Bicyclic compounds as CDK inhibitors

Abstract

Disclosed herein are bicyclic compound derivatives for use as inhibitors of cyclin-dependent kinases. Disclosed herein are the use of these inhibitors to inhibit cyclin-dependent kinases and the use of such compounds to treat cancer. Cyclin-dependent kinases (CDKs), a family of Ser / Thr protein kinases, function as drivers of the cell cycle. During the cell cycle, CDK4 and CDK6 initiate phosphorylation of retinoblastoma (Rb) by binding to cyclin D, partially releasing the transcription factor E2F.

Description

[Technical Field]

[0001] Disclosed herein are bicyclic compound derivatives for use as inhibitors of cyclin-dependent kinases. Disclosed herein are the use of these inhibitors to inhibit cyclin-dependent kinases and the use of such compounds to treat cancer. [Background technology]

[0002] Cyclin-dependent kinases (CDKs), a family of Ser / Thr protein kinases, function as drivers of the cell cycle (Norbury, C. and Nurse, P., Annu Rev Biochem, 61, 441-470). During the cell cycle, CDK4 and CDK6 bind to cyclin D to initiate phosphorylation of retinoblastoma (Rb), partially releasing the transcription factor E2F. CDK2 then forms a complex with cyclin E to fully phosphorylate Rb, fully 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 largely dispensable for the cell cycle, but in some cancer cells, the kinase activity of CDK2 plays an important role in the abnormal growth process (Caruso, JA et al., Cancer Res, 78(19), 5481-5491).

[0003] Cancer cells with CCNE gene amplification or cyclin E overexpression overactivate CDK2 and dysregulate Rb phosphorylation, resulting in cancer cell proliferation (Wood, DJ et al., Cell Chem Biol, 26(1), 121-130). Aberrant CCNE has been demonstrated as a disease driver in multiple cancer types, including ovarian, esophageal, bladder, and pancreatic cancer, 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, YPet 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). Furthermore, one of the mechanisms of clinical drug resistance to CDK4 / 6i (such as palbociclib, ribociclib, and abemaciclib) in ER+HER2- breast cancer patients is overexpression of CCNE and activation of CDK2 (Knudsen, ES et al., Cell Rep, 38(9), 110448). CDK2 siRNA knockdown in palbociclib-resistant breast cancer cell lines and mouse models has shown that CDK2 inhibition can overcome CDK4 / 6 inhibitor resistance (Pandey, K. et al., Cancers (Basel), 12(12)). Another possible use of CDK2 inhibitors is based on the mechanism of trastuzumab resistance. The incidence of trastuzumab resistance in HER2+ BC patients with cyclin E amplification or overexpression is approximately 35%, which is associated with a worsening clinical benefit, while trastuzumab-resistant cells are highly sensitive to CDK2 inhibition (Scaltriti, M. et al., Proc Natl Acad Sci USA, 108(9), 3761-3766). CCNE1 amplification predicts response to CDK2 inhibition in a wide range of cancer types, indicating CDK2 as a potentially impactful therapeutic target.

[0004] Animal models have also demonstrated that targeting CDK2 has low toxicity. CDK2 knockout mice are viable and develop normally, with the exception of abnormal germline cells (Berthet, C. et al., Curr Biol, 13(20), 1775-1785). Single knockout of CDK1 or double knockout of CDK4 and CDK6 mice is embryonic lethal (Satyanarayana, A. and Kaldis, P., Oncogene, 28(33), 2925-2939). The crystal structure of CDK2, especially its kinase domain, is highly similar to that of CDK1, and most commercially available CDK2 inhibitors have low CDK1 selectivity (Wells, CI et al., Nat Commun, 11(1), 2743). It is desirable to realize cancer-specific drugs to obtain highly selective CDK2 inhibitors that spare CDK family members to limit off-target CDK-driven toxicity, especially CDK1 / CDK4 / CDK6. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Norbury, C. and Nurse, P., Annu Rev Biochem, 61, 441-470. [Non-patent document 2] Harbor, JW et al., Cell, 98(6), 859-869. [Non-patent document 3] Echalier, A. et al., Biochim Biophys Acta, 1804(3), 511-519 [Non-patent document 4] Caruso, JA et al., Cancer Res, 78(19), 5481-5491 [Non-Patent Document 5] Wood, DJ et al., Cell Chem Biol, 26(1), 121-130 [Non-patent document 6] Au-Yeung, G. et al., Clin Cancer Res, 23(7), 1862-1874 [Non-Patent Document 7] DeLair, DFet al., J Pathol, 243(2), 230-241 [Non-patent document 8] Fu,YPet al.,Cancer Res,74(20),5808-5818 [Non-Patent Document 9] Huber,ARet al.,BMC Gastroenterol,15,80 [Non-Patent Document 10] Miller, CTet al., Clin Cancer Res, 9(13), 4819-4825 [Non-Patent Document 11] Knudsen,ESet al.,Cell Rep,38(9),110448 [Non-Patent Document 12] Pandey,K.et al.,Cancers(Basel),12(12) [Non-Patent Document 13] Scaltriti, M. et al., Proc Natl Acad Sci USA, 108(9), 3761-3766 Summary of the Invention [Means for solving the problem]

[0006] In one embodiment, disclosed herein are bicyclic compound derivatives of formula (I). The embodiment includes the following aspects:

[0007] Aspect 1. A compound of formula (I): [ka] 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, 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 simultaneously 0; [ka] each is independently a single bond or a double bond, provided that no two double bonds are directly connected; X 1 , X 2 , X 3 , and X 4 are each independently N, C, S(=O) 2 or S(=O), where each N is selected from 0 or 1 R as allowed by valence. Xa groups, and each C is independently substituted with one or two R groups as allowed by valence. Xb substituted with a group; R Xa are each independently 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; -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R Xaa optionally substituted with; R Xaa are each independently hydrogen, deuterium, halogen, or -C1-C8 alkyl. 、 -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 Aryl, 5-12 membered heteroaryl, oxo (=O), -OR Xab , -CN, -SO2R Xab , -SO2NRXab 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 and selected from -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 is selected from the group consisting of halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo (=O), -CN, -OR Xad , -SO2R Xad , -SO2N RXad 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 optionally substituted with; R Xab , R Xac , R Xad and R Xae are each independently hydrogen, deuterium, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12aryl, or 5- to 12-membered heteroaryl; 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 selected from the group consisting of halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 optionally substituted with aryl, 5-12 membered heteroaryl, oxo (=O), -CN, -OH, or -C1-C8 alkoxyl; R Xb are each independently hydrogen, halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5-12 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 said -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl is Xbc is replaced by; or The Two R's Xb together with the atom(s) to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or optionally sulfur oxide as ring member(s), said ring containing at least one substituent R Xbc optionally substituted with; RXba and R Xbb are each independently 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, and is selected from the group consisting of -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R Xbd optionally substituted with; R Xbc and R Xbd are each independently hydrogen, deuterium, halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5-12 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; R Xbe and R Xbf are each independently -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 3are each independently selected from O, C, or N, where C and N are each independently selected from one or two R 5 independently substituted with a group or a hydrogen atom; Q is O or NR Q Selected from; R 1 , R 2 , R 3 and R Q are each independently 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, and is selected from the group consisting of -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent R 1a optionally substituted with; or (R 1 and R 2 ), (R 1 and R Q ), or (R Q and R 2 ) together with the atom(s) to which they are attached form a 3-12 membered ring, said ring containing 0-3 additional heteroatoms as ring members independently selected from nitrogen, oxygen, or optionally sulfur oxide, said ring optionally containing at least one substituent R 1b is replaced by; R 1a and R 1b is hydrogen, halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 Aryl, 5-12 membered heteroaryl, oxo (=O), -OR 1c , -CN, -SO2R 1c , -SO2NR 1c R 1d , -C(O)R 1c , -CO2R 1c , -C(O)NR1c R 1d , -NR 1c R 1d , -NR 1c COR 1d , -NR 1c CO2R 1d or -NR 1c SO2R 1d and wherein each of the following is independently selected from: -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 is selected from the group consisting of halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5-12 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 optionally substituted with; R 1c , R 1d , R 1e and R 1f are hydrogen and -C, respectively. 1- C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; R 4 and R 5are each 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 are each independently -CR Z or N; R Z is, at each occurrence, hydrogen, halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5-12 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 heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl is Zc optionally substituted with; R Za and R Zb are respectively 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; and 12 Each aryl or 5- to 12-membered heteroaryl may contain at least one substituent RZd optionally substituted with; R Zc and R Zd are each a halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5-12 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 SO2R Zf or -CN; R Ze and R Zf are respectively -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.

[0008] In some embodiments, X 1 , X 2 , X 3 and X 4 At least one of the is N and X 1 , X 2 , X 3 and X 4 At least one of the groups is S(=O)2 or S(=O).

[0009] In some embodiments, Y 1 , Y 2 and Y 3At most one of is selected from O or N, and Y 1 , Y 2 and Y 3 The other two are both C.

[0010] Aspect 2. The compound of aspect 1, wherein the compound is selected from formula (IIa), (IIb), (IIc), and (IId): [ka] Preferably, the compound is selected from the group consisting of (IIe), (IIf), (IIg), (IIh), (IIi), and (IIj): [ka]

[0011] Aspect 3. A compound according to aspect 1 selected from (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), and (IIIh): [ka]

[0012] Aspect 4. 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); [ka] [ka] [ka] Preferably, the compound is selected from (Va) and (VIa): [ka] Preferably, the compound is selected from (Vb), (Vc), (VIb) and (VIc), [ka] More preferably, the compound is selected from (Vd) and (VId): [ka] Even more preferably, the compound according to embodiment 1 is selected from (Ve), (Vf), (VIe) and (VIf): [ka]

[0013] Embodiment 5. A compound of any one of the preceding embodiments, wherein R 1 , R 2 , R 3 and R Q are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 -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 may be selected from the group consisting of aryl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, 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, and 5- to 12-membered heteroaryl may be selected from the group consisting of aryl, 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, and 5- to 12-membered heteroaryl. 1a optionally substituted with; R 1aare independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 1d independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, Each of the 5- to 12-membered heteroaryls is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 arbitrarily selected in; R 1c , R 1d , R 1e and R 1fare each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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, and each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclooctyl, each of pentyl, cyclohexyl, cycloheptyl, 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-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, 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, pentoxy, hexoxy, heptoxy, or octoxy; 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, iso-butyl 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; More preferably, R 1 , R 2 , R 3 and R Q are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl); Even more preferably, R 1 and R 2 are each independently hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl), [ka] iso-butyl [ka] or tert-butyl); [ka] and R 3 and R Q are each independently hydrogen.

[0014] In another embodiment, R 1 and R2 is independently a substituted or unsubstituted bridging group, spiro group, or fused cyclic group, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[2.1.1]hexyl, or bicyclo[1.1.1]pentyl.

[0015] Aspect 6. A compound according to any one of the preceding aspects, wherein R 1are independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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; Each of methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 may be selected from the group consisting of methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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, may be selected from the group consisting of methyl, ethyl, propyl, propyl, butyl, sec-butyl, iso-butyl or tert-butyl, pentyl, hexyl, azetidinyl, oxetanyl, oxanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[2.3]hexanyl or tetrahydrofuranyl, may be selected from the group consisting of methyl, ethyl, propyl, propyl, butyl, butyl, sec-butyl, iso-butyl or tert-butyl, pentyl, hexyl, azetidinyl, oxetanyl, oxanyl, bicyclo[1.1.1]pentanyl, spiro[3.3]heptanyl, spiro[2.3]hexanyl or tetrahydrofuranyl, each selected from the group consisting of methyl, ethyl, propyl, butyl, butyl, butyl, sec-butyl, iso- 1a optionally substituted with; R 1a is 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]heptanyl, spiro[2.3]hexanyl, tetrahydrofuranyl, or -OR 1c each of said methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl is independently selected from the group consisting of OR 1c optionally substituted with; R 1c are independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl; R 2 is hydrogen; Preferably, R 1is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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, and wherein said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, cyclo Each of 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 selected from OH, CHOH, 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; R 2 is hydrogen; More preferably, R 1 are independently methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl) [ka] iso-butyl [ka] or tert-butyl); [ka] Selected from;R 2 is hydrogen.

[0016] Embodiment 7. A compound of any one of the preceding embodiments, comprising (R 1 and R 2 ), (R 1 and R Q ) or (R Q and R 2 ), together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 additional heteroatoms independently selected from nitrogen, oxygen, or optionally sulfur oxide as ring member(s), said ring containing at least one substituent R 1b optionally substituted with; R 1b are independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 1dindependently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, Each of the 5- to 12-membered heteroaryls is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 arbitrarily selected in; R 1c , R 1d , R 1e and R 1fare each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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, and each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclooctyl, each of pentyl, cyclohexyl, cycloheptyl, 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-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, 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, pentoxy, hexoxy, heptoxy, or octoxy; Preferably, (R 1 and R 2 ), (R 1 and R Q ), or (R Q and R 2 ), together with the atom(s) to which they are attached, form a 4-, 5-, or 6-membered ring, said ring containing at least one substituent R 1b optionally substituted with; R 1bis hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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, -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 are independently selected from; R 1c and R 1dare each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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, and each independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclooctyl, each of pentyl, cyclohexyl, cycloheptyl, 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-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, 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, pentoxy, hexoxy, heptoxy, or octoxy; More preferably, (R 1 and R 2 ), (R 1 and R Q ), or (R Q and R 2 ) together with the atom(s) to which they are attached form a 4-, 5- or 6-membered ring; said ring contains at least one substituent R 1b optionally substituted with; R 1bis independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -CN, or -NH; Even more preferably, R 1 and R 2 together with the nitrogen atom to which they are attached form a four- or five-membered ring; said ring contains at least one substituent R 1b optionally substituted with; R 1b are independently selected from hydrogen, —F, —Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), or —OH.

[0017] Aspect 8. The part [ka] but, [ka]

[0023] The compound of any one of the preceding aspects, wherein

[0018] Aspect 9. A compound according to any one of the preceding aspects, wherein R 4 and R 5 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; Preferably, R 4 and R 5 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl; Even more preferably, R 4 and R 5 are each independently selected from hydrogen.

[0019] Embodiment 10. A compound according to any one of the preceding embodiments, The part [ka] teeth, [ka] Selected from; Preferably, said portion [ka] teeth, [ka] Selected from; More preferably, The part [ka] teeth, [ka] Selected from; Even more preferably, The part [ka] teeth, [ka] The compound is selected from

[0020] Embodiment 11. A compound according to any one of the preceding embodiments, wherein Z 1 , Z 2 and Z 3 At most two of are N; preferably, Z 1 , Z 2 , and Z 3 At most one of is N; More preferably, Z 1 is N and Z 2 and Z 3 But, -CR Z or Z 2 is N and Z 1 and Z 3 But, -CR Z or Z 3 is N and Z 1 and Z 2 Ga-CR Z The compound,

[0021] Aspect 12. A compound according to any one of the preceding aspects, wherein R Z which, at each occurrence, independently represent hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 ZaCO2R Zb or -NR Za SO2R Zb or —CN, wherein each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 selected from at least one R Zc optionally substituted with; R Za and R Zb are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 may be selected from the group consisting of at least one substituent R Zd optionally substituted with; R Zc and R Zdeach independently represents -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -NR Ze R Zf , -OR Ze , -SR Ze , -SO2R Ze , -SO2NR Ze R Zf , -C(O)R Ze , -CO2R Ze , -C(O)NR Ze R Zf , -NR Ze COR Zf , -NR Ze CO2R Zf or -NR Ze SO2R Zf or -CN; R Ze and R Zf are each independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 Zis independently, at each occurrence, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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; R Za and R Zb are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 Zis independently selected at each occurrence from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHCF, -NH, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy 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, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CHF, -CHF, -CF, -CHCHF, -CHOH, -CHCHF, -CHCF, -NH, -OH, -OCHF, methoxy, ethoxy, propoxy, or butoxy.

[0022] Embodiment 13. A compound according to any one of the preceding embodiments, The part [ka] teeth, [ka] Selected from; Preferably, said portion [ka] teeth, [ka] The compound is selected from

[0023] Embodiment 14. A compound according to any one of the preceding embodiments, wherein X 1 , X 2 , X 3 and X 4 are independently N and NR Xa , C.R. Xb , C(R Xb )2, S(=O)2, where X 1 , X 2 , X 3 and X 4 is allowed by the valence; preferably, X 1 , X 2 , X 3 and X 4 At most one of Xa Selected from X 1 , X 2 , X 3 and X 4 wherein at most one of is selected from S(=O)2 or S(=O).

[0024] Embodiment 15. A compound according to any one of the preceding embodiments, wherein R Xa are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 may be selected from the group consisting of at least one substituent R Xaa optionally substituted with; RXaa is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 Xac independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, Each of the 5- to 12-membered heteroaryls is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 , -SO2RXad , -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 arbitrarily selected in; R Xab , R Xac , R Xad and R Xaeare each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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, and each independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclooctyl, each of pentyl, cyclohexyl, cycloheptyl, 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-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, 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, pentoxy, hexoxy, heptoxy, or octoxy; Preferably, R Xaare each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3- to 8-membered heterocyclyl, and each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3- to 8-membered heterocyclyl is selected from the group consisting of at least one substituent R Xaa optionally substituted with; R Xaa is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 Xacindependently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, Each of the 5- to 12-membered heteroaryls is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 optionally substituted with; R Xab , R Xac , R Xad and R Xaeare each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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, and each independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclooctyl, each of pentyl, cyclohexyl, cycloheptyl, 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-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, 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, pentoxy, hexoxy, heptoxy, or octoxy; More preferably, R Xaare each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydrofuranyl, azetidinyl or pyrrolidinyl, wherein each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydrofuranyl, azetidinyl, oxetanyl or pyrrolidinyl is selected from the group consisting of at least one substituent R Xaa optionally substituted with; R Xaa are independently hydrogen, -F, -Cl, -Br, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxo (=O), -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, -CN, benzyl, -NMe2, -NH2, -SO2Me, -COCH3, [ka] each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, or azetidinyl is independently selected from F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, -OR Xad , -SO2R Xad , -C(O)R Xad optionally substituted with; R Xadis selected from hydrogen, methyl, and ethyl; Even more preferably, R Xa are respectively hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, -C2H4OH, -C2H4OMe, -C3H6OH, -C3H6OMe, -CH2OMe, -C(CH3)2OH, [ka] The compound is independently selected from:

[0025] Embodiment 16. A compound according to any one of the preceding embodiments, wherein R Xb is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 Xbbor —CN, wherein each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 independently selected from at least one R Xbc optionally substituted with; R Xba and R Xbb are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 may be selected from the group consisting of at least one substituent R Xbd optionally substituted with; R Xbc and R Xbdrespectively represent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -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; R Xbe and R Xbf are each independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 Xbis hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 , -CO2R Xba , -C(O)NR Xba R Xbb , -NR Xba COR Xbb , -NR Xba CO2R Xbb or -NR Xba SO2R Xbb or -CN; R Xba and R Xbb are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 Xbare independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, -CD3, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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, pentoxy, hexoxy, heptoxy, octoxy or -CN; Even more preferably, R Xb are independently selected from hydrogen, -F, -Cl, methyl, -CD3, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, oxo (=O), or -OH.

[0026] Embodiment 17. The compound of any one of the preceding embodiments, wherein two R Xb together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring; said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally sulfur oxide as ring member(s), said ring containing at least one substituent R Xbc optionally substituted with; R Xbcrespectively represent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -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; R Xbe and R Xbf are each independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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, two R Xb together with the atom(s) to which they are attached form a 3-, 4-, 5-, or 6-membered ring; said ring containing at least one substituent R Xbc optionally substituted with; R Xbcare each independently selected from -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxo (=O), or -CN; More preferably, two R Xb form, together with the atom(s) to which they are attached, a 3-, 4-, 5-, or 6-membered ring.

[0027] Embodiment 18. A compound according to any one of the preceding embodiments, The part [ka] but, [ka] [ka] [ka] [ka] The compound is selected from

[0028] Embodiment 19. The compound of any one of the preceding embodiments, selected from: [ka] [ka] [ka] [ka] [ka]

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[0029] Embodiment 20. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer, or prodrug thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0030] Aspect 21. A method of treating cancer, comprising administering to a subject in need thereof a compound according to any one of Aspects 1 to 19, or a pharmaceutically acceptable salt, or stereoisomer, tautomer, or prodrug thereof. DETAILED DESCRIPTION OF THE INVENTION

[0031] The following terms have the meanings indicated throughout this specification: As used herein, including in the accompanying embodiments, singular terms such as "a," "an," and "the" include references to their corresponding plural forms unless the context clearly requires otherwise.

[0032] The term "or" means, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0033] The term "alkyl" refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups containing 1 to 18 carbon atoms, for example, 1 to 12 carbon atoms, further for example, 1 to 10 carbon atoms, even further for example, 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6Examples 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 iso-butyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-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.

[0034] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0035] The term "aryl," used alone or in combination with other terms, refers to a group selected from: 5- and 6-membered carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems, such as 7-12 membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl; and - Tricyclic ring systems, such as 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic (eg, fluorenyl).

[0036] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0037] The term "aryl-alkyl-" refers to an alkyl group, as defined above, further substituted with an aryl group. Examples of aryl-alkyl groups include aryl-C groups such as phenylethyl, or phenylmethyl (benzyl). 1-8 Examples of alkyl include: The term "heteroaryl" refers to a group selected from: - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example, 1 to 4, or in some embodiments 1 to 3, and in some embodiments 1 to 2 heteroatoms, selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring atoms being carbon; - a 7-12 membered bicyclic ring containing at least one heteroatom selected from N, O, and S, e.g., 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring; and - An 11-14 membered tricyclic ring containing at least one heteroatom (e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms) selected from N, O, and S, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being present in an aromatic ring.

[0038] When the total number of S and O atoms in the heteroaryl group exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less. When a heteroaryl group contains two or more heteroatom ring members, the heteroatoms may be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group may be oxidized to form an N-oxide. As used herein, the term "C-linked heteroaryl" means that a heteroaryl group is attached to a core molecule by a bond originating from a C atom of the heteroaryl ring.

[0039] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, including 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring members being carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic, 5- to 6-membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8-10 membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0040] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group 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 spirocyclic rings, i.e., monocyclic, heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups. As used herein, the term "optionally oxidized sulfur" refers to S, SO, or SO.

[0041] "Hydrogen" and "H" are interchangeable, and protium ( 1 H), deuterium ( 2 H) or tritium ( 3 H). A "deuterated analog" refers to one or more protium ( 1 H) with an equal number of deuterium ( 2 H).

[0042] The compounds disclosed herein may have asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to the broader class of stereoisomers. All such possible stereoisomers are intended to be encompassed, including substantially pure separated enantiomers, racemic mixtures thereof, and diastereomeric mixtures. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0043] As used herein, the term "substantially pure" means that the target stereoisomer contains 35% by weight or less, such as 30% by weight or less, further such as 25% by weight or less, such as even further such as 20% by weight or less of any other stereoisomer(s). In some embodiments, the term "substantially pure" means that the target stereoisomer contains 10% by weight or less, such as 5% by weight or less, such as 1% by weight or less of any other stereoisomer(s).

[0044] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bonds are meant to include both E and Z geometric isomers.

[0045] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring may adopt cis and trans configurations, where cis means that the two substituents on the carbon are both found on the top side, whereas trans means that the two substituents are on opposite sides.

[0046] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps may be separated and / or purified (hereinafter, "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include a variety of 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 analytical, 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 technique most likely to achieve the desired separation.

[0047] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0048] Some of the compounds disclosed herein may exist in different points of hydrogen attachment, called tautomers. For example, compounds containing a carbonyl -CHC(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both the keto and enol forms, as well as mixtures thereof, are intended to be included.

[0049] [ka] undergoes tautomerization [ka] where *A and *B refer to the positions where the substituents are attached to the pyrazole.

[0050] "Pharmaceutically acceptable salt" refers to salts that 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 that correspond to 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 function with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0051] In addition, if a compound disclosed herein is obtained as an acid addition salt, 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 (such as 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, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0052] As defined herein, "pharmaceutically acceptable salts thereof" includes salts of at least one compound of formula (I) and salts of stereoisomers of compounds of formula (I), e.g., salts of enantiomers and / or diastereomers.

[0053] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or bodily fluid, refer to contacting an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or bodily fluid. Treatment of a cell encompasses contact of a cell with a reagent, as well as contact of a fluid with a reagent when the fluid is in contact with the cell. The terms "administration" and "treatment" also refer to treatment of a cell with a reagent, diagnostic, binding compound, or with another cell, e.g., in vitro and ex vivo. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0054] 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 treatment for such disease, disorder, or condition. A "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject receiving treatment, and / or the weight of the subject receiving treatment. The appropriate amount in any given case will be apparent to one of ordinary skill 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, that is effective in "treating" a disease or disorder in a subject, as defined above. In the case of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combined components to effectively treat a disease, disorder, or condition.

[0055] Pharmaceutical compositions comprising the compounds disclosed herein can be administered to subjects in need thereof by oral, inhalation, rectal, parenteral or topical administration.For oral administration, pharmaceutical compositions can be conventional solid preparations such as tablets, powders, granules, capsules and the like, liquid preparations such as aqueous or oily suspensions, or other liquid preparations such as syrups, solutions, suspensions or the like; for parenteral administration, pharmaceutical compositions can be solutions, aqueous solutions, oily suspension concentrates, lyophilized powders or the like.Preferably, the dosage form of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal drops or injections, and more preferably tablets or capsules.The pharmaceutical composition can be a single dose with a precise dosage.In addition, the pharmaceutical composition can further comprise additional active ingredients.

[0056] All formulations of the pharmaceutical compositions disclosed herein can be prepared by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to prepare the desired formulation. "Pharmaceutically acceptable excipients" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles such as water, various organic solvents, excipients such as starch, sucrose, binders such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone (PVP); wetting agents such as glycerol; disintegrants such as agar, calcium carbonate, sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as hexadecanol; absorption carriers such as kaolin and soap clay; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition may further comprise other pharmaceutically acceptable excipients, such as dispersing agents, stabilizers, thickening agents, complexing agents, buffers, penetration enhancers, polymers, flavoring agents, sweetening agents, and dyes.

[0057] The term "disease" refers to any disease, ailment, illness, symptom or sign, and is interchangeable with the terms "disorder" or "condition."

[0058] Throughout this specification and embodiments thereof, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the word "comprising" may be replaced with the words "containing," "including," or, in some cases, "having."

[0059] Throughout this specification and embodiments thereunder, "C n-m The term " refers to a range inclusive of the endpoints, where n and m are integers and refer to the number of carbon atoms. Examples include C 1-8 , C 1-6 These include:

[0060] Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0061] Abbreviation [Table 3-1] [Table 3-2] [Table 3-3] [Example]

[0062] The following examples are intended to be merely illustrative and should not be construed as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be expected. Temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise indicated. Unless otherwise indicated, the reactions described below were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents using drying tubes; reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven-dried and / or heat-dried.

[0063] 1 1 H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. 1 H NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, with tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; DO: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants given are reported in Hertz (Hz).

[0064] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity), detector: MWD (190-400 nm), mass detector: 6120SQ, mobile phase: A: water and 0.1% formic acid, B: acetonitrile and 0.1% formic acid, column: Poroshell 120EC-C18, 4.6 x 50 mm, 2.7 pm, gradient method: flow rate: 1.8 mL / min, time (min) A (%) B (%) [Table 4]

[0065] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile, column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm, gradient method: flow rate: 1.8 mL / min, time (min) A (%) B (%) [Table 5]

[0066] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile, column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm, gradient method: flow rate: 1.2 mL / min, time (min) A (%) B (%) [Table 6]

[0067] Preparative HPLC was performed on a column (150 x 21.2 mm ID, 5 pm, Gemini NXC18) with a flow rate of 20 ml / min, an injection volume of 2 ml, room temperature, and UV detection at 214 nm and 254 nm.

[0068] Example 1: cis-3-(3-((5-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: Methyl 1,4-dioxaspiro[4.4]nonane-7-carboxylate [ka] 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 under a nitrogen atmosphere for 4 h. Each batch was quenched separately with saturated aqueous NaHCO3, then the two baths 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, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give PE / EA (1:1, R f =0.43) to give 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).

[0069] Step 2: 3-Oxo-3-(1,4-dioxaspiro[4.4]nonan-7-yl)propanenitrile [ka] Two parallel reactions were performed. To a solution of methyl 1,4-dioxaspiro[4.4]nonane-7-carboxylate (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%) under a nitrogen atmosphere at 0 °C. The resulting mixture was heated to reflux and stirred for 4 h. The two batches were combined and poured into saturated aqueous NH4Cl solution (500 mL) at 0 °C and stirred for 30 min. The layers were separated, and the aqueous layer was extracted with EA (500 mL x 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give PE / EA (10:1, R f =0.29) to give 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).

[0070] Step 3: 1-(tert-butyl)-3-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrazol-5-amine [ka] To a solution of 3-oxo-3-(1,4-dioxaspiro[4.4]nonan-7-yl)propanenitrile (30.0 g, 153.68 mmol) and tert-butylhydrazine monohydrochloride (57.45 g, 461.03 mmol) in ethyl alcohol (300 mL) was added triethylamine (46.65 g, 461.03 mmol) at 20 °C. The resulting mixture was heated to reflux and stirred under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give PE / EA (5:1, R f =0.24) to give the product (27 g, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ = 5.22 (s, 1H), 4.71 (s, 2H), 3.86 - 3.76 (m, 4H), 2.89 (tt, J = 7.8, 9.9 Hz, 1H), 2.04 (dd, J = 8.0, 13.4 Hz, 1H), 1.96 - 1.82 (m, 2H), 1.78 - 1.66 (m, 2H), 1.65 - 1.53 (m, 1H), 1.47 (s, 9H).

[0071] Step 4: Benzyl (1-(tert-butyl)-3-(1,4-dioxaspiro[4.4]nonan-7-yl)-1H-pyrazol-5-yl)carbamate [ka] 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) was added benzyl carbonochloridate (23.14 g, 135.67 mmol) in portions at 0 °C. The mixture was stirred at room temperature for 2 h, and then NaHCO (18.24 g, 217.07 mmol) was added in portions. The mixture was stirred at this temperature for an additional 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.

[0072] Step 5: Benzyl (1-(tert-butyl)-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl)carbamate [ka] 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 hours. The reaction mixture was concentrated under reduced pressure to remove most of the acetone. The aqueous residue was extracted with DCM (500 mL x 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous NaSO, then filtered and concentrated in vacuo. 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 (400 MHz,DMSO- d6)δ=9.12 (br s,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).

[0073] Step 6: cis-benzyl (1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate [ka] 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. for 1.5 h under a nitrogen atmosphere. 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 NaSO, then filtered and concentrated in vacuo. The residue was purified by preparative-HPLC (column; mobile phase: [water (NHHCO)-acetone]; B%: 40%-65%, 20 min). Benzyl (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (11 g, 57% yield) was obtained. 1 H NMR (400 MHz, 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 = 4.4 Hz, 1H), 4.22 - 4.06 (m, 1H), 2.89 (q, J = 8.6 Hz, 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).

[0074] Step 7: cis-benzyl (1-(tert-butyl)-3-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate [ka] To a solution of cis-benzyl (1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (10 g, 28.01 mmol) in DCM (100 mL) were added pyridine (11.1 g, 140 mmol), DMAP (169 mg, 1.4 mmol), and 4-nitrophenyl carbonochloridate (6.7 g, 33.5 mmol) in succession. 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.

[0075] Step 8: cis-benzyl (1-(tert-butyl)-3-(3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate [ka] To a solution of cis-benzyl (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 hour. 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.

[0076] Step 9: cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a solution of cis-benzyl (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 under a hydrogen balloon at room temperature for 3 hours. The mixture was filtered, and the filter cake was washed with EA (50 mx L). 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.

[0077] Step 10: Methyl 4-bromo-2-(chlorosulfonyl)-5-fluorobenzoate [ka] 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. The resulting mixture was stirred at −5° C. for 30 min after the addition. Next, a solution of sodium bisulfite (12.6 g, 121.4 mmol) in HCl (6 M, 15 mL) was added dropwise, followed by CuCl (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 the 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.

[0078] Step 11: 6-Bromo-5-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide [ka] To a stirred solution of methyl 4-bromo-2-(chlorosulfonyl)-5-fluorobenzoate (2.5 g, 7.5 mmol) in THF (30 mL) was added dropwise aqueous ammonia (25%, 4 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo, and the residue was treated with EA and filtered to give the product (1.9 g, 90% yield). LC-MS (ESI): m / z [M+H] + = 280.1.

[0079] Step 12: 6-Bromo-5-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 under a nitrogen atmosphere at 0°C. The resulting solution was heated to reflux and stirred under a nitrogen atmosphere for 3 hours. 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%). LC-MS (ESI): m / z [M+H] + = 266.1.

[0080] Step 13: cis-3-(1-(tert-butyl)-5-((5-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of 6-bromo-5-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.38 mmol) and cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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 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 (115 mg, 62% yield). LC-MS (ESI): m / z [M+H] + = 494.3.

[0081] Step 14: cis-3-(3-((5-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] A solution of cis-3-(1-(tert-butyl)-3-((5-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (80 mg, 0.16 mmol) in DCM (10 mL) was treated dropwise with triflic acid (0.5 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched and basified with saturated aqueous NaHCO3 at 0 °C until pH = 8. The layers were separated, and the aqueous layer was extracted with DCM (100 m × L3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. 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 racemic form of the product (32.3 mg, 46%), which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 1a, 98.6% ee); retention time: 6.47 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.61 (d, J = 7.5 Hz, 1H), 7.72 (t, J = 4.9 Hz, 1H), 7.34 (d, J = 11.4 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 5.79 (s, 1H), 5.00 (s, 1H), 4.27 (d, J = 4.8 Hz, 2H), 3.58 (m, 1H), 2.48 - 2.41 (m, 1H), 2.02 (m, 1H), 1.95 - 1.83 (m, 1H), 1.79 - 1.43 (m, 3H), 1.03 (d, J = 6.3 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 438.2.

[0082] Enantiomer 2 (Example 1b, 95.6% ee); retention time: 7.07 min. 1H NMR (500 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.61 (d, J = 7.5 Hz, 1H), 7.72 (t, J = 4.9 Hz, 1H), 7.34 (d, J = 11.4 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 5.79 (s, 1H), 5.00 (s, 1H), 4.27 (d, J = 4.8 Hz, 2H), 3.58 (m, 1H), 2.48 - 2.41 (m, 1H), 2.02 (m, 1H), 1.95 - 1.83 (m, 1H), 1.79 - 1.43 (m, 3H), 1.03 (d, J = 6.3 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 438.2.

[0083] Chiral analytical method: Column: I-Cellulose-5, 4.6 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.1% 2M NH3MeOH); Gradient: Mobile phase A:Mobile phase B = 60:40 (v / v); HPLC apparatus: HPLC-Agilent; Back pressure: 100 bar; Column temperature: 35 °C.

[0084] Chiral preparative HPLC conditions: Column: I-Cellulose-5, 21.2 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.2% 2M NH3MeOH); 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.

[0085] Example 2: cis-3-(3-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 under a nitrogen atmosphere at 0 °C. The resulting solution was heated to reflux and stirred under a nitrogen atmosphere for 3 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 (550 mg, 78%). LC-MS (ESI): m / z [M+H] + = 248.3.

[0086] Step 2: cis-3-(1-(tert-butyl)-5-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of 5-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.40 mmol) and cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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 (50 mg, 26%). LC-MS (ESI): m / z [M+H] + = 476.4.

[0087] Step 3: cis-3-(3-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] A solution of cis-3-(1-(tert-butyl)-5-((1,1-dioxide-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 hours. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters XSelect C18:RD-CO-094 column, eluted with 27%-52% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (12 mg, 27%). 1 H NMR (500 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.00 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.50 - 7.38 (m, 2H), 7.30 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 6.9 Hz, 1H), 5.70 (s, 1H), 5.06-4.93 (m, 1H), 4.29 (d, J = 4.9 Hz, 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 = 6.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 420.5.

[0088] Example 3: cis-3-(3-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0089] Step 1: 6-Bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 under a nitrogen atmosphere at 0 °C. The resulting solution was heated to reflux and stirred under a nitrogen atmosphere for 3 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 (350 mg, 62%). LC-MS (ESI): m / z [M+H] + = 248.3.

[0090] Step 2: cis-3-(1-(tert-butyl)-5-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of 6-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.40 mmol) and cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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.

[0091] Step 3: cis-3-(3-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] A solution of cis-3-(1-(tert-butyl)-5-((1,1-dioxide-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 hours. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire C18:RD-CO-095 column, eluting with 25% to 55% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (10 mg, 57%). 1H NMR (500 MHz, DMSO-d6) δ 11.83 (brs, 1H), 8.84 (s, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.38 (dd, J = 8.5, 1.6 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 6.4 Hz, 1H), 5.63 (s, 1H), 5.06 - 4.93 (m, 1H), 4.30 - 4.20 (m, 2H), 3.52 - 3.40 (m 1H), 3.13 - 2.99 (m, 1H), 2.45 (dd, J = 13.8, 7.2 Hz, 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 = 6.3 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 420.3.

[0092] Example 4: cis-3-(5-((3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate

[0093] Step 1: 6-Bromo-3-chlorobenzo[d]isothiazole 1,1-dioxide [ka] 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 a nitrogen atmosphere 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.

[0094] Step 2: 6-Bromo-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 under nitrogen at −5° C. The solution was warmed to room temperature and stirred under nitrogen 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). 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.

[0095] Step 3: cis-3-(1-(tert-butyl)-5-((3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of 6-bromo-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.362 mmol) and cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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 give the product (120 mg, 66%). LC-MS (ESI): m / z [M+H] + = 504.5.

[0096] Step 4: cis-3-(3-((3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a stirred solution of cis-3-(1-(tert-butyl)-5-((3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (120 mg, 0.238 mmol) in DCM (5 mL) was added triflic 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 NaHCO3 at 0 °C. The layers were separated and the aqueous layer was extracted with DCM (100 m × L). 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-058 column, eluted with 34%-49% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (85 mg, 80%). 1 H NMR (500 MHz, DMSO-d6) δ 11.83 (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 = 5.6 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 448.3.

[0097] Example 5: cis-3-(5-((3-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate Step 1: 6-Bromo-3-methylbenzo[d]isothiazole 1,1-dioxide [ka] 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 under nitrogen atmosphere at −5° C. The solution was stirred at room temperature for 3 hours. 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 phase was 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.

[0098] Step 2: 6-Bromo-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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.

[0099] Step 3: cis-3-(1-(tert-butyl)-5-((3-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of 6-bromo-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (200 mg, 0.763 mmol), cis-3-(5-amino-1-(tert-butyl)1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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.

[0100] Step 4: cis-3-(5-((3-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a stirred solution of cis-3-(1-(tert-butyl)-5-((3-methyl-1,1-dioxide-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 triflic acid (0.5 mL). The solution was stirred at room temperature for 3 hours. The solution was diluted with DCM (50 mL), basified with saturated aqueous NaHCO to pH = 8, and extracted with DCM (50 mL x 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18:RD-CO-095 column, eluted with 28%-53% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the racemic form of the product (90 mg, 85%), which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 5a, 100% ee); retention time: 10.46 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.86 (s, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.72 (d, J = 4.2 Hz, 1H), 7.39 (dd, J = 8.5, 1.9 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 5.62 (d, J = 1.9 Hz, 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 = 6.6 Hz, 3H), 1.03 (d, J = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 434.3.

[0101] Enatoplast 2 (Example 5b, 95.4%ee); retention time: 12.06 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.86 (s, 1H), 7.95 (s, 1H), 7.72 (d, J = 4.3 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 7.9 Hz, 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 = 6.6 Hz, 3H), 1.03 (d, J = 6.3 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 434.4.

[0102] Enatoplast 3 (Example 5c, 100%ee); retention time: 13.10 minutes. 1H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.85 (s, 1H), 7.95 (s, 1H), 7.72 (d, J = 4.3 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 7.3 Hz, 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 = 6.6 Hz, 3H), 1.03 (d, J = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 434.1.

[0103] エナンチオマー4 (Example 5d, 99.1%ee); retention time: 15.48 minutes. 1H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.86 (s, 1H), 7.95 (d, J = 1.3 Hz, 1H), 7.72 (d, J = 4.3 Hz, 1H), 7.38 (dd, J = 8.5, 1.8 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 7.7 Hz, 1H), 5.62 (d, J = 1.8 Hz, 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 = 6.6 Hz, 3H), 1.04 (d, J = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 434.3.

[0104] キラル analysis method: カラム: CHIRALPAK IE, 4.6mmx250mm, 5μm; mobile phase: Aは, ヘキサン and びBは, EtOH (0.1% 2M NH3MeOH); blending: mobile phase A: mobile phase B = 50:50 (v / v), HPLC device: HPLC-Agilent, back pressure: 100bar; KURAL temperature: 35°C.

[0105] キラル HPLC conditions: CHIRALPAK IE 20mmx250mm, 5μm; mobile phase: Aは, ヘキサン and びBは, EtOH (0.2%2M NH3MeOH); blending: mobile phase A: mobile phase B=50:50 (v / v), flow rate: 18mL / min, wavelength: UV200nm and び270nm, fractionation HPLC device: fractionation HPLC-Gilson, back pressure: 100bar; Kura temperature: 25°C.

[0106] Example 6: cis-3-(3-((3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-3-chlorobenzo[d]isothiazole 1,1-dioxide [ka] A mixture of 5-bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (500 mg, 1.91 mmol) in POCl (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.

[0107] Step 2: 5-Bromo-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 under nitrogen atmosphere at −5° C. 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×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.

[0108] Step 3: cis-3-(1-(tert-butyl)-5-((3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of 5-bromo-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.362 mmol) and cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (111.6 mg, 0.36 mmol) in anhydrous 1,4-dioxide (10 mL), Pd(dba) (33 mg, 0.04 mmol), XantPhos (42 mg, 0.07 mmol), and KPO (230 mg, 1.09 mmol) were added. 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.

[0109] Step 4: cis-3-(3-((3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a stirred solution of cis-3-(1-(tert-butyl)-5-((3,3-dimethyl-1,1-dioxide-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 dropwise triflic acid (0.5 mL). The solution was stirred at room temperature for 3 hours. The mixture was diluted with DCM (50 mL), basified with saturated aqueous NaHCO to pH = 8, and extracted with DCM (50 mL x 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire C18:RD-CO-095 column, eluting with 34% to 49% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (25 mg, 35%). 1 H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.01 (s, 1H), 7.54 (d, J = 11.4 Hz, 2H), 7.48 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 5.68 (s, 1H), 5.06-4.95 (m, 1H), 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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 448.4.

[0110] 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

[0111] Step 1: cis-benzyl (1-(tert-butyl)-3-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate [ka] To a solution of cis-benzyl (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 equiv.) and imidazole (57.1 mg, 8.39 mmol, 1.5 equiv.). The mixture was stirred at 25 °C for 1 hour. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL x 3), dried over anhydrous NaSO, and then filtered. The filtrate was concentrated in vacuo to give a residue. This product was used in the next step without further purification. The title compound (200 mg, 4.24 mmol, 76% yield) was obtained. 1H NMR (400 MHz, chloroform-d) δ 7.35 (br s, 5H), 6.74 - 6.38 (m, 1H), 6.08 (br s, 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, 3.88 Hz, 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).

[0112] Step 2: 1-(tert-butyl)-3-(cis-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine [ka] To a solution of cis-benzyl (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 under a H atmosphere (15 psi) at 25° C. for 2 hours. The reaction mixture was filtered over 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 H NMR (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).

[0113] 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 [ka] 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 a nitrogen atmosphere for 3 hours. 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.

[0114] Step 4: cis-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide [ka] 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 hours. 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.

[0115] Step 5: 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 [ka] 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) were added pyridine (52.5 mg, 0.66 mmol), DMAP (2 mg, 0.02 mmol), and 4-nitrophenyl carbonochloridate (132 mg, 0.66 mmol) in succession. 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.

[0116] Step 6: cis-3-(1-(tert-butyl)-5-((1-(isopropylcarbamoyl)-2,2-dioxide-1,3-dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] 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 hour. 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.

[0117] Step 7: cis-3-(3-((2,2-dioxide-1,3-dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a solution of cis-3-(1-(tert-butyl)-5-((1-(isopropylcarbamoyl)-2,2-dioxide-1,3-dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (34 mg, 0.06 mmol) in DCM (5 mL) was added triflic acid (0.2 mL) dropwise. The solution was stirred at room temperature for 2 hours. The solution was diluted with DCM (30 mL), basified with saturated aqueous NaHCO to pH = 8, and extracted with DCM (30 mL x 2). The combined organic layers were dried over anhydrous NaSO, 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: [ka] Enantiomer 1 ((1R,3S)-3-(3-((2,2-dioxide-1,3-dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. Example 7a, 100% ee); retention time: 5.02 min. 1H NMR (500 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.75 (s, 1H), 8.19 (s, 1H), 7.37 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 6.71 (d, J = 8.6 Hz, 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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 420.2. [ka]

[0118] Enantiomer 2 ((1S,3R)-3-(3-((2,2-dioxide-1,3-dihydrobenzo[c]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate, Example 7b, 100% ee); retention time: 7.89 min. 1H NMR (500 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.75 (s, 1H), 8.19 (s, 1H), 7.37 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 6.71 (d, J = 8.6 Hz, 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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 420.2.

[0119] Chiral analytical method: Column: CHIRALPAK IE, 4.6 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.1% 2M NH3MeOH); Gradient: Mobile phase A:Mobile phase B = 20:80 (v / v); HPLC apparatus: HPLC-Agilent; Back pressure: 100 bar; Column temperature: 35 °C.

[0120] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm x 250 mm, 5 μm; mobile phase: A is hexane and B is EtOH (0.2% 2M NH3MeOH); gradient: mobile phase A:mobile phase B = 20:80 (v / v); flow rate: 18 mL / min; wavelength: UV 270 nm and 300 nm; preparative HPLC equipment: preparative HPLC-Gilson; back pressure: 100 bar; column temperature: RT.

[0121] Example 8: cis-3-(3-((5-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0122] Step 1: 6-Bromo-3-chloro-5-fluorobenzo[d]isothiazole 1,1-dioxide [ka] A mixture of 6-bromo-5-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (1 g, 3.58 mmol) in POCl (20 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, 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.

[0123] Step 2: 6-Bromo-5-fluoro-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 dropwise MeMgBr (1 M, 16.83 mL, 16.83 mmol) under nitrogen atmosphere at −5° C. The solution was stirred at −5° C. for 3 hours. 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). 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.

[0124] Step 3: cis-3-(1-(tert-butyl)-3-((5-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] 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-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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 give the product (120 mg, 66%). LC-MS (ESI): m / z [M+H] + = 522.2.

[0125] Step 4: cis-3-(3-((5-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a stirred solution of cis-3-(1-(tert-butyl)-3-((5-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (80 mg, 0.153 mmol) in DCM (5 mL) was added dropwise triflic acid (0.5 mL). The solution was stirred at room temperature for 3 hours. The solution was diluted with DCM (50 mL), basified with saturated aqueous NaHCO to pH = 8, and extracted with DCM (50 mL x 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire C18:RD-CO-058 column, eluting with 40% to 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, 6.5 Hz, 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, 10.4 Hz, 2H), 1.60 (d, J = 8.2 Hz, 1H), 1.48 (s, 6H), 1.03 (d, J = 6.3 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 466.2.

[0126] Example 9: cis-3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: Methyl 6-amino-3-bromo-2-fluorobenzoate [ka] To a solution of 6-amino-3-bromo-2-fluorobenzoic acid (1.0 g, 4.27 mmol) in methanol (20 mL) was added SOCl (2.5 g, 21.3 mmol) dropwise. The reaction mixture was stirred under reflux for 16 h. The resulting mixture was cooled to room temperature, concentrated, neutralized with saturated aqueous NaHCO and extracted with EA. The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. 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.

[0127] Step 2: Methyl 3-bromo-6-(chlorosulfonyl)-2-fluorobenzoate [ka] To a suspension of methyl 6-amino-3-bromo-2-fluorobenzoate (3.0 g, 12.1 mmol) in hydrochloric acid (12 M, 60 mL) was added dropwise a solution of sodium nitrite (835 mg, 12.1 mmol) in 5 mL of water at 0 °C. The resulting mixture was kept below 5 °C and stirred for 30 min after the addition. To the reaction mixture were successively added CuCl (813 mg, 6.05 mmol), sodium bisulfite (18.9 g, 181.5 mmol), and hydrochloric acid solution (5.5 M, 20 mL). 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 NaSO, and filtered. The filtrate was concentrated and dried in vacuo to give the crude product (3.2 g), which was used in the next step without further purification.

[0128] Step 3: 5-Bromo-4-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide [ka] To a solution of methyl 3-bromo-6-(chlorosulfonyl)-2-fluorobenzoate (crude 3.2 g) in THF (50 mL) was added aqueous (25% ammonia, 10 mL) dropwise. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated in vacuo, and the residue was treated 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.

[0129] Step 4: 5-Bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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.

[0130] Step 5: cis-3-(1-(tert-butyl)-3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.377 mmol) and cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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.

[0131] Step 6: cis-3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a solution of cis-3-(1-(tert-butyl)-3-((4-fluoro-1,1-dioxide-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 hours. The resulting mixture was neutralized with saturated aqueous NaCO solution and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18: 19 x 150 mm, 5 μm, eluted with 33%-45% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product in racemic form. This was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 9a, 100% ee); retention time: 6.472 min. 1 H NMR (500 MHz, 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), 3.13 - 2.99 (m, 1H), 2.45 (m, 1H), 2.03 (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.

[0132] Enantiomer 2 (Example 9b, 100% ee); retention time: 14.841 min. 1H NMR (500 MHz, 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), 4.41 (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.

[0133] Chiral analysis method: Column: CHIRALPAK IE4.6*250mm 5μm; Mobile phase: A is MtBE (0.1% 2M NH3MeOH) and B is MeOH:DCM=50:50(v / v); Gradient: Mobile phase A:Mobile phase B=50:50(v / v); HPLC apparatus: HPLC-Agilent; Column temperature: 35℃.

[0134] Chiral preparative HPLC conditions: CHIRALPAK IE2 1.2 mm × 250 mm, 5 μm; mobile phase: A is MtBE and B is DCM:MeOH = 50:50 (v / v) (0.2% 2 M NH3 MeOH); gradient: mobile phase A:mobile phase B = 50:50 (v / v); flow rate: 18 mL / min; wavelength: UV 280 nm and 300 nm; preparative HPLC equipment: preparative HPLC-Gilson; column temperature: 25 °C.

[0135] Example 10: cis-3-(3-((4-methoxy-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-4-methoxybenzo[d]isothiazol-3(2H)-one 1,1-dioxide [ka] 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 Cl, 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.

[0136] Step 2: 5-Bromo-4-methoxy-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] To a stirred solution of 5-bromo-4-methoxybenzo[d]isothiazole-3(2H)-1,1-dioxide (280 mg, 0.92 mmol) in THF (5 mL) was added BH3-Me2S (2 M, 2.0 mL, 3.85 mmol) dropwise under a nitrogen atmosphere at 0 °C. 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 [M+H] + = 275.8.

[0137] Step 3: cis-3-(1-(tert-butyl)-3-((4-methoxy-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of 5-bromo-4-methoxy-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (131 mg, 0.47 mmol) and cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (146 mg, 0.47 mmol) in anhydrous 1,4-dioxane (5 mL) was added Pd(dba) (22 mg, 0.02 mmol), XantPhos (27 mg, 0.05 mmol), and KPO (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.

[0138] Step 4: cis-3-(3-((4-methoxy-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a solution of cis-3-(1-(tert-butyl)-3-((4-methoxy-1,1-dioxide-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 triflic acid (3 drops). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was neutralized with saturated aqueous NaCO and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18: 19 x 150 mm, 5 μm, eluted with 30%-50% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (4.0 mg, 21%). 1 H NMR (500 MHz, 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.

[0139] Example 11: cis-3-(3-((2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-2-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 overnight at 50 °C in a round-bottom flask. The mixture was evaporated in vacuo, and the residue was purified by silica gel column chromatography (gradient elution, PE:EA = 3:1 to 1:2) to give the product (0.18 g, 64%). LC-MS (ESI): m / z [M+H] + = 262.1.

[0140] Step 2: cis-3-(1-(tert-butyl)-5-((2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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.

[0141] Step 3: cis-3-(3-((2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a solution of cis-3-(1-(tert-butyl)-5-((2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (170 mg, 0.348 mmol) in DCM (8 mL) was added triflic acid (1.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h. The mixture was quenched with MeOH (7N, 4.0 mL) containing NH and evaporated under reduced pressure. The residue was purified by preparative HPLC (Sunfire C18 column, eluted with a 34%-44% gradient of acetonitrile / water containing 0.1% FA, flow rate 17 mL / min) to give the product (109 mg, 72%). 1 H NMR (500 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.05 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 9.8 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 5.71 (s, 1H), 5.04 - 4.95 (m, 1H), 4.28 (s, 2H), 3.58 (td, J = 12.8, 6.2 Hz, 1H), 3.12 - 3.00 (m, 1H), 2.74 (s, 3H), 2.46 (dd, J = 13.8, 7.1 Hz, 1H), 2.06 - 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 = 6.3 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 434.3.

[0142] Example 12: cis-3-(3-((6-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-bromo-2-(chlorosulfonyl)-4-fluorobenzoate methyl [ka] 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 8 mL of aqueous sodium nitrite (918.4 mg, 13.31 mmol) at 0 °C. The resulting mixture was maintained below 5 °C and stirred for 30 min after the addition. To the reaction mixture were successively added CuCl (813 mg, 6.05 mmol), sodium bisulfite (18.9 g, 181.5 mmol), and hydrochloric acid solution (6 M, 88 mL). 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 NaSO, and filtered. The filtrate was concentrated and dried in vacuo to give the crude product (3.0 g), which was used in the next step without further purification. Step 2: 5-Bromo-6-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide [ka] To a mixture of methyl 5-bromo-2-(chlorosulfonyl)-4-fluorobenzoate (3 g, crude) dissolved in THF (10 mL) was added aqueous ammonium chloride (25%, 20 mL). The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated in vacuo, and the residue was treated with EA and filtered to give the crude product (2.0 g). LC-MS (ESI): m / z [M+H] + = 277.9.

[0143] Step 3: 5-Bromo-6-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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. Step 4: cis-3-(1-(tert-butyl)-5-((6-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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.

[0144] Step 5: cis-3-(3-((6-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a solution of cis-3-(1-(tert-butyl)-5-((6-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (90 mg, 0.18 mmol) in DCM (8 mL) was added triflic 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 containing MeOH (2.0 mL, 7N) and evaporated under reduced pressure. The residue was purified by preparative HPLC (Sunfire C18 column, eluted with a gradient of 31-50% acetonitrile / water containing 0.1% FA at a flow rate of 17 mL / min) to give the product in racemic form, which was further purified by chiral preparative HPLC to give: Enantiomer 1 (Example 12a, 100% ee); retention time: 6.78 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.74 (s, 1H), 8.13 (d, J = 4.7 Hz, 1H), 7.64 (d, J = 10.0 Hz, 2H), 6.94 (d, J = 7.3 Hz, 1H), 5.85 (s, 1H), 5.00 (s, 1H), 4.30 (s, 2H), 3.58 (dd, J = 13.4, 6.7 Hz, 1H), 3.12 - 3.02 (m, 1H), 2.46 (dd, J = 14.0, 7.2 Hz, 1H), 2.02 (dd, J = 16.0, 7.6 Hz, 1H), 1.96 - 1.86 (m, 1H), 1.78 - 1.65 (m, 2H), 1.60 (d, J = 13.6 Hz, 1H), 1.03 (d, J = 6.3 Hz, 6H). LC-MS (ESI): m / z [M+H]+ = 438.3.

[0145] Enatoplast 2 (Example 12b, 100%ee); retention time: 8.10 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.74 (s, 1H), 8.13 (d, J = 4.7 Hz, 1H), 7.64 (d, J = 10.0 Hz, 2H), 6.94 (d, J = 7.3 Hz, 1H), 5.85 (s, 1H), 5.00 (s, 1H), 4.30 (s, 2H), 3.58 (dd, J = 13.4, 6.7 Hz, 1H), 3.12 - 3.02 (m, 1H), 2.46 (dd, J = 14.0, 7.2 Hz, 1H), 2.02 (dd, J = 16.0, 7.6 Hz, 1H), 1.96 - 1.86 (m, 1H), 1.78 - 1.65 (m, 2H), 1.60 (d, J = 13.6 Hz, 1H), 1.03 (d, J = 6.3 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 438.3.

[0146] キラル analysis method: カラム: CHIRALPAK IF, 4.6mmx150mm, 5μm; mobile phase: Aは, ヘキサン and びBは, EtOH (0.1% 2M NH3MeOH); blending: mobile phase A: mobile phase B = 40:60 (v / v), HPLC device: HPLC-Agilent, back pressure: 100bar; カラム temperature: 35℃.

[0147] Kirar fractionation HPLC conditions: cartridge: CHIRALPAK IF 20 mm x 250 mm, 5 μm; mobile phase: A is Hexam and B is EtOH (0.2% 2 M NH3MeOH); mixture: mobile phase A: mobile phase B = 40:60 (v / v), flow rate: 18 mL / min, wavelength: UV 200 nm and UV 270 nm, fractionation HPLC apparatus: fractionation HPLC-Gilson, back pressure: 100 bar; cartridge temperature: 25°C.

[0148] Example 13: cis-3-(3-((7-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 8. 1 H NMR (500 MHz, 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.

[0149] Example 14: cis-3-(3-((6-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 8. 1H NMR (500 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.73 (s, 1H), 7.58 (d, J = 10.1 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 5.84 (s, 1H), 4.99 (d, J = 2.9 Hz, 1H), 3.58 (qd, J = 12.2, 5.3 Hz, 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 = 6.1 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 466.3.

[0150] Example 15: cis-3-(3-((6-methoxy-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 9. 1H NMR (500 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.02 (d, J = 19.2 Hz, 2H), 7.48 (s, 1H), 7.22 (s, 1H), 6.95 (d, J = 7.3 Hz, 1H), 5.90 (s, 1H), 4.99 (s, 1H), 4.26 (s, 2H), 3.94 (s, 3H), 3.58 (dd, J = 13.1, 6.5 Hz, 1H), 3.06 (dd, J = 16.9, 8.4 Hz, 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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 450.4.

[0151] Example 16: cis-3-(3-((1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 3. 1H NMR (500 MHz, DMSO-d6) δ 12.11 (s, 1H), 9.72 (s, 1H), 8.12 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 7.5 Hz, 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 = 7.2 Hz, 1H), 1.72 (s, 2H), 1.61 (s, 1H), 1.03 (d, J = 5.4 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 434.4. Example 17: cis-3-(3-((1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 3. 1 H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.45 (s, 1H), 8.02 (s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 6.2 Hz, 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), 1.95-1.85 (m, 1H), 1.79-1.66 (m, 2H), 1.65-1.55 (m, 1H), 1.03 (d, J = 4.4 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 434.3.

[0152] Example 18: cis-3-(3-((1,1,1',1'-tetraoxide-2',3'-dihydro-3H-[2,5'-bibenzo[d]isothiazol]-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0153] Step 1: cis-3-(1-(tert-butyl)-5-((1,1,1',1'-tetraoxide-2',3'-dihydro-3H-[2,5'-bibenzo[d]isothiazol]-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] To a mixture of 5-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.40 mmol) and cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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.

[0154] Step 2: cis-3-(3-((1,1,1',1'-tetraoxide-2',3'-dihydro-3H-[2,5'-bibenzo[d]isothiazol]-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] A solution of cis-3-(1-(tert-butyl)-5-((1,1,1',1'-tetraoxide-2',3'-dihydro-3H-[2,5'-bibenzo[d]isothiazol]-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (30 mg, 0.05 mmol) in formic acid (5 mL) was stirred at 75°C for 16 hours. The solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire C18:RD-CO-095 column, eluting with 25% to 55% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (5 mg, 19%). 1 H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 9.25 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 7.2 Hz, 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 = 5.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 587.4.

[0155] Example 19: cis-1-(3-(3-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-3-isopropylurea Step 1: Benzyl (3-(3-(benzylamino)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate [ka] 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 hours. Water (100 mL) was added to the mixture, and the layers were separated. The aqueous layer was extracted with DCM (50 mL x 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.

[0156] Step 2: Benzyl (3-(3-(1-benzyl-3-isopropylureido)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate [ka] 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 the 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.

[0157] Step 3: 1-(3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)-3-isopropylurea [ka] 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 mL) in THF / HO (20 mL / 2 mL) was degassed and purged with hydrogen three times. The resulting mixture was stirred under a hydrogen balloon at room temperature for 15 hours. The mixture was filtered through a pad of Celite, and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated in vacuo to give the product (310.0 mg, 97%). LC-MS (ESI): m / z [M+H] + = 308.3.

[0158] Step 4: cis-1-(3-(1-(tert-butyl)-5-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl)-3-isopropylurea [ka] 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 (gradient elution, PE:EA = 3:1 to 1:2) to give the product (0.1 g, 65%). LC-MS (ESI): m / z [M+H] + = 475.3.

[0159] Step 5: cis-1-(3-(3-((1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-3-isopropylurea [ka] To a solution of cis-1-(3-(1-(tert-butyl)-3-((1,1-dioxide-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, eluted with a 34%-44% gradient of acetonitrile / water containing 0.1% FA, flow rate 17 mL / min) to give the product (20 mg, 23%). 1H NMR (500 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.00 (s, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.46 (s, 2H), 7.30 (d, J = 8.1 Hz, 1H), 5.80 (dd, J = 23.0, 7.2 Hz, 1H), 5.69 (d, J = 3.6 Hz, 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, 1.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 419.4.

[0160] Example 20: cis-3-(3-((1,1-dioxide-6-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: Methyl 2-amino-5-bromo-4-(trifluoromethyl)benzoate [ka] 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 in vacuo. 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.

[0161] Step 2: 5-Bromo-6-(trifluoromethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide [ka] The title compound was synthesized using the same procedure as in Example 1, Steps 10 and 11. LC-MS (ESI): m / z [M+H] + = 327.9. Step 3: 5-Bromo-6-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] The title compound was synthesized using the same procedure as in Example 1, Step 12. LC-MS (ESI): m / z [M+H] + = 316.3.

[0162] Step 4: cis-3-(3-((1,1-dioxide-6-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 1, Steps 13 and 14. 1H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 7.93 (s, 2H), 7.81-7.68 (m, 2H), 6.93 (d, J = 5.0 Hz, 1H), 6.00 (s, 1H), 5.05-4.96 (m, 1H), 4.34 (d, J = 5.0 Hz, 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.

[0163] Example 21: cis-3-(3-((3,3-dimethyl-1,1-dioxide-6-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 8. 1 H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.88 (d, J = 10.0 Hz, 2H), 6.93 (d, J = 5.0 Hz, 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.

[0164] Example 22: cis-3-(3-((1,1-dioxide-4-(trifluoromethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 1. 1 H NMR (500 MHz, DMSO-d6) δ 12.35 (s, 1H), 7.95 (s, 1H), 7.84-7.78 (m, 1H), 7.76-7.65 (m, 2H), 6.64 (d, J = 10 Hz, 1H), 5.98 (s, 1H), 5.00 (d, J = 5.0 Hz, 1H), 4.46 (s, 1H), 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.

[0165] Example 23: cis-3-(3-((6-methoxy-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-6-methoxybenzo[d]isothiazol-3(2H)-one 1,1-dioxide [ka] The title compound was synthesized using the same procedure as in Example 1, Steps 10 and 11. LC-MS (ESI): m / z [M+H] + = 290.0.

[0166] Step 2: cis-3-(3-((6-methoxy-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 6. 1 H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.10 (s, 1H), 7.55 (s, 1H), 7.15 (s, 1H), 6.94 (d, J = 7.4 Hz, 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 = 5.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 478.2.

[0167] Example 24: cis-3-(3-((4-methoxy-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 6. 1H NMR (500 MHz, 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.

[0168] Example 25: cis-3-(3-((6-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 1. 1 H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 7.82 (s, 1H), 7.74 (s, 1H), 7.46 - 7.40 (m, 2H), 6.94 (d, J = 7.3 Hz, 1H), 5.88 (s, 1H), 5.00 (s, 1H), 4.25 (d, J = 4.6 Hz, 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, 1H), 1.94 - 1.85 (m, 1H), 1.78 - 1.65 (m, 2H), 1.65 - 1.55 (m, 1H), 1.03 (d, J = 6.3 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 434.2.

[0169] Example 26: cis-3-(3-((7-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 1. 1 H NMR (500 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.82 (s, 1H), 7.37 (t, J = 5 Hz, 1H), 7.19 (s, 1H), 7.03 (s, 1H), 6.87 (d, J = 5 Hz, 1H), 5.62 (s, 1H), 4.97-4.89 (m, 1H), 4.17 (d, J = 5 Hz, 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.

[0170] Example 27: cis-3-(3-((6-chloro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 1. 1H NMR (500 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.58 (t, J = 5.1 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 5.91 (s, 1H), 4.93 (s, 1H), 4.23 (d, J = 5.3 Hz, 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 = 6.3 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 454.2.

[0171] Example 28: cis-3-(3-((1,1-dioxide-6-(trifluoromethoxy)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: tert-butyl (2-bromo-5-(trifluoromethoxy)phenyl)carbamate [ka] 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. Then, di-tert-butyl dicarbonate (1.02 g, 4.7 mmol) was added, and the mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated NH4Cl (aq.) (10 mL) and then adjusted to pH = 7-8 with 2 N 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.

[0172] Step 2: Ethyl 2-((tert-butoxycarbonyl)amino)-4-(trifluoromethoxy)benzoate [ka] 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 CO2 (gas, 4 MPa) for 12 h. 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.

[0173] Step 3: Ethyl 2-amino-4-(trifluoromethoxy)benzoate [ka] 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 h. The mixture was quenched with saturated NaHCO3 (aq) (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 (2.02 g, 94.4%). LC-MS (ESI): m / z [M+H] + = 250.1.

[0174] Step 4: Ethyl 2-amino-5-bromo-4-(trifluoromethoxy)benzoate [ka] To a solution of ethyl 2-amino-4-(trifluoromethoxy)benzoate (2.02 g, 8.10 mmol) in DMF (30 mL) was added NBS (1.58 g, 8.91 mmol) at 0 °C. The mixture was then stirred at 0 °C for 1 h. 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.

[0175] Step 5: cis-3-(3-((1,1-dioxide-6-(trifluoromethoxy)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 1. 1 H NMR (500 MHz, DMSO-d6)) δ 12.07 (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 = 5.2 Hz, 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 = 5.9 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 504.2.

[0176] Example 29: cis-3-(3-((7-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 1. 1 H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 9.28 (s, 1H), 7.71 (s, 1H), 7.29 (d, J = 10 Hz, 1 H), 7.11 (s, 1H), 6.94 (d, J = 5 Hz, 1 H), 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, 1H), 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.

[0177] Example 30: cis-3-(3-((4,6-difluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0178] Step 1: Methyl 6-amino-3-bromo-2,4-difluorobenzoate [ka] The title compound was synthesized using a procedure similar to that of Example 20, Step 1. LC-MS (ESI): m / z [M+H] + = 266.1

[0179] Step 2: cis-3-(3-((4,6-difluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 1. 1 H NMR (500 MHz, 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.

[0180] Example 31: cis-3-(3-((1,1-dioxide-2,3-dihydroisothiazolo[5,4-b]pyridin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 2-(benzylthio)-5-bromo-3-methylpyridine [ka] To a mixture of phenylmethanethiol (1.2 g, 9.69 mmol) in THF (50 mL), NaH (60% dispersion in mineral oil, 465 mg, 11.63 mmol) was added in one portion and stirred at room temperature for 30 min. 5-Bromo-2-chloro-3-methylpyridine (2.0 g, 9.69 mmol) in THF (10 mL) was added dropwise over 5 min, and the reaction mixture was stirred at room temperature for 16 h. 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.

[0181] Step 2: 5-Bromo-N-(tert-butyl)-3-methylpyridine-2-sulfonamide [ka] 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, stirred for 30 min, quenched with water, and the organic phase was separated, washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give a solid. The solid was redissolved in DCM (15 mL), t-BuNH2 (0.5 mmol) was added, and stirred at room temperature for an additional 16 h. 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.

[0182] Step 3: 5-Bromo-3-(bromomethyl)-N-(tert-butyl)pyridine-2-sulfonamide [ka] 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 under reflux for 16 h. The resulting mixture was cooled to room temperature, filtered, and the filtrate was concentrated and dried in vacuo to give the crude product (1.2 g, crude). LC-MS (ESI): m / z [M+H] + = 385.1.

[0183] Step 4: 5-Bromo-2-(tert-butyl)-2,3-dihydroisothiazolo[5,4-b]pyridine 1,1-dioxide [ka] 5-Bromo-3-(bromomethyl)-N-(tert-butyl)pyridine-2-sulfonamide (1.2 g crude) was dissolved in THF (50 mL), NaH (60% mineral oil dispersion, 200 mg, 5 mmol) was added in one portion, and the reaction was stirred at room temperature for 4 h. The resulting mixture was quenched with water and extracted with EA (3 × 50 mL). The combined organic phases were washed with brine, dried over NaSO, filtered, concentrated under reduced pressure, dried in vacuo, and recrystallized from PE / EA (10:1) to give the product (153 mg, 19%, 2 steps). LC-MS (ESI): m / z [M+H] + = 305.1.

[0184] Step 5: cis-3-(1-(tert-butyl)-5-((2-(tert-butyl)-1,1-dioxide-2,3-dihydroisothiazolo[5,4-b]pyridin-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] 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-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (505 mg, 0.164 mmol) in 1,4-dioxane (5 mL) was added Pd(dba) (15 mg, 0.016 mmol), XantPhos (19 mg, 0.032 mmol), and KPO (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.

[0185] Step 6: cis-3-(3-((1,1-dioxide-2,3-dihydroisothiazolo[5,4-b]pyridin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] cis-3-(1-(tert-butyl)-5-((2-(tert-butyl)-1,1-dioxide-2,3-dihydroisothiazolo[5,4-b]pyridin-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (63 mg, 0.12 mmol) was dissolved in formic acid (5 mL). The reaction mixture was stirred at 80° C. for 16 h. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, redissolved in DCM (5 mL), 2N aqueous HCl (1 mL) was added, and stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (Waters X-select Prep C18 OBD 19×150 mm, 5 μm, eluted with 27% to 42% acetonitrile (containing 0.1% FA) in water (containing 0.1% FA)) to give the product (10 mg, 20%). 1H NMR (500 MHz, 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.

[0186] Example 32: cis-3-(3-((2-methyl-1,1-dioxide-2,3-dihydroisothiazolo[5,4-b]pyridin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 31. 1 H NMR (500 MHz, 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.

[0187] Example 33: cis-3-(3-((1,1-dioxide-2,3-dihydroisothiazolo[4,5-b]pyridin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 31. 1 H NMR (500 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.03 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.64 (t, J = 5.0 Hz, 1H), 7.24 (s, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.21 (s, 1H), 5.10-4.92 (m, 1H), 4.27 (d, J = 4.8 Hz, 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 = 6.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 421.3.

[0188] Example 34: cis-3-(3-((4-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0189] Step 1: 5-Bromo-4-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] The title compound was synthesized in the same manner as in Example 1, Steps 10 to 12. LC-MS (ESI): m / z [M+H] + = 262.3.

[0190] Step 2: cis-benzyl (5-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamate [ka] To a round-bottom flask containing cis-benzyl (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 directly in the next step without further purification.

[0191] Step 3: cis-3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a solution of cis-benzyl (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.

[0192] Step 4: cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a solution of cis-3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (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 under a hydrogen balloon at room temperature for 3 h. The mixture was filtered, and the filter cake was washed with EA (50 mx L). 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.

[0193] Step 5: cis-3-(3-((4-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] A mixture of 5-bromo-4-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (90 mg, 0.33 mmol), cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (65.5 mg, 0.26 mmol), Brettphos Pd G3 (29.9 mg, 0.033 mmol), and K2CO3 (135 mg, 0.98 mmol) in t-BuOH (5 mL) was stirred at 110 °C for 16 h under a nitrogen atmosphere. LCMS showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (0-100%) to give the product (51.9 mg, 31.6%). 1H NMR (500 MHz, DMSO-d6) δ 11.96 (s, 1H), 7.90-7.80 (brs, 1H), 7.77 (s, 1H), 7.51 (t, J = 5 Hz, 1H), 7.43 (d, J = 10 Hz, 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.

[0194] Example 35: cis-3-(3-((2,4-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-2,4-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] To a mixture of 5-bromo-4-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (170 mg, 0.65 mmol) and CsCO (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 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 in vacuo. 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.

[0195] Step 2: cis-3-(3-((2,4-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized using a procedure similar to that of Example 34, Step 5. 1 H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.92-7.84 (brs, 1H), 7.82 (s, 1H), 7.48 (t, J = 10 Hz, 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.

[0196] Example 36: cis-3-(3-((2-(2-methoxyethyl)-4-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.89 (t, J = 5 Hz, 1H), 7.82 (s, 1H), 7.47 (d, J = 10 Hz, 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 = 5 Hz, 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.

[0197] Example 37: cis-3-(3-((2-(2-hydroxyethyl)-4-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0198] Step 1: cis-3-(3-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 36. LC-MS (ESI): m / z [M+H] + = 592.4.

[0199] Step 2: cis-3-(3-((2-(2-hydroxyethyl)-4-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a flask containing cis-3-(3-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-methyl-1,1-dioxide-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 in vacuo, 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% to 40%) to give the product (59 mg, 12%). 1 H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.47 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 5.85 (s, 1H), 5.00 (s, 1H), 4.40 (s, 2H), 3.69 (t, J = 6.0 Hz, 2H), 3.58 (dd, J = 13.1, 6.3 Hz, 1H), 3.20 (t, J = 6.0 Hz, 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, 8.0 Hz, 1H), 1.80 - 1.66 (m, 2H), 1.65 - 1.52 (m, 1H), 1.02 (d, J = 6.1 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 492.2.

[0200] Example 38: cis-3-(3-((4-chloro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 1, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 38a, 100% ee); retention time: 4.59 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.15 (brs, 1H), 8.25 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.74 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 6.9 Hz, 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 = 6.1 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 454.27.

[0201] Enantiomer 2 (Example 38b, 100% ee); retention time: 7.29 min. 1H NMR (500 MHz, DMSO-d6) δ 12.10 (brs, 1H), 8.25 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.61 (d, J = 8.7 Hz, 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.

[0202] Chiral analytical method: Column: CHIRALPAK IF, 4.6 mm x 150 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.1% 2M NH3MeOH); Gradient: Mobile phase A:Mobile phase B = 40:60 (v / v); HPLC apparatus: HPLC-Agilent; Back pressure: 100 bar; Column temperature: 35 °C.

[0203] Chiral preparative HPLC conditions: Column: CHIRALPAK IF 20 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.2% 2M NH3MeOH); Gradient: Mobile phase A:Mobile phase B = 40:60 (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. Example 39: cis-3-(3-((4-chloro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate

[0204] Step 1: cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentylpropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 34, Steps 3 and 4. LC-MS (ESI): m / z [M+H] + = 253.2.

[0205] Step 2: cis-3-(3-((4-chloro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate [ka] The title compound was synthesized in racemic form using a procedure similar to Example 34, Step 5, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 39a, 100% ee); retention time: 4.32 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.73 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.04 (t, J = 5.4 Hz, 1H), 5.96 (s, 1H), 5.08-4.95 (m, 1H), 4.30 (d, J = 3.7 Hz, 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 = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 454.20.

[0206] Enantiomer 2 (Example 39b, 100% ee); retention time: 5.73 min. 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.73 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.04 (t, J = 5.4 Hz, 1H), 5.96 (s, 1H), 5.08-4.95 (m, 1H), 4.30 (d, J = 3.7 Hz, 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 = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 454.20.

[0207] Chiral analytical method: Column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; Mobile phase: A is MtBE (0.1% 2M NH3MeOH) (%) and B is MeOH / DCM (50:50) (%); Gradient: Mobile phase A:Mobile phase B = 20:80 (v / v); HPLC apparatus: HPLC-Agilent, back pressure: 100 bar; Column temperature: 35 °C.

[0208] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm × 250 mm, 5 μm; mobile phase: A is MtBE (0.2%, 2 M NH3MeOH) (%), and B is MeOH / DCM (50:50) (%); gradient: mobile phase A:mobile phase B = 20:80 (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.

[0209] Example 40: cis-3-(3-((4-chloro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate

[0210] Step 1: cis-3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] To a solution of cis-benzyl (5-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamate (10 g, 21.5 mmol) in 100 mL THF was added 1-methylcyclopropylamine hydrochloride (11.5 g, 107 mmol) and DIEA (27.6 g, 214 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure and dissolved in EA (200 mL). The mixture was washed with water (200 mL x 3), dried over Na2SO4, and concentrated. The residue was treated with MTBE and filtered to give the product (3.6 g, 42% yield). LC-MS (ESI): m / z [M+H] + = 399.3.

[0211] Step 2: cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] To a solution of cis-3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (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 under a hydrogen balloon at room temperature for 3 hours. The mixture was filtered, and the filter cake was washed with EA (200 mL x 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.

[0212] Step 3: cis-3-(3-((4-chloro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] The title compound was synthesized in racemic form using a procedure similar to Example 34, Step 5, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 40a, 100% ee); retention time: 4.40 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.11 (brs, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.34 (s, 1H), 5.95 (s, 1H), 5.10-4.90 (m, 1H), 4.30 (s, 2H), 3.18-3.01 (m, 1H), 2.57-2.53 (m, 1H), 2.08-1.97(m, 1H), 1.96-1.85 (m, 1H), 1.78-1.64 (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.

[0213] Enantiomer 2 (Example 40b, 100% ee); retention time: 5.64 min. 1H NMR (500 MHz, DMSO-d6) δ 12.11 (brs, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.34 (s, 1H), 5.95 (s, 1H), 5.10-4.90 (m, 1H), 4.30 (s, 2H), 3.18-3.01 (m, 1H), 2.57-2.53 (m, 1H), 2.08-1.97(m, 1H), 1.96-1.85 (m, 1H), 1.78-1.64 (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.

[0214] Chiral analytical method: Column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; Mobile phase: A is MtBE (0.1% 2M NH3MeOH) (%) and B is MeOH / DCM (50:50) (%); Gradient: Mobile phase A:Mobile phase B = 40:60 (v / v); HPLC apparatus: HPLC-Agilent, back pressure: 100 bar; Column temperature: 35 °C.

[0215] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm × 250 mm, 5 μm; mobile phase: A is MtBE (0.2%, 2 M NH3MeOH) (%), and B is MeOH / DCM (50:50) (%); gradient: mobile phase A:mobile phase B = 40:60 (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.

[0216] Example 41: cis-3-(3-((4-chloro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate

[0217] Step 1: cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate [ka] The title compound was synthesized in the same manner as in Example 34, Steps 3 and 4. LC-MS (ESI): m / z [M+H] + = 267.3.

[0218] Step 2: cis-3-(3-((4-chloro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate [ka]

[0219] The title compound was synthesized in the same manner as in Example 34, Steps 3 and 4. 1 H NMR (500 MHz, DMSO-d6) δ 12.17 (brs, 1H), 8.24 (d, J = 4.5 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 8.1 Hz, 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.

[0220] Example 42: cis-3-(3-((6-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 34, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 42a, 99.44% ee); retention time: 6.023 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.73 (s, 1H), 8.14 (s, 1H), 7.85 - 7.83 (m, 2H), 7.04 (t, J = 5.5 Hz, 1H), 5.85 (s, 1H), 5.01 (s, 1H), 4.30 (d, J = 4.3 Hz, 2H), 3.08 (dd, J = 17.1, 8.6 Hz, 1H), 2.92 (dd, J = 12.9, 6.6 Hz, 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 = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 438.30. Enantiomer 2 (Example 42b, 97.65% ee); retention time: 7.2 min. 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.73 (s, 1H), 8.14 (s, 1H), 7.85 - 7.83 (m, 2H), 7.04 (t, J = 5.5 Hz, 1H), 5.85 (s, 1H), 5.01 (s, 1H), 4.30 (d, J = 4.3 Hz, 2H), 3.08 (dd, J = 17.1, 8.6 Hz, 1H), 2.92 (dd, J = 12.9, 6.6 Hz, 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 = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 438.30.

[0221] Chiral analytical method: Column: CHIRALPAK IE, 4.6 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.1% 2M NH3MeOH); Gradient: Mobile phase A:Mobile phase B = 40:60 (v / v); HPLC apparatus: HPLC-Agilent; Back pressure: 100 bar; Column temperature: 35 °C.

[0222] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm x 250 mm, 5 μm; mobile phase: A is hexane and B is EtOH (0.2% 2M NH3MeOH); gradient: mobile phase A:mobile phase B = 40:60 (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.

[0223] Example 43: cis-3-(3-((6-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate [ka] The title compound was synthesized in the same manner as in Example 34. 1H NMR (500 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.66 (s, 1H), 8.08 (s, 1H), 7.65 - 7.43 (m, 2H), 6.81 (d, J = 7.7 Hz, 1H), 5.78 (s, 1H), 4.93 (s, 1H), 4.23 (d, J = 5.0 Hz, 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 - 1.59 (m, 2H), 1.63 - 1.53 (m, 1H), 1.28 (s, 2H), 0.94 (d, J = 6.1 Hz, 3H), 0.73 (q, J = 6.9 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 452.30.

[0224] Example 44: cis-3-(3-((6-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 34, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 44a, 100% ee); retention time: 7.49 min. 1H NMR (500 MHz, DMSO-d6) δ 11.97 (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 = 4.8 Hz, 2H), 3.12-3.00 (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. Enatoplast 2 (Example 44b, 99.6%ee); retention time: 9.29 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 11.97 (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 = 4.8 Hz, 2H), 3.12-3.00 (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.

[0225] Kirar analysis method: Cartridge: CHIRALPAK IE, 4.6 mm x 250 mm, 5 μm; Mobile phase: A: Hexane and B: EtOH (0.2% 2 M NH3MeOH); Mixing: Mobile phase A: Mobile phase B = 50:50 (v / v); HPLC apparatus: HPLC-Agilent, back pressure: 100 bar; Cartridge temperature: 35°C.

[0226] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm x 250 mm, 5 μm; mobile phase: A is Hex and B is EtOH (0.2% 2M NH3MeOH); gradient: mobile phase A:mobile phase B = 50:50 (v / v), flow rate: 18 mL / min, wavelength: UV 270 nm and 310 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: RT.

[0227] Example 45: cis-3-(3-((6-fluoro-2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1 H NMR (500 MHz, 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), 2.06 - 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.

[0228] Example 46: cis-3-(3-((6-fluoro-2-(methyl-d3)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1 H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.82 (s, 1H), 8.20 (d, J = 10 Hz, 1H), 7.72 (d, J = 10 Hz, 1H), 6.95 (d, J = 5 Hz, 1H), 5.85 (s, 1H), 5.04-4.95 (m, 1H), 4.30 (s, 2H), 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.

[0229] Example 47: cis-3-(3-((6-fluoro-2-(2-hydroxyethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 37. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.71 (d, J = 10.1 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 5.85 (s, 1H), 5.00 (s, 1H), 4.88 (t, J = 5.5 Hz, 1H), 4.42 (s, 2H), 3.65 (q, J = 5.7 Hz, 2H), 3.58 (dd, J = 12.9, 6.5 Hz, 1H), 3.18 (t, J = 5.9 Hz, 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 = 5.9 Hz, 7H). LC-MS (ESI): m / z [M+H] + = 482.3.

[0230] Example 48: cis-3-(3-((6-fluoro-2-(2-methoxyethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.73 (s, 1H), 8.15-8.06 (m, 1H), 7.65 (d, J = 10 Hz, 1H), 6.86 (d, J = 5 Hz, 1H), 5.79 (s, 1H), 4.98-4.88 (m, 1H), 4.34 (s, 2H), 3.51 (d, J = 5 Hz, 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.

[0231] Example 49: cis-3-(3-((6-fluoro-2-isopropyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.64 (s, 1H), 8.06 (s, 1H), 7.52 (d, J = 10 Hz, 1H), 6.81 (d, J = 5 Hz, 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), 1.83-1.73 (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.

[0232] Example 50: 3-(3-((6-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclobutylpropylcarbamate Step 1: 3-(3,3-dimethoxycyclobutyl)-3-oxopropanenitrile [ka] To a solution of acetonitrile (0.52 g, 12.68 mmol) in THF (20 mL) was added dropwise n-BuLi (4.78 mL, 2.4 M, 11.48 mmol) at -70 °C. The mixture was stirred at -70 °C for 30 min. Methyl 3,3-dimethoxycyclobutane-1-carbamate (1 g, 5.74 mmol) was added and stirred at -50 to -70 °C for 60 min. The mixture was quenched with saturated NH4Cl(aq) (10 mL). The resulting mixture was extracted with EtOAc (30 mL x 3), and the combined organic phase was 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.

[0233] Step 2: 1-(tert-butyl)-3-(3,3-dimethoxycyclobutyl)-1H-pyrazol-5-amine [ka] To a mixture of 3-(3,3-dimethoxycyclobutyl)-3-oxopropanenitrile (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.

[0234] Step 3: Benzyl (1-(tert-butyl)-3-(3,3-dimethoxycyclobutyl)-1H-pyrazol-5-yl)carbamate [ka]

[0235] To a mixture of 1-(tert-butyl)-3-(3,3-dimethoxycyclobutyl)-1H-pyrazol-5-amine (0.9 g, 3.55 mmol) and NaHCO3 (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 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EA (50 mL), washed with brine (30 mL x 3), and concentrated to give the crude product, which was used in the next step without purification (1.2 g, crude). LC-MS (ESI): m / z [M+H] + = 388.2.

[0236] Step 4: Benzyl (1-(tert-butyl)-3-(3-oxocyclobutyl)-1H-pyrazol-5-yl)carbamate [ka] 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 h. The mixture was quenched with saturated NaHCO (aq) 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.

[0237] Step 5: cis-benzyl (1-(tert-butyl)-3-(3-hydroxycyclobutyl)-1H-pyrazol-5-yl)carbamate [ka]

[0238] 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 NaBH (0.14 g, 3.68 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was quenched with saturated aqueous NH Cl (10 mL) and extracted with DCM (30 mL x 3). The DCM layer was concentrated under reduced pressure to give the crude product, which was used in the next step without purification (0.7 g, crude). LC-MS (ESI): m / z [M+H] + = 344.2.

[0239] Step 6: cis-benzyl (1-(tert-butyl)-3-(3-(((4-nitrophenoxy)carbonyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)carbamate [ka] To a mixture of cis-benzyl (1-(tert-butyl)-3-(3-hydroxycyclobutyl)-1H-pyrazol-5-yl)carbamate (0.7 g, 2.04 mmol) and 4-nitrophenyl carbonochloridate (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 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with E / EtOAc (5:1 to 2:1) to give the product (0.8 g, 77.6%). LC-MS (ESI): m / z [M+H] + = 509.2.

[0240] Step 7: cis-benzyl (1-(tert-butyl)-3-(3-((propylcarbamoyl)oxy)cyclobutyl)-1H-pyrazol-5-yl)carbamate [ka] To a mixture of cis-benzyl (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.

[0241] Step 8: cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclobutylpropylcarbamate [ka] To a mixture of cis-benzyl (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 under a H balloon at 25 °C for 2 h. 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.

[0242] Step 9: 3-(3-((6-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclobutylpropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 34, Steps 4 and 5. 1H NMR (500 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.76 (s, 1H), 8.13 (d, J = 7.1 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.14 (s, 1H), 5.88 (s, 1H), 4.81 (t, J = 7.4 Hz, 1H), 4.30 (d, J = 4.3 Hz, 2H), 3.12 - 3.03 (m, 1H), 2.91 (dd, J = 13.1, 6.6 Hz, 2H), 2.72 - 2.63 (m, 2H), 2.11 - 2.04 (m, 2H), 1.39 (dd, J = 14.4, 7.2 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 424.2.

[0243] Example 51: cis-3-(3-((4-fluoro-3-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-3-chloro-4-fluorobenzo[d]isothiazole 1,1-dioxide [ka] 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 in vacuo. 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.

[0244] Step 2: 5-Bromo-4-fluoro-3-methylbenzo[d]isothiazole 1,1-dioxide [ka] 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, 1N) under nitrogen atmosphere at 0° C. The mixture was stirred at 0° C. for 3 h. LCMS showed the reaction was complete. The mixture was quenched with water (20 mL) and extracted with EA (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the product (250 mg, crude), which was used directly in the next step. LC-MS (ESI): m / z [M+H] + = 278.2.

[0245] Step 3: 5-Bromo-4-fluoro-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 NaBH (41 mg, 1.08 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The mixture was quenched with ice water (50 mL) and extracted with EA (3 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. 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.

[0246] Step 4: cis-3-(3-((4-fluoro-3-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] A mixture of 5-bromo-4-fluoro-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (200 mg, 0.72 mmol), cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (144.5 mg, 0.57 mmol), Brettphos PdG (66.1 mg, 0.073 mmol), and KCO (298 mg, 2.16 mmol) in t-BuOH (10 mL) was stirred at 110 °C for 16 h under a nitrogen atmosphere. LCMS indicated the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Waters SunFire C18:19 150 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: 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), 1.96 - 1.85 (m, 1H), 1.71-1.65 (m, 2H), 1.58-1.48 (m, 1H), 1.49 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 5.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 452.2. Enantioma 2 (Example 51b, 100% ee); holding time: 4.86 minutes. 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), 1.96 - 1.85 (m, 1H), 1.71-1.65 (m, 2H), 1.58-1.48 (m, 1H), 1.49 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 5.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 452.2. Enantioma 3 (Example 51c, 100% ee); holding time: 5.56 minutes. 1 H 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), 1.96 - 1.85 (m, 1H), 1.71-1.65 (m, 2H), 1.58-1.48 (m, 1H), 1.49 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 5.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 452.2. Enatoplast 4 (Example 51d, 100%ee); retention time: 8.36 minutes. 1 H 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), 1.96 - 1.85 (m, 1H), 1.71-1.65 (m, 2H), 1.58-1.48 (m, 1H), 1.49 (d, J = 6.6 Hz, 3H), 1.03 (d, J = 5.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 452.2.

[0247] Kirul analysis method: Caramel: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; mobile phase: A: MtBE (0.1% 2 M NH3MeOH) and B: EtOH; mobile phase A: mobile phase B = 30:70 (v / v); HPLC apparatus: HPLC-Agilent, back pressure: 100 bar; caramel temperature: 35°C.

[0248] Kiral fractionation HPLC conditions: CHIRALPAK IE 21.2 mm x 250 mm, 5 μm; mobile phase: A is MtBE, and B is EtOH (0.2% 2 M NH3MeOH); mixture: mobile phase A: mobile phase B = 30:70 (v / v); flow rate: 18 mL / min, wavelength: UV 280 nm and UV 300 nm, fractionation HPLC apparatus: fractionation HPLC-Gilson, back pressure: 100 bar; temperature: RT.

[0249] Example 52: cis-3-(3-((4-fluoro-3-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 51, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 52a, 100% ee); retention time: 4.57 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.68 (s, 1H), 8.23 ​​(s, 1H), 7.82 (d, J = 4.7 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.34 (s, 1H), 5.82 (s, 1H), 4.98 (s, 1H), 4.86 - 4.69 (m, 1H), 3.132-2.95 (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), 1.49 (d, J = 6.6 Hz, 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. Enantiomer 2 (Example 52b, 100% ee); retention time: 5.81 min. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.68 (s, 1H), 8.23 ​​(s, 1H), 7.82 (d, J = 4.7 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.34 (s, 1H), 5.82 (s, 1H), 4.98 (s, 1H), 4.86 - 4.69 (m, 1H), 3.132-2.95 (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), 1.49 (d, J = 6.6 Hz, 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. Enatoplast 3 (Example 52c, 96.1%ee); retention time: 6.65 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.68 (s, 1H), 8.23 ​​(s, 1H), 7.82 (d, J = 4.7 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.34 (s, 1H), 5.82 (s, 1H), 4.98 (s, 1H), 4.86 - 4.69 (m, 1H), 3.132-2.95 (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), 1.49 (d, J = 6.6 Hz, 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. エナンチオマー4 (Example 52d, 99.8%ee); retention time: 11.98 minutes. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.68 (s, 1H), 8.23 ​​(s, 1H), 7.82 (d, J = 4.7 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.34 (s, 1H), 5.82 (s, 1H), 4.98 (s, 1H), 4.86 - 4.69 (m, 1H), 3.132-2.95 (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), 1.49 (d, J = 6.6 Hz, 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.

[0250] Chiral analytical method: Column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; Mobile phase: A is MtBE (0.1% 2M NH3MeOH) (%) and B is DCM:MeOH = 50:50 (v / v); Gradient: Mobile phase A:Mobile phase B = 60:40 (v / v); HPLC apparatus: HPLC-Agilent, back pressure: 100 bar; Column temperature: 35 °C.

[0251] Chiral preparative HPLC conditions: CHIRALPAK IE 21.2 mm x 250 mm, 5 μm; mobile phase: A is MtBE, and B is 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: UV 280 nm and 300 nm, preparative HPLC equipment: preparative HPLC-Gilson, back pressure: 100 bar; column temperature: RT.

[0252] Example 53: cis-3-(3-((4-fluoro-3-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 51, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 53a, 100% ee); retention time: 4.02 min. 1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.69 (s, 1H), 8.24 (t, J = 8.0 Hz, 1H), 7.83 (d, J = 4.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.04 (t, J = 5.5 Hz, 1H), 5.83 (d, J = 1.9 Hz, 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), 1.75-1.65 (m, 2H), 1.63 - 1.56 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H), 1.44-1.34 (m, 3H), 0.82 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 452.2.

[0253] Enantiomer 2 (Example 53b, 100% ee); retention time: 7.19 min. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.69 (s, 1H), 8.24 (t, J = 8.0 Hz, 1H), 7.83 (d, J = 4.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.04 (t, J = 5.5 Hz, 1H), 5.83 (d, J = 1.9 Hz, 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), 1.75-1.65 (m, 2H), 1.63 - 1.56 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H), 1.44-1.34 (m, 3H), 0.82 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 452.2.

[0254] Enatoplast 3 (Example 53c, 98.6%ee); retention time: 8.43 minutes. 11H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.69 (s, 1H), 8.24 (t, J = 8.0 Hz, 1H), 7.83 (d, J = 4.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.04 (t, J = 5.5 Hz, 1H), 5.83 (d, J = 1.9 Hz, 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), 1.75 - 1.65 (m, 2H), 1.63 - 1.56 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H), 1.44 - 1.34 (m, 3H), 0.82 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 452.2。

[0255] Enantiomer 4 (Example 53d, 100% ee); retention time: 9.11 min. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.69 (s, 1H), 8.24 (t, J = 8.0 Hz, 1H), 7.83 (d, J = 4.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.04 (t, J = 5.5 Hz, 1H), 5.83 (d, J = 1.9 Hz, 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), 1.75-1.65 (m, 2H), 1.63 - 1.56 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H), 1.44-1.34 (m, 3H), 0.82 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 452.2.

[0256] キラル analysis method: カラム: CHIRALPAK IE 4.6mm×250mm, 5μm; mobile phase: Aは, MtBE (0.1%2M NH3MeOH) (%) and びBは, DCM: MeOH=50:50 (v / v); blending: mobile phase A: mobile phase B = 40:60 (v / v); HPLC device: HPLC-Agilent, back pressure: 100bar; カラム temperature: 35°C.

[0257] KIRALPAK HPLC conditions: CHIRALPAK IE 21.2mmx250mm, 5μm; mobile phase: Aは, MtBE, and びBは, DCM: MeOH=50:50 (v / v) (0.2% 2M NH3 MeOH); blending: mobile phase A: mobile phase B = 40:60 (v / v); flow rate: 18mL / min, wavelength: UV280nm and び300nm, fractionation HPLC device: fractionation HPLC-Gilson, back pressure: 100bar; Kura temperature: RT.

[0258] Example 54: cis-3-(3-((4-fluoro-3-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 51, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 54a, 100% ee); retention time: 3.82 min. 1 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 = 6.7 Hz, 3H), 1.43 - 1.30 (m, 2H), 1.01 (d, J = 6.5 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 466.2.

[0259] Enantiomer 2 (Example 54b, 99.7% ee); retention time: 4.86 min. 1H 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 = 6.7 Hz, 3H), 1.43 - 1.30 (m, 2H), 1.01 (d, J = 6.5 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 466.2.

[0260] Enatoplast 3 (Example 54c, 96.5%ee); retention time: 5.21 minutes. 1H 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 = 6.7 Hz, 3H), 1.43 - 1.30 (m, 2H), 1.01 (d, J = 6.5 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 466.2.

[0261] Enonomic 4 (Example 54d, 100%ee); retention time: 9.68 minutes. 1H 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 = 6.7 Hz, 3H), 1.43 - 1.30 (m, 2H), 1.01 (d, J = 6.5 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 466.2.

[0262] キラル analysis method: カラム: CHIRALPAK IE4.6mm×250mm, 5μm; mobile phase: Aは, MtBE (0.1%2M NH3MeOH) and びBは, EtOH: blending: mobile phase A: mobile phase B = 30:70 (v / v); HPLC device: HPLC-Agilent, back pressure: 100bar; カラム temperature: 35℃.

[0263] キラル HPLC conditions: CHIRALPAK IE 21.2mmx250mm, 5μm; mobile phase: Aは, MtBE, and びBは, EtOH (0.2%2M NH3MeOH); blending: mobile phase A: mobile phase B=30:70 (v / v); flow rate: 18mL / min, wavelength: UV280nm and び300nm, fractionation HPLC device: fractionation HPLC-Gilson, back pressure: 100bar; Kura temperature: RT.

[0264] Example 55: cis-3-(3-((4-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-4-fluoro-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] The title compound was synthesized in the same manner as in Example 8, Steps 1 and 2. LC-MS (ESI): m / z [M+H] + = 294.0.

[0265] Step 2: cis-3-(3-((4-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized using a procedure similar to that of Example 34, Step 5. 1 H NMR (500 MHz, 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.

[0266] Example 56: cis-3-(3-((4-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] The title compound was synthesized in the same manner as in Example 55. 1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.66 (s, 1H), 8.20 (s, 1H), 7.84 (s, 1H), 7.42 (d, J = 8.6 Hz, 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 = 5.3 Hz, 2H). LC-MS (ESI): m / z [M+H] + = 478.2.

[0267] Example 57: cis-3-(3-((4-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate [ka] The title compound was synthesized in the same manner as in Example 55. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.69 (s, 1H), 8.20 (d, J = 32.0 Hz, 1H), 7.83 (d, J = 4.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 5.83 (s, 1H), 4.84 - 4.71 (m, 1H), 3.37 (dd, J = 13.8, 7.1 Hz, 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, 2H), 1.58-1.48 (m, 1H), 1.49 (s, 6H), 1.36 (d, J = 5.0 Hz, 2H), 1.06 - 0.95 (m, 3H), 0.80 (q, J = 7.2 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 480.2.

[0268] Example 58: cis-3-(3-((4-fluoro-3,3-dimethyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 55. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.69 (s, 1H), 8.23 ​​(s, 1H), 7.83 (d, J = 4.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.04 (t, J = 5.2 Hz, 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 = 6.6 Hz, 6H), 1.43-1.35 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 466.2.

[0269] Example 59: cis-3-(3-((4-fluoro-1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 8. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.92 (s, 1H), 8.47 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 5.86 (s, 1H), 5.00 (s, 1H), 3.62 - 3.55 (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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 452.3.

[0270] Example 60: cis-3-(3-((2-ethyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.29 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 5.84 (s, 1H), 5.00 (s, 1H), 4.46 (s, 2H), 3.69 - 3.50 (m, 1H), 3.20 (q, J = 7.2 Hz, 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 = 7.2 Hz, 3H), 1.03 (d, J = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 466.2.

[0271] Example 61: cis-3-(3-((4-fluoro-2-(1-methylpiperidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 1-Methylpiperidin-3-yl methanesulfonate [ka] 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 h. The mixture was diluted with DCM (20 mL) and washed with brine (30 mL×3). The DCM layer was concentrated under reduced pressure to give the product, which was used in the next step without purification (0.45 g, 77.5%). LC-MS (ESI): m / z [M+H] + = 194.

[0272] Step 2: 5-Bromo-4-fluoro-2-(1-methylpiperidin-3-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 h. The mixture was quenched with water (20 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 (0.15 g, 75%). LC-MS (ESI): m / z [M+Na] + = 385.3.

[0273] Step 3: cis-3-(3-((4-fluoro-2-(1-methylpiperidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 34, Steps 3 and 4. 1H NMR (500 MHz, DMSO-d6)) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.29 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.57 (dd, J = 61.0, 14.3 Hz, 2H), 3.63 - 3.52 (m, 1H), 3.27 (d, J = 3.8 Hz, 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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 535.3.

[0274] Example 62: cis-3-(3-((4-fluoro-2-(1-methylpiperidin-4-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-4-fluoro-2-(1-methylpiperidin-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 h. 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.

[0275] Step 2: cis-3-(3-((4-fluoro-2-(1-methylpiperidin-4-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 34, Steps 3 and 4. 1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.77 (s, 1H), 8.27 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.5 Hz, 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 = 11.5 Hz, 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 = 6.1 Hz, 6H). LC-MS (ESI): m / z [M+H] += 535.3.

[0276] Example 63: cis-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 isopropylcarbamate Step 1: tert-butyl 4-(5-bromo-4-fluoro-1,1-dioxidebenzo[d]isothiazol-2(3H)-yl)piperidine-1-carboxylate [ka] 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 N for 12 h. 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.

[0277] Step 2: 5-Bromo-4-fluoro-2-(piperidin-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] To a solution of tert-butyl 4-(5-bromo-4-fluoro-1,1-dioxidebenzo[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 h. The mixture was quenched with saturated aqueous NaHCO3 (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 (0.42 g, 98.4%). LC-MS (ESI): m / z [M+H] + = 349.

[0278] Step 3: 2-(1-benzylpiperidin-4-yl)-5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 one drop of HOAc. The mixture was stirred at 25 °C for 2 h. 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.

[0279] Step 4: cis-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 isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 34. 1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.76 (s, 1H), 8.29 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.37 - 7.29 (m, 4H), 7.25 (t, J = 6.3 Hz, 1H), 6.94 (d, J = 6.8 Hz, 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 = 11.5 Hz, 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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 611.3.

[0280] Example 64: cis-3-(3-((4-fluoro-2-(2-methoxyethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.79 (s, 1H), 8.15-8.06 (m, 1H), 7.54 (d, J = 5 Hz, 1H), 6.94 (d, J = 5 Hz, 1H), 5.84 (s, 1H), 5.04-4.97 (m, 1H), 4.53 (s, 2H), 3.62 (t, J = 5 Hz, 2H), 3.60-3.54 (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.

[0281] Example 65: cis-3-(3-((4-fluoro-2-isopropyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.76 (s, 1H), 8.36-8.24 (m, 1H), 7.52-7.47 (m, 1H), 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.

[0282] Example 66: cis-3-(3-((4-fluoro-1,1-dioxide-2-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.87 (s, 1H), 8.38-8.26 (m, 1H), 7.62 (d, J = 5 Hz, 1H), 6.94 (d, J = 5 Hz, 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.

[0283] Example 67: cis-3-(3-((2-cyclobutyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.71 (s, 1H), 8.22-8.19 (m, 1H), 7.43 (d, J = 10 Hz, 1H), 6.87 (d, J = 5 Hz, 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), 2.00-1.91 (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.

[0284] Example 68: cis-3-(3-((2-cyclopentyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.70 (s, 1H), 8.22 (s, 1H), 7.43 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 5.76 (s, 1H), 4.93 (s, 1H), 4.40 (s, 2H), 3.68 (p, J = 7.4 Hz, 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 - 1.81 (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.

[0285] 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 Step 1: 5-Bromo-4-fluoro-2-(tetrahydrofuran-3-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 small 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(aq) (10 mL) and extracted with EtOAc (30 mL x 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.

[0286] Step 2: cis-3-(3-((4-fluoro-1,1-dioxide-2-(tetrahydrofuran-3-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized using a procedure similar to that of Example 34, Step 5. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.80 (s, 1H), 8.30 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 5.84 (s, 1H), 5.07-4.94 (m, 1H), 4.53 (q, J = 14.1 Hz, 2H), 4.25-4.15 (m, 1H), 3.97 - 3.90 (m, 2H), 3.80 (dd, J = 9.6, 6.3 Hz, 1H), 3.68 (dd, J = 15.3, 8.1 Hz, 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.

[0287] Example 70: cis-3-(3-((4-fluoro-2-(1-methylpyrrolidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6)) δ 11.99 (s, 1H), 8.79 (s, 1H), 8.29 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 6.9 Hz, 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), 3.12 - 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 = 5.9 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 521.3.

[0288] Example 71: cis-3-(3-((2-(2,3-dihydroxypropyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: cis-3-(3-((2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a solution of cis-3-(3-((4-fluoro-1,1-dioxide-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 in vacuo, 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.

[0289] Step 2: cis-3-(3-((2-(2,3-dihydroxypropyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a flask containing cis-3-(3-((2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (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 in vacuo, 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% to 40%) to give the product (28 mg, 50%). 1H NMR (500 MHz, 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.

[0290] Example 72: cis-3-(1-(2,3-dihydroxypropyl)-3-((2-(2,3-dihydroxypropyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 71. 1H NMR (500 MHz, 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 (dd, 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.

[0291] Example 73: cis-3-(3-((2-(3-(dimethylamino)propyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.78 (s, 1H), 8.28 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.48 (s, 2H), 3.67 - 3.51 (m, 2H), 3.19 (t, J = 7.0 Hz, 2H), 3.11 - 3.01 (m, 1H), 2.50-2.46 (m, 2H), 2.28 (s, 6H), 2.08-2.00 (m, 1H), 1.96-1.88 (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.

[0292] Example 74: cis-3-(3-((2-(2-(dimethylamino)ethyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.84 (s, 1H), 8.32 (s, 1H), 7.59 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 5.84 (s, 1H), 5.00 (s, 1H), 4.56 (s, 2H), 3.64-3.54 (m, 1H), 3.46 (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 = 6.1 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 509.2.

[0293] Example 75: cis-3-(3-((2-benzyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.78 (s, 1H), 8.32 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.47 - 7.38 (m, 4H), 7.36-7.32 (m, 1H), 6.94 (d, J = 7.3 Hz, 1H), 5.82 (s, 1H), 5.00 (s, 1H), 4.35 (d, J = 15.5 Hz, 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.

[0294] Example 76: cis-3-(3-((4-fluoro-2-(2-hydroxy-2-methylpropyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (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.

[0295] Example 77: cis-3-(3-((4-fluoro-2-(1-(methylsulfonyl)piperidin-4-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-4-fluoro-2-(1-(methylsulfonyl)piperidin-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] To a solution of tert-butyl 4-(5-bromo-4-fluoro-1,1-dioxidebenzo[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 25 °C for 1 h. 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.

[0296] Step 2: cis-3-(3-((4-fluoro-2-(1-(methylsulfonyl)piperidin-4-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized using a procedure similar to that of Example 34, Step 5. 1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.78 (s, 1H), 8.30 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 6.4 Hz, 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 = 6.0 Hz, 6H). LC-MS (ESI): m / z [M+H] += 599.3.

[0297] Example 78: cis-3-(3-((2-(1-acetylpiperidin-4-yl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 1-(4-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidin-1-yl)ethan-1-one [ka] To a solution of tert-butyl 4-(5-bromo-4-fluoro-1,1-dioxidebenzo[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 h. 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 (5:1 to 3:1) to give the product (0.1 g, 49.7%). LC-MS (ESI): m / z [M+H] + = 391.5.

[0298] Step 2: cis-3-(3-((2-(1-acetylpiperidin-4-yl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized using a procedure similar to that of Example 34, Step 5. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.76 (s, 1H), 8.29 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 6.9 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.51 (s, 2H), 4.35 (d, J = 13.5 Hz, 1H), 3.86 (d, J = 13.5 Hz, 1H), 3.74 (t, J = 10.9 Hz, 1H), 3.62 - 3.54 (m, 1H), 3.20 (t, J = 11.6 Hz, 1H), 3.10 - 3.02 (m, 1H), 2.75 (t, J = 11.6 Hz, 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 = 6.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 563.3.

[0299] Example 79: cis-3-(3-((4-fluoro-1,1-dioxide-2-(2-oxopyrrolidin-3-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.80 (s, 1H), 8.31 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 5.84 (s, 1H), 5.00 (s, 1H), 4.71 (s, 1H), 4.37 (dd, J = 23.3, 11.9 Hz, 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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 521.2.

[0300] Example 80: cis-3-(3-((2-(1-acetylpyrrolidin-3-yl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 12.01 (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 = 6.9 Hz, 1H), 2.05 - 2.00 (m, 1H), 1.96 (d, J = 4.9 Hz, 3H), 1.93 - 1.86 (m, 1H), 1.76 - 1.55 (m, 3H), 1.03 (d, J = 6.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 549.3.

[0301] Example 81: cis-3-(3-((4-fluoro-1,1-dioxide-2-(2-oxopiperidin-4-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 4-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidin-2-one [ka] A mixture of 5,6-dihydropyridin-2(1H)-one (0.33 g, 3.4 mmol), CsCO (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 h. 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 PE / EtOAc (5:1 to 3:1) followed by silica gel column chromatography eluting with DCM / MeOH (10:1) to give the product (0.077 g, 18.8%). LC-MS (ESI): m / z [M+H] + = 363.2.

[0302] Step 2: cis-3-(3-((4-fluoro-1,1-dioxide-2-(2-oxopiperidin-4-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.78 (s, 1H), 8.30 (t, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.53 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 6.6 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.59 (d, J = 14.2 Hz, 1H), 4.50 (d, J = 14.0 Hz, 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, 9.9 Hz, 2H), 2.48 - 2.44 (m, 1H), 2.14 - 1.89 (m, 4H), 1.75 - 1.55 (m, 3H), 1.03 (d, J = 6.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 535.3.

[0303] Example 82: cis-3-(3-((4-fluoro-1,1-dioxide-2-(6-oxopiperidin-3-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.79 (s, 1H), 8.31 (t, J = 7.9 Hz, 1H), 7.55 - 7.47 (m, 2H), 6.93 (d, J = 6.7 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.56 (d, J = 27.0 Hz, 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 = 5.9 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 535.3.

[0304] Example 83: cis-3-(3-((4-fluoro-2-(1-methyl-6-oxopiperidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidin-2-one [ka] 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 N 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.

[0305] Step 2: 5-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-1-methylpiperidin-2-one [ka] To a solution of 5-(5-bromo-4-fluoro-1,1-dioxidebenzo[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 h. CHI (0.2 g, 1.43 mmol) was added, and the mixture was stirred at 0 °C for 1 h. The mixture was quenched with saturated NH Cl (aq) (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.

[0306] Step 3: cis-3-(3-((4-fluoro-2-(1-methyl-6-oxopiperidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized using a procedure similar to that of Example 34, Step 5. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.81 (s, 1H), 8.31 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 7.2 Hz, 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 = 6.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 549.3.

[0307] Example 84: 3-(3-((4-fluoro-2-(3-hydroxycyclobutyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.78 (s, 1H), 8.29 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 5.83 (d, J = 1.7 Hz, 1H), 5.18 (dd, J = 17.4, 6.1 Hz, 1H), 4.99 (s, 1H), 4.46 (s, 2H), 4.32 (dd, J = 11.7, 6.5 Hz, 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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 508.2.

[0308] Example 85: cis-3-(3-((4-fluoro-2-(1-(methylsulfonyl)pyrrolidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.83 (s, 1H), 8.32 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.5 Hz, 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 - 2.42 (m, 1H), 2.28 (q, J = 7.2 Hz, 2H), 2.06 - 1.88 (m, 2H), 1.77 - 1.55 (m, 3H), 1.03 (d, J = 5.9 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 585.2.

[0309] Example 86: cis-3-(3-((4-fluoro-1,1-dioxide-2-(2-oxopiperidin-3-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.75 (s, 1H), 8.30 (s, 1H), 7.74 (s, 1H), 7.52 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.69 (d, J = 14.1 Hz, 1H), 4.42 (d, J = 14.0 Hz, 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 = 5.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 535.3.

[0310] Example 87: cis-3-(3-((2-(1-benzylpyrrolidin-3-yl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.79 (s, 1H), 8.29 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 4.3 Hz, 4H), 7.28 - 7.22 (m, 1H), 6.94 (d, J = 6.6 Hz, 1H), 5.84 (s, 1H), 4.99 (s, 1H), 4.55 (dd, J = 29.9, 14.2 Hz, 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 = 6.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 597.3.

[0311] Example 88: cis-3-(3-((4-fluoro-2-(1-methyl-2-oxopiperidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.75 (s, 1H), 8.30 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 5.83 (s, 1H), 4.99 (s, 1H), 4.66 (d, J = 14.1 Hz, 1H), 4.39 (d, J = 14.1 Hz, 1H), 4.29 (dd, J = 11.6, 5.9 Hz, 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 = 6.1 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 549.3.

[0312] Example 89: cis-3-(3-((4-fluoro-2-(1-(methylsulfonyl)azetidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, 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.

[0313] Example 90: cis-3-(3-((2-(1-acetylazetidin-3-yl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ = 12.01 (s, 1H), 8.85 (s, 1H), 8.32 (s, 1H), 7.56 (d, J = 8.7, 1H), 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.

[0314] Example 91: cis-3-(3-((4-fluoro-2-(1-methylazetidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ = 12.00 (s, 1H), 8.81 (s, 1H), 8.29 (s, 1H), 7.53 (d, J = 8.6, 1H), 6.94 (d, J = 7.1, 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.

[0315] Example 92: cis-3-(3-((2-(1-benzylazetidin-3-yl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, 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.

[0316] Example 93: cis-3-(3-((4-fluoro-2-(1-methyl-2-oxopyrrolidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 3-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)pyrrolidin-2-one [ka] 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 Tol (10 mL) was added cinomethylenetributylphosphorane (546 mg, 2.26 mmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. LCMS indicated the reaction was complete. The mixture was concentrated in vacuo. 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.

[0317] Step 2: 3-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-1-methylpyrrolidin-2-one [ka] To a mixture of NaH (15 mg, 0.37 mmol) in THF was added 3-(5-bromo-4-fluoro-1,1-dioxidebenzo[d]isothiazol-2(3H)-yl)pyrrolidin-2-one (100 mg, 0.28 mmol) under a nitrogen atmosphere at 0 °C. The mixture was stirred at 0 °C for 30 min, and then CHCl (49 mg, 0.34 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The mixture was quenched with ice water (50 mL) and extracted with EA (3 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. 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.

[0318] Step 3: cis-3-(3-((4-fluoro-2-(1-methyl-2-oxopyrrolidin-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] A mixture of 3-(5-bromo-4-fluoro-1,1-dioxidebenzo[d]isothiazol-2(3H)-yl)-1-methylpyrrolidin-2-one (55 mg, 0.15 mmol), cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (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 a nitrogen atmosphere for 16 hours. LCMS showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give the product (37.59 mg, 46.4%). 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.80 (s, 1H), 8.35-8.28 (m, 1H), 7.55 (d, J = 10 Hz, 1H), 6.94 (d, J = 5 Hz, 1H), 5.83 (s, 1H), 5.04-4.96 (m, 1H), 4.69-4.63 (m, 1H), 4.47 (t, J = 10 Hz, 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.

[0319] Example 94: cis-3-(3-((2-(1-benzhydrylazetidin-3-yl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, 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), 4.64 (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), 2.48 - 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.

[0320] Example 95: cis-3-(3-((2-(cyclopropylmethyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, MeOD) δ 7.92 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 5.91 (s, 1H), 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 = 7.0 Hz, 2H), 2.62 - 2.48 (m, 1H), 2.13 (d, J = 8.1 Hz, 1H), 2.03 - 1.72 (m, 4H), 1.19 - 1.01 (m, 7H), 0.70 - 0.59 (m, 2H), 0.35 (q, J = 5.0 Hz, 2H). LC-MS (ESI): m / z [M+H] + = 492.2.

[0321] Example 96: cis-3-(3-((2-(cyclobutylmethyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-2-(cyclobutylmethyl)-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide. [ka] 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 CsCO (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.

[0322] Step 2: 3-(3-((2-(cyclobutylmethyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] A mixture of 5-bromo-2-(cyclobutylmethyl)-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (50 mg, 0.15 mmol), cis-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (37.8 mg, 0.15 mmol), Brettphos PdG (13.5 mg, 0.015 mmol), and KCO (62.1 mg, 0.45 mmol) in t-BuOH (10 mL) was stirred at 110 °C under a N 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 (WatersXSelect C18:RD-CO-094 column, eluted with a gradient of acetonitrile / water (containing 0.1% FA), 20%-40%) to give the product (72.6 mg, 96.1%). 1 H NMR (500 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.7 Hz, 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, 2H), 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.

[0323] Example 97: cis-3-(3-((4-fluoro-2-(oxetan-3-ylmethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-4-fluoro-2-(oxetan-3-ylmethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 oxetan-3-ylmethanol (166.03 mg, 1.89 mmol) and CMBP (688.1 mg, 2.82 mmol). The solution was stirred at 90 °C under a N 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.

[0324] Step 2: cis-3-(3-((4-fluoro-2-(oxetan-3-ylmethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] 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-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (60.2 mg, 0.24 mmol), Brettphos Pd G3 (21.6 mg, 0.024 mmol), and K2CO3 (99.3 mg, 0.72 mmol) in t-BuOH (20 mL) was stirred at 110 °C for 16 h under a N2 atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to give 80 mg of product. The residue was purified by preparative HPLC (Waters XSelect C18:RD-CO-094 column, eluted with a gradient of acetonitrile / water containing 0.1% FA, 20% to 40%) to give the product (79.1 mg). 1 H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.78 (s, 1H), 8.30 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.69 (dd, J = 7.5, 6.3 Hz, 2H), 4.46 (s, 2H), 4.36 (t, J = 6.0 Hz, 2H), 3.62-3.56 (m, 1H), 3.47 (d, J = 7.5 Hz, 2H), 3.40-3.36 (m, 1H), 3.15 - 2.97 (m, 1H), 2.47 - 2.40 (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), 1.10 - 0.93 (m, 6H). LC-MS (ESI): m / z [M+H] + = 508.3.

[0325] Example 98: cis-3-(3-((2-((S)-2-amino-3,3-dimethylbutyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1 H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.79 (s, 1H), 8.29 (s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 6.9 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.61 (d, J = 14.2 Hz, 1H), 4.49 (d, J = 14.1 Hz, 1H), 3.60-3.58 (m, 1H), 3.26 (d, J = 13.4 Hz, 1H), 3.10-3.02 (m, 1H), 2.94 - 2.85 (m, 1H), 2.77 (d, J = 10.3 Hz, 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 = 5.9 Hz, 6H), 0.92 (s, 9H). LC-MS (ESI): m / z [M+H] + = 537.2.

[0326] Example 99: cis-3-(3-((2-((R)-2-amino-3,3-dimethylbutyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.79 (s, 1H), 8.29 (s, 1H), 7.56 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 6.9 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.61 (d, J = 14.2 Hz, 1H), 4.49 (d, J = 14.1 Hz, 1H), 3.60-3.58 (m, 1H), 3.26 (d, J = 13.4 Hz, 1H), 3.10-3.02 (m, 1H), 2.94 - 2.85 (m, 1H), 2.77 (d, J = 10.3 Hz, 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 = 5.9 Hz, 6H), 0.92 (s, 9H). LC-MS (ESI): m / z [M+H] + = 537.2.

[0327] Example 100: cis-3-(3-((4-fluoro-2-(1-methyl-2-oxopiperidin-4-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. LC-MS (ESI): m / z [M+H] + = 549.2. Example 101: cis-3-(3-((4-fluoro-2-iso-butyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.77 (s, 1H), 8.30 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 5.83 (s, 1H), 4.99 (s, 1H), 4.47 (s, 2H), 3.58 (d, J = 6.7 Hz, 1H), 3.13 - 3.03 (m, 1H), 2.92 (d, J = 7.3 Hz, 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 = 6.2 Hz, 6H), 0.95 (d, J = 6.6 Hz, 7H). LC-MS (ESI): m / z [M+H] + = 494.2.

[0328] Examples 102 and 103: cis-3-(3-((4-fluoro-2-(2-hydroxycyclobutyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 2-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)cyclobutan-1-one [ka] A mixture of 2-bromocyclobutan-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 h. 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.

[0329] Step 2: 5-Bromo-4-fluoro-2-(2-hydroxycyclobutyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] To a mixture of 2-(5-bromo-4-fluoro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)cyclobutan-1-one (0.3 g, 0.9 mmol) in EtOH (20 mL) was added NaBH (0.055 g, 1.45 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was quenched with saturated aqueous NH Cl (10 mL) and extracted with DCM (30 mL x 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.

[0330] Step 3: cis-3-(3-((4-fluoro-2-(2-hydroxycyclobutyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized using a procedure similar to that of Example 34, Step 5. Diastereoisomer 1 (Example 102): 1 H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.76 (s, 1H), 8.28 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 6.92 (s, 1H), 5.83 (s, 1H), 5.50 (d, J = 7.4 Hz, 1H), 5.00 (s, 1H), 4.60 (d, J = 14.2 Hz, 1H), 4.39 (d, J = 14.2 Hz, 1H), 4.23 - 4.11 (m, 1H), 3.61 (dt, J = 13.0, 7.5 Hz, 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 = 5.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 508.3. Diastereoisomer 2 (Example 103): 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.76 (s, 1H), 8.29 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 6.92 (s, 1H), 5.83 (s, 1H), 5.39 (d, J = 5.3 Hz, 1H), 5.00 (s, 1H), 4.79 (d, J = 14.5 Hz, 1H), 4.59 (d, J = 14.5 Hz, 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 = 5.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 508.3.

[0331] Example 104: cis-3-(3-((4-fluoro-2-(1-(oxetan-3-yl)ethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.76 (s, 1H), 8.29 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 6.5 Hz, 1H), 5.83 (s, 1H), 4.99 (s, 1H), 4.66 (t, J = 7.0 Hz, 1H), 4.59 (t, J = 6.9 Hz, 1H), 4.49 (d, J = 14.1 Hz, 1H), 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 = 6.5 Hz, 3H), 1.03 (d, J = 5.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 522.3.

[0332] Example 105: cis-3-(3-((2-(azetidin-3-ylmethyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.81 (s, 1H), 8.65 (s, 1H), 8.54 (s, 1H), 8.31 (s, 1H), 7.57 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 6.9 Hz, 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 = 7.4 Hz, 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 = 5.6 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 507.2.

[0333] Example 106: cis-3-(3-((4-fluoro-2-((1-methylazetidin-3-yl)methyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.78 (s, 1H), 8.28 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.1 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.46 (s, 2H), 3.65 - 3.54 (m, 1H), 3.48 (t, J = 7.6 Hz, 2H), 3.36 (d, J = 7.4 Hz, 2H), 3.15 (t, J = 6.7 Hz, 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 = 5.7 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 521.2.

[0334] Example 107: cis-3-(3-((2-((1-acetylazetidin-3-yl)methyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka]

[0335] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.80 (s, 1H), 8.31 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 6.5 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.50 (s, 2H), 4.21 (t, J = 8.3 Hz, 1H), 3.98 - 3.81 (m, 2H), 3.66 - 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 - 1.97 (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 = 3.6 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 549.2.

[0336] Example 108: cis-3-(3-((2-(cyclohexylmethyl)-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka]

[0337] To a solution of 3-(3-((4-fluoro-1,1-dioxide-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) was added cinomethylenetributylphoslan (84 mg, 0.34 mmol). The mixture was stirred at 95° C. under a nitrogen atmosphere for 16 hours. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give the product (6.8 mg, 9.3%).1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.77 (s, 1H), 8.34-8.25 (m, 1H), 7.53 (d, J = 10 Hz, 1H), 6.94 (d, J = 10 Hz, 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.

[0338] Example 109: cis-3-(3-((4-fluoro-2-(2-hydroxycyclopentyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, 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.

[0339] Example 110: cis-3-(3-((4-fluoro-1,1-dioxide-2-((2-oxopyrrolidin-3-yl)methyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.79 (s, 1H), 8.31 (t, J = 10 Hz, 1H), 7.78 (s, 1H), 7.55 (d, J = 10 Hz, 1H), 6.94 (d, J = 5 Hz, 1H), 5.83 (s, 1H), 5.05-4.95 (m, 1H), 4.56-4.44 (m, 2H), 3.64-3.53 (m, 1H), 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.

[0340] Example 111: cis-3-(3-((4-fluoro-2-((1-methyl-2-oxopyrrolidin-3-yl)methyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1HNMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.79 (s, 1H), 8.34-8.25 (m, 1H), 7.55 (t, J = 10 Hz, 1H), 6.94 (t, J = 10 Hz, 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, 1H), 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.

[0341] Example 112: cis-3-(3-((4-fluoro-2-(2-morpholinoethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, 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.

[0342] Example 113: cis-3-(3-((4-fluoro-2-(3-hydroxypropyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 37. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.53 (d, J = 8.6 Hz, 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 = 6.1 Hz, 2H), 3.21 (t, J = 6.1 Hz, 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.

[0343] Example 114: cis-3-(3-((4-fluoro-1,1-dioxide-2-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 63. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.78 (s, 1H), 8.30 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.47 (s, 2H), 3.83 (dd, J = 10.9, 3.6 Hz, 2H), 3.63 - 3.53 (m, 1H), 3.31 - 3.24 (m, 2H), 3.17 (t, J = 6.8 Hz, 2H), 3.11 - 3.03 (m, 1H), 2.48 - 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.

[0344] Example 115: cis-3-(3-((4-fluoro-1,1-dioxide-2-(1-(tetrahydrofuran-3-yl)ethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0345] Step 1: 1-(tetrahydrofuran-3-yl)ethan-1-ol [ka] 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 h. The mixture was quenched with saturated NH4Cl(aq) (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.

[0346] Step 2: 5-Bromo-4-fluoro-2-(1-(tetrahydrofuran-3-yl)ethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] 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 for 12 h. 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.

[0347] Step 3: cis-3-(3-((4-fluoro-1,1-dioxide-2-(1-(tetrahydrofuran-3-yl)ethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized using a procedure similar to that of Example 34, Step 5. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.77 (s, 1H), 8.31 (s, 1H), 7.56 - 7.48 (m, 1H), 6.94 (d, J = 7.3 Hz, 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, 6.6 Hz, 3H), 1.03 (d, J = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 536.3.

[0348] Example 116: cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: Methyl 3-bromo-6-(N-cyclopropylsulfamoyl)-2-fluorobenzoate [ka] To a solution of cyclopropanamine (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 the reaction was complete. The mixture was concentrated in vacuo. 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.

[0349] Step 2: 3-Bromo-6-(N-cyclopropylsulfamoyl)-2-fluorobenzoic acid [ka] 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 hours. LCMS showed the reaction was complete. The mixture was adjusted to pH = 6 with 1 N HCl (aq) and then extracted with EA (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo 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.

[0350] Step 3: 5-Bromo-2-cyclopropyl-4-fluorobenzo[d]isothiazol-3(2H)-one 1,1-dioxide [ka] 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 in vacuo 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.

[0351] Step 4: 5-Bromo-2-cyclopropyl-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] To 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 the reaction was complete. The mixture was slowly quenched with MeOH. The mixture was concentrated in vacuo. 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.

[0352] Step 5: cis-3-(1-(tert-butyl)-5-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] A mixture of 5-bromo-2-cyclopropyl-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (70 mg, 0.23 mmol), cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (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 indicated the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EA / PE (0-80%) to give the product (104 mg, 85.2%). LC-MS (ESI): m / z [M+H] + = 534.2.

[0353] Step 6: cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] To a solution of 3-(1-(tert-butyl)-5-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-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 hours. LCMS showed the reaction was complete. The mixture was quenched with aqueous NaHCO (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the desired product in racemic form, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 116a, 100% ee); retention time: 6.43 min 1 H NMR (500 MHz, DMSO-d6)δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 5 Hz, 1H), 7.52 (d, J = 10 Hz, 1H), 6.94 (d, J = 10 Hz, 1H), 5.83 (s, 1H), 5.02-4.98 (m, 1H), 4.52 (s, 2H), 3.63-3.52 (m, 1H), 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. Enantiomer 2 (Example 116b, 100% ee); retention time: 11.73 min. 1 H NMR (500 MHz, DMSO-d6)δ 12.00 (s, 1H), 8.78 (s, 1H), 8.29 (t, J = 5 Hz, 1H), 7.52 (d, J = 10 Hz, 1H), 6.94 (d, J = 10 Hz, 1H), 5.83 (s, 1H), 5.03-4.97 (m, 1H), 4.52 (s, 2H), 3.62-3.52 (m, 1H), 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. Chiral analytical method: Column: I-Cellulose-5, 4.6 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.1% 2M NH3MeOH); Gradient: Mobile phase A:Mobile phase B = 60:40 (v / v); HPLC apparatus: HPLC-Agilent; Back pressure: 100 bar; Column temperature: 35 °C. Chiral preparative HPLC conditions: Column: I-Cellulose-5, 21.2 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.2% 2M NH3MeOH); 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.

[0354] Example 117: cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate Step 1: cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentan-1-ol [ka] To a solution of cis-benzyl (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 three times. The resulting mixture was stirred under a hydrogen balloon at room temperature for 3 hours. The mixture was filtered, and the filter cake was washed with EA (50 mx L). 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.

[0355] Step 2: 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 [ka] 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 a nitrogen atmosphere for 16 h. LCMS indicated the reaction was complete. The mixture was concentrated in vacuo. 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.

[0356] Step 3: cis-3-(1-(tert-butyl)-5-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate [ka] 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-nitrophenylcarbonochloridinate (61.2 mg, 0.3 mmol). The mixture was stirred at 50 °C for 16 h. LCMS indicated the reaction was complete. The mixture was concentrated in vacuo. 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.

[0357] Step 3: cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate [ka] A solution of cis-3-(1-(tert-butyl)-5-((2-cyclopropyl-4-fluoro-1,1-dioxide-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 the reaction was complete. The mixture was concentrated in vacuo 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.

[0358] Step 4: cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate [ka] A mixture of cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxide-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 hours. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC to give the desired product (3.53 mg, 16.5%) in racemic form, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 117a, 100% ee); retention time: 5.67 min. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 10 Hz, 1H), 7.52 (d, J = 10 Hz, 1H), 6.88 (d, J = 10 Hz, 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. エナンチオマー2 (Example 117b, 100%ee); retention time: 10.41 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 10 Hz, 1H), 7.52 (d, J = 10 Hz, 1H), 6.88 (d, J = 10 Hz, 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.

[0359] Chiral analytical method: Column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; Mobile phase: A is MtBE (0.1% 2M NH3MeOH) (%) and B is EtOH; Gradient: Mobile phase A:Mobile phase B = 10:90 (v / v); HPLC apparatus: HPLC-Agilent, Back pressure: 100 bar; Column temperature: 35 °C.

[0360] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm x 250 mm, 5 μm; mobile phase: A is MtBE (0.2% 2M NH3MeOH) (%) and B is 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.

[0361] Example 118: cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 117, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 118a, 100% ee); retention time: 6.27 min. 11H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 10 Hz, 1H), 7.52 (d, J = 10 Hz, 1H), 7.04 (t, J = 10 Hz, 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。 Enantiomer 2 (Example 118b, 100% ee); retention time: 10.50 min. 1 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 10 Hz, 1H), 7.52 (d, J = 10 Hz, 1H), 7.04 (t, J = 10 Hz, 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。

[0362] Chiral analytical method: Column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; Mobile phase: A is MtBE (0.1% 2M NH3MeOH) (%) and B is EtOH; Gradient: Mobile phase A:Mobile phase B = 10:90 (v / v); HPLC apparatus: HPLC-Agilent, Back pressure: 100 bar; Column temperature: 35 °C.

[0363] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm x 250 mm, 5 μm; mobile phase: A is MtBE (0.2% 2M NH3MeOH) (%) and B is 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.

[0364] Example 119: cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 117, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 119a, 100% ee); retention time: 6.27 min. 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 10 Hz, 1H), 7.52 (d, J = 10 Hz, 1H), 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), 2.48-2.44 (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. Enatoplast 2 (Example 119b, 100%ee); retention time: 10.50 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 10 Hz, 1H), 7.52 (d, J = 10 Hz, 1H), 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), 2.48-2.44 (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. Chiral analytical method: Column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; Mobile phase: A is MtBE (0.1% 2M NH3MeOH) (%) and B is EtOH; Gradient: Mobile phase A:Mobile phase B = 10:90 (v / v); HPLC apparatus: HPLC-Agilent, Back pressure: 100 bar; Column temperature: 35 °C. Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm x 250 mm, 5 μm; mobile phase: A is MtBE (0.2% 2M NH3MeOH) (%) and B is 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.

[0365] Example 120: cis-3-(3-((2-cyclopropyl-4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-1-hydroxypropan-2-yl)carbamate [ka] The title compound was synthesized in the same manner as in Example 117. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (brs, 1H), 7.52 (d, J = 10 Hz, 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), 1.96-1.86 (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.

[0366] Example 121: cis-3-(3-((4-fluoro-2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate Step 1: 5-Bromo-4-fluoro-2-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide [ka] To a mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (266 mg, 1 mmol) and K2CO3 (166 mg, 1.2 mmol) in DMF (10 mL) was added CHCl (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 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. 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.

[0367] Step 2: cis-3-(3-((4-fluoro-2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in racemic form using a procedure similar to Example 34, Step 5, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 121a, 100% ee); retention time: 13.25 min. 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.78 (s, 1H), 8.29 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 5.84 (s, 1H), 5.00 (s, 1H), 4.43 (s, 2H), 3.62 - 3.55 (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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 452.2. Enantioma 2 (Example 121b, 100% ee); holding time: 14.99 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.78 (s, 1H), 8.29 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 5.84 (s, 1H), 5.00 (s, 1H), 4.43 (s, 2H), 3.62 - 3.55 (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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 452.2.

[0368] Chiral analytical method: Column: CHIRALPAK i-Cellulose-5, 4.6 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.1% 2M NH3MeOH); Gradient: Mobile phase A:Mobile phase B = 70:30 (v / v); HPLC apparatus: HPLC-Agilent; Back pressure: 100 bar; Column temperature: 35 °C.

[0369] Chiral preparative HPLC conditions: Column: CHIRALPAK i-cellulose-5 20 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.2% 2M NH3MeOH); 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.

[0370] Example 122: cis-3-(3-((4-fluoro-2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 121, which was further purified by chiral-preparative HPLC to give: Enantiomer 1 (Example 122a, 100% ee); retention time: 6.266 min. 11H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 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, 1H), 1.80 - 1.66 (m, 2H), 1.65 - 1.55 (m, 1H), 1.44 - 1.32 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 452.60。 Enantiomer 2 (Example 122b, 100% ee); retention time: 11.396 min. 1 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 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, 1H), 1.80 - 1.66 (m, 2H), 1.65 - 1.55 (m, 1H), 1.44 - 1.32 (m, 2H), 0.82 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 452.60。

[0371] Chiral analytical method: Column: CHIRALPAK i-Cellulose-5, 4.6 mm x 250 mm, 5 μm; Mobile phase: A is MTBE (0.1% 2M NH3MeOH) and B is MeOH / DCM (1 / 1); Gradient: Mobile phase A:Mobile phase B = 70:30 (v / v); HPLC apparatus: HPLC-Agilent; Back pressure: 100 bar; Column temperature: 35 °C.

[0372] Chiral preparative HPLC conditions: Column: CHIRALPAK i-cellulose-5 20 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.2% 2M NH3MeOH); 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.

[0373] Example 123: cis-3-(3-((4-fluoro-2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 121, which was further purified by chiral-preparative HPLC to give: Enantiomer 1 (Example 122a, 100% ee); retention time: 5.514 min. 11H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 6.9 Hz, 1H), 5.83 (s, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.45 - 3.35 (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 = 7.1 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 466.2。 Enantiomer 2 (Example 122b, 100% ee); retention time: 11.385 minutes. 1 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 6.9 Hz, 1H), 5.83 (s, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.45 - 3.35 (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 = 7.1 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 466.2。 Chiral analytical method: Column: CHIRALPAK i-Cellulose-5, 4.6 mm x 250 mm, 5 μm; Mobile phase: A is MTBE (0.1% 2M NH3MeOH) and B is MeOH / DCM (1 / 1); Gradient: Mobile phase A:Mobile phase B = 70:30 (v / v); HPLC apparatus: HPLC-Agilent; Back pressure: 100 bar; Column temperature: 35 °C. Chiral preparative HPLC conditions: Column: CHIRALPAK i-cellulose-5 20 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.2% 2M NH3MeOH); 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.

[0374] Example 124: cis-3-(3-((4-fluoro-2-methyl-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] The title compound was synthesized in the same manner as in Example 121. 1 H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 7.54 (d, J = 8.6 Hz, 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.

[0375] Example 125: cis-3-(3-((4-fluoro-2-(2-hydroxyethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 37, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 125a, 100% ee); retention time: 14.34 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.4 Hz, 1H), 5.83 (s, 1H), 4.99 (s, 1H), 4.91 (t, J = 5.6 Hz, 1H), 4.54 (s, 2H), 3.68 (q, J = 5.7 Hz, 2H), 3.62 - 3.54 (m, 1H), 3.21 (t, J = 5.8 Hz, 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 = 6.1 Hz, 7H). LC-MS (ESI): m / z [M+H] + = 482.2. Enantiomer 2 (Example 125b, 98.8% ee); retention time: 15.95 min. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.78 (s, 1H), 8.30 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.92 (t, J = 5.5 Hz, 1H), 4.54 (s, 2H), 3.68 (q, J = 5.7 Hz, 2H), 3.62 - 3.56 (m, 1H), 3.21 (t, J = 5.8 Hz, 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 = 6.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 482.2.

[0376] Chiral analytical method: Column: CHIRALPAK i-Cellulose-5, 4.6 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.1% 2M NH3MeOH); Gradient: Mobile phase A:Mobile phase B = 70:30 (v / v); HPLC apparatus: HPLC-Agilent; Back pressure: 100 bar; Column temperature: 35 °C.

[0377] Chiral preparative HPLC conditions: Column: CHIRALPAK i-cellulose-5 20 mm x 250 mm, 5 μm; Mobile phase: A is hexane and B is EtOH (0.2% 2M NH3MeOH); 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.

[0378] Example 126: cis-3-(3-((4-fluoro-2-(2-hydroxyethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 37. 1 H NMR (500 MHz, 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.

[0379] Example 127: cis-3-(3-((4-fluoro-2-(2-hydroxyethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate [ka] The title compound was synthesized in the same manner as in Example 37. 1H NMR (500 MHz, 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.

[0380] Example 128: cis-3-(3-((4-fluoro-2-(2-hydroxyethyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 37, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 128a, 100% ee); retention time: 6.156 min. 11H NMR (500 MHz, 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。 Enantiomer 2 (Example 128b, 100% ee); retention time: 11.817 min. 1 1H NMR (500 MHz, 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), 1.88 (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。 Chiral analysis method: Column: CHIRALPAK IE4.6*250mm 5μm; Mobile phase: A is MtBE (0.1% 2M NH3MeOH) and B is MeOH:DCM=20:80(v / v); Gradient: Mobile phase A:Mobile phase B=50:50(v / v); HPLC apparatus: HPLC-Agilent; Column temperature: 35℃. Chiral preparative HPLC conditions: CHIRALPAK IE20*250 mm, 5 μm; mobile phase: A is MtBE and B is MeOH:DCM=50:50 (0.1% 2M NH3 MeOH); 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.

[0381] Example 129: cis-3-(3-((4-fluoro-2-(methyl-d3)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 35, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 129a, 100% ee); retention time: 5.906 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 5.83 (s, 1H), 4.99 (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. Enantiomer 2 (Example 129b, 100% ee); retention time: 1.718 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 5.83 (s, 1H), 5.00 (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. Chiral analytical method: Column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; Mobile phase: A is MTBE (0.1% 2M NH3MeOH) and B is MeOH / DCM (1 / 1); Gradient: Mobile phase A:Mobile phase B = 10:90 (v / v); HPLC apparatus: HPLC-Agilent, Back pressure: 100 bar; Column temperature: 35 °C.

[0382] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm x 250 mm, 5 μm; mobile phase: A is MTBE (0.1% 2M NH3MeOH) and B is 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.

[0383] Example 130: cis-3-(3-((4-fluoro-2-(methyl-d3)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentylpropylcarbamate [ka] The title compound was synthesized in the same manner as in Example 35. 1 H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.04 (s, 1H), 5.83 (s, 1H), 5.00 (s, 1H), 4.42 (s, 2H), 3.12 - 3.03 (m, 1H), 2.91 (dd, J = 13.1, 6.6 Hz, 2H), 2.48 - 2.43 (m, 1H), 2.06 - 1.88 (m, 2H), 1.78 - 1.55 (m, 3H), 1.39 (dd, J = 14.5, 7.2 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 455.3.

[0384] Example 131: cis-3-(3-((4-fluoro-2-(methyl-d3)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ((S)-sec-butyl)carbamate [ka]

[0385] The title compound was synthesized in the same manner as in Example 35. 1H NMR (500 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 5.84 (s, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.44 - 3.35 (m, 1H), 3.12 - 3.02 (m, 1H), 2.46 - 2.44 (m, 1H), 2.06 - 1.85 (m, 2H), 1.77 - 1.56 (m, 3H), 1.41 - 1.26 (m, 2H), 1.02 - 0.96 (m, 3H), 0.80 (q, J = 7.2 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 469.2.

[0386] Example 132: cis-3-(3-((4-fluoro-2-(methyl-d3)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 35, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 132a, 100% ee); retention time: 6.279 min. 1H NMR (500 MHz, 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. Enatoplast 2 (Example 132b, 100%ee); retention time: 10.24 minutes. 1 H NMR (500 MHz, 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 0.57 (m, 2H), 0.53 - 0.41 (m, 2H). LC-MS (ESI): m / z [M+H] + = 467.34.

[0387] Kirar analysis method: cartridge: CHIRALPAK IE 4.6*250 mm 5 μm; mobile phase: A: MtBE (0.1% 2 M NH3MeOH) and B: MeOH:DCM = 20:80 (v / v); blending: mobile phase A: mobile phase B = 50:50 (v / v); HPLC apparatus: HPLC-Agilent; cartridge temperature: 35°C.

[0388] Chiral preparative HPLC conditions: CHIRALPAK IE20*250 mm, 5 μm; mobile phase: A is MtBE and B is MeOH:DCM=50:50 (0.1% 2M NH3 MeOH); 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.

[0389] Example 133: cis-3-(3-((4-fluoro-2-(oxetan-3-yl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] The title compound was synthesized in racemic form using a procedure similar to that of Example 63, which was further separated by chiral preparative HPLC to give: Enantiomer 1 (Example 133a, 100% ee); retention time: 5.684 min. 1 H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.84 (s, 1H), 8.32 (t, J = 8.1 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 6.8 Hz, 1H), 5.84 (d, J = 1.9 Hz, 1H), 5.00 (s, 1H), 4.87 (t, J = 6.1 Hz, 2H), 4.76 (dq, J = 8.2, 6.3 Hz, 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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 494.2. Enantiomer 2 (Example 133b, 100% ee); retention time: 10.123 min. 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.84 (s, 1H), 8.32 (t, J = 8.1 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 6.8 Hz, 1H), 5.84 (d, J = 1.9 Hz, 1H), 5.00 (s, 1H), 4.87 (t, J = 6.1 Hz, 2H), 4.76 (dq, J = 8.2, 6.3 Hz, 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 = 6.2 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 494.2.

[0390] Chiral analytical method: Column: CHIRALPAK IE 4.6 mm × 250 mm, 5 μm; Mobile phase: A is MTBE (0.1% 2M NH3MeOH) and B is MeOH / DCM (1 / 1); Gradient: Mobile phase A:Mobile phase B = 10:90 (v / v); HPLC apparatus: HPLC-Agilent, Back pressure: 100 bar; Column temperature: 35 °C.

[0391] Chiral preparative HPLC conditions: CHIRALPAK IE 20 mm x 250 mm, 5 μm; mobile phase: A is MTBE (0.1% 2M NH3MeOH) and B is 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.

[0392] Example 134: cis-3-(3-((4-fluor...

Claims

1. A compound of formula (I), 【Chemistry 905】 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, 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 simultaneously 0; 【Chemistry 906】 each is independently a single bond or a double bond, provided that no two double bonds are directly connected; X １ , X ２ , X ３ , and X ４ are each independently N, C, S(=O) ２ or S(=O), where each N is selected from 0 or 1 R as allowed by valence. Ｘａ groups, and each C is independently substituted with one or two R groups as allowed by valence. Ｘｂ substituted with a group; R Ｘａ are each independently hydrogen, —C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C ３ -C ８ cycloalkyl, 3- to 12-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Each aryl or 5- to 12-membered heteroaryl has at least one substituent R Ｘａａ optionally substituted with; R Ｘａａ are each independently hydrogen, deuterium, halogen, or —C １ -C ８ Alkyl 、 -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, —C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR Ｘａｂ , -CN, -SO ２ R Ｘａｂ , -SO ２ NR Ｘａｂ R Ｘａｃ , -C(O)R Ｘａｂ , -CO ２ R Ｘａｂ , —C(O)NR Ｘａｂ R Ｘａｃ , -NR Ｘａｂ R Ｘａｃ , -NR Ｘａｂ COR Ｘａｃ , -NR Ｘａｂ CO ２ R Ｘａｃ or -NR Ｘａｂ SO ２ R Ｘａｃ -C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C １ -C ８ Alkoxy, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, —C ６ -C １２ Each of the aryl or 5- to 12-membered heteroaryl is halogen-C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR Ｘａｄ , -SO ２ R Ｘａｄ , -SO ２ N ＲＸａｄ R Ｘａｅ , -C(O)R Ｘａｄ , -CO ２ R Ｘａｄ , —C(O)NR Ｘａｄ R Ｘａｅ , -NR Ｘａｄ R Ｘａｅ , -NR Ｘａｄ COR Ｘａｅ , -NR Ｘａｄ CO ２ R Ｘａｅ or -NR Ｘａｄ SO ２ R Ｘａｅ optionally substituted with; R Ｘａｂ , R Ｘａｃ , R Ｘａｄ and R Ｘａｅ are each independently hydrogen, deuterium, or —C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Each of the aryl or 5- to 12-membered heteroaryl is halogen-C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OH or -C １ -C ８ optionally substituted with alkoxyl; R Ｘｂ are each independently hydrogen, halogen, or —C １ -C ８ Alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Ｘｂａ R Ｘｂｂ , -OR Ｘｂａ , -SR Ｘｂａ , -SO ２ R Ｘｂａ , -SO ２ NR Ｘｂａ R Ｘｂｂ , -C(O)R Ｘｂａ , -CO ２ R Ｘｂａ , —C(O)NR Ｘｂａ R Ｘｂｂ , -NR Ｘｂａ COR Ｘｂｂ , -NR Ｘｂａ CO ２ R Ｘｂｂ or -NR Ｘｂａ SO ２ R Ｘｂｂ or -CN, wherein said -C １ -C ８ Alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Each aryl, or 5- to 12-membered heteroaryl is Ｘｂｃ is replaced by; or Two R's Ｘｂ together with the atom(s) to which they are attached form a 3- to 12-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or optionally sulfur oxide as ring member(s), said ring containing at least one substituent R Ｘｂｃ optionally substituted with; R Ｘｂａ and R Ｘｂｂ are each independently hydrogen, deuterium, or —C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Each aryl or 5- to 12-membered heteroaryl has at least one substituent R Ｘｂｄ optionally substituted with; R Ｘｂｃ and R Ｘｂｄ are each independently hydrogen, deuterium, halogen, hydroxy, -C １ -C ８ Alkyl, —C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Ｘｂｅ R Ｘｂｆ , -OR Ｘｂｅ , -SR Ｘｂｅ , -SO ２ R Ｘｂｅ , -SO ２ NR Ｘｂｅ R Ｘｂｆ , -C(O)R Ｘｂｅ , -CO ２ R Ｘｂｅ , —C(O)NR Ｘｂｅ R Ｘｂｆ , -NR Ｘｂｅ COR Ｘｂｆ , -NR Ｘｂｅ CO ２ R Ｘｂｆ or -NR Ｘｂｅ SO ２ R Ｘｂｆ or -CN; R Ｘｂｅ and R Ｘｂｆ are each independently -C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; Y １ , Y ２ , and Y ３ are each independently selected from O, C, or N, where C and N are each independently selected from one or two R ５ independently substituted with a group or a hydrogen atom; Q is O or NR Ｑ Selected from: R １ , R ２ , R ３ and R Ｑ are each independently hydrogen, —C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, —C ６ -C １２ aryl or 5- to 12-membered heteroaryl, １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Each aryl or 5- to 12-membered heteroaryl is at least one substituent R １ａ optionally substituted with; or (R １ and R ２ ), (R １ and R Ｑ ), or (R Ｑ and R ２ ) together with the atom(s) to which they are attached form a 3- to 12-membered ring, said ring containing 0-3 additional heteroatoms as ring members independently selected from nitrogen, oxygen, or optionally sulfur oxide, said ring optionally containing at least one substituent R １ｂ is replaced by; R １ａ and R １ｂ is hydrogen, halogen, -C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, —C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR １ｃ , -CN, -SO ２ R １ｃ , -SO ２ NR １ｃ R １ｄ , -C(O)R １ｃ , -CO ２ R １ｃ , —C(O)NR １ｃ R １ｄ , -NR １ｃ R １ｄ , -NR １ｃ COR １ｄ , -NR １ｃ CO ２ R １ｄ or -NR １ｃ SO ２ R １ｄ are independently selected from: １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C １ -C ８ Alkoxy, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, —C ６ -C １２ Each aryl or 5- to 12-membered heteroaryl may be selected from the group consisting of halogen, —C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR １ｅ , -SO ２ R １ｅ , -SO ２ NR １ｅ R １ｆ , -C(O)R １ｅ , -CO ２ R １ｆ , —C(O)NR １ｅ R １ｆ , -NR １ｅ R １ｆ , -NR １ｅ COR １ｆ , -NR １ｅ CO ２ R １ｆ or -NR １ｅ SO ２ R １ｆ optionally substituted with; R １ｃ , R １ｄ , R １ｅ and R １ｆ are hydrogen and -C, respectively. １－ C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R ４ and R ５ are hydrogen, halogen, and -C, respectively. １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C １ -C ８ Alkoxy, or -C ３ -C ８ independently selected from cycloalkyl; Z １ , Z ２ and Z ３ are each independently -CR Ｚ or N; R Ｚ represents, at each occurrence, hydrogen, halogen, -C １ -C ８ Alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, —NR Ｚａ R Ｚｂ , -OR Ｚａ , -SR Ｚａ , -SO ２ R Ｚａ , -SO ２ NR Ｚａ R Ｚｂ , -C(O)R Ｚａ , -CO ２ R Ｚａ , —C(O)NR Ｚａ R Ｚｂ , -NR Ｚａ COR Ｚｂ , -NR Ｚａ CO ２ R Ｚｂ or -NR Ｚａ SO ２ R Ｚｂ or -CN, wherein C １ -C ８ Alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Each aryl, or 5- to 12-membered heteroaryl is Ｚｃ optionally substituted with; R Ｚａ and R Ｚｂ are hydrogen and -C, respectively. １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Each aryl or 5- to 12-membered heteroaryl has at least one substituent R Ｚｄ optionally substituted with; R Ｚｃ and R Ｚｄ are halogen, hydroxy, and —C １ -C ８ Alkyl, —C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, oxo (=O), -NR Ｚｅ R Ｚｆ , -OR Ｚｅ , -SR Ｚｅ , -SO ２ R Ｚｅ , -SO ２ NR Ｚｅ R Ｚｆ , -C(O)R Ｚｅ , -CO ２ R Ｚｅ , —C(O)NR Ｚｅ R Ｚｆ , -NR Ｚｅ COR Ｚｆ , -NR Ｚｅ CO ２ R Ｚｆ or -NR Ｚｅ SO ２ R Ｚｆ or -CN; R Ｚｅ and R Ｚｆ are respectively, -C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl.

2. 10. The compound of claim 1, wherein the compound is selected from formulas (IIa), (IIb), (IIc), and (IId): 【Chemistry 907】 Preferably, the compound is selected from (IIe), (IIf), (IIg), (IIh), (IIi), and (IIj): 【Chemistry 908】

3. The compound of claim 1 selected from (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg) and (IIIh): 【Chemistry 909】

4. 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); 【Chemistry 910】 【911】 【Hua912】 Preferably, the compound is selected from (Va) and (VIa): 【Hua913】 Preferably, the compound is selected from (Vb), (Vc), (VIb) and (VIc): 【Hua914】 More preferably, the compound is selected from (Vd) and (VId): 【Hua915】 Even more preferably, the compound according to claim 1 is selected from (Ve), (Vf), (VIe) and (VIf). 【Hua916】

5. 10. A compound according to any one of the preceding claims, wherein R １ , R ２ , R ３ and R Ｑ are each independently hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and including said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may be selected from the group consisting of at least one substituent R １ａ optionally substituted with; R １ａ are independently hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -OR １ｃ , -CN, -SO ２ R １ｃ , -SO ２ NR １ｃ R １ｄ , -C(O)R １ｃ , -CO ２ R １ｃ , —C(O)NR １ｃ R １ｄ , -NR １ｃ R １ｄ , -NR １ｃ COR １ｄ , -NR １ｃ CO ２ R １ｄ or -NR １ｃ SO ２ R １ｄ and wherein said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR １ｅ , -SO ２ R １ｅ , -SO ２ NR １ｅ R １ｆ , -C(O)R １ｅ , -CO ２ R １ｆ , —C(O)NR １ｅ R １ｆ , -NR １ｅ R １ｆ , -NR １ｅ COR １ｆ , -NR １ｅ CO ２ R １ｆ or -NR １ｅ SO ２ R １ｆ optionally selected from R １ｃ , R １ｄ , R １ｅ and R １ｆ respectively represent hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, including methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ optionally substituted with 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, pentoxy, hexoxy, heptoxy, or octoxy; Preferably, R １ , R ２ , R ３ and R Ｑ respectively represent hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ independently selected from 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 are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl); Even more preferably, R １ and R ２ are each independently hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl 【Hua917】 isobutyl 【Hua918】 or tert-butyl); 【Hua919】 and R ３ and R Ｑ are each independently hydrogen.

6. 10. A compound according to any one of the preceding claims, wherein R １ are independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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; Each of the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 may be substituted with at least one substituent R １ａ optionally substituted with; R １ａ is 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]heptanyl, spiro[2.3]hexanyl, tetrahydrofuranyl, or —OR １ｃ each of said methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is independently selected from OR １ｃ optionally substituted with; R １ｃ is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl; R ２ is hydrogen; Preferably, R １ are independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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; and each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 selected from the group consisting of OH, CH ２ OH, CH ２ optionally substituted with at least one substituent selected from OMe, 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: R ２ is hydrogen; More preferably, R １ are independently methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl 【Hua920】 isobutyl 【Hua921】 or tert-butyl); 【Hua922】 is selected from: R ２ is hydrogen.

7. 10. A compound according to any one of the preceding claims, comprising (R １ and R ２ ), (R １ and R Ｑ ) or (R Ｑ and R ２ ), together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 additional heteroatoms as ring member(s) independently selected from nitrogen, oxygen, or optionally sulfur oxide, said ring containing at least one substituent R １ｂ optionally substituted with; R １ｂ are independently hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -OR １ｃ , -CN, -SO ２ R １ｃ , -SO ２ NR １ｃ R １ｄ , -C(O)R １ｃ , -CO ２ R １ｃ , —C(O)NR １ｃ R １ｄ , -NR １ｃ R １ｄ , -NR １ｃ COR １ｄ , -NR １ｃ CO ２ R １ｄ or -NR １ｃ SO ２ R １ｄ and wherein said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR １ｅ , -SO ２ R １ｅ , -SO ２ NR １ｅ R １ｆ , -C(O)R １ｅ , -CO ２ R １ｆ , —C(O)NR １ｅ R １ｆ , -NR １ｅ R １ｆ , -NR １ｅ COR １ｆ , -NR １ｅ CO ２ R １ｆ or -NR １ｅ SO ２ R １ｆ optionally selected from R １ｃ , R １ｄ , R １ｅ and R １ｆ respectively represent hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, including methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ optionally substituted with 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, pentoxy, hexoxy, heptoxy, or octoxy; Preferably, (R １ and R ２ ), (R １ and R Ｑ ), or (R Ｑ and R ２ ), together with the atom(s) to which they are attached, form a 4-, 5-, or 6-membered ring, said ring containing at least one substituent R １ｂ optionally substituted with; R １ｂ is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, —OR １ｃ , -CN, -SO ２ R １ｃ , -SO ２ NR １ｃ R １ｄ , -C(O)R １ｃ , -CO ２ R １ｃ , —C(O)NR １ｃ R １ｄ , -NR １ｃ R １ｄ , -NR １ｃ COR １ｄ , -NR １ｃ CO ２ R １ｄ or -NR １ｃ SO ２ R １ｄ are independently selected from R １ｃ and R １ｄ is hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ each independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ optionally substituted with 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, pentoxy, hexoxy, heptoxy, or octoxy; More preferably, (R １ and R ２ ), (R １ and R Ｑ ), or (R Ｑ and R ２ ) together with the atom(s) to which they are attached form a 4-, 5- or 6-membered ring; said ring contains at least one substituent R １ｂ optionally substituted with; R １ｂ is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —CN, or —NH ２ are independently selected from Even more preferably, R １ and R ２ together with the nitrogen atom to which they are attached form a four- or five-membered ring; said ring contains at least one substituent R １ｂ optionally substituted with; R １ｂ are independently selected from hydrogen, —F, —Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), or —OH.

8. A compound according to any one of the preceding claims, wherein the moiety 【Hua923】 but, 【Hua924】 The compound is selected from

9. 10. A compound according to any one of the preceding claims, wherein R ４ and R ５ are each independently hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ selected from alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; Preferably, R ４ and R ５ are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl; Even more preferably, R ４ and R ５ are each independently selected from hydrogen.

10. The part 【Hua925】 teeth, 【Hua926】 is selected from Preferably, said portion 【Hua927】 teeth, 【Hua928】 Selected from: More preferably, the part 【Hua929】 teeth, 【Chemistry 930】 Selected from: Even more preferably, said portion 【Hua931】 teeth, 【Hua932】 10. A compound according to any one of the preceding claims, selected from:

11. A compound according to any one of the preceding claims, wherein Z １ , Z ２ and Z ３ At most two of Z are N; preferably １ , Z ２ , and Z ３ at most one of is N; More preferably, Z １ is N and Z ２ and Z ３ But, -CR Ｚ or Z ２ is N and Z １ and Z ３ But, -CR Ｚ or Z ３ is N and Z １ and Z ２ Ga-CR Ｚ The compound,

12. 10. A compound according to any one of the preceding claims, wherein R Ｚ each occurrence independently represents hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 , -SO ２ R Ｚａ , -SO ２ NR Ｚａ R Ｚｂ , -C(O)R Ｚａ , -CO ２ R Ｚａ , —C(O)NR Ｚａ R Ｚｂ , -NR Ｚａ COR Ｚｂ , -NR Ｚａ CO ２ R Ｚｂ or -NR Ｚａ SO ２ R Ｚｂ or —CN, wherein each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 selected from at least one R Ｚｃ optionally substituted with; R Ｚａ and R Ｚｂ are each independently hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, including methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may be selected from the group consisting of at least one substituent R Ｚｄ optionally substituted with; R Ｚｃ and R Ｚｄ are each independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, —NR Ｚｅ R Ｚｆ , -OR Ｚｅ , -SR Ｚｅ , -SO ２ R Ｚｅ , -SO ２ NR Ｚｅ R Ｚｆ , -C(O)R Ｚｅ , -CO ２ R Ｚｅ , —C(O)NR Ｚｅ R Ｚｆ , -NR Ｚｅ COR Ｚｆ , -NR Ｚｅ CO ２ R Ｚｆ or -NR Ｚｅ SO ２ R Ｚｆ or -CN; R Ｚｅ and R Ｚｆ each independently represents methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl; Preferably, R Ｚ is, at each occurrence, independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, —CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -NR Ｚａ R Ｚｂ , -OR Ｚａ , -SR Ｚａ , -SO ２ R Ｚａ , -SO ２ NR Ｚａ R Ｚｂ , -C(O)R Ｚａ , -CO ２ R Ｚａ , —C(O)NR Ｚａ R Ｚｂ , -NR Ｚａ COR Ｚｂ , -NR Ｚａ CO ２ R Ｚｂ or -NR Ｚａ SO ２ R Ｚｂ or -CN; R Ｚａ and R Ｚｂ are each independently hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; More preferably, R Ｚ is, at each occurrence, independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, —CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -NH ２ , —OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy or —CN; Even more preferably, R Ｚ is, at each occurrence, independently selected from hydrogen, —F, —Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ OH, -CH ２ CHF ２ , -CH ２ CF ３ , -NH ２ , -OH, -OCHF ２ , methoxy, ethoxy, propoxy, or butoxy.

13. A compound according to any one of the preceding claims, wherein the moiety 【Hua933】 teeth, 【Hua934】 is selected from Preferably, said portion 【Chemistry 935】 teeth, 【Hua936】 The compound is selected from

14. 10. A compound according to any one of the preceding claims, wherein X １ , X ２ , X ３ and X ４ are each independently N, NR Ｘａ , C.R. Ｘｂ , C(R Ｘｂ ) ２ , S(=O) ２ where X is selected from １ , X ２ , X ３ and X ４ is allowed by the valence; preferably, X １ , X ２ , X ３ and X ４ At most one of Ｘａ is selected from X １ , X ２ , X ３ and X ４ At most one of them is S(=O) ２ or S(=O).

15. 10. A compound according to any one of the preceding claims, wherein R Ｘａ are each independently hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, including methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may be selected from the group consisting of at least one substituent R Ｘａａ optionally substituted with; R Ｘａａ is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -OR Ｘａｂ , -CN, -SO ２ R Ｘａｂ , -SO ２ NR Ｘａｂ R Ｘａｃ , -C(O)R Ｘａｂ , -CO ２ R Ｘａｂ , —C(O)NR Ｘａｂ R Ｘａｃ , -NR Ｘａｂ R Ｘａｃ , -NR Ｘａｂ COR Ｘａｃ , -NR Ｘａｂ CO ２ R Ｘａｃ or -NR Ｘａｂ SO ２ R Ｘａｃ and wherein said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR Ｘａｄ , -SO ２ R Ｘａｄ , -SO ２ NR Ｘａｄ R Ｘａｅ , -C(O)R Ｘａｄ , -CO ２ R Ｘａｄ , —C(O)NR Ｘａｄ R Ｘａｅ , -NR Ｘａｄ R Ｘａｅ , -NR Ｘａｄ COR Ｘａｅ , -NR Ｘａｄ CO ２ R Ｘａｅ or -NR Ｘａｄ SO ２ R Ｘａｅ optionally selected from R Ｘａｂ , R Ｘａｃ , R Ｘａｄ and R Ｘａｅ is hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ each independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ optionally substituted with 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, pentoxy, hexoxy, heptoxy, or octoxy; Preferably, R Ｘａ are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3- to 8-membered heterocyclyl, and each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3- to 8-membered heterocyclyl is selected from the group consisting of at least one substituent R Ｘａａ optionally substituted with; R Ｘａａ is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ 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 and wherein said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR Ｘａｄ , -SO ２ R Ｘａｄ , -C(O)R Ｘａｄ or -NR Ｘａｄ R Ｘａｅ optionally substituted with; R Ｘａｂ , R Ｘａｃ , R Ｘａｄ and R Ｘａｅ is hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ each independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each independently selected from methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is selected from the group consisting of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ optionally substituted with 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, pentoxy, hexoxy, heptoxy, or octoxy; More preferably, R Ｘａ are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydrofuranyl, azetidinyl or pyrrolidinyl, wherein each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, tetrahydrofuranyl, azetidinyl, oxetanyl or pyrrolidinyl is selected from the group consisting of at least one substituent R Ｘａａ optionally substituted with; R Ｘａａ are independently hydrogen, —F, —Cl, —Br, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxo (═O), —OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, —CN, benzyl, —NMe ２ , -NH ２ , -SO ２ Me, -COCH ３ , 【Hua937】 each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl or azetidinyl is independently selected from F, —Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, —OR Ｘａｄ , -SO ２ R Ｘａｄ , -C(O)R Ｘａｄ optionally substituted with; R Ｘａｄ is selected from hydrogen, methyl, and ethyl; Even more preferably, R Ｘａ respectively represent hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, -C ２ H ４ OH, -C ２ H ４ OMe, -C ３ H ６ OH, -C ３ H ６ OMe, -CH ２ OMe, -C(CH ３ ) ２ OH, 【Hua938】 The compound is independently selected from:

16. 10. A compound according to any one of the preceding claims, wherein R Ｘｂ is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 , -SO ２ R Ｘｂａ , -SO ２ NR Ｘｂａ R Ｘｂｂ , -C(O)R Ｘｂａ , -CO ２ R Ｘｂａ , —C(O)NR Ｘｂａ R Ｘｂｂ , -NR Ｘｂａ COR Ｘｂｂ , -NR Ｘｂａ CO ２ R Ｘｂｂ or -NR Ｘｂａ SO ２ R Ｘｂｂ or —CN, wherein each of said methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl 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 independently selected from at least one R Ｘｂｃ optionally substituted with; R Ｘｂａ and R Ｘｂｂ are each independently hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, including methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may be selected from the group consisting of at least one substituent R Ｘｂｄ optionally substituted with; R Ｘｂｃ and R Ｘｂｄ respectively represent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ 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 , -SO ２ R Ｘｂｅ , -SO ２ NR Ｘｂｅ R Ｘｂｆ , -C(O)R Ｘｂｅ , -CO ２ R Ｘｂｅ , —C(O)NR Ｘｂｅ R Ｘｂｆ , -NR Ｘｂｅ COR Ｘｂｆ , -NR Ｘｂｅ CO ２ R Ｘｂｆ or -NR Ｘｂｅ SO ２ R Ｘｂｆ or -CN; R Ｘｂｅ and R Ｘｂｆ respectively represent methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl; Preferably, R Ｘｂ is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, —CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , oxo (=O), -NR Ｘｂａ R Ｘｂｂ , -OR Ｘｂａ , -SR Ｘｂａ , -SO ２ R Ｘｂａ , -SO ２ NR Ｘｂａ R Ｘｂｂ , -C(O)R Ｘｂａ , -CO ２ R Ｘｂａ , —C(O)NR Ｘｂａ R Ｘｂｂ , -NR Ｘｂａ COR Ｘｂｂ , -NR Ｘｂａ CO ２ R Ｘｂｂ or -NR Ｘｂａ SO ２ R Ｘｂｂ or -CN; R Ｘｂａ and R Ｘｂｂ are each independently hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; More preferably, R Ｘｂ represents hydrogen, -F, -Cl, -Br, -I, methyl, -CD ３ , ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, —CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , -NH ２ , —OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, or —CN; Even more preferably, R Ｘｂ is hydrogen, -F, -Cl, methyl, -CD ３ , ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , oxo (=O), or -OH.

17. A compound according to any one of the preceding claims, comprising two R Ｘｂ together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring; said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally sulfur oxide as ring member(s), said ring containing at least one substituent R Ｘｂｃ optionally substituted with; R Ｘｂｃ respectively represent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ 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 , -SO ２ R Ｘｂｅ , -SO ２ NR Ｘｂｅ R Ｘｂｆ , -C(O)R Ｘｂｅ , -CO ２ R Ｘｂｅ , —C(O)NR Ｘｂｅ R Ｘｂｆ , -NR Ｘｂｅ COR Ｘｂｆ , -NR Ｘｂｅ CO ２ R Ｘｂｆ or -NR Ｘｂｅ SO ２ R Ｘｂｆ or -CN; R Ｘｂｅ and R Ｘｂｆ respectively represent methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl; Preferably, two R Ｘｂ together with the atom(s) to which they are attached form a 3-, 4-, 5-, or 6-membered ring; said ring contains at least one substituent R Ｘｂｃ optionally substituted with; R Ｘｂｃ are each independently selected from -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl or tert-butyl), methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxo (=O), or -CN; More preferably, two R Ｘｂ form, together with the atom(s) to which they are attached, a 3-, 4-, 5-, or 6-membered ring.

18. A compound according to any one of the preceding claims, wherein the moiety 【Hua939】 but, 【Chemistry 940】 【Hua941】 【Hua942】 【Hua943】 The compound is selected from

19. 10. A compound according to any one of the preceding claims, selected from: 【Hua944】 【Chemistry 945】 【Hua946】 【Hua947】 【Hua948】 【Hua949】 【Chemistry 950】 【Chemistry 951】 【Hua952】 【Chemistry 953】 【Chemistry 954】 【Chemistry 955】 【Hua956】 【Hua957】 【Chemistry 958】 【Hua959】 【Chemistry 960】 【Hua961】 【Hua962】 【Hua963】 【Hua964】 【Chemistry 965】 【Hua966】 【Hua967】 【Hua968】 【Hua969】 【Chemistry 970】 【Chemistry 971】 【Hua972】 【Hua973】 【Hua974】 【Chemistry 975】 【Hua976】 【Hua977】 【Hua978】 【Hua979】 【Chemistry 980】 【Chemistry 981】 【Chemistry 982】 【Chemistry 983】 【Chemistry 984】

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

21. 20. A method of treating cancer, comprising administering to a subject in need thereof a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, or stereoisomer, tautomer, or prodrug thereof.

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