for 4 h under a nitrogen atmosphere. Each batch was quenched with saturated aqueous NaHCO3, and the two batches were combined and concentrated under reduced pressure. The residue was diluted with EA (2 L) and washed with aqueous NaHCO3 (500 mL). The aqueous layer was further extracted with EA (500 mL×2). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (1:1; R f =0.43) to afford the product (34 g, 26% yield). 1 H NMR (400 MHz, chloroform-d) δ = 4.00-3.84 (m, 4H), 3.68 (s, 3H), 2.98-2.85 (m, 1H), 2.09 (d, J = 8.9 Hz, 2H), 2.06-1.88 (m, 3H), 1.85-1.78 (m, 1H).

[0229] Step 2: 3-Oxo-3-(1,4-dioxaspiro[4.4]nonan-7-yl)propionitrile

[0230]

[0231] Two parallel reactions were performed. To a solution of 1,4-dioxaspiro[4.4]nonane-7-carboxylic acid methyl ester (16.0 g, 85.93 mmol) in THF (320 mL) was added acetonitrile (10.58 g, 257.78 mmol) and sodium hydride (10.31 g, 257.78 mmol, 60%) at 0°C under a nitrogen atmosphere. The resulting mixture was heated to reflux and stirred for 4 h. The two batches were combined and poured into saturated aqueous NH4Cl (500 mL) at 0°C and stirred for 30 min. The layers were separated and the aqueous layer was extracted with EA (500 mL×3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography using PE / EA (10:1; R f =0.29) to afford the product (30.1 g, 90% yield). 1 H NMR (400 MHz, chloroform-d) δ = 3.96-3.86 (m, 4H), 3.54 (d, J = 0.7 Hz, 2H), 3.25-3.10 (m, 1H), 2.11-2.00 (m, 3H), 1.98-1.78 (m, 3H).

[0232] Step 3: 1-(tert-Butyl)-3-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrazol-5-amine

[0233]

[0234] To a solution of 3-oxo-3-(1,4-dioxaspiro[4.4]nonan-7-yl)propionitrile (30.0 g, 153.68 mmol) and tert-butylhydrazine monohydrochloride (57.45 g, 461.03 mmol) in ethyl alcohol (300 mL) at 20° C. was added triethylamine (46.65 g, 461.03 mmol). The resulting mixture was heated to reflux and stirred under nitrogen for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using PE / EA (5:1; R f =0.24) to afford the product (27 g, 64% yield). 1 H NMR (400MHz, DMSO-d6) δ = 5.22 (s, 1H), 4.71 (s, 2H), 3.86-3.76 (m, 4H), 2.89 (tt, J = 7.8, 9.9Hz, 1H), 2.04(dd,J=8.0,13.4Hz,1H),1.96-1.82(m,2H),1.78-1.66(m,2H),1.65-1.53(m,1H),1.47(s,9H).

[0235] Step 4: (1-(tert-Butyl)-3-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrazol-5-yl)amino Benzyl ester

[0236]

[0237] To a solution of 1-(tert-butyl)-3-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrazol-5-amine (18 g, 67.83 mmol) in acetone (1 L) at 0°C was added benzyl chloroformate (23.14 g, 135.67 mmol) in portions. The mixture was stirred at room temperature for 2 h, then NaHCO (18.24 g, 217.07 mmol) was added in portions. The mixture was further stirred at this temperature for 26 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product (28.5 g, >99% yield), which was used in the next step without further purification.

[0238] Step 5: Benzyl (1-(tert-butyl)-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl)carbamate

[0239]

[0240] A solution of benzyl (1-(tert-butyl)-3-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrazol-5-yl)carbamate (27.5 g, 68.84 mmol) in acetone (3 L) and water (300 mL) was treated with 4-toluenesulfonic acid (1.54 g, 8.95 mmol). The mixture was stirred at 60 ° C under a nitrogen atmosphere for 4 h. The reaction mixture was concentrated under reduced pressure to remove most of the acetone. The aqueous residue was extracted with DCM (500 mL×3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, then filtered and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with PE / EA (10:1) to give the product (23 g, 87% yield). 1 H NMR (400MHz, DMSO-d6) δ = 9.12 (brs, 1H), 7.44-7.28 (m, 5H), 6.03 (s, 1H), 5.12 (s, 2H), 3 .35-3.32(m,1H),2.48-2.41(m,1H),2.33-2.18(m,4H),1.97-1.87(m,1H),1.48(s,9H).

[0241] Step 6: Benzyl cis-(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate

[0242]

[0243] A solution of benzyl (1-(tert-butyl)-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl)carbamate (19 g, 53.46 mmol) in THF (200 mL) was cooled to -65 ° C. A solution of LiBHEt (1 M, 106.9 mL) was added dropwise, and the resulting mixture was stirred at -65 ° C under a nitrogen atmosphere for 1.5 h. The reaction mixture was quenched with saturated aqueous NaHCO (50 mL). Water (200 mL) was added, and the mixture was extracted with EA (100 mL × 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na SO, then filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column; mobile phase: [water (NH HCO) -acetone]; B%: 40%-65%, 20 min). Benzyl (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate was obtained (11 g, 57% yield). 1H NMR(400MHz,DMSO-d6)δ=9.06(br s,1H),7.57-7.12(m,5H),5.92(s,1H),5.75(s,1H),5.12(s,2H),4.57(d,J=4.4Hz,1H),4.22-4.06(m,1H),2.89 (q,J=8.6Hz,1H),2.25-2.13(m,1H),1.89-1.80(m,1H),1.76-1.66(m,2H),1.60-1.55(m,1H),1.54-1.41(m,9H).

[0244] Step 7: cis-(1-(tert-butyl)-3-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrrolidone Benzyl oxazol-5-yl)carbamate

[0245]

[0246] To a solution of cis-(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)benzyl carbamate (10 g, 28.01 mmol) in DCM (100 mL) was added pyridine (11.1 g, 140 mmol), DMAP (169 mg, 1.4 mmol), and 4-nitrophenyl chloroformate (6.7 g, 33.5 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography, eluting with PE / EA (3: 1) to give the product (11.7 g, 80% yield). LC-MS (ESI): m / z[M+H] + =523.2.

[0247] Step 8: cis-(1-(tert-butyl)-3-(3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazole- Benzyl 5-aminobenzoate

[0248]

[0249] To a solution of benzyl cis-(1-(tert-butyl)-3-(3-((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (11.7 g, 22.4 mmol) in THF (100 mL) was added propan-2-amine (6.6 g, 112.1 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EA=1:1) to give the product (7.7 g, 80% yield). LC-MS (ESI): m / z[M+H] + =443.3.

[0250] Step 9: cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate

[0251]

[0252] To a solution of benzyl cis-(1-(tert-butyl)-3-(3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (7.5 g, 16.9 mmol) in THF (100 mL) was added Pd / C (10%, wet, 3 g). The suspension was degassed and purged with hydrogen three times. The resulting mixture was stirred at room temperature under a hydrogen balloon for 3 h. The mixture was filtered, and the filter cake was washed with EA (50 mL×3). The filtrate was concentrated under reduced pressure to give the product (4.5 g, 84% yield). LC-MS (ESI): m / z[M+H] + =309.3.

[0253] Step 10: Methyl 4-bromo-2-(chlorosulfonyl)-5-fluorobenzoate

[0254]

[0255] To a solution of methyl 2-amino-4-bromo-5-fluorobenzoate (2 g, 8.1 mmol) in HCl (6 M, 30 mL) and acetic acid (10 mL) was added dropwise a solution of sodium nitrite (0.6 g, 8.9 mmol) in water (5 ml) at -5 ° C. After addition, the resulting mixture was stirred at -5 ° C for 30 min. A solution of sodium bisulfite (12.6 g, 121.4 mmol) in HCl (6 M, 15 mL) was then added dropwise, followed by the addition of CuCl2 (0.4 g, 4.1 mmol). The resulting suspension was warmed to room temperature and stirred for 3 h. The reaction mixture was poured into ice water (20 ml) and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (2.5 g, 94% yield, LC-MS (ESI): m / z [M + H] + =331.5), which was used in the next step without further purification.

[0256] Step 11: 6-Bromo-5-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide

[0257]

[0258] To a stirred solution of methyl 4-bromo-2-(chlorosulfonyl)-5-fluorobenzoate (2.5 g, 7.5 mmol) in THF (30 mL) was added aqueous ammonia (25%, 4 mL) dropwise. The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum, and the residue was triturated with EA and filtered to give the product (1.9 g, 90% yield). LC-MS (ESI): m / z [M+H] + =280.1.

[0259] Step 12: 6-Bromo-5-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0260]

[0261] To a stirred solution of 6-bromo-5-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (600 mg, 2.15 mmol) in THF (30 mL) was added BH3-THF (1 M, 10.7 mL, 10.75 mmol) dropwise at 0 ° C under a nitrogen atmosphere. The resulting solution was heated to reflux and stirred for 3 h under a nitrogen atmosphere. The solution was cooled to 0 ° C, quenched with MeOH (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1: 1) to give the product (450 mg, 79% yield). LC-MS (ESI): m / z[M+H] + =266.1.

[0262] Step 13: cis-isopropylcarbamic acid 3-(1-(tert-butyl)-5-(5-fluoro-1,1-dioxy-2,3-dihydro Benzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[0263]

[0264] To a mixture of 6-bromo-5-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.38 mmol) and cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (116.6 mg, 0.38 mmol) in anhydrous 1,4-dioxane (10 mL) was added Pd(dba) (36.7 mg, 0.04 mmol), XantPhos (44.0 mg, 0.08 mmol) and KPO (241.6 mg, 1.1 mmol). The reaction mixture was stirred at 90 ° C for 16 h under a nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:9) to obtain the product (115 mg, 62% yield). LC-MS(ESI):m / z[M+H] + =494.3.

[0265] Step 14: cis-isopropylcarbamate 3-(3-(5-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazolyl) (1H-pyrazol-5-yl)cyclopentyl ester

[0266]

[0267] A solution of cis-isopropylcarbamic acid 3-(1-(tert-butyl)-3-((5-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazole-5-yl)cyclopentyl ester (80 mg, 0.16 mmol) in DCM (10 mL) was added dropwise with trifluoromethanesulfonic acid (0.5 mL). The resulting mixture was stirred at room temperature for 2 h. At 0 ° C, the reaction mixture was quenched and basified to pH = 8 with saturated aqueous NaHCO 3. The layers were separated and the aqueous layer was extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire C18:RD-CO-058 column eluting with 28%-48% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product in racemic form (32.3 mg, 46%), which was further separated by chiral preparative HPLC to give:

[0268] Enantiomer 1 (Example 1a, 98.6% ee); retention time: 6.47 min. 1 H NMR(500MHz,DMSO-d6)δ11.91(s,1H),8.66(d,J=1.9Hz,1H),8.61(d,J=7.5H z,1H),7.72(t,J=4.9Hz,1H),7.34(d,J=11.4Hz,1H),6.95(d,J=7.4Hz,1H),5 .79(s,1H),5.00(s,1H),4.27(d,J=4.8Hz,2H),3.58(m,1H),2.48-2.41(m,1 H), 2.02 (m, 1H), 1.95-1.83 (m, 1H), 1.79-1.43 (m, 3H), 1.03 (d, J = 6.3Hz, 6H). LC-MS(ESI):m / z[M+H] + =438.2.

[0269] Enantiomer 2 (Example 1b, 95.6% ee); retention time: 7.07 min. 1H NMR(500MHz,DMSO-d6)δ11.91(s,1H),8.66(d,J=1.9Hz,1H),8.61(d,J=7.5H z,1H),7.72(t,J=4.9Hz,1H),7.34(d,J=11.4Hz,1H),6.95(d,J=7.4Hz,1H),5 .79(s,1H),5.00(s,1H),4.27(d,J=4.8Hz,2H),3.58(m,1H),2.48-2.41(m,1 H), 2.02 (m, 1H), 1.95-1.83 (m, 1H), 1.79-1.43 (m, 3H), 1.03 (d, J = 6.3Hz, 6H). LC-MS(ESI):m / z[M+H] + =438.2.

[0270] Chiral analysis method: column: I-Cellulose-5, 4.6 mm × 250 mm, 5 um; mobile phase: A: hexane, and B: EtOH (0.1% 2M NH3MeOH); gradient: mobile phase A: mobile phase B = 60:40 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35 ° C.

[0271] Chiral preparative HPLC conditions: column: I-Cellulose-5, 21.2 mm × 250 mm, 5 um; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH3MeOH); gradient: mobile phase A: mobile phase B = 60:40 (v / v); flow rate: 20 mL / min, wavelength: UV200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25 ° C.

[0272] Example 2: cis-3-(3-((1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0273] Step 1: 5-Bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0274]

[0275] To a stirred solution of 5-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (750 mg, 2.86 mmol) in THF (30 mL) was added BH3-Me2S (4 M, 2.86 mL, 11.44 mmol) dropwise at 0°C under a nitrogen atmosphere. The resulting solution was heated to reflux and stirred for 3 h under a nitrogen atmosphere. The resulting mixture was cooled to 0°C, quenched with MeOH (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give the product (550 mg, 78%). LC-MS (ESI): m / z[M+H] + =248.3.

[0276] Step 2: cis-isopropylcarbamate 3-(1-(tert-butyl)-5-(1,1-dioxido-2,3-dihydrobenzo[d] (5-Isothiazol-1H-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[0277]

[0278] To a mixture of 5-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.40 mmol) and cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (123.2 mg, 0.40 mmol) in anhydrous 1,4-dioxane (10 mL) was added Pd2(dba)3 (36.7 mg, 0.04 mmol), XantPhos (46.2 mg, 0.08 mmol) and K3PO4 (254.4 mg, 1.2 mmol). The reaction mixture was stirred at 90°C under nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:9) to give the product (50 mg, 26%). LC-MS (ESI): m / z [M+H] + =476.4.

[0279] Step 3: cis-isopropylcarbamate 3-(3-((1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)-1-ol (4-(2-Yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0280]

[0281] A solution of cis-3-(1-(tert-butyl)-5-((1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (50 mg, 0.10 mmol) in formic acid (5 mL) was stirred at 75° C. for 16 h. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters XSelect C18:RD-CO-094 column, eluting with 27%-52% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (12 mg, 27%). 1 H NMR(500MHz,DMSO-d6)δ11.90(s,1H),9.00(s,1H),7.53(d,J=8.5Hz,1H),7.50-7.38(m ,2H),7.30(d,J=8.5Hz,1H),6.95(d,J=6.9Hz,1H),5.70(s,1H),5.06-4.93(m,1H),4.2 9(d,J=4.9Hz,2H),3.65-3.50(m,1H),3.15-2.95(m,1H),2.39-2.28(m,1H),2.08-1.98 (m,1H),1.96-1.84(m,1H),1.81-1.66(m,2H),1.65-1.54(m,1H),1.03(d,J=6.0Hz,6H). LC-MS(ESI):m / z[M+H] + =420.5

[0282] Example 3: cis-3-(3-((1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0283] Step 1: 6-Bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0284]

[0285] To a stirred solution of 6-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (600 mg, 2.29 mmol) in THF (20 mL) was added BH3-Me2S (4 M, 2.29 mL, 9.16 mmol) dropwise at 0°C under a nitrogen atmosphere. The resulting solution was heated to reflux and stirred for 3 h under a nitrogen atmosphere. The resulting mixture was cooled to 0°C, quenched with MeOH (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give the product (350 mg, 62%). LC-MS (ESI): m / z[M+H] +=248.3.

[0286] Step 2: cis-isopropylcarbamate 3-(1-(tert-butyl)-5-(1,1-dioxido-2,3-dihydrobenzo[d] (isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[0287]

[0288] To a mixture of 6-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.40 mmol) and cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (123.2 mg, 0.40 mmol) in anhydrous 1,4-dioxane (10 mL) was added Pd(dba) (36.7 mg, 0.04 mmol), XantPhos (46.2 mg, 0.08 mmol) and KPO (254.4 mg, 1.2 mmol). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:9) to give the product (20 mg, 10%). LC-MS(ESI):m / z[M+H] + =476.4.

[0289] Step 3: cis-isopropylcarbamate 3-(3-((1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)- (4-(2-Yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0290]

[0291] A solution of cis-3-(1-(tert-butyl)-5-((1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (20 mg, 0.04 mmol) in formic acid (5 mL) was stirred at 75° C. for 16 h. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18:RD-CO-095 column, eluting with 25%-55% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (10 mg, 57%). 1H NMR(500MHz,DMSO-d6)δ11.83(brs,1H),8.84(s,1H),7.97(s,1H),7.62(s,1H),7.38(dd,J= 8.5,1.6Hz,1H),7.30(d,J=8.5Hz,1H),6.93(d,J=6.4Hz,1H),5.63(s,1H),5.06-4.93(m,1H) ,4.30-4.20(m,2H),3.52-3.40(m1H),3.13-2.99(m,1H),2.45(dd,J-13.8,7.2Hz,1H),2.07 -1.97(m,1H),1.96-1.85(m,1H),1.8-1.66(m,2H),1.65-1.55(m,1H),1.03(d,J=6.3Hz,6H). LC-MS(ESI):m / z[M+H] + =420.3

[0292] Example 4: cis-3-(5-((3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate

[0293] Step 1: 6-Bromo-3-chlorobenzo[d]isothiazole 1,1-dioxide

[0294]

[0295] A mixture of 6-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.5 g, 5.72 mmol) in POCl (20 mL) was heated to reflux and stirred under nitrogen for 16 h. The mixture was concentrated under reduced pressure, and the residue was slurried with PE / EA (8:1, 20 mL) and filtered to give the crude product (1.2 g, 75%, LC-MS (ESI): m / z [M-Cl + MeOH] + =276.3), which was used in the next step without further purification.

[0296] Step 2: 6-Bromo-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0297]

[0298] To a stirred mixture of 6-bromo-3-chlorobenzo[d]isothiazole 1,1-dioxide (1.2 g, 4.28 mmol) and LiCl (0.72 g, 17.12 mmol) in THF (30 mL) was added MeMgBr (1 M, 34.24 mL, 34.24 mmol) dropwise at -5°C under a nitrogen atmosphere. The solution was warmed to room temperature and stirred under a nitrogen atmosphere for 3 h. The solution was cooled to 0°C and quenched with saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give the product (0.5 g, 43%). LC-MS (ESI): m / z [M+H] + =276.3.

[0299] Step 3: cis-isopropylcarbamate 3-(1-(tert-butyl)-5-(3,3-dimethyl-1,1-dioxy-2,3- dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[0300]

[0301] To a mixture of 6-bromo-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.362 mmol) and cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (111.6 mg, 0.362 mmol) in anhydrous 1,4-dioxane (10 mL) was added Pd(dba) (33 mg, 0.036 mmol), XantPhos (42 mg, 0.072 mmol) and KPO (230 mg, 1.086 mmol). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:9) to obtain the product (120 mg, 66%). LC-MS(ESI):m / z[M+H] + =504.5.

[0302] Step 4: cis-isopropylcarbamate 3-(3-((3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d] (isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0303]

[0304] To a stirred solution of cis-isopropylcarbamic acid 3-(1-(tert-butyl)-5-((3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester (120 mg, 0.238 mmol) in DCM (5 mL) was added trifluoromethanesulfonic acid (0.5 mL) dropwise. The solution was stirred at room temperature for 3 h. At 0 ° C, the solution was diluted with DCM (50 mL) and basified to pH = 8 with saturated aqueous NaHCO 3. The layers were separated and the aqueous layer was extracted with DCM (100 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18:RD-CO-058 column, eluting with 34%-49% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (85 mg, 80%). 1 H NMR(500MHz,DMSO-d6)δ11.83(s,1H),8.83(s,1H),7.90(s,1H),7.80-7.6(m,1H),7.52-7.25(m,2H),6.96(s,1H),5.62(s,1H),5.15-4.90(m, 1H),3.70-3.50(m,1H),3.19-3.93(m,1H),2.47-2.40(m,1H),2.19-1. 83(m,2H),1.82-1.57(m,3H),1.55-1.36(m,6H),1.03(d,J=5.6Hz,6H). LC-MS(ESI):m / z[M+H] + =448.3.

[0305] Example 5: cis-3-(5-((3-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate

[0306] Step 1: 6-Bromo-3-methylbenzo[d]isothiazole 1,1-dioxide

[0307]

[0308] To a stirred mixture of 6-bromo-3-chlorobenzo[d]isothiazole 1,1-dioxide (1.2 g, 4.28 mmol) and LiCl (0.72 g, 17.12 mmol) in THF (30 mL) was added MeMgBr (1 M, 34.24 mL, 34.24 mmol) dropwise at -5 ° C under a nitrogen atmosphere. The solution was stirred at room temperature for 3 h. The solution was cooled to 0 ° C and quenched with saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EA (100 mL × 3), and the combined organic phases were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1: 1) to give the product (0.3 g, 27%). LC-MS (ESI): m / z [M + H] + =260.3.

[0309] Step 2: 6-Bromo-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0310]

[0311] To a stirred solution of 6-bromo-3-methylbenzo[d]isothiazole 1,1-dioxide (0.3 g, 1.15 mmol) in MeOH (20 mL) was added NaBH4 (131 mg, 3.45 mmol) at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the product (0.2 g, 66%). LC-MS (ESI): m / z [M+H] + =262.3.

[0312] Step 3: cis-isopropylcarbamate 3-(1-(tert-butyl)-5-(3-methyl-1,1-dioxy-2,3-dihydro Benzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[0313]

[0314] To a mixture of 6-bromo-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (200 mg, 0.763 mmol), cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (235 mg, 0.763 mmol) in anhydrous 1,4-dioxane (20 mL) was added Pd(dba) (70 mg, 0.076 mmol), XantPhos (88 mg, 0.153 mmol) and KPO (485 mg, 2.289 mmol). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:9) to give the product (120 mg, 32%). LC-MS(ESI):m / z[M+H] + =490.5

[0315] Step 4: cis-isopropylcarbamate 3-(5-(3-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazide) (1H-pyrazol-3-yl)cyclopentyl ester

[0316]

[0317] To a stirred solution of cis-3-(1-(tert-butyl)-5-((3-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (120 mg, 0.245 mmol) in DCM (5 mL) was added trifluoromethanesulfonic acid (0.5 mL). The solution was stirred at room temperature for 3 h. The solution was diluted with DCM (50 mL), basified to pH = 8 with saturated aqueous NaHCO₃, and extracted with DCM (50 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18:RD-CO-095 column, eluting with 28%-53% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product in racemic form (90 mg, 85%), which was further separated by chiral preparative HPLC to give:

[0318] Enantiomer 1 (Example 5a, 100% ee); retention time: 10.46 min. 1H NMR (500MHz, DMSO-d6) δ11.83(s,1H),8.86(s,1H),7.95(d,J=1.4Hz,1H),7.72(d,J=4.2Hz,1H),7.3 9(dd,J=8.5,1.9Hz,1H),7.34(d,J=8.5Hz,1H),6.95(d,J=7.5Hz,1H),5.62(d,J=1.9Hz,1H),5.00(s, 1H),4.60-4.52(m,1H),3.65-3.52(m,1H),3.13-3.00(m,1H),2.48-2.41(m,1H),2.08-1.98(m,1H),1 .95-1.85(m,1H),1.80-1.66(m,2H),1.64-1.55(m,1H),1.39(d,J=6.6Hz,3H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =434.3.

[0319] Enantiomer 2 (Example 5b, 95.4% ee); retention time: 12.06 min. 1 H NMR (500MHz, DMSO-d6) δ11.83(s,1H),8.86(s,1H),7.95(s,1H),7.72(d,J=4.3Hz,1H),7.38(d, J=8.4Hz,1H),7.34(d,J=8.5Hz,1H),6.95(d,J=7.9Hz,1H),5.62(s,1H),5.05-4.95(m,1H),4.60 -4.52(m,1H),3.62-3.55(m,1H),3.11-3.02(m,1H),2.48-2.41(m,1H),2.06-1.97(m,1H),1.94- 1.85(m,1H),1.77-1.67(m,2H),1.64-1.55(m,1H),1.39(d,J=6.6Hz,3H),1.03(d,J=6.3Hz,6H). LC-MS(ESI):m / z[M+H] + =434.4.

[0320] Enantiomer 3 (Example 5c, 100% ee); retention time: 13.10 min. 1H NMR (500MHz, DMSO-d6) δ11.83(s,1H),8.85(s,1H),7.95(s,1H),7.72(d,J=4.3Hz,1H),7.38(d, J=7.8Hz,1H),7.34(d,J=8.5Hz,1H),6.95(d,J=7.3Hz,1H),5.62(s,1H),5.06-4.93(m,1H),4.63 -4.49(m,1H),3.64-3.52(m,1H),3.11-3.00(m,1H),2.49-2.42(m,1H),2.08-1.97(m,1H),1.96- 1.85(m,1H),1.78-1.67(m,2H),1.65-1.56(m,1H),1.39(d,J=6.6Hz,3H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =434.1.

[0321] Enantiomer 4 (Example 5d, 99.1% ee); retention time: 15.48 min. 1 H NMR (500MHz, DMSO-d6) δ11.83(s,1H),8.86(s,1H),7.95(d,J=1.3Hz,1H),7.72(d,J=4.3Hz,1H),7.38( dd,J=8.5,1.8Hz,1H),7.34(d,J=8.5Hz,1H),6.95(d,J=7.7Hz,1H),5.62(d,J=1.8Hz,1H),5.08-4.95( m,1H),4.62-4.51(m,1H),3.65-3.52(m,1H),3.13-2.99(m,1H),2.48-2.40(m,1H),2.07-1.98(m,1H), 1.95-1.85(m,1H),1.80-1.67(m,2H),1.65-1.55(m,1H),1.39(d,J=6.6Hz,3H),1.04(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =434.3.

[0322] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.1% 2M NH 3 MeOH); gradient: mobile phase A: mobile phase B = 50:50 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[0323] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH3MeOH); gradient: mobile phase A: mobile phase B = 50:50 (v / v); flow rate: 18 mL / min, wavelength: UV200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[0324] Example 6: cis-3-(3-((3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0325] Step 1: 5-Bromo-3-chlorobenzo[d]isothiazole 1,1-dioxide

[0326]

[0327] A mixture of 5-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (500 mg, 1.91 mmol) in POCl3 (15 mL) was heated to reflux and stirred under a nitrogen atmosphere for 16 h. The mixture was concentrated under reduced pressure. The residue was slurried with PE / EA (8:1, 9 mL) and filtered to give the crude product (450 mg, 84%, LC-MS (ESI): m / z [M-Cl + MeOH] + =276.3), which was used in the next step without further purification.

[0328] Step 2: 5-Bromo-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0329]

[0330] To a stirred mixture of 5-bromo-3-chlorobenzo[d]isothiazole 1,1-dioxide (450 mg, 1.61 mmol) and LiCl (270 mg, 6.44 mmol) in THF (20 mL) was added MeMgBr (1 M, 19.3 mL, 19.32 mmol) dropwise at -5°C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 16 h. The mixture was cooled to 0°C and quenched with saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give the product (0.5 g, 43%). LC-MS (ESI): m / z [M+H] + =276.3.

[0331] Step 3: cis-isopropylcarbamate 3-(1-(tert-butyl)-5-(3,3-dimethyl-1,1-dioxy-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[0332]

[0333] To a mixture of 5-bromo-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.362 mmol) and cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (111.6 mg, 0.36 mmol) in anhydrous 1,4-dioxane (10 mL) was added Pd(dba) (33 mg, 0.04 mmol), XantPhos (42 mg, 0.07 mmol), and KPO (230 mg, 1.09 mmol). The reaction mixture was stirred at 90° C. under a nitrogen atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give the product (80 mg, 44%). LC-MS(ESI):m / z[M+H] + =504.4.

[0334] Step 4: cis-isopropylcarbamate 3-(3-((3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d] (5-Isothiazol-1H-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0335]

[0336] To a stirred solution of cis-3-(1-(tert-butyl)-5-((3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (80 mg, 0.159 mmol) in DCM (5 mL) was added trifluoromethanesulfonic acid (0.5 mL) dropwise. The solution was stirred at room temperature for 3 h. The mixture was diluted with DCM (50 mL) and basified to pH = 8 with saturated aqueous NaHCO 3 and extracted with DCM (50 mL×2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18:RD-CO-095 column, eluting with 34%-49% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (25 mg, 35%). 1H NMR (500MHz, DMSO-d6) δ11.96(s,1H),9.01(s,1H),7.54(d,J=11.4Hz,2H),7.48(d,J= 8.6Hz,1H),7.31(d,J=7.9Hz,1H),6.94(d,J=7.5Hz,1H),5.68(s,1H),5.06-4.95(m,1 H),3.63-3.56(m,1H),3.13-2.98(m,1H),2.47-2.42(m,1H),2.07-1.97(m,1H),1.96- 1.85(m,1H),1.79-1.66(m,2H),1.65-1.56(m,1H),1.47(s,6H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =448.4.

[0337] Example 7: cis-3-(3-((2,2-dioxido-1,3-dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate and (1S,3R)-3-(3-((2,2-dioxido-1,3-dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0338] Step 1: cis-(1-(tert-butyl)-3-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrrolidone Benzyl oxazol-5-yl)carbamate

[0339]

[0340] To a solution of benzyl cis-(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (200 mg, 5.6 mmol) in DMF (20 mL) was added tert-butyldimethylsilyl chloride (109.6 mg, 7.3 mmol, 0.89 mL, 1.3 eq) and imidazole (57.1 mg, 8.39 mmol, 1.5 eq). The mixture was stirred at 25 ° C for 1 hr. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (50 mL × 3), dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated in vacuo to give a residue. The product was used in the next step without further purification. The title compound (200 mg, 4.24 mmol, 76% yield) was obtained. 1H NMR (400MHz, chloroform-d) δ7.35(br s,5H),6.74-6.38(m,1H),6.08(brs,1H),5.19-5.14(m,2H),4.32-4.22(m,1H),2.97(br s,1H),2.33-2.22(m,1H),1.94(dd,J=7.63,3.88Hz,1H),1.87-1.75(m,2H), 1.69-1.60(m,2H),1.57-1.54(m,9H),0.88-0.85(m,9H),0.05-0.01(m,6H).

[0341] Step 2: 1-(tert-butyl)-3-(cis-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrrolidone 5-Azolidine

[0342]

[0343] To a solution of benzyl cis-(1-(tert-butyl)-3-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (200 mg, 4.2 mmol) in THF (50 mL) was added Pd / C (200 mg, 10% purity, wet). The mixture was stirred at 25 ° C under an H atmosphere (15 psi) for 2 h. The reaction mixture was filtered through Celite, washed with MeOH, and the filtrate was concentrated under reduced pressure to give a residue. The title compound (100 mg, 70% yield) was obtained. 1 HNMR (400 MHz, CHLOROFORM-d) δ 5.48 (s, 1H), 4.29 (dd, J = 6.17, 4.71 Hz, 1H), 3.49 (br s, 2H), 2.95 (t, J = 8.80 Hz, 1H), 2.36-2.24 (m, 1H), 2.01-1.90 (m, 1H), 1.87-1.77 (m, 2H), 1.62 (s, 6H), 0.86-0.93 (m, 14H), 0.06 (d, J = 1.71 Hz, 6H).

[0344] Step 3: cis-5-((1-(tert-butyl)-3-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)- 1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide

[0345]

[0346] To a mixture of 5-bromo-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide (200 mg, 0.81 mmol) and 1-(tert-butyl)-3-(cis-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (289.8 mg, 0.81 mmol) in anhydrous t-BuOH (10 mL) was added BrettPhos Pd G2 (74.4 mg, 0.08 mmol) and LiHMDS (1 M, 3.24 ml, 3.24 mmol). The reaction mixture was heated to reflux and stirred under nitrogen for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:9) to give the product (200 mg, 58%). LC-MS (ESI): m / z [M+H] + =505.3.

[0347] Step 4: cis-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-diol Hydrobenzo[c]isothiazole 2,2-dioxide

[0348]

[0349] A solution of cis-5-((1-(tert-butyl)-3-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide (200 mg, 0.39 mmol) in formic acid (5 mL) was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:2) to give the product (135 mg, 85%). LC-MS (ESI): m / z [M+H] + =391.2.

[0350] Step 5: cis-5-((1-(tert-butyl)-3-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H- 4-Nitrophenyl pyrazol-5-yl)amino)benzo[c]isothiazole-1(3H)-carboxylate 2,2-dioxide

[0351]

[0352] To a solution of cis-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide (130 mg, 0.33 mmol) in DCM (20 mL) was added pyridine (52.5 mg, 0.66 mmol), DMAP (2 mg, 0.02 mmol), and 4-nitrophenyl chloroformate (132 mg, 0.66 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with PE / EA (1:1) to give the product (148 mg, 61%). LC-MS (ESI): m / z [M+H] + =721.2.

[0353] Step 6: cis-isopropylcarbamic acid 3-(1-(tert-butyl)-5-((1-(isopropylcarbamoyl)-2,2- 1,3-Dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl dioxide

[0354]

[0355] To a stirred solution of cis-4-nitrophenyl 5-((1-(tert-butyl)-3-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)benzo[c]isothiazole-1(3H)-carboxylate 2,2-dioxide (148 mg, 0.27 mmol) in THF (10 mL) was added propan-2-amine (79 mg, 1.33 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EA (1:9) to give the product (50 mg, 40%). LC-MS (ESI): m / z [M+H] + =561.3.

[0356] Step 7: cis-isopropylcarbamate 3-(3-(2,2-dioxido-1,3-dihydrobenzo[c]isothiazol-5-yl)- (4-(2-Yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0357]

[0358] To a solution of cis-isopropylcarbamic acid 3-(1-(tert-butyl)-5-((1-(isopropylcarbamoyl)-2,2-dioxido-1,3-dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester (34 mg, 0.06 mmol) in DCM (5 mL) was added trifluoromethanesulfonic acid (0.2 mL) dropwise. The solution was stirred at room temperature for 2 h. The solution was diluted with DCM (30 mL) and basified to pH = 8 with saturated aqueous NaHCO 3 and extracted with DCM (30 mL×2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18:RD-CO-058 column, eluting with 34%-49% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product in racemic form, which was further purified by chiral preparative HPLC to give:

[0359]

[0360] Enantiomer 1 ((1R,3S)-3-(3-((2,2-dioxido-1,3-dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate, Example 7a, 100% ee); retention time: 5.02 min. 1 H NMR(500MHz,DMSO-d6)δ11.63(s,1H),9.75(s,1H),8.19(s,1H),7.37(s,1H),7.16(d ,J=7.8Hz,1H),6.95(d,J=6.8Hz,1H),6.71(d,J=8.6Hz,1H),5.58(s,1H),4.99(s,1H) ,4.44(s,2H),3.62-3.58(m,1H),3.11-2.94(m,1H),2.50-2.44(m,1H),2.05-1.97(m ,1H),1.95-1.84(m,1H),1.70-1.65(m,2H),1.65-1.59(m,1H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =420.2.

[0361]

[0362] Enantiomer 2 ((1S,3R)-3-(3-((2,2-dioxido-1,3-dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate, Example 7b, 100% ee); retention time: 7.89 min. 1 H NMR(500MHz,DMSO-d6)δ11.63(s,1H),9.75(s,1H),8.19(s,1H),7.37(s,1H),7.16(d ,J=7.8Hz,1H),6.95(d,J=6.8Hz,1H),6.71(d,J=8.6Hz,1H),5.58(s,1H),4.99(s,1H) ,4.44(s,2H),3.62-3.58(m,1H),3.11-2.94(m,1H),2.50-2.44(m,1H),2.05-1.97(m ,1H),1.95-1.84(m,1H),1.70-1.65(m,2H),1.65-1.59(m,1H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =420.2

[0363] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: 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.

[0364] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm × 250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH3MeOH); gradient: mobile phase A: mobile phase B = 20:80 (v / v); flow rate: 18 mL / min, wavelength: UV270 nm and 300 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: RT.

[0365] Example 8: cis-3-(3-((5-fluoro-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0366] Step 1: 6-Bromo-3-chloro-5-fluorobenzo[d]isothiazole 1,1-dioxide

[0367]

[0368] A mixture of 6-bromo-5-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (1 g, 3.58 mmol) in POCl3 (20 mL) was heated to reflux and stirred under nitrogen for 16 h. The mixture was concentrated under reduced pressure. The residue was slurried with PE / EA (8:1, 20 mL) and filtered to give the crude product (800 mg, 80%, LC-MS (ESI): m / z [M-Cl + MeOH] + =293.9), which was used in the next step without further purification.

[0369] Step 2: 6-Bromo-5-fluoro-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0370]

[0371] To a stirred mixture of 6-bromo-3-chloro-5-fluorobenzo[d]isothiazole 1,1-dioxide (500 mg, 1.68 mmol) in THF (30 mL) was added MeMgBr (1 M, 16.83 mL, 16.83 mmol) dropwise at -5°C under a nitrogen atmosphere. The solution was stirred at -5°C for 3 h. The solution was cooled to 0°C and quenched with saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with EA (100 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the product (0.3 g, 63%). LC-MS (ESI): m / z [M+H] + =293.9.

[0372] Step 3: cis-isopropylcarbamic acid 3-(1-(tert-butyl)-3-(5-fluoro-3,3-dimethyl-1,1-dioxy (2,3-Dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0373]

[0374] To a mixture of 6-bromo-5-fluoro-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.342 mmol) and cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (105.8 mg, 0.342 mmol) in anhydrous 1,4-dioxane (10 mL) was added Pd(dba) (32 mg, 0.034 mmol), XantPhos (39 mg, 0.068 mmol) and KPO (217.5 mg, 1.026 mmol). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:9) to obtain the product (120 mg, 66%). LC-MS(ESI):m / z[M+H] + =522.2.

[0375] Step 4: cis-isopropylcarbamate 3-(3-((5-fluoro-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzene) (d)isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0376]

[0377] To a stirred solution of cis-isopropylcarbamic acid 3-(1-(tert-butyl)-3-((5-fluoro-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester (80 mg, 0.153 mmol) in DCM (5 mL) was added trifluoromethanesulfonic acid (0.5 mL) dropwise. The solution was stirred at room temperature for 3 h. The solution was diluted with DCM (50 mL) and basified to pH = 8 with saturated aqueous NaHCO 3 and extracted with DCM (50 mL×2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire C18: RD-CO-058 column, eluting with 40%-55% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA) to give the product (37.6 mg, 53%). 1H NMR (500 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.64 (s, 1H), 8.52 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.52 (d, J = 11.6 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 5.79 (s, 1H), 5.00 (s, 1H), 3.58 (dd, J = 13.1, 6.5Hz,1H),3.12-3.00(m,1H),2.48-2.38(m,1H),2.08-1.97(m,1H),1.96-1.84(m,1H), 1.70 (dd, J=20.1, 10.4Hz, 2H), 1.60 (d, J=8.2Hz, 1H), 1.48 (s, 6H), 1.03 (d, J=6.3Hz, 6H). LC-MS(ESI):m / z[M+H] + =466.2.

[0378] Example 9: cis-3-(3-((4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0379] Step 1: 6-amino-3-bromo-2-fluorobenzoic acid methyl ester

[0380]

[0381] To a solution of 6-amino-3-bromo-2-fluorobenzoic acid (1.0 g, 4.27 mmol) in methanol (20 mL) was added SOCl2 (2.5 g, 21.3 mmol) dropwise. The reaction mixture was stirred at reflux for 16 hours. The resulting mixture was cooled to room temperature, concentrated, neutralized with saturated aqueous NaHCO3 and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give the product (346 mg, 33%). LC-MS (ESI): m / z[M+H] + =248.0.

[0382] Step 2: Methyl 3-bromo-6-(chlorosulfonyl)-2-fluorobenzoate

[0383]

[0384] At 0 ° C, a solution of sodium nitrite (835 mg, 12.1 mmol) in 5 mL of water was added dropwise to a suspension of methyl 6-amino-3-bromo-2-fluorobenzoate (3.0 g, 12.1 mmol) in hydrochloric acid (12 M, 60 mL). After addition, the resulting mixture was kept below 5 ° C and stirred for 30 min. CuCl2 (813 mg, 6.05 mmol), sodium bisulfite (18.9 g, 181.5 mmol) and hydrochloric acid solution (5.5 M, 20 mL) were added to the reaction mixture in sequence. The reaction mixture was warmed to room temperature and stirred for 3 h. The resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and dried under vacuum to obtain a crude product (3.2 g), which was used in the next step without further purification.

[0385] Step 3: 5-Bromo-4-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide

[0386]

[0387] To a solution of methyl 3-bromo-6-(chlorosulfonyl)-2-fluorobenzoate (3.2 g crude) in THF (50 mL) was added aqueous ammonia (25%, 10 mL) dropwise. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum, and the residue was triturated with EA and filtered to give the crude product (3.0 g, LC-MS (ESI): m / z [M+H] + =279.9), which was used in the next step without further purification.

[0388] Step 4: 5-Bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0389]

[0390] To a stirred solution of 5-bromo-4-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (210 mg, 0.75 mmol) in THF (5 mL) was added BH3-Me2S (2 M, 1.5 mL, 3.0 mmol) dropwise at 0°C under a nitrogen atmosphere. The solution was heated to reflux and stirred for 3 h. The resulting mixture was cooled to 0°C, quenched with MeOH (1.0 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give the product (184 mg, 93%). LC-MS (ESI): m / z[M+H] + =265.8

[0391] Step 5: cis-isopropylcarbamate 3-(1-(tert-butyl)-3-(4-fluoro-1,1-dioxido-2,3-dihydrobenzene) (d)isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0392]

[0393] To a mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.377 mmol) and cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (116 mg, 0.377 mmol) in anhydrous 1,4-dioxane (10 mL) was added Pd(dba) (17 mg, 0.02 mmol), XantPhos (22 mg, 0.04 mmol) and KPO (240 mg, 1.13 mmol). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20: 1) to give the product (26 mg, 14%). LC-MS(ESI):m / z[M+H] + =494.3.

[0394] Step 6: cis-isopropylcarbamate 3-(3-((4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazide) (5-pyrazol-1-yl)amino)cyclopentyl ester

[0395]

[0396] To a solution of cis-3-(1-(tert-butyl)-3-((4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (26 mg, 0.053 mmol) in DCM (1.5 mL) was added trifluoromethanesulfonic acid (3 drops). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was neutralized with saturated aqueous Na2CO3 and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine, dried over NaSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18: 19 x 150 mm, 5 μm, eluting with 33%-45% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA) to give the product in racemic form, which was further separated by chiral preparative HPLC to give:

[0397] Enantiomer 1 (Example 9a, 100% ee); retention time: 6.472 min. 1 H NMR(500MHz,DMSO-d6)δ=11.99(s,1H),8.72(s,1H),8.25(s,1H),7.70(t ,J=5.0,1H),7.48(d,J=8.6,1H),6.95(d,J-7.3,1H),5.83(s,1H),5.00(s ,1H),4.41(d,J=5.1,2H),3.58(m,1H),3.132.99(m,1H),2.45(m,1H),2.0 3(m,1H),1.91(m,1H),1.83-1.64(m,2H),1.60(m,1H),1.11-0.93(m,6H). LC-MS(ESI):m / z[M+H] + =438.4.

[0398] Enantiomer 2 (Example 9b, 100% ee); retention time: 14.841 min. 1H NMR (500MHz, DMSO-d6) δ = 11.98 (s, 1H), 8.72 (s, 1H), 8.26 (s, 1H), 7.70 (t, J = 5 .1,1H),7.48(d,J=8.5,1H),6.95(d,J=7.2,1H),5.83(s,1H),5.00(s,1H),4.4 1(d,J=5.2,2H),3.60-3.55(m,1H),3.10-3.03(m,1H),2.47-2.43(m,1H),2.07 -1.98(m,1H),1.98-1.85(m,1H),1.81-1.64(m,2H),1.60(m,1H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =438.3;

[0399] Chiral analysis method: column: CHIRALPAK IE 4.6*250mm5μm; mobile phase: A: MtBE (0.1% 2MNH3MeOH), and B: MeOH: DCM = 50:50 (v / v); gradient: mobile phase A: mobile phase B = 50:50 (v / v); HPLC equipment: HPLC-Agilent; column temperature: 35°C.

[0400] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm × 250 mm, 5 um; mobile phase: A: MtBE, and B: DCM: MeOH = 50:50 (v / v) (0.2% 2M NH3·MeOH); gradient: mobile phase A: mobile phase B = 50:50 (v / v); flow rate: 18 mL / min, wavelength: UV280 nm and 300 nm, preparative HPLC equipment: preparative HPLC-Gilson; column temperature: 25 ° C.

[0401] Example 10: cis-3-(3-((4-methoxy-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0402] Step 1: 5-Bromo-4-methoxybenzo[d]isothiazol-3(2H)-one with 1,1-dioxide

[0403]

[0404] To a solution of 5-bromo-4-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (1.0 g, 3.58 mmol) in MeOH (5 mL) was added a solution of sodium methoxide in MeOH (5.4 M, 3.3 mL, 17.92 mmol). The reaction mixture was stirred at 40 ° C for 1 h. The resulting mixture was quenched with water (30 mL), adjusted to pH = 4 with 1N HCl, and extracted with EA (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and dried in vacuo to give the crude product (740 mg, 71%, LC-MS (ESI): m / z [M+H] + =291.9), which was used in the next step without further purification.

[0405] Step 2: 5-Bromo-4-methoxy-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0406]

[0407] To a stirred solution of 5-bromo-4-methoxybenzo[d]isothiazol-3(2H)-one 1,1-dioxide (280 mg, 0.92 mmol) in THF (5 mL) was added BH3-Me2S (2M, 2.0 mL, 3.85 mmol) dropwise at 0°C under a nitrogen atmosphere. The solution was heated to reflux and stirred for 3 h. The resulting mixture was cooled to 0°C, quenched with MeOH (1.0 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give the product (131 mg, 49%). LC-MS (ESI): m / z [MH] - =275.8

[0408] Step 3: cis-isopropylcarbamic acid 3-(1-(tert-butyl)-3-((4-methoxy-1,1-dioxido-2,3-diol) (4-Methylbenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0409]

[0410] To a mixture of 5-bromo-4-methoxy-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (131 mg, 0.47 mmol) and cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (146 mg, 0.47 mmol) in anhydrous 1,4-dioxane (5 mL) was added Pd2(dba)3 (22 mg, 0.02 mmol), XantPhos (27 mg, 0.05 mmol) and K3PO4 (300 mg, 1.42 mmol). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1: 1) to give the product (21 mg, 9%). LC-MS (ESI): m / z[M+H] + =506.4.

[0411] Step 4: cis-isopropylcarbamic acid 3-(3-((4-methoxy-1,1-dioxido-2,3-dihydrobenzo[d]isopropylcarbamate) (5-thiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0412]

[0413] To a solution of cis-3-(1-(tert-butyl)-3-((4-methoxy-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (21 mg, 0.04 mmol) in DCM (1.5 mL) was added trifluoromethanesulfonic acid (3 drops). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was neutralized with saturated aqueous Na2CO3 and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine, dried over NaSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18: 19 x 150 mm, 5 μm, eluting with 30%-50% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA) to give the product (4.0 mg, 21%). 1HNMR(500MHz,DMSO-d6)δ=11.92(s,1H),8.19(s,2H),7.53(t,J=5.1,1H),7 .37(d,J=8.5,1H),6.94(d,J=7.3,1H),5.88(s,1H),5.00(m,1H),4.40(d,J= 5.1,2H),3.80(s,3H),3.62-3.50(m,1H),3.13-2.99(m,1H),2.46(m,1H),2 .02(m,1H),1.96-1.85(m,1H),1.71(m,2H),1.60(m,1H),1.09-0.93(m,6H). LC-MS(ESI):m / z[M+H] + =450.4.

[0414] Example 11: cis-3-(3-((2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0415] Step 1: 5-Bromo-2-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0416]

[0417] To a mixture of 5-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (200 mg, 0.81 mmol) and K2CO3 (223.6 mg, 1.62 mmol) in ethanol (15 mL) was added iodomethane (172.5 mg, 1.22 mmol). The reaction was stirred in a round-bottom flask at 50 ° C overnight. The mixture was evaporated in vacuo, and the residue was purified by silica gel column chromatography (PE:EA=3:1 to 1:2 gradient elution) to give the product (0.18 g, 64%). LC-MS (ESI): m / z [M + H] + =262.1.

[0418] Step 2: cis-isopropylcarbamate 3-(1-(tert-butyl)-5-(2-methyl-1,1-dioxy-2,3-dihydro Benzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[0419]

[0420] To a mixture of cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (177 mg, 0.575 mmol) and 5-bromo-2-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (180 mg, 0.69 mmol) in anhydrous 1,4-dioxane (35 mL) was added Pa2dba3 (52.7 mg, 0.0575 mmol), Xantphos (66.5 mg, 0.115 mmol) and K3PO4 (365.7 mg, 1.725 mmol). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE; EA = 3: 1 to 1: 2 gradient elution) to give the product (0.18 g, 64%). LC-MS(ESI):m / z[M+H] + =490.5.

[0421] Step 3: cis-isopropylcarbamate 3-(3-(2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazide) (5-pyrazol-1-yl)amino)cyclopentyl ester

[0422]

[0423] To a solution of cis-isopropylcarbamic acid 3-(1-(tert-butyl)-5-((2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester (170 mg, 0.348 mmol) in DCM (8 mL) was added trifluoromethanesulfonic acid (1.0 mL) at 25 ° C. The mixture was stirred at 25 ° C for 2 h. The mixture was quenched with NH3 (7N, 4.0 mL) in MeOH and evaporated under reduced pressure. The residue was purified by preparative HPLC (Sunfire C18 column, eluted with a gradient of acetonitrile / water (containing 0.1% FA, 34%-44%) at a flow rate of 17 mL / min) to give the product (109 mg, 72%). 1H NMR (500MHz, DMSO-d6) δ11.93(s,1H),9.05(s,1H),7.58(d,J=8.6Hz,1H),7.48(d,J=9.8Hz,1H ),7.33(d,J=8.5Hz,1H),6.95(d,J=7.4Hz,1H),5.71(s,1H),5.04-4.95(m,1H),4.28(s,2H),3 .58(td,J=12.8,6.2Hz,1H),3.12-3.00(m,1H),2.74(s,3H),2.46(dd,J-13.8,7.1Hz,1H),2.0 6-1.98(m,1H),1.96-1.86(m,1H),1.78-1.66(m,2H),1.65-1.55(m,1H),1.03(d,J=6.3Hz,6H). LC-MS(ESI):m / z[M+H] + =434.3.

[0424] Example 12: cis-3-(3-((6-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0425] Step 1: Methyl 5-bromo-2-(chlorosulfonyl)-4-fluorobenzoate

[0426]

[0427] To a suspension of methyl 2-amino-5-bromo-4-fluorobenzoate (3.0 g, 12.1 mmol) in acetic acid (20 mL) and hydrochloric acid (12 M, 54 mL) was added dropwise a solution of sodium nitrite (918.4 mg, 13.31 mmol) in 8 mL of water at 0 ° C. After the addition, the resulting mixture was kept below 5 ° C and stirred for 30 min. CuCl2 (813 mg, 6.05 mmol), sodium bisulfite (18.9 g, 181.5 mmol) and hydrochloric acid solution (6 M, 88 mL) were added sequentially to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 3 h. The resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and dried under vacuum to obtain a crude product (3.0 g), which was used in the next step without further purification.

[0428] Step 2: 5-Bromo-6-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide

[0429]

[0430] To a mixture of methyl 5-bromo-2-(chlorosulfonyl)-4-fluorobenzoate (3 g crude product) dissolved in THF (10 mL) was added aqueous ammonia (25%, 20 mL). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum, and the residue was triturated with EA and filtered to give a crude product (2.0 g). LC-MS (ESI): m / z [MH] - =277.9.

[0431] Step 3: 5-Bromo-6-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0432]

[0433] To a stirred solution of 5-bromo-6-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (300 mg, 1.08 mmol) in THF (10 mL) was added BH3-Me2S (2 M, 2.7 mL, 5.4 mmol) dropwise at 0°C under a nitrogen atmosphere. The solution was heated to reflux and stirred for 16 h. The resulting mixture was cooled to 0°C, quenched with MeOH (10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give the product (260 mg, 91%). LC-MS (ESI): m / z[M+H] + =266 / 268.

[0434] Step 4: cis-isopropylcarbamate 3-(1-(tert-butyl)-5-(6-fluoro-1,1-dioxido-2,3-dihydrobenzene (d)isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[0435]

[0436] To a mixture of cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (100 mg, 0.324 mmol) and 5-bromo-6-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (86 mg, 0.324 mmol) in anhydrous 1,4-dioxane (25 mL) was added Pa2dba3 (30 mg, 0.0324 mmol), Xantphos (37.5 mg, 0.0648 mmol) and K3PO4 (206 mg, 0.972 mmol). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA=3:1 to 1:2 gradient elution) to give the product (0.1 g, 62.5%). LC-MS(ESI):m / z[M+H] + =494.3.

[0437] Step 5: cis-isopropylcarbamate 3-(3-(6-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazolyl) (5-pyrazol-1-yl)amino)cyclopentyl ester

[0438]

[0439] To a solution of cis-isopropylcarbamic acid 3-(1-(tert-butyl)-5-((6-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester (90 mg, 0.18 mmol) in DCM (8 mL) was added trifluoromethanesulfonic acid (0.5 mL) at 25 ° C. The mixture was stirred at 25 ° C for 1 h. The reaction was monitored by LCMS. The mixture was quenched with NH3 in MeOH (2.0 mL, 7N) and evaporated under reduced pressure. The residue was purified by preparative HPLC (Sunfire C18 column, eluting with a gradient of acetonitrile / water (containing 0.1% FA, 31%-50%), flow rate of 17 mL / min) to give the product in racemic form, which was further purified by chiral preparative HPLC to give:

[0440] Enantiomer 1 (Example 12a, 100% ee); retention time: 6.78 min. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.74(s,1H),8.13(d,J=4.7Hz,1H),7.64(d,J=10. 0Hz,2H),6.94(d,J=7.3Hz,1H),5.85(s,1H),5.00(s,1H),4.30(s,2H),3.58(dd,J=13.4 ,6.7Hz,1H),3.12-3.02(m,1H),2.46(dd,J=14.0,7.2Hz,1H),2.02(dd,J=16.0,7.6Hz,1 H), 1.96-1.86 (m, 1H), 1.78-1.65 (m, 2H), 1.60 (d, J = 13.6Hz, 1H), 1.03 (d, J = 6.3Hz, 6H). LC-MS(ESI):m / z[M+H] + =438.3.

[0441] Enantiomer 2 (Example 12b, 100% ee); retention time: 8.10 min. 1H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.74(s,1H),8.13(d,J=4.7Hz,1H),7.64(d,J=10. 0Hz,2H),6.94(d,J=7.3Hz,1H),5.85(s,1H),5.00(s,1H),4.30(s,2H),3.58(dd,J=13.4 ,6.7Hz,1H),3.12-3.02(m,1H),2.46(dd,J=14.0,7.2Hz,1H),2.02(dd,J=16.0,7.6Hz,1 H), 1.96-1.86 (m, 1H), 1.78-1.65 (m, 2H), 1.60 (d, J = 13.6Hz, 1H), 1.03 (d, J = 6.3Hz, 6H). LC-MS(ESI):m / z[M+H] + =438.3.

[0442] Chiral analysis method: column: CHIRALPAK IF 4.6 mm×150 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.1% 2M NH 3 MeOH); gradient: mobile phase A: mobile phase B = 40:60 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[0443] Chiral preparative HPLC conditions: CHIRALPAK IF 20 mm × 250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH3MeOH); gradient: mobile phase A: mobile phase B = 40:60 (v / v); flow rate: 18 mL / min, wavelength: UV200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25 ° C.

[0444] Example 13: cis-3-(3-((7-fluoro-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0445]

[0446] The title compound was synthesized in a similar manner to the procedure of Example 8. 1H NMR (500MHz, DMSO-d6) δ=11.92(s,1H),8.48(s,1H),8.30(t,J=7.5,1H),8.02(s,1H),7.29(d,J=8.5,1H),6.94(d,J=7.5,1H),5.77(s,1H),5.00 (m,1H),3.58(m,1H),3.12-2.97(m,1H),2.46(m,1H),2.02(m,1H),1.96 -1.85(m,1H),1.70(m,2H),1.59(m,1H),1.50(s,6H),1.09-0.95(m,6H). LC-MS(ESI):m / z[M+H] + =466.3.

[0447] Example 14: cis-3-(3-((6-fluoro-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0448]

[0449] The title compound was synthesized in a similar manner to the procedure of Example 8. 1 H NMR (500MHz, DMSO-d6) δ12.06(s,1H),8.81(d,J=2.2Hz,1H),8.28(d,J=5.2Hz,1H),7.73( s,1H),7.58(d,J=10.1Hz,1H),6.93(d,J=7.3Hz,1H),5.84(s,1H),4.99(d,J=2.9Hz,1H), 3.58(qd,J=12.2,5.3Hz,1H),3.11-2.99(m,1H),2.49-2.40(m,1H),2.06-1.97(m,1H),1. 96-1.85(m,1H),1.78-1.63(m,2H),1.63-1.54(m,1H),1.47(s,6H),1.03(d,J=6.1Hz,6H). LC-MS(ESI):m / z[M+H] + =466.3.

[0450] Example 15: cis-3-(3-((6-methoxy-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0451]

[0452] The title compound was synthesized in a similar manner to the procedure of Example 9. 1 H NMR(500MHz,DMSO-d6)δ11.93(s,1H),8.02(d,J=19.2Hz,2H),7.48(s,1H),7.22(s,1 H),6.95(d,J=7.3Hz,1H),5.90(s,1H),4.99(s,1H),4.26(s,2H),3.94(s,3H),3.58(d d,J=13.1,6.5Hz,1H),3.06(dd,J=16.9,8.4Hz,1H),2.49-2.40(m,1H),2.06-1.97(m ,1H),1.95-1.85(m,1H),1.79-1.64(m,2H),1.64-1.53(m,1H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =450.4.

[0453] Example 16: cis-3-(3-((1,1-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0454]

[0455] The title compound was synthesized in a similar manner to the procedure of Example 3. 1 H NMR (500MHz, DMSO-d6) δ12.11(s,1H),9.72(s,1H),8.12(s,1H),7.77(d,J=8. 6Hz,1H),7.52(d,J=8.3Hz,1H),6.95(d,J=7.5Hz,1H),5.75(s,1H),5.10-4.93 (m,1H),3.70-3.40(m,1H),3.19-2.95(m,1H),2.39-2.21(m,2H),2.11-1.98( m, 1H), 1.92 (d, J = 7.2Hz, 1H), 1.72 (s, 2H), 1.61 (s, 1H), 1.03 (d, J = 5.4Hz, 6H). LC-MS(ESI):m / z[M+H] + =434.4.

[0456] Example 17: cis-3-(3-((1,1-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0457]

[0458] The title compound was synthesized in a similar manner to the procedure of Example 3. 1 H NMR(500MHz,DMSO-d6)δ12.05(s,1H),9.45(s,1H),8.02(s,1H),7.86(d,J= 8.6Hz,1H),7.65(d,J=8.5Hz,1H),6.95(d,J=6.2Hz,1H),5.72(s,1H),5.10 -4.90(m,1H),3.61-3.45(m,3H),3.15-3.01(m,1H),2.08-1.98(m,1H),1.9 5-1.85(m,1H),1.79-1.66(m,2H),1.65-1.55(m,1H),1.03(d,J=4.4Hz,6H). LC-MS(ESI):m / z[M+H] + =434.3.

[0459] Example 18: cis-3-(3-((1,1,1',1'-tetrahydro-2',3'-dihydro-3H-[2,5'-bibenzo[d]isothiazol]-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0460] Step 1: cis-isopropylcarbamate 3-(1-(tert-butyl)-5-(1,1,1',1'-tetraoxy-2',3'-dicarbamate) 3H-[2,5'-bibenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[0461]

[0462] To a mixture of 5-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.40 mmol) and cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (123.2 mg, 0.40 mmol) in anhydrous 1,4-dioxane (10 mL) was added Pd(dba) (36.7 mg, 0.04 mmol), XantPhos (46.2 mg, 0.08 mmol) and KPO (254.4 mg, 1.2 mmol). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the product (30 mg, 10%). LC-MS(ESI):m / z[M+H] + =643.2.

[0463] Step 2: cis-3-(3-((1,1,1,1'-tetrahydro-2',3'-dihydro-3H-[2,5'-bibenzo[d]isothiazol]-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0464]

[0465] A solution of 3-(1-(tert-butyl)-5-((1,1,1',1'-tetrahydro-2',3'-dihydro-3H-[2,5'-bibenzo[d]isothiazol]-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl cis-isopropylcarbamate (30 mg, 0.05 mmol) in formic acid (5 mL) was stirred at 75° C. for 16 h. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18:RD-CO-095 column, eluting with 25%-55% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA) to give the product (5 mg, 19%). 1 H NMR (500MHz, DMSO-d6) δ12.00(s,1H),9.25(s,1H),7.90(d,J=8.6Hz,1H),7.76(d,J=8.8Hz,2H),7.65 (s,1H),7.56(d,J=8.6Hz,1H),7.49(s,1H),7.43(d,J=8.1Hz,1H),6.95(d,J=7.2Hz,1H),5.74(s,1H) ,5.06(s,2H),5.04-4.96(m,1H),4.43(s,2H),3.65-3.53(m,1H),3.12-3.05(m,1H),2.47-2.44(m,1H ),2.08-2.01(m,1H),1.96-1.85(m,1H),1.79-1.67(m,2H),1.65-1.58(m,1H),1.03(d,J=5.8Hz,6H). LC-MS(ESI):m / z[M+H] + =587.4.

[0466] Example 19: cis-1-(3-(3-((1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-3-isopropylurea

[0467] Step 1: Benzyl (3-(3-(benzylamino)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate

[0468]

[0469] To a solution of benzyl (1-(tert-butyl)-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl)carbamate (1.0 g, 2.8 mmol) in 1,2-dichloroethane (100 mL) was added benzylamine (360 mg, 3.36 mmol), potassium acetate (1.372 g, 14 mmol) and sodium triacetoxyborohydride (1.19 g, 5.6 mmol). The resulting mixture was stirred at 50 ° C for 2 h. Water (100 mL) was added to the mixture, and the layers were separated. The aqueous layer was extracted with DCM (50 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=10:1 to 4:1 gradient elution) to give the product (1.12 g, 90%). LC-MS (ESI): m / z[M+H] + =447.4.

[0470] Step 2: (3-(3-(1-benzyl-3-isopropylureido)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)amino Benzyl formate

[0471]

[0472] To a mixture of benzyl (3-(3-(benzylamino)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (500 mg, 1.12 mmol) and DIPEA (434 mg, 3.36 mmol) in DCM (20 mL) was added 2-isocyanatopropane (286 mg, 3.36 mmol). The mixture was stirred at 25 ° C. for 16 h. The mixture was concentrated in vacuo to give a crude product, which was further purified by silica gel column chromatography (PE:EA=2:1 to 1:3 gradient elution) to give the product (550 mg, 92%). LC-MS (ESI): m / z [M + H] + =532.5.

[0473] Step 3: 1-(3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)-3-isopropylurea

[0474]

[0475] A suspension of benzyl (3-(3-(benzylamino)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (550 mg, 1.036 mmol) and Pd / C (100 mg, 10%, wet) in THF / HO (20 mL / 2 mL) was degassed and purged with hydrogen three times. The resulting mixture was stirred at room temperature under a hydrogen balloon for 15 h. The mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under vacuum to obtain the product (310.0 mg, 97%). LC-MS (ESI): m / z[M+H] +=308.3.

[0476] Step 4: cis-1-(3-(1-(tert-butyl)-5-(1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)- 1H-pyrazol-3-yl)amino)cyclopentyl)-3-isopropylurea

[0477]

[0478] To a mixture of cis-1-(3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)-3-isopropylurea (100 mg, 0.326 mmol), 5-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (80 mg, 0.326 mmol) in anhydrous 1,4-dioxane (20 mL) was added Pa2dba3 (30 mg, 0.033 mmol), Xantphos (38 mg, 0.063 mmol) and K3PO4 (207.3 mg, 0.98 mmol). The reaction mixture was stirred in a round-bottom flask at 90 ° C under nitrogen for 16 h. The mixture was concentrated in vacuo, and the residue was further purified by silica gel column chromatography (PE:EA=3:1 to 1:2 gradient elution) to give the product (0.1 g, 65%). LC-MS (ESI): m / z[M+H] + =475.3.

[0479] Step 5: cis-1-(3-(3-((1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H- Pyrazol-5-yl)cyclopentyl)-3-isopropylurea

[0480]

[0481] To a solution of cis-1-(3-(1-(tert-butyl)-3-((1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-3-isopropylurea (100 mg, 0.21 mmol) in DCM (8 mL) was added trifluoromethanesulfonic acid (1.0 mL). The mixture was stirred at 25 °C for 30 min. The mixture was quenched with NH3 in MeOH (7N, 2.0 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Sunfire C18 column eluting with a gradient of acetonitrile / water (containing 0.1% FA, 34%-44%) at a flow rate of 17 mL / min) to give the product (20 mg, 23%). 1H NMR(500MHz,DMSO-d6)δ11.90(s,1H),9.00(s,1H),7.53(d,J=8.6Hz,1H),7.46(s,2H),7.30 (d,J=8.1Hz,1H),5.80(dd,J=23.0,7.2Hz,1H),5.69(d,J=3.6Hz,1H),5.51(dd,J=23.0,7.6 Hz,1H),4.29(s,2H),4.08-3.91(m,1H),3.71-3.58(m,1H),3.21-2.97(m,1H),2.38-2.27(m ,1H),2.10-1.75(m,2H),1.73-1.54(m,1H),1.50-1.31(m,2H),1.01(dd,J=6.5,1.8Hz,6H). LC-MS(ESI):m / z[M+H] + =419.4.

[0482] Example 20: cis-3-(3-((1,1-dioxido-6-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0483] Step 1: Methyl 2-amino-5-bromo-4-(trifluoromethyl)benzoate

[0484]

[0485] To a solution of methyl 2-amino-5-bromo-4-(trifluoromethyl)benzoate (6 g, 27.4 mmol) in DMF (100 mL) was added NBS (4.8 g, 27.4 mmol). The resulting solution was stirred at room temperature for 16 h. The solution was poured into 200 mL of water and extracted with EA (100 mL×3). The combined EA layers were dried and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1 to 2:1) to give the product (5.1 g, 63%). LC-MS (ESI): m / z[M+H] + =298.1

[0486] Step 2: 5-Bromo-6-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide

[0487]

[0488] The title compound was synthesized by a procedure similar to that of Step 10 to Step 11 of Example 1. LC-MS (ESI): m / z [MH] + =327.9.

[0489] Step 3: 5-Bromo-6-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0490]

[0491] The title compound was synthesized by a procedure similar to that of Example 1, Step 12. LC-MS (ESI): m / z [M+H] + =316.3.

[0492] Step 4: cis-isopropylcarbamate 3-(3-((1,1-oxo-6-(trifluoromethyl)-2,3-dihydrobenzo[d] (5-Isothiazol-1H-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0493]

[0494] The title compound was synthesized in a similar manner to the procedure of Example 1, Step 13 to Step 14. 1 H NMR(500MHz,DMSO-d6)δ12.26(s,1H),7.93(s,2H),7.81-7.68(m,2H),6.93 (d,J=5.0Hz,1H),6.00(s,1H),5.05-4.96(m,1H),4.34(d,J=5.0Hz,2H),3. 63-3.51(m,1H),3.14-3.04(m,1H),2.47-2.43(m,1H),2.09-1.99(m,1H),1 .96-1.85(m,1H),1.78-1.68(m,2H),1.65-1.57(m,1H),1.07-0.96(m,6H). LC-MS(ESI):m / z[M+H] + =488.2.

[0495] Example 21: cis-3-(3-((3,3-dimethyl-1,1-dioxido-6-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0496]

[0497] The title compound was synthesized in a similar manner to the procedure of Example 8. 1H NMR(500MHz,DMSO-d6)δ12.26(s,1H),8.06(s,1H),8.00(s,1H),7.88(d,J=1 0.0Hz,2H),6.93(d,J=5.0Hz,1H),6.01(s,1H),5.02-4.95(m,1H),3.61-3.53 (m,1H),3.12-3.03(m,1H),2.46-2.41(m,1H),2.08-1.99(m,1H),1.95-1.86( m,1H),1.77-1.66(m,2H),1.65-1.58(m,1H),1.46(m,6H),1.06-0.95(m,6H). LC-MS(ESI):m / z[M+H] + =516.2.

[0498] Example 22: cis-3-(3-((1,1-dioxido-4-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0499]

[0500] The title compound was synthesized in a similar manner to the procedure of Example 1. 1 H NMR(500MHz,DMSO-d6)δ12.35(s,1H),7.95(s,1H),7.84-7.78(m,1H),7.76-7 .65(m,2H),6.64(d,J=10Hz,1H),5.98(s,1H),5.00(d,J=5.0Hz,1H),4.46(s,1 H),3.55-3.51(m,1H),3.14-3.05(m,1H),2.48-2.43(m,1H),2.09-1.99(m,1H ),1.86-1.86(m,1H),1.79-1.68(m,2H),1.66-1.58(m,1H),1.07-0.97(m,6H). LC-MS(ESI):m / z[M+H] + =488.2.

[0501] Example 23: cis-3-(3-((6-methoxy-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0502] Step 1: 5-Bromo-6-methoxybenzo[d]isothiazol-3(2H)-one 1,1-dioxide

[0503]

[0504] The title compound was synthesized by a procedure similar to that of Step 10 to Step 11 of Example 1. LC-MS (ESI): m / z [MH] - =290.0.

[0505] Step 2: cis-isopropylcarbamic acid 3-(3-((6-methoxy-3,3-dimethyl-1,1-dioxido-2,3-dicarbamic acid) (4-Methylbenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0506]

[0507] The title compound was synthesized in a similar manner to the procedure of Example 6. 1 H NMR(500MHz,DMSO-d6)δ11.98(s,1H),8.10(s,1H),7.55(s,1H),7.15(s,1 H),6.94(d,J=7.4Hz,1H),5.90(s,1H),4.99(s,1H),3.69-3.34(m,5H),3. 10-2.98(m,1H),2.45-2.37(m,1H),2.07-1.97(m,1H),1.97-1.86(m,1H), 1.79-1.66(m,2H),1.63-1.53(m,1H),1.47(s,6H),1.03(d,J=5.8Hz,6H). LC-MS(ESI):m / z[M+H] + =478.2.

[0508] Example 24: cis-3-(3-((4-methoxy-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0509]

[0510] The title compound was synthesized in a similar manner to the procedure of Example 6. 1 H NMR (500MHz, DMSO-d6) δ=11.96(s,1H),8.15(s,1H),8.06(s,1H),7.62(s,1H),7.32(d,J=8.6,1H),6.94(d,J=7.6,1H),5.87(s,1H),4.99(s, 1H),3.78(s,3H),3.60(m,1H),3.11-3.00(m,1H),2.47(m,1H),2.03(m ,1H),1.97-1.85(m,1H),1.72(m,2H),1.60(m,7H),1.07-0.93(m,6H). LC-MS(ESI):m / z[M+H] + =478.2.

[0511] Example 25: cis-3-(3-((6-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0512]

[0513] The title compound was synthesized in a similar manner to the procedure of Example 1. 1 H NMR(500MHz,DMSO-d6)δ11.96(s,1H),7.82(s,1H),7.74(s,1H),7.46-7.40(m,2 H),6.94(d,J=7.3Hz,1H),5.88(s,1H),5.00(s,1H),4.25(d,J=4.6Hz,2H),3.62- 3.54(m,1H),3.11-3.03(m,1H),2.48-2.42(m,1H),2.29(s,3H),2.08-1.95(m,1 H), 1.941.85 (m, 1H), 1.78-1.65 (m, 2H), 1.651.55 (m, 1H), 1.03 (d, J = 6.3Hz, 6H). LC-MS(ESI):m / z[M+H] + =434.2.

[0514] Example 26: cis-3-(3-((7-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0515]

[0516] The title compound was synthesized in a similar manner to the procedure of Example 1. 1 H NMR(500MHz,DMSO-d6)δ11.82(s,1H),8.82(s,1H),7.37(t,J=5Hz,1H),7.19(s,1H) ,7.03(s,1H),6.87(d,J=5Hz,1H),5.62(s,1H),4.97-4.89(m,1H),4.17(d,J=5Hz,2H ),3.56-3.47(m,1H),3.03-2.93(m,1H),2.41-2.35(m,1H),2.31(s,3H),1.99-1.91 (m,1H),1.88-1.78(m,1H),1.71-1.59(m,2H),1.57-1.48(m,1H),1.01-0.90(m,6H). LC-MS(ESI):m / z[M+H]+ =434.2.

[0517] Example 27: cis-3-(3-((6-chloro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0518]

[0519] The title compound was synthesized in a similar manner to the procedure of Example 1. 1 H NMR(500MHz,DMSO-d6)δ12.03(s,1H),8.12(s,1H),7.92(s,1H),7.77(s,1H),7.5 8(t,J=5.1Hz,1H),6.87(d,J7.7Hz,1H),5.91(s,1H),4.93(s,1H),4.23(d,J=5.3H z,2H),3.57-3.47(m,1H),3.06-2.94(m,1H),2.50-2.37(m,1H),1.96-1.92(m,1H ),1.90-1.80(m,1H),1.70-1.60(m,2H),1.54-1.48(m,1H),0.96(d,J=6.3Hz,6H). LC-MS(ESI):m / z[M+H] + =454.2.

[0520] Example 28: cis-3-(3-((1,1-dioxido-6-(trifluoromethoxy)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0521] Step 1: tert-Butyl (2-bromo-5-(trifluoromethoxy)phenyl)carbamate

[0522]

[0523] To a solution of 2-bromo-5-(trifluoromethoxy)aniline (1.0 g, 3.9 mmol) in THF (20 mL) was added NaHMDS (9.77 mL, 9.77 mmol) at 0-5 ° C. Di-tert-butyl dicarbonate (1.02 g, 4.7 mmol) was then added, and the mixture was stirred at 25 ° C for 12 hours. The mixture was quenched with saturated NH4Cl (aqueous) (10 mL) and then adjusted to pH = 7-8 with 2N HCl. The mixture was extracted with EA (30 mL × 3). The EA layer was concentrated under reduced pressure to give the product, which was used in the next step without purification (1.01 g). LC-MS (ESI): m / z [M+H] + =356.4.

[0524] Step 2: Ethyl 2-((tert-Butoxycarbonyl)amino)-4-(trifluoromethoxy)benzoate

[0525]

[0526] A mixture of tert-butyl (2-bromo-5-(trifluoromethoxy)phenyl)carbamate (1.42 g, 5.55 mmol), TEA (1.68 g, 16.64 mmol) and Pd(dppf)Cl2 (0.4 g, 0.55 mmol) in EtOH (30 mL) was heated under CO (gas, 4 MPa) for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (9:1) to give the product (0.6 g, 31.1%). LC-MS (ESI): m / z [M+H] + =350.2

[0527] Step 3: Ethyl 2-amino-4-(trifluoromethoxy)benzoate

[0528]

[0529] To a solution of ethyl 2-((tert-butoxycarbonyl)amino)4-(trifluoromethoxy)benzoate (3.0 g, 8.6 mmol) in DCM (30 mL) was added TFA (30 mL) at 25°C. The mixture was then stirred at 25°C for 1 hr. The mixture was quenched with saturated NaHCO3 (aqueous) (20 mL). The mixture was extracted with DCM (30 mL x 3). The DCM layer was concentrated under reduced pressure to give the product, which was used in the next step without purification (2.02 g, 94.4%). LC-MS (ESI): m / z [M+H] + =250.1

[0530] Step 4: Ethyl 2-amino-5-bromo-4-(trifluoromethoxy)benzoate

[0531]

[0532] To a solution of ethyl 2-amino-4-(trifluoromethoxy)benzoate (2.02 g, 8.10 mmol) in DMF (30 mL) at 0°C was added NBS (1.58 g, 8.91 mmol). The mixture was then stirred at 0°C for 1 hr. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1 to 2:1) to give the product (1.9 g, 71.7%). LC-MS (ESI): m / z [M+H] + =328.1

[0533] Step 5: cis-isopropylcarbamate 3-(3-(1,1-dioxido-6-(trifluoromethoxy)-2,3-dihydrobenzene) (d)isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0534]

[0535] The title compound was synthesized in a similar manner to the procedure of Example 1. 1 H NMR(500MHz,DMSO-d6))δ12.07(s,1H),8.74(s,1H),8.15(s,1H),7.76-7.67 (m,2H),7.09-6.78(m,1H),5.92(s,1H),5.01(s,1H),4.33(d,J=5.2Hz,2H),3 .62-3.55(m,1H),3.15-3.03(m,1H),2.48-2.42(m,1H),2.10-2.01(m,1H),1. 95-1.86(m,1H),1.78-1.65(m,2H),1.65-1.55(m,1H),1.03(d,J=5.9Hz,6H). LC-MS(ESI):m / z[M+H] + =504.2.

[0536] Example 29: cis-3-(3-((7-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0537]

[0538] The title compound was synthesized in a similar manner to the procedure of Example 1. 1 H NMR(500MHz,DMSO-d6)δ12.01(s,1H),9.28(s,1H),7.71(s,1H),7.29(d,J=10H z,1H),7.11(s,1H),6.94(d,J=5Hz,1H),5.72(s,1H),5.04-4.96(m,1H),4.32(s ,2H),3.62-3.55(m,1H),3.12-3.02(m,1H),2.48-2.43(m,1H),2.06-1.98(m,1 H),1.96-1.85(m,1H),1.78-1.67(m,2H),1.65-1.55(m,1H),1.08-0.97(m,6H). LC-MS(ESI):m / z[M+H] + =438.2.

[0539] Example 30: cis-3-(3-((4,6-difluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0540] Step 1: 6-amino-3-bromo-2,4-difluorobenzoic acid methyl ester

[0541]

[0542] The title compound was synthesized by a procedure similar to that of Example 20, Step 1. LC-MS (ESI): m / z [M+H] + =266.1

[0543] Step 2: cis-isopropylcarbamic acid 3-(3-((4,6-difluoro-1,1-dioxido-2,3-dihydrobenzo[d]isopropylcarbamate) (5-thiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0544]

[0545] The title compound was synthesized in a similar manner to the procedure of Example 1. 1 H NMR (500MHz, DMSO-d6) δ=11.81(s,1H),8.13(s,1H),7.93(t,J=5.0,1H),7.66(d,J=8.6,1H),6.94(d,J=7.4,1H),5.63(s,1H),4.98(s,1H),4 .37(d,J=5.3,2H),3.57(m,1H),3.07-2.95(m,1H),2.47-2.39(m,1H), 1.99(m,1H),1.95-1.84(m,1H),1.69(m,2H),1.57(s,1H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =456.2.

[0546] Example 31: cis-3-(3-((1,1-dioxido-2,3-dihydroisothiazolo[5,4-b]pyridin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0547] Step 1: 2-(Benzylthio)-5-bromo-3-methylpyridine

[0548]

[0549] To a mixture of benzylmercaptan (1.2 g, 9.69 mmol) in THF (50 mL) was added NaH (60% dispersion in mineral oil, 465 mg, 11.63 mmol) in one portion, followed by stirring at room temperature for 30 minutes. 5-Bromo-2-chloro-3-methylpyridine (2.0 g, 9.69 mmol) in THF (10 mL) was then added dropwise over 5 minutes, and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the crude product (2.95 g crude). LC-MS (ESI): m / z [M+H] + =294.1.

[0550] Step 2: 5-Bromo-N-(tert-butyl)-3-methylpyridine-2-sulfonamide

[0551]

[0552] 2-(Benzylthio)-5-bromo-3-methylpyridine (300 mg, 1.02 mmol) was dissolved in DCM (15 mL), SO2Cl2 (700 mg, 5.1 mmol) was added, and the mixture was stirred for 30 minutes. The mixture was quenched with water, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and dried under vacuum to give a solid. The solid was redissolved in DCM (15 mL), t-BuNH2 (0.5 mmol) was added, and the mixture was stirred at room temperature for another 16 hours. The resulting mixture was concentrated and purified by silica gel column chromatography, eluting with PE / EA (3:1) to give the product (205 mg, 66%). LC-MS (ESI): m / z [M+H] + =307.3.

[0553] Step 3: 5-Bromo-3-(bromomethyl)-N-(tert-butyl)pyridine-2-sulfonamide

[0554]

[0555] To a solution of 5-bromo-N-(tert-butyl)-3-methylpyridine-2-sulfonamide (800 mg, 2.61 mmol) in CCl4 (50 mL) was added NBS (930 mg, 5.23 mmol) and AIBN (43 mg, 0.26 mmol), and the reaction mixture was stirred at reflux for 16 hours. The resulting mixture was cooled to room temperature, filtered, and the filtrate was concentrated and dried under vacuum to give the crude product (1.2 g crude product). LC-MS (ESI): m / z [M+H] + =385.1.

[0556] Step 4: 5-Bromo-2-(tert-butyl)-2,3-dihydroisothiazolo[5,4-b]pyridine 1,1-dioxide

[0557]

[0558] 5-Bromo-3-(bromomethyl)-N-(tert-butyl)pyridine-2-sulfonamide (1.2 g crude product) was dissolved in THF (50 mL), and NaH (60% dispersion in mineral oil, 200 mg, 5 mmol) was added in one portion. The reaction was stirred at room temperature for 4 hours. The resulting mixture was quenched with water and extracted with EA (3 x 50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, dried in vacuo, and recrystallized from PE / EA (10:1) to give the product (153 mg, 19% over 2 steps). LC-MS (ESI): m / z [M+H] + =305.1.

[0559] Step 5: cis-isopropylcarbamate 3-(1-(tert-butyl)-5-((2-(tert-butyl)-1,1-dioxido-2,3- dihydroisothiazolo[5,4-b]pyridin-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[0560]

[0561] To a mixture of 5-bromo-2-(tert-butyl)-2,3-dihydroisothiazolo[5,4-b]pyridine 1,1-dioxide (50 mg, 0.164 mmol) and cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (505 mg, 0.164 mmol) in anhydrous 1,4-dioxane (5 mL) was added Pd2(dba)3 (15 mg, 0.016 mmol), XantPhos (19 mg, 0.032 mmol), and K3PO4 (104 mg, 0.492 mmol). The reaction mixture was stirred at 95°C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give the product (63 mg, 72%). LC-MS(ESI):m / z[M+H] + =533.4.

[0562] Step 6: cis-isopropylcarbamate 3-(3-(1,1-dioxido-2,3-dihydroisothiazolo[5,4-b]pyrrolidone) (5-pyridin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0563]

[0564] 3-(1-(tert-butyl)-5-((2-(tert-butyl)-1,1-dioxido-2,3-dihydroisothiazolo[5,4-b]pyridin-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl cis-isopropylcarbamate (63 mg, 0.12 mmol) was dissolved in formic acid (5 mL). The reaction mixture was stirred at 80°C for 16 hours. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, redissolved in DCM (5 mL), and 2N HCl (aqueous, 1 mL) was added and stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (Waters X-select Prep C18 OBD 19×150 mm, 5 μm, eluting with 27%-42% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (10 mg, 20%). 1 HNMR(500MHz,DMSO-d6)δ=12.08(s,1H),9.42(s,1H),8.56(d,J=2.0,1H), 8.07(s,1H),7.73(t,J=4.6,1H),7.01(d,J=7.4,1H),5.80(s,1H),5.06(s ,1H),4.40(d,J=4.8,2H),3.64(m,6.4,1H),3.19-3.06(m,1H),2.51(m,1H ),2.09(m,1H),2.02-1.91(m,1H),1.79(m,2H),1.68(m,1H),1.09(m,6H). LC-MS(ESI):m / z[M+H] + =421.2.

[0565] Example 32: cis-3-(3-((2-methyl-1,1-dioxido-2,3-dihydroisothiazolo[5,4-b]pyridin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0566]

[0567] The title compound was synthesized in a similar manner to the procedure of Example 31. 1H NMR (500MHz, DMSO-d6) δ = 12.03 (s, 1H), 9.41 (s, 1H), 8.51 (s, 1H), 8.05 (s, 1H), 6.95 (d, J = 7.5, 1H), 5.74 (s, 1H), 5.00 (s, 1H), 4.33 (s, 2H),3.58(m,1H),3.14-3.02(m,1H),2.79(s,3H),2.48-2.44(m,1H),2.03(m,1H),1.91(m,1H),1.73(m,2H),1.61(m,1H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =435.3.

[0568] Example 33: cis-3-(3-((1,1-dioxido-2,3-dihydroisothiazolo[4,5-b]pyridin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0569]

[0570] The title compound was synthesized in a similar manner to the procedure of Example 31. 1 H NMR (500MHz, DMSO-d6) δ12.08(s,1H),10.03(s,1H),7.95(d,J=8.8Hz,1H),7.64(t,J= 5.0Hz,1H),7.24(s,1H),6.94(d,J=7.5Hz,1H),6.21(s,1H),5.10-4.92(m,1H),4.27( d,J=4.8Hz,2H),3.68-3.52(m,1H),3.13-3.02(m,1H),2.48-2.42(m,1H),2.07-1.97( m,1H),1.96-1.86(m,1H),1.80-1.69(m,2H),1.66-1.56(m,1H),1.03(d,J=6.0Hz,6H). LC-MS(ESI):m / z[M+H] + =421.3.

[0571] Example 34: cis-3-(3-((4-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0572] Step 1: 5-Bromo-4-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0573]

[0574] The title compound was synthesized by a procedure similar to that of steps 10 to 12 of Example 1. LC-MS (ESI): m / z [M+H] + =262.3.

[0575] Step 2: cis-(5-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino Benzyl formate

[0576]

[0577] To a round-bottom flask charged with benzyl cis-(1-(tert-butyl)-3-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (30 g, 57.5 mmol) was added 100 mL of formic acid. The resulting mixture was stirred at 75° C. overnight. The solvent was removed under vacuum to give 26 g of crude product, which was used in the next step without further purification.

[0578] Step 3: cis-isopropylcarbamic acid 3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl) ring Amyl ester

[0579]

[0580] To a solution of benzyl cis-(5-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamate (7 g, 15 mmol) in 100 mL of THF was added propan-2-amine (2.6 g, 45 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EA=2:1) ​​to give the product (4.6 g, 80% yield). LC-MS (ESI): m / z [M+H] + =387.3.

[0581] Step 4: cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0582]

[0583] To a solution of cis-isopropylcarbamic acid 3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl ester (4.6 g, 12 mmol) in THF (100 mL) was added Pd / C (10%, wet, 3 g). The suspension was degassed and purged with hydrogen three times. The resulting mixture was stirred at room temperature under a hydrogen balloon for 3 h. The mixture was filtered, and the filter cake was washed with EA (50 mL×3). The filtrate was concentrated under reduced pressure to give the product (2.5 g, 82% yield). LC-MS (ESI): m / z[M+H] + =253.4.

[0584] Step 5: cis-isopropylcarbamate 3-(3-((4-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazide) (5-pyrazol-1-yl)amino)cyclopentyl ester

[0585]

[0586] A mixture of 5-bromo-4-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (90 mg, 0.33 mmol), cis-isopropylcarbamic acid 3-(3-amino-1H-pyrazol-5-yl)cyclopentyl ester (65.5 mg, 0.26 mmol), Brettphos PdG3 (29.9 mg, 0.033 mmol), and K2CO3 (135 mg, 0.98 mmol) in t-BuOH (5 mL) was stirred at 110°C under a nitrogen atmosphere for 16 h. LCMS indicated the reaction was complete. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (0%-100%) to give the product (51.9 mg, 31.6%). 1 HNMR(500MHz,DMSO-d6)δ11.96(s,1H),7.90-7.80(brs,1H),7.77(s,1H),7.51(t,J=5H z,1H),7.43(d,J=10Hz,1H),6.97-6.91(m,1H),5.84(s,1H),5.04-4.96(m,1H),4.32-4. 25(m,2H),3.63-3.53(m,1H),3.12-3.02(m,1H),2.46-2.4(m,1H),2.12(s,3H),2.06-1 .99(m,1H),1.95-1.86(m,1H),1.78-1.66(m,2H),1.65-1.57(m,1H),1.07-1.00(m,6H). LC-MS(ESI):m / z[M+H] + =434.2.

[0587] Example 35: cis-3-(3-((2,4-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0588] Step 1: 5-Bromo-2,4-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0589]

[0590] To a mixture of 5-bromo-4-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (170 mg, 0.65 mmol) and Cs2CO3 (255 mg, 0.78 mmol) in DMF (10 mL) was added iodomethane (102 mg, 0.71 mmol). The mixture was stirred at 50°C for 2 h. LCMS showed that the reaction was complete. The mixture was diluted with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:2) to give the product (90 mg, 50%). LC-MS (ESI): m / z [M+H] + =276.2.

[0591] Step 2: cis-isopropylcarbamate 3-(3-(2,4-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d] (5-Isothiazol-1H-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0592]

[0593] The title compound was synthesized by a procedure similar to that of Example 34, Step 5. 1 H NMR(500MHz,DMSO-d6)δ11.98(s,1H),7.92-7.84(brs,1H),7.82(s,1H),7.48(t, J=10Hz,1H),6.96-6.91(m,1H),5.04-4.95(m,1H),4.29(s,2H),3.62-3.53(m,1H) ),3.13-3.02(m,1H),2.78(s,3H),2.48-2.43(m,1H),2.12(s,3H),2.06-1.98(m, 1H),1.96-1.66(m,1H),1.78-1.66(m,2H),1.65-1.55(m,1H),1.09-0.96(m,6H). LC-MS(ESI):m / z[M+H] + =448.2.

[0594] Example 36: cis-3-(3-((2-(2-methoxyethyl)-4-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0595]

[0596] The title compound was synthesized in a similar manner to the procedure of Example 35. 1H NMR(500MHz,DMSO-d6)δ11.98(s,1H),7.89(t,J=5Hz,1H),7.82(s,1H),7.47(d,J=10Hz, 1H),6.98-6.90(m,1H),5.85(s,1H),5.05-4.96(m,1H),4.39(s,2H),3.62(t,J=5Hz,2H), 3.60-3.52(m,1H),3.30(s,3H),3.11-3.03(m,1H),2.49-2.42(m,3H),2.12(s,3H),2.07- 1.99(m,1H),1.96-1.85(m,1H),1.76-1.66(m,2H),1.64-1.56(m,1H),1.08-0.95(m,6H). LC-MS(ESI):m / z[M+H] + =492.2.

[0597] Example 37: cis-3-(3-((2-(2-hydroxyethyl)-4-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0598] Step 1: cis-3-(3-((2-(2-(tert-butyldimethylsilyl)oxy)ethyl)isopropylcarbamate (4-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0599]

[0600] The title compound was synthesized in a similar manner to the procedure of Example 36. LC-MS (ESI): m / z [M+H] + =592.4.

[0601] Step 2: cis-isopropylcarbamic acid 3-(3-((2-(2-hydroxyethyl)-4-methyl-1,1-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0602]

[0603] To a flask charged with cis-3-(3-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (101 mg, 0.17 mmol) was added TFA (1 mL) and DCM (3 mL). The resulting solution was stirred at room temperature for 2 h. The solvent was removed under vacuum, and the residue was purified by preparative HPLC (Waters XSelect C18:RD-CO-094 column, eluting with a gradient of acetonitrile / water (containing 0.1% FA, 20%-40%)) to give the product (59 mg, 12%).1 H NMR (500MHz, DMSO-d6) δ11.98(s,1H),7.89(s,1H),7.82(s,1H),7.47(d,J=8.7Hz,1H),6.94(d,J=7 .2Hz,1H),5.85(s,1H),5.00(s,1H),4.40(s,2H),3.69(t,J=6.0Hz,2H),3.58(dd,J=13.1,6.3Hz,1 H),3.20(t,J=6.0Hz,2H),3.14-3.01(m,1H),2.49-2.43(m,1H),2.13(s,3H),2.03(dd,J=15.5,7.8 Hz,1H),1.91(dt,J=16.2,8.0Hz,1H),1.80-1.66(m,2H),1.65-1.52(m,1H),1.02(d,J=6.1Hz,6H). LC-MS(ESI):m / z[M+H] + =492.2.

[0604] Example 38: cis-3-(3-((4-chloro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0605]

[0606] The title compound was synthesized in racemic form in analogy to the procedure of Example 1, which was further separated by chiral preparative HPLC to give:

[0607] Enantiomer 1 (Example 38a, 100% ee); retention time: 4.59 min. 1 H NMR(500MHz,DMSO-d6)δ12.15(brs,1H),8.25(s,1H),8.05(d,J=7.7Hz,1H),7.74(s ,1H),7.61(d,J=8.7Hz,1H),6.94(d,J=6.9Hz,1H),5.96(s,1H),5.06-4.93(m,1H),4 .30(s,2H),3.65-3.50(m,1H),3.23-2.98(m,1H),2.48-2.40(m,1H),2.10-1.99(m, 1H), 1.98-1.86 (m, 1H), 1.80-1.66 (m, 2H), 1.65-1.55 (m, 1H), 1.03 (d, J = 6.1Hz, 6H). LC-MS (ESI): m / z[M+H]=454.27.

[0608] Enantiomer 2 (Example 38b, 100% ee); retention time: 7.29 min. 1 H NMR(500MHz,DMSO-d6)δ12.10(brs,1H),8.25(s,1H),8.05(d,J=7.8Hz,1H),7 .74(s,1H),7.61(d,J=8.7Hz,1H),5.96(s,1H),5.07-4.93(m,1H),4.30(s,2H ),3.65-3.41(m,1H),3.24-2.98(m,1H),2.49-2.40(m,1H),2.10-1.99(m,1H) ,1.98-1.85(m,1H),1.80-1.66(m,2H),1.65-1.55(m,1H),1.10-0.97(m,6H). LC-MS(ESI):m / z[M+H] + =454.27.

[0609] Chiral analysis method: column: CHIRALPAK IF 4.6 mm×150 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.1% 2M NH 3 MeOH); gradient: mobile phase A: mobile phase B = 40:60 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[0610] Chiral preparative HPLC conditions: CHIRALPAK IF 20 mm × 250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH3MeOH); gradient: mobile phase A: mobile phase B = 40:60 (v / y); flow rate: 18 mL / min, wavelength: UV200 nm and 270 nm, preparative HPLC equipment: preparative HPLC Gilson, back pressure: 100 bar; column temperature: 25 ° C.

[0611] Example 39: cis-3-(3-((4-chloro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl propylcarbamate

[0612] Step 1: cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentylpropylcarbamate

[0613]

[0614] The title compound was synthesized by a procedure similar to that of Step 3 to Step 4 of Example 34. LC-MS (ESI): m / z [M+H] + =253.2.

[0615] Step 2: cis-propylcarbamic acid 3-(3-((4-chloro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)- (4-(2-Methyl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0616]

[0617] The title compound was synthesized in racemic form by a procedure analogous to Example 34, Step 5, which was further separated by chiral preparative HPLC to give:

[0618] Enantiomer 1 (Example 39a, 100% ee); retention time: 4.32 min. 1 H NMR(500MHz,DMSO-d6)δ12.12(s,1H),8.24(s,1H),8.07(s,1H),7.73(s,1H),7.61(d,J= 8.7Hz,1H),7.04(t,J=5.4Hz,1H),5.96(s,1H),5.08-4.95(m,1H),4.30(d,J=3.7Hz,2H) ,3.14-3.04(m,1H),2.95-2.85(m,2H),2.48-2.43(m,1H),2.08-2.01(m,1H),1.96-1.86 (m,1H),1.80-1.68(m,2H),1.66-1.57(m,1H),1.43-1.31(m,2H),0.81(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =454.20.

[0619] Enantiomer 2 (Example 39b, 100% ee); retention time: 5.73 min. 1 H NMR(500MHz,DMSO-d6)δ12.12(s,1H),8.24(s,1H),8.07(s,1H),7.73(s,1H),7.61(d,J= 8.7Hz,1H),7.04(t,J=5.4Hz,1H),5.96(s,1H),5.08-4.95(m,1H),4.30(d,J=3.7Hz,2H) ,3.14-3.04(m,1H),2.95-2.85(m,2H),2.48-2.43(m,1H),2.08-2.01(m,1H),1.96-1.86 (m,1H),1.80-1.68(m,2H),1.66-1.57(m,1H),1.43-1.31(m,2H),0.81(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =454.20.

[0620] Chiral analysis method: column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; mobile phase: A: MtBE (0.1% 2M NH3MeOH) (%), and B: MeOH / DCM (50:50) (%); gradient: mobile phase A: mobile phase B = 20:80 (v / y); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35 ° C.

[0621] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm × 250 mm, 5 μm; mobile phase: A: MtBE (0.2% 2M NH3MeOH) (%), and B: MeOH / DCM (50:50) (%); gradient: mobile phase A: mobile phase B = 20:80 (v / y); flow rate: 18 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25 ° C.

[0622] Example 40: cis-3-(3-((4-chloro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate

[0623] Step 1: cis-(1-methylcyclopropyl)carbamic acid 3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazole- 5-amino)cyclopentyl ester

[0624]

[0625] To a solution of benzyl cis-(5-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamate (10 g, 21.5 mmol) in 100 mL of THF was added 1-methylcyclopropylamine hydrochloride (11.5 g, 107 mmol) and DIEA (27.6 g, 214 mmol). The resulting mixture was stirred at room temperature for 12 h. The resulting mixture was concentrated under reduced pressure and dissolved in EA (200 mL). The mixture was washed with water (200 mL×3), dried over Na2SO4, and concentrated. The residue was triturated with MTBE and filtered to give the product (3.6 g, 42% yield). LC-MS (ESI): m / z[M+H] + =399.3.

[0626] Step 2: cis-(1-methylcyclopropyl)carbamic acid 3-(3-amino-1H-pyrazol-5-yl)cyclopentyl ester

[0627]

[0628] To a solution of cis-(1-methylcyclopropyl)carbamic acid 3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl ester (3.6 g, 9 mmol) in THF (100 mL) was added Pd / C (10%, wet, 2 g). The suspension was degassed and purged with hydrogen three times. The resulting mixture was stirred at room temperature under a hydrogen balloon for 3 h. The mixture was filtered, and the filter cake was washed with EA (200 mL×3). The filtrate was concentrated under reduced pressure to give the product (2.2 g, 92% yield). LC-MS (ESI): m / z[M+H] + =265.3.

[0629] Step 3: cis-(1-methylcyclopropyl)carbamic acid 3-(3-((4-chloro-1,1-dioxido-2,3-dihydrobenzoyl) [d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0630]

[0631] The title compound was synthesized in racemic form by a procedure analogous to Example 34, Step 5, which was further separated by chiral preparative HPLC to give:

[0632] Enantiomer 1 (Example 40a, 100% ee); retention time: 4.40 min. 1 H NMR(500MHz,DMSO-d6)δ12.11(brs,1H),8.24(s,1H),8.04(s,1H),7.73(s,1H),7. 61(d,J=8.7Hz,1H),7.34(s,1H),5.95(s,1H),5.10-4.90(m,1H),4.30(s,2H),3.1 8-3.01(m,1H),2.57-2.53(m,1H),2.08-1.97(m,1H),1.96-1.85(m,1H),1.78-1.6 4(m,2H),1.63-1.52(m,1H),1.23(s,3H),0.65-0.53(m,2H),0.0.52-0.45(m,2H). LC-MS(ESI):m / z[M+H] + =466.30.

[0633] Enantiomer 2 (Example 40b, 100% ee); retention time: 5.64 min. 1H NMR(500MHz,DMSO-d6)δ12.11(brs,1H),8.24(s,1H),8.04(s,1H),7.73(s,1H),7. 61(d,J=8.7Hz,1H),7.34(s,1H),5.95(s,1H),5.10-4.90(m,1H),4.30(s,2H),3.1 8-3.01(m,1H),2.57-2.53(m,1H),2.08-1.97(m,1H),1.96-1.85(m,1H),1.78-1.6 4(m,2H),1.63-1.52(m,1H),1.23(s,3H),0.65-0.53(m,2H),0.0.52-0.45(m,2H). LC-MS(ESI):m / z[M+H] + =466.30.

[0634] Chiral analysis method: column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; mobile phase: A: MtBE (0.1% 2M NH3MeOH) (%), and B: MeOH / DCM (50:50) (%); gradient: mobile phase A: mobile phase B = 40:60 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35 ° C.

[0635] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm × 250 mm, 5 μm; mobile phase: A: MtBE (0.2% 2M NH3MeOH) (%), and B: MeOH / DCM (50:50) (%); gradient: mobile phase A: mobile phase B = 40:60 (v / y); flow rate: 18 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25 ° C.

[0636] Example 41: 3-(3-((4-chloro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-((S)-sec-butyl)carbamate

[0637] Step 1: cis-((S)-sec-butyl)carbamic acid 3-(3-amino-1H-pyrazol-5-yl)cyclopentyl ester

[0638]

[0639] The title compound was synthesized by a procedure similar to that of Step 3 to Step 4 of Example 34. LC-MS (ESI): m / z [M+H] + =267.3.

[0640] Step 2: cis-((S)-sec-butyl)carbamic acid 3-(3-((4-chloro-1,1-dioxido-2,3-dihydrobenzo[d] (5-Isothiazol-1H-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0641]

[0642] The title compound was synthesized by a procedure similar to that in Example 34, Step 3 to Step 4. 1 H NMR(500MHz,DMSO-d6)δ12.17(brs,1H),8.24(d,J=4.5Hz,1H),8.04(d,J=7.3Hz,1H),7.73(s, 1H),7.61(d,J=8.7Hz,1H),6.88(d,J=8.1Hz,1H),5.96(s,1H),5.10-4.90(m,1H),4.30(s,2H), 3.43-3.26(m,1H),3.17-2.96(m,1H),2.48-2.42(m,1H),2.10-1.99(m,1H),1.98-1.86(m,1H), 1.80-1.67(m,2H),1.66-1.55(m,1H),1.43-1.27(m,2H),1.10-0.93(m,3H),0.89-0.70(m,3H). LC-MS(ESI):m / z[M+H] + =468.30.

[0643] Example 42: cis-3-(3-((6-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate

[0644]

[0645] The title compound was synthesized in racemic form in analogy to the procedure of Example 34, which was further separated by chiral preparative HPLC to give:

[0646] Enantiomer 1 (Example 42a, 99.44% ee); retention time: 6.023 min. 1H NMR(500MHz,DMSO-d6)δ11.97(s,1H),8.73(s,1H),8.14(s,1H),7.85-7.83(m,2H),7.0 4(t,J=5.5Hz,1H),5.85(s,1H),5.01(s,1H),4.30(d,J=4.3Hz,2H),3.08(dd,J=17.1,8. 6Hz,1H),2.92(dd,J=12.9,6.6Hz,2H),2.45-2.37(m,1H),2.07-1.97(m,1H),1.97-1.86 (m,1H),1.79-1.66(m,2H),1.63-1.53(m,1H),1.44-1.34(m,2H),0.82(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =438.30.

[0647] Enantiomer 2 (Example 42b, 97.65% ee); retention time: 7.2 min. 1 H NMR(500MHz,DMSO-d6)δ11.97(s,1H),8.73(s,1H),8.14(s,1H),7.85-7.83(m,2H),7.0 4(t,J=5.5Hz,1H),5.85(s,1H),5.01(s,1H),4.30(d,J=4.3Hz,2H),3.08(dd,J=17.1,8. 6Hz,1H),2.92(dd,J=12.9,6.6Hz,2H),2.45-2.37(m,1H),2.07-1.97(m,1H),1.97-1.86 (m,1H),1.79-1.66(m,2H),1.63-1.53(m,1H),1.44-1.34(m,2H),0.82(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =438.30.

[0648] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.1% 2M NH 3 MeOH); gradient: mobile phase A: mobile phase B = 40:60 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[0649] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH3MeOH); gradient: mobile phase A: mobile phase B = 40:60 (v / v); flow rate: 18 mL / min, wavelength: UV200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[0650] Example 43: 3-(3-((6-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-((S)-sec-butyl)carbamate

[0651]

[0652] The title compound was synthesized in a similar manner to the procedure of Example 34. 1 H NMR(500MHz,DMSO-d6)δ11.90(s,1H),8.66(s,1H),8.08(s,1H),7.65-7.43(m,2H),6. 81(d,J=7.7Hz,1H),5.78(s,1H),4.93(s,1H),4.23(d,J=5.0Hz,2H),3.37-3.29(m,1H) ,3.05-2.95(m,1H),2.41-2.34(m,1H),2.03-1.92(m,1H),1.97-1.86(m,1H),1.75-1.5 9(m,2H),1.63-1.53(m,1H),1.28(s,2H),0.94(d,J=6.1Hz,3H),0.73(q,J=6.9Hz,3H). LC-MS (ESI): m / z[M+H]=452.30.

[0653] Example 44: cis-3-(3-((6-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate

[0654]

[0655] The title compound was synthesized in racemic form in analogy to the procedure of Example 34, which was further separated by chiral preparative HPLC to give:

[0656] Enantiomer 1 (Example 44a, 100% ee); retention time: 7.49 min. 1H NMR(500MHz,DMSO-d6)δ11.97(s,1H),8.73(s,1H),8.14(s,1H),7.71-7.43(m ,2H),7.34(s,1H),5.84(s,1H),4.99(s,1H),4.30(d,J=4.8Hz,2H),3.12-3.0 0(m,1H),2.43-2.38(m,1H),2.10-1.98(m,1H),1.96-1.85(m,1H),1.75-1.65 (m,2H),1.58-1.52(m,1H),1.23(s,3H),0.61-0.56(m,2H),0.49-0.45(m,2H). LC-MS(ESI):m / z[M+H] + =450.2

[0657] Enantiomer 2 (Example 44b, 99.6% ee); retention time: 9.29 min. 1 H NMR(500MHz,DMSO-d6)δ11.97(s,1H),8.73(s,1H),8.14(s,1H),7.71-7.43(m ,2H),7.34(s,1H),5.84(s,1H),4.99(s,1H),4.30(d,J=4.8Hz,2H),3.12-3.0 0(m,1H),2.43-2.38(m,1H),2.10-1.98(m,1H),1.96-1.85(m,1H),1.75-1.65 (m,2H),1.58-1.52(m,1H),1.23(s,3H),0.61-0.56(m,2H),0.49-0.45(m,2H). LC-MS(ESI):m / z[M+H] + =450.2

[0658] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A: Hex, and B: EtOH (0.2% 2M NH 3 MeOH); gradient: mobile phase A: mobile phase B = 50:50 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[0659] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm × 250 mm, 5 μm; mobile phase: A: Hex, and B: EtOH (0.2% 2M NH3MeOH); gradient: mobile phase A: mobile phase B = 50:50 (v / v); flow rate: 18 mL / min, wavelength: UV270 nm and 310 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: RT.

[0660] Example 45: cis-3-(3-((6-fluoro-2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0661]

[0662] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR(500MHz,DMSO-d6)δ=11.99(s,1H),8.80(s,1H),8.19(d,J=7.3,1H),7 .72(d,J=10.1,1H),6.94(d,J=7.2,1H),5.85(s,1H),5.00(s,1H),4.30(s ,2H),3.58(m,1H),3.11-3.00(m,1H),2.76(s,3H),2.48-2.40(m,1H),2.0 6-1.97(m,1H),1.97-1.83(m,1H),1.70(m,2H),1.59(m,1H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =452.3.

[0663] Example 46: cis-3-(3-((6-fluoro-2-(methyl-d3)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0664]

[0665] The title compound was synthesized in a similar manner to the procedure of Example 35. 1H NMR(500MHz,DMSO-d6)δ12.02(s,1H),8.82(s,1H),8.20(d,J=10Hz,1H),7.72 (d,J=10Hz,1H),6.95(d,J=5Hz,1H),5.85(s,1H),5.04-4.95(m,1H),4.30(s,2 H),3.62-3.53(m,1H),3.12-3.01(m,1H),2.48-2.43(m,1H),2.06-1.98(m,1H ),1.96-1.85(m,1H),1.77-1.64(m,2H),1.63-1.54(m,1H),1.07-0.95(m,6H). LC-MS(ESI):m / z[M+H] + =455.3.

[0666] Example 47: cis-3-(3-((6-fluoro-2-(2-hydroxyethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0667]

[0668] The title compound was synthesized in a similar manner to the procedure of Example 37. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.79(s,1H),8.18(s,1H),7.71(d,J=10.1Hz,1H),6.94(d ,J=7.0Hz,1H),5.85(s,1H),5.00(s,1H),4.88(t,J=5.5Hz,1H),4.42(s,2H),3.65(q,J=5.7Hz,2 H),3.58(dd,J=12.9,6.5Hz,1H),3.18(t,J=5.9Hz,2H),3.11-2.99(m,1H),2.48-2.41(m,1H),2. 07-1.97(m,1H),1.96-1.84(m,1H),1.81-1.64(m,2H),1.62-1.54(m,1H),1.03(d,J=5.9Hz,7H). LC-MS(ESI):m / z[M+H] + =482.3.

[0669] Example 48: cis-3-(3-((6-fluoro-2-(2-methoxyethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0670]

[0671] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR(500MHz,DMSO-d6)δ11.92(s,1H),8.73(s,1H),8.15-8.06(m,1H),7.65(d,J=10H z,1H),6.86(d,J=5Hz,1H),5.79(s,1H),4.98-4.88(m,1H),4.34(s,2H),3.51(d,J=5H z,3H),3.25(s,3H),3.24-3.21(m,2H),3.04-2.94(m,1H),2.41-2.37(m,1H),1.98-1. 92(m,1H),1.88-1.79(m,1H),1.66-1.58(m,2H),1.55-1.50(m,1H),1.0-0.94(m,6H). LC-MS(ESI):m / z[M+H] + =496.2.

[0672] Example 49: cis-3-(3-((6-fluoro-2-isopropyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0673]

[0674] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR(500MHz,DMSO-d6)δ11.93(s,1H),8.64(s,1H),8.06(s,1H),7.52(d,J=10Hz,1H) ,6.81(d,J=5Hz,1H),5.72(s,1H),4.90-4.85(m,1H),4.22(s,2H),3.74-3.66(m,1H), 3.48-3.41(m,1H),2.98-2.87(m,1H),2.35-2.30(m,1H),1.95-1.85(m,1H),1.83-1.7 3(m,1H),1.65-1.53(m,2H),1.50-1.42(m,1H),1.16-1.10(m,6H),0.96-0.84(m,6H). LC-MS(ESI):m / z[M+H] + =480.2.

[0675] Example 50: 3-(3-((6-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclobutyl propylcarbamate

[0676] Step 1: 3-(3,3-dimethoxycyclobutyl)-3-oxopropionitrile

[0677]

[0678] To a solution of acetonitrile (0.52 g, 12.68 mmol) in THF (20 mL) was added n-BuLi (4.78 mL, 2.4 M, 11.48 mmol) dropwise at -70 ° C. The mixture was stirred at -70 ° C for 30 min. 3,3-dimethoxycyclobutane-1-carboxylic acid methyl ester (1 g, 5.74 mmol) was added and stirred at -50 ° C to -70 ° C for 60 min. The mixture was quenched with saturated NH4Cl (aqueous) (10 mL). The resulting mixture was extracted with EtOAc (30 mL × 3), and the combined organic phases were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1: 1) to give the product (0.92 g, 87.6%). LC-MS (ESI): m / z [M + H] + =184.

[0679] Step 2: 1-(tert-Butyl)-3-(3,3-dimethoxycyclobutyl)-1H-pyrazol-5-amine

[0680]

[0681] To a mixture of 3-(3,3-dimethoxycyclobutyl)-3-oxopropionitrile (0.9 g, 4.92 mmol) and tert-butylhydrazine hydrochloride (0.61 g, 4.92 mmol) in EtOH (20 mL) was added DIEA (0.635 g, 4.92 mmol). The mixture was stirred at 75 ° C for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1: 1 to 1: 5) to give the product (0.9 g, 72%). LC-MS (ESI): m / z [M + H] + =254.2

[0682] Step 3: Benzyl (1-(tert-butyl)-3-(3,3-dimethoxycyclobutyl)-1H-pyrazol-5-yl)carbamate

[0683]

[0684] To a mixture of 1-(tert-butyl)-3-(3,3-dimethoxycyclobutyl)-1H-pyrazol-5-amine (0.9 g, 3.55 mmol) and NaHCO 3 (0.45 g, 5.33 mmol) in acetonitrile (20 mL) was added CbzCl (0.67 g, 3.92 mmol). The mixture was stirred at 25 ° C for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EA (50 mL), washed with brine (30 mL×3) and concentrated to give a crude product, which was used in the next step without purification (1.2 g, crude product). LC-MS (ESI): m / z[M+H] + =388.2

[0685] Step 4: Benzyl (1-(tert-butyl)-3-(3-oxocyclobutyl)-1H-pyrazol-5-yl)carbamate

[0686]

[0687] To a mixture of benzyl (1-(tert-butyl)-3-(3,3-dimethoxycyclobutyl)-1H-pyrazol-5-yl)carbamate (1.2 g, 4.74 mmol) in acetonitrile (10 mL) and water (10 mL) was added PTSA (0.96 g, 5.57 mmol). The mixture was stirred at 60 ° C for 12 hours. The mixture was quenched with saturated NaHCO 3 (aqueous) to pH = 7 and extracted with EA (30 mL × 3). The EA layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10: 1 to 5: 1) to give the product (0.7 g, 75%). LC-MS (ESI): m / z [M + H] + =342.2

[0688] Step 5: Benzyl cis-(1-(tert-butyl)-3-(3-hydroxycyclobutyl)-1H-pyrazol-5-yl)carbamate

[0689]

[0690] To a mixture of benzyl (1-(tert-butyl)-3-(3-oxocyclobutyl)-1H-pyrazol-5-yl)carbamate (1.0 g, 2.93 mmol) in EtOH (20 mL) was added NaBH4 (0.14 g, 3.68 mmol). The mixture was stirred at 25 ° C for 2 hours. The mixture was quenched with saturated NH4Cl (aqueous) (10 mL) and extracted with DCM (30 mL×3). The DCM layer was concentrated under reduced pressure to give a crude product, which was used in the next step without purification (0.7 g, crude product). LC-MS (ESI): m / z [M+H] + =344.2

[0691] Step 6: cis-(1-(tert-butyl)-3-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclobutyl)-1H-pyrrolidone Benzyl oxazol-5-yl)carbamate

[0692]

[0693] To a mixture of benzyl cis-(1-(tert-butyl)-3-(3-hydroxycyclobutyl)-1H-pyrazol-5-yl)carbamate (0.7 g, 2.04 mmol) and 4-nitrophenyl chloroformate (0.615 g, 3.06 mmol) in THF (10 mL) was added pyridine (0.245 g, 4.08 mmol). The mixture was stirred at 25 ° C. for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5: 1 to 2: 1) to give the product (0.8 g, 77.6%). LC-MS (ESI): m / z [M + H] + =509.2

[0694] Step 7: cis-(1-(tert-butyl)-3-(3-((propylcarbamoyl)oxy)cyclobutyl)-1H-pyrazole-5-yl)- Benzyl)carbamate

[0695]

[0696] To a mixture of benzyl cis-(1-(tert-butyl)-3-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)carbamate (0.7 g, 1.38 mmol) and propylamine (0.13 g, 2.07 mmol) in THF (15 mL) was added DIEA (0.36 g, 2.76 mmol). The mixture was stirred at 25 ° C for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10: 1) to give the product (0.5 g, 59%). LC-MS (ESI): m / z [M + H] + =429.3

[0697] Step 8: cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutyl propylcarbamate

[0698]

[0699] To a mixture of benzyl cis-(1-(tert-butyl)-3-(3-((propylcarbamoyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)carbamate (0.5 g, 1.17 mmol) in MeOH (10 mL) was added 10% Pd / C (0.1 g). The mixture was stirred at 25 ° C under a H2 balloon for 2 hours. The mixture was filtered and washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure to give the crude product (0.4 g, crude), which was used in the next step without purification. LC-MS (ESI): m / z [M+H] + =295.3

[0700] Step 9: cis-propylcarbamate 3-(3-((6-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)- (4-(2-Yl)amino)-1H-pyrazol-5-yl)cyclobutyl ester

[0701]

[0702] The title compound was synthesized by a procedure similar to that in Example 34, Step 4 to Step 5. 1 H NMR(500MHz,DMSO-d6)δ12.07(s,1H),8.76(s,1H),8.13(d,J=7.1Hz,1H),7 .67-7.61(m,2H),7.14(s,1H),5.88(s,1H),4.81(t,J=7.4Hz,1H),4.30(d,J =4.3Hz,2H),3.12-3.03(m,1H),2.91(dd,J=13.1,6.6Hz,2H),2.72-2.63(m, 2H), 2.11-2.04 (m, 2H), 1.39 (dd, J=14.4, 7.2Hz, 2H), 0.83 (t, J=7.4Hz, 3H). LC-MS(ESI):m / z[M+H] + =424.2.

[0703] Example 51: cis-3-(3-((4-fluoro-3-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0704] Step 1: 5-Bromo-3-chloro-4-fluorobenzo[d]isothiazole 1,1-dioxide

[0705]

[0706] A mixture of 5-bromo-4-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (1 g, 3.58 mmol) in POCl3 (15 mL) was stirred at 110°C for 2 days. LCMS showed the reaction was complete. The mixture was concentrated under vacuum. The residue was treated with EA (30 mL) to give the product (870 mg, 81.3%), which was used directly in the next step. LC-MS (ESI): m / z [M+H] + =298.2.

[0707] Step 2: 5-Bromo-4-fluoro-3-methylbenzo[d]isothiazole 1,1-dioxide

[0708]

[0709] To a mixture of 5-bromo-3-chloro-4-fluorobenzo[d]isothiazole 1,1-dioxide (300 mg, 1.01 mmol) in THF (10 mL) was added methylmagnesium bromide (1.01 mL, 1 N) at 0 ° C under a nitrogen atmosphere. The mixture was stirred at 0 ° C for 3 h. LCMS showed that the reaction was complete. The mixture was quenched with water (20 mL) and extracted with EA (3x30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give the product (250 mg, crude), which was used directly in the next step. LC-MS (ESI): m / z[M+H] + =278.2.

[0710] Step 3: 5-Bromo-4-fluoro-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0711]

[0712] To a solution of 5-bromo-4-fluoro-3-methylbenzo[d]isothiazole 1,1-dioxide (250 mg, 0.90 mmol) in MeOH (10 mL) was added NaBH4 (41 mg, 1.08 mmol) at 0°C. The mixture was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The mixture was quenched with ice water (50 mL) and extracted with EA (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (0%-40%) to give the product (200 mg, 79.4%). LC-MS (ESI): m / z[M+H] + =280.1.

[0713] Step 4: cis-isopropylcarbamic acid 3-(3-((4-fluoro-3-methyl-1,1-dioxido-2,3-dihydrobenzoyl)- [d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0714]

[0715] A mixture of 5-bromo-4-fluoro-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (200 mg, 0.72 mmol), cis-isopropylcarbamic acid 3-(3-amino-1H-pyrazol-5-yl)cyclopentyl ester (144.5 mg, 0.57 mmol), BrettphosPdG3 (66.1 mg, 0.073 mmol), and K2CO3 (298 mg, 2.16 mmol) in t-BuOH (10 mL) was stirred at 110° C. under a nitrogen atmosphere for 16 h. LCMS showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (Waters SunFire C18: 19 x 150 mm, 5 μm, eluting with 30%-50% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product in racemic form, which was further separated by chiral preparative HPLC to give:

[0716] Enantiomer 1 (Example 51a, 100% ee); retention time: 3.83 min. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.69 (s, 1H), 8.24 (t, J = 7.5 Hz, 1H), 7.83 (d, J = 4.4 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.84-4.71 (m, 1H),3.65-3.58(m,1H),3.13-2.97(m,1H),2.55-2.46(m,1H),2.03-1.98(m,1H),1.961.85 (m,1H),1.71-1.65(m,2H),1.58-1.48(m,1H),1.49(d,J=6.6Hz,3H),1.03(d,J=5.8Hz,6H). LC-MS(ESI):m / z[M+H] + =452.2.

[0717] Enantiomer 2 (Example 51b, 100% ee); retention time: 4.86 min. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.69 (s, 1H), 8.24 (t, J = 7.5 Hz, 1H), 7.83 (d, J = 4.4 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.84-4.71 (m ,1H),3.65-3.58(m,1H),3.13-2.97(m,1H),2.55-2.46(m,1H),2.03-1.98(m,1H),1.961.8 5(m,1H),1.71-1.65(m,2H),1.58-1.48(m,1H),1.49(d,J=6.6Hz,3H),1.03(d,J5.8Hz,6H). LC-MS(ESI):m / z[M+H] + =452.2.

[0718] Enantiomer 3 (Example 51c, 100% ee); retention time: 5.56 min. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.69(s,1H),8.24(t,J=7.5Hz,1H),7.83(d,J=4.4Hz ,1H),7.45(d,J=8.6Hz,1H),6.94(d,J=7.3Hz,1H),5.83(s,1H),5.00(s,1H),4.84-4.71(m, 1H),3.65-3.58(m,1H),3.13-2.97(m,1H),2.55-2.46(m,1H),2.03-1.98(m,1H),1.96-1.85 (m,1H),1.71-1.65(m,2H),1.58-1.48(m,1H),1.49(d,J=6.6Hz,3H),1.03(d,J=5.8Hz,6H). LC-MS(ESI):m / z[M+H] + =452.2.

[0719] Enantiomer 4 (Example 51d, 100% ee); retention time: 8.36 min. 1H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.69(s,1H),8.24(t,J=7.5Hz,1H),7.83(d,J=4.4Hz ,1H),7.45(d,J=8.6Hz,1H),6.94(d,J=7.3Hz,1H),5.83(s,1H),5.00(s,1H),4.84-4.71(m, 1H),3.65-3.58(m,1H),3.13-2.97(m,1H),2.55-2.46(m,1H),2.03-1.98(m,1H),1.96-1.85 (m,1H),1.71-1.65(m,2H),1.58-1.48(m,1H),1.49(d,J=6.6Hz,3H),1.03(d,J=5.8Hz,6H). LC-MS(ESI):m / z[M+H] + =452.2.

[0720] Chiral analysis method: column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; mobile phase: A: MtBE (0.1% 2M NH3MeOH), and B: EtOH; gradient: mobile phase A: mobile phase B = 30:70 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35 ° C.

[0721] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm × 250 mm, 5 μm; mobile phase: A: MtBE, and B: EtOH (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B = 30:70 (v / v); flow rate: 18 mL / min, wavelength: UV280 nm and 300 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: RT.

[0722] Example 52: 3-(3-((4-fluoro-3-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-(1-methylcyclopropyl)carbamate

[0723]

[0724] The title compound was synthesized in racemic form in analogy to the procedure of Example 51, which was further separated by chiral preparative HPLC to give:

[0725] Enantiomer 1 (Example 52a, 100% ee); retention time: 4.57 min. 1H NMR (500MHz, DMSO-d6) δ11.98(s,1H),8.68(s,1H),8.23(s,1H),7.82(d,J=4.7Hz,1H),7. 45(d,J=8.6Hz,1H),7.34(s,1H),5.82(s,1H),4.98(s,1H),4.86-4.69(m,1H),3.132-2.9 5(m,1H),2.43-2.38(m,1H),2.10-1.98(m,1H),1.96-1.85(m,1H),1.75-1.65(m,2H),1.5 8-1.52(m,1H),1.49(d,J=6.6Hz,3H),1.23(s,3H),0.64-0.52(m,2H),0.48-0.40(m,2H). LC-MS(ESI):m / z[M+H] + =464.2

[0726] Enantiomer 2 (Example 52b, 100% ee); retention time: 5.81 min. 1 H NMR (500MHz, DMSO-d6) δ11.98(s,1H),8.68(s,1H),8.23(s,1H),7.82(d,J=4.7Hz,1H),7. 45(d,J=8.6Hz,1H),7.34(s,1H),5.82(s,1H),4.98(s,1H),4.86-4.69(m,1H),3.132-2.9 5(m,1H),2.43-2.38(m,1H),2.10-1.98(m,1H),1.96-1.85(m,1H),1.75-1.65(m,2H),1.5 8-1.52(m,1H),1.49(d,J=6.6Hz,3H),1.23(s,3H),0.64-0.52(m,2H),0.48-0.40(m,2H). LC-MS(ESI):m / z[M+H] + =464.2

[0727] Enantiomer 3 (Example 52c, 96.1% ee); retention time: 6.65 min. 1H NMR (500MHz, DMSO-d6) δ11.98(s,1H),8.68(s,1H),8.23(s,1H),7.82(d,J=4.7Hz,1H),7. 45(d,J=8.6Hz,1H),7.34(s,1H),5.82(s,1H),4.98(s,1H),4.86-4.69(m,1H),3.132-2.9 5(m,1H),2.43-2.38(m,1H),2.10-1.98(m,1H),1.96-1.85(m,1H),1.75-1.65(m,2H),1.5 8-1.52(m,1H),1.49(d,J=6.6Hz,3H),1.23(s,3H),0.64-0.52(m,2H),0.48-0.40(m,2H). LC-MS(ESI):m / z[M+H] + =464.2

[0728] Enantiomer 4 (Example 52d, 99.8% ee); retention time: 11.98 min. 1 H NMR (500MHz, DMSO-d6) δ11.98(s,1H),8.68(s,1H),8.23(s,1H),7.82(d,J=4.7Hz,1H),7. 45(d,J=8.6Hz,1H),7.34(s,1H),5.82(s,1H),4.98(s,1H),4.86-4.69(m,1H),3.132-2.9 5(m,1H),2.43-2.38(m,1H),2.10-1.98(m,1H),1.96-1.85(m,1H),1.75-1.65(m,2H),1.5 8-1.52(m,1H),1.49(d,J=6.6Hz,3H),1.23(s,3H),0.64-0.52(m,2H),0.48-0.40(m,2H). LC-MS(ESI):m / z[M+H] + =464.2

[0729] Chiral analysis method: column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; mobile phase: A: MtBE (0.1% 2M NH3 MeOH), and B: DCM: MeOH = 50:50 (v / v); gradient: mobile phase A: mobile phase B = 60:40 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35°C.

[0730] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm × 250 mm, 5 um; mobile phase: A: MtBE, and B: DCM: MeOH = 50:50 (v / v) (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B = 60:40 (v / v); flow rate: 18 mL / min, wavelength: UV280 nm and 300 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: RT.

[0731] Example 53: cis-3-(3-((4-fluoro-3-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl propylcarbamate

[0732]

[0733] The title compound was synthesized in racemic form in analogy to the procedure of Example 51, which was further separated by chiral preparative HPLC to give:

[0734] Enantiomer 1 (Example 53a, 100% ee); retention time: 4.02 min. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.69(s,1H),8.24(t,J=8.0Hz,1H),7.83(d,J=4.5Hz,1H),7 .45(d,J=8.6Hz,1H),7.04(t,J=5.5Hz,1H),5.83(d,J=1.9Hz,1H),5.01(s,1H),4.84-4.77(m,1H), 3.13-3.02(m,1H),2.95-2.89(m,2H),2.47-2.40(m,1H),2.10-1.98(m,1H),1.96-1.86(m,1H),1.7 5-1.65(m,2H),1.63-1.56(m,1H),1.49(d,J=6.7Hz,3H),1.44-1.34(m,3H),0.82(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =452.2

[0735] Enantiomer 2 (Example 53b, 100% ee); retention time: 7.19 min. 1H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.69(s,1H),8.24(t,J=8.0Hz,1H),7.83(d,J=4.5Hz,1H),7 .45(d,J=8.6Hz,1H),7.04(t,J=5.5Hz,1H),5.83(d,J=1.9Hz,1H),5.01(s,1H),4.84-4.77(m,1H), 3.13-3.02(m,1H),2.95-2.89(m,2H),2.47-2.40(m,1H),2.10-1.98(m,1H),1.96-1.86(m,1H),1.7 5-1.65(m,2H),1.63-1.56(m,1H),1.49(d,J=6.7Hz,3H),1.44-1.34(m,3H),0.82(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =452.2.

[0736] Enantiomer 3 (Example 53c, 98.6% ee); retention time: 8.43 min. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.69(s,1H),8.24(t,J=8.0Hz,1H),7.83(d,J=4.5Hz,1H),7 .45(d,J=8.6Hz,1H),7.04(t,J=5.5Hz,1H),5.83(d,J=1.9Hz,1H),5.01(s,1H),4.84-4.77(m,1H), 3.13-3.02(m,1H),2.95-2.89(m,2H),2.47-2.40(m,1H),2.10-1.98(m,1H),1.96-1.86(m,1H),1.7 5-1.65(m,2H),1.63-1.56(m,1H),1.49(d,J=6.7Hz,3H),1.44-1.34(m,3H),0.82(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =452.2.

[0737] Enantiomer 4 (Example 53d, 100% ee); retention time: 9.11 min. 1H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.69(s,1H),8.24(t,J=8.0Hz,1H),7.83(d,J=4.5Hz,1H),7 .45(d,J=8.6Hz,1H),7.04(t,J=5.5Hz,1H),5.83(d,J=1.9Hz,1H),5.01(s,1H),4.84-4.77(m,1H), 3.13-3.02(m,1H),2.95-2.89(m,2H),2.47-2.40(m,1H),2.10-1.98(m,1H),1.96-1.86(m,1H),1.7 5-1.65(m,2H),1.63-1.56(m,1H),1.49(d,J=6.7Hz,3H),1.44-1.34(m,3H),0.82(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =452.2.

[0738] Chiral analysis method: column: CHIRALPAK IE 4.6 mm × 250 mm, 5 um; mobile phase: A: MtBE (0.1% 2M NH3MeOH), and B: DCM: MeOH = 50:50 (v / v); gradient: mobile phase A: mobile phase B = 40:60 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35 ° C.

[0739] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm × 250 mm, 5 um; mobile phase: A: MtBE, and B: DCM: MeOH = 50:50 (v / v) (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B = 40:60 (v / v); flow rate: 18 mL / min, wavelength: UV280 nm and 300 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: RT.

[0740] Example 54: 3-(3-((4-fluoro-3-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-((S)-sec-butyl)carbamate

[0741]

[0742] The title compound was synthesized in racemic form in analogy to the procedure of Example 51, which was further separated by chiral preparative HPLC to give:

[0743] Enantiomer 1 (Example 54a, 100% ee); retention time: 3.82 min. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.68(s,1H),8.23(s,1H),7.83(d,J=4.6Hz,1H),7.45(d,J=8. 6Hz,1H),6.88(d,J=8.2Hz,1H),5.83(s,1H),5.04-4.96(m,1H),4.88-4.70(m,1H),3.43-3.35(m,1H) ,3.13-3.00(m,1H),2.47-2.40(m,1H),2.06-1.98(m,1H),1.96-1.86(m,1H),1.75-1.65(m,2H),1.63 -1.56(m,1H),1.49(d,J=6.7Hz,3H),1.43-1.30(m,2H),1.01(d,J=6.5Hz,3H),0.80(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =466.2.

[0744] Enantiomer 2 (Example 54b, 99.7% ee); retention time: 4.86 min. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.68(s,1H),8.23(s,1H),7.83(d,J=4.6Hz,1H),7.45(d,J=8. 6Hz,1H),6.88(d,J=8.2Hz,1H),5.83(s,1H),5.04-4.96(m,1H),4.88-4.70(m,1H),3.43-3.35(m,1H) ,3.13-3.00(m,1H),2.47-2.40(m,1H),2.06-1.98(m,1H),1.96-1.86(m,1H),1.75-1.65(m,2H),1.63 -1.56(m,1H),1.49(d,J=6.7Hz,3H),1.43-1.30(m,2H),1.01(d,J=6.5Hz,3H),0.80(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =466.2.

[0745] Enantiomer 3 (Example 54c, 96.5% ee); retention time: 5.21 min. 1H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.68(s,1H),8.23(s,1H),7.83(d,J=4.6Hz,1H),7.45(d,J=8. 6Hz,1H),6.88(d,J=8.2Hz,1H),5.83(s,1H),5.04-4.96(m,1H),4.88-4.70(m,1H),3.43-3.35(m,1H) ,3.13-3.00(m,1H),2.47-2.40(m,1H),2.06-1.98(m,1H),1.96-1.86(m,1H),1.75-1.65(m,2H),1.63 -1.56(m,1H),1.49(d,J=6.7Hz,3H),1.43-1.30(m,2H),1.01(d,J=6.5Hz,3H),0.80(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =466.2.

[0746] Enantiomer 4 (Example 54d, 100% ee); retention time: 9.68 min. H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.68 (s, 1H), 8.23 ​​(s, 1H), 7.83 (d, J = 4.6 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.83 (s, 1H), 5.04-4.96 (m, 1H), 4.88-4.70 (m, 1H), 3.43-3.35 (m, 1H) ,3.13-3.00(m,1H),2.47-2.40(m,1H),2.06-1.98(m,1H),1.96-1.86(m,1H),1.75-1.65(m,2H),1.63 -1.56(m,1H),1.49(d,J=6.7Hz,3H),1.43-1.30(m,2H),1.01(d,J=6.5Hz,3H),0.80(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =466.2.

[0747] Chiral analysis method: column: CHIRALPAK IE 4.6 mm × 250 mm, 5 um; mobile phase: A: MtBE (0.1% 2M NH3MeOH), and B: EtOH; gradient: mobile phase A: mobile phase B = 30:70 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35 ° C.

[0748] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm × 250 mm, 5 um; mobile phase: A: MtBE, and B: EtOH (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B = 30:70 (v / v); flow rate: 18 mL / min, wavelength: UV280 nm and 300 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: RT.

[0749] Example 55: cis-3-(3-((4-fluoro-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0750] Step 1: 5-Bromo-4-fluoro-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0751]

[0752] The title compound was synthesized by a procedure similar to that of Step 1 to Step 2 of Example 8. LC-MS (ESI): m / z [M+H] + =294.0.

[0753] Step 2: cis-isopropylcarbamate 3-(3-((4-fluoro-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzene) (d)isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0754]

[0755] The title compound was synthesized by a procedure similar to that of Example 34, Step 5. 1 H NMR (500MHz, DMSO-d6) δ=11.99(s,1H),8.66(s,1H),8.19(s,1H),7.84(s,1H),7.42(d,J=8.6,1H),6.93(s,1H),5.83(s,1H),5.00 (s,1H),3.57(m,1H),3.13-3.01(m,1H),2.47(m,1H),2.03(m,1H),1.95-1.84(m,1H),1.71(m,2H),1.60(m,7H),1.07-0.96(m,6H). LC-MS(ESI):m / z[M+H] + =466.3.

[0756] Example 56: 3-(3-((4-fluoro-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-(1-methylcyclopropyl)carbamate

[0757]

[0758] The title compound was synthesized in a similar manner to the procedure of Example 55. 1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),8.66(s,1H),8.20(s,1H),7.84(s,1H ),7.42(d,J=8.6Hz,1H),7.34(s,1H),5.82(S,1H),3.13-2.99(m,1H),2.50- 2.45(m,1H),2.03-1.98(m,1H),1.96-1.85(m,1H),1.71-1.65(m,2H),1.58 -1.48(m,1H),1.60(s,6H),1.23(s,6H),0.59(s,2H),0.47(t,J=5.3Hz,2H). LC-MS(ESI):m / z[M+H] + =478.2.

[0759] Example 57: 3-(3-((4-fluoro-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-((S)-sec-butyl)carbamate

[0760]

[0761] The title compound was synthesized in a similar manner to the procedure of Example 55. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.69(s,1H),8.20(d,J=32.0Hz,1H),7.83(d,J=4.5Hz,1H),7 .45(d,J=8.6Hz,1H),6.88(d,J=7.9Hz,1H),5.83(s,1H),4.84-4.71(m,1H),3.37(dd,J=13.8,7.1H z,1H),3.12-3.01(m,1H),2.50-2.45(m,1H),2.07-1.97(m,1H),1.96-1.85(m,1H),1.71-1.65(m,2 H), 1.58-1.48 (m, 1H), 1.49 (s, 6H), 1.36 (d, J = 5.0Hz, 2H), 1.06-0.95 (m, 3H), 0.80 (q, J = 7.2Hz, 3H). LC-MS(ESI):m / z[M+H] + =480.2.

[0762] Example 58: cis-3-(3-((4-fluoro-3,3-dimethyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl propylcarbamate

[0763]

[0764] The title compound was synthesized in a similar manner to the procedure of Example 55. 1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),8.69(s,1H),8.23(s,1H),7.83(d,J=4.5Hz,1H),7.4 5(d,J=8.6Hz,1H),7.04(t,J=5.2Hz,1H),5.83(s,1H),4.83-4.77(m,1H),3.10-3.02(m,1H ),2.94-2.89(m,2H),2.50-2.45(m,1H),2.06-1.99(m,1H),1.96-1.86(m,1H),1.78-1.66( m,2H),1.65-1.57(m,1H),1.43(d,J=6.6Hz,6H),1.43-1.35(m,2H),0.82(t,J=7.4Hz,3H). LC-MS(ESI):m / z[M+H] + =466.2.

[0765] Example 59: cis-3-(3-((4-fluoro-1,1-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0766]

[0767] The title compound was synthesized in a similar manner to the procedure of Example 8. 1 H NMR (500MHz, DMSO-d6) δ12.05(s,1H),8.92(s,1H),8.47(s,1H),7.62(d,J=8.6Hz,1H),6.95(d,J=7.8Hz,1H),5.86(s,1H),5.00(s,1H),3.62-3.5 5(m,1H),3.13-3.04(m,1H),2.46-2.44(m,1H),2.08-1.98(m,1H),1.98- 1.88(m,1H),1.78-1.66(m,2H),1.65-1.55(m,1H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] +=452.3.

[0768] Example 60: cis-3-(3-((2-ethyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0769]

[0770] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR(500MHz,DMSO-d6)δ12.00(s,1H),8.77(s,1H),8.29(s,1H),7.52(d,J=8.6Hz,1H), 6.94(d,J=7.2Hz,1H),5.84(s,1H),5.00(s,1H),4.46(s,2H),3.69-3.50(m,1H),3.20(q ,J=7.2Hz,2H),3.12-3.00(m,1H),2.50-2.46(m,1H),2.06-1.99(m,1H),1.96-1.86(m, 1H), 1.78-1.66 (m, 2H), 1.65-1.57 (m, 1H), 1.26 (t, J = 7.2Hz, 3H), 1.03 (d, J = 6.2Hz, 6H). LC-MS(ESI):m / z[M+H] + =466.2.

[0771] Example 61: cis-3-(3-((4-fluoro-2-(1-methylpiperidin-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0772] Step 1: 1-Methylpiperidin-3-yl methanesulfonate

[0773]

[0774] To a solution of 1-methylpiperidin-3-ol (0.35 g, 3.04 mmol) and TEA (0.47 g, 4.56 mmol) in DCM (10 mL) was added MsCl (0.38 g, 3.34 mmol) at 0 ° C. The mixture was then stirred at 25 ° C for 1 hr. The mixture was diluted with DCM (20 mL) and washed with brine (30 mL x 3). The DCM layer was concentrated under reduced pressure to give the product, which was used in the next step without purification (0.45 g, 77.5%). LC-MS (ESI): m / z [M + H] + =194.

[0775] Step 2: 5-Bromo-4-fluoro-2-(1-methylpiperidin-3-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0776]

[0777] A mixture of 1-methylpiperidin-3-yl methanesulfonate (0.3 g, 1.55 mmol), Cs2CO3 (0.375 g, 1.14 mmol) and 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.15 g, 0.56 mmol) in DMF (5 mL) was stirred at 80 ° C for 3 hr. The mixture was quenched with water (20 mL). The mixture was extracted with DCM (20 mL x 3). The DCM layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10: 1 to 5: 1) to give the product (0.15 g, 75%). LC-MS (ESI): m / z[M+Na] + =385.3.

[0778] Step 3: cis-isopropylcarbamic acid 3-(3-((4-fluoro-2-(1-methylpiperidin-3-yl)-1,1-dioxido- 2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0779]

[0780] The title compound was synthesized by a procedure similar to that in Example 34, Step 3 to Step 4. 1 H NMR(500MHz,DMSO-d6))δ12.00(s,1H),8.77(s,1H),8.29(s,1H),7.54(d,J=8.6Hz,1H),6 .94(d,J=7.0Hz,1H),5.83(s,1H),5.00(s,1H),4.57(dd,J=61.0,14.3Hz,2H),3.63-3.52( m,1H),3.27(d,J=3.8Hz,1H),3.12-2.94(m,3H),2.48-2.43(m,1H),2.35(s,3H),2.22-2. 11(m,1H),2.05-1.98(m,1H),1.95-1.85(m,2H),1.76-1.56(m,7H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =535.3.

[0781] Example 62: cis-3-(3-((4-fluoro-2-(1-methylpiperidin-4-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0782] Step 1: 5-Bromo-4-fluoro-2-(1-methylpiperidin-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0783]

[0784] A mixture of 4-bromo-1-methylpiperidine (1 g, 5.62 mmol), Cs2CO3 (1.1 g, 3.36 mmol) and 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.3 g, 1.12 mmol) in DMF (10 mL) was stirred at 50 ° C for 12 hr. The mixture was quenched with water (30 mL). The mixture was extracted with DCM (20 mL×3). The DCM layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10: 1 to 5: 1) to give the product (0.07 g, 17.1%). LC-MS (ESI): m / z[M+Na] + =385.3.

[0785] Step 2: cis-isopropylcarbamic acid 3-(3-((4-fluoro-2-(1-methylpiperidin-4-yl)-1,1-dioxido- 2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0786]

[0787] The title compound was synthesized by a procedure similar to that in Example 34, Step 3 to Step 4. 1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),8.77(s,1H),8.27(s,1H),7.51(d,J=8.6Hz,1H ),6.94(d,J=7.5Hz,1H),5.83(s,1H),5.00(s,1H),4.50(s,2H),3.62-3.54(m,1H),3. 45-3.38(m,1H),3.10-3.01(m,1H),2.86(d,J=11.5Hz,2H),2.48-2.43(m,1H),2.22(s ,3H),2.15-1.99(m,3H),1.97-1.83(m,5H),1.78-1.55(m,3H),1.03(d,J=6.1Hz,6H). LC-MS(ESI):m / z[M+H] + =535.3.

[0788] Example 63: cis-3-(3-((2-(1-benzylpiperidin-4-yl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0789] Step 1: tert-Butyl 4-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidine-1-carboxylate ester

[0790]

[0791] A mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 5.01 mmol), CMBP (2.7 g, 11.2 mmol) and 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (1 g, 3.76 mmol) in toluene (20 mL) was stirred at 95 ° C under N2 for 12 hr. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (9: 1 to 3: 1) to give the product (0.7 g, 41.7%). LC-MS (ESI): m / z [M+H] + =449.

[0792] Step 2: 5-Bromo-4-fluoro-2-(piperidin-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0793]

[0794] To a solution of tert-butyl 4-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidine-1-carboxylate (0.55 g, 1.22 mmol) in DCM (10 mL) was added TFA (5 mL) at 25 ° C. The mixture was then stirred at 25 ° C for 0.5 hr. The mixture was quenched with saturated aqueous NaHCO3 (20 mL). The mixture was extracted with DCM (30 mL×3). The DCM layer was concentrated under reduced pressure to give the product, which was used in the next step without purification (0.42 g, 98.4%). LC-MS (ESI): m / z[M+H] + =349.

[0795] Step 3: 2-(1-Benzylpiperidin-4-yl)-5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0796]

[0797] To a mixture of 5-bromo-4-fluoro-2-(piperidin-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.18 g, 0.52 mmol) and benzaldehyde (0.11 g, 1.04 mmol) in DCM (10 mL) was added sodium triacetoxyborohydride (0.22 g, 1.04 mmol) and 1 drop of HOAc. The mixture was stirred at 25 ° C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10: 1 to 5: 1) to give the product (0.1 g, 44.2%). LC-MS (ESI): m / z [M + H] + =439.

[0798] Step 4: cis-isopropylcarbamic acid 3-(3-((2-(1-benzylpiperidin-4-yl)-4-fluoro-1,1-dioxide- 2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0799]

[0800] The title compound was synthesized in a similar manner to the procedure of Example 34. 1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),8.76(s,1H),8.29(s,1H),7.50(d,J=8.6Hz,1H),7.37 -7.29(m,4H),7.25(t,J=6.3Hz,1H),6.94(d,J=6.8Hz,1H),5.83(s,1H),5.00(s,1H),4.51(s ,2H),3.62-3.53(m,1H),3.50-3.41(m,3H),3.11-3.02(m,1H),2.86(d,J=11.5Hz,2H),2.48- 2.43(m,1H),2.13-1.98(m,3H),1.98-1.83(m,5H),1.78-1.55(m,3H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =611.3.

[0801] Example 64: cis-3-(3-((4-fluoro-2-(2-methoxyethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0802]

[0803] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR(500MHz,DMSO-d6)δ12.00(s,1H),8.79(s,1H),8.15-8.06(m,1H),7.54(d,J=5Hz,1H) ,6.94(d,J=5Hz,1H),5.84(s,1H),5.04-4.97(m,1H),4.53(s,2H),3.62(t,J=5Hz,2H),3.6 0-3.54(m,1H),3.34-3.33(m,1H),3.33-3.31(m,3H),3.30(s,2H),2.48-2.44(m,1H),2.08 -1.99(m,1H),1.97-1.86(m,1H),1.79-1.66(m,2H),1.64-1.55(m,1H),1.09-0.98(m,6H). LC-MS(ESI):m / z[M+H] +=496.2.

[0804] Example 65: cis-3-(3-((4-fluoro-2-isopropyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0805]

[0806] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),8.76(s,1H),8.36-8.24(m,1H),7.52-7.47(m,1 H),6.97-6.91(m,1H),5.83(s,1H),5.05-4.96(m,1H),4.47(s,2H),3.90-3.81(m,1H) ,3.63-3.53(m,1H),3.12-3.01(m,1H),2.45-2.40(m,1H),2.07-1.98(m,1H),1.96-1. 86(m,1H),1.78-1.65(m,2H),1.64-1.55(m,1H),1.34-1.26(m,6H),1.08-0.99(m,6H). LC-MS(ESI):m / z[M+H] + =480.2.

[0807] Example 66: cis-3-(3-((4-fluoro-1,1-dioxido-2-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0808]

[0809] The title compound was synthesized in a similar manner to the procedure of Example 35. 1H NMR(500MHz,DMSO-d6)δ12.03(s,1H),8.87(s,1H),8.38-8.26(m,1H),7.62(d,J= 5Hz,1H),6.94(d,J=5Hz,1H),5.85(s,1H),5.06-4.96(m,1H),4.73(s,2H),4.23-4 .09(m,2H),3.66-3.52(m,1H),3.14-3.00(m,1H),2.48-2.44(m,1H),2.09-1.99(m ,1H),1.97-1.86(m,1H),1.80-1.65(m,2H),1.64-1.55(m,1H),1.11-0.95(m,6H). LC-MS(ESI):m / z[M+H] + =520.2.

[0810] Example 67: cis-3-(3-((2-cyclobutyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0811]

[0812] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR(500MHz,DMSO-d6)δ11.93(s,1H),8.71(s,1H),8.22-8.19(m,1H),7.43(d,J=10Hz,1H) ,6.87(d,J=5Hz,1H),5.76(s,1H),4.97-4.89(m,1H),4.43(s,2H),4.0-3.92(m,1H),3.55-3 .47(m,1H),3.06-2.95(m,1H),2.41-2.36(m,1H),2.34-2.24(m,2H),2.14-2.05(m,2H),2.0 0-1.91(m,1H),1.89-1.79(m,1H),1.76-1.60(m,4H),1.57-1.48(m,1H),1.02-0.89(m,6H). LC-MS(ESI):m / z[M+H] + =492.2.

[0813] Example 68: cis-3-(3-((2-cyclopentyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0814]

[0815] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR(500MHz,DMSO-d6)δ11.92(s,1H),8.70(s,1H),8.22(s,1H),7.43(d,J=8.6Hz,1H) ,6.87(d,J=7.3Hz,1H),5.76(s,1H),4.93(s,1H),4.40(s,2H),3.68(p,J=7.4Hz,1H), 3.58-3.48(m,1H),3.03-2.94(m,1H),2.40-2.33(m,1H),1.99-1.93(m,1H),1.92-1.8 1(m,3H),1.80-1.75(m,2H),1.70-1.64(m,4H),1.58-1.47(m,3H),1.01-0.91(m,6H). LC-MS(ESI):m / z[M+H] + =506.2.

[0816] Example 69: cis-3-(3-((4-fluoro-1,1-dioxido-2-(tetrahydrofuran-3-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0817] Step 1: 5-Bromo-4-fluoro-2-(tetrahydrofuran-3-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0818]

[0819] To a solution of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.5 g, 1.88 mmol) in DMF (10 mL) was added NaH (150 mg, 3.76 mmol) in portions at 0 ° C. After stirring for 0.5 h, 3-iodotetrahydrofuran (560 mg, 2.82 mmol) was added. The resulting mixture was stirred at 80 ° C for 16 h. The mixture was quenched by adding saturated NH4Cl (aqueous) (10 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (2:1) to give the product (100 mg, 16%), LC-MS (ESI): m / z [M+H] + =336.2.

[0820] Step 2: cis-isopropylcarbamic acid 3-(3-((4-fluoro-1,1-dioxido-2-(tetrahydrofuran-3-yl)-2, 3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0821]

[0822] The title compound was synthesized by a procedure similar to that of Example 34, Step 5. 1 H NMR (500MHz, DMSO-d6) δ12.00(s,1H),8.80(s,1H),8.30(s,1H),7.54(d,J=8.6Hz,1H),6.95(d,J=7.3Hz,1H) ,5.84(s,1H),5.07-4.94(m,1H),4.53(q,J=14.1Hz,2H),4.25-4.15(m,1H),3.97-3.90(m,2H),3.80(dd,J=9 .6,6.3Hz,1H),3.68(dd,J=15.3,8.1Hz,1H),3.62-3.54(m,1H),3.11-3.02(m,1H),2.48-2.43(m,1H),2.29- 2.14(m,2H),2.08-1.97(m,1H),1.95-1.86(m,1H),1.78-1.66(m,2H),1.64-1.55(m,1H),1.09-0.97(m,6H). LC-MS(ESI):m / z[M+H] + =508.4.

[0823] Example 70: cis-3-(3-((4-fluoro-2-(1-methylpyrrolidin-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0824]

[0825] The title compound was synthesized in a similar manner to the procedure of Example 63. 1H NMR (500MHz, DMSO-d6)) δ11.99(s,1H),8.79(s,1H),8.29(s,1H),7.52(d,J=8.6Hz,1H),6.94(d ,J=6.9Hz,1H),5.83(s,1H),5.00(s,1H),4.61-4.48(m,2H),4.17(s,1H),3.63-3.54(m,1H),3.1 2-3.03(m,1H),2.88-2.73(m,2H),2.64(s,1H),2.48-2.43(m,1H),2.36(s,1H),2.31(s,3H),2. 20-2.13(m,1H),2.08-1.98(m,2H),1.95-1.86(m,1H),1.78-1.55(m,3H),1.03(d,J=5.9Hz,6H). LC-MS(ESI):m / z[M+H] + =521.3.

[0826] Example 71: cis-3-(3-((2-(2,3-dihydroxypropyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0827] Step 1: cis-isopropylcarbamic acid 3-(3-((2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl) 4-Fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0828]

[0829] To a solution of cis-3-(3-((4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (50 mg, 0.11 mmol) in toluene (10 mL) was added (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (29 mg, 0.22 mmol) and CMBP (106 mg, 0.44 mmol). The mixture was stirred at 100 °C for 12 h. The solvent was removed under vacuum and the residue was purified by silica gel column chromatography eluting with EtOAc (100%) to give the product (70 mg, 95%). LC-MS (ESI): m / z [M+H] + =552.4.

[0830] Step 2: cis-isopropylcarbamic acid 3-(3-((2-(2,3-dihydroxypropyl)-4-fluoro-1,1-dioxide-2, 3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0831]

[0832] To a flask containing cis-isopropylcarbamic acid 3-(3-((2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester (70 mg, 0.11 mmol) was added TFA (1 mL) and DCM (3 mL). The resulting solution was stirred at room temperature for 2 h. The solvent was removed under vacuum, and the residue was purified by preparative HPLC (Waters XSelect C18:RD-CO-094 column, eluting with a gradient of acetonitrile / water (containing 0.1% FA, 20%-40%) to give the product (28 mg, 50%). 1 H NMR (500MHz, DMSO-d6)) δ = 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.54 (d, J = 8.6, 1H), 6.94 (d, J=7.3,1H),5.83(s,1H),5.00(s,1H),4.61(d,J=14.4,1H),4.51(d,J=14.4,1H),4.42(brs,2H), 3.75(s,1H),3.58(s,1H),3.42(s,1H),3.35-3.30(m,2H),3.12-3.04(m,1H),3.00(s,1H),2.47- 2.42(m,1H),2.12-1.97(m,1H),1.97-1.85(m,1H),1.72-1.65(m,2H),1.59(m,1H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =512.4.

[0833] Example 72: cis-3-(1-(2,3-dihydroxypropyl)-3-((2-(2,3-dihydroxypropyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0834]

[0835] The title compound was synthesized in a similar manner to the procedure of Example 71. 1H NMR (500MHz, DMSO-d6) δ=8.67(d,J=127.6,1H),8.27(t,J=8.0,0.5H),7.54(dd,J=14.5,8.6,1H),7.10(t,J=6.7 ,0.5H),6.98-6.87(m,1H),5.94(d,J=94.5,1H),5.22(brs,4H),4.99(s,1H),4.62(dd,J=14.5,8.2,1H),4.52(d d,J=14.5,9.3,1H),4.05(m,1H),3.94-3.73(m,3H),3.62-3.53(m,1H),3.45-3.28(m,5H),3.09(m,2H),2.54(m, 0.5H),2.44-2.35(m,0.5H),2.00(m,1H),1.94-1.82(m,1H),1.74(m,2H),1.66-1.45(m,1H),1.08-0.97(m,6H). LC-MS(ESI):m / z[M+H] + =586.5.

[0836] Example 73: cis-3-(3-((2-(3-(dimethylamino)propyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0837]

[0838] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR (500MHz, DMSO-d6) δ11.97(s,1H),8.78(s,1H),8.28(t,J=7.6Hz,1H),7.53(d,J=8.6Hz ,1H),6.94(d,J=7.3Hz,1H),5.83(s,1H),5.00(s,1H),4.48(s,2H),3.67-3.51(m,2H),3.19 (t,J=7.0Hz,2H),3.11-3.01(m,1H),2.50-2.46(m,2H),2.28(s,6H),2.08-2.00(m,1H),1.9 6-1.88(m,1H),1.86-1.80(m,2H),1.76-1.66(m,2H),1.64-1.59(m,1H),1.11-0.96(m,6H). LC-MS(ESI):m / z[M+H] + =523.2.

[0839] Example 74: cis-3-(3-((2-(2-(dimethylamino)ethyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0840]

[0841] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR(500MHz,DMSO-d6)δ12.01(s,1H),8.84(s,1H),8.32(s,1H),7.59(d,J=8.7Hz,1H) ,6.93(d,J=7.4Hz,1H),5.84(s,1H),5.00(s,1H),4.56(s,2H),3.64-3.54(m,1H),3.4 6(s,2H),3.23(s,1H),3.11-3.01(m,2H),2.68(s,6H),2.48-2.40(m,1H),2.06-1.98( m,1H),1.96-1.85(m,1H),1.79-1.66(m,2H),1.63-1.53(m,1H),1.03(d,J=6.1Hz,6H). LC-MS(ESI):m / z[M+H] + =509.2.

[0842] Example 75: cis-3-(3-((2-benzyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0843]

[0844] The title compound was synthesized in a similar manner to the procedure of Example 35. 1H NMR (500MHz, DMSO-d6) δ12.00(s,1H),8.78(s,1H),8.32(t,J=8.0Hz,1H),7.59(d,J=8.7H z,1H),7.47-7.38(m,4H),7.36-7.32(m,1H),6.94(d,J7.3Hz,1H),5.82(s,1H),5.00(s,1 H),4.35(d,J=15.5Hz,4H),3.62-3.52(m,1H),3.15-2.94(m,1H),2.48-2.40(m,1H),2.06 -1.99(m,1H),1.96-1.85(m,1H),1.79-1.66(m,2H),1.63-1.53(m,1H),1.08-0.97(m,6H). LC-MS(ESI):m / z[M+H] + =528.2.

[0845] Example 76: cis-3-(3-((4-fluoro-2-(2-hydroxy-2-methylpropyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0846]

[0847] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),8.77(s,1H),8.36-8.24(m,1H),7.58-7.50( m,1H),6.98-6.89(m,1H),5.83(s,1H),5.04-4.94(m,1H),4.67-4.55(m,3H),3.63- 3.51(m,1H),3.11.2.99(m,3H),2.43-2.40(m,1H),2.08-1.96(m,1H),1.95-1.84( m,1H),1.78-1.66(m,2H),1.64-1.53(m,1H),1.23-1.12(m,6H),1.08-1.94(m,6H). LC-MS(ESI):m / z[M+H] + =510.2.

[0848] Example 77: cis-3-(3-((4-fluoro-2-(1-(methylsulfonyl)piperidin-4-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0849] Step 1: 5-Bromo-4-fluoro-2-(1-(methylsulfonyl)piperidin-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1- dioxide

[0850]

[0851] To a solution of tert-butyl 4-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidine-1-carboxylate (0.18 g, 0.52 mmol) and DIEA (0.33 g, 2.56 mmol) in DCM (10 mL) was added MsCl (0.07 g, 0.61 mmol) at 0°C. The mixture was then stirred at 259°C for 1 hr. The mixture was diluted with DCM (20 mL) and washed with brine (30 mL x 3). The DCM layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1 to 4:1) to give the product (0.1 g, 45.4%). LC-MS (ESI): m / z [M+H] + =427.3.

[0852] Step 2: cis-isopropylcarbamic acid 3-(3-((4-fluoro-2-(1-(methylsulfonyl)piperidin-4-yl)-1,1- 2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl dioxide

[0853]

[0854] The title compound was synthesized by a procedure similar to that of Example 34, Step 5. 1 H NMR(500MHz,DMSO-d6)o11.99(s,1H),8.78(s,1H),8.30(t,J=7.8Hz,1H),7. 52(d,J=8.7Hz,1H),6.93(d,J=6.4Hz,1H),5.83(s,1H),5.00(s,1H),4.54(s, 2H),3.68-3.55(m,4H),3.12-3.03(m,1H),2.98-2.93(m,2H),2.89(s,3H),2. 46-2.43(m,1H),2.07-1.88(m,6H),1.75-1.55(m,3H),1.03(d,J=6.0Hz,6H). LC-MS(ESI):m / z[M+H] + =599.3.

[0855] Example 78: cis-3-(3-((2-(1-acetylpiperidin-4-yl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0856] Step 1: 1-(4-(5-Bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidin-1-yl)ethyl- 1-Keto

[0857]

[0858] To a solution of tert-butyl 4-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidine-1-carboxylate (0.18 g, 0.52 mmol) and DIEA (0.33 g, 2.56 mmol) in DCM (10 mL) was added AcCl (0.049 g, 0.62 mmol) at 0 ° C. The mixture was then stirred at 25 ° C for 1 hr. The mixture was diluted with DCM (20 mL) and washed with brine (30 mL×3). The DCM layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5: 1 to 3: 1) to give the product (0.1 g, 49.7%). LC-MS (ESI): m / z[M+H] + =391.5.

[0859] Step 2: cis-isopropylcarbamic acid 3-(3-((2-(1-acetylpiperidin-4-yl)-4-fluoro-1,1-dioxy (2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0860]

[0861] The title compound was synthesized by a procedure similar to that of Example 34, Step 5. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.76(s,1H),8.29(s,1H),7.51(d,J=8.6Hz,1H),6.93(d,J=6. 9Hz,1H),5.83(s,1H),5.00(s,1H),4.51(s,2H),4.35(d,J=13.5Hz,1H),3.86(d,J13.5Hz,1H),3.74( t,J=10.9Hz,1H),3.62-3.54(m,1H),3.20(t,J=11.6Hz,1H),3.10-3.02(m,1H),2.75(t,J=11.6Hz,1H ),2.48-2.43(m,1H),2.05-1.98(m,4H),1.96-1.80(m,4H),1.77-1.55(m,4H),1.03(d,J=6.0Hz,6H). LC-MS(ESI):m / z[M+H] + =563.3.

[0862] Example 79: cis-3-(3-((4-fluoro-1,1-dioxido-2-(2-oxopyrrolidin-3-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0863]

[0864] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ12.00(s,1H),8.80(s,1H),8.31(s,1H),8.13(d,J=7.8Hz,1H),7. 55(d,J=8.7Hz,1H),6.94(d,J=7.2Hz,1H),5.84(s,1H),5.00(s,1H),4.71(s,1H),4.37(d d,J=23.3,11.9Hz,2H),3.62-3.55(m,1H),3.28-3.21(m,2H),3.09-3.02(m,1H),2.48-2. 43(m,1H),2.38-2.25(m,2H),2.08-1.85(m,2H),1.78-1.55(m,3H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =521.2

[0865] Example 80: cis-3-(3-((2-(1-acetylpyrrolidin-3-yl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0866]

[0867] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ12.01(s,1H),8.81(s,1H),8.31(s,1H),7.59-7.51(m,1H),6.94(d,J=6.8 Hz,1H),5.84(s,1H),5.00(s,1H),4.60-4.53(m,2H),4.20-3.98(m,1H),3.78-3.46(m,4H),3.29- 3.25(m,1H),3.10-3.02(m,1H),2.46-2.44(m,1H),2.33-2.27(m,1H),2.20(q,J=6.9Hz,1H),2.05 -2.00(m,1H),1.96(d,J=4.9Hz,3H),1.93-1.86(m,1H),1.76-1.55(m,3H),1.03(d,J=6.0Hz,6H). LC-MS(ESI):m / z[M+H]+ =549.3.

[0868] Example 81: cis-3-(3-((4-fluoro-1,1-dioxido-2-(2-oxopiperidin-4-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0869] Step 1: 4-(5-Bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidin-2-one

[0870]

[0871] A mixture of 5,6-dihydropyridin-2(1H)-one (0.33 g, 3.4 mmol), Cs2CO3 (0.37 g, 1.14 mmol) and 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.3 g, 1.12 mmol) in THF / water (10 / 10 mL) was stirred at 55 ° C for 48 hr. The mixture was quenched with water (20 mL). The mixture was extracted with EA (20 mL×3). The EA layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1 to 3:1) and then with DCM / MeOH (10:1) to give the product (0.077 g, 18.8%). LC-MS (ESI): m / z[M+H] + =363.2.

[0872] Step 2: cis-isopropylcarbamic acid 3-(3-((4-fluoro-1,1-dioxido-2-(2-oxopiperidin-4-yl)- 2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0873]

[0874] The title compound was synthesized in a similar manner to the procedure of Example 63. 1H NMR (500MHz, DMSO-d6)811.99(s,1H),8.78(s,1H),8.30(t,J=8.0Hz,1H),7.61(s,1H),7.53(d,J= 8.6Hz,1H),6.93(d,J=6.6Hz,1H),5.83(s,1H),5.00(s,1H),4.59(d,J=14.2Hz,1H),4.50(d,J=14 .0Hz,1H),3.98-3.89(m,1H),3.62-3.54(m,1H),3.26-3.19(m,2H),3.09-3.03(m,1H),2.61(dd,J =17.0,9.9Hz,2H),2.48-2.44(m,1H),2.14-1.89(m,4H),1.75-1.55(m,3H),1.03(d,J=6.0Hz,6H). LC-MS(ESI):m / z[M+H] + =535.3.

[0875] Example 82: cis-3-(3-((4-fluoro-1,1-dioxido-2-(6-oxopiperidin-3-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0876]

[0877] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR(500MHz,DMSO-d6)δ11.99(s,1H),8.79(s,1H),8.31(t,J7.9Hz,1H),7.55-7.47(m,2H ),6.93(d,J=6.7Hz,1H),5.83(s,1H),5.00(s,1H),4.56(d,J=27.0Hz,2H),3.85-3.78(m, 1H),3.62-3.53(m,1H),3.50-3.37(m,2H),3.12-3.03(m,1H),2.47-2.43(m,1H),2.36-2. 31(m,2H),2.19-1.99(m,3H),1.95-1.85(m,1H),1.76-1.55(m,3H),1.03(d,J=5.9Hz,6H). LC-MS(ESI):m / z[M+H] + =535.3.

[0878] Example 83: cis-3-(3-((4-fluoro-2-(1-methyl-6-oxopiperidin-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0879] Step 1: 5-(5-Bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidin-2-one

[0880]

[0881] To a stirred solution of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (250 mg, 1 mmol) in toluene (20 mL) was added 5-hydroxypiperidin-2-one (265 mg, 2 mmol) and CMBP (964 mg, 4 mmol). The solution was stirred at 90 ° C under a N2 atmosphere for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1) to give the product (203 mg, 56%), [M+H] + =363.4.

[0882] Step 2: 5-(5-Bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-1-methylpiperidin-2-one

[0883]

[0884] To a solution of 5-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidin-2-one (0.343 g, 0.95 mmol) in THF (10 mL) was added NaH (0.04 g, 1.0 mmol) at 0°C. The mixture was stirred for 0.5 hr. CHI (0.2 g, 1.43 mmol) was added, and the mixture was stirred at 0°C for 1 hr. The mixture was quenched with saturated NHCl (aqueous) (10 mL). The mixture was extracted with EA (20 mL×3). The EA layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1) to give the product (0.19 g, 53.4%). LC-MS (ESI): m / z[M+H] + =377.4.

[0885] Step 3: cis-isopropylcarbamic acid 3-(3-((4-fluoro-2-(1-methyl-6-oxopiperidin-3-yl)-1,1- 2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl dioxide

[0886]

[0887] The title compound was synthesized by a procedure similar to that of Example 34, Step 5. 1H NMR(500MHz,DMSO-d6)δ12.00(s,1H),8.81(s,1H),8.31(s,1H),7.54(d,J=8.7 Hz,1H),6.94(d,J=7.2Hz,1H),5.84(s,1H),5.00(s,1H),4.57(dd,J=40.3,14.0 Hz,2H),3.97-3.89(m,1H),3.66-3.51(m,3H),3.12-3.02(m,1H),2.83(s,3H), 2.46-2.35(m,3H),2.85-1.85(m,4H),1.78-1.55(m,3H),1.03(d,J=6.0Hz,6H). LC-MS(ESI):m / z[M+H] + =549.3.

[0888] Example 84: 3-(3-((4-fluoro-2-(3-hydroxycyclobutyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0889]

[0890] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.78(s,1H),8.29(t,J=8.0Hz,1H),7.50(d,J=8.6Hz,1H),6.94(d,J=7. 3Hz,1H),5.83(d,J=1.7Hz,1H),5.18(dd,J=17.4,6.1Hz,1H),4.99(s,1H),4.46(s,2H),4.32(dd,J=11.7,6.5H z,1H),4.11-3.97(m,1H),3.68-3.52(m,1H),3.16-2.97(m,1H),2.70-2.57(m,2H),2.50-2.44(m,1H),2.15-2 .10(m,2H),2.06-1.94(m,1H),1.95-1.85(m,1H),1.77-1.65(m,2H),1.65-1.55(m,1H),1.03(d,J=6.2Hz,6H). LC-MS(ESI):m / z[M+H] + =508.2.

[0891] Example 85: cis-3-(3-((4-fluoro-2-(1-(methylsulfonyl)pyrrolidin-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0892]

[0893] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR (500MHz, DMSO-d6) δ12.01(s,1H),8.83(s,1H),8.32(t,J=7.7Hz,1H),7.56(d,J=8.6Hz, 1H),6.94(d,J=7.5Hz,1H),5.84(s,1H),4.99(s,1H),4.59(s,2H),4.18-4.11(m,1H),3.62-3 .54(m,2H),3.52-3.42(m,2H),3.35-3.31(m,1H),3.10-3.03(m,1H),2.96(s,3H),2.47-2.4 2(m,1H),2.28(q,J=7.2Hz,2H),2.06-1.88(m,2H),1.77-1.55(m,3H),1.03(d,J=5.9Hz,6H). LC-MS(ESI):m / z[M+H] + =585.2.

[0894] Example 86: cis-3-(3-((4-fluoro-1,1-dioxido-2-(2-oxopiperidin-3-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0895]

[0896] The title compound was synthesized in a similar manner to the procedure of Example 63. 1H NMR(500MHz,DMSO-d6)δ11.99(s,1H),8.75(s,1H),8.30(s,1H),7.74(s,1H),7.52(d,J =8.7Hz,1H),6.95(d,J7.5Hz,1H),5.83(s,1H),5.00(s,1H),4.69(d,J=14.1Hz,1H),4.4 2(d,J=14.0Hz,1H),4.27-4.19(m,1H),3.65-3.55(m,1H),3.19-3.03(m,3H),2.48-2.44 (m,1H),2.14-2.00(m,3H),1.96-1.81(m,3H),1.78-1.55(m,3H),1.03(d,J=5.8Hz,6H). LC-MS(ESI):m / z[M+H] + =535.3.

[0897] Example 87: cis-3-(3-((2-(1-benzylpyrrolidin-3-yl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0898]

[0899] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ12.00(s,1H),8.79(s,1H),8.29(s,1H),7.50(d,J=8.6Hz,1H),7.33(d,J=4 .3Hz,4H),7.28-7.22(m,1H),6.94(d,J=6.6Hz,1H),5.84(s,1H),4.99(s,1H),4.55(dd,J=29.9,14 .2Hz,2H),4.14(s,1H),3.65-3.55(m,3H),3.11-3.04(m,1H),2.78-2.62(m,4H),2.41-2.35(m,1H) ,2.22-2.12(m,1H),2.09-1.99(m,2H),1.95-1.86(m,1H),1.77-1.55(m,3H),1.03(d,J=6.0Hz,6H). LC-MS(ESI):m / z[M+H] + =597.3.

[0900] Example 88: cis-3-(3-((4-fluoro-2-(1-methyl-2-oxopiperidin-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0901]

[0902] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR(500MHz,DMSO-d6)811.99(s,1H),8.75(s,1H),8.30(s,1H),7.51(d,J=8.6Hz,1H),6.95(d, J=7.4Hz,1H),5.83(s,1H),4.99(s,1H),4.66(d,J=14.1Hz,1H),4.39(d,J=14.1Hz,1H),4.29(d d,J=11.6,5.9Hz,1H),3.61-3.53(m,1H),3.29-3.24(m,2H),3.10-3.02(m,1H),2.83(s,3H),2. 39-2.33(m,1H),2.20-2.00(m,3H),1.98-1.85(m,3H),1.78-1.55(m,3H),1.03(d,J=6.1Hz,6H). LC-MS(ESI):m / z[M+H] + =549.3.

[0903] Example 89: cis-3-(3-((4-fluoro-2-(1-(methylsulfonyl)azetidin-3-yl)1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0904]

[0905] The title compound was synthesized in a similar manner to the procedure of Example 63. 1H NMR (500MHz, DMSO-d6) δ=12.02(s,1H),8.86(s,1H),8.32(s,1H),7.57(d,J= 8.7,1H),6.94(d,J=7.5,1H),5.84(s,1H),5.00(s,1H),4.76(s,2H),4.51(m, 1H),4.27(m,2H),4.14(m,2H),3.58(m,1H),3.11(s,3H),3.07(m,1H),2.47(m ,1H),2.03(m,1H),1.91(m,1H),1.72(m,2H),1.60(m,1H),1.10-0.94(m,6H). LC-MS(ESI):m / z[M+H] + =571.3.

[0906] Example 90: cis-3-(3-((2-(1-acetylazetidin-3-yl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0907]

[0908] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR(500MHz,DMSO-d6)δ=12.01(s,1H),8.85(s,1H),8.32(s,1H),7.56(d,J=8.7,1 H),6.94(d,J=7.1,1H),5.84(s,1H),5.00(s,1H),4.70(m,2H),4.43(m,2H),4.38(m ,1H),4.19-4.07(m,2H),3.58(m,1H),3.13-2.98(m,1H),2.48-2.42(m,1H),2.02(m ,1H),1.95-1.85(m,1H),1.79(s,3H),1.72(m,2H),1.60(m,1H),1.09-0.96(m,6H). LC-MS(ESI):m / z[M+H] + =535.3.

[0909] Example 91: cis-3-(3-((4-fluoro-2-(1-methylazetidin-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0910]

[0911] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR(500MHz,DMSO-d6)δ-12.00(s,1H),8.81(s,1H),8.29(s,1H),7.53(d,J=8.6,1 H),6.94(d,J7.1,1H),5.84(s,1H),4.99(s,1H),4.61(s,2H),4.11(m,1H),3.64-3. 54(m,1H),3.50(m,2H),3.34(m,2H),3.13-2.97(m,1H),2.46(dm,1H),2.28(s,3H), 2.07-1.96(m,1H),1.96-1.84(m,1H),1.82-1.65(m,2H),1.59(m,1H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =507.5.

[0912] Example 92: cis-3-(3-((2-(1-benzylazetidin-3-yl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0913]

[0914] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ = 12.00 (s, 1H), 8.81 (s, 1H), 8.30 (s, 1H), 7.53 (d, J = 8.7, 1H), 7.35 -7.27(m,4H),7.25(t,J=6.7,1H),6.94(d,J=7.0,1H),5.84(s,1H),5.00(s,1H),4.62(s,2H ),4.16(m,1H),3.64(s,2H),3.58(m,1H),3.49(m,2H),3.38(m,2H),3.15-2.96(m,1H),2.45 (m,1H),2.08-1.98(m,1H),1.98-1.84(m,1H),1.80-1.64(m,2H),1.60(m,1H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =583.6.

[0915] Example 93: cis-3-(3-((4-fluoro-2-(1-methyl-2-oxopyrrolidin-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0916] Step 1: 3-(5-Bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)pyrrolidin-2-one

[0917]

[0918] To a mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (200 mg, 0.75 mmol) and 3-hydroxypyrrolidin-2-one (152.5 mg, 1.51 mmol) in toluene (10 mL) was added cyanomethylenetributylphosphorane (546 mg, 2.26 mmol). The mixture was stirred at 100 ° C under a nitrogen atmosphere for 16 h. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EA / PE (0%-75%) to give the product (180 mg, 68.7%). LC-MS (ESI): m / z [M+H] + =349.0.

[0919] Step 2: 3-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-1-methylpyrrolidine-2-yl ketone

[0920]

[0921] To a mixture of NaH (15 mg, 0.37 mmol) in THF at 0°C under a nitrogen atmosphere was added 3-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)pyrrolidin-2-one (100 mg, 0.28 mmol). The mixture was stirred at 0°C for 30 min, followed by the addition of CHI (49 mg, 0.34 mmol). The resulting mixture was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The mixture was quenched with ice water (50 mL) and extracted with EA (3 x 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EA / PE (0%-40%) to give the product (55 mg, 52.9%). LC-MS (ESI): m / z[M+H] + =363.1.

[0922] Step 3: cis-isopropylcarbamic acid 3-(3-((4-fluoro-2-(1-methyl-2-oxopyrrolidin-3-yl)-1, 2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl 1-dioxide

[0923]

[0924] A mixture of 3-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-1-methylpyrrolidin-2-one (55 mg, 0.15 mmol), cis-isopropylcarbamic acid 3-(3-amino-1H-pyrazol-5-yl)cyclopentyl ester (31.8 mg, 0.13 mmol), Brettphos Pd G3 (11.5 mg, 0.012 mmol) and K2CO3 (53 mg, 0.378 mmol) in t-BuOH (5 mL) was stirred at 110°C under nitrogen atmosphere for 16 h. LCMS showed the reaction was complete. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to give the product (37.59 mg, 46.4%). 1 HNMR(500MHz,DMSO-d6)δ12.00(s,1H),8.80(s,1H),8.35-8.28(m,1H),7.55(d,J=10Hz,1H),6.94(d,J=5H z,1H),5.83(s,1H),5.04-4.96(m,1H),4.69-4.63(m,1H),4.47(t,J=10Hz,1H),4.34-4.28(m,1H),3.62-3. 52(m,1H),3.39-3.33(m,2H),3.11-3.01(m,1H),2.80(s,3H),2.48-2.43(m,1H),2.38-2.29(m,1H),2.28-2 .19(m,1H),2.08-1.98(m,1H),1.96-1.85(m,1H),1.77-1.66(m,2H),1.64-1.55(m,1H),1.07-0.97(m,6H). LC-MS(ESI):m / z[M+H] + =535.2.

[0925] Example 94: cis-3-(3-((2-(1-benzhydrylazetidin-3-yl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0926]

[0927] The title compound was synthesized in a similar manner to the procedure of Example 63. 1H NMR (500MHz, DMSO-d6) δ=12.01(s,1H),8.81(s,1H),8.29(s,1H),7.52(d,J=8.6,1H),7.46(d,J=7 .4,4H),7.30(t,J=7.6,4H),7.20(t,J=7.3,2H),6.94(d,J=7.4,1H),5.84(s,1H),5.00(s,1H),4.6 4(s,2H),4.55(s,1H),4.17(m,1H),3.58(m,1H),3.40(m,2H),3.30(m,2H),3.11-2.98(m,1H),2.4 8-2.43(m,1H),2.12-1.98(m,1H),1.98-1.84(m,1H),1.78-1.64(m,2H),1.60(m,1H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =659.4.

[0928] Example 95: cis-3-(3-((2-(cyclopropylmethyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0929]

[0930] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR(500MHz,MeOD)δ7.92(t,J=7.8Hz,1H),7.41(d,J=8.6Hz,1H),5.91(s,1 H),5.09(s,1H),4.85(s,5H),4.53(s,2H),3.76-3.60(m,1H),3.21-3.15(m ,1H),3.11(d,J=7.0Hz,2H),2.62-2.48(m,1H),2.13(d,J=8.1Hz,1H),2.03 -1.72(m,4H),1.19-1.01(m,7H),0.70-0.59(m,2H),0.35(q,J=5.0Hz,2H). LC-MS(ESI):m / z[M+H] + =492.2.

[0931] Example 96: cis-3-(3-((2-(cyclobutylmethyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0932] Step 1: 5-Bromo-2-(cyclobutylmethyl)-4-fluoro-2,3 - Dihydrobenzo[d]isothiazole 1,1-dioxide.

[0933]

[0934] To a stirred solution of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (220.5 mg, 0.75 mmol) in DMF (10 mL) was added Cs2CO3 (489.5 mg, 1.50 mmol) and (bromomethyl)cyclobutane (820.7 mg, 1.50 mmol). The solution was stirred at 50°C for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give the product (235 mg, 75%), [M+H] + =333.9.

[0935] Step 2: 3-(3-(2-(cyclobutylmethyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzene)isopropylcarbamate [d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester.

[0936]

[0937] A mixture of 5-bromo-2-(cyclobutylmethyl)-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (50 mg, 0.15 mmol), cis-isopropylcarbamic acid 3-(3-amino-1H-pyrazol-5-yl)cyclopentyl ester (37.8 mg, 0.15 mmol), Brettphos Pd G3 (13.5 mg, 0.015 mmol), and K2CO3 (62.1 mg, 0.45 mmol) in t-BuOH (10 mL) was stirred at 110°C under an N2 atmosphere for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The residue was purified by preparative HPLC (Waters XSelect C18:RD-CO-094 column, eluting with a gradient of acetonitrile / water (containing 0.1% FA, 20%-40%)) to afford the product (72.6 mg, 96.1%). 1 H NMR (500 MHz, DMSO-d d)δ11.70(s,1H),8.04(s,1H),7.91(s,1H),6.88(d,J=8.2Hz,1H),6.68(d,J=8. 7Hz,1H),5.68(s,1H),4.99(s,1H),4.72(s,2H),3.44-3.34(m,1H),3.08-2.94( m,1H),2.50-2.44(m,1H),2.06-1.94(m,1H),1.95-1.85(m,1H),1.77-1.65(m,2 H),1.65-1.55(m,1H),1.40-1.30(m,2H),1.06-0.94(m,3H),0.84-0.78(m,3H). LC-MS(ESI):m / z[M+H] + =506.2.

[0938] Example 97: cis-3-(3-((4-fluoro-2-(oxetan-3-ylmethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0939] Step 1: 5-Bromo-4-fluoro-2-(oxetan-3-ylmethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide Chemical

[0940]

[0941] To a stirred solution of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (250 mg, 0.94 mmol) in toluene (20 mL) was added oxetane-3-ylmethanol (166.03 mg, 1.89 mmol) and CMBP (688.1 mg, 2.82 mmol). The solution was stirred at 90 ° C under N2 atmosphere for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1) to give the product (380 mg, 41.8%), [M+H] + =335.9.

[0942] Step 2: cis-isopropylcarbamic acid 3-(3-((4-fluoro-2-(oxetane-3-ylmethyl)-1,1-dioxo- (2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0943]

[0944] A mixture of 5-bromo-4-fluoro-2-(oxetan-3-ylmethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (80 mg, 0.24 mmol), cis-isopropylcarbamic acid 3-(3-amino-1H-pyrazol-5-yl)cyclopentyl ester (60.2 mg, 0.24 mmol), Brettphos Pd G3 (21.6 mg, 0.024 mmol), K2CO3 (99.3 mg, 0.72 mmol) in t-BuOH (20 mL) was stirred at 110 ° C. under N2 atmosphere for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA to give the product (80 mg). The residue was purified by preparative HPLC (Waters XSelect C18:RD-CO-094 column, eluting with a gradient of acetonitrile / water (containing 0.1% FA, 20%-40%)) to give the product (79.1 mg). 1 H NMR (500MHz, DMSO-d6) δ12.00(s,1H),8.78(s,1H),8.30(s,1H),7.54(d,J=8.6Hz,1H),6.94(d,J= 7.4Hz,1H),5.83(s,1H),5.00(s,1H),4.69(dd,J=7.5,6.3Hz,2H),4.46(s,2H),4.36(t,J=6.0Hz,2 H),3.62-3.56(m,1H),3.47(d,J=7.5Hz,2H),3.40-3.36(m,1H),3.15-2.97(m,1H),2.47-2.40(m,1 H),2.06-1.99(m,1H),1.96-1.86(m,1H),1.78-1.66(m,2H),1.65-1.57(m,1H),1.10-0.93(m,6H). LC-MS(ESI):m / z[M+H] + =508.3.

[0945] Example 98: cis-3-(3-((2-((S)-2-amino-3,3-dimethylbutyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0946]

[0947] The title compound was synthesized in a similar manner to the procedure of Example 63. 1H NMR (500MHz, DMSO-d6) δ12.00(s,1H),8.79(s,1H),8.29(s,1H),7.56(d,J=8.6Hz,1H),6.94(d,J=6.9Hz, 1H),5.83(s,1H),5.00(s,1H),4.61(d,J=14.2Hz,1H),4.49(d,J=14.1Hz,1H),3.60-3.58(m,1H),3.26(d ,J=13.4Hz,1H),3.10-3.02(m,1H),2.94-2.85(m,1H),2.77(d,J=10.3Hz,1H),2.50-2.46(m,1H),2.06-1 .94(m,1H),1.95-1.85(m,1H),1.77-1.65(m,2H),1.65-1.55(m,1H),1.03(d,J=5.9Hz,6H),0.92(s,9H). LC-MS(ESI):m / z[M+H] + =537.2.

[0948] Example 99: cis-3-(3-((2-((R)-2-amino-3,3-dimethylbutyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0949]

[0950] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ12.00(s,1H),8.79(s,1H),8.29(s,1H),7.56(d,J=8.6Hz,1H),6.94(d,J=6.9Hz, 1H),5.83(s,1H),5.00(s,1H),4.61(d,J=14.2Hz,1H),4.49(d,J=14.1Hz,1H),3.60-3.58(m,1H),3.26(d ,J=13.4Hz,1H),3.10-3.02(m,1H),2.94-2.85(m,1H),2.77(d,J=10.3Hz,1H),2.50-2.46(m,1H),2.06-1 .94(m,1H),1.95-1.85(m,1H),1.77-1.65(m,2H),1.65-1.55(m,1H),1.03(d,J=5.9Hz,6H),0.92(s,9H). LC-MS(ESI):m / z[M+H] +=537.2.

[0951] Example 100: cis-3-(3-((4-fluoro-2-(1-methyl-2-oxopiperidin-4-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0952]

[0953] The title compound was synthesized in a similar manner to the procedure of Example 63. LC-MS (ESI): m / z [M+H] + =549.2.

[0954] Example 101: cis-3-(3-((4-fluoro-2-isobutyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0955]

[0956] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.77(s,1H),8.30(t,J=7.6Hz,1H),7.54(d,J=8.6Hz ,1H),6.94(d,J=7.4Hz,1H),5.83(s,1H),4.99(s,1H),4.47(s,2H),3.58(d,J=6.7Hz,1H), 3.13-3.03(m,1H),2.92(d,J=7.3Hz,2H),2.44-2.38(m,1H),2.10-1.95(m,2H),1.93-1.84 (m,1H),1.75-1.65(m,2H),1.59-1.52(m,1H),1.03(d,J=6.2Hz,6H),0.95(d,J=6.6Hz,7H). LC-MS(ESI):m / z[M+H] + =494.2.

[0957] Examples 102 and 103: cis-3-(3-((4-fluoro-2-(2-hydroxycyclobutyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0958] Step 1: 2-(5-Bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)cyclobutane-1-one

[0959]

[0960] A mixture of 2-bromocyclobutane-1-one (0.252 g, 1.69 mmol), K2CO3 (0.233 g, 1.69 mmol) and 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.3 g, 1.12 mmol) in DMF (10 mL) was stirred at 50 ° C for 12 hours. The mixture was quenched with water (30 mL). The mixture was extracted with DCM (20 mL×3). The DCM layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give the product (0.3 g, 79.8%). LC-MS (ESI): m / z[M+H] + =334.2.

[0961] Step 2: 5-Bromo-4-fluoro-2-(2-hydroxycyclobutyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0962]

[0963] To a mixture of 2-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)cyclobutane-1-one (0.3 g, 0.9 mmol) in EtOH (20 mL) was added NaBH4 (0.055 g, 1.45 mmol). The mixture was stirred at 25 ° C for 2 hours. The mixture was quenched with saturated NH4Cl (aqueous) (10 mL) and extracted with DCM (30 mL×3). The DCM layer was concentrated under reduced pressure to give the crude product, which was used in the next step without purification (0.26 g, 86.1%). LC-MS (ESI): m / z[M+H] + =336.2.

[0964] Step 3: cis-isopropylcarbamic acid 3-(3-((4-fluoro-2-(2-hydroxycyclobutyl)-1,1-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[0965]

[0966] The title compound was synthesized by a procedure similar to that of Example 34, Step 5.

[0967] Diastereomer 1 (Example 102): 1H NMR(500MHz,DMSO-d6)δ11.98(s,1H),8.76(s,1H),8.28(s,1H),7.51(d,J=8.6Hz,1H),6.92(s, 1H),5.83(s,1H),5.50(d,J=7.4Hz,1H),5.00(s,1H),4.60(d,J=14.2Hz,1H),4.39(d,J=14.2Hz ,1H),4.23-4.11(m,1H),3.61(dt,J=13.0,7.5Hz,2H),3.15-3.04(m,1H),2.48-2.43(m,1H),2. 14-1.99(m,2H),1.95-1.85(m,2H),1.78-1.65(m,3H),1.65-1.52(m,2H),1.03(d,J=5.8Hz,6H). LC-MS(ESI):m / z[M+H] + =508.3.

[0968] Diastereomer 2 (Example 103): 1 H NMR (500MHz, DMSO-d6) δ11.98(s,1H),8.76(s,1H),8.29(s,1H),7.52(d,J=8.6Hz,1H),6.92(s, 1H),5.83(s,1H),5.39(d,J=5.3Hz,1H),5.00(s,1H),4.79(d,J=14.5Hz,1H),4.59(d,J=14.5Hz, 1H),4.42(s,1H),4.0-3.93(m,1H),3.62-3.53(s,1H),3.11-3.02(m,1H),2.48-2.43(m,1H),2. 14-1.99(m,2H),1.95-1.85(m,2H),1.78-1.55(m,3H),1.65-1.52(m,2H),1.03(d,J=5.8Hz,6H). LC-MS(ESI):m / z[M+H] + =508.3.

[0969] Example 104: cis-3-(3-((4-fluoro-2-(1-(oxetan-3-yl)ethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0970]

[0971] The title compound was synthesized in a similar manner to the procedure of Example 63. 1H NMR (500MHz, DMSO-d6) δ11.99(s,1H),8.76(s,1H),8.29(s,1H),7.52(d,J=8.6Hz,1H),6.93(d,J=6. 5Hz,1H),5.83(S,1H),4.99(s,1H),4.66(t,J=7.0Hz,1H),4.59(t,J=6.9Hz,1H),4.49(d,J=14.1Hz,1 H),4.41-4.25(m,4H),4.12-4.03(m,1H),3.62-3.53(m,1H),3.29-3.23(m,1H),3.12-3.02(m,1H),2 .48-2.43(m,1H),2.07-1.86(m,2H),1.77-1.55(m,3H),1.20(d,J=6.5Hz,3H),1.03(d,J=5.8Hz,6H). LC-MS(ESI):m / z[M+H] + =522.3.

[0972] Example 105: cis-3-(3-((2-(azetidin-3-ylmethyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0973]

[0974] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR(500MHz,DMSO-d6)δ12.02(s,1H),8.81(s,1H),8.65(s,1H),8.54(s,1H),8.31(s,1H),7.57(d,J=8 .7Hz,1H),6.93(d,J=6.9Hz,1H),5.84(s,1H),5.00(s,1H),4.51(s,2H),3.85-3.75(m,2H),3.65-3.55 (m,1H),3.46(d,J=7.4Hz,2H),3.25-3.15(m,1H),3.11-2.98(m,1H),2.48-2.40(m,1H),2.10-1.98(m, 1H), 1.96-1.85 (m, 1H), 1.84-1.72 (m, 1H), 1.75-1.65 (m, 2H), 1.58-1.52 (m, 1H), 1.03 (d, J = 5.6Hz, 6H). LC-MS(ESI):m / z[M+H] + =507.2.

[0975] Example 106: cis-3-(3-((4-fluoro-2-((1-methylazetidin-3-yl)methyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0976]

[0977] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ12.05(s,1H),8.78(s,1H),8.28(t,J=7.8Hz,1H),7.54(d,J=8.6Hz,1H),6.94(d ,J=7.1Hz,1H),5.83(s,1H),5.00(s,1H),4.46(s,2H),3.65-3.54(m,1H),3.48(t,J=7.6Hz,2H),3.36(d ,J=7.4Hz,2H),3.15(t,J=6.7Hz,2H),3.10-3.00(m,1H),2.81-2.78(m,1H),2.48-2.40(m,1H),2.35(s, 3H), 2.10-1.99 (m, 1H), 1.96-1.84 (m, 1H), 1.81-1.67 (m, 2H), 1.58-1.52 (m, 1H), 1.03 (d, J = 5.7Hz, 6H). LC-MS(ESI):m / z[M+H] + =521.2.

[0978] Example 107: cis-3-(3-((2-((1-acetylazetidin-3-yl)methyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0979]

[0980] The title compound was synthesized in a similar manner to the procedure of Example 63. 1H NMR (500MHz, DMSO-d6) δ12.00(s,1H),8.80(s,1H),8.31(t,J=7.7Hz,1H),7.55(d,J=8.7Hz,1H),6.94 (d,J=6.5Hz,1H),5.83(s,1H),5.00(s,1H),4.50(s,2H),4.21(t,J=8.3Hz,1H),3.98-3.81(m,2H),3.6 6-3.50(m,2H),3.43-3.37(m,2H),3.12-3.04(m,1H),3.02-2.90(m,1H),2.50-2.44(m,1H),2.07-1.9 7(m,1H),1.96-1.85(m,1H),1.74(s,3H),1.75-1.65(m,2H),1.58-1.52(m,1H),1.03(d,J=3.6Hz,6H). LC-MS(ESI):m / z[M+H] + =549.2.

[0981] Example 108: cis-3-(3-((2-(cyclohexylmethyl)-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0982]

[0983] To a mixture of 3-(3-((4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (60 mg, 0.14 mmol) and cyclohexylmethanol (23.4 mg, 0.01 mmol) in toluene was added cyanomethylenetributylphosphorane (84 mg, 0.34 mmol). The mixture was stirred at 95 ° C under a nitrogen atmosphere for 16 h. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC to give the product (6.8 mg, 9.3%). 1H NMR(500MHz,DMSO-d6)δ11.99(s,1H),8.77(s,1H),8.34-8.25(m,1H),7.53(d,J=10Hz, 1H),6.94(d,J=10Hz,1H),5.83(s,1H),5.03-4.96(m,1H),4.47(s,3H),3.62-3.53(m,1H ),3.11-3.03(m,1H),2.98-2.92(m,2H),2.48-2.43(m,1H),2.06-1.98(m,1H),1.95-1. 86(m,1H),1.83-1.51(m,10H),1.30-1.12(m,1H),1.07-0.98(m,6H),0.97-0.89(m,2H). LC-MS(ESI):m / z[M+H] + =534.2.

[0984] Example 109: cis-3-(3-((4-fluoro-2-(2-hydroxycyclopentyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0985]

[0986] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ = 11.99 (s, 1H), 8.76 (s, 1H), 8.29 (s, 1H), 7.52 (d, J = 8.6, 1H), 6.94 (d,J=7.1,1H),5.83(s,1H),4.99(s,1H),4.73(d,J=4.1,1H),4.66(d,J=14.3,1H),4.58(d ,J=14.3,1H),4.22(m,1H),3.58(m,1H),3.47(m,1H),3.13-2.97(m,1H),2.48-2.43(m,1H) ,2.03(m,2H),1.90(m,2H),1.85-1.76(m,2H),1.76-1.65(m,2H),1.58(m,3H),1.03(m,6H). LC-MS(ESI):m / z[M+H] + =522.32.

[0987] Example 110: cis-3-(3-((4-fluoro-1,1-dioxido-2-((2-oxopyrrolidin-3-yl)methyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0988]

[0989] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ12.00(s,1H),8.79(s,1H),8.31(t,J=10Hz,1H),7.78(s,1H),7.55(d,J= 10Hz,1H),6.94(d,J=5Hz,1H),5.83(s,1H),5.05-4.95(m,1H),4.56-4.44(m,2H),3.64-3.53(m,1 H),3.52-3.46(m,1H),3.26-3.13(m,3H),3.12-3.01(m,1H),2.73-2.62(m,1H),2.47-2.44(m,1H ),2.31-2.22(m,1H),2.06-1.87(m,3H),1.77-1.67(m,2H),1.64-1.55(m,1H),1.10-1.95(m,6H). LC-MS(ESI):m / z[M+H] + =535.2.

[0990] Example 111: cis-3-(3-((4-fluoro-2-((1-methyl-2-oxopyrrolidin-3-yl)methyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0991]

[0992] The title compound was synthesized in a similar manner to the procedure of Example 63. 1H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.79 (s, 1H), 8.34-8.25 (m, 1H), 7.55 (t, J=10Hz, 1H), 6.94 ( t, J=10Hz, 1H), 5.83 (s, 1H), 5.04-4.96 (m, 1H), 4.52-4.46 (m, 2H), 3.62-3.47 (m, 2H), 3.30-3.26 (m , 2H), 3.23-3.16(m, 1H), 3.11-3.02(m, 1H), 2.80-2.72(m, 4H), 2.48-2.43(m, 1H), 2.25-2.17(m, 1 H), 2.07-1.99 (m, 1H), 1.96-1.84 (m, 2H), 1.77-1.65 (m, 2H), 1.64-1.55 (m, 1H), 1.08-0.96 (m, 6H). LC-MS(ESI):m / z[M+H] + =549.2.

[0993] Example 112: cis-3-(3-((4-fluoro-2-(2-morpholinoethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0994]

[0995] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ = 12.00 (s, 1H), 8.77 (s, 1H), 8.29 (t, J = 7.8, 1H), 7.54 ( d, J=8.6, 1H), 6.94 (d, J=7.4, 1H), 5.84 (s, 1H), 5.00 (s, 1H), 4.56 (s, 2H), 3.62 -3.51 (m, 5H), 3.29 (t, J = 6.6, 2H), 3.12-3.00 (m, 1H), 2.63 (t, J = 6.6, 2H), 2.45 (m, 5H), 2.03 (m, 1H), 1.91 (m, 1H), 1.70 (m, 2H), 1.60 (m, 1H), 1.08-0.96 (m, 6H). LC-MS(ESI):m / z[M+H] + =551.36.

[0996] Example 113: cis-3-(3-((4-fluoro-2-(3-hydroxypropyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0997]

[0998] The title compound was synthesized in a similar manner to the procedure of Example 37. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.53 (d, J=8.6Hz, 1H), 7.02 -6.87(m, 1H), 5.83(s, 1H), 5.04-4.92(m, 1H), 4.47(s, 2H), 3.65-3.57(m, 2H), 3.51(t, J=6. 1Hz, 2H), 3.21 (t, J=6.1Hz, 2H), 3.14-3.00 (m, 1H), 2.48-2.42 (m, 1H), 2.08-1.99 (m, 1H), 1. 97-1.87 (m, 1H), 1.86-1.78 (m, 2H), 1.77-1.66 (m, 2H), 1.65-1.54 (m, 1H), 1.09-0.98 (m, 6H). LC-MS(ESI):m / z[M+H] + =496.29.

[0999] Example 114: cis-3-(3-((4-fluoro-1,1-dioxido-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[1000]

[1001] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.78 (s, 1H), 8.30 (t, J=8.0Hz, 1H), 7.53 (d, J=8.7Hz , 1H), 6.94 (d, J=7.0Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.47 (s, 2H), 3.83 (dd, J=10.9, 3.6H z, 2H), 3.63-3.53 (m, 1H), 3.31-3.24 (m, 2H), 3.17 (t, J=6.8Hz, 2H), 3.11-3.03 (m, 1H), 2.4 8-2.43 (m, 1H), 2.08-1.87 (m, 2H), 1.74-1.58 (m, 8H), 1.25-1.14 (m, 2H), 1.07-0.99 (m, 6H). LC-MS(ESI):m / z[M+H] +=550.3.

[1002] Example 115: cis-3-(3-((4-fluoro-1,1-dioxido-2-(1-(tetrahydrofuran-3-yl)ethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[1003] Step 1: 1-(Tetrahydrofuran-3-yl)ethan-1-ol

[1004]

[1005] To a solution of tetrahydrofuran-3-carbaldehyde (2.0 g, 20 mmol) in THF (40 mL) was added MeMgBr (30 mL, 30 mmol) at 0°C. The mixture was then stirred at 25°C for 1 hr. The mixture was quenched with saturated NH4Cl (aqueous) (20 mL). The mixture was extracted with EA (30 mL×3). The EA layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give the product (1.5 g, 64.6%). LC-MS (ESI): m / z[M+H] + =117.1.

[1006] Step 2: 5-Bromo-4-fluoro-2-(1-(tetrahydrofuran-3-yl)ethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dihydro- oxides

[1007]

[1008] A mixture of 1-(tetrahydrofuran-3-yl)ethan-1-ol (0.197 g, 1.7 mmol), CMBP (0.816 g, 3.38 mmol) and 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (0.3 g, 1.13 mmol) in toluene (10 mL) was stirred at 95° C. under N 2 for 12 hr. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1 to 5:1) to give the product (0.33 g, 80.5%). LC-MS (ESI): m / z [M+H] + =364.

[1009] Step 3: cis-isopropylcarbamate 3-(3-((4-fluoro-1,1-dioxido-2-(1-(tetrahydrofuran-3-yl)ethyl) 2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[1010]

[1011] The title compound was synthesized by a procedure similar to that of Example 34, Step 5. 1H NMR (500MHz, DMSO-d6) δ11.99 (s, 1H), 8.77 (s, 1H), 8.31 (s, 1H), 7.56-7.48 (m, 1H), 6.94(d, J=7.3Hz, 1H), 5.83(s, 1H), 5.00(s, 1H), 4.57-4.45(m, 2H), 3.89-3.72(m, 2H) ), 3.67-3.51(m, 3H), 3.47-3.43(m, 1H), 3.11-3.02(m, 1H), 2.48-2.43(m, 1H), 2.11- 1.80 (m, 4H), 1.76-1.58 (m, 4H), 1.26 (dd, J=34.0, 6.6Hz, 3H), 1.03 (d, J=6.2Hz, 6H). LC-MS(ESI):m / z[M+H] + =536.3.

[1012] Example 116: cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[1013] Step 1: Methyl 3-bromo-6-(N-cyclopropylsulfamoyl)-2-fluorobenzoate

[1014]

[1015] To a solution of cyclopropylamine (2.7 g, 48 mmol) and TEA (12.1 g, 120 mmol) in DCM (150 mL) was added dropwise a solution of methyl 3-bromo-6-(chlorosulfonyl)-2-fluorobenzoate (13.3 g, 40 mmol) in DCM (30 mL) at 0°C. The mixture was stirred at room temperature for 1 h. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EA / PE (0%-40%) to give the product (6.6 g, 46.5%). LC-MS (ESI): m / z[M+H] + =352.2.

[1016] Step 2: 3-Bromo-6-(N-cyclopropylsulfamoyl)-2-fluorobenzoic acid

[1017]

[1018] To a solution of methyl 3-bromo-6-(N-cyclopropylsulfamoyl)-2-fluorobenzoate (6.6 g, 18.8 mmol) in THF (80 mL) was added LiHMDS (28.2 mL, 28.2 mmol). The mixture was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The mixture was adjusted to pH = 6 with 1N HCl (aqueous) and then extracted with EA (3x100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give the product (6.1 g, 96.2%), which was used directly in the next step. LC-MS (ESI): m / z [M+H] + =338.

[1019] Step 3: 5-Bromo-2-cyclopropyl-4-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide

[1020]

[1021] A solution of 3-bromo-6-(N-cyclopropylsulfamoyl)-2-fluorobenzoic acid (6.1 g, 18.1 mmol) in SOCl2 (70 mL) was stirred at 75°C for 3 h. LCMS showed the reaction was complete. The mixture was concentrated under vacuum to give the product (5.5 g, 95.3%), which was used directly in the next step. LC-MS (ESI): m / z [M+H] + =320.

[1022] Step 4: 5-Bromo-2-cyclopropyl-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[1023]

[1024] To a solution of 5-bromo-2-cyclopropyl-4-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (5.5 g, 17.2 mmol) in THF (70 mL) was added BH3 (86 mL, 86.2 mmol). The mixture was stirred at 75 ° C for 16 h. LCMS showed that the reaction was complete. The mixture was slowly quenched by MeOH. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EA / PE (0%-45%) to give the product (3.2 g, 60.8%). LC-MS (ESI): m / z [M+H] + =306.

[1025] Step 5: cis-isopropylcarbamic acid 3-(1-(tert-butyl)-5-(2-cyclopropyl-4-fluoro-1,1-dioxy- 2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[1026]

[1027] By 5-bromo-2-cyclopropyl-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (70 mg, 0.23 mmol), cis-isopropylcarbamic acid 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (71 mg, 0.23 mmol), Pd(dba) (21 mg, 0.023 mmol), Xantphos (26.6 mg, 0.046 mmol) and KPO (146 mg, 0.69 mmol) in dioxane (10 mL) was stirred at 90 ° C under a nitrogen atmosphere for 16 h. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, wherein eluted with EA / PE (0%-80%) to obtain the product (104 mg, 85.2%). LC-MS (ESI): m / z [M+H] + =534.2.

[1028] Step 6: cis-isopropylcarbamic acid 3-(3-(2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzoyl) [d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[1029]

[1030] To a solution of 3-(1-(tert-butyl)-5-((2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazole-3-yl)cyclopentyl isopropylcarbamate (104 mg, 0.19 mmol) in DCM (15 mL) was added TfOH (3 mL). The mixture was stirred at room temperature for 2 h. LCMS showed that the reaction was complete. The mixture was quenched with aqueous NaHCO (50 mL) and extracted with DCM (3x50 mL). The combined organic layer was dried over Na SO, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the product in the desired racemic form, which was further separated by chiral preparative HPLC to provide:

[1031] Enantiomer 1 (Example 116a, 100% ee); retention time: 6.43 min, 1H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J=5Hz, 1H), 7.52 (d, J=10Hz , 1H), 6.94 (d, J=10Hz, 1H), 5.83 (s, 1H), 5.02-4.98 (m, 1H), 4.52 (s, 2H), 3.63-3.52 (m, 1 H), 3.12-3.00(m, 1H), 2.48-2.43(m, 2H), 2.07-1.98(m, 1H), 1.95-1.85(m, 1H), 1.78-1 .64 (m, 2H), 1.64-1.55 (m, 1H), 1.08-0.97 (m, 6H), 0.87-0.81 (m, 2H), 0.76-0.70 (m, 2H). LC-MS(ESI):m / z[M+H] + =478.2.

[1032] Enantiomer 2 (Example 116b, 100% ee); retention time: 11.73 min, 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.78 (s, 1H), 8.29 (t, J=5Hz, 1H), 7.52 (d, J=10Hz , 1H), 6.94 (d, J=10Hz, 1H), 5.83 (s, 1H), 5.03-4.97 (m, 1H), 4.52 (s, 2H), 3.62-3.52 (m, 1 H), 3.12-3.01(m, 1H), 2.47-2.42(m, 2H), 2.08-1.98(m, 1H), 1.97-1.86(m, 1H), 1.78-1 .64 (m, 2H), 1.64-1.55 (m, 1H), 1.08-0.96 (m, 6H), 0.87-0.82 (m, 2H), 0.76-0.71 (m, 2H). LC-MS(ESI):m / z[M+H] + =478.3.

[1033] Chiral analysis method: column: I-Cellulose-5, 4.6 mm × 250 mm, 5 um; mobile phase: A: hexane, and B: EtOH (0.1% 2M NH3MeOH); gradient: mobile phase A: mobile phase B = 60:40 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35 ° C.

[1034] Chiral preparative HPLC conditions: column: I-Cellulose-5, 21.2 mm×250 mm, 5 um; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH 3 MeOH); gradient: mobile phase A: mobile phase B = 60:40 (v / v); flow rate: 20 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25° C.

[1035] Example 117: 3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-((S)-sec-butyl)carbamate

[1036] Step 1: cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentan-1-ol

[1037]

[1038] To a solution of benzyl cis-(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (3.6 g, 10 mmol) in THF (100 mL) was added Pd / C (10%, wet, 2 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 h. The mixture was filtered, and the filter cake was washed with EA (50 mL×3). The filtrate was concentrated under reduced pressure to give the product (2.1 g, 91% yield). LC-MS (ESI): m / z[M+H] + =224.3.

[1039] Step 2: cis-5-((1-tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-cyclopropane 4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[1040]

[1041] A mixture of 5-bromo-2-cyclopropyl-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (140 mg, 0.46 mmol), cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentan-1-ol (102.6 mg, 0.46 mmol), Pd2dba3 (42 mg, 0.046 mmol), Xantphos (53.2 mg, 0.092 mmol) and K3PO4 (293 mg, 1.38 mmol) in dioxane (10 mL) was stirred at 90° C. under nitrogen atmosphere for 16 h. LCMS showed the reaction was complete. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EA / PE (0%-80%) to give the product (114 mg, 55.3%). LC-MS (ESI): m / z [M+H] + =449.2.

[1042] Step 3: cis-(4-nitrophenyl)carbonate 3-(1-(tert-butyl)-5-(2-cyclopropyl-4-fluoro-1,1-dioxy- 2,3-Dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester

[1043]

[1044] To a mixture of cis-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-cyclopropyl-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (114 mg, 0.25 mmol), DMAP (10 mg, 0.13 mmol) and pyridine (155 mg, 1.27 mmol) in THF (15 mL) was added 4-nitrophenyl chloroformate (61.2 mg, 0.3 mmol). The mixture was stirred at 50° C. for 16 h. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EA / PE (0%-55%) to give the product (80 mg, 73%). LC-MS (ESI): m / z [M+H] + =614.3.

[1045] Step 3: cis-(4-nitrophenyl)carbonate 3-(3-(2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzene) (d)isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[1046] A solution of cis-3-(1-(tert-butyl)-5-((2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (80 mg, 0.13 mmol) in FA (10 mL) was stirred at 75 ° C for 1 day. LCMS showed that the reaction was complete. The mixture was concentrated under vacuum to give the desired product (75 mg, crude), which was used directly in the next step. LC-MS (ESI): m / z [M+H] + =558.2.

[1047] Step 4: cis-((S)-sec-butyl)carbamic acid 3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-diol) (4-Methylbenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[1048]

[1049] A mixture of cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate (25 mg, 0.045 mmol), (S)-butan-2-amine (7.3 mg, 0.067 mmol) and DIEA (17.4 mg, 0.135 mmol) in THF (10 mL) was stirred at 50° C. for 16 h. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC to give the desired product in racemic form (3.53 mg, 16.5%), which was further separated by chiral preparative HPLC to give:

[1050] Enantiomer 1 (Example 117a, 100% ee); retention time: 5.67 min. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 10Hz, 1H), 7.52 (d, J = 10Hz, 1H ), 6.88 (d, J=10Hz, 1H), 5.83 (s, 1H), 5.03-4.96 (m, 1H), 4.52 (s, 2H), 3.42-3.34 (m, 1H), 3.11 -3.01(m, 1H), 2.48-2.43(m, 2H), 2.09-1.98(m, 1H), 1.96-1.85(m, 1H), 1.78-1.65(m, 2H), 1. 63-1.55 (m, 1H), 1.41-1.29 (m, 2H), 1.03-0.96 (m, 3H), 0.87-0.76 (m, 5H), 0.76-0.70 (m, 2H). LC-MS(ESI):m / z[M+H] + =492.4.

[1051] Enantiomer 2 (Example 117b, 100% ee); retention time: 10.41 min. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 10Hz, 1H), 7.52 (d, J = 10Hz, 1H ), 6.88 (d, J=10Hz, 1H), 5.83 (s, 1H), 5.03-4.96 (m, 1H), 4.52 (s, 2H), 3.42-3.34 (m, 1H), 3.11 -3.01(m, 1H), 2.48-2.43(m, 2H), 2.09-1.98(m, 1H), 1.96-1.85(m, 1H), 1.78-1.65(m, 2H), 1. 63-1.55 (m, 1H), 1.41-1.29 (m, 2H), 1.03-0.96 (m, 3H), 0.87-0.76 (m, 5H), 0.76-0.70 (m, 2H). LC-MS(ESI):m / z[M+H] + =492.4.

[1052] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A: MtBE (0.1% 2M NH 3 MeOH) (%), and B: EtOH; gradient: mobile phase A: mobile phase B = 10:90 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[1053] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm×250 mm, 5 μm; mobile phase: A: MtBE (0.2% 2M NH3 MeOH) (%), and B: EtOH; gradient: mobile phase A: mobile phase B = 10:90 (v / v); flow rate: 18 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[1054] Example 118: cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl propylcarbamate

[1055]

[1056] The title compound was synthesized in racemic form in analogy to the procedure of Example 117, which was further separated by chiral preparative HPLC to give:

[1057] Enantiomer 1 (Example 118a, 100% ee); retention time: 6.27 min. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J=10Hz, 1H), 7.52 (d, J=10H z, 1H), 7.04 (t, J=10Hz, 1H), 5.83 (s, 1H), 5.04-4.96 (m, 1H), 4.52 (s, 2H), 3.12-3.01 (m, 1H), 2.95-2.87(m, 2H), 2.49-2.43(m, 2H), 2.06-2.00(m, 1H), 1.96-1.85(m, 1H), 1.78-1 .65(m, 2H), 1.65-1.55(m, 1H), 1.43-1.33(m, 2H), 0.88-0.77(m, 5H), 0.76-0.70(m, 2H). LC-MS(ESI):m / z[M+H] + =478.1.

[1058] Enantiomer 2 (Example 118b, 100% ee); retention time: 10.50 min. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J=10Hz, 1H), 7.52 (d, J=10H z, 1H), 7.04 (t, J=10Hz, 1H), 5.83 (s, 1H), 5.04-4.96 (m, 1H), 4.52 (s, 2H), 3.12-3.01 (m, 1H), 2.95-2.87(m, 2H), 2.49-2.43(m, 2H), 2.06-2.00(m, 1H), 1.96-1.85(m, 1H), 1.78-1 .65(m, 2H), 1.65-1.55(m, 1H), 1.43-1.33(m, 2H), 0.88-0.77(m, 5H), 0.76-0.70(m, 2H). LC-MS(ESI):m / z[M+H] + =478.1.

[1059] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A: MtBE (0.1% 2M NH 3 MeOH) (%), and B: EtOH; gradient: mobile phase A: mobile phase B = 10:90 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[1060] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm × 250 mm, 5 μm; mobile phase: A: MtBE (0.2% 2M NH3MeOH) (%), and B: EtOH; gradient: mobile phase A: mobile phase B = 10: 90 (v / v); flow rate: 18 mL / min, wavelength: UV200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25 ° C.

[1061] Example 119: 3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-(1-methylcyclopropyl)carbamate

[1062]

[1063] The title compound was synthesized in racemic form in analogy to the procedure of Example 117, which was further separated by chiral preparative HPLC to give:

[1064] Enantiomer 1 (Example 119a, 100% ee); retention time: 6.27 min. 1 H NMR (500MHz, DMSO-d6) δ11.99 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 10Hz, 1H), 7.52 (d, J = 10Hz, 1 H), 7.36-7.52(m, 1H), 5.82(s, 1H), 5.06-4.95(m, 1H), 4.52(s, 2H), 3.12-3.00(m, 1H), 2.4 8-2.44(m, 2H), 2.09-1.97(m, 1H), 1.95-1.84(m, 1H), 1.76-1.63(m, 2H), 1.61-1.52(m, 1H) , 1.23 (s, 3H), 0.88-0.81 (m, 2H), 0.77-0.70 (m, 2H), 0.62-0.55 (m, 2H), 0.50-0.44 (m, 2H). LC-MS(ESI):m / z[M+H] + =490.2.

[1065] Enantiomer 2 (Example 119b, 100% ee); retention time: 10.50 min. 1H NMR (500MHz, DMSO-d6) δ11.99 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 10Hz, 1H), 7.52 (d, J = 10Hz, 1 H), 7.36-7.52(m, 1H), 5.82(s, 1H), 5.06-4.95(m, 1H), 4.52(s, 2H), 3.12-3.00(m, 1H), 2.4 8-2.44(m, 2H), 2.09-1.97(m, 1H), 1.95-1.84(m, 1H), 1.76-1.63(m, 2H), 1.61-1.52(m, 1H) , 1.23 (s, 3H), 0.88-0.81 (m, 2H), 0.77-0.70 (m, 2H), 0.62-0.55 (m, 2H), 0.50-0.44 (m, 2H). LC-MS(ESI):m / z[M+H] + =490.2.

[1066] Chiral analysis method: column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; mobile phase: A: MtBE (0.1% 2M NH3MeOH) (%), and B: EtOH; gradient: mobile phase A: mobile phase B = 10: 90 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35 ° C.

[1067] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm × 250 mm, 5 μm; mobile phase: A: MtBE (0.2% 2M NH3MeOH) (%), and B: EtOH; gradient: mobile phase A: mobile phase B = 10: 90 (v / v); flow rate: 18 mL / min, wavelength: UV200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25 ° C.

[1068] Example 120: 3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-((S)-1-hydroxypropan-2-yl)carbamate

[1069]

[1070] The title compound was synthesized in a similar manner to the procedure of Example 117. 1H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (brs, 1H), 7.52 (d, J=10Hz, 1H), 6.83-6.76 (m, 1H ), 5.83(s, 1H), 5.05-4.97(m, 1H), 4.65-4.58(m, 1H), 4.52(s, 2H), 3.53-3.43(m, 1H), 3.35-3.33(m, 1H), 3.30-3.28(m, 1H), 3.21-3.14(m, 1H), 3.11-3.02(m, 1H), 3.48-3.44(m, 1H), 2.06-1.99(m, 1H), 1.96-1.8 6 (m, 1H), 1.79-1.65 (m, 2H), 1.64-1.56 (m, 1H), 1.04-0.96 (m, 3H), 0.84-0.81 (m, 2H), 0.76-0.70 (m, 2H). LC-MS(ESI):m / z[M+H] + =494.2.

[1071] Example 121: cis-3-(3-((4-fluoro-2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[1072] Step 1: 5-Bromo-4-fluoro-2-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[1073]

[1074] To a mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (266 mg, 1 mmol) and KCO (166 mg, 1.2 mmol) in DMF (10 mL) was added CHI (170 mg, 1.2 mmol). The mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The mixture was diluted with water (50 mL) and extracted with EA (3×50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (3:2) to give the product (196 mg, 70%). LC-MS (ESI): m / z [M+H] + =280.2.

[1075] Step 2: cis-isopropylcarbamic acid 3-(3-((4-fluoro-2-methyl-1,1-difluoro-2,3-dihydrobenzoyl)- [d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester

[1076]

[1077] The title compound was synthesized in racemic form by a procedure analogous to Example 34, Step 5, which was further separated by chiral preparative HPLC to give:

[1078] Enantiomer 1 (Example 121a, 100% ee); retention time: 13.25 min. 1 H NMR (500MHz, DMSO-d6) δ12.01 (s, 1H), 8.78 (s, 1H), 8.29 (s, 1H), 7.55 (d, J=8.7 Hz, 1H), 6.95 (d, J=6.8Hz, 1H), 5.84 (s, 1H), 5.00 (s, 1H), 4.43 (s, 2H), 3.62-3.5 5(m, 1H), 3.12-3.02(m, 1H), 2.79(s, 3H), 2.48-2.42(m, 1H), 2.07-1.95(m, 1H), 1.95-1.85 (m, 1H), 1.78-1.66 (m, 2H), 1.65-1.56 (m, 1H), 1.03 (d, J=6.2Hz, 6H). LC-MS(ESI):m / z[M+H] + =452.2.

[1079] Enantiomer 2 (Example 121b, 100% ee); retention time: 14.99 min. 1 H NMR (500MHz, DMSO-d6) δ12.01 (s, 1H), 8.78 (s, 1H), 8.29 (s, 1H), 7.55 (d, J=8.7 Hz, 1H), 6.95 (d, J=6.8Hz, 1H), 5.84 (s, 1H), 5.00 (s, 1H), 4.43 (s, 2H), 3.62-3.5 5(m, 1H), 3.12-3.02(m, 1H), 2.79(s, 3H), 2.48-2.42(m, 1H), 2.07-1.95(m, 1H), 1.95-1.85 (m, 1H), 1.78-1.66 (m, 2H), 1.65-1.56 (m, 1H), 1.03 (d, J=6.2Hz, 6H). LC-MS(ESI):m / z[M+H] + =452.2.

[1080] Chiral analysis method: column: CHIRALPAK i-cellulose-54.6 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.1% 2M NH 3 MeOH); gradient: mobile phase A: mobile phase B = 70:30 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[1081] Chiral preparative HPLC conditions: CHIRALPAK i-cellulose-520 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B = 70:30 (v / v); flow rate: 18 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[1082] Example 122: cis-3-(3-((4-fluoro-2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl propylcarbamate

[1083]

[1084] The title compound was synthesized in racemic form in analogy to the procedure of Example 121 and further purified by chiral preparative HPLC to give:

[1085] Enantiomer 1 (Example 122a, 100% ee); retention time: 6.266 min. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.54 (d, J=8.6Hz, 1 H), 7.04 (s, 1H), 5.83 (s, 1H), 5.05-4.93 (m, 1H), 4.43 (s, 2H), 3.14-3.02 (m, 1H), 2. 96-2.86(m, 2H), 2.78(s, 3H), 2.48-2.40(m, 1H), 2.07-1.99(m, 1H), 1.98-1.85(m, 1 H), 1.80-1.66 (m, 2H), 1.65-1.55 (m, 1H), 1.44-1.32 (m, 2H), 0.82 (t, J=7.4Hz, 3H). LC-MS(ESI):m / z[M+H] + =452.60.

[1086] Enantiomer 2 (Example 122b, 100% ee); retention time: 11.396 min. 1H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.54 (d, J=8.6Hz, 1 H), 7.04 (s, 1H), 5.83 (s, 1H), 5.05-4.93 (m, 1H), 4.43 (s, 2H), 3.14-3.02 (m, 1H), 2. 96-2.86(m, 2H), 2.78(s, 3H), 2.48-2.40(m, 1H), 2.07-1.99(m, 1H), 1.98-1.85(m, 1 H), 1.80-1.66 (m, 2H), 1.65-1.55 (m, 1H), 1.44-1.32 (m, 2H), 0.82 (t, J=7.4Hz, 3H). LC-MS(ESI):m / z[M+H] + =452.60.

[1087] Chiral analysis method: column: CHIRALPAK i-cellulose-5 4.6 mm×250 mm, 5 μm; mobile phase: A: MTBE (0.1% 2 M NH 3 MeOH), and B: MeOH / DCM (1 / 1); gradient: mobile phase A: mobile phase B = 70:30 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[1088] Chiral preparative HPLC conditions: CHIRALPAK i-cellulose-5 20 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B = 70:30 (v / v); flow rate: 18 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[1089] Example 123: 3-(3-((4-fluoro-2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-((S)-sec-butyl)carbamate

[1090]

[1091] The title compound was synthesized in racemic form in analogy to the procedure of Example 121 and further purified by chiral preparative HPLC to give:

[1092] Enantiomer 1 (Example 122a, 100% ee); retention time: 5.514 min. 1H NMR (500MHz, DMSO-d6) δ11.99 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 7.54 (d, J=8.6 Hz, 1H), 6.87 (d, J=6.9Hz, 1H), 5.83 (s, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.45-3.3 5(m, 1H), 3.10-3.05(m, 1H), 2.78(s, 3H), 2.47-2.42(m, 1H), 2.05-1.85(m, 2H), 1.78-1.53 ​​(m, 3H), 1.40-1.28 (m, 2H), 1.03-0.96 (m, 3H), 0.80 (q, J=7.1Hz, 3H). LC-MS(ESI):m / z[M+H] + =466.2.

[1093] Enantiomer 2 (Example 122b, 100% ee); retention time: 11.385 min. 1 H NMR (500MHz, DMSO-d6) δ11.99 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 7.54 (d, J=8.6 Hz, 1H), 6.87 (d, J=6.9Hz, 1H), 5.83 (s, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.45-3.3 5(m, 1H), 3.10-3.05(m, 1H), 2.78(s, 3H), 2.47-2.42(m, 1H), 2.05-1.85(m, 2H), 1.78-1.53 ​​(m, 3H), 1.40-1.28 (m, 2H), 1.03-0.96 (m, 3H), 0.80 (q, J=7.1Hz, 3H). LC-MS(ESI):m / z[M+H] + =466.2.

[1094] Chiral analysis method: column: CHIRALPAK i-cellulose-5 4.6 mm×250 mm, 5 μm; mobile phase: A: MTBE (0.1% 2 M NH 3 MeOH), and B: MeOH / DCM (1 / 1); gradient: mobile phase A: mobile phase B = 70:30 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[1095] Chiral preparative HPLC conditions: CHIRALPAK i-cellulose-520 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B = 70:30 (v / v); flow rate: 18 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[1096] Example 124: 3-(3-((4-fluoro-2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-(1-methylcyclopropyl)carbamate

[1097]

[1098] The title compound was synthesized in analogy to the procedure of Example 121. 1 H NMR (500MHz, DMSO-d6) δ11.99 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 7.54 (d, J = 8.6Hz, 1H), 7.33 (s, 1H), 5.83 (s, 1H), 4.99 (s, 1H), 4.42 (s , 2H), 3.10-3.02(m, 1H), 2.78(s, 3H), 2.46-2.42(m, 1H), 2.10-1.85(m, 2H), 1.78-1.55(m, 3H), 1.23(s, 3H), 0.59(s, 2H), 0.47(s, 2H). LC-MS(ESI):m / z[M+H] + =464.2.

[1099] Example 125: cis-3-(3-((4-fluoro-2-(2-hydroxyethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[1100]

[1101] The title compound was synthesized in racemic form in analogy to the procedure of Example 37, which was further separated by chiral preparative HPLC to give:

[1102] Enantiomer 1 (Example 125a, 100% ee); retention time: 14.34 min. 1H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.29 (d, J = 7.7Hz, 1H), 7.54 (d, J = 8.6Hz, 1H) , 6.94 (d, J=7.4Hz, 1H), 5.83 (s, 1H), 4.99 (s, 1H), 4.91 (t, J=5.6Hz, 1H), 4.54 (s, 2H), 3.68 (q, J =5.7Hz, 2H), 3.62-3.54 (m, 1H), 3.21 (t, J = 5.8Hz, 2H), 3.12-3.01 (m, 1H), 2.29-2.23 (m, 1H), 2. 05-1.96 (m, 1H), 1.96-1.86 (m, 1H), 1.75-1.65 (m, 2H), 1.64-1.55 (m, 1H), 1.03 (d, J=6.1Hz, 7H). LC-MS(ESI):m / z[M+H] + =482.2.

[1103] Enantiomer 2 (Example 125b, 98.8% ee); retention time: 15.95 min. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.78 (s, 1H), 8.30 (t, J=7.8Hz, 1H), 7.54 (d, J=8 .6Hz, 1H), 6.95 (d, J=7.8Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.92 (t, J=5.5Hz, 1H), 4.5 4(s, 2H), 3.68(q, J=5.7Hz, 2H), 3.62-3.56(m, 1H), 3.21(t, J=5.8Hz, 2H), 3.10-3.01( m, 1H), 2.47-2.43 (m, 1H), 2.07-1.87 (m, 2H), 1.78-1.55 (m, 3H), 1.03 (d, J=6.0Hz, 6H). LC-MS(ESI):m / z[M+H] + =482.2.

[1104] Chiral analysis method: column: CHIRALPAK i-cellulose-54.6 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.1% 2M NH 3 MeOH); gradient: mobile phase A: mobile phase B = 70:30 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[1105] Chiral preparative HPLC conditions: CHIRALPAK i-cellulose-5 20 mm×250 mm, 5 μm; mobile phase: A: hexane, and B: EtOH (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B = 70:30 (v / v); flow rate: 18 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[1106] Example 126: cis-3-(3-((4-fluoro-2-(2-hydroxyethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl propylcarbamate

[1107]

[1108] The title compound was synthesized in a similar manner to the procedure of Example 37. 1 H NMR (500MHz, DMSO-d6) δ = 12.00 (s, 1H), 8.76 (s, 1H), 8.28 (s, 1H), 7.54 (d, J = 8.6, 1H) , 7.03 (t, J=5.1, 1H), 5.84 (s, 1H), 5.00 (m, 1H), 4.54 (s, 2H), 3.68 (t, J=5.8, 2H), 3.21 (t, J=5.8, 2H), 3.11-3.02 (m, 1H), 2.92 (m, 2H), 2.47-2.41 (m, 1H), 2.03 (m, 1H), 1.98 -1.83 (m, 1H), 1.81-1.65 (m, 2H), 1.65-1.54 (m, 1H), 1.39 (m, 2H), 0.82 (t, J=7.4, 3H). LC-MS(ESI):m / z[M+H] + =482.2.

[1109] Example 127: 3-(3-((4-fluoro-2-(2-hydroxyethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-((S)-sec-butyl)carbamate

[1110]

[1111] The title compound was synthesized in a similar manner to the procedure of Example 37. 1H NMR (500MHz, DMSO-d6) δ = 11.99 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 7.53 (d, J = 8.6, 1H ), 6.87 (d, J=7.9, 1H), 5.84 (s, 1H), 4.99 (s, 1H), 4.54 (s, 2H), 3.68 (t, J=5.8, 2H), 3 .39(m, 1H), 3.21(t, J=5.8, 2H), 3.11-3.03(m, 1H), 2.47-2.43(m, 1H), 2.03(m, 1H), 1.93 (m, 1H), 1.73 (m, 2H), 1.60 (m, 1H), 1.35 (m, 2H), 1.05-0.93 (m, 3H), 0.80 (m, 3H). LC-MS(ESI):m / z[M+H] + =496.3.

[1112] Example 128: 3-(3-((4-fluoro-2-(2-hydroxyethyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-(1-methylcyclopropyl)carbamate

[1113]

[1114] The title compound was synthesized in racemic form in analogy to the procedure of Example 37, which was further separated by chiral preparative HPLC to give:

[1115] Enantiomer 1 (Example 128a, 100% ee); retention time: 6.156 min. 1 H NMR (500MHz, DMSO-d6) δ = 11.99 (s, 1H), 8.77 (s, 1H), 8.29 (t, J = 8.0, 1H), 7.54 (d, J =8.6, 1H), 7.34 (s, 1H), 5.82 (s, 1H), 4.99 (m, 1H), 4.91 (t, J = 5.5, 1H), 4.54 (s, 2H) , 3.68 (q, J=5.7, 2H), 3.21 (t, J=5.8, 2H), 3.06 (m, 1H), 2.46 (m, 1H), 2.02 (m, 1H), 1 .90 (m, 1H), 1.69 (m, 2H), 1.57 (m, 1H), 1.23 (s, 3H), 0.57 (m, 2H), 0.53-0.40 (m, 2H). LC-MS(ESI):m / z[M+H] + =494.28.

[1116] Enantiomer 2 (Example 128b, 100% ee); retention time: 11.817 min. 1 H NMR (500MHz, DMSO-d6) δ = 11.99 (s, 1H), 8.77 (s, 1H), 8.29 (s, 1H), 7.54 (d, J = 8.6 , 1H), 7.34 (s, 1H), 5.83 (s, 1H), 4.99 (m, 1H), 4.91 (t, J=5.5, 1H), 4.54 (s, 2H), 3. 68 (q, J=5.7, 2H), 3.21 (t, J=5.8, 2H), 3.05 (m, 1H), 2.47 (m, 1H), 2.02 (m, 1H), 1.8 8 (m, 1H), 1.69 (m, 2H), 1.57 (m, 1H), 1.23 (s, 3H), 0.59 (m, 2H), 0.53-0.43 (m, 2H). LC-MS(ESI):m / z[M+H] + =494.26.

[1117] Chiral analysis method: column: CHIRALPAK IE 4.6*250mm 5μm; mobile phase: A: MtBE (0.1% 2M NH3MeOH), and B: 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.

[1118] Chiral preparative HPLC conditions: CHIRALPAK IE 20*250mm 5μm; mobile phase: A: MtBE, and B: MeOH: DCM = 50: 50 (0.1% 2M NH3MeOH): gradient: mobile phase A: mobile phase B = 20: 80 (v / v); flow rate: 18 mL / min, wavelength: UV 280 nm and 300 nm, preparative HPLC equipment: preparative HPLC-Gilson; column temperature: 25°C.

[1119] Example 129: cis-3-(3-((4-fluoro-2-(methyl-d3)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[1120]

[1121] The title compound was synthesized in racemic form in analogy to the procedure of Example 35, which was further separated by chiral preparative HPLC to give:

[1122] Enantiomer 1 (Example 129a, 100% ee); retention time: 5.906 min. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 7.8Hz, 1H), 7.54 (d, J = 8.6Hz, 1H), 6.94 (d, J = 7.3Hz, 1H), 5.83 (s, 1H), 4.9 9(s, 1H), 4.42(s, 2H), 3.64-3.47(m, 1H), 3.12-3.01(m, 1H), 2.48-2.43(m, 1H), 2.07-1.85(m, 2H), 1.77-1.56(m, 3H), 1.10-0.96(m, 6H). LC-MS(ESI):m / z[M+H] + =455.2.

[1123] Enantiomer 2 (Example 129b, 100% ee); retention time: 1.718 min. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 7.9Hz, 1H), 7.54 (d, J = 8.6Hz, 1H), 6.94 (d, J = 7.3Hz, 1H), 5.83 (s, 1H), 5.0 0 (s, 1H), 4.42 (s, 2H), 3.62-3.53 (m, 1H), 3.11-3.03 (m, 1H), 2.48-2.43 (m, 1H), 2.07-1.85 (m, 2H), 1.77-1.56 (m, 3H), 1.10-0.96 (m, 6H). LC-MS(ESI):m / z[M+H] + =455.2.

[1124] Chiral analysis method: column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; mobile phase: A: MTBE (0.1% 2M NH3MeOH), and B: MeOH / DCM (1 / 1); gradient: mobile phase A: mobile phase B = 10:90 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35 ° C.

[1125] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm×250 mm, 5 μm; mobile phase: A: MTBE (0.1% 2M NH 3 MeOH), and B: MeOH / DCM (1 / 1); gradient: mobile phase A: mobile phase B = 10:90 (v / v); flow rate: 18 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25° C.

[1126] Example 130: cis-3-(3-((4-fluoro-2-(methyl-d3)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl propylcarbamate

[1127]

[1128] The title compound was synthesized in a similar manner to the procedure of Example 35. 1 H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.54 (d, J =8.6Hz, 1H), 7.04(s, 1H), 5.83(s, 1H), 5.00(s, 1H), 4.42(s, 2H), 3.12-3.0 3(m, 1H), 2.91(dd, J=13.1, 6.6Hz, 2H), 2.48-2.43(m, 1H), 2.06-1.88(m, 2 H), 1.78-1.55 (m, 3H), 1.39 (dd, J=14.5, 7.2Hz, 2H), 0.82 (t, J=7.4Hz, 3H). LC-MS (ESI): m / z [M+H] + =455.3.

[1129] Example 131: 3-(3-((4-fluoro-2-(methyl-d3)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-((S)-sec-butyl)carbamate

[1130]

[1131] The title compound was synthesized in a similar manner to the procedure of Example 35. 1H NMR (500MHz, DMSO-d6) δ12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.54 (d, J=8 .6Hz, 1H), 6.88 (d, J=8.6Hz, 1H), 5.84 (s, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.4 4-3.35(m, 1H), 3.12-3.02(m, 1H), 2.46-2.44(m, 1H), 2.06-1.85(m, 2H), 1.7 7-1.56 (m, 3H), 1.41-1.26 (m, 2H), 1.02-0.96 (m, 3H), 0.80 (q, J=7.2Hz, 3H). LC-MS(ESI):m / z[M+H] + =469.2.

[1132] Example 132: 3-(3-((4-fluoro-2-(methyl-d3)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-(1-methylcyclopropyl)carbamate

[1133]

[1134] The title compound was synthesized in racemic form in analogy to the procedure of Example 35, which was further separated by chiral preparative HPLC to give:

[1135] Enantiomer 1 (Example 132a, 100% ee); retention time: 6.279 min. 1 H NMR (500MHz, DMSO-d6) δ = 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 8.0, 1H), 7.54 (d, J = 8.6, 1H), 7.34 (s, 1H), 5.83 (s, 1H), 4.99 (m, 1H), 4.42 (s, 2H), 3.06 (m, 1H), 2.46 (m, 1H), 2.02 (m, 1H), 1.97-1.85 (m, 1H), 1.69 (m, 2H), 1.57 (m, 1H), 1.23 (s, 3H), 0.59 (m, 2H), 0.51-0.44 (m, 2H). LC-MS(ESI):m / z[M+H] + =467.33.

[1136] Enantiomer 2 (Example 132b, 100% ee); retention time: 10.24 min. 1H NMR (500MHz, DMSO-d6) δ = 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 7.8, 1H), 7.54 (d, J = 8.6, 1H), 7.34 (s, 1H), 5.83 (s, 1H), 4.99 (m, 1H), 4. 42 (s, 2H), 3.06 (m, 1H), 2.46 (m, 1H), 2.02 (m, 1H), 1.90 (m, 1H), 1.69 (m, 2H), 1.57 (m, 1H), 1.23 (s, 3H), 0.57 (m, 2H), 0.53-0.41 (m, 2H). LC-MS(ESI):m / z[M+H] + =467.34.

[1137] Chiral analysis method: column: CHIRALPAK IE 4.6*250mm 5μm; mobile phase: A: MtBE (0.1% 2M NH3MeOH), and B: 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.

[1138] Chiral preparative HPLC conditions: CHIRALPAK IE 20*250mm 5μm; mobile phase: A: MtBE, and B: MeOH: DCM = 50: 50 (0.1% 2M NH3MeOH); gradient: mobile phase A: mobile phase B = 20: 80 (v / v); flow rate: 18 mL / min, wavelength: UV 280 nm and 300 nm, preparative HPLC equipment: preparative HPLC-Gilson: column temperature: 25°C.

[1139] Example 133: cis-3-(3-((4-fluoro-2-(oxetan-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[1140]

[1141] The title compound was synthesized in racemic form in analogy to the procedure of Example 63, which was further separated by chiral preparative HPLC to give:

[1142] Enantiomer 1 (Example 133a, 100% ee); retention time: 5.684 min. 1H NMR (500MHz, DMSO-d6) δ12.01 (s, 1H), 8.84 (s, 1H), 8.32 (t, J=8.1Hz, 1H), 7.56 (d , J=8.7Hz, 1H), 6.94 (d, J=6.8Hz, 1H), 5.84 (d, J=1.9Hz, 1H), 5.00 (s, 1H), 4.87 (t , J=6.1Hz, 2H), 4.76 (dq, J=8.2, 6.3Hz, 5H), 3.62-3.53 (m, 1H), 3.12-3.03 (m, 1H) , 2.48-2.43 (m, 1H), 2.06-1.87 (m, 2H), 1.78-1.55 (m, 3H), 1.03 (d, J=6.2Hz, 6H). LC-MS(ESI):m / z[M+H] + =494.2.

[1143] Enantiomer 2 (Example 133b, 100% ee); retention time: 10.123 min. 1 H NMR (500MHz, DMSO-d6) δ12.01 (s, 1H), 8.84 (s, 1H), 8.32 (t, J=8.1Hz, 1H), 7.56 (d , J=8.7Hz, 1H), 6.94 (d, J=6.8Hz, 1H), 5.84 (d, J=1.9Hz, 1H), 5.00 (s, 1H), 4.87 (t , J=6.1Hz, 2H), 4.76 (dq, J=8.2, 6.3Hz, 5H), 3.62-3.53 (m, 1H), 3.12-3.03 (m, 1H) , 2.48-2.43 (m, 1H), 2.06-1.87 (m, 2H), 1.78-1.55 (m, 3H), 1.03 (d, J=6.2Hz, 6H). LC-MS(ESI):m / z[M+H] + =494.2.

[1144] Chiral analysis method: column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; mobile phase: A: MTBE (0.1% 2M NH3MeOH), and B: MeOH / DCM (1 / 1); gradient: mobile phase A: mobile phase B = 10:90 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35 ° C.

[1145] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm×250 mm, 5 μm; mobile phase: A: MTBE (0.1% 2M NH 3 MeOH), and B: MeOH / DCM (1 / 1); gradient: mobile phase A: mobile phase B = 10:90 (v / v); flow rate: 18 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25°C.

[1146] Example 134: 3-(3-((4-fluoro-2-(oxetan-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-((S)-sec-butyl)carbamate

[1147]

[1148] The title compound was synthesized in racemic form in analogy to the procedure of Example 63, which was further separated by chiral preparative HPLC to give:

[1149] Enantiomer 1 (Example 134a, 100% ee); retention time: 5.451 min. 1 H NMR (500MHz, DMSO-d6) δ12.01 (s, 1H), 8.84 (s, 1H), 8.31 (s, 1H), 7.55 (d, J = 8.7Hz, 1H), 6.88 (d, J=7.8Hz, 1H), 5.84 (s, 1H), 4.99 (s, 1H), 4.87 (t, J=6.1Hz, 2H), 4.81-4 .72(m, 5H), 3.43-3.35(m, 1H), 3.10-3.02(m, 1H), 2.47-2.45(m, 1H), 2.10-1.85(m, 2H), 1.78-1.55 (m, 3H), 1.40-1.28 (m2H), 1.04-0.98 (m, 3H), 0.80 (q, J=7.2Hz, 3H). LC-MS(ESI):m / z[M+H] + =508.3.

[1150] Enantiomer 2 (Example 134b, 100% ee); retention time: 10.665 min. 1H NMR (500MHz, DMSO-d6) δ12.01 (s, 1H), 8.84 (s, 1H), 8.31 (s, 1H), 7.55 (d, J = 8.7Hz, 1H), 6.88 (d, J = 7.8Hz, 1H), 5.84 (s, 1H), 4.99 (s, 1H), 4.87 (t , J=6.1Hz, 2H), 4.81-4.72(m, 5H), 3.43-3.35(m, 1H), 3.10-3.02(m, 1H) , 2.47-2.45(m, 1H), 2.10-1.85(m, 2H), 1.78-1.55(m, 3H), 1.40-1.28(m 2H), 1.04-0.98 (m, 3H), 0.80 (q, J=7.2Hz, 3H). LC-MS(ESI):m / z[M+H] + =508.3.

[1151] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A: MTBE (0.1% 2M NH 3 MeOH), and B: MeOH / DCM (1 / 1); gradient: mobile phase A: mobile phase B = 10:90 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[1152] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm×250 mm, 5 μm; mobile phase: A: MTBE (0.1% 2M NH 3 MeOH), and B: MeOH / DCM (1 / 1); gradient: mobile phase A: mobile phase B = 10:90 (v / v); flow rate: 18 mL / min, wavelength: UV 200 nm and 270 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: 25° C.

[1153] Example 135: 3-(3-((4-fluoro-2-(oxetan-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl cis-(1-methylcyclopropyl)carbamate

[1154]

[1155] The title compound was synthesized in a similar manner to the procedure of Example 63. 1H NMR (500MHz, DMSO-d6) δ12.01 (s, 1H), 8.84 (s, 1H), 8.31 (s, 1H), 7.55 (d, J = 8.7Hz, 1H), 7.34 (s, 1H), 5.83 (s, 1H), 4.98 (s, 1H), 4.87 (t, J = 6.1Hz, 2H ), 4.82-4.68(m, 5H), 3.12-3.02(m, 1H), 2.45-2.41(m, 1H), 2.11-1.85(m , 2H), 1.75-1.55 (m, 3H), 1.23 (s, 3H), 0.59 (s, 2H), 0.47 (q, J=4.6Hz, 2H). LC-MS (ESI): m / z [M+H] + =506.2.

[1156] Example 136: cis-3-(3-((4-fluoro-2-(oxetan-3-yl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl propylcarbamate

[1157]

[1158] The title compound was synthesized in a similar manner to the procedure of Example 63. 1 H NMR (500MHz, DMSO-d6)) δ12.02 (s, 1H), 8.84 (s, 1H), 8.31 (t, J=8.0Hz, 1H), 7.55 (d, J=8. 7Hz, 1H), 7.04 (t, J=5.4Hz, 1H), 5.84 (s, 1H), 5.00 (d, J=4.8Hz, 1H), 4.87 (t, J=6.1Hz, 2H) , 4.81-4.73 (m, 5H), 3.11-3.02 (m, 1H), 2.92 (dd, J=13.1, 6.6Hz, 2H), 2.48-2.43 (m, 1H), 2 .08-1.88 (m, 2H), 1.78-1.57 (m, 3H), 1.39 (dd, J=14.4, 7.2Hz, 2H), 0.82 (t, J=7.4Hz, 3H). LC-MS(ESI):m / z[M+H] + =494.2.

[1159] Example 137: 3-(3-((4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclobutyl isopropylcarbamate

[1160]

[1161] The title compound was synthesized in a similar manner to the procedure of Example 50. 1 H NMR (500MHz, DMSO-d6) δ12.07 (s, 1H), 8.74 (s, 1H), 8.25 (s, 1H), 7.69 (dd, J=10.0, 4.9Hz, 1H), 7.48 (d, J=8.6Hz, 1H), 7.09-7.02 (m, 1H), 5.87 (s, 1H), 4.85-4.77 (m, 1H), 4.41 (d, J=3.5Hz, 2H), 3.64-3.56 (m, 1H), 3.12-3 .05 (m, 1H), 2.72-2.64 (m, 2H), 2.12-2.05 (m, 2H), 1.04 (d, J=6.6Hz, 6H). LC-MS (ESI): m / z [M+H] + =424.2.

[1162] Example 138: cis-3-(3-((4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl propylcarbamate

[1163] Step 1: cis-propylcarbamic acid 3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentane esters

[1164]

[1165] To a solution of benzyl cis-(5-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamate (7 g, 15 mmol) in 100 mL of THF was added propylamine (2.6 g, 45 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EA=2:1) ​​to give the product (4.6 g, 80% yield). LC-MS (ESI): m / z[M+H] + =387.3.

[1166] Step 2: cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentylpropylcarbamate

[1167]

[1168] To a solution of cis-propylcarbamic acid 3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl ester (4.6 g, 12 mmol) in THF (100 mL) was added Pd / C (10%, wet, 3 g). The suspension was degassed and purged with hydrogen three times. The resulting mixture was stirred at room temperature under a hydrogen balloon for 3 h. The mixture was filtered, and the filter cake was washed with MeOH (50 mL×3). The filtrate was concentrated under reduced pressure to give the product (2.6 g, 86% yield). LC-MS (ESI): m / z[M+H] + =253.4.

[1169] Step 3: cis-propylcarbamic acid 3-(3-((4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazolyl- 5-amino)-1H-pyrazol-5-yl)cyclopentyl ester

[1170]

[1171] A mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (150 mg, 0.57 mmol), cis-propylcarbamic acid 3-(3-amino-1H-pyrazol-5-yl)cyclopentyl ester (144.2 mg, 0.19 mmol), Brettphos PdG3 (51.3 mg, 0.057 mmol), K2CO3 (235.9 mg, 1.71 mmol) in t-BuOH (20 mL) was stirred at 110° C. under N2 atmosphere for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 100% EA to give the product. The residue was purified by preparative HPLC (Waters XSelect C18: RD-CO-094 column eluting with a gradient of acetonitrile / water (containing 0.1% FA, 20%-40%) to give the product in racemic form, which was further separated by chiral preparative HPLC to give:

[1172]

[1173] Enantiomer 1 ((1R,3S)-3-(3-((4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate, Example 138a, 100% ee); retention time: 5.204 min. 1H NMR (500MHz, DMSO-d6)) δ11.99 (s, 1H), 8.71 (s, 1H), 8.25 (s, 1H), 7.70 (t, J=4.9Hz, 1H) , 7.48 (d, J=8.6Hz, 1H), 7.03 (m, 1H), 5.83 (s, 1H), 5.01 (s, 1H), 4.41 (d, J=5.2Hz, 2H), 3 .13-3.03(m, 1H), 2.96-2.88(m, 2H), 2.48-2.41(m, 1H), 2.07-1.98(m, 1H), 1.97-1.87( m, 1H), 1.80-1.67 (m, 2H), 1.67-1.55 (m, 1H), 1.46-1.32 (m, 2H), 0.82 (t, J=7.4Hz, 3H). LC-MS(ESI):m / z[M+H] + =438.2.

[1174]

[1175] Enantiomer 2 ((1S,3R)-3-(3-((4-fluoro-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate, Example 138b, 100% ee); retention time: 8.999 min. 1 H NMR (500MHz, DMSO-d6)) δ11.99 (s, 1H), 8.71 (s, 1H), 8.25 (s, 1H), 7.70 (t, J=4.9Hz, 1H) , 7.48 (d, J=8.6Hz, 1H), 7.03 (m, 1H), 5.83 (s, 1H), 5.01 (s, 1H), 4.41 (d, J=5.2Hz, 2H), 3 .13-3.03(m, 1H), 2.96-2.88(m, 2H), 2.48-2.41(m, 1H), 2.07-1.98(m, 1H), 1.97-1.87( m, 1H), 1.80-1.67 (m, 2H), 1.67-1.55 (m, 1H), 1.46-1.32 (m, 2H), 0.82 (t, J=7.4Hz, 3H). LC-MS(ESI):m / z[M+H] + =438.2.

[1176] Chiral analysis method: column: CHIRALPAK IE 4.6 mm×250 mm, 5 μm; mobile phase: A: MtBE (0.1% 2M NH 3 MeOH), and B: EtOH; gradient: mobile phase A: mobile phase B = 20:80 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; column temperature: 35° C.

[1177] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm × 250 mm, 5 μm; mobile phase: A: MtBE, and B: EtOH (0.2% 2M NH3 MeOH); gradient: mobile phase A: mobile phase B = 20: 80 (v / v); flow rate: 18 mL / min, wavelength: UV280 nm ...

Claims

1. A compound having formula (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: 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 or 1, provided that n5 and n6 are not 0 at the same time; each independently a single bond or a double bond, provided that the two double bonds are not directly connected; X 1 , X 2 , X 3 and X 4 Each is independently selected from N, C, S(=O)2 or S(=O), wherein each N is independently replaced by 0 or 1 R when the valence permits Xa and each C is independently replaced by one or two R Xb group substitution; R Xa Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 12 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 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R Xaa replace; R Xaa Each is independently selected from hydrogen, deuterium, 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 Xab 、-CN、-SO2R Xab 、-SO2NR Xab R Xac 、-C(O)R Xab 、-CO2R Xab 、-C(O)NR Xab R Xac 、-NR Xab R Xac 、-NR Xab COR Xac 、-NR Xab CO2R Xac or -NR Xab S02R Xac wherein the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -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 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 Xad 、-SO2R Xad 、-SO2NR Xad R Xae 、-C(O)R Xad 、-CO2R Xad 、-C(O)NR Xad R Xae 、-NR Xad R Xae 、-NR Xad COR Xae 、-NR Xad CO2R Xae or -NR Xad S02R Xae replace: R Xab , R Xac , R Xad and R Xae 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-C 12 Each of the aryl, or 5 to 12 membered heteroaryl 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, —OH, or —C1-C8 alkoxy substituted: R Xb Each is independently selected from hydrogen, halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Xba R Xbb 、-OR Xba 、-SR Xba 、-SO2R Xba 、-SO2NR Xba R Xbb 、-C(O)R Xba 、-CO2R Xba 、-C(O)NR Xba R Xbb 、-NR Xba COR Xbb 、-NR Xba CO2R Xbb or -NR Xba S02R Xbb or -CN, wherein the -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl group, or the 5- to 12-membered heteroaryl group is optionally substituted by at least one R Xbc replace; or Two R's Xb Together with the one or more atoms to which they are attached, they form a 3- to 12-membered ring comprising, as one or more ring members, 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; said ring is optionally substituted with at least one substituent R Xbc replace; R Xba and R Xbb 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-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent R Xbd replace; R Xbc and R Xbd 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 Xbe R Xbf 、-OR Xbe 、-SR Xbe 、-SO2R Xbe 、-SO2NR Xbe R Xbf 、-C(O)R Xbe 、-CO2R Xbe 、-C(O)NR Xbe R Xbf 、-NR Xbe COR Xbf 、-NR Xbe CO2R Xbf or -NR Xbe S02R Xbf or -CN; R Xbe and R Xbf 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 Each is independently selected from O, C or N, wherein C and N are independently replaced by 1 or 2 R 5 radical or hydrogen atom substitution; Q is selected from O or NR Q ; R 1 , R 2 , 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 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 1a replace; or (R 1 and R 2 )、(R 1 and R Q ) or (R Q and R 2 ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0-3 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; said ring is optionally substituted with at least one substituent R 1b replace; R 1a and R 1b Each is 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 1c 、-CN、-SO2R 1c 、-SO2NR 1c R 1d 、-C(O)R 1c 、-CO2R 1c 、-C(O)NR 1c R 1d 、-NR 1c R 1d 、-NR 1c COR 1d 、-NR 1c CO2R 1d or -NR 1c S02R 1d , wherein -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -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 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 1e 、-SO2R 1e 、-SO2NR 1e R 1f 、-C(O)R 1e 、-CO2R 1f 、-C(O)NR 1e R 1f 、-NR 1e R 1f 、-NR 1e COR 1f 、-NR 1e CO2R 1f or -NR 1e S02R 1f replace; R 1c , R 1d , R 1e and R 1f 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 and R 5 Each is independently 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 or -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 group, or the 5- to 12-membered heteroaryl group is optionally substituted by 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 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 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent 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 or -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 a 5- to 12-membered heteroaryl.

2. The compound of claim 1, wherein the compound is selected from (IIa), (IIb), (IIc) and (IId): Preferably, the compound is selected from (IIe), (IIf), (IIg), (IIh), (IIi) and (IIj):

3. The compound of claim 1, wherein the compound is selected from (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg) and (IIIh):

4. The compound of claim 1, wherein the compound is selected from (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (IVl), (IVm), (IVn), (IVo), (IVp), (IVq), (IVr), (IVs), (IVt), (IVu), (IVv), (IVw) and (IVx): Preferably, the compound is selected from (Va) and (VIa): Preferably, the compound is selected from (Vb), (Vc), (VIb) and (VIc): More preferably, the compound is selected from (Vd) and (VId) Even more preferably, the compound is selected from (Ve), (Vf), (VIe) and (VIf):

5. A compound as claimed in any one of the preceding claims, wherein R 1 , R 2 , 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, cyclononyl, cyclodecyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, wherein each of 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, cyclononyl, cyclodecyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl is optionally substituted by at least one substituent R 1a replace; R 1a 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, oxo (=O), -OR 1c 、-CN、-SO2R 1c 、-SO2NR 1c R 1d 、-C(O)R 1c 、-CO2R 1c 、-C(O)NR 1c R 1d 、-NR 1c R 1d 、-NR 1c COR 1d 、-NR 1c CO2R 1d or -NR 1c S02R 1d 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 heterocyclyl, phenyl, 5 to 12 membered heteroaryl Each of the groups 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 1e 、-SO2R 1e 、-SO2NR 1e R 1f 、-C(O)R 1e 、-CO2R 1f 、-C(O)NR 1e R 1f 、-NR 1e R 1f 、-NR 1e COR 1f 、-NR 1e CO2R 1f or -NR 1e S02R 1f replace: R 1c , R 1d , R 1e and R 1f 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 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 heptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or i-propyl), butyl (n-, sec-, i-, or t-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 1 , R 2 , 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 1 , R 2 , 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 1 and R 2 Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl Isobutyl or tert-butyl); And R 3 and R Q are each independently hydrogen.

6. A compound as claimed in any one of the preceding claims, wherein R 1 R is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxetanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[2.3]hexanyl or tetrahydrofuranyl, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxetanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[2.3]hexanyl or tetrahydrofuranyl is optionally substituted with at least one substituent R 1a replace; R 1a independently selected from hydrogen, -F, -Cl, -Br, -I, oxo (=O), methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptyl, spiro[2.3]hexanyl, tetrahydrofuranyl, or -OR 1c wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by OR 1c replace; R 1e are independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl: and R 2 It is hydrogen: Preferably, R 1 is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptyl, spiro[2.3]hexanyl or tetrahydrofuranyl, wherein the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptyl, spiro[2.3]hexanyl or tetrahydrofuranyl each of cyclobutane, oxetanyl, oxanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[2.3]hexanyl, or tetrahydrofuranyl is optionally substituted with at least one substituent selected from OH, CH2OH, CHOMe, F, Cl, Br, oxo(═O), OMe, OEt, methyl, ethyl, cyclopropyl, cyclopropyl-OH, cyclobutyl, azetidinyl, oxetanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[2.3]hexanyl, or tetrahydrofuranyl; and R 2 It is hydrogen; More preferably, R 1 independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl Isobutyl or tert-butyl; And R 2 It's hydrogen.

7. A compound as claimed in any one of the preceding claims, wherein (R 1 and R 2 )、(R 1 and R Q ) or (R Q and R 2 ) together with the atom or atoms to which they are attached form a 3, 4, 5, 6, 7 or 8 membered ring comprising 0, 1, 2 or 3 further heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; said ring optionally being substituted with at least one substituent R 1b replace; R 1b 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 1c 、-CN、-SO2R 1c 、-SO2NR 1c R 1d 、-C(O)R 1c 、-CO2R 1c 、-C(O)NR 1c R 1d 、-NR 1c R 1d 、-NR 1c COR 1d 、-NR 1c CO2R 1d or -NR 1c S02R 1d 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 heterocyclyl, phenyl, 5 to 12 membered heteroaryl Each of the groups 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 1e 、-SO2R 1e 、-SO2NR 1e R 1f 、-C(O)R 1e 、-CO2R 1f 、-C(O)NR 1e R 1f 、-NR 1e R 1f 、-NR 1e COR 1f 、-NR 1e CO2R 1f or -NR 1e S02R 1f replace: R 1c , R 1d , R 1e and R 1f 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 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 heptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or i-propyl), butyl (n-, sec-, i-, or t-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 1 and R 2 )、(R 1 and R Q ) or (R Q and R 2 ) together with the one or more atoms to which they are attached form a 4, 5 or 6 membered ring; said ring is optionally substituted with at least one substituent R 1b replace; R 1b 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 1c 、-CN、-SO2R 1c 、-SO2NR 1c R 1d 、-C(O)R 1c 、-CO2R 1c 、-C(O)NR 1c R 1d 、-NR 1c R 1d 、-NR 1c COR 1d 、-NR 1c CO2R 1d or -NR 1c S02R 1d ; R 1c and R 1d 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 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 heptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or i-propyl), butyl (n-, sec-, i-, or t-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; More preferably, (R 1 and R 2 )、(R 1 and R Q ) or (R Q and R 2 ) together with the one or more atoms to which they are attached form a 4, 5 or 6 membered ring; said ring is optionally substituted with at least one substituent R 1b replace; R 1b independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -CN, or -NH2; Even more preferably, R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 4- or 5-membered ring; the ring is optionally substituted with at least one substituent R 1b replace; R 1b Independently selected from hydrogen, -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl) or -OH.

8. A compound as claimed in any one of the preceding claims, wherein the Partially selected 9. A compound as claimed in any one of the preceding claims, wherein R 4 and R 5 Each is 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, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; Preferably, R 4 and R 5 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl; Even more preferably, R 4 and R 5 are each independently selected from hydrogen.

10. A compound as claimed in any one of the preceding claims, wherein the Partially selected Preferably, the Partially selected More preferably, the Partially selected Even more preferably, the Partially selected 11. A compound 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 is N, and Z 2 and Z 3 Yes-CR Z ; or Z 2 is N, and Z 1 and Z 3 Yes-CR Z ; or Z 3 is N, and Z 1 and Z 2 Yes-CR Z .

12. A compound 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 or -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 R is 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-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 is optionally substituted by at least one substituent R Zd replace; R Z c 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, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -NR Z eR 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 or -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 or -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, -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, -CH2OH, -CH2CHF2, -CH2CF3, -NH2, -OH, -OCHF2, methoxy, ethoxy, propoxy, or butoxy.

13. A compound as claimed in any one of the preceding claims, wherein the Partially selected Preferably, the Partially selected 14. A compound as claimed in any one of the preceding claims, wherein X 1 , X 2 , X 3 and X 4 Each independently selected from N, NR Xa , CR Xb , C(R Xb )2, S(=O)2, the condition is X 1 , X 2 , X 3 and X 4 is valence-permitted; preferably, X 1 , X 2 , X 3 and X 4 At most one of N or NR Xa , X 1 , X 2 , X 3 and X 4 At most one of them is selected from S(=O)2 or S(=O).

15. A compound as claimed in any one of the preceding claims, wherein R Xa R is 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-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 is optionally substituted by at least one substituent R Xaa replace; R Xaa 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, oxo (=O), -OR Xab 、-CN、-SO2R Xab 、-SO2NR Xab R Xac 、-C(O)R Xab 、-CO2R Xab 、-C(O)NR Xab R Xac 、-NR Xab R Xac 、-NR Xab COR Xac 、-NR Xab CO2R Xac or -NR Xab S02R Xac 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 heterocyclyl, phenyl, 5 to 12 membered heteroaryl Each of the groups 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 Xad 、-SO2R Xad 、-SO2NR Xad R Xae 、-C(O)R Xad 、-CO2R Xad 、-C(O)NR Xad R Xae 、-NR Xad R Xae 、-NR Xad COR Xae 、-NR Xad CO2R Xae or -NR Xad S02R Xae replace; R Xab , R Xac , R Xad and R Xae 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 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 heptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or i-propyl), butyl (n-, sec-, i-, or t-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 Xa 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 or 3 to 8 membered heterocyclic radicals 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3 to 8 membered heterocyclic radicals, 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 or 3 to 8 membered heterocyclic radicals is optionally substituted by at least one substituent R Xaa replace; R Xaa 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, oxo (=O), -OR Xab 、-CN、-C(O)R Xab or -NR Xab R Xac 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 heterocyclyl, phenyl, 5 to 12 membered heteroaryl Each of the groups 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 Xad 、-SO2R Xad 、-C(O)R Xad or -NR Xad R Xae replace; R Xab , R Xac , R Xad and R Xae 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 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 heptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with -F, -Cl, -Br, -I, methyl, ethyl, propyl (n- or i-propyl), butyl (n-, sec-, i-, or t-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; More preferably, R Xa R is each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydrofuranyl, azetidinyl, or pyrrolidinyl, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydrofuranyl, azetidinyl, oxetanyl, or pyrrolidinyl is optionally substituted by at least one substituent R Xaa replace; R Xaa independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxo (=O), -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, -CN, benzyl, -NMe2, -NH2, -SO2Me, -COCH3, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, or azetidine is optionally replaced by F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, -OR Xad 、-SO2R Xad 、-C(O)R Xad replace; R Xad Selected from hydrogen, methyl, and ethyl: Even more preferably, R Xa Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, -C2H4OH, -C2H4OMe, -C3H6OH, -C3H6OMe, -CH2OMe, -C(CH3)2OH, -CD3, -CH2CF3, 16. A compound as claimed in any one of the preceding claims, wherein R Xb 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 Xba R Xbb 、-OR Xba 、-SR Xba 、-SO2R Xba 、-SO2NR Xba R Xbb 、-C(O)R Xba 、-CO2R Xba 、-C(O)NR Xba R Xbb 、-NR Xba COR Xbb 、-NR Xba CO2R Xbb or -NR Xba S02R Xbb 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 Xbc replace; R Xba and R Xbb R is 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-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 is optionally substituted by at least one substituent R Xbd replace; R Xbc and R Xbd 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, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo (=O), -NR Xbe R Xbf 、-OR Xbe 、-SR Xbe 、-SO2R Xbe 、-SO2NR Xbe R Xbf 、-C(O)R Xbe 、-CO2R Xbe 、-C(O)NR Xbe R Xbf 、-NRX be COR Xbf 、-NR Xbe CO2R Xbf or -NR Xbe S02R Xbf or -CN; R Xbe and R Xbf 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, 5 to 12 membered heteroaryl: Preferably, R Zb 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 Xba R Zbb 、-OR Xba 、-SR Xba 、-SO2R Xba 、-SO2NR Xba R Xbb 、-C(O)R Xba 、-CO2R Xba 、-C(O)NR Xba R Xbb 、-NR Xba COR Xbb 、-NR Xba CO2R Xbb or -NR Xba S02R Xbb or -CN; R Zba and R Xbb 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 Xb independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, -CD3, 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, -NH2, -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or -CN; Even more preferably, R Xb Independently selected from hydrogen, -F, -Cl, methyl, -CD3, 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.

17. A compound as claimed in any one of the preceding claims, wherein two R Xb Together with the one or more atoms to which they are attached, they form a 3, 4, 5, 6, 7 or 8 membered ring comprising, as one or more ring members, 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; said ring being optionally substituted with at least one substituent R Xbc replace; R Xbc 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, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo (=O), -NR Xbe R Xbf 、-OR Xbe 、-SR Xbe 、-SO2R Xbe 、-SO2NR Xbe R Xbf 、-C(O)R Xbe 、-CO2R Xbe 、-C(O)NR Xbe R Xbf 、-NRX be COR Xbf 、-NR Xbe CO2R Xbf or -NR Xbe S02R Xbf or -CN; R Xbe and R Xbf 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, 5 to 12 membered heteroaryl: Preferably, the two R Xb Together with the one or more 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 Xbc replace; R Xbc 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 Xb Together with the atom or atoms to which they are attached they form a 3-, 4-, 5- or 6-membered ring.

18. A compound as claimed in any one of the preceding claims, wherein the Partially selected 19. A compound as claimed in any one of the preceding claims, wherein the compound is selected from 20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a tautomer thereof, or a prodrug thereof, and at least one pharmaceutically acceptable carrier or excipient.

21. A method for treating cancer, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a tautomer thereof, or a prodrug thereof.

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