4-((5-(3-(4-(pyridin-2-yl) cyclopentyl)-1h-pyrazol-3-yl) amino)-benzenesulfonamide derivatives and similar compounds as CDK inhibitors for treatment of cancer

Abstract

Disclosed herein are compounds of Formula (I) useful as cyclin dependent kinase inhibitors for the treatment of cancer.

Description

Technical Field

[0001] This article discloses compounds used as inhibitors of cyclin-dependent kinases. It also discloses the use of these inhibitors in inhibiting cyclin-dependent kinases and the use of such compounds in cancer treatment. Background Technology

[0002] Cyclin-dependent kinases (CDKs) are a family of Ser / Thr protein kinases that drive the cell cycle (Norbury, C. and Nurse, P., Annu Rev Biochem (61, 441-470). During the cell cycle, CDK4 and CDK6 initiate retinoblastoma (Rb) phosphorylation by binding to cyclin D and partially release the transcription factor E2F. CDK2 then forms a complex with cyclin E to fully phosphorylate Rb, fully release E2F, and initiate S phase (Harbour, JW et al.). Cell , 98(6), 859-869). Then, during the S phase, CDK2 forms a complex with cyclin A (Echalier, A. et al., , Biochim Biophys Acta , 1804(3), 511-519). Interestingly, in normal cells, CDK2 is mostly not essential for the cell cycle, but in some cancer cells, CDK2 kinase activity plays a key role in abnormal growth (Caruso, JA et al., , Cancer Res , 78(19), 5481-5491).

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

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

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

[0006] In one embodiment, a compound of formula (I) is disclosed herein. The embodiment includes the following aspects: Aspect 1. A compound of formula (I) Formula (I) Or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, wherein: m can be 0, 1, 2, 3 or 4, provided that the valence theory is satisfied; n can be 0, 1, 2, 3, 4 or 5, provided that the valence theory is satisfied; It can be a single bond or a double bond independently; Ring A is selected from heteroaryl rings and aryl rings; X 1 It is a single bond or O; X 2 X 3 X 4 and X 5 Each is independently selected from N and C; R 1 Each of the following is independently selected from halogens, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -CN, and -OH, wherein each of the -C1-C8 alkyl, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclic groups is optionally selected from at least one of the following: halogens, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -OH, -C6-C 12 Substitution with aryl, 5- to 12-membered heteroaryl, and oxo (=O) substituents; R 5 Selected from -SO2R 5a and -SO2NR 5a R 5b , where R 5a and R 5b Each is independently selected from hydrogen and -C1-C3 alkyl groups; R 6 Selected from hydrogen, -C1-C3 alkyl, and -C3-C8 cycloalkyl; or R 5 and R 6 Together with the atoms to which they are attached, they form 5- to 12-membered rings, the rings comprising S(=O)₂ or S(=O), and 0-2 additional heteroatoms independently selected from nitrogen and oxygen as one or more ring members; the rings are optionally substituents R. 5c replace; R 5c Each is independently selected from halogens, -C1-C8 alkyl groups, -C3-C8 cycloalkyl groups, 3- to 8-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, and oxy-group (=O); Ring B is selected from 5- to 7-membered heterocyclic groups, phenyl groups, and 5- to 7-membered heteroaryl groups; R 2 Each is independently selected from halogens, -C1-C8 alkyl groups, -C2-C8 alkenyl groups, -C2-C8 alkynyl groups, -C3-C8 cycloalkyl groups, 3- to 8-membered heterocyclic groups, and -C6-C... 12 aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 2a -CN, -C(O)R 2a -CO2R 2a -NR 2a R 2b -NR 2a COR 2b , and -NR 2a CO2R 2b The -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally selected independently from at least one of the following: halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 2c -C1-C8 alkyl-OR 2c -C(O)R 2c -CO2R 2c -NR 2c R 2d -NR 2c COR 2d , and -NR 2c CO2R 2d Substituents of the substituents; R 2a R 2b R 2c and R 2d Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, C6-C 12 aryl, and 5- to 12-membered heteroaryl, wherein the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally selected from at least one group selected from halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12Substitution with aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OH, and -C1-C8 alkoxy groups; R 7 Selected from hydrogen, -C1-C3 alkyl, and -C3-C8 cycloalkyl; or Adjacent R 2 and R 7 Together with the atoms to which they are attached, they form 3- to 12-membered rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur as one or more ring members; the rings are optionally substituents R. 7a replace; R 7a Each is independently selected from halogens, -C1-C8 alkyl groups, -C3-C8 cycloalkyl groups, 3- to 8-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, and oxy-group (=O); R 3 and R 4 Each is independently selected from hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, and -C(O)R 3a Each of the -C1-C8 alkyl and C3-C8 cycloalkyl groups is optionally selected independently from at least one halogen, oxo group (=O), -CN, -OR. 3b and -NR 3b R 3c Substituents; and R 3a R 3b and R 3c Each is independently selected from hydrogen, -C1-C8 alkyl, and C3-C8 cycloalkyl; wherein each of the -C1-C8 alkyl and C3-C8 cycloalkyl is optionally substituted by at least one substituent independently selected from halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, oxo (=O), -CN, -OH, and -C1-C8 alkoxy.

[0007] Aspect 2. The compound as described in Aspect 1, wherein ring A is a 6-membered heteroaryl ring, and X 2 X 3 X 4 and X 5 Three of them are N; preferably, ring A is a 6-membered heteroaryl ring, and X 2 X 3 X 4 and X 5 Two of them are N; more preferably, ring A is a 6-membered heteroaryl ring, and X 2 X 3 X 4 and X 5One of them is N; even more preferably, ring A is a 6-membered heteroaryl ring, and X 2 It is N.

[0008] Aspect 3. The compound as described in aspect 1, wherein the compound is selected from (IIa), (IIb), (IIc), and (IId): Preferably, the compound is selected from (IIIa), (IIIb), (IIIc), and (IIId): Aspect 4. The compound as described in any of the preceding aspects, wherein m can be 0, 1, 2, 3 or 4, provided that the valence theory is satisfied; R 1 Each of the following groups is independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, -CN, and -OH, wherein methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, ... Each of cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3- to 8-membered heterocyclic groups is optionally selected independently from at least one of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, -OH, -C6-C 12 Substitution with aryl, 5- to 12-membered heteroaryl, and oxo (=O) substituents; Preferably, m is 0, 1, 2, 3 or 4, provided that the valence theory is satisfied; R 1 Each of the following groups is independently selected from -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, 3- to 8-membered heterocyclic groups, -CN, and -OH, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, or 3- to 8-membered heterocyclic groups is optionally selected from at least one group independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, 3- to 8-membered heterocyclic groups, -OH, -C6-C 12Substitution with aryl, 5- to 12-membered heteroaryl, and oxo (=O) groups; More preferably, m is 0 or 1, provided that the valence theory is satisfied; R 1 Each of the following is independently selected from -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, -CN, and -OH; wherein the methyl group is replaced by -OH. Even more preferably, m is 0 or 1, provided that valence theory is satisfied; R 1 It is -F or CH2OH.

[0009] Aspect 5. The compound as described in any of the preceding aspects, wherein R 5 Selected from -SO2R 5a and -SO2NR 5a R 5b , where R 5a and R 5b Each is independently selected from hydrogen, methyl, ethyl, and propyl (n-propyl or isopropyl); Preferably, R 5 Selected from -SO2R 5a and -SO2NR 5a R 5b , where R 5a and R 5b Each is independently selected from hydrogen and methyl; More preferably, R 5 Selected from -SO2R 5a and -SO2NR 5a R 5b , where R 5a and R 5b Each is hydrogen; Even more preferably, R 5 It is -SO2NH2.

[0010] Aspect 6. The compound as described in any of the preceding aspects, wherein R 6 Selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; Preferably, R 6 Selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, and cyclopentyl; More preferably, R 6 Selected from hydrogen, methyl, ethyl, and cyclopropyl; Even more preferably, R 6 It is hydrogen.

[0011] Aspect 7. The compound as described in any one of Aspects 1 to 4, wherein Adjacent R 5 and R 6 Together with the atoms to which they are attached, they form 3- to 12-membered rings, the rings comprising S(=O)₂ or S(=O), and 0-2 additional heteroatoms independently selected from nitrogen and oxygen as one or more ring members; the rings are optionally substituents R. 5c replace; R 5c Each group is independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, and -C6-C. 12 Aryl, 5- to 12-membered heteroaryl, and oxy-group (=O); Preferably, adjacent R 5 and R 6 Together with the atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered rings, the rings comprising S(=O)₂ or S(=O), and 0-2 additional heteroatoms independently selected from nitrogen and oxygen as one or more ring members; the rings are optionally substituents R. 5c replace; R 5c Each is independently selected from -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, and oxy-group (=O); More preferably, adjacent R 5 and R 6 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the ring comprising S(=O)₂ or S(=O), and 0-1 additional nitrogen atoms as ring members; the ring is optionally substituented by at least one R. 5c replace; R 5c Each is independently selected from -F, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, 3- to 8-membered heterocyclic groups, 5- to 12-membered heteroaryl groups, and oxo groups (=O); Even more preferably, adjacent R 5 and R 6 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, which contains S(=O)2 or S(=O) and an additional 0-1 nitrogen atoms as ring members; the ring is optionally substituted with methyl groups.

[0012] Aspect 8. The compound as described in any of the preceding aspects, wherein Ring B is selected from 5- or 6-membered heterocyclic groups, phenyl groups, and 5- or 6-membered heteroaryl groups; Preferably, ring B is selected from 5-membered heterocyclic groups, 5-membered heteroaryl groups, 6-membered heteroaryl groups, and phenyl groups; wherein the 5-membered heterocyclic group, 5-membered heteroaryl group, or 6-membered heteroaryl group comprises 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur as one or more ring members; More preferably, ring B is selected from a 5-membered heterocyclic group comprising 1-2 heteroatoms independently selected from oxygen and nitrogen as one or more ring members, a 5-membered heteroaryl group comprising 1-3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur as one or more ring members, a 6-membered heteroaryl group comprising 1-2 nitrogen atoms as one or more ring members, and phenyl. Even more preferably, ring B is selected from furanyl, pyridinyl, oxazolyl, pyrimidinyl, pyridazinyl, pyrazolyl, thiazolyl, oxadiazolyl, phenyl, tetrahydrofuranyl, imidazolyl, triazolyl, pyrroleyl, pyrrolidinyl, imidazolyl, isothiazolyl, and isoxazolyl.

[0013] Aspect 9. The compound as described in any of the preceding aspects, wherein n can be 0, 1, 2, 3, 4 or 5, provided that the valence theory is satisfied; R 2 Each group is independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 2a -CN, -C(O)R 2a -CO2R 2a -NR 2a R 2b -NR 2a COR 2b , and -NR 2a CO2R 2b The methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, -C6-C 12Each of the aryl or 5- to 12-membered heteroaryl groups is optionally selected independently from at least one of the following: -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 2c -C1-C8 alkyl-OR 2c -C(O)R 2c -CO2R 2c -NR 2c R 2d -NR 2c COR 2d , and -NR 2c CO2R 2d Substituents of the substituents; R 2a R 2b R 2c and R 2d Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, C6-C 12 aryl, and 5- to 12-membered heteroaryl, wherein the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally selected independently from at least one of the following: -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, C6-C 12 Substituents of aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, and octoxy; Preferably, n is 0, 1, 2, 3, 4 or 5, provided that the valence theory is satisfied; R2 Each is independently selected from -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), -C2-C8 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 2a -CN, -C(O)R 2a -CO2R 2a -NR 2a R 2b -NR 2a COR 2b , and -NR 2a CO2R 2b The methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), -C2-C8 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally selected independently from at least one group selected from -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, 3- to 8-membered heterocyclic groups, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 2c -C1-C8 alkyl-OR 2c -C(O)R 2c -CO2R 2c -NR 2c R 2d -NR 2c COR 2d , and -NR 2c CO2R 2d Substituents of the substituents; R 2a R 2b R 2c and R 2d Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, 3- to 8-membered heterocyclic groups, C6-C 12 aryl, and 5- to 12-membered heteroaryl, wherein the methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, 3- to 8-membered heterocyclic group, C6-C 12Each of the aryl or 5- to 12-membered heteroaryl groups is optionally selected independently from at least one of -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, C6-C 12 Substitution of aryl, oxo (=O), -CN, -OH, methoxy, and ethoxy groups; More preferably, n is 0, 1, 2, 3, 4 or 5, provided that the valence theory is satisfied; R 2 Each is independently selected from -Cl, methyl, ethyl, isopropyl, tert-butyl, vinyl, cyclopropyl, cyclobutyl, phenyl, oxo (=O), -OR 2a and -CO2R 2a The methyl, ethyl, isopropyl, tert-butyl, vinyl, cyclopropyl, cyclobutyl, or phenyl group is optionally selected from at least one group independently of -F, methyl, -C1-C8 alkyl, or -OR. 2c and -OR 2c Substituents of the substituents; R 2a and R 2c Each is independently selected from hydrogen, methyl, and ethyl; Even more preferably, n is 0, 1, 2, 3, 4 or 5, provided that the valence theory is satisfied; R 2 Each of the following groups is independently selected from -Cl, methyl, ethyl, isopropyl, tert-butyl, vinyl, cyclopropyl, cyclobutyl, phenyl, oxo (=O), CF3, methoxy, -OH, -CH2OCH3, CH2OH, -CO2CH3, and -CO2CH2CH3, wherein each of the ethyl, isopropyl, tert-butyl, vinyl, or cyclopropyl groups is optionally substituted by at least one substituent independently selected from methyl, -CH2OH, and -OH.

[0014] Aspect 10. The compound as described in any of the preceding aspects, wherein R 7 Selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; Preferably, R 7 Selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, and cyclopentyl; More preferably, R 7 Selected from hydrogen, methyl, ethyl, and cyclopropyl; Even more preferably, R 7 It is hydrogen.

[0015] Aspect 11. The compound as described in any one of Aspects 1 to 9, wherein n can be 2, 3, 4, or 5, provided that valence theory is satisfied; adjacent R 2 and R 7 Together with the atoms to which they are attached, they form 5-, 6-, 7-, 8-, or 9-membered rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur as one or more ring members; the rings are optionally substituents R. 7a replace; R 7a Each group is independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, and -C6-C. 12 Aryl, 5- to 12-membered heteroaryl, and oxy-group (=O); Preferably, n is 2, 3, 4, or 5, provided that valence theory is satisfied; adjacent R 2 and R 7 Together with the atoms to which they are attached, they form 5-, 6-, 7-, 8-, or 9-membered rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen and oxygen as one or more ring members; the rings are optionally substituents R. 7a replace; R 7a Each is independently selected from -F, -Cl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Aryl and oxy (=O); More preferably, n is 2, 3, or 4, provided that valence theory is satisfied; adjacent R 2 and R 7 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the ring containing 0-1 heteroatoms selected from nitrogen and oxygen atoms as ring members; the ring is optionally substituented by at least one R. 7a replace; R 7a Each is independently selected from -F, methyl, ethyl, cyclopropyl, cyclobutyl, -C6-C 12 Aryl and oxy (=O); Even more preferably, n is 2, provided that valence theory is satisfied; adjacent R 2 and R 7 Together with the atoms to which they are attached, they form cyclopentyl, cyclohexyl, ethylene oxide, tetrahydrofuranyl, phenyl, or pyridyl groups; wherein the cyclopentyl, cyclohexyl, ethylene oxide, or tetrahydrofuranyl groups are optionally substituted with two methyl substituents.

[0016] Aspect 12. The compound as described in any of the preceding aspects, wherein R 3 and R 4 Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -C(O)R 3a The methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl group is optionally selected from at least one group independently from -F, -Cl, -Br, -I, -CN, or -OR. 3b and -NR 3b R 3c Substituents of the substituents; R 3a R 3b and R 3c Each of the following is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; wherein the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl Each of the groups is optionally substituted by at least one substituent independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo (=O), -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, and octyloxy; Preferably, R 3 and R 4 Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, and -C(O)R. 3a The methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), cyclopropyl, cyclobutyl, or cyclopentyl group is optionally selected independently from at least one group chosen from -F and -NR. 3b R 3c Substituents of the substituents; R 3a R 3b and R3c Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; More preferably, R 3 and R 4 Each is independently selected from hydrogen, methyl, and -C(O)R 3a ;R 3a Selected from hydrogen, methyl, and ethyl; Even more preferably, R 3 and R 4 Each is hydrogen on its own.

[0017] Aspect 13. The compound as described in any of the preceding aspects, wherein Partially selected from , , , , , , , , , , , , , , , , and .

[0018] Aspect 14. The compound as described in any of the preceding aspects, wherein Partially selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0019] Aspect 15. The compound as described in any of the preceding aspects, wherein the compound is selected from... Aspect 16. A pharmaceutical composition comprising a compound as described in any one of Aspects 1 to 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer, or prodrug thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0020] Aspect 17. A method of treating cancer, the method comprising administering to a subject in need a compound, as described in any one of Aspects 1 to 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer thereof, or prodrug thereof.

[0021] Aspect 18. The method of using a compound, a pharmaceutically acceptable salt, or a stereoisomer, tautomer, or prodrug as described in any one of Aspects 1 to 15, for treating cancer.

[0022] Aspect 19. The compound as described in aspect 18, wherein the cancer is breast cancer, ovarian cancer, bladder cancer, stomach cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer and / or thyroid cancer. Detailed Implementation

[0023] The following terms have the meanings indicated throughout this specification: As used herein (including the appended aspects), unless the context clearly indicates otherwise, the singular forms of words such as “a / an” and “the” include their corresponding plural referents.

[0024] Unless the context clearly specifies otherwise, the term “or” is used to mean “and / or” and is used interchangeably.

[0025] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18, such as 1 to 12, further such as 1 to 10, even further such as 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C64) 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 isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0026] 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 screwed cycloalkyl groups.

[0027] The term "aryl" used alone or in combination with other terms refers to a group selected from the following: - 5- and 6-membered carbon rings, aromatic rings, such as phenyl; - Bicyclic systems, such as 7- to 12-membered bicyclic systems, wherein at least one ring is a carbocyclic and aromatic, such as naphthyl and indanyl; and - Tricyclic systems, such as decacyclic to 15-membered tricyclic systems, wherein at least one ring is a carbocyclic ring and an aromatic ring, such as fluorene.

[0028] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 cyclic carbon atoms (i.e., C64, C16, C2 ... 5-10 Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0029] The term "aryl-alkyl-" refers to an alkyl group as defined above that is further substituted with an aryl group. Examples of aryl-alkyl groups include aryl-C 1-8 Alkyl groups, such as phenylethyl or phenylmethyl (benzyl).

[0030] The term "heteroaryl" refers to a group selected from the following: A 5-, 6-, or 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1 to 4, or in some embodiments 1 to 3, or in some embodiments 1 to 2 heteroatoms, the remaining ring atoms being carbon; A 7- to 12-membered bicyclic ring comprising at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and The 11- to 14-membered tricyclic ring contains at least one heteroatom selected from N, O, and S, for example, 1 to 4, or 1 to 3 in some embodiments, or 1 or 2 heteroatoms in other embodiments, the remaining ring atoms being carbon, and at least one ring being aromatic and at least one heteroatom being present in the aromatic ring.

[0031] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. The nitrogen atom in one or more rings of the heteroaryl group can be oxidized to form an N-oxide. As used herein, the term "C-linked heteroaryl group" means that the heteroaryl group is linked to the core molecule by a bond from a C atom of the heteroaryl ring. The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 cyclic members, wherein 1, 2, 3, or 4 heteroatomic ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring, which is bicyclic and has one or two heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0032] The terms “heterocyclic group,” “heterocyclic,” or “heterocyclic” are interchangeable and include non-aromatic heterocyclic groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridging, and spirocyclic groups, i.e., containing monocyclic, bridging, spirocyclic, and fused heterocyclic groups. The term “optionally oxidized sulfur” as used herein refers to S, SO, or SO2.

[0033] "Hydrogen" and "H" are interchangeable, and both refer to protium (H+). 1 H), deuterium ( 2 H) or tritium ( 3 Any one of (H). "Deuterated analogue" refers to one or more protium (H) groups of a compound. 1 H) is equal to the amount of deuterium ( 2 H) substitution.

[0034] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. Where the compounds disclosed herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. This is intended to include all such possible stereoisomers in the form of substantially pure, separated enantiomers, racemic mixtures thereof, and mixtures of diastereomers. This is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically indicated, reference to one isomer applies to any possible isomer. All possible isomers are included unless the isomer composition is specified.

[0035] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight (e.g., no more than 30%, further such as no more than 25%, or even further such as no more than 20%) of any other stereoisomer. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight (e.g., no more than 5%, such as no more than 1%) of any other stereoisomer.

[0036] Unless otherwise stated, when the compounds disclosed herein contain olefinic double bonds, such double bonds are intended to include both E and Z geometric isomers.

[0037] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can be in cis or trans form. The cis form means that both substituents are located above the two substituent positions on the carbon atom, while the trans form means that they are located on opposite sides.

[0038] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter separated) to a desired degree of homogeneity using techniques commonly used in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reversed-phase and normal-phase; size exclusion; ion exchange; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus; small-scale analytical; simulated moving bed (“SMB”) and preparative thin-layer or thick-layer chromatography, as well as techniques for small-scale thin-layer and rapid chromatography. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

[0039] "Diarrhetinic isomers" refer to stereoisomers of compounds having two or more chiral centers that are not mirror images of each other. Mixtures of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods well-known to those skilled in the art, such as chromatography and / or stepwise crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher's acid chloride) to convert the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0040] Some of the compounds disclosed herein can exist at different hydrogen attachment sites, referred to as tautomers. For example, compounds comprising a carbonyl -CH2C(O)- group (ketone form) can undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both single ketone and enol forms, as well as mixtures thereof, are also intended to be included.

[0041] It can undergo tautomerism to form .in A and B refers to the position where the substituent is attached to the pyrazole.

[0042] "Pharmaceutically acceptable salts" are those salts that, within the bounds of reasonable medical judgment, are suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and whose benefits / risks are commensurate with a reasonable ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0043] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing the acid salt solution. Conversely, if the product is a free base, the addition salt, such as a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and / or water and treating the solution with acid. Those skilled in the art will recognize that various synthetic methods can be used to prepare non-toxic, pharmaceutically acceptable addition salts without excessive experimentation.

[0044] As defined herein, “pharmaceutically acceptable salts” include salts of at least one compound of formula (I) and salts of stereoisomers of the compound of formula (I), such as enantiomer salts and / or diastereomer salts.

[0045] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the terms “administration” and “treatment” herein mean contact between an exogenous drug, therapeutic agent, diagnostic agent, or composition and an animal, human, subject, cell, tissue, organ, or biological fluid. Cellular treatment encompasses contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid contacts the cell. The terms “administration” and “treatment” also mean, for example, in vitro and ex vivo treatment of cells by means of a reagent, diagnostic agent, conjugated compound, or by means of another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0046] The term "effective amount" or "therapeutic effective amount" refers to an amount of active ingredient (such as a compound) sufficient to affect such treatment against a disease, condition, or symptom when administered to a subject to treat a disease, or at least one clinical symptom of a disease or condition. The term "therapeutic effective amount" can vary depending on the compound; the disease, condition, and / or the symptoms of the disease or condition; the severity of the disease, condition, and / or the symptoms of the disease or condition; the age of the subject to be treated; and / or the weight of the subject to be treated. In any given case, the appropriate amount may be obvious to those skilled in the art or may be determined by routine experiments. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof that effectively "treats" a subject's disease or condition as defined above. In the case of combination therapies, "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat a disease, condition, or symptom.

[0047] Pharmaceutical compositions comprising the compounds disclosed herein may be administered to subjects in need via oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition may be a conventional solid formulation, such as tablets, powders, granules, capsules, etc.; a liquid formulation, such as an aqueous or oil suspension, or other liquid formulations, such as syrups, solutions, suspensions, etc.; for parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oil suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition may be administered as a single unit with a precise dosage. Additionally, the pharmaceutical composition may contain additional active ingredients.

[0048] All formulations of the pharmaceutical compositions disclosed herein can be produced using conventional methods in the pharmaceutical industry. For example, the active ingredient can be mixed with one or more excipients and then formulated into the desired formulation. "Pharmaceutically acceptable excipients" refer to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as: diluents; mediators, such as water, various organic solvents, etc.; fillers, such as starch, sucrose, etc.; binders, such as cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP); wetting agents, such as glycerin; disintegrants, such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as cetyl alcohol; absorbent carriers, such as kaolin and soap clay; lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical compositions may also contain other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, flavorings, sweeteners, and dyes.

[0049] The term “disease” means any illness, discomfort, ailment, symptom or indication and is interchangeable with the terms “symptom” or “illness”.

[0050] Throughout this specification and the appended aspects, unless the context otherwise requires, the term "comprise" and its variations (such as "comprises / comprising") are intended to specify the presence of the feature that follows, but do not exclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced by the terms "contains," "including," or sometimes "has."

[0051] Throughout this specification and the appended aspects, the term "C" is used. n-m The indicator includes a range of endpoints, where n and m are integers and indicate the number of carbon atoms. Examples include C. 1-8 C 1-6 wait.

[0052] Unless otherwise explicitly defined elsewhere in this document, all other technical and scientific terms used herein shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0053] abbreviation

[0054] Example The following examples are intended to be entirely exemplary and should not be considered as limiting in any way. Efforts have been made to ensure accuracy regarding the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be accounted for. Unless otherwise indicated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise indicated. Unless otherwise indicated, the reactions described below were carried out under positive pressure nitrogen or argon or in anhydrous solvents using a drying tube; the reaction flasks were equipped with rubber septa for introducing the substrate and reagents via syringe; and the glassware was dried by drying and / or heat-drying.

[0055] Recording on an Agilent instrument operating at 400 MHz 1 ¹H NMR spectroscopy was performed using CDCl₃, CD₂Cl₂, CD₃OD, D₂O, d₆-DMSO, d₆-acetone, or (CD₃)₂CO as solvents, and tetramethylsilane (0.00 ppm) or residual solvents (CDCl₃: 7.25 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm; d₆-DMSO: 2.50 ppm; d₆-acetone: 2.05 ppm; (CD₃)₃CO: 2.05 ppm) as reference standards. 1 HNMR spectra. When reporting peak multiplicity, the following abbreviations are used: s (single), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet). Coupling constants are reported in Hertz (Hz).

[0056] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity), detector: MWD (190-400 nm), mass detector: 6120 SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120EC-C18, 4.6 × 50 mm, 2.7 pm, gradient method: flow rate: 1.8 mL / min, time (min) A (%) B (%)

[0057] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120 EC-C18, 4.6 × 50 mm, 2.7 pm, gradient method: flow rate: 1.2 mL / min, time (min) A (%) B (%)

[0058] LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm, gradient method: flow rate: 1.8 mL / min, time (min) A (%) B (%)

[0059] UPLC-MS: UPLC: Waters Acquity UPLC H-Class, Detector: MWD (190-400 nm), Mass Detector: Waters QDA, Mobile Phase: A: Water containing 0.05% TFA, B: Acetonitrile containing 0.05% TFA, Column: WatersAcquity UPLC BEH C18, 2.1 × 50 mm, 1.7 μm, Gradient Method: Flow Rate: 0.8 mL / min, Time (min) A (%) B (%)

[0060] Preparative HPLC was performed on a column (150 × 21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml / min, an injection volume of 2 ml, at room temperature, and with UV detection at 214 nm and 254 nm.

[0061] Example 1: 4-((5-(3-(4-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-3-fluorobenzenesulfonamide Step 1: Methyl 1,4-dioxaspiro[4,4]nonane-7-carboxylate Two parallel reactions were performed. A solution of methyl 3-oxocyclopentanecarbamate (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 nitrogen atmosphere for 4 h. Each batch was quenched individually with saturated aqueous NaHCO3 solution, and the two batches were then combined and concentrated under reduced pressure. The residue was diluted with EA (2 L) and washed with aqueous NaHCO3 solution (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 subjected to silica gel column chromatography with PE / EA (1:1; R f = 0.43) eluted to purify 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).

[0062] Step 2: 3-oxo-3-(1,4-dioxaspiro[4.4]nonane-7-yl)propionitrile Two parallel reactions were performed. Acetonitrile (10.58 g, 257.78 mmol) and sodium hydride (10.31 g, 257.78 mmol, 60%) were added to a solution of methyl 1,4-dioxane[4.4]nonane-7-carboxylate (16.0 g, 85.93 mmol) in THF (320 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was heated to reflux and stirred for 4 h. The two batches were combined and poured into a saturated aqueous solution of NH4Cl (500 mL) at 0 °C and stirred for 30 min. The layers were separated and the aqueous layer was extracted with EA (500 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to silica gel chromatography with PE / EA (10:1; R f = 0.29) eluted to purify 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).

[0063] Step 3: 1-(tert-butyl)-3-(1,4-dioxaspiro[4.4]nonane-7-yl)-1H-pyrazole-5-amine Triethylamine (46.65 g, 461.03 mmol) was added to a solution of 3-oxo-3-(1,4-dioxaspiro[4.4]nonane-7-yl)propionitrile (30.0 g, 153.68 mmol) and tert-butylhydrazine monohydrochloride (57.45 g, 461.03 mmol) in ethanol (300 mL) at 20 °C. The resulting mixture was heated to reflux and stirred under nitrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was then subjected to silica gel chromatography using PE / EA (5:1; R f = 0.24) eluted to purify the product (27 g, 64% yield). 1 H NMR (400 MHz, DMSO- d 6 ) 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).

[0064] Step 4: (1-(tert-butyl)-3-(1,4-dioxaspiro[4.4]nonane-7-yl)-1H-pyrazole-5-yl)aminomethyl benzyl ester Benzyl chloroformate (23.14 g, 135.67 mmol) was added in portions to a solution of 1-(tert-butyl)-3-(1,4-dioxaspiro[4.4]nonane-7-yl)-1H-pyrazole-5-amine (18 g, 67.83 mmol) in acetone (1 L) at 0 °C. The mixture was stirred at room temperature for 2 h, followed by the addition of NaHCO3 (18.24 g, 217.07 mmol) in portions. The mixture was further stirred at this temperature for 26 h. The reaction mixture was filtered and concentrated under reduced pressure to give a crude product (28.5 g, >99% yield), which was used for the next step without further purification.

[0065] Step 5: (1-(tert-butyl)-3-(3-oxocyclopentyl)-1H-pyrazole-5-yl)carbamate benzyl ester A solution of (1-(tert-butyl)-3-(1,4-dioxaspiro[4.4]nonane-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 for 4 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove most of the acetone. The aqueous residue was extracted with DCM (500 mL × 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with PE / EA (10:1) elution to give the product (23 g, 87% yield). 1 H NMR (400 MHz, DMSO- d 6) 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).

[0066] Step 6: Trifluoromethanesulfonic acid 3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazole-3-yl) ring Pentyl-1-en-1-yl ester Bis(trimethylsilyl)aminolithium (56 mmol, 1 M in THF) was added dropwise to a solution of (1-(tert-butyl)-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl)carbamate (10 g, 28.1 mmol) in 100 mL of THF at -78 °C. The solution was stirred further at this temperature for 1 h and then 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (11 g, 31 mmol) was added via syringe to 50 mL of THF. The mixture was allowed to slowly return to room temperature and stirred overnight. The reaction was quenched with aqueous NH4Cl solution and extracted with EA (500 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with PE / EA (4:1) elution to give the product (9.5 g, 69% yield). LC-MS (ESI): m / z [M+H] + = 488.3.

[0067] Step 7: (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclo pent-2-en-1-yl)-1H-pyrazol-5-yl) benzyl carbamate A solution of 3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopent-1-en-1-yl trifluoromethanesulfonic acid (9.5 g, 19.5 mmol) in 100 mL of dioxane was mixed with bis(pinacol)diboron (10.1 g, 40 mmol), Pd(dppf)Cl2 (1.46 mg, 2 mmol), and K3PO4 (12.4 g, 58.5 mmol). The mixture was heated to 100 °C and stirred under nitrogen for 4 h. The solution was removed under vacuum, and the residue was purified by silica gel chromatography with PE / EA (4:1) elution to give the product (5.1 g, 56% yield). LC-MS (ESI): m / z [M+H] + = 466.3.

[0068] Step 8: (1-(tert-butyl)-3-(3-(4-(tert-butyl)pyridin-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole- 5-yl) benzyl carbamate 2-Bromo-4-(tert-butyl)pyridine (639 mg, 3 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), and K2CO3 (828 mg, 6 mmol) were added to a solution of (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole-5-yl)carbamate (930 mg, 2 mmol) in a mixture of dioxane and H2O (10:1). The mixture was heated to 100 °C and stirred under nitrogen for 3 h. The solution was removed under vacuum, and the residue was purified by silica gel chromatography with PE / EA (1:1) elution to give the product (566 mg, 60% yield). LC-MS (ESI): m / z [M+H] + = 473.4.

[0069] Step 9: 1-(tert-butyl)-3-(3-(4-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazole-5-amine Pd / C (10%, wet, 200 mg) was added to a solution of (1-(tert-butyl)-3-(3-(4-(tert-butyl)pyridin-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (566 mg, 1.2 mmol) in THF (20 mL). The suspension was degassed and purged three times with hydrogen. 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 (10 mL × 3). The filtrate was concentrated under reduced pressure to give the product (322 mg, 79% yield). LC-MS (ESI): m / z [M+H] + = 341.4.

[0070] Step 10: 4-((1-(tert-butyl)-3-(3-(4-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazole-5-yl) (amino)-3-fluorobenzenesulfonamide 4-Bromo-3-fluorobenzenesulfonamide (38 mg, 0.15 mmol) and 1-(tert-butyl)-3-(3-(4-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazole-5-amine (50 mg, 0.15 mmol) were reacted in anhydrous water. t BrettPhos Pd G3 (9 mg, 0.01 mmol) and K2CO3 (61 mg, 0.45 mmol) were added to the mixture in BuOH (5 mL). The reaction mixture was heated to 110 °C and stirred under nitrogen atmosphere for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (0% to 70%) as elution to give the product (44 mg, 57%). LC-MS (ESI): m / z [M+H] + =514.4.

[0071] Step 11: 4-((5-(3-(4-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-3-fluoro Benzenesulfonamide TfOH (3 mL) was added to a solution of 4-((1-(tert-butyl)-3-(3-(4-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazol-5-yl)amino)-3-fluorobenzenesulfonamide (44 mg, 0.09 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 2 h. The mixture was quenched at 0 °C with an aqueous solution of NaHCO3 (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with PE / EA (0% to 100%) elution to give the product (7.8 mg, 19% yield). 1 H NMR (500MHz, DMSO- d 6) δ 12.04 (s, 1H), 8.63 (d, J = 2.2 Hz, 1H), 8.41 (d, J = 5.2 Hz,1H), 8.20 (s, 1H), 7.50 (d, J = 9.7 Hz, 2H), 7.27 (t, J = 2.9 Hz, 1H), 7.21 (dd, J = 5.3, 1.8 Hz, 1H), 7.17 (s, 2H), 5.86 (s, 1H), 3.45-3.35 (m, 1H), 3.28-3.18(m, 1H), 2.42 – 2.34 (m, 1H), 2.25-2.05 (m, 2H), 2.02 – 1.75 (m, 3H), 1.27 (s, 9H). LC-MS (ESI): m / z [M+H] + = 458.36.

[0072] Example 2: 4-((5-(3-(4-(tert-butyl)-6-methylpyridin-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-3-fluorobenzenesulfonamide Step 1: 4-tert-butyl-2-methyl-pyridine 1-oxide Methylrhenium trioxide (VII) (46 mg, 0.19 mmol) was added to a solution of 2-methyl-4-tert-butylpyridine (5.5 g, 37 mmol) in DCM (100 mL) under vigorous stirring. 30% hydrogen peroxide (13 mL) was added, and the mixture was stirred vigorously for 18 h. The reaction was quenched by dropwise addition of an aqueous manganese dioxide solution. The layers were separated, and the aqueous layer was re-extracted with dichloromethane (3 × 30 mL). The combined organic layers were filtered, dried, and concentrated to yield the product (5.5 g, 89%). LC-MS (ESI), m / z [M+H] + = 166.

[0073] Step 2: 2-Chloro-6-methyl-4-tert-butyl-pyridine 4-tert-butyl-2-methylpyridine 1-oxide (2.00 g, 12.10 mmol) was added to phosphorus oxychloride (15 mL) and stirred at 100 °C for 36 h. The mixture was concentrated under vacuum, treated with ice water, and alkalized with an aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 × 75 mL). The combined organic layers were filtered, dried, and concentrated. The residue was purified by silica gel column chromatography with EA / PE (0–10%) elution to give the product (812 mg, 36.6%). LC-MS (ESI): m / z [M+H] + = 184.2.

[0074] Step 3: 4-((5-(3-(4-(tert-butyl)-6-methylpyridin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino 3-Fluorobenzenesulfonamide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.15(s, 1H), 8.64 (s, 1H), 8.18(s, 1H), 7.53-7.50 (m, 1H), 7.49-7.48 (m, 1H),7.26-7.05 (m, 4H), 5.88 (s, 1H), 3.29-3.20 (m, 2H), 2.51 (s, 3H), 2.44-2.34(m, 1H), 2.25-2.07 (m, 2H), 2.01-1.79 (m, 3H), 1.27 (s, 9H). LC-MS (ESI): m / z[M+H] + = 472.4.

[0075] Example 3: 4-((5-(3-(5-(tert-butyl)pyridazine-3-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-3-fluorobenzenesulfonamide Step 1: (1-(tert-butyl)-3-(3-(5-(tert-butyl)-6-chloropyridazine-3-yl)cyclopent-2-en-1-yl)-1H- pyrazole-5-yl) benzyl carbamate A mixture of 4-(tert-butyl)-3,6-dichloropyridazine (510 mg, 2.5 mmol), (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (1.4 g, 3 mmol), Pd(dppf)Cl2 (203 mg, 0.25 mmol), and Na2CO3 (795 mg, 7.5 mmol) in dioxane (20 mL) and H2O (5 mL) was stirred at 80 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0-45%) elution to give the product (1.15 g, 90.6%). LC-MS (ESI): m / z [M+H] + = 508.2.

[0076] Step 2: 1-(tert-butyl)-3-(3-(5-(tert-butyl)pyridazin-3-yl)cyclopentyl)-1H-pyrazole-5-amine Pd / C (150 mg) was added to a solution of (1-(tert-butyl)-3-(3-(5-(tert-butyl)-6-chloropyridazin-3-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (1.15 g, 2.3 mmol) in MeOH (20 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 5 h. The mixture was filtered and the filtrate was concentrated under vacuum to give the product (567 mg, crude). LC-MS (ESI): m / z [M+H] + = 342.2.

[0077] Step 3: 4-((1-(tert-butyl)-3-(3-(5-(tert-butyl)pyridazin-3-yl)cyclopentyl)-1H-pyrazole-5-yl) (amino)-3-fluorobenzenesulfonamide A mixture of 4-bromo-3-fluorobenzenesulfonamide (48 mg, 0.19 mmol), 1-(tert-butyl)-3-(3-(5-(tert-butyl)pyridazin-3-yl)cyclopentyl)-1H-pyrazole-5-amine (45 mg, 0.13 mmol), Brettphos Pd G3 (17.2 mg, 0.02 mmol), and K2CO3 (79 mg, 0.57 mmol) in t-BuOH (5 mL) was stirred at 110 °C for 16 h under nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0-100%) elution to give the product (58 mg, 59.3%). LC-MS (ESI): m / z [M+H] + = 515.3.

[0078] Step 4: 4-((5-(3-(5-(tert-butyl)pyridazine-3-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-3-fluorobenzene sulfonamide TfOH (1 mL) was added to a solution of 4-((1-(tert-butyl)-3-(3-(5-(tert-butyl)pyridazin-3-yl)cyclopentyl)-1H-pyrazole-5-yl)amino)-3-fluorobenzenesulfonamide (58 mg, 0.11 mmol) in DCM (5 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The mixture was diluted with DCM (50 mL) and washed with saturated NaHCO3 (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the product (4.07 mg, 7.9%). 1 H NMR (500 MHz, DMSO- d 6) δ 12.06 (s, 1H),9.21 (s, 1H), 8.65 (s, 1H), 8.24-8.15 (m, 1H), 7.56-7.47 (m, 3H), 7.17 (s,2H), 5.88 (s, 1H), 3.63-3.45 (m, 1H), 3.31-3.22 (m, 1H), 2.48-2.44 (m, 1H), 2.31-2.12 (m, 2H), 2.07-1.94 (m, 2H), 1.93-1.84 (m, 1H), 1.31 (s, 9H). LC-MS(ESI): m / z [M+H] + = 459.2.

[0079] Example 4: 4-((5-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-3-fluorobenzenesulfonamide Step 1: (1-(tert-butyl)-3-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole- 5-yl) benzyl carbamate Pd(dppf)Cl2 (99.6 mg, 0.107 mmol) and K3PO4 (683.7 mg, 3.225 mmol) were added to a solution of (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (500 mg, 1.075 mmol) and 4-(tert-butyl)-2-chloropyrimidine (277.2 mg, 1.612 mmol) in dioxane / H2O (10:2 mL). The reaction mixture was stirred at 100 °C for 6 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (400 mg, 78.5%). LC-MS (ESI): m / z [M+H] + = 475.3.

[0080] Step 2: 1-(tert-butyl)-3-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazole-5-amine Pd / C (10% on carbon, 200 mg) was added to a solution of (1-(tert-butyl)-3-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (400 mg, 0.84 mmol) in MeOH (10 mL). The reaction mixture was degassed and purged three times with hydrogen and stirred at room temperature for 2 hours. The resulting mixture was filtered and the filtrate was concentrated under vacuum to give the product (200 mg, 69%). LC-MS (ESI): m / z [M+H]+ = 343.3.

[0081] Step 3: 4-((1-(tert-butyl)-3-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazole-5-yl) (amino)-3-fluorobenzenesulfonamide Pd2dba3 (13.5 mg, 0.015 mmol), Xantphos (17.28 mg, 0.030 mmol), and K3PO4 (92.86 mg, 0.438 mmol) were added to a solution of 1-(tert-butyl)-3-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazole-5-amine (50 mg, 0.146 mmol) and 4-bromo-3-fluorobenzenesulfonamide (36.9 mg, 0.146 mmol) in dioxane (5 mL). The reaction mixture was stirred at 90 °C for 6 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with elution using EA to give the product (300 mg, 44.1%). LC-MS (ESI): m / z [M+H] + = 516.3.

[0082] Step 4: 4-((5-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-3-fluorobenzene sulfonamide TfOH (1 mL) was added to a solution of 4-((1-(tert-butyl)-3-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazol-5-yl)amino)-3-fluorobenzenesulfonamide (90 mg, 0.138 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was neutralized with aqueous Na2CO3 at 0 °C and extracted with EA (3 × 10 mL). The combined organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel with 100% EA elution to give crude product (20 mg), which was further purified by preparative HPLC (Waters XSelect C18: RD-CO-094 column, eluted with a gradient of acetonitrile / water (containing 0.1% FA) (20%–40%) to give product (3.0 mg, 11.2%). 1 H NMR (500 MHz, DMSO- d 6) δ 12.04 (s, 1H), 8.64 (d, J = 5.3 Hz, 2H), 8.17 (t, J = 8.4 Hz, 1H), 7.50 (d, J = 10.2 Hz, 2H), 7.34(d, J= 5.3 Hz, 1H), 7.17 (s, 2H), 5.84 (s, 1H), 3.50 – 3.40 (m, 1H), 3.27 –3.13 (m, 1H), 2.48-2.43 (m, 2H), 2.20 – 1.95 (m, 4H), 1.86-1.79 (m, 1H), 1.29 (s, 9H). LC-MS (ESI): m / z [M+H] + = 459.2.

[0083] Example 5: 3-Fluoro-4-((5-(3-(4-isopropylpyrimidin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)benzenesulfonamide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.01 (s, 1H), 8.62 (d, J = 5.1 Hz, 2H), 8.20 (t, J = 8.6 Hz, 1H), 7.50 (d, J = 9.9Hz, 2H), 7.22 (d, J = 5.2 Hz, 1H), 7.17 (s, 2H), 5.86 (d, J = 10.8 Hz, 1H), 3.47– 3.47 (m, 1H), 2.99 – 2.89 (m, 1H), 2.44 (s, 2H), 2.12 (dd, J = 14.4, 7.2 Hz, 2H), 2.05 (d, J = 8.5 Hz, 1H), 1.99 (dd, J = 22.3, 10.9 Hz, 1H), 1.82 (s, 1H), 1.26 – 1.20 (m, 6H). LC-MS (ESI): m / z [M+H] + = 445.2.

[0084] Example 6: 4-((5-(3-(5-(tert-butyl)oxazol-2-yl)cyclopentyl)-1 H -pyrazole-3-yl)amino)-3-fluorobenzenesulfonamide Step 1: cis-3-oxabicyclo[3.2.1]octane-2,4-dione Cis-cyclopentane-1,3-dicarboxylic acid (50.0 g, 316.45 mmol) and Ac₂O (100 mL) were added to a 1 L round-bottom flask at room temperature. The resulting mixture was stirred overnight at 140 °C. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using PE / EA (5:1) elution to give the product (30.0 g, 67.71%).

[0085] Step 2: cis-3-((3,3-dimethyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylic acid At room temperature, 1-amino-3,3-dimethylbut-2-one (49.28 g, 428.57 mmol) and TEA (43.29 g, 428.57 mmol) were added to a solution of cis-3-oxabicyclo[3.2.1]octane-2,4-dione (30.0 g, 214.28 mmol) in THF (300 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give the product (45.0 g, 82.35%). LC-MS (ESI): m / z [MH] - = 254.15.

[0086] Step 3: Methyl cis-3-((3,3-dimethyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylate H₂SO₄ (17.0 g, 176.47 mmol) was added to a solution of cis-3-((3,3-dimethyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylic acid (45.0 g, 176.47 mmol) in MeOH (250 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was neutralized to pH 7 with aqueous sodium bicarbonate solution and extracted with 300 mL DCM. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the product (43.0 g, 90.58%). LC-MS (ESI): m / z [M+H] + = 270.2.

[0087] Step 4: Methyl cis-3-(5-(tert-butyl)oxazol-2-yl)cyclopentane-1-carboxylate Methyl cis-3-((3,3-dimethyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylate (41.0 g, 152.41 mmol) and POCl3 (50 mL) were added to a 500-mL round-bottom flask at room temperature. The resulting mixture was stirred at 60 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (100:0–50:50) elution to give the product (35.0 g, 91.49%). LC-MS (ESI): m / z [M+H] + = 251.2.

[0088] Step 5: 3-(3-(5-(tert-butyl)oxazol-2-yl)cyclopentyl)-3-oxopropionitrile n-BuLi (2.5 M, 95.61 mL, 239.02 mmol) was added dropwise to a solution of CH3CN (9.8 g, 239.02 mmol) in THF (100 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 30 min under a nitrogen atmosphere. Methyl cis-3-(5-(tert-butyl)oxazol-2-yl)cyclopentane-1-carboxylate (30.0 g, 119.52 mmol) in THF (50 mL) was added dropwise at -78 °C, and the mixture was stirred further at -78 °C for 1 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C and extracted with ethyl acetate (3 × 400 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether:ethyl acetate (100:0–50:50) elution to give the product (25.0 g, 80.44% yield). LC-MS (ESI): m / z [M+H] + = 260.2.

[0089] Step 6: 5-(3-(5-(tert-butyl)oxazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine The mixture was added to a solution of 3-(3-(5-(tert-butyl)oxazol-2-yl)cyclopentyl)-3-oxopropionitrile (4.0 g, 15.38 mmol), NH₂NH₂·H₂O (0.85 g, 16.92 mmol), PTSA (160.0 mg), and EtOH (40 mL) at room temperature. The resulting mixture was stirred at 90 °C for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with DCM / MeOH (100:0–95:5) to give the product (1.9024 g, 45.13%). 1H NMR (300MHz, DMSO- d 6) δ 6.65 (d, J = 1.2 Hz, 1H), 5.21 (d, J = 8.3 Hz, 1H), 3.33 (s, 2H), 2.35 (dt, J = 13.6Hz, 1H), 2.01 (s, 5H), 2.08 – 1.73 (m, 1H), 1.66 (s, 1H), 1.23 (s, 9H). LC-MS (ESI): m / z [M+H] + = 274.3.

[0090] Step 7: 4-((5-(3-(5-(tert-butyl)oxazol-2-yl)cyclopentyl)-1 H -pyrazole-3-yl)amino)-3-fluorobenzene sulfonamide The title compound in its racemic form was synthesized in a procedure similar to step 10 of Example 1, and further separated by chiral preparative HPLC to obtain: Enantiomer 1 (Example 6a, 100% ee); retention time: 4.965 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.01 (s, 1H), 8.63 (d, J = 1.8, 1H), 8.19 (t, J = 8.5, 1H), 7.51 (s,1H), 7.49 (s, 1H), 7.17 (s, 2H), 6.66 (s, 1H), 5.83 (s, 1H), 3.40 – 3.35 (m,1H), 3.23 – 3.13 (m, 1H), 2.48 – 2.40 (m, 1H), 2.15 – 2.06 (m, 2H), 1.97 (m,1H), 1.89 (m, 1H), 1.78 – 1.68 (m, 1H), 1.23 (s, 9H). LC-MS (ESI): m / z [M+H] + =448.34.

[0091] Enantiomer 2 (Example 6b, 100% ee); retention time: 4.485 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.01 (s, 1H), 8.63 (d, J= 1.8, 1H), 8.19 (t, J = 8.5, 1H), 7.51 (s,1H), 7.49 (s, 1H), 7.17 (s, 2H), 6.66 (s, 1H), 5.83 (s, 1H), 3.40 – 3.35 (m,1H), 3.23 – 3.13 (m, 1H), 2.48 – 2.40 (m, 1H), 2.15 – 2.06 (m, 2H), 1.97 (m,1H), 1.89 (m, 1H), 1.78 – 1.68 (m, 1H), 1.23 (s, 9H). LC-MS (ESI): m / z [M+H] + =448.34; Enantiomer 3 (Example 6c, 100% ee); retention time: 4.980 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 8.64 (s, 1H), 8.19 (t, J = 7.8, 1H), 7.51 (s, 1H),7.49 (s, 1H), 7.18 (s, 2H), 6.67 (s, 1H), 5.86 (s, 1H), 3.44 (m, 1H), 3.27 –3.22 (m, 1H), 2.28 (m, 1H), 2.22 – 2.11 (m, 2H), 2.08 – 1.99 (m, 1H), 1.98 –1.88 (m, 1H), 1.77 – 1.66 (m, 1H), 1.24 (s, 9H). LC-MS (ESI): m / z [M+H] + =448.30.

[0092] Enantiomer 4 (Example 6d, 100% ee); retention time: 4.860 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 8.64 (s, 1H), 8.19 (t, J= 7.8, 1H), 7.51 (s, 1H),7.49 (s, 1H), 7.18 (s, 2H), 6.67 (s, 1H), 5.86 (s, 1H), 3.44 (m, 1H), 3.27 –3.22 (m, 1H), 2.28 (m, 1H), 2.22 – 2.11 (m, 2H), 2.08 – 1.99 (m, 1H), 1.98 –1.88 (m, 1H), 1.77 – 1.66 (m, 1H), 1.24 (s, 9H). LC-MS (ESI): m / z [M+H] + =448.33; Chiral analysis method: Column: CHIRALPAK IE 4.6 250 mm 5 μm; Mobile phase: A is MtBE (0.1% 2MNH3MeOH) and B is EtOH; Gradient: Mobile phase A: Mobile phase B = 20:80 (v / v); HPLC equipment: HPLC-Agilent; Column temperature: 35℃.

[0093] Chiral preparative HPLC conditions: CHIRALPAK ID 20 250 mm 5 μm; Mobile phase: A is MtBE and B is MeOH:DCM=50:50; Gradient: Mobile phase A:Mobile phase B = 60:40 (v / v); Flow rate: 20 mL / min; Wavelength: UV 220nm; Preparative HPLC equipment: Preparative HPLC-Gilson; Column temperature: 25℃.

[0094] Example 7: 3-Fluoro-4-((5-(3-(5-isopropyloxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)benzenesulfonamide Step 1: cis-3-((3-methyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylic acid 1-Amino-3-methylbut-2-one hydrochloride (4.9 g, 35.7 mmol) and TEA (5.55 g, 55 mmol) were added to a solution of cis-3-oxabicyclo[3.2.1]octane-2,4-dione (3.85 g, 27.5 mmol) in THF (100 mL) at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give the crude product (6.6 g). LC-MS (ESI): m / z [MH] - = 242.

[0095] Step 2: Methyl cis-3-((3-methyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylate H₂SO₄ (1 mL) was added to a solution of cis-3-((3-methyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylic acid (6.6 g, 27.38 mmol) in MeOH (100 mL), and the mixture was stirred at 65 °C for 2 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE:EA (100:0 to 70:30) elution to give the product (7.2 g, 95% yield). LCMS (ESI) m / z [M+H] + = 256.

[0096] Step 3: Methyl cis-3-(5-isopropyloxazol-2-yl)cyclopentane-1-carboxylate Methyl cis-3-((3-methyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylate (7.2 g, 28.2 mmol) was dissolved in POCl3 (40 mL). The resulting solution was stirred at 60 °C for 1 h. The resulting mixture was concentrated under vacuum, and H2O (100 mL) was added. The mixture was adjusted to pH = 8 with Na2CO3 solution (2 M) and extracted with 2 × 80 mL DCM. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE:EA (100:0 to 85:15) elution to give the product (6.2 g, 92.6%). LC-MS (ESI): m / z [M+H] + = 238.

[0097] Step 4: 3-(3-(5-isopropyloxazol-2-yl)cyclopentyl)-3-oxopropionitrile n-BuLi (2.5 M, 95.61 mL, 239.02 mmol) was added dropwise to a solution of CH3CN (1.38 g, 33.75 mmol) in THF (100 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 30 min under a nitrogen atmosphere. Then, a solution of methyl cis-3-(5-isopropyloxazol-2-yl)cyclopentane-1-carboxylate (30.0 g, 119.52 mmol) in THF (50 mL) was added dropwise and the mixture was stirred further at -78 °C for 1 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at 0 °C and extracted with ethyl acetate (3 × 400 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using petroleum ether:ethyl acetate (100:0-72:28) to give the product (3.9 g, 93.8% yield). LC-MS (ESI): m / z [M+H] + = 247.2.

[0098] Step 5: 5-(3-(5-isopropyloxazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine A solution of 3-(3-(5-isopropyloxazol-2-yl)cyclopentyl)-3-oxopropionitrile (3.9 g, 15.8 mmol) in EtOH (80 mL) was added with hydrazine hydrate (868 mg, 17.3 mmol) and TsOH (50 mg). The resulting mixture was stirred at 90 °C for 1 h. The reaction was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE:EA (100:0 to 70:30) to give the product (2.2 g, 53.4%). 1 H NMR (500 MHz, DMSO- d 6) δ 11.14(s, 1H), 6.68 (s, 1H), 5.21 (s, 1H), 4.35 (s, 2H), 4.10 (q, J = 5.2 Hz, 1H), 3.29 (q, J = 8.5 Hz, 1H), 3.18 (d, J = 5.5 Hz, 2H), 3.06 – 3.00 (m, 1H), 2.93 (p, J = 6.5 Hz, 1H), 2.36 (d, J = 13.0 Hz, 1H), 2.04 (tq, J= 14.6, 5.9, 4.5 Hz, 2H),2.00 – 1.89 (m, 1H), 1.82 (q, J = 11.0 Hz, 1H), 1.68 (dd, J = 11.3, 6.5 Hz, 1H), 1.19 (d, J = 6.5 Hz, 6H). LCMS (ESI) m / z [M+H] + = 261.

[0099] Step 6: 3-Fluoro-4-((5-(3-(5-isopropyloxazol-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)benzenesulfonate amide The title compound was synthesized in a procedure similar to step 10 of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 8.64 (s, 1H), 8.16 (t, J = 8.4 Hz, 1H), 7.50 (d, J = 9.9 Hz, 2H), 7.18 (d, J =9.5 Hz, 2H), 6.69 (s, 1H), 5.83 (s, 1H), 3.36 (dt, J = 16.7, 8.2 Hz, 2H), 3.18(dt, J = 9.9, 7.7 Hz, 1H), 2.93 (dq, J = 13.8, 6.9 Hz, 1H), 2.48 – 2.41 (m, 1H), 2.18 – 2.06 (m, 2H), 2.02 – 1.94 (m, 1H), 1.89 (dd, J = 22.5, 10.3 Hz, 1H),1.78 – 1.66 (m, 1H), 1.19 (t, J = 5.7 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 434.2.

[0100] Example 8: 4-((5-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-3-fluorobenzenesulfonamide Step 1: (4,4-Dimethyl-3-oxopentane-2-yl)tert-butyl carbamate n-BuLi (45.26 mL, 113.15 mmol) was added dropwise to a solution of (1-(methoxy(methyl)amino)-1-oxopropane-2-yl)carbamate tert-butyl ester (10.50 g, 45.26 mmol) in Et₂O (150 mL) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 2 h. The reaction was quenched at 0 °C with saturated NH₄Cl (aqueous solution) and then extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with PE / EA (100:0–90:10) elution to give the product (1.8 g, 17.37%). LC-MS (ESI): m / z [M+H] + = 230.3.

[0101] Step 2: 4-Amino-2,2-dimethylpentan-3-one chloride (4,4-Dimethyl-3-oxopentane-2-yl)tert-butyl carbamate (1.8 g, 13.95 mmol) and HCl-dioxane (4 M, 20 mL) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give the product (1.0 g, 98.62% yield). LC-MS (ESI): m / z [M+H] + =130.3.

[0102] Step 3: cis-3-((4,4-dimethyl-3-oxopent-2-yl)carbamoyl)cyclopentane-1-carboxylic acid A solution of cis-3-oxabicyclo[3.2.1]octane-2,4-dione (1.09 g, 7.75 mmol) in THF (30 mL) was mixed with 4-amino-2,2-dimethylpentan-3-one (1.0 g, 7.75 mmol) and TEA (1.57 g, 15.5 mmol). The resulting mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to give the product (2.0 g, 95.91%). LC-MS (ESI): m / z [M+H] + = 270.3.

[0103] Step 4: cis-3-((4,4-dimethyl-3-oxopentane-2-yl)carbamoyl)cyclopentane-1-carboxylic acid ester 2.05 g (7.62 mmol) of cis-3-((4,4-dimethyl-3-oxopent-2-yl)carbamoyl)cyclopentane-1-carboxylic acid was dissolved in MeOH (50 mL) and H₂SO₄ (1.49 g, 15.24 mmol) was added. The resulting mixture was stirred at room temperature for 3 h. The mixture was neutralized to pH 7 with aqueous Na₂CO₃ and extracted with 150 mL of EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using PE / EtOAc (100:0–70:30) elution to give the product (1.90 g, 88% yield). LC-MS (ESI): m / z [M+H] + = 284.3.

[0104] Step 5: Methyl cis-3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentane-1-carboxylate Methyl cis-3-((4,4-dimethyl-3-oxopentane-2-yl)carbamoyl)cyclopentane-1-carboxylate (1.90 g, 6.71 mmol) was added to POCl3 (40 mL). The resulting mixture was stirred at 60 °C for 5 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (100:0–40:60) elution to give the product (1.60 g, 89.93%). LC-MS (ESI): m / z [M+H] + = 266.2.

[0105] Step 6: 3-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-3-oxopropionitrile CH3CN (496.1 mg, 12.1 mmol) in 20 mL of THF was placed in a 100-mL three-necked round-bottom flask purged with nitrogen. Then, n-BuLi (4.84 mL, 12.1 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 30 min, and then added dropwise at -78 °C to a solution of methyl cis-3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentane-1-carboxylate (1.60 g, 6.04 mmol) in 50 mL of THF. The resulting mixture was stirred at -78 °C for 2 h. The reaction was quenched at 0 °C with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using PE / EA (100:0–60:40) elution to give the product (0.92 g, 55.61% yield). LC-MS (ESI): m / z [M+H] + = 275.3.

[0106] Step 7: 5-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine Hydrazine hydrate (180.5 mg, 3.61 mmol) and TsOH (50 mg) were added to a solution of 3-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-3-oxopropionitrile (900.0 mg, 3.28 mmol) in EtOH (20 mL). The resulting mixture was stirred at 90 °C for 1 h. The reaction was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE:EA (100:0 to 80:20) to give the product (844.6 mg, 89.28% yield). 1 H NMR (300MHz, DMSO- d 6) δ 5.19 (s, 1H), 3.21 (p, J = 8.1 Hz, 1H), 3.10 – 2.94 (m, 1H), 2.39 – 2.24 (m, 1H), 2.10 (s, 4H), 2.08 – 1.85 (m, 3H), 1.88 – 1.59 (m, 1H), 1.27 (s, 9H). LC-MS (ESI): m / z [M+H] + = 289.3.

[0107] Step 8: 4-((5-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino 3-Fluorobenzenesulfonamide The title compound was synthesized in a procedure similar to step 10 of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 8.65-8.59 (m, 1H), 8.22-8.12 (m, 1H), 7.52-7.49 (m, 1H), 7.48(s, 1H), 7.17 (s, 2H), 5.82 (s, 1H), 3.30-3.21 (m, 1H), 3.20-3.12 (m, 1H),2.45-2.37 (m, 1H), 2.17-2.01 (m, 5H), 2.00-1.90 (m, 1H), 1.89-1.81 (m, 1H),1.77-1.67 (m, 1H), 1.27 (s, 9H). LC-MS (ESI): m / z [M+H] + = 462.3.

[0108] Example 9: 4-((5-(3-(5-cyclopropyloxazol-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-3-fluorobenzenesulfonamide Step 1: cis-3-carbamoylcyclopentane-1-carboxylic acid NH3-MeOH (59.18 mL, 414.29 mmol) was added to a solution of cis-3-oxa-bicyclo[3.2.1]octane-2,4-dione (14.50 g, 103.57 mmol) in THF (200 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give the product (16.00 g, 98.40%). LC-MS (ESI): m / z [M+H] + = 158.2.

[0109] Step 2: Methyl cis-3-carbamoylcyclopentane-1-carboxylate H₂SO₄ (39.95 g, 407.64 mmol) was added to a solution of cis-3-carbamoylcyclopentane-1-carboxylic acid (16.00 g, 101.91 mmol) in MeOH (100 mL). The resulting mixture was stirred overnight at room temperature. The mixture was neutralized to pH 7 with aqueous Na₂CO₃ and extracted twice with 300 mL EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution using DCM / MeOH (100:0–90:10) to give the product (6.40 g, 36.73% yield). LC-MS (ESI): m / z [M+H] + = 172.2.

[0110] Step 3: Methyl cis-3-cyanocyclopentane-1-carboxylate Methyl cis-3-carbamoylcyclopentane-1-carboxylate (6.40 g, 37.43 mmol) was added to a solution of TEA (11.34 g, 112.28 mmol) and TFAA (17.29 g, 82.35 mmol) in DCM (200 mL). The resulting mixture was stirred at room temperature for 2 h. Water (200 mL) was added, and the resulting mixture was extracted twice with DCM (400 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with PE / EtOAc (100:0–80:20) to give the product (5.14 g, 89.76%). 1 ¹H NMR (300 MHz, chloroform-d) δ 3.71 (s, 3H), 2.94 – 2.72 (m, 2H), 2.38 (dt, J = 13.3 Hz, 1H), 2.27 – 1.90 (m, 5H). LC-MS (ESI): m / z [M+H] + = 154.2.

[0111] Step 4: Methyl 3-(5-cyclopropyloxazol-2-yl)cyclopentane-1-carboxylate Ph3PAuNTf2 (724 mg, 0.979 mmol) and 8-methylquinoline 1-oxide (4.05 g, 25.46 mmol) were added to a solution of methyl 3-cyanocyclopentane-1-carboxylate (3 g, 19.59 mmol) in trimethyl((1-methylcyclopropyl)ethynyl)silane (5.4 g, 39.18 mmol). The resulting mixture was stirred at 60 °C for 4 h under a nitrogen atmosphere. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE / EtOAc (100:0 to 90:10) elution to give the product (1.5 g, 32.6%). LC-MS (ESI): m / z [M+H] + = 236.

[0112] Step 5: 3-(3-(5-cyclopropyloxazol-2-yl)cyclopentyl)-3-oxopropionitrile n-BuLi (2.5 M) (4.4 mL, 11.06 mmol) was added to a solution of CH3CN (453 mg, 11.06 mmol) in THF (35 mL) at -78 °C, and the mixture was stirred for 1 h under a N2 atmosphere. Methyl 3-(5-cyclopropyloxazol-2-yl)cyclopentane-1-carboxylate (1.3 g, 5.53 mmol) was added to the mixture at -78 °C, and the mixture was stirred for another 1 h. The reaction was quenched with NH4Cl solution (50 mL) and extracted with EtOAc (3 × 35 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography using PE / EtOAc (100:0 to 65:35) to give the product (550 mg, 40.7% yield). LC-MS (ESI): m / z [M+H] + = 245.

[0113] Step 6: 5-(3-(5-cyclopropyloxazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine Hydrazine hydrate (124 mg, 2.48 mmol) and TsOH (15 mg) were added to a solution of 3-(3-(5-cyclopropyloxazol-2-yl)cyclopentyl)-3-oxopropionitrile (550 mg, 2.25 mmol) in EtOH (10 mL). The resulting solution was stirred at 90 °C for 1 h. The reaction was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE:EA (100:0 to 63:35) to give the product (296.8 mg, 51% yield). 1H NMR (300 MHz, chloroform-) d ) δ6.62 (d, J = 0.9 Hz, 1H), 5.49 (s, 1H), 4.78 (s, 2H), 3.39 (q, J = 6.6 Hz, 1H), 3.25 (q, J = 8.1 Hz, 1H), 2.48 (dt, J = 13.5, 8.7 Hz, 1H), 2.30 – 2.16 (m, 1H), 2.15 – 1.97 (m, 3H), 1.94 – 1.73 (m, 2H), 1.00 – 0.87 (m, 2H), 0.82 – 0.71(m, 2H). LC-MS (ESI): m / z [M+H] + = 259.2.

[0114] Step 7: 4-((5-(3-(5-cyclopropyloxazol-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-3-fluorobenzenesulfonate amide The title compound was synthesized in a procedure similar to step 10 of Example 1. 1 H NMR (500 MHz, DMSO- d 6)δ 12.00 (s, 1H), 8.63 (s, 1H), 8.19 (t, J = 8.6 Hz, 1H), 7.50 (d, J = 9.8 Hz,2H), 7.17 (s, 2H), 6.70 (s, 1H), 5.82 (s, 1H), 3.39 - 3.34 (m, 1H), 3.21 -3.13 (m, 1H), 2.45 - 2.39 (m, 1H), 2.14 - 2.04(m, 2H), 1.99 – 1.83 (m, 3H), 1.77 – 1.68 (m, 1H), 0.94 – 0.86 (m, 2H), 0.71 – 0.66 (m, 2H). LC-MS (ESI): m / z[M+H] + = 432.3.

[0115] Example 10: 5-((3-(3-(5-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazole-5-yl)amino)-6-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: Methyl 5-bromo-2-(chlorosulfonyl)-4-fluorobenzoate A solution of sodium nitrite (918.4 mg, 13.31 mmol) in 8 mL of water was added dropwise 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) at 0 °C. The resulting mixture was kept below 5 °C and stirred for 30 min after the addition. CuCl2 (813 mg, 6.05 mmol), sodium bisulfite (18.9 g, 181.5 mmol), and hydrochloric acid solution (6 M, 88 mL) were added sequentially to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 3 h. The resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and dried under vacuum to give a crude product (3.0 g), which was used for the next step without further purification.

[0116] Step 2: 5-Bromo-6-fluorobenzo[ d Isothiazine-3(2) H )-Ketone 1,1-dioxide An aqueous ammonium solution (25%, 20 mL) was added to a mixture of methyl 5-bromo-2-(chlorosulfonyl)-4-fluorobenzoate (3 g crude) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum, and the residue was milled with EA and filtered to give the crude product (2.0 g). LC-MS (ESI): m / z [MH] - = 277.9.

[0117] Step 3: 5-Bromo-6-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide In a nitrogen atmosphere at 0°C, 5-bromo-6-fluorobenzo[ d Isothiazine-3(2) H 1,1-dioxide (300 mg, 1.08 mmol) of 1,1-ketoketone was added dropwise to a stirred solution of BH3-Me2S (2 M, 2.7 mL, 5.4 mmol) in THF (10 mL). 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 with PE / EA (1:1) elution to give the product (260 mg, 91%). LC-MS (ESI): m / z [M+H] + = 266 / 268.

[0118] Step 4: 5-((5-(3-(5-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-6-fluoro- 2,3-Dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.05 (s, 1H), 8.74 (d, J =10 Hz, 1H), 8.56 (d, J =10 Hz, 1H), 8.19-8.11 (m, 1H), 7.74-7.68 (m, 1H), 7.66-7.59 (m, 2H), 7.22 (d, J =10 Hz, 1H), 5.89 (s, 1H), 4.30 (d, J =5 Hz, 2H), 3.37-3.33 (m, 1H), 3.28-3.18 (m, 1H), 2.41-2.33 (m, 1H), 2.19-2.03 (m, 2H), 1.98-1.85 (m, 2H), 1.84-1.73 (m, 1H), 1.30 (s, 9H). LC-MS (ESI): m / z [M+H] + = 470.2.

[0119] Example 11: 6-Fluoro-5-((5-(3-(6-methoxypyridin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.02(s, 1H), 8.76-8.72 (m, 1H), 8.19-8.12 (m, 1H), 7.66-7.56 (m, 3H), 6.89-6.85(m, 1H), 6.61 (d, J=10 Hz, 1H), 5.88 (s, 1H), 4.32-4.27 (m, 2H), 3.84 (s, 3H), 3.30-3.18 (m, 2H), 2.42-2.34 (m, 1H), 2.18-2.01 (m, 2H), 1.99-1.72 (m, 3H). LC-MS (ESI): m / z [M+H] + = 444.1.

[0120] Example 12: 6-Fluoro-5-((5-(3-(6-methylpyridin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.12(s, 1H), 8.77-8.72 (m, 1H), 8.19-8.10 (m, 1H), 7.68-7.56 (m, 3H), 7.13-7.03(m, 2H), 5.89 (s, 1H), 4.32-4.28 (m, 2H), 3.31-3.28 (m, 1H), 3.27-3.19 (m,1H), 2.45 (s, 3H), 2.41-2.34 (m, 1H), 2.24-2.04 (m, 2H), 1.98-1.76 (m, 3H). LC-MS (ESI): m / z [M+H] + = 428.1.

[0121] Example 13: 5-((5-(3-(4-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-6-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.79 (d, J = 2.5 Hz, 1H), 8.65 (d, J = 5.9 Hz, 1H), 8.14 (d, J= 7.3Hz, 1H), 7.79 (d, J = 11.5 Hz, 2H), 7.65 (d, J = 10.0 Hz, 2H), 5.93 (s, 1H), 4.30(s, 2H), 3.60-3.50 (m, 1H), 3.35-3.22 (m, 1H), 2.48-2.43 (m, 1H), 2.32-2.15(m, 2H), 2.05-1.85 (m, 3H), 1.35 (d, J = 5.0 Hz, 9H). LC-MS (ESI): m / z [M+H] + =470.34.

[0122] Example 14: 5-((5-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-6-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: (1-(tert-butyl)-3-(3-(5-(tert-butyl)-6-chloropyridazine-3-yl)cyclopent-2-en-1-yl)-1H- pyrazole-5-yl) benzyl carbamate A mixture of 4-(tert-butyl)-3,6-dichloropyridazine (510 mg, 2.5 mmol), (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (1.4 g, 3 mmol), Pd(dppf)Cl2 (203 mg, 0.25 mmol), and Na2CO3 (795 mg, 7.5 mmol) in dioxane (20 mL) and H2O (5 mL) was stirred at 80 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0-45%) elution to give the product (1.15 mg, 90.6%). LC-MS (ESI): m / z [M+H] + = 508.2.

[0123] Step 2: 1-(tert-butyl)-3-(3-(5-(tert-butyl)pyridazin-3-yl)cyclopentyl)-1H-pyrazole-5-amine Pd / C (150 mg) was added to a solution of (1-(tert-butyl)-3-(3-(5-(tert-butyl)-6-chloropyridazin-3-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (1.15 g, 2.3 mmol) in MeOH (20 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 5 h. The mixture was filtered and the filtrate was concentrated under vacuum to give (567 mg, crude product). The residue was used directly in the next step without further purification. LC-MS (ESI): m / z [M+H] + =342.2.

[0124] Step 3: 5-((5-(3-(5-(tert-butyl)pyridazine-3-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-6-fluoro- 2,3-Dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.08 (s, 1H), 9.20 (d, J =5 Hz, 1H), 8.78-8.75 (m, 1H), 8.19-8.13 (m, 1H), 7.67-7.61(m, 2H), 7.54-7.51 (m, 1H), 5.91 (s, 1H), 4.34-4.28 (m, 2H), 3.62-3.48 (m,1H), 3.33-3.24 (m, 1H), 2.48-2.45 (m, 1H), 2.32-2.15 (m, 2H), 2.09-1.83 (m,3H), 1.31 (s, 9H). LC-MS (ESI): m / z [M+H] + = 471.2.

[0125] Example 15: 4-((5-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-3-fluorobenzenesulfonamide Step 1: (1-(tert-butyl)-3-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole- 5-yl) benzyl carbamate Pd(dppf)Cl2 (99.6 mg, 0.107 mmol) and K3PO4 (683.7 mg, 3.225 mmol) were added to a solution of (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (500 mg, 1.075 mmol) and 4-(tert-butyl)-2-chloropyrimidine (277.2 mg, 1.612 mmol) in dioxane / H2O (10:2 mL). The reaction mixture was stirred at 100 °C for 6 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (400 mg, 78.5%). LC-MS (ESI): m / z [M+H] + = 475.3.

[0126] Step 2: 1-(tert-butyl)-3-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazole-5-amine (1-(tert-butyl)-3-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)benzyl carbamate (400 mg, 0.84 mmol) was dissolved in MeOH (10 mL), and Pd / C (10% on carbon, 200 mg) was added. The reaction mixture was degassed and purged three times with hydrogen and stirred at room temperature for 2 hours. The resulting mixture was filtered, and the filtrate was concentrated under vacuum to give the product (200 mg, 69%). LC-MS (ESI): m / z [M+H]+ = 343.3.

[0127] Step 3: 5-((5-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-6-fluoro- 2,3-Dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ =12.03 (s, 1H), 8.74 (d, J = 2.6 Hz, 1H), 8.63 (d, J = 5.3, 3.0 Hz, 1H), 8.16 (s,1H), 7.81 – 7.55 (m, 2H), 7.33 (d, J = 5.3 Hz, 1H), 5.87 (s, 1H), 4.30 (d, J=4.8 Hz, 2H), 3.52-3.44 (m, 3H), 3.26-3.20 (m, 1H), 2.48-2.42 (m, 1H), 2.25 –1.96 (m, 4H), 1.89 – 1.76 (m, 1H), 1.30 (s, 9H). LC-MS (ESI): m / z [M+H] + =471.2.

[0128] Example 16: 6-Fluoro-5-((5-(3-(4-isopropylpyrimidin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.04 (s, 1H), 8.75 (d, J = 2.5 Hz, 1H), 8.67 – 8.56 (m, 1H), 8.16 (d, J = 5.6Hz, 1H), 7.63 (d, J = 10.0 Hz, 2H), 7.22 (d, J = 5.2 Hz, 1H), 5.88 (s, 1H), 4.23(d, J = 73.5 Hz, 2H), 3.46 (dt, J = 15.9, 8.1 Hz, 1H), 3.28 – 3.19 (m, 1H), 3.01– 2.90 (m, 1H), 2.44 (dd, J = 12.9, 6.3 Hz, 1H), 2.24 – 2.09 (m, 2H), 2.09 –2.03 (m, 1H), 1.99 (dd, J = 22.7, 10.7 Hz, 1H), 1.88 – 1.72 (m, 1H), 1.23 (dd, J = 6.9, 3.5 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 457.2.

[0129] Example 17: 5-((5-(3-(5-(tert-butyl)oxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-6-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound in its racemic form was synthesized in a procedure similar to that of Example 6, and further separated by chiral preparative HPLC to obtain four isomers: Enantiomer 1 (Example 17a, 100% ee); retention time: 2.861 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.03 (s, 1H), 8.74 (s, 1H), 8.14 (d, J = 5 Hz, 1H), 7.66-7.61 (m,2H), 6.67 (s, 1H), 5.85 (s, 1H), 4.30 (d, J = 5 Hz, 2H), 3.41-3.33 (m, 1H), 3.24-3.15 (m, 1H), 2.48-2.40 (m, 1H), 2.16-2.04 (m, 2H), 2.02-1.84 (m, 2H), 1.78-1.68 (m, 1H), 1.23 (s, 9H). LC-MS (ESI): m / z [M+H] + = 460.2.

[0130] Enantiomer 2 (Example 17b, 99.1% ee); retention time: 4.871 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.03 (s, 1H), 8.74 (s, 1H), 8.14 (d, J = 5 Hz, 1H), 7.66-7.61 (m,2H), 6.67 (s, 1H), 5.85 (s, 1H), 4.30 (d, J= 5 Hz, 2H), 3.41-3.33 (m, 1H), 3.24-3.15 (m, 1H), 2.48-2.40 (m, 1H), 2.16-2.04 (m, 2H), 2.02-1.84 (m, 2H), 1.78-1.68 (m, 1H), 1.23 (s, 9H). LC-MS (ESI): m / z [M+H] + = 460.2.

[0131] Enantiomer 3 (Example 17c, 98.3% ee); retention time: 6.269 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.03 (s, 1H), 8.74 (s, 1H), 8.14 (d, J = 5 Hz, 1H), 7.66-7.61 (m,2H), 6.67 (s, 1H), 5.85 (s, 1H), 4.30 (d, J = 5 Hz, 2H), 3.41-3.33 (m, 1H), 3.24-3.15 (m, 1H), 2.48-2.40 (m, 1H), 2.16-2.04 (m, 2H), 2.02-1.84 (m, 2H), 1.78-1.68 (m, 1H), 1.23 (s, 9H). LC-MS (ESI): m / z [M+H] + = 460.2.

[0132] Enantiomer 4 (Example 17d, 99.7% ee); retention time: 5.628 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.03 (s, 1H), 8.74 (s, 1H), 8.14 (d, J = 5 Hz, 1H), 7.66-7.61 (m,2H), 6.67 (s, 1H), 5.85 (s, 1H), 4.30 (d, J= 5 Hz, 2H), 3.41-3.33 (m, 1H), 3.24-3.15 (m, 1H), 2.48-2.40 (m, 1H), 2.16-2.04 (m, 2H), 2.02-1.84 (m, 2H), 1.78-1.68 (m, 1H), 1.23 (s, 9H). LC-MS (ESI): m / z [M+H] + = 460.2.

[0133] Chiral analysis method: Column: CHIRALPAK IA-3, 4.6 50 mm 3 μm; Mobile phase: A is Hex (0.1% FA) and B is EtOH; Gradient: Mobile phase A: Mobile phase B = 70:30 (v / v); Flow rate: 20 mL / min; Wavelength: UV 254 nm and 220 nm; Preparative HPLC equipment: Preparative HPLC-Gilson; Back pressure: 100 bar; Column temperature: 25℃.

[0134] Chiral preparative HPLC conditions: CHIRALPAK IA, 2 250 mm 5 μm; Mobile phase: A is Hex (0.1% FA) and B is EtOH; Gradient: Mobile phase A: Mobile phase B = 70:30 (v / v); Flow rate: 20 mL / min; Wavelength: UV 254 nm and 220 nm; Preparative HPLC equipment: Preparative HPLC-Gilson; Back pressure: 100 bar; Column temperature: 25℃.

[0135] Example 18: 6-Fluoro-5-((5-(3-(5-isopropyloxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 7. 1 H NMR (500 MHz, DMSO- d 6) δ 12.04 (s, 1H), 8.75 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 6.0 Hz, 1H), 7.71 – 7.53(m, 2H), 6.69 (d, J = 1.0 Hz, 1H), 5.87 (d, J = 11.7 Hz, 1H), 4.30 (d, J= 4.5 Hz, 2H), 3.42 (dd, J = 16.8, 10.9 Hz, 1H), 3.19 (dt, J = 17.5, 8.8 Hz, 1H), 2.93 (dq, J = 13.9, 7.0 Hz, 1H), 2.48 – 2.41 (m, 1H), 2.20 – 2.05 (m, 2H), 1.98 (dt, J =12.2, 7.9 Hz, 1H), 1.89 (dd, J = 22.5, 10.3 Hz, 1H), 1.77 – 1.66 (m, 1H), 1.19(dd, J = 6.8, 4.5 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 446.2.

[0136] Example 19: 5-((5-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-6-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 8. 1 H NMR (500 MHz, DMSO- d 6) δ 12.03(s, 1H), 8.77-8.71 (m, 1H), 8.20-8.09 (m, 1H), 7.68-7.59 (m, 2H), 5.85 (s,1H), 4.30 (d, J = 5 Hz, 2H), 3.30-3.22 (m, 1H), 3.21-3.12 (m, 1H), 2.45-2.38(m, 1H), 2.18-2.02 (m, 5H), 1.99-1.90 (m, 1H), 1.89-1.81 (m, 1H), 1.78-1.67(m, 1H), 1.27(s, 9H). LC-MS (ESI): m / z [M+H] + = 474.2.

[0137] Example 20: 5-((5-(3-(5-cyclopropyloxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-6-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 9. 1 H NMR (500 MHz, DMSO- d 6) δ 12.03 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.14 (s, 1H), 7.67 – 7.62 (m, 2H), 6.70 (s, 1H), 5.85 (s, 1H), 4.30 (d, J = 5.0 Hz, 2H), 3.36 - 3.32 (m, 1H), 3.23– 3.15 (m, 1H), 2.47 - 2.39 (m, 1H), 2.13 - 2.04 (m, 2H), 2.00 - 1.83 (m,3H), 1.76 - 1.69 (m, 1H), 0.92 – 0.86 (m, 2H), 0.71 – 0.65 (m, 2H). LC-MS(ESI): m / z [M+H] + = 444.3.

[0138] Example 21: cis-2-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)pyridazine-3(2H)-one Step 1: Methyl 6-amino-3-bromo-2-fluorobenzoate SOCl2 (2.5 g, 21.3 mmol) was added dropwise to a solution of 6-amino-3-bromo-2-fluorobenzoic acid (1.0 g, 4.27 mmol) in methanol (20 mL). The reaction mixture was stirred under reflux for 16 hours. The resulting mixture was cooled to room temperature, concentrated, neutralized with a saturated aqueous solution of NaHCO3, and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography with PE / EA (5:1) elution to give the product (346 mg, 33%). LC-MS (ESI): m / z [M+H] + = 248.0.

[0139] Step 2: Methyl 3-bromo-6-(chlorosulfonyl)-2-fluorobenzoate A solution of sodium nitrite (835 mg, 12.1 mmol) in 5 mL of water was added dropwise to a suspension of methyl 6-amino-3-bromo-2-fluorobenzoate (3.0 g, 12.1 mmol) in hydrochloric acid (12 M, 60 mL) at 0 °C. The resulting mixture was kept below 5 °C and stirred for 30 min after the addition. CuCl2 (813 mg, 6.05 mmol), sodium bisulfite (18.9 g, 181.5 mmol), and hydrochloric acid solution (5.5 M, 20 mL) were added sequentially to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 3 h. The resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and dried under vacuum to give a crude product (3.2 g), which was used for the next step without further purification.

[0140] Step 3: 5-Bromo-4-fluorobenzo[ d Isothiazine-3(2) H )-Ketone 1,1-dioxide An aqueous solution (25% ammonia, 10 mL) was added dropwise to a solution of methyl 3-bromo-6-(chlorosulfonyl)-2-fluorobenzoate (3.2 g crude) in THF (50 mL). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum, and the residue was milled 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.

[0141] Step 4: 5-Bromo-4-fluoro-2,3-dihydrobenzo[ d] Isothiazole 1,1-dioxide In a nitrogen atmosphere at 0°C, 5-bromo-4-fluorobenzo[ d Isothiazine-3(2) H 1,1-dioxide (210 mg, 0.75 mmol) of 1,1-ketoketone was added dropwise to a stirred solution of BH3-Me2S (2 M, 1.5 mL, 3.0 mmol) in THF (5 mL). 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 with DCM / MeOH (5:1) elution to give the product (184 mg, 93%). LC-MS (ESI): m / z [M+H] + = 265.8.

[0142] Step 5: 5-Bromo-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide To a solution of 1,1-dioxide (13 g, 50 mmol) of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazolium in 100 mL of DMF, K₂CO₃ (13.8 g, 100 mL) and 1-(chloromethyl)-4-methoxybenzene (8.6 g, 55 mmol) were added. The resulting mixture was stirred overnight at room temperature. The mixture was poured into water and filtered. The filtrate was washed with water and dried to obtain the product (15.3 g, 85% yield). LC-MS (ESI): m / z [M+H] + = 385.9.

[0143] Step 6: cis-(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H 5-pyrazole-5-yl)benzyl carbamate A solution of (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. LiBHEt3 solution (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 a saturated aqueous solution of NaHCO3 (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 Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column; mobile phase: [water (NH4HCO3)-acetone]; B%: 40%–65%, 20 min). The product was obtained (11 g, 57% yield). 1 H NMR (400 MHz, DMSO- d 6 ) 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).

[0144] Step 7: trans-4-nitrobenzoic acid 3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazole- 3-yl)cyclopentyl ester cis-(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H PPh3 (3.1 g, 12 mmol) was added to a solution of pyrazol-5-yl)carbamate (2.14 g, 6 mmol) in THF (100 mL). Then, a solution of DIAD (2.38 g, 12 mmol) in THF (20 mL) was added to the reaction mixture via syringe at 0 °C. The resulting solution was stirred at room temperature under a nitrogen atmosphere for 1 h. Water (100 mL) was added, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EtOAc / PE = 25% elution to give the product (2.27 g, 75%). LCMS (ESI) m / z [M+H] + = 507.3.

[0145] Step 8: trans-(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazole-5-yl)carbamate K₂CO₃ (621 mg, 4.5 mmol) was added to a solution of trans-4-nitrobenzoic acid 3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (2.27 g, 4.5 mmol) in MeOH (100 mL). The resulting solution was stirred at room temperature for 3 h. The resulting mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography with EtOAc / PE = 45% elution to give the product (1.17 g, 82%). LCMS (ESI) m / z [M+H] + = 358.3.

[0146] Step 9: trans-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentan-1-ol Pd / C (10%, wet, 1 g) was added to a solution of trans-4-nitrobenzoic acid 3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (1.17 g, 3.3 mmol) in THF (100 mL). The suspension was degassed and purged three times with hydrogen. 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 MeOH (50 mL × 3). The filtrate was concentrated under reduced pressure to give the product (677 mg, 92% yield). LC-MS (ESI): m / z [M+H] + = 224.3.

[0147] Step 10: trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro- 2-(4-Methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide A mixture of 5-bromo-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide (1.16 g, 3.0 mmol), trans-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentan-1-ol (677 mg, 3.0 mmol), Brettphos Pd G3 (272 mg, 0.3 mmol), and K2CO3 (1.2 g, 9 mmol) in t-BuOH (100 mL) was stirred at 110 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with EA / PE (4:1) elution to obtain the product (618 mg, 39% yield). LC-MS (ESI): m / z [M+H] + = 529.3.

[0148] Step 11: cis-2-(3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1,1-dioxide-2, 3-Dihydrobenzo[d]isothiazolyl)amino)-1H-pyrazole-3-yl)cyclopentyl)pyridazine-3(2H)-one A mixture of trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide (0.1 g, 0.189 mmol), pyridazine-3(2H)-one (0.055 g, 0.573 mmol), and cyanomethylenetributylphosphine (0.137 g, 0.568 mmol) in toluene (5 mL) was heated at 95 °C for 15 h under N2. After cooling to 25 °C, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EtOAc (1:1) elution to give the product (0.077 g, 66.95%). LC-MS (ESI): m / z [M+H] + = 607.3.

[0149] Step 12: cis-2-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazo-5-yl)amino )-1H-pyrazole-5-yl)cyclopentyl)pyridazine-3(2H)-one Trifluoromethanesulfonic acid (2 mL) was added dropwise to a stirred solution of cis-2-(3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1,1-dioxy-2,3-dihydrobenzo[d]isothiazo-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl)pyridazine-3(2H)-one (77 mg, 0.127 mmol) in DCM (5 mL). The solution was stirred at room temperature for 2 h. The solution was diluted with DCM (20 mL) and alkalized to pH = 8 with saturated NaHCO3 aqueous solution at 0 °C. The layers were separated, and the aqueous layer was extracted with DCM (30 mL × 3). 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 10%-49% water (containing 0.1% FA) in acetonitrile) to obtain the product (12 mg, 21.94%). 1 H NMR (500 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.99 (dd, J = 3.8, 1.6Hz, 1H), 7.70 (t, J = 5.1 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.40 (dd,J = 9.4, 3.8Hz, 1H), 6.92 (dd, J = 9.4, 1.7 Hz, 1H), 5.88 (s, 1H), 5.49 – 5.42 (m, 1H), 4.41 (s, 2H), 3.25 – 3.18 (m, 1H), 2.48 – 2.41 (m, 1H), 2.16 – 2.07 (m, 2H),2.00 – 1.84 (m, 3H). LC-MS (ESI): m / z [M+H] + = 431.3.

[0150] Example 22: cis-4-fluoro-5-((5-(3-(pyridazin-3-yloxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: cis-5-((1-(tert-butyl)-3-(3-(pyridazin-3-yloxy)cyclopentyl)-1H-pyrazol-5-yl)amino 1,1-dioxide of 4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium A mixture of trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide (0.1 g, 0.189 mmol), pyridazine-3(2H)-one (0.055 g, 0.573 mmol), and cyanomethylenetributylphosphine (0.137 g, 0.568 mmol) in toluene (5 mL) was heated at 95 °C for 15 h under N2. After cooling to 25 °C, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EtOAc (1:1) elution to give the product (22.1 mg, 19.4%). LC-MS (ESI): m / z [M+H] + = 607.3.

[0151] Step 2: cis-4-fluoro-5-((5-(3-(pyridazin-3-yloxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2, 3-Dihydrobenzo[d]isothiazolium 1,1-dioxide Trifluoromethanesulfonic acid (2 mL) was added dropwise to a stirred solution of cis-5-((1-(tert-butyl)-3-(3-(pyridazin-3-yloxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (22.1 mg, 0.037 mmol) in DCM (5 mL). The solution was stirred at room temperature for 2 h. The solution was diluted with DCM (20 mL) and alkalized to pH = 8 with saturated NaHCO3 aqueous solution at 0 °C. The layers were separated, and the aqueous layer was extracted with DCM (30 mL × 3). 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 10%-49% water (containing 0.1% FA) in acetonitrile) to give the product (12 mg, 21.94%). 1 H NMR (500 MHz, DMSO- d 6) δ 12.03 (s, 1H), 8.87 (d, J = 3.3 Hz, 1H), 8.72 (s, 1H), 8.27 (s, 1H), 7.69(s, 1H), 7.61 (dd, J = 8.9, 4.4 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.9Hz, 1H), 5.85 (s, 1H), 5.60 (s, 1H), 4.40 (d, J = 5.1 Hz, 2H), 3.24 – 3.13 (m,1H), 2.74 – 2.66 (m, 1H), 2.17 – 2.08 (m, 2H), 1.96 – 1.78 (m, 3 H). LC-MS (ESI): m / z [M+H] + = 431.3.

[0152] Example 23: cis-2-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[] d Isothiazol-5-yl)amino)-1 H -pyrazol-5-yl)cyclopentyl)-4-methylpyridazine-3(2 H )-ketone Step 1: cis-2-(3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1,1-dioxide-2,3- dihydrobenzo[ d Isothiazol-5-yl)amino)-1 H -pyrazol-3-yl)cyclopentyl)-4-methylpyridazine-3(2 H )-ketone to trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d CMBP (137 mg, 0.57 mmol) was added to a solution of isothiazole 1,1-dioxide (100 mg, 0.19 mmol) and 4-methylpyridazine-3-phenol (21 mg, 0.19 mmol) in toluene (3 mL). The reaction mixture was stirred at 100 °C for 16 h under nitrogen. The resulting mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (110 mg, 93%). LC-MS (ESI): m / z [M+H] + =621.4.

[0153] Step 2: cis-2-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[] d Isothiazol-5-yl)amino (base)-1 H -pyrazol-5-yl)cyclopentyl)-4-methylpyridazine-3(2 H )-ketone The title compound was synthesized in a procedure similar to step 12 of Example 21. 1 H NMR (500 MHz, DMSO- d 6)δ = 12.06 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 7.88 (d, J = 3.9, 1H), 7.69 (s,1H), 7.48 (d, J = 8.6, 1H), 7.28 (dd, J = 3.9, 1.1, 1H), 5.87 (s, 1H), 5.53 –5.41 (m, 1H), 4.41 (s, 2H), 3.26 – 3.17 (m, 1H), 2.41 (m, 1H), 2.16 – 2.05(m, 5H), 1.96 (m, 2H), 1.87 (m, 1H). LC-MS (ESI): m / z [M+H] + = 445.1.

[0154] Example 24: cis-4-fluoro-5-((5-(3-((4-methylpyridazin-3-yl)oxy)cyclopentyl)-1 H -pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide Step 1: cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentan-1-ol Pd / C (10%, wet, 2 g) was added to a solution of cis-(1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (3.6 g, 10 mmol) in THF (100 mL). The suspension was degassed and purged three times with hydrogen. 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 mL × 3). The filtrate was concentrated under reduced pressure to give the product (2.1 g, 91% yield). LC-MS (ESI): m / z [M+H] + = 224.3.

[0155] Step 2: cis-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2- (4-Methoxybenzyl)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide A mixture of 5-bromo-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide (1.16 g, 3.0 mmol), cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentan-1-ol (677 mg, 3.0 mmol), Brettphos Pd G3 (272 mg, 0.3 mmol), and K2CO3 (1.2 g, 9 mmol) in t-BuOH (100 mL) was stirred at 110 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with EA / PE (4:1) elution to obtain the product (618 mg, 39% yield). LC-MS (ESI): m / z [M+H] + = 529.3.

[0156] Step 3: cis-5-((1-(tert-butyl)-3-(3-((4-methylpyridazin-3-yl)oxy)cyclopentyl)-1 H -pyr (Azol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide cis-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 HPd2dba3 (26 mg, 0.028 mmol), Binap (35 mg, 0.057 mmol), and t-BuONa (82 mg, 0.852 mmol) were added to a solution of pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide (150 mg, 0.284 mmol) and 3-chloro-4-methylpyridazine (37 mg, 0.284 mmol) in toluene (5 mL). The reaction mixture was stirred at 95 °C for 4 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (60 mg, 34%). LC-MS (ESI): m / z [M+H] + = 621.3.

[0157] Step 4: cis-4-fluoro-5-((5-(3-((4-methylpyridazin-3-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl) (amino)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide The title compound was synthesized in a procedure similar to step 12 of Example 21. 1 H NMR (500 MHz, DMSO- d 6)δ = 12.03 (s, 1H), 8.72 (s, 1H), 8.69 (d, J = 4.6, 1H), 8.27 (d, J = 9.0, 1H),7.69 (s, 1H), 7.47 (d, J = 8.6, 1H), 7.44 (d, J = 4.5, 1H), 5.84 (s, 1H), 5.63(s, 1H), 4.40 (d, J = 4.5, 2H), 3.25 – 3.16 (m, 1H), 2.71 – 2.61 (m, 1H), 2.13(s, 3H), 2.09 (m, 2H), 1.95 (m, 1H), 1.91 – 1.79 (m, 2H). LC-MS (ESI): m / z [M+H] + = 445.1.

[0158] Example 25: cis-5-((5-(3-((4-ethylpyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: cis-5-((1-(tert-butyl)-3-(3-((4-ethylpyridazine-3-yl)oxy)cyclopentyl)-1H-pyridine (Azol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide cis-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d A solution of isothiazole 1,1-dioxide (150 mg, 0.284 mmol) and 3-chloro-4-ethylpyridazine (61 mg, 0.284 mmol) in toluene (15 mL) was reacted with Pd2dba3 (26 mg, 0.028 mmol), Binap (35 mg, 0.059 mmol), and t-BuONa (82 mg, 0.852 mmol). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (90 mg, 48%). LC-MS (ESI): m / z [M+H] + = 636.3.

[0159] Step 2: cis-5-((5-(3-((4-ethylpyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino 1,1-dioxide of 4-fluoro-2,3-dihydrobenzo[d]isothiazolium FA (10 mL) was added to a stirred solution of cis-5-((1-(tert-butyl)-3-(3-(((4-ethylpyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (50 mg, 0.086 mmol), and the solution was stirred at 75 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 100% EA elution to obtain the crude product, which was further purified by preparative HPLC (Waters XSelect C18: RD-CO-094 column, with acetonitrile / water (containing 0.1% FA) (20%-40%) gradient elution) to obtain the product (5 mg, 17.8%). 1 H NMR (500 MHz, DMSO- d 6) δ 12.03 (s, 1H),8.76 – 8.65 (m, 1H), 8.26 (s, 0H), 7.69 (t, J = 4.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 0H), 7.41 (d, J= 4.5 Hz, 1H), 5.83 (s, 1H), 5.64 (s, 1H), 4.40 (d, J = 5.0 Hz,2H), 3.25 – 3.13 (m, 1H), 2.74 – 2.63 (m, 1H), 2.16-2.06 (m, 1H), 2.00-1.80(m, 2H), 1.12 (t, J = 7.5 Hz, 2H). LC-MS (ESI): m / z [M+H] + = 459.2.

[0160] Example 26: cis-2-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-4-isopropylpyridazine-3(2H)-one The title compound was synthesized in a procedure similar to that of Example 21. 1 H NMR (500 MHz, DMSO- d 6) δ12.05 (s, 1H), 8.73 (s, 1H), 8.27 (s, 1H), 7.94 (d, J = 4.1 Hz, 1H), 7.69 (t, J =5.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 4.1 Hz, 1H), 5.88 (s, 1H), 5.50 (dd, J = 15.4, 7.7 Hz, 1H), 4.41 (d, J = 5.3 Hz, 2H), 3.26 – 3.18 (m, 1H), 3.11 – 3.03 (m, 1H), 2.48 – 2.41 (m, 1H), 2.16 – 2.05 (m, 2H), 2.00 – 1.85(m, 3H), 1.14 (d, J = 6.9 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 473.3.

[0161] Example 27: cis-4-fluoro-5-((5-(3-((4-isopropylpyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazole-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 22. 1 H NMR (500 MHz, DMSO- d 6) δ 12.03 (s, 1H), 8.76 (d, J = 4.7 Hz, 1H), 8.72 (s, 1H), 8.26 (s, 1H), 7.69 (t, J =4.8 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 4.7 Hz, 1H), 5.83 (s, 1H), 5.66 (s, 1H), 4.40 (d, J = 5.2 Hz, 2H), 3.24 - 3.18 (m, 1H), 3.03 - 2.97 (m,1H), 2.72 - 2.65 (m, 1H), 2.17 - 2.08 (m, 2H), 2.01 - 1.82 (m, 3H), 1.14 (dd, J = 6.7, 4.4 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 473.3.

[0162] Example 28: cis-4-cyclopropyl-2-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazo-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)pyridazine-3(2H)-one Step 1: cis-2-(3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1,1-dioxide-2,3- Dihydrobenzo[d]isothiazo-5-yl)amino)-1H-pyrazole-3-yl)cyclopentyl)-4-chloropyridazine-3(2H)-one CMBP (274 mg, 1.14 mmol) was added to a mixture of trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide (200 mg, 0.38 mmol) and 4-chloropyridazine-3-phenol (103 mg, 0.76 mmol) in toluene (10 mL). The mixture was stirred at 95 °C for 16 h under nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0-65%) elution to give the product (153 mg, 62.9%). LC-MS (ESI): m / z [M+H] + = 641.

[0163] Step 2: cis-2-(3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1,1-dioxide-2,3- Dihydrobenzo[d]isothiazo-5-yl)amino)-1H-pyrazole-3-yl)cyclopentyl)-4-cyclopropylpyridazine-3(2H)-one Cis-2-(3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1,1-dioxane-2,3-dihydrobenzo[d]isothiazo-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl)-4-chloropyridazine-3(2H)-one (153 mg, 0.24 mmol) was added to a solution of dioxane (10 mL) and H₂O (1 mL) with cyclopropylboronic acid (31 mg, 0.36 mmol), Pd(OAc)₂ (2.8 mg, 0.012 mmol) and PCy₃ (8 mg, 0.03 mmol). The mixture was stirred at 110 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0-80%) elution to give the product (135 mg, 87%). LC-MS (ESI): m / z [M+H] + = 647.

[0164] Step 3: cis-4-cyclopropyl-2-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazol- 5-yl)amino)-1H-pyrazole-5-yl)cyclopentyl)pyridazine-3(2H)-one The title compound was synthesized in a procedure similar to that of Example 21. 1 H NMR (500 MHz, DMSO- d 6) δ 12.05 (s, 1H), 8.72 (d, J = 5 Hz, 1H), 8.29-8.20 (m, 1H),7.84 (d, J= 5 Hz, 1H), 7.71-7.65 (m, 1H), 7.48 (d, J = 5 Hz, 1H), 6.87 (d, J = 5 Hz, 1H), 5.87 (s, 1H), 5.52-5.43 (m, 1H), 4.40 (s, 2H), 3.25-3.18 (m, 1H), 2.46-2.30 (m, 1H), 2.20-2.04(m, 3H), 2.01-1.82 (m, 2H), 1.15-0.97 (m, 2H), 0.84-0.78 (m, 2H). LC-MS (ESI): m / z [M+H] + = 471.2.

[0165] Example 29: cis-5-((5-(3-((4-cyclopropylpyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: cis-5-((1-(tert-butyl)-3-(3-((4-chloropyridazine-3-yl)oxy)cyclopentyl)-1H-pyrazole- 5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide CMBP (274 mg, 1.14 mmol) was added to a mixture of trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide (200 mg, 0.38 mmol) and 4-chloropyridazine-3-phenol (103 mg, 0.76 mmol) in toluene (10 mL). The mixture was stirred at 95 °C for 16 h under nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0-65%) elution to give the product (50 mg, 20.4%). LC-MS (ESI): m / z [M+H] + = 641.

[0166] Step 2: cis-5-((1-(tert-butyl)-3-(3-((4-cyclopropylpyridazine-3-yl)oxy)cyclopentyl)-1H-pyridine (Azol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Cyclopentyl cyclo ... LC-MS (ESI): m / z [M+H] + = 647.

[0167] Step 3: cis-5-((5-(3-((4-cyclopropylpyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino 1,1-dioxide of 4-fluoro-2,3-dihydrobenzo[d]isothiazolium A solution of cis-5-((1-(tert-butyl)-3-(3-(((4-cyclopropylpyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazole-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (46 mg, 0.07 mmol) in DCM (10 mL) was mixed with TfOH (1 mL). The mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (50 mL) and washed with saturated NaHCO3 (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the product (2.5 mg, 7.5%). 1 HNMR (500 MHz, DMSO- d 6) δ 12.05 (s, 1H), 8.74 (d, J = 5 Hz, 1H), 8.71-8.68 (m,1H), 8.28-8.17 (m, 1H), 7.75-7.62 (m, 1H), 7.46 (d, J = 10 Hz, 1H), 7.19 (d, J=5 Hz, 1H), 5.85 (s, 1H), 5.66-5.58 (m, 1H), 4.40 (s, 2H), 3.27-3.14 (m, 1H), 2.75-2.63 (m, 1H), 2.18-2.08 (m, 2H), 2.05-1.94 (m, 2H), 1.93-1.83 (m, 2H), 1.10-1.00 (m, 2H), 0.90-0.83 (m, 2H). LC-MS (ESI): m / z [M+H] + = 471.2.

[0168] Example 30: cis-2-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-4-phenylpyridazine-3(2H)-one The title compound was synthesized in a procedure similar to that of Example 21. 1 H NMR (500 MHz, DMSO- d 6) δ 12.04 (s, 1H), 8.93 (d, J =5 Hz, 1H), 8.71-8.65 (m, 1H), 8.29-8.16 (m, 1H), 7.72-7.61(m, 4H), 7.50-7.38 (m, 4H), 5.79 (s, 1H), 5.73-5.66 (m, 1H), 4.40 (d, J =5 Hz,2H), 3.24-3.15 (m, 1H), 2.75-2.66 (m, 1H), 2.21-2.06 (m, 2H), 2.00-1.90 (m,1H), 1.90-1.77 (m, 2H). LC-MS (ESI): m / z [M+H] + = 507.2.

[0169] Example 31: cis-4-fluoro-5-((5-(3-((4-phenylpyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 22. 1 H NMR (500 MHz, DMSO- d 6) δ 12.05(s, 1H), 8.70 (s, 1H), 8.30-8.20 (m, 1H), 8.09-8.04 (m, 1H), 7.85-7.78 (m,2H), 7.69-7.62 (m, 1H), 7.58-7.53 (m, 1H), 7.50-7.40 (m, 4H), 5.90 (s, 1H),5.60-5.50 (m, 1H), 4.40 (s, 2H), 3.30-3.19 (m, 1H), 3.47-3.42 (m, 1H), 2.20-2.10 (m, 2H), 2.08-1.97 (m, 2H), 1.96-1.85 (m, 1H). LC-MS (ESI): m / z [M+H] + =507.2.

[0170] Example 32: cis-2-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-5-(prop-1-en-2-yl)pyridazine-3(2H)-one Step 1: cis-2-(3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1,1-dioxide-2,3- Dihydrobenzo[d]isothiazo-5-yl)amino)-1H-pyrazole-3-yl)cyclopentyl)-5-chloropyridazine-3(2H)-one CMBP (274 mg, 1.14 mmol) was added to a mixture of trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide (200 mg, 0.38 mmol) and 4-chloropyridazine-3-phenol (103 mg, 0.76 mmol) in toluene (10 mL). The mixture was stirred at 95 °C for 16 h under nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0-65%) elution to give the product (50 mg, 20.4%). LC-MS (ESI): m / z [M+H] + = 641.

[0171] Step 2: cis-2-(3-(1-(tert-butyl)-5-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazolyl) (azol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl)-5-(prop-1-en-2-yl)pyridazine-3(2H)-one A solution of cis-2-(3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1,1-dioxane-2,3-dihydrobenzo[d]isothiazo-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl)-5-chloropyridazine-3(2H)-one (50 mg, 0.08 mmol) in dioxane / H₂O (5 / 1 mL) was mixed with potassium isopropenyltrifluoroborate (15 mg, 0.1 mmol), Pd(dppf)Cl₂ (7 mg, 0.01 mmol), and K₂CO₃ (33 mg, 0.24 mmol). The mixture was stirred at 100 °C for 4 h under nitrogen. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography with EA / PE (0-50%) elution to give the product (25.6 mg, 61%). LC-MS (ESI): m / z [M+H] + = 527.4.

[0172] Step 3: cis-2-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazo-5-yl)amino (1H-pyrazol-5-yl)cyclopentyl)-5-(prop-1-en-2-yl)pyridazine-3(2H)-one The title compound was synthesized in a procedure similar to step 11 of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.73 (s, 1H), 8.31 (d, J =5 Hz, 1H), 8.30-8.23 (m, 1H), 7.72-7.66 (m, 1H), 7.48 (d, J =10 Hz, 1H), 6.81 (d, J =5 Hz, 1H), 5.86 (d, J =5 Hz, 2H),5.47 (s, 1H), 5.45-5.38 (m, 1H), 4.44-4.38 (m, 2H), 3.28-3.16 (m, 1H), 2.47-2.39 (m, 1H), 2.18-2.07 (m, 2H), 2.04 (s, 3H), 2.00-1.83 (m, 3H). LC-MS (ESI): m / z [M+H] + = 471.2.

[0173] Example 33: cis-2-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-5-isopropylpyridazine-3(2H)-one Cis-2-(3-(3-(((4-fluoro-1,1-dioxy-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-5-(prop-1-en-2-yl)pyridazin-3(2H)-one (20 mg, 0.038 mmol) was dissolved in THF (20 mL), and Pd / C (10% on carbon, 10 mg) was added. The reaction mixture was stirred at room temperature for 1 hour at 1 atm H2. The resulting mixture was filtered, the filtrate was concentrated, and purified by silica gel column chromatography with EA / PE (0-100%) elution to give the product (14 mg, 78%). 1 H NMR (500 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.73 (s,1H), 8.33-8.23 (m, 1H), 8.02-7.98 (m, 1H), 7.69 (t, J =5 Hz, 1H), 7.48 (d, J =10Hz, 1H), 6.68-6.66 (m, 1H), 5.87 (s, 1H), 5.46-5.37 (m, 1H), 4.41 (d, J =5 Hz,2H), 3.28-3.16 (m, 1H), 2.84-2.75 (m, 1H), 2.45-2.35 (m, 1H), 2.17-2.03 (m,2H), 2.00-1.81 (m, 3H), 1.17 (d, J =5 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 473.2.

[0174] Example 34: cis-2-(3-(3-((4-fluoro-1,1-dioxy-2,3-dihydrobenzo[d]isothiazolyl)amino)-1H-pyrazol-5-yl)cyclopentyl)pyrido[3,4-d]pyridazine-1(2H)-one The title compound was synthesized in a procedure similar to that of Example 21. 1H NMR (500 MHz, DMSO- d 6) δ12.07 (s, 1H), 9.34 (s, 1H), 8.99 (d, J = 5.3 Hz, 1H), 8.74 (s, 1H), 8.68 (s,1H), 8.29 (t, J = 7.9 Hz, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J =8.6 Hz, 1H), 5.90 (s, 1H), 5.62 – 5.53 (m, 1H), 4.41 (d, J = 3.3 Hz, 2H), 3.30- 3.21 (m, 1H), 2.47 – 2.43 (m, 1H), 2.20 – 2.11 (m, 2H), 2.09 – 1.99 (m,2H), 1.97 – 1.89 (m, 1H). LC-MS (ESI): m / z [M+H] + = 482.3.

[0175] Example 35: cis-5-((5-(3-((4-cyclobutylpyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: 3-Chloro-4-cyclobutylpyridazine To a solution of 3-chloropyridazine hydrochloride (15 g, 99.3 mmol) in MeCN (708 mL) and H₂O (708 mL), cyclobutanecarboxylic acid (9.9 g, 99.3 mmol), (NH₄)₂S₂O₈ (113.2 g, 496.5 mmol), and AgNO₃ (67.5 g, 397.2 mmol) were added. The resulting solution was stirred at 55 °C for 2 h under a nitrogen atmosphere. The solid was filtered off, and the filtrate was extracted with EtOAc (3 × 150 mL). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (EtOAc / PE = 22%) to give the product (1.3 g, 7.8%). 1 H NMR (300 MHz, DMSO- d 6) δ 9.18(d, J = 5.0 Hz, 1H), 7.76 (m,J = 5.1, 1.1 Hz, 1H), 3.77 – 3.62 (m, 1H), 2.45 – 2.32 (m, 2H), 2.22 – 2.03 (m, 3H), 1.92 – 1.75 (m, 1H).

[0176] Step 2: cis-5-((5-(3-((4-cyclobutylpyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazole-3-yl)amino 1,1-dioxide of 4-fluoro-2,3-dihydrobenzo[d]isothiazolium The title compound was synthesized in a procedure similar to that of Example 29. 1 H NMR (500 MHz, DMSO- d 6) δ =12.03 (s, 1H), 8.84 – 8.70 (m, 2H), 8.27 (s, 1H), 7.69 (t, J = 5.0 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.40 (d, J = 4.6 Hz, 1H), 5.83 (s, 1H), 5.62 (s, 1H), 4.40 (d, J = 5.1 Hz, 2H), 3.52-3.44 (m, 1H), 3.24-3.14 (m, 1H), 2.71 – 2.62 (m,1H), 2.28 – 2.17 (m, 2H), 2.13 – 1.99 (m, 4H), 1.98-1.90 (m, 2H), 1.90 – 1.79 (m, 2H), 1.79 – 1.69 (m, 1H). LC-MS (ESI): m / z [M+H]+ = 485.2.

[0177] Example 36: trans-5-((5-(3-((4-(tert-butyl)pyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: 4-(tert-butyl)-3-chloropyridazine Neopentanoic acid (6.1 g, 59.6 mmol), (NH4)2S2O8 (75.5 g, 331 mmol), and AgNO3 (45 g, 264.8 mmol) were added to a solution of 3-chloropyridazine hydrochloride (10 g, 66.2 mmol) in MeCN (475 mL) and H2O (475 mL). The resulting solution was stirred at 55 °C for 2 h under a nitrogen atmosphere. The solid was filtered off. The resulting mixture was concentrated under vacuum. The resulting solution was then extracted with 3 × 100 mL EtOAc. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography (EtOAc / PE = 16%) to give the product (2 g, 17.7%). 1 H NMR (300 MHz, DMSO- d 6)δ 9.15 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 5.2 Hz, 1H), 1.44 (s, 9H).

[0178] Step 2: trans-5-((5-(3-((4-(tert-butyl)pyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazole-3-yl) (amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ =12.07 (s, 1H), 8.76 (d, J = 4.9 Hz, 2H), 8.27 (t, J = 7.9 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 4.9 Hz, 1H), 5.88 (s, 1H), 5.79 (s, 1H), 4.41 (d, J = 4.4 Hz, 2H), 3.41-3.35 (m, 1H), 2.40-2.30 (m, 6.4 Hz, 2H), 2.28-2.22 (m, 1H), 2.12-2.04 (m, 1H), 1.94 – 1.83 (m, 1H), 1.79 – 1.68 (m, 1H), 1.36 (s, 9H). LC-MS (ESI): m / z [M+H]+ = 487.2.

[0179] Example 37: cis-5-((5-(3-((4-(tert-butyl)pyridazin-3-yl)oxy)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. ¹H NMR (500 MHz, DMSO-) d 6) δ =12.06 (s, 1H), 8.82 – 8.58 (m, 2H), 8.25 (s, 1H), 7.69 (s, 1H), 7.47 (d, J =8.6 Hz, 1H), 7.40 (d, J = 4.9 Hz, 1H), 5.82 (s, 1H), 5.76 – 5.57 (m, 1H), 4.40(d, J = 4.3 Hz, 2H), 3.23 – 3.15 (m, 1H), 2.79 – 2.71 (m, 1H), 2.20-2.06 (m,2H), 2.04-1.96 (m, 1H), 1.92 – 1.79 (m, 2H), 1.31 (s, 9H). LC-MS (ESI): m / z [M+H]+ = 487.2.

[0180] Example 38: cis-5-((5-(3-((6-(tert-butyl)pyrimidin-4-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ =12.03 (s, 1H), 8.72 (d, J = 2.2, 1H), 8.71 (d, J = 1.0, 1H), 8.26 (s, 1H), 7.69(t, J = 5.2, 1H), 7.47 (d, J = 8.6, 1H), 6.79 (d, J= 1.0, 1H), 5.85 (s, 1H), 5.49(s, 1H), 4.40 (d, J = 5.1, 2H), 3.15 (m, 1H), 2.70 – 2.60 (m, 1H), 2.08 (m,2H), 1.90 (m, 1H), 1.86 – 1.68 (m, 2H), 1.26 (s, 9H). LC-MS (ESI): m / z [M+H] + =487.3.

[0181] Example 39: cis-4-fluoro-5-((5-(3-(pyridin-3-yloxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: cis-5-((1-(tert-butyl)-3-(3-(pyridin-3-yloxy)cyclopentyl)-1H-pyrazol-5-yl)amino 1,1-dioxide of 4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium to trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d CMBP (137 mg, 0.57 mmol) was added to a solution of isothiazole 1,1-dioxide (100 mg, 0.19 mmol) and pyridine-3-phenol-methane (1 / 1) (21 mg, 0.19 mmol) in toluene (3 mL). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (110 mg, 93%). LC-MS (ESI): m / z [M+H] + = 607.4.

[0182] Step 2: cis-4-fluoro-5-((5-(3-(pyridin-3-yloxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2, 3-Dihydrobenzo[d]isothiazolium 1,1-dioxide FA (10 mL) was added to a stirred solution of cis-5-((1-(tert-butyl)-3-(3-(pyridin-3-yloxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (50 mg, 0.082 mmol), and the solution was stirred at 75 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution by EA to give 40 mg of product. The 40 mg residue was purified by preparative HPLC (Waters XSelect C18: RD-CO-094 column, with gradient elution of acetonitrile / water (containing 0.1% FA) (20%-40%) to give product (5 mg, 17.8%). ¹H NMR (500 MHz, DMSO- d 6) δ = 12.03 (s, 1H), 8.20(d, J = 2.4 Hz, 1H), 8.10 (d, J = 4.3 Hz, 1H), 7.86 (s, 1H), 7.44-7.32 (m, 4H), 5.92 (s, 1H), 5.06 – 4.96 (m, 1H), 4.44 (s, 2H), 3.80 (s, 1H), 3.29 – 3.20(m, 2H), 2.74 – 2.60 (m, 1H), 2.24-2.16 (m, 1H), 2.12-1.90 (m, 5H). LC-MS(ESI): m / z [M+H] + = 430.2.

[0183] Example 40: cis-4-fluoro-5-((5-(3-((2-methylpyridin-3-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 22. 1 H NMR (500 MHz, DMSO- d 6) δ =12.04 (s, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 8.11 (d, J = 4.6, 1H), 7.69 (t, J =5.0, 1H), 7.59 (s, 1H), 7.47 (d,J = 8.6, 1H), 7.40 (s, 1H), 5.84 (s, 1H), 5.02(s, 1H), 4.40 (d, J = 4.8, 2H), 3.21 – 3.17 (m, 1H), 2.63 (m, 1H), 2.38 (s, 3H), 2.14 – 1.98 (m, 2H), 1.96 – 1.76 (m, 3H). LC-MS (ESI): m / z [M+H] + = 444.2.

[0184] Example 41: cis-5-((5-(3-((4-cyclopropylpyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 22. 1 H NMR (500 MHz, DMSO- d 6) δ 12.04(s, 1H), 8.71 (s, 1H), 8.29-8.20 (m, 2H), 8.02 (d, J =5 Hz, 1H), 7.69 (t, J =10Hz, 1H), 7.47 (d, J =5 Hz, 1H), 6.77 (d, J =5 Hz, 1H), 5.85 (s, 1H), 5.08-5.00(m, 1H), 4.40 (d, J =5 Hz, 2H), 3.22-3.12 (m, 1H), 2.69-2.58 (m, 1H), 2.15-2.00(m, 3H), 2.00-1.79 (m, 3H), 1.02-0.89 (m, 2H), 0.76-0.66 (m, 2H). LC-MS (ESI): m / z [M+H] + = 470.2.

[0185] Example 42: cis-4-fluoro-5-((5-(3-((4-methylpyridin-3-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 22. 1 H NMR (500 MHz, DMSO- d 6) δ =12.02 (s, 1H), 8.72 (s, 1H), 8.48 (s, 1H), 8.38 (d, J = 5.1, 1H), 8.22 (s, 1H), 7.74 (s, 1H), 7.70 (s, 1H), 7.47 (d, J = 8.6, 1H), 5.85 (s, 1H), 5.14 (s, 1H), 4.40 (s, 2H), 3.27 – 3.15 (m, 1H), 2.70 – 2.61 (m, 1H), 2.30 (s, 3H), 2.17 –2.04 (m, 2H), 1.96 (m, 1H), 1.93 – 1.77 (m, 2H). LC-MS (ESI): m / z [M+H] + =444.34.

[0186] Example 43: cis-4-fluoro-5-((5-(3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide Step 1: cis-5-((3-(3-((4-bromopyridin-3-yl)oxy)cyclopentyl)-1-(tert-butyl)-1 H -pyrazole- 5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide to trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d CMBP (137 mg, 0.57 mmol) was added to a solution of isothiazole 1,1-dioxide (100 mg, 0.19 mmol) and 4-bromopyridine-3-phenol (33 mg, 0.19 mmol) in toluene (3 mL). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (117 mg, 90%). LC-MS (ESI): m / z [M+H] + =684.7.

[0187] Step 2: cis-5-((1-(tert-butyl)-3-(3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentane )-1H-pyrazole-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium-1,1-dioxide thing cis-5-((3-(3-((4-bromopyridin-3-yl)oxy)cyclopentyl)-1-(tert-butyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d A solution of isothiazole 1,1-dioxide (117 mg, 0.171 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxane (43 mg, 0.257 mmol) in dioxane (10 mL) was supplemented with Pd(dppf)Cl2 (13 mg, 0.017 mmol) and K2CO3 (71 mg, 0.513 mmol) in H2O (1 mL). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (73 mg, 66%). LC-MS (ESI): m / z [M+H] + = 646.4.

[0188] Step 3: cis-4-fluoro-5-((5-(3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1 H - Pyrazol-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to step 11 of Example 1. 1 H NMR (500 MHz, DMSO- d 6)δ = 12.03 (s, 1H), 8.71 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.15 (d, J = 4.7,1H), 7.69 (t, J = 5.1, 1H), 7.47 (d, J = 8.6, 1H), 7.18 (d, J = 4.7, 1H), 5.82 (s,1H), 5.24 (s, 2H), 5.06 (d, J = 3.7, 1H), 4.40 (d, J= 5.1, 2H), 3.20 – 3.09 (m,1H), 2.74 – 2.60 (m, 1H), 2.14 – 1.99 (m, 5H), 1.92 (m, 1H), 1.87 – 1.73 (m,2H). LC-MS (ESI): m / z [M+H] + = 470.3.

[0189] Example 44: cis-4-fluoro-5-((5-(3-((5-isopropylpyridin-3-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide Step 1: cis-5-((1-(tert-butyl)-3-(3-((5-isopropylpyridin-3-yl)oxy)cyclopentyl)-1 H -pyr (azolyl-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide Cis-5-((1-(tert-butyl)-3-(3-((5-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (120 mg, 0.185 mmol) was dissolved in THF (20 mL), and Pd / C (10% on carbon, 10 mg) was added. The reaction mixture was stirred at room temperature for 1 hour at 1 atm H2. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the product (120 mg, 99%). LC-MS (ESI): m / z [M+H] + = 648.5.

[0190] Step 2: cis-4-fluoro-5-((5-(3-((5-isopropylpyridin-3-yl)oxy)cyclopentyl)-1 H -pyrazole-3- (amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to step 11 of Example 1. 1 H NMR (500 MHz, DMSO- d 6)δ = 12.02 (s, 1H), 8.73 (s, 1H), 8.27 (s, 1H), 8.10 (d, J = 2.7, 1H), 8.07 (s,1H), 7.69 (t, J = 5.2, 1H), 7.47 (d, J= 8.6, 1H), 7.20 (s, 1H), 5.86 (s, 1H), 5.00 (s, 1H), 4.40 (d, J = 5.2, 2H), 3.21 – 3.10 (m, 1H), 2.92 (m, 1H), 2.67 –2.59 (m, 1H), 2.13 – 2.01 (m, 2H), 1.88 (m, 1H), 1.82 (m, 1H), 1.75 (m, 1H),1.22 (d, J = 6.9, 6H). LC-MS (ESI): m / z [M+H] + = 472.36.

[0191] Example 45: cis-5-((5-(3-((2-(tert-butyl)pyridin-3-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 22. 1 H NMR (500 MHz, DMSO- d 6) δ =12.05 (s, 1H), 8.72 (d, J = 1.9, 1H), 8.27 (s, 1H), 8.01 (m, 1H), 7.69 (t, J =5.1, 1H), 7.47 (d, J = 8.6, 1H), 7.31 (d, J = 8.3, 1H), 7.18 (m, 1H), 5.80 (s,1H), 5.05 – 4.91 (m, 1H), 4.40 (d, J = 5.1, 2H), 3.21 – 3.07 (m, 1H), 2.77 –2.67 (m, 1H), 2.16 – 2.10 (m, 1H), 2.10 – 2.02 (m, 1H), 2.00 – 1.90 (m, 1H),1.83 (m, 1H), 1.75 (m, 1H), 1.34 (s, 9H). LC-MS (ESI): m / z [M+H] + = 486.33.

[0192] Example 46: cis-4-fluoro-5-((5-(3-(pyridin-2-yloxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide Step 1: cis-5-((1-(tert-butyl)-3-(3-(pyridin-2-yloxy)cyclopentyl)-1 H -pyrazole-5-yl)amino )-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide cis-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide (170 mg, 0.322 mmol) was dissolved in DMF (8 mL) and NaH (38 mg, 0.966 mmol) was added. The mixture was stirred at room temperature for one hour. Then, 2-fluoropyridine (62 mg, 0.644 mmol) was added to DMF (2 mL), and the reaction mixture was stirred at 65 °C for 16 hours. The resulting mixture was cooled to room temperature, diluted with water, extracted with EA, and the combined organic phases were washed with water and then with brine. The mixture was dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 1:1) to give the product (80 mg, 41%). LC-MS (ESI): m / z [M+H] + = 606.2.

[0193] Step 2: cis-4-fluoro-5-((5-(3-(pyridin-2-yloxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2, 3-Dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to step 11 of Example 1. 1 H NMR (500 MHz, DMSO- d 6)δ = 12.02 (s, 1H), 8.72 (d, J = 2.0, 1H), 8.26 (s, 1H), 8.16 (dd, J = 5.0, 1.8,1H), 7.68 (m, 2H), 7.47 (d, J = 8.6, 1H), 6.95 (dd, J = 6.9, 5.1, 1H), 6.78 (d, J =8.3, 1H), 5.85 (s, 1H), 5.46 – 5.38 (m, 1H), 4.40 (d, J= 5.0, 2H), 3.19 – 3.10(m, 1H), 2.65 – 2.57 (m, 1H), 2.12 – 2.00 (m, 2H), 1.91 – 1.78 (m, 2H), 1.78– 1.71 (m, 1H). LC-MS (ESI): m / z [M+H] + = 430.31.

[0194] Example 47: cis-5-((5-(3-((4-(tert-butyl)pyridin-2-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide Step 1: cis-5-((1-(tert-butyl)-3-(3-(pyridin-2-yloxy)cyclopentyl)-1 H -pyrazole-5-yl)amino )-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide cis-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d A solution of isothiazole 1,1-dioxide (150 mg, 0.284 mmol) and 2-bromo-4-(tert-butyl)pyridine (61 mg, 0.284 mmol) in toluene (15 mL) was reacted with Pd2dba3 (26 mg, 0.028 mmol), Binap (35 mg, 0.059 mmol), and t-BuONa (82 mg, 0.852 mmol). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (90 mg, 48%). LC-MS (ESI): m / z [M+H] + = 662.5.

[0195] Step 2: cis-5-((5-(3-((4-(tert-butyl)pyridin-2-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl) (amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to step 11 of Example 1. 1 H NMR (500 MHz, DMSO- d 6)δ = 12.02 (s, 1H), 8.72 (d, J = 2.0, 1H), 8.25 (t, J = 7.4, 1H), 8.05 (d,J = 5.5,1H), 7.69 (t, J = 5.0, 1H), 7.47 (d, J = 8.6, 1H), 6.98 (dd, J = 5.5, 1.4, 1H), 6.68 (d, J = 1.3, 1H), 5.86 (s, 1H), 5.47 – 5.32 (m, 1H), 4.40 (d, J = 4.8, 2H),3.16 – 3.11 (m, 1H), 2.66 – 2.57 (m, 1H), 2.14 – 1.99 (m, 2H), 1.91 – 1.77(m, 2H), 1.77 – 1.69 (m, 1H), 1.24 (s, 9H). LC-MS (ESI): m / z [M+H] + = 486.33.

[0196] Example 48: cis-4-fluoro-5-((5-(3-(isoxazo-3-yloxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 22. 1 H NMR (500 MHz, DMSO- d 6) δ11.96 (s, 1H), 8.66 (s, 1H), 8.59 (d, J = 1.8 Hz, 1H), 8.18 (s, 1H), 7.62 (t, J =5.1 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 6.23 (d, J = 1.8 Hz, 1H), 5.77 (s, 1H), 5.01 (dd, J = 8.8, 4.6 Hz, 1H), 4.34 (d, J = 5.4 Hz, 2H), 3.11 – 3.03 (m, 1H), 2.61 – 2.52 (m, 1H), 2.05 – 1.85 (m, 3H), 1.77 – 1.69 (m, 2H). LC-MS (ESI): m / z[M+H] + = 420.3.

[0197] Example 49: cis-2-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)isoxazol-3(2H)-one The title compound was synthesized in a procedure similar to that of Example 21. 1 H NMR (500 MHz, DMSO- d 6) δ12.07 (s, 1H), 8.74 (s, 1H), 8.53 (dd, J = 2.6, 1.0 Hz, 1H), 8.25 (s, 1H), 7.70(s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 5.94 (d, J = 2.6 Hz, 1H), 5.87 (s, 1H), 4.89 –4.81 (m, 1H), 4.41 (d, J = 5.4 Hz, 2H), 3.18 - 3.02 (m, 1H), 2.44 - 2.38 (m,1H), 2.12 - 2.01 (m, 2H), 1.86 - 1.74 (m, 3H). LC-MS (ESI): m / z [M+H] + = 420.3.

[0198] Example 50: cis-4-fluoro-5-((5-(3-(isothiazolyl-3-yloxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 22. 1 H NMR (500 MHz, DMSO- d 6) δ 11.95 (s, 1H), 8.81 (d, J = 4.7 Hz, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 7.62 (t, J =5.1 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 4.7 Hz, 1H), 5.77 (s, 1H), 5.24 (dd,J = 9.5, 5.0 Hz, 1H), 4.34 (d, J = 5.3 Hz, 2H), 3.12 – 3.04 (m, 1H), 2.62 – 2.53 (m, 1H), 2.05 – 1.96 (m, 2H), 1.90 – 1.81 (m, 1H), 1.76 – 1.67(m, 2H). LC-MS (ESI): m / z [M+H] + = 436.3.

[0199] Example 51: cis-2-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)isothiazolyl-3(2H)-one The title compound was synthesized in a procedure similar to that of Example 21. 1 H NMR (500 MHz, DMSO- d 6) δ12.10 (s, 1H), 8.75 (s, 1H), 8.49 (d, J = 6.2 Hz, 1H), 8.26 (s, 1H), 7.70 (s,1H), 7.49 (d, J = 8.6 Hz, 1H), 6.19 (d, J = 6.2 Hz, 1H), 5.89 (s, 1H), 4.83 (d, J =8.0 Hz, 1H), 4.41 (d, J = 5.2 Hz, 2H), 3.24 - 3.18 (m, 1H), 2.20 - 2.10 (m,2H), 1.90 - 1.74 (m, 3H), 1.52 - 1.38 (m, 1H). LC-MS (ESI): m / z [M+H] + = 436.3.

[0200] Example 52: cis-4-fluoro-5-((5-(3-((4-(prop-1-en-2-yl)isothiazo-3-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide Step 1: 3-(benzyloxy)isothiazol K₂CO₃ (4.1 g, 29.7 mmol) was added to a solution of isothiazol-3-phenol (1.5 g, 14.8 mmol) and (bromomethyl)benzene (2.54 g, 14.8 mmol) in DMF (50 mL), and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water, extracted with EA, and the combined organic phases were washed with water and then with brine, dried over Na₂SO₄, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 20:1) to give the product (1.89 g, 67%). LC-MS (ESI): m / z [M+H] + = 192.1.

[0201] Step 2: 3-(benzyloxy)-4-bromoisothiazol NBS (932 mg, 5.24 mmol) was added to a solution of 3-(benzyloxy)isothiazolium (1.0 g, 5.24 mmol) in DMF (10 mL), and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water, extracted with EA, and the combined organic phases were washed with water and then with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure and dried under vacuum to give the crude product (1.25 g). LC-MS (ESI): m / z [M+H] + = 270.0.

[0202] Step 3: 3-(benzyloxy)-4-cyclopropylisothiazolium Pd(dppf)Cl2 (136 mg, 0.186 mmol) and Cs2CO3 (1.8 g, 5.58 mmol) were added to a solution of 3-(benzyloxy)-4-bromoisothiazol (500 mg, 1.86 mmol) and cyclopropylboronic acid (1.6 g, 18.6 mmol) in dioxane (20 mL) and H2O (2 mL). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with PE / EA (5:1) elution to give the product (222 mg, 52%). LC-MS (ESI): m / z [M+H] + = 232.0.

[0203] Step 4: 4-Cyclopropylisothiazol-3-phenol 3-(benzyloxy)-4-cyclopropylisothiazol (222 mg, 0.96 mmol) was dissolved in concentrated HCl aqueous solution (5 mL), and the reaction mixture was stirred at 50 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and dried under vacuum to give the product (126 mg, 93%). LC-MS (ESI): m / z [M+H] + = 141.7.

[0204] Step 5: cis-5-((1-(tert-butyl)-3-(3-((4-cyclopropylisothiazolyl-3-yl)oxy)cyclopentyl)-1 H - Pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide to trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d CMBP (137 mg, 0.57 mmol) was added to a solution of isothiazole 1,1-dioxide (100 mg, 0.19 mmol) and 4-cyclopropylisothiazol-3-phenol (27 mg, 0.19 mmol) in toluene (3 mL). The reaction mixture was stirred at 95 °C for 16 h under nitrogen. The resulting mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (90 mg, 73%). LC-MS (ESI): m / z [M+H] + = 652.4.

[0205] Step 6: cis-4-fluoro-5-((5-(3-((4-(prop-1-en-2-yl)isothiazo-3-yl)oxy)cyclopentyl)- 1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide cis-5-((1-(tert-butyl)-3-(3-(((4-cyclopropylisothiazo-3-yl)oxy)cyclopentyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d A solution of isothiazole 1,1-dioxide (90 mg, 0.138 mmol) was dissolved in DCM (1 mL), and TfOH (1 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was neutralized with aqueous Na2CO3 solution, extracted with EA, and the combined organic phases were washed with brine, dried over Na2SO4, and purified by column chromatography on silica gel (dichloromethane:methanol = 10:1) to give the product (6 mg, 9%). 1 H NMR (500 MHz, DMSO- d6) δ = 12.03 (s, 1H), 8.72 (s, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 7.69 (s, 1H), 7.47 (d, J = 8.6, 1H), 6.26 (M, 2H), 5.84 (s, 1H), 5.36 (m, 1H), 4.40 (s, 2H), 3.16 (m, 1H), 2.66 – 2.59 (m, 1H), 2.13 – 2.02(m, 2H), 1.93 (m, 1H), 1.88 – 1.80 (m, 2H), 1.76 (d, J = 6.0, 3H). LC-MS (ESI): m / z [M+H] + = 476.2.

[0206] Example 53: cis-5-((5-(3-((4-cyclopropylisothiazolyl-3-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide cis-5-((1-(tert-butyl)-3-(3-(((4-cyclopropylisothiazo-3-yl)oxy)cyclopentyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide (70 mg, 0.11 mmol) was dissolved in formic acid (3 mL), and the reaction mixture was stirred at 85 °C for 16 hours. The resulting mixture was cooled to room temperature, and the residue was redissolved in methanol (3 mL). K₂CO₃ (80 mg, 0.55 mmol) was added, and the mixture was stirred for another 30 min. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel (dichloromethane:methanol = 10:1) to give the product (9 mg, 17%). 1 H NMR (500 MHz, DMSO- d 6) δ = 12.03 (s, 1H), 8.71 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.69 (s, 1H), 7.47 (d, J = 8.6, 1H),5.85 (s, 1H), 5.33 (s, 1H), 4.40 (d, J0.83 (m, 2H), 0.64 (m, 2H). LC-MS (ESI): m / z [M+H] + = 476.4.

[0207] Example 54: cis-4-cyclopropyl-2-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[] d Isothiazol-5-yl)amino)-1 H -pyrazole-5-yl)cyclopentyl)isothiazol-3(2) H )-ketone The title compound was synthesized using a procedure similar to that of Example 21. LC-MS (ESI): m / z [M+H] + = 476.3.

[0208] Example 55: cis-4-fluoro-5-((5-(3-((4-isopropylisothiazolyl-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide Step 1: 3-(benzyloxy)-4-cyclopropylisothiazolium 3-(benzyloxy)-4-bromoisothiazol (1.34 g, 5 mmol) was dissolved in concentrated HCl aqueous solution (15 mL), and the reaction mixture was stirred at 50 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and dried under vacuum to give the product (850 mg, 95% yield). LC-MS (ESI): m / z [M+H] + = 180.1.

[0209] Step 2: cis-5-((3-(3-((4-bromoisothiazo-3-yl)oxy)cyclopentyl)-1-(tert-butyl)-1H-pyridine (Azol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide to trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1 H -pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[ dCMBP (1.37 g, 5.7 mmol) was added to a solution of isothiazole 1,1-dioxide (1 g, 1.9 mmol) and 3-(benzyloxy)-4-cyclopropylisothiazolium (340 mg, 1.9 mmol) in toluene (15 mL). The reaction mixture was stirred at 95 °C for 16 h under nitrogen. The resulting mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (916 mg, 70%). LC-MS (ESI): m / z [M+H] + = 690.2.

[0210] Step 3: cis-5-((1-(tert-butyl)-3-(3-((4-(prop-1-en-2-yl)isothiazolyl-3-yl)oxy)cyclo (pentyl)-1H-pyrazole-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium-1,1-dioxane compounds A mixture of cis-5-((3-(3-(((4-bromoisothiazol-3-yl)oxy)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (270 mg, 0.392 mmol), potassium trifluoro(prop-1-en-2-yl)borate (116 mg, 0.784 mmol), XPhos Pd G2 (31 mg, 0.039 mmol), and Cs2CO3 (383 mg, 1.176 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) was stirred in a sealed tube at 100 °C for 3 h under a nitrogen atmosphere. The solution was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (1:1) elution to obtain the product (240 mg, 94%). LC-MS (ESI): m / z [M+H] + = 652.3.

[0211] Step 4: cis-5-((1-(tert-butyl)-3-(3-((4-isopropylisothiazo-3-yl)oxy)cyclopentyl)-1H- Pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide A mixture of cis-5-((1-(tert-butyl)-3-(3-((4-(prop-1-en-2-yl)isothiazo-3-yl)oxy)cyclopentyl)-1H-pyrazole-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (60 mg, 0.092 mmol) and Pd / C (10 mg) in THF (10 mL) was stirred at 20 °C for 2 h under a H2 atmosphere. The mixture was filtered to give the product (50 mg, 83%). LC-MS (ESI): m / z [M+H] + = 654.4.

[0212] Step 5: cis-4-fluoro-5-((5-(3-((4-isopropylisothiazolyl-3-yl)oxy)cyclopentyl)-1H-pyrazole- 3-yl)amino)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide The title compound was synthesized in a procedure similar to step 11 of Example 1. 1 H NMR (500 MHz, DMSO- d 6)δ 12.03 (s, 1H), 8.72 (s, 1H), 8.45 (d, J = 0.6 Hz, 1H), 8.25 (s, 1H), 7.69 (t, J = 4.8 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 5.83 (s, 1H), 5.40-5.30 (m, 1H), 4.40(d, J = 4.6 Hz, 2H), 3.21 – 3.10 (m, 1H), 2.85-2.73 (m, 1H), 2.68 – 2.59 (m,1H), 2.13 – 1.99 (m, 2H), 1.97-1.89 (m 1H), 1.86 – 1.75 (m, 2H), 1.14 (dd, J =6.7, 3.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 478.23.

[0213] Example 56: cis-5-((5-(3-((4-(tert-butyl)isothiazolyl-3-yl)oxy)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolyl 1,1-dioxide Step 1: 3-(benzyloxy)-4-(tert-butyl)isothiazol CuI (150 mg, 0.785 mmol) and t-BuMgBr (30 mL, 15.7 mmol) were added to a solution of 3-(benzyloxy)-4-iodoisothiazol (5 g, 15.7 mmol) in THF (75 mL) at 0 °C. The mixture was stirred at 50 °C for 2 h. The reaction was quenched with NH4Cl solution (80 mL). The resulting solution was extracted with 3 × 50 mL EtOAc, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography using PE:EA (100:0 to 60:40) as elution. The residue was the product (400 mg, 12%). LCMS (ESI) m / z [M+H] + = 248.

[0214] Step 2: 4-(tert-butyl)isothiazol-3-phenol BBr3 (8 mL, 8 mmol) was added to a solution of 3-(benzyloxy)-4-(tert-butyl)isothiazol (400 mg, 1.6 mmol) in DCM (10 mL) for 1 h at 0 °C. The mixture was stirred at room temperature for 12 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with PE:EA (100:0 to 60:40) elution to give the product (136 mg, 53%). 1 H NMR (300 MHz, DMSO- d 6) δ 11.46 (s, 1H), 8.20 (d, J = 37.8 Hz, 1H), 1.27 (s, 9H). LCMS (ESI) m / z [M+H] + =158.

[0215] Step 3: cis-5-((5-(3-((4-(tert-butyl)isothiazolyl-3-yl)oxy)cyclopentyl)-1H-pyrazole-3- (amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 21. 1 H NMR (500 MHz, DMSO- d 6) δ =12.04 (s, 1H), 8.72 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.26 (s, 1H), 7.69 (t, J =5.0 Hz, 1H), 7.47 (d, J= 8.6 Hz, 1H), 5.81 (s, 1H), 5.42 – 5.23 (m, 1H), 4.40(d, J = 4.9 Hz, 2H), 3.19 – 3.10 (m, 1H), 2.72 – 2.61 (m, 1H), 2.15 – 1.99 (m,2H), 1.98-1.90 (m, 1H), 1.86-1.76 (m, 2H), 1.24 (s, 9H). LC-MS (ESI): m / z [M+H]+ = 492.2.

[0216] Example 57: cis-4-fluoro-5-((5-(3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)-1H-pyrazole-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: Isopropyl phenyl carbamate Phenyl chloroformate (2 g, 12.7 mmol) was added dropwise to a stirred solution of propane-2-amine (2 g) in DCM (100 mL) at 0 °C. The mixture was stirred at 0 °C for 2 hours. The desired product was detected by LCMS. The precipitated solid was collected by filtration and washed with water (2 × 50 mL). The resulting solid was dried under a nitrogen atmosphere to give phenyl isopropylcarbamate (2 g, 87.7 %). The crude product was used directly in the next step without further purification.

[0217] Step 2: N-Isopropylhydrazine formamide A solution of isopropyl phenyl carbamate (2 g, 17.1 mmol) and NH₂NH₂-H₂O (1.71 g, 34.2 mmol) in EtOH (20 mL) was stirred at 80 °C for 3 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give N-isopropylhydrazine carboxamide (1 g, 76.9%). The crude product was used directly in the next step without further purification.

[0218] Step 3: 4-Isopropyl-4H-1,2,4-triazol-3-ol A solution of 1-amino-3-methylurea (2.5 g, 28.059 mmol, 1 equivalent) in HCOOH (20 mL) was stirred at 105 °C for 36 h. The desired product was detected by LCMS. The resulting solution was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography and concentrated under reduced pressure to give 4-isopropyl-4H-1,2,4-triazol-3-ol (180 mg, 16.7%).

[0219] Step 4: cis-4-fluoro-5-((5-(3-((4-isopropyl-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)- 1H-pyrazole-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium-1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 22. 1 H NMR (500 MHz, DMSO- d 6) δ10.26 (s, 1H), 7.99 (s, 1H), 7.93 (d, J = 64.6 Hz, 2H), 7.86 (s, 1H), 6.70 (s,1H), 6.60 (d, J = 8.6 Hz, 1H), 5.71 (d, J = 12.4 Hz, 1H), 4.60 (s, 2H), 3.24 –3.11 (m, 2H), 2.66 – 2.59 (m, 3H), 2.46 – 2.38 (m, 1H), 2.20 – 2.11 (m, 1H),2.08 (dd, J = 14.3, 7.0 Hz, 1H), 2.02 – 1.93 (m, 1H), 1.88 (dd, J = 22.7, 10.3Hz, 1H), 1.79 – 1.66 (m, 1H), 1.16 (td, J = 7.5, 3.9 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 462.2.

[0220] Example 58: cis-4-fluoro-5-((5-(3-((4-(1-methylcyclopropyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)-1H-pyrazole-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 57. 1H NMR (500 MHz, DMSO- d 6) δ11.97 (s, 1H), 8.67 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 7.41(d, J = 8.6 Hz, 1H), 5.79 (s, 1H), 4.60 – 4.49 (m, 1H), 4.34 (s, 2H), 3.13 –3.02 (m, 1H), 2.28 (dt, J = 14.4, 7.4 Hz, 1H), 2.06 – 1.97 (m, 1H), 1.96 – 1.89(m, 1H), 1.82 (dt, J = 23.9, 11.9 Hz, 2H), 1.73 (dd, J = 18.3, 9.5 Hz, 1H), 1.31(s, 3H), 0.91 (t, J = 5.8 Hz, 2H), 0.73 (t, J = 6.0 Hz, 2H). LC-MS (ESI): m / z [M+H] + = 474.2.

[0221] Example 59: (cis)-5-((5-(3-((4-(tert-butyl)-4H-1,2,4-triazol-3-yl)oxy)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 57. 1 H NMR (500 MHz, DMSO- d 6) δ12.02 (s, 1H), 8.74 (s, 1H), 8.27 (t, J = 7.5 Hz, 1H), 8.20 (s, 1H), 7.69 (s,1H), 7.47 (d, J = 8.6 Hz, 1H), 5.85 (s, 1H), 5.10 (s, 1H), 4.40 (d, J= 4.8 Hz,2H), 3.18 – 3.04 (m, 1H), 2.69 – 2.56 (m, 1H), 2.10 – 1.95 (m, 2H), 1.89 (d, J = 13.4 Hz, 1H), 1.84 – 1.68 (m, 2H), 1.48 (s, 9H). LC-MS (ESI): m / z [M+H] + =476.2.

[0222] Example 60: cis-4-fluoro-5-((5-(3-((4-isopropyl-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: 4-Isopropyl-1H-pyrazole-3-ol Ethyl 2-cyano-3-methylbut-2-enoate (1.53 g, 10 mmol), anhydrous THF (30 mL), and triethylamine (204 mg, 2 mmol) were added to a round-bottom flask equipped with a stir bar under a nitrogen atmosphere. The mixture was cooled in an ice / water bath. DIBAL-H (30 mL, 30 mmol, 1.0 M in THF) was then added dropwise over 10–15 min. After the addition was complete, the cooling bath was removed, and the reaction was stirred for another 1 h before being cooled again in an ice / water bath. The reaction was then quenched with an aqueous solution of NaOH and water. The suspension was filtered through diatomaceous earth, washed with EA, and then the filtrate was concentrated under vacuum. The residue was dissolved in 2-propanol (15 mL), and hydrazine (2–4 equivalents) was added. The mixture was heated and stirred at 70 °C. The reaction was concentrated under vacuum, and the residue was purified by silica gel chromatography with elution of DCM / MeOH (20:1 to 5:1) to give the product (806 mg, 64% yield). LC-MS (ESI): m / z [M+H] + = 127.3.

[0223] Step 2: tert-butyl 3-hydroxy-4-isopropyl-1H-pyrazole-1-carboxylate A solution of 4-isopropyl-1H-pyrazole-3-ol (806 mg, 6.4 mmol), TEA (1.96 g, 19.2 mmol), and di-tert-butyl dicarbonate (1.4 g, 6.4 mmol) in EtOH (20 mL) was stirred at 80 °C for 3 h. The desired product was detected by LC-MS. The resulting mixture was concentrated under reduced pressure to give a crude product, which was washed with EA and PE to give the title compound (1.05 g, 73%). LC-MS (ESI): m / z [M+H] + = 227.4.

[0224] Step 3: cis-3-((3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1,1-dioxide-2, 3-Dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazole-3-yl)cyclopentyl)oxy)-4-isopropyl-1H-pyrazole-1- tert-butyl formate A mixture of trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (100 mg, 0.189 mmol), tert-butyl 3-hydroxy-4-isopropyl-1H-pyrazol-1-carboxylate (136 mg, 0.6 mmol), and cyanomethylenetributylphosphine (0.137 g, 0.568 mmol) in toluene (5 mL) was heated at 95 °C for 15 h under N2. After cooling to 25 °C, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EtOAc (1:1) elution to give the product (24 mg, 17.2%). LC-MS (ESI): m / z [M+H] + = 737.4.

[0225] Step 4: cis-4-fluoro-5-((5-(3-((4-isopropyl-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazolyl (Azol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to step 11 of Example 1. 1 H NMR (500 MHz, MeOD- d 4) δ 7.82 (s, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 9.3 Hz, 1H), 5.92 (s, 1H), 4.44 (s, 2H), 2.71 (dt, J = 13.5, 6.7 Hz, 1H), 2.64 – 2.54 (m, 1H), 2.25 (dt,J =14.8, 7.2 Hz, 1H), 2.19 – 2.13 (m, 1H), 2.03 (d, J = 9.6 Hz, 2H), 1.98 – 1.93(m, 2H), 1.58 (d, J = 8.2 Hz, 1H), 1.29 (m, 6H). LC-MS (ESI): m / z [M+H] + = 462.2.

[0226] Example 61: cis-5-((5-(3-((4-(tert-butyl)-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: Ethyl 2-formyl-3,3-dimethylbutyrate LDA (11 mL, 11 mmol) was added to a solution of ethyl 3,3-dimethylbutyrate (1.44 g, 10 mmol) in dry THF (20 mL) at -70 °C. The mixture was stirred at -70 °C for 30 min. A solution of ethyl formate (740 mg, 11 mmol) in dry THF (3 mL) was slowly added. The mixture was stirred at -70 °C for 2 h and then elevated to room temperature overnight. The mixture was poured into saturated NH4Cl and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude product was used for the next step without purification.

[0227] Step 2: 4-(tert-butyl)-1H-pyrazole-3-ol A solution of ethyl 2-formyl-3,3-dimethylbutyrate (2 g, 11.6 mmol) and NH₂NH₂-H₂O (2 g, 40 mmol) in EtOH (20 mL) was stirred at 80 °C for 3 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give 4-(tert-butyl)-1H-pyrazole-3-ol (0.8 g, 49.1%).

[0228] Step 3: 4-(tert-butyl)-3-hydroxy-1H-pyrazole-1-carboxylic acid tert-butyl ester A solution of 4-(tert-butyl)-1H-pyrazole-3-ol (0.8 g, 5.7 mmol), TEA (1.73 g, 17.1 mmol), and ditert-butyl dicarbonate (1.3 g, 5.7 mmol) in EtOH (20 mL) was stirred at 80 °C for 3 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure to give a crude product, which was washed with EA and PE to give the title compound (1 g, 76.9% yield).

[0229] Step 4: cis-5-((5-(3-((4-(tert-butyl)-1H-pyrazole-5-yl)oxy)cyclopentyl)-1H-pyrazole-3- (amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 60. 1 H NMR (500 MHz, DMSO- d 6) δ12.01 (s, 1H), 11.43 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.23 ​​(s, 1H), 7.69 (s,1H), 7.47 (d, J = 8.6 Hz, 1H), 7.19 (s, 1H), 5.81 (s, 1H), 5.16 – 4.98 (m, 1H), 4.40 (d, J = 4.4 Hz, 2H), 3.16 – 3.05 (m, 1H), 2.59 – 2.55 (m, 1H), 2.09 – 2.02(m, 1H), 1.99 – 1.88 (m, 2H), 1.77 (ddd, J = 14.7, 13.8, 7.6 Hz, 2H), 1.17 (s,9H). LC-MS (ESI): m / z [M+H] + = 475.2.

[0230] Example 62: cis-5-((5-(3-((1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ11.92 (d, J= 85.1 Hz, 2H), 8.73 (s, 1H), 8.24 (d, J = 16.2 Hz, 1H), 7.69 (t, J =5.1 Hz, 1H), 7.54 – 7.46 (m, 2H), 5.84 (s, 1H), 5.65 (d, J = 2.2 Hz, 1H), 4.94(s, 1H), 4.40 (d, J = 4.7 Hz, 2H), 3.15 – 3.05 (m, 1H), 2.59 – 2.52 (m, 1H), 2.07 – 1.85 (m, 3H), 1.82 – 1.71 (m, 2H). LC-MS (ESI): m / z [M+H] + = 419.3.

[0231] Example 63: cis-4-fluoro-5-((5-(3-((1-methyl-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ12.04 (s, 1H), 8.74 (s, 1H), 8.27 (t, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J =8.6 Hz, 1H), 7.20 (d, J = 1.9 Hz, 1H), 5.84 (s, 1H), 5.62 (d, J = 1.9 Hz, 1H), 4.79 (d, J = 2.6 Hz, 1H), 4.40 (d, J = 4.4 Hz, 2H), 3.49 (s, 3H), 3.20 – 3.12 (m,1H), 2.62 – 2.57 (m, 1H), 2.12 – 2.04 (m, 1H), 2.02 – 1.93 (m, 2H), 1.87 –1.80 (m, 2H). LC-MS (ESI): m / z [M+H] + = 433.3.

[0232] Example 64: cis-4-fluoro-5-((5-(3-((1-methyl-1H-pyrazol-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. ¹H NMR (500 MHz, DMSO-) d 6) δ =11.99 (s, 1H), 8.78 (s, 1H), 8.29 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.98 (d, J =7.3 Hz, 1H), 5.84 (s, 1H), 5.00 (s, 1H), 4.43 (s, 2H), 4.29 (s, 1H), 3.67 (s,1H), 3.12 – 3.02 (m, 1H), 2.78 (s, 3H), 2.50-2.40 (m, 1H), 2.10-2.00 (m, 1H), 1.97 – 1.84 (m, 1H), 1.78-1.66 (m, 2H), 1.64-1.52 (m, 5H), 1.48-1.38 (m, 4H). LC-MS (ESI): m / z [M+H] + = 433.2.

[0233] Example 65: cis-4-fluoro-5-((5-(3-((3-methyl-1) H -pyrazole-5-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ =11.99 (s, 1H), 11.50 (s, 1H), 8.72 (s, 1H), 8.27 (s, 1H), 7.69 (t, J = 5.1,1H), 7.47 (d, J= 8.6, 1H), 5.83 (s, 1H), 5.41 (s, 1H), 4.89 (s, 1H), 4.40 (d, J = 5.1, 2H), 3.08 (m, 1H), 2.64 (m, 1H), 2.13 (s, 3H), 2.02 (m, 1H), 1.94 (m,1H), 1.90 – 1.83 (m, 1H), 1.81 – 1.67 (m, 2H). LC-MS (ESI): m / z [M+H] + = 433.31.

[0234] Example 66: cis-4-fluoro-5-((5-(3-((3-methyl-1-phenyl-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. ¹H NMR (500 MHz, DMSO-) d 6) δ =12.06 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.23 ​​(s, 1H), 7.69 (t, J = 5.1 Hz, 1H),7.61 – 7.55 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.22 – 7.15(m, 1H), 5.82 (s, 1H), 5.70 (s, 1H), 4.88 (dd, J = 7.5, 4.4 Hz, 1H), 4.40 (d, J =5.0 Hz, 2H), 3.23 – 3.14 (m, 1H), 2.68 – 2.57 (m, 1H), 2.16 (s, 3H), 2.13 –2.08 (m, 1H), 2.06 – 1.98 (m, 2H), 1.95 – 1.88 (m, 1H), 1.88 – 1.78 (m, 1H). LC-MS (ESI): m / z [M+H] + = 509.2.

[0235] Example 67: cis-5-((5-(3-((1H-indazol-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ11.99 (brs, 1H), 8.75 (s, 1H), 8.34 – 8.17 (m, 1H), 7.70 (s, 1H), 7.61 (d, J =8.0 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.37 – 7.28 (m,2H), 6.99 (t, J = 7.4 Hz, 1H), 5.89 (s, 1H), 5.35-5.25 (m, 1H), 5.17 – 5.03 (m,1H), 4.41 (d, J = 2.8 Hz, 2H), 3.28-3.10 (m, 1H), 2.72 – 2.62 (m, 1H), 2.20 –1.98 (m, 4H), 1.98 – 1.82 (m, 2H). LC-MS (ESI): m / z [M+H] + = 469.30.

[0236] Example 68: Ethyl cis-5-((3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)oxy)-1H-pyrazol-4-carboxylic acid The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ12.54 (s, 1H), 11.96 (s, 1H), 8.71 (d, J = 1.9 Hz, 1H), 8.22 (t, J = 8.0 Hz, 1H),8.08 (s, 1H), 7.68 (s, 1H), 7.46 (d, J= 8.6 Hz, 1H), 5.87 (d, J = 2.1 Hz, 1H),5.18-5.06 (m, 1H), 4.40 (d, J = 4.3 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.20 –3.08 (m, 1H), 2.60-2.57 (m, 1H), 2.13 – 2.04 (m, 1H), 2.03 – 1.89 (m, 2H),1.86 – 1.75 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H). LC-MS (ESI): m / z [M+H] + = 491.27.

[0237] Example 69: cis-4-fluoro-5-((5-(3-((3-(trifluoromethyl)-1 H -pyrazole-5-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ =13.24 (s, 1H), 12.03 (s, 1H), 8.72 (d, J = 2.0, 1H), 8.25 (s, 1H), 7.69 (t, J =5.0, 1H), 7.48 (d, J = 8.6, 1H), 6.14 (s, 1H), 5.84 (s, 1H), 4.90 (s, 1H), 4.40(d, J = 4.9, 2H), 3.21 – 3.09 (m, 1H), 2.63 (m, 1H), 2.13 – 2.06 (m, 1H), 2.02(m, 1H), 1.93 (m, 1H), 1.85 – 1.61 (m, 2H). LC-MS (ESI): m / z [M+H] + = 487.21.

[0238] Example 70: (cis)-4-fluoro-5-((5-(3-((1-phenyl-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: 1-Phenylon-1H-pyrazole-5-ol Phenylated hydrazine (2.49 g, 23.1 mmol) was added to a solution of methyl 3-methoxyacrylate (3 g, 23.1 mmol). The reaction was stirred at 110 °C for 12 hours, then cooled to room temperature and concentrated to give the crude product. The residue was purified by silica gel column chromatography using PE / EtOAc (10:1 to 1:1) elution to give 1-phenyl-1H-pyrazole-5-ol (400 mg, 10.8%). LC-MS (ESI): m / z [M+H] + = 161.2.

[0239] Step 2: cis-4-fluoro-5-((5-(3-((1-phenyl-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol- 3-yl)amino)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 22. 1 H NMR (500 MHz, DMSO- d 6) δ12.04 (s, 1H), 8.73 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.27 (t, J = 8.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, 2H), 7.69 (s, 1H), 7.46 (dd, J = 16.9, 9.0 Hz, 3H), 7.22 (t, J = 7.4 Hz, 1H), 6.03 (d, J = 2.6 Hz, 1H), 5.87 (s, 1H), 5.10 (s, 1H), 4.40 (d, J = 2.9 Hz, 2H), 3.19 – 3.09 (m, 1H), 2.74 – 2.61 (m, 1H), 2.15 – 2.03 (m, 2H), 1.95 (d, J = 12.9 Hz, 1H), 1.88 – 1.69 (m, 2H). LC-MS (ESI): m / z [M+H] += 495.2.

[0240] Example 71: cis-5-((5-(3-((3-(tert-butyl)-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. ¹H NMR (500 MHz, DMSO-) d 6) δ =12.00 (s, 1H), 11.53 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 7.69 (t, J = 5.0 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 5.84 (s, 1H), 5.42 (s, 1H), 4.90 (s, 1H), 4.40(d, J = 5.0 Hz, 2H), 3.10 (dd, J = 16.6, 8.9 Hz, 1H), 2.58-2.54 (m, 1H), 2.06 –2.00 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.84 (m, 1H), 1.80-1.68 (m, 2H), 1.21(s, 9H). LC-MS (ESI): m / z [M+H] + = 475.2.

[0241] Example 72: cis-5-((5-(3-((4-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: cis-4-(tert-butyl)-3-((3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1, 1-Dioxide-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazole-3-yl)cyclopentyl)oxy)-1H-pyrazole- 1-Tert-butyl formate To a solution of trans-5-((1-(tert-butyl)-3-(3-hydroxycyclopentyl)-1H-pyrazole-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (264 mg, 0.5 mmol) in toluene (10 mL), tert-butyl 4-(tert-butyl)-3-hydroxy-1H-pyrazole-1-carboxylic acid (140 mg, 1 mmol) and CMBP (361 mg, 1.5 mmol) were added. The mixture was stirred at 95 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0-55%) elution to give the product (190 mg, 50.5%). LC-MS (ESI): m / z [M+H] + = 751.

[0242] Step 2: cis-5-((1-(tert-butyl)-3-(3-((4-(tert-butyl)-1H-pyrazol-5-yl)oxy)cyclopentane )-1H-pyrazole-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium-1,1-dioxide thing A mixture of cis-4-(tert-butyl)-3-((3-(1-(tert-butyl)-5-((4-fluoro-2-(4-methoxybenzyl)-1,1-dioxide-2,3-dihydrobenzo[d]isothiazolyl)amino)-1H-pyrazol-3-yl)cyclopentyl)oxy)-1H-pyrazol-1-carboxylic acid tert-butyl ester (190 mg, 0.25 mmol) in dioxane (10 mL) in 4 N HCl was stirred at room temperature for 3 h. The mixture was concentrated under vacuum to give the product (200 mg, crude), which was used directly in the next step without further purification. LC-MS (ESI): m / z [M+H] + = 651.

[0243] Step 3: cis-5-((1-(tert-butyl)-3-(3-((4-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)oxy) Cyclopentyl)-1H-pyrazole-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium-1,1-di oxides A solution of cis-5-((1-(tert-butyl)-3-(3-((4-(tert-butyl)-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (150 mg, 0.23 mmol) in DMF (5 mL) was mixed with Cs₂CO₃ (150 mg, 0.46 mmol) and CH₃I (49 mg, 0.28 mmol). The mixture was stirred at room temperature for 16 h. The mixture was diluted with H₂O (50 mL) and extracted with EA (3 × 30 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0-65%) as elution to give the product (65 mg, 39.2%). LC-MS (ESI): m / z [M+H] + = 665.3.

[0244] Step 4: cis-5-((5-(3-((4-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H- Pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide A mixture of cis-5-((1-(tert-butyl)-3-(3-((4-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide in FA (10 mL) was stirred at 75 °C for 16 h. The mixture was concentrated under vacuum. The residue was dissolved in MeOH (10 mL) and K₂CO₃ (58 mg) was added. The mixture was stirred at room temperature for 30 min. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC to give the product (10.55 mg, 22.1%). 1 H NMR (500 MHz, DMSO- d 6) δ 11.42 (s, 1H), 7.96-7.83 (m, 1H), 7.59-7.53 (m, 1H), 7.44 (t, J=5 Hz,1H), 7.17 (s, 1H), 5.62 (s, 1H), 5.07-5.01 (m, 1H), 4.38 (s, 2H), 3.27 (s,3H), 3.13-3.03 (m, 1H), 2.57-2.55 (m, 2H), 2.08-1.99 (m, 1H), 1.96-1.84 (m, 2H), 1.82-1.71 (m, 2H), 1.12 (s, 9H). LC-MS (ESI): m / z [M+H] + = 489.2.

[0245] Example 73: cis-4-fluoro-5-((5-(3-((3-isopropyl-1H-pyrazol-4-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ 12.00(s, 1H), 8.72 (s, 1H), 8.31-8.20 (m, 1H), 7.69 (t, J =5 Hz, 1H), 7.47 (t, J =10Hz, 1H), 7.26 (s, 1H), 5.83 (s, 1H), 4.54-4.47 (m, 1H), 4.40 (d, J =5 Hz, 2H),3.15-3.04 (m, 1H), 2.93-2.81 (m, 1H), 2.49-2.46 (m, 2H), 2.09-1.99 (m, 1H),1.94-1.83 (m, 2H), 1.82-1.70 (m, 2H), 1.20-1.12 (m, 6H). LC-MS (ESI): m / z [M+H] + = 461.2.

[0246] Example 74: cis-5-((5-(3-((3-(tert-butyl)-1H-pyrazol-4-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound in racemic form was synthesized in a procedure similar to that in Example 24, and further separated by chiral preparative HPLC to obtain: Enantiomer 1 (Example 74a, 97.2% ee); retention time: 11.153 min. 1 H NMR (500 MHz, DMSO- d 6) 12.00 (s, 1H), 11.90-11.6 (m, 1H), 8.72 (s, 1H), 8.26 (t, J =10 Hz, 1H), 7.68 (t, J =5 Hz, 1H), 7.46 (d, J =5 Hz, 1H), 7.28 (s, 1H), 5.81 (s, 1H), 4.58-4.50 (m, 1H), 4.40 (d, J =10 Hz, 2H), 3.13-3.04 (m, 1H), 2.61-2.55 (m,1H), 2.10-2.00 (m, 1H), 1.95-1.84 (m, 2H), 1.82-1.69 (m, 2H), 1.23 (m, 9H). LC-MS (ESI): m / z [M+H] + = 475.2.

[0247] Enantiomer 2 (Example 74b, 100% ee); retention time: 13.671 min. 1 H NMR (500 MHz, DMSO- d 6) 12.00 (s, 1H), 11.77 (s, 1H), 8.72 (s, 1H), 8.26 (t, J =5 Hz, 1H), 7.68 (t, J =5 Hz, 1H), 7.46 (d, J =5 Hz, 1H), 7.35-7.18 (m, 1H), 5.81 (s, 1H), 4.62-4.45 (m, 1H), 4.40 (d, J =10 Hz, 2H), 3.14-3.02 (m, 1H), 2.61-2.56 (m,1H), 2.11-1.99 (m, 1H), 1.97-1.84 (m, 2H), 1.82-1.67 (m, 2H), 1.23 (m, 9H). LC-MS (ESI): m / z [M+H]+ = 475.2.

[0248] Chiral analysis method: Column: YMC Cellulose-C, 4.6 250 mm 5 μm; Mobile phase: A is Hex and B is EtOH (0.1% 2M NH3MeOH); Gradient: Mobile phase A: Mobile phase B = 80:20 (v / v); HPLC equipment: HPLC-Agilent, back pressure: 100 bar; Column temperature: 35℃.

[0249] Chiral preparative HPLC conditions: YMC Cellulose-C, 4.6 250 mm 5 μm; Mobile phase: A is Hex and B is EtOH (0.2% 2M NH3MeOH); Gradient: Mobile phase A: Mobile phase B = 80:20 (v / v); Flow rate: 18 mL / min; Wavelength: UV 254 nm and 280 nm; Preparative HPLC equipment: Preparative HPLC-Gilson; Back pressure: 100 bar; Column temperature: 25℃.

[0250] Example 75: cis-5-((5-(3-((3,5-dimethyl-1H-pyrazol-4-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. ¹H NMR (500 MHz, DMSO-) d 6) δ =11.99 (s, 2H), 8.74 (s, 1H), 8.27 (s, 1H), 7.69 (t, J = 5.1 Hz, 1H), 7.48 (d, J =8.6 Hz, 1H), 5.87 (s, 1H), 4.41 (d, J = 5.1 Hz, 3H), 3.12-3.02 (m, 1H), 2.42 –2.35 (m, 2H), 2.06 (s, 6H), 2.02-1.99 (m, 1H), 1.92 – 1.71 (m, 5H). LC-MS(ESI): m / z [M+H] + = 447.2.

[0251] Example 76: cis-5-((5-(3-((1H-pyrazol-4-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ =12.34 (s, 1H), 12.00 (s, 1H), 8.73 (s, 1H), 8.27 (t, J = 7.2, 1H), 7.69 (t, J =4.5, 1H), 7.47 (d, J = 8.6, 1H), 7.37 (s, 1H), 7.25 (s, 1H), 5.84 (s, 1H), 4.59– 4.52 (m, 1H), 4.40 (d, J = 4.3, 2H), 3.14 – 3.02 (m, 1H), 2.54 (m, 1H), 2.04(m, 1H), 1.92 (m, 2H), 1.82 – 1.67 (m, 2H). C-MS (ESI): m / z [M+H] + = 419.3.

[0252] Example 77: cis-4-fluoro-5-((5-(3-((1-methyl-1) H -pyrazole-4-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 21. 1 H NMR (500 MHz, DMSO- d 6) δ =12.00 (s, 1H), 8.72 (s, 1H), 8.27 (t, J = 7.7, 1H), 7.69 (t, J = 5.1, 1H), 7.47(d, J= 8.6, 1H), 7.40 (s, 1H), 7.14 (s, 1H), 5.83 (s, 1H), 4.57 – 4.48 (m,1H), 4.40 (d, J = 5.1, 2H), 3.72 (s, 3H), 3.14 – 3.03 (m, 1H), 2.54 (m, 1H), 2.03 (m, 1H), 1.90 (m, 2H), 1.80 – 1.67 (m, 2H). LC-MS (ESI): m / z [M+H] + =433.28.

[0253] Example 78: cis-4-fluoro-5-((5-(3-((1-isopropyl-1H-pyrazol-4-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 21. ¹H NMR (500 MHz, DMSO-) d 6) δ =12.02 (s, 1H), 8.75 (d, J = 1.9 Hz, 1H), 8.27 (s, 1H), 7.71 (s, 1H), 7.48 (d, J =10.7 Hz, 2H), 7.15 (s, 1H), 5.84 (s, 1H), 4.59 – 4.50 (m, 1H), 4.41 (d, J = 3.5Hz, 2H), 4.37-4.30 (m, 1H), 3.15 – 3.02 (m, 1H), 2.57 – 2.52 (m, 1H), 2.12 –2.00 (m, 1H), 1.98-1.86 (m, 2H), 1.82 – 1.66 (m, 2H), 1.35 (d, J = 6.7 Hz, 6H). LC-MS (ESI): m / z [M+H]+ = 461.2.

[0254] Example 79: cis-4-fluoro-5-((5-(3-((3-methyl-1H-pyrazol-4-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 24. 1 H NMR (500 MHz, DMSO- d 6) δ 11.93 (s, 2H), 8.66 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 11.6 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.21 (s, 1H), 5.78 (s, 1H), 4.46 – 4.40 (m, 1H), 4.34(d, J = 4.3 Hz, 2H), 3.02 (dt, J = 17.7, 9.0 Hz, 1H), 2.42 – 2.37 (m, 1H), 2.01 –1.93 (m, 4H), 1.85 – 1.77 (m, 2H), 1.76 – 1.64 (m, 2H). LC-MS (ESI): m / z [M+H] + = 433.2.

[0255] Example 80: cis-5-((5-(3-((3-(tert-butyl)-5-methyl-1 H -pyrazole-4-yl)oxy)cyclopentyl)-1 H -pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide Step 1: 1-(benzyloxy)-3,3-dimethylbut-2-one NaH (60% dispersion in mineral oil, 2.0 g, 50.27 mmol) was added to a solution of phenylmethanol (4.5 g, 41.67 mmol) in THF (80 mL) at 0 °C, and the mixture was stirred for 30 min. Then, 1-bromo-3,3-dimethylbutanone (5.0 g, 27.93 mmol) was added to THF (20 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The resulting mixture was quenched with saturated NH4Cl aqueous solution, extracted with EA, dried over Na2SO4, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 10:1) to give the product (3.38 g, 59%). LC-MS (ESI): m / z [M+Na] + =229.1.

[0256] Step 2: 2-(benzyloxy)-1-(dimethylamino)-4,4-dimethylpent-1-en-3-one 1-(benzyloxy)-3,3-dimethylbut-2-one (3.38 g, 16.4 mmol) was dissolved in 1,1-dimethoxy- N , N The mixture was stirred in dimethyl methylamine (50 mL) at 100 °C for 16 hours. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and dried under vacuum to give the crude product (4.2 g). LC-MS (ESI): m / z [M+H] + = 262.1.

[0257] Step 3: 4-(benzyloxy)-3-(tert-butyl)-1 H -Pyrazole 2-(benzyloxy)-1-(dimethylamino)-4,4-dimethylpent-1-en-3-one (4.2 g crude) and hydrazine hydrate (5 mL) were dissolved in ethanol (50 mL), and the reaction mixture was stirred at 55 °C for 3 hours. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate d = 1:1) to give the product (550 mg, 15% (2 steps)). LC-MS (ESI): m / z [M+H] + = 231.1.

[0258] Step 4: 4-(benzyloxy)-5-bromo-3-(tert-butyl)-1 H -Pyrazole 4-(benzyloxy)-3-(tert-butyl)-1 H A solution of pyrazole (50 mg, 0.217 mmol) was dissolved in DMF (2 mL), and NBS (41 mg, 0.228 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water, extracted with EA, and the combined organic phases were washed with water and then with brine. The mixture was dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 3:1) to give the product (27 mg, 40%). LC-MS (ESI): m / z [M+H] + = 309.2.

[0259] Step 5: 4-(benzyloxy)-5-bromo-3-(tert-butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H -Pyrazole and 4-(benzyloxy)-3-bromo-5-(tert-butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyr azole At 0°C, 4-(benzyloxy)-5-bromo-3-(tert-butyl)-1 Hβ-pyrazole (250 mg, 0.81 mmol) was added to a solution in DMF (5 mL) with NaH (60% dispersion in mineral oil, 40 mg, 0.97 mmol), and the mixture was stirred for 30 min. SEMCl (150 mg, 0.89 mmol) was then added, and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was diluted with water, extracted with EA, and the combined organic phases were washed with water and then with brine. The mixture was dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 4:1) to give the product (300 mg, 85%). LC-MS (ESI): m / z [M+H] + = 439.1.

[0260] Step 6: 4-(benzyloxy)-3-(tert-butyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl (base)-1 H -Pyrazole and 4-(benzyloxy)-5-(tert-butyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H -Pyrazole 4-(benzyloxy)-5-bromo-3-(tert-butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -Pyrazole and 4-(benzyloxy)-3-bromo-5-(tert-butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H A solution of pyrazole (300 mg, 0.68 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaboranecyclohexane (3.5 M, 0.4 mL, 1.37 mmol in THF) in THF (10 mL) was added to a solution of Pd(PPh3)4 (80 mg, 0.068 mmol) and KOH (76 mg, 1.36 mmol) in H2O (1 mL). The reaction mixture was stirred at 100 °C for 1 hour under nitrogen. The resulting mixture was cooled to room temperature, diluted with water, extracted with EA, and the combined organic phases were washed with water and then with brine, dried over Na2SO4, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 4:1) to give the product (93 mg, 37%). LC-MS (ESI): m / z [M+H] + = 375.3.

[0261] Step 7: 3-(tert-butyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4- Alcohols and 5-(tert-butyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-ol 4-(benzyloxy)-3-(tert-butyl)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-Pyrazole and 4-(benzyloxy)-5-(tert-butyl)-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H β-pyrazole (93 mg, 0.25 mmol) was dissolved in THF (10 mL), and Pd / C (10%, 30 mg on carbon) was added. The reaction mixture was stirred at room temperature for 2 hours at 1 atm H2. The resulting mixture was filtered, the filtrate was concentrated, and dried under vacuum to give the product (61 mg, 86%). LC-MS (ESI): m / z [M+H] + = 285.3.

[0262] Step 8: cis-5-((5-(3-((3-(tert-butyl)-5-methyl-1 H -pyrazole-4-yl)oxy)cyclopentyl)-1 H - Pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 60. 1 H NMR (500 MHz, DMSO- d 6) δ =12.02 (s, 1H), 11.70 (s, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 7.69 (s, 1H), 7.48(d, J = 8.6, 1H), 5.85 (s, 1H), 4.56 – 4.49 (m, 1H), 4.41 (s, 2H), 3.09 – 3.01(m, 1H), 2.47 – 2.43 (m, 1H), 2.13 (s, 3H), 2.06 – 1.99 (m, 1H), 1.95 – 1.90 (m, 1H), 1.90 – 1.85 (m, 1H), 1.84 – 1.76 (m, 2H), 1.26 (s, 9H). LC-MS (ESI): m / z [M+H] + = 489.3.

[0263] Example 81: cis-1-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl)amino)-1H-pyrazole-5-yl)cyclopentyl)-3,3-dimethylpyrrolidine-2,5-dione Step 1: 1-Isopropylimidazolidine-2,4-dione Isopropylamine (3.54 g, 60 mmol) was added to a solution of N-carbamoyl-2-chloroacetamide (4.1 g, 30 mmol) in DMF (100 mL) at room temperature. The resulting mixture was stirred at 135 °C for 6 h under nitrogen. DMF was removed under vacuum, and the residue was purified by column chromatography with DCM / EA = 2:1 elution to give the product (1.07 g, 25% yield). LC-MS (ESI): m / z [M+H] + = 143.3.

[0264] Step 2: cis-(1-(tert-butyl)-3-(3-(3-isopropyl-2,5-dioxoimidazolidine-1-yl)cyclopentyl)- 1H-pyrazole-5-yl) benzyl carbamate DIAD (731 mg, 4.2 mmol) was added dropwise to a solution of 1-isopropylimidazolium-2,4-dione (596 mg, 4.2 mmol), trans-4-nitrobenzoic acid 3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (1 g, 2.8 mmol), and triphenylphosphine (1.1 g, 4.2 mmol) in THF (50 mmol) at 0 °C. The mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by column chromatography with PE / EA = 1:1 elution to give the product (1.09 g, 81% yield). LC-MS (ESI): m / z [M+H] + =482.4.

[0265] Step 3: cis-(1-(tert-butyl)-3-(3-(3-isopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl) Cyclopentyl)-1H-pyrazole-5-yl)benzyl carbamate A solution of cis-(1-(tert-butyl)-3-(3-(3-isopropyl-2,5-dioxoimidazol-1-yl)cyclopentyl)-1H-pyrazole-5-yl)carbamate (100 mg, 0.2 mmol) in toluene (3 mL) was reacted with sodium bis(2-methoxyethoxy)aluminum hydride (0.6 mL, 2 mmol, 3.6 M in toluene). The resulting solution was stirred at room temperature for 1 h. The reaction was quenched with aqueous NH4Cl solution and extracted with EA (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography with PE / EA = 2:3 elution to give the product (53 mg, 57% yield). LC-MS (ESI): m / z [M+H] + = 466.4.

[0266] Step 4: cis-1-(3-(5-amino-1-(tert-butyl)-1H-pyrazole-3-yl)cyclopentyl)-3-isopropylimidazolium Alkyl-2-one cis-(1-(tert-butyl)-3-(3-(3-isopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)cyclopentyl)-1H-pyrazole-5-yl)carbamate (150 mg, 0.32 mmol) was dissolved in MeOH (10 mL), and Pd / C (10% on carbon, 200 mg) was added. The reaction mixture was stirred at room temperature for 2 hours at 1 atm H2. After filtration, the filtrate was concentrated to give the product (103 mg, 91%). LC-MS (ESI): m / z [M+H] + = 334.5.

[0267] Step 5: cis-1-(3-(1-(tert-butyl)-5-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazide) (Azol-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl)-3-isopropylimidazolidine-2-one A solution of cis-1-(3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)-3-isopropylimidazolidine-2-one (174 mg, 0.5 mmol) and 4-bromo-3-fluorobenzenesulfonamide (200 mg, 0.75 mmol) in dioxane (5 mL) was supplemented with Pd2dba3 (46 mg, 0.05 mmol), Xantphos (30 mg, 0.05 mmol), and K3PO4 (320 mg, 1.5 mmol). The reaction mixture was stirred at 90 °C for 6 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with 100% EA elution to give the product (96 mg, 37%). LC-MS (ESI): m / z [M+H] + = 519.3.

[0268] Step 6: cis-1-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazo-5-yl)amino 1H-pyrazole-5-yl)cyclopentyl)-3-isopropylimidazolidine-2-one A solution of cis-1-(3-(1-(tert-butyl)-5-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-3-yl)cyclopentyl)-3-isopropylimidazolidine-2-one (96 mg, 0.185 mmol) in DCM (15 mL) was mixed with TfOH (3 mL). The mixture was stirred at room temperature for 2 h. The mixture was quenched at 0 °C with an aqueous solution of NaHCO3 (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography with PE / EA (0% to 100%) to give the product (9.4 mg, 11% yield). 1 H NMR (500 MHz, DMSO- d 6) δ 11.95 (s, 1H), 8.65 (d, J = 2.6 Hz, 1H), 8.17 (s, 1H), 7.62 (t, J = 5.2 Hz, 1H), 7.41 (d, J = 8.6 Hz,1H), 5.78 (s, 1H), 4.34 (d, J = 5.4 Hz, 2H), 3.84 (p, J = 6.7 Hz, 1H), 3.21 –3.09 (m, 4H), 3.00 (p, J = 8.0 Hz, 1H), 2.02 (dt, J = 13.0, 6.9 Hz, 1H), 1.95 (d, J = 7.7 Hz, 1H), 1.72 (dt, J = 13.1, 8.0 Hz, 1H), 1.67 – 1.51 (m, 1H), 0.96 (dd, J = 6.7, 2.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 463.4.

[0269] Example 82: cis-3-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-1-isopropylimidazolidine-2,4-dione Step 1: cis-3-(3-(5-amino-1-(tert-butyl)-1H-pyrazole-3-yl)cyclopentyl)-1-isopropylimidazolium Alkyl-2,4-dione cis-(1-(tert-butyl)-3-(3-(3-isopropyl-2,5-dioxoimidazol-1-yl)cyclopentyl)-1H-pyrazole-5-yl)carbamate (150 mg, 0.31 mmol) was dissolved in MeOH (10 mL), and Pd / C (10 wt%, 100 mg) was added. The reaction mixture was stirred at room temperature for 2 hours at 1 atm H2. After filtration, the filtrate was concentrated to give the product (99 mg, 92%). LC-MS (ESI): m / z [M+H] + = 348.5.

[0270] Step 2: cis-3-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazo-5-yl)amino 1H-pyrazole-5-yl)cyclopentyl)-1-isopropylimidazolidine-2,4-dione The title compound was synthesized in a procedure similar to that of Example 81. 1 H NMR (500 MHz, DMSO- d 6) δ 12.01 (s, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.28 (s, 1H), 7.69 (t, J = 5.2 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 5.86 (s, 1H), 4.52 – 4.43 (m, 1H), 4.41 (d, J = 5.1 Hz, 2H), 4.13 (p, J = 6.7 Hz, 1H), 3.90 (s, 2H), 3.07 (q, J = 8.8 Hz, 1H), 2.16 (t, J =9.1 Hz, 2H), 2.11 – 2.01 (m, 2H), 1.98 – 1.84 (m, 2H), 1.12 (d, J = 6.7 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 477.3.

[0271] Example 83: cis-1-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl)-3-isopropyl-1,3-dihydro-2H-imidazol-2-one Step 1: cis-1-(3-(5-amino-1-(tert-butyl)-1H-pyrazole-3-yl)cyclopentyl)-3-isopropyl-1,3- dihydro-2H-imidazol-2-one cis-(1-(tert-butyl)-3-(3-(3-isopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)cyclopentyl)-1H-pyrazole-5-yl)carbamate (150 mg, 0.32 mmol) was dissolved in EA (10 mL), and Pd / C (10% on carbon, 200 mg) was added. The reaction mixture was stirred at room temperature for 1 hour at 1 atm H2. After filtration, the filtrate was concentrated to give the product (88 mg, 83%). LC-MS (ESI): m / z [M+H] + = 332.5.

[0272] Step 2: 1-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazo-5-yl)amino)-1H- Pyrazol-5-yl)cyclopentyl)-3-isopropyl-1,3-dihydro-2H-imidazol-2-one The title compound was synthesized in a procedure similar to that of Example 81. 1 H NMR (500 MHz, DMSO- d 6) δ 12.07 (s, 1H), 8.74 (d, J = 2.6 Hz, 1H), 8.24 (s, 1H), 7.69 (t, J = 5.2 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 6.60 (s, 2H), 5.88 (s, 1H), 4.49 (p, J = 8.0 Hz, 1H), 4.41 (d, J = 5.1 Hz, 2H), 4.19 (h, J = 6.8 Hz, 1H), 3.20 – 3.13 (m, 1H), 2.33(dt, J = 13.2, 7.2 Hz, 1H), 2.12 - 2.05 (m, 2H), 1.89 - 1.72 (m, 3H), 1.21 (d, J = 6.8 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 461.3.

[0273] Example 84: cis-3-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl)amino)-1H-pyrazol-5-yl)cyclopentyl)-5,5-dimethylimidazolidine-2,4-dione The title compound in racemic form was synthesized in a procedure similar to that in Example 81 and separated by chiral HPLC to obtain: Enantiomer 1 (Example 84a, 100% ee); retention time: 4.694 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 8.73 (s, 1H), 8.28 (s, 2H), 7.68 (t, J = 5.3 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 5.87 (s, 1H), 4.45 (d, J = 8.0 Hz, 1H), 4.40 (d, J = 5.2Hz, 2H), 3.09 (s, 1H), 2.20 – 2.10 (m, 2H), 2.09 – 2.02 (m, 2H), 1.96 – 1.89(m, 2H), 1.26 (s, 6H). LC-MS (ESI): m / z [M+H] + = 463.3.

[0274] Enantiomer 2 (Example 84b, 100% ee); retention time: 11.253 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 8.73 (s, 1H), 8.28 (s, 2H), 7.68 (t, J = 5.3 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 5.87 (s, 1H), 4.45 (d, J = 8.0 Hz, 1H), 4.40 (d, J = 5.2Hz, 2H), 3.09 (s, 1H), 2.20 – 2.10 (m, 2H), 2.09 – 2.02 (m, 2H), 1.96 – 1.89(m, 2H), 1.26 (s, 6H). LC-MS (ESI): m / z [M+H] + = 463.3.

[0275] Chiral analysis method: Column: CHIRALPAK IF-3 4.6 250 mm 5 μm; Mobile phase: A is MtBE (0.1% DEA) and B is MeOH:DCM = 1:1; Gradient: Mobile phase A: Mobile phase B = 50:50 (v / v); HPLC equipment: HPLC-Agilent; Column temperature: 35℃.

[0276] Chiral preparative HPLC conditions: CHIRALPAK IF-3 20 250 mm 5 μm; Mobile phase: A is MtBE (0.1% DEA) and B is MeOH:DCM=1:1; Gradient: Mobile phase A: Mobile phase B = 50:50 (v / v); Flow rate: 20 mL / min; Wavelength: UV 220 nm; Preparative HPLC equipment: Preparative HPLC-Gilson; Column temperature: 25℃.

[0277] Example 85: cis-1-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl)amino)-1H-pyrazol-5-yl)cyclopentyl)-4,4-dimethylimidazolidine-2-one The title compound was synthesized in a procedure similar to that of Example 81. 1 H NMR (500 MHz, DMSO- d 6) δ12.01 (s, 1H), 8.71 (s, 1H), 8.25 (s, 1H), 7.68 (d, J = 4.6 Hz, 1H), 7.47 (d, J =8.5 Hz, 1H), 6.39 (s, 1H), 5.85 (s, 1H), 4.40 (d, J = 5.1 Hz, 2H), 4.23 (d, J =9.5 Hz, 1H), 3.11 - 3.02 (m, 2H), 2.48 - 2.41 (m, 1H), 2.11 - 2.00 (m, 2H), 1.82 - 1.74 (m, 1H), 1.69 - 1.59 (m, 3H), 1.17 (d, J = 2.6 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 449.3.

[0278] Example 86: cis-3-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl)amino)-1H-pyrazol-5-yl)cyclopentyl)-1,5,5-trimethylimidazolidine-2,4-dione The title compound was synthesized in a procedure similar to that of Example 81. 1 H NMR (500 MHz, DMSO- d 6) δ 12.01 (s, 1H), 8.74 (d, J = 2.6 Hz, 1H), 8.28 (s, 1H), 7.69 (t, J = 5.2 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 5.87 (s, 1H), 4.48 (ddd, J = 14.5, 9.5, 7.0 Hz, 1H),4.41 (d, J = 5.1 Hz, 2H), 3.14 – 3.04 (m, 1H), 2.79 (s, 3H), 2.22 – 2.10 (m,2H), 2.10 – 1.99 (m, 2H), 1.99 – 1.88 (m, 2H), 1.28 (d, J = 2.4 Hz, 6H). LC-MS(ESI): m / z [M+H] + = 477.3.

[0279] Example 87: cis-1-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazo-5-yl)amino)-1H-pyrazole-5-yl)cyclopentyl)-3,3-dimethylpyrrolidine-2,5-dione The title compound was synthesized in a procedure similar to that of Example 21. 1 H NMR (500 MHz, DMSO- d 6) δ 12.02(s, 1H), 8.74 (s, 1H), 8.29 (t, J =5 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J=10 Hz,1H), 5.86 (s, 1H), 4.58-4.49 (m, 1H), 4.45-4.37 (m, 2H), 3.13-3.04 (m, 1H), 2.55 (s, 2H), 2.21-1.87 (m, 6H), 1.23-1.17 (m, 6H). LC-MS (ESI): m / z [M+H] + =462.1.

[0280] Example 88: cis-5-((5-(3-(4-(tert-butyl)-1H-imidazol-1-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 21. 1 H NMR (500 MHz, DMSO- d 6) δ12.08 (s, 1H), 8.75 (s, 1H), 8.24 (s, 1H), 7.69 (d, J = 5.1 Hz, 1H), 7.48 (d, J =8.6 Hz, 1H), 7.27 – 7.02 (m, 1H), 5.89 (d, J = 14.8 Hz, 1H), 4.68 (s, 1H), 4.41(d, J = 5.0 Hz, 2H), 3.28 – 3.19 (m, 2H), 2.61 – 2.53 (m, 1H), 2.31 – 2.12 (m,2H), 2.00 – 1.87 (m, 3H), 1.22 (s, 9H). LC-MS (ESI): m / z [M+H] + = 459.3.

[0281] Example 89: cis-5-((5-(3-(4-(tert-butyl)-1H-pyrazol-1-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 21. 1 H NMR (500 MHz, DMSO- d6) δ12.07 (s, 1H), 8.74 (s, 1H), 8.27 (s, 1H), 7.69 (t, J = 5.1 Hz, 1H), 7.57 (d, J =0.7 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.34 (s, 1H), 5.88 (s, 1H), 4.74 (dd, J =15.3, 7.8 Hz, 1H), 4.41 (d, J = 5.2 Hz, 2H), 3.23 – 3.15 (m, 1H), 2.46 – 2.43(m, 1H), 2.19 – 1.98 (m, 4H), 1.93 – 1.82 (m, 1H), 1.20 (s, 9H). LC-MS (ESI): m / z [M+H] + = 459.3.

[0282] Example 90: cis-5-((5-(3-(4-(tert-butyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: trans -Methanesulfonic acid 3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazole-3-yl) ring Amyl ester At 0℃ trans 3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (506 mg, 1 mmol) was added to a solution in DCM (20 mL) with pyridine (160 mg, 2 mmol) and methanesulfonyl chloride (115 mg, 1 mmol). The mixture was stirred at room temperature for 2 h. Water (20 mL) was added, and the mixture was extracted by DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography on silica gel with PE:EA (100:0 to 2:1) elution to give the product (360 mg, 83%). LC-MS (ESI): m / z [M+H] + = 436.4.

[0283] Step 2: cis-(3-(3-azidocyclopentyl)-1-(tert-butyl)-1H-pyrazole-5-yl)carbamate Towards trans 3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl methanesulfonate (360 mg, 0.83 mmol) was dissolved in DMF (10 mL) with sodium azide (267 mg, 4.1 mmol). The resulting mixture was stirred at room temperature for 3 h. Water (30 mL) was added, and the mixture was extracted by DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography on silica gel with PE:EA (100:0 to 2:1) elution to give the product (289 mg, 91%). LC-MS (ESI): m / z [M+H] + = 383.4.

[0284] Step 3: cis-(1-(tert-butyl)-3-(3-(4-(tert-butyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)- 1H-pyrazole-5-yl) benzyl carbamate cis-(3-(3-azidocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (402 mg, 1.1 mmol) was added to a solution in t-BuOH / H2O (10 / 10 mL) with 3,3-dimethyl-1-butyne (130 mg, 1.5 mmol), sodium ascorbate (80 mg, 0.4 mmol), and copper(II) sulfate pentahydrate (30 mg, 0.1 mmol). The resulting mixture was stirred at room temperature for 1 h. Water (10 mL) was added, and the mixture was extracted by EA (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography on silica gel with PE:EA (100:0 to 1:1) to give the product (403 mg, 79%). LC-MS (ESI): m / z[M+H] + = 465.4.

[0285] Step 4: cis-1-(tert-butyl)-3-(3-(4-(tert-butyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)-1H- Pyrazole-5-amine cis-(1-(tert-butyl)-3-(3-(4-(tert-butyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)-1H-pyrazole-5-yl)carbamate (403 mg, 0.87 mmol) was dissolved in THF / H₂O (10 / 1 mL), and Pd / C (10% on carbon, 200 mg) was added. The reaction mixture was stirred at room temperature for 1 hour at 1 atm H₂. After filtration, the filtrate was concentrated to give the product (273 mg, 95%). LC-MS (ESI): m / z [M+H] + = 331.4.

[0286] Step 5: cis-5-((1-(tert-butyl)-3-(3-(4-(tert-butyl)-1H-1,2,3-triazol-1-yl)cyclopentane 1H-pyrazole-5-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium-1,1-dioxide A mixture of cis-1-(tert-butyl)-3-(3-(4-(tert-butyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)-1H-pyrazole-5-amine (160 mg, 0.5 mmol), 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazolium-1,1-dioxide (130 mg, 0.5 mmol), Pd2dba3 (48 mg, 0.05 mmol), Xantphos (58 mg, 0.1 mmol), and K3PO3 (320 mg, 2.5 mmol) in dioxane (10 mL) was stirred in a sealed tube at 100 °C for 6 h under N2 atmosphere. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with 100% EtOAc elution to give the product (144 mg, 56%). LC-MS (ESI): m / z [M+H] + = 516.3.

[0287] Step 6: cis-5-((5-(3-(4-(tert-butyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)-1H-pyrazole-3- (amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Cis-5-((1-(tert-butyl)-3-(3-(4-(tert-butyl)-1H-1,2,3-triazol-1-yl)cyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (144 mg, 0.28 mmol) was dissolved in formic acid (10 mL) and stirred at 75 °C for 6 h. The mixture was concentrated under vacuum, and 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%–40%) to give the product (47.5 mg, 37%). 1H NMR (500 MHz, DMSO- d 6) δ 12.1 (brs, 1H), 8.76 (d, J = 2.6 Hz, 1H), 8.26 (s, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 7.48 (d, J =8.6 Hz, 1H), 5.91 (s, 1H), 5.05 (tt, J = 8.9, 7.0 Hz, 1H), 4.41 (s, 2H), 3.26(ddd, J = 17.8, 10.2, 7.7 Hz, 1H), 2.66 (dt, J = 13.6, 7.2 Hz, 1H), 2.22 – 2.02(m, 3H), 2.01 – 1.88 (m, 1H), 1.27 (s, 9H). LC-MS (ESI): m / z [M+H] + = 460.2.

[0288] Example 91: cis-5-((5-(3-(5-(tert-butyl)oxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound in its racemic form was synthesized in a procedure similar to that of Example 6, and further separated by chiral preparative HPLC to obtain: Enantiomer 1 (Example 91a, 100% ee); retention time: 1.742 min. 1 H NMR (500 MHz, DMSO- d 6) δ = 12.04 (s, 1H), 8.72 (s, 1H), 8.26 (t, J = 7.5 Hz, 1H), 7.69 (t, J =5.1 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 6.67 (s, 1H), 5.84 (s, 1H), 4.40 (d, J=5.2 Hz, 2H), 3.40-3.33 (m, 1H), 3.25 – 3.13 (m, 1H), 2.48-2.42 (m, 1H), 2.16– 2.05 (m, 2H), 2.03 – 1.85 (m, 2H), 1.79 – 1.67 (m, 1H), 1.23 (s, 9H). LC-MS(ESI): m / z [M+H] + = 460.2.

[0289] Enantiomer 2 (Example 91b, 99.35% ee); retention time: 2.238 min. 1 H NMR (500 MHz, DMSO- d 6) δ = 12.04 (s, 1H), 8.72 (s, 1H), 8.26 (t, J = 7.5 Hz, 1H), 7.69 (t, J =5.1 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 6.67 (s, 1H), 5.84 (s, 1H), 4.40 (d, J =5.2 Hz, 2H), 3.40-3.33 (m, 1H), 3.25 – 3.13 (m, 1H), 2.48-2.42 (m, 1H), 2.16– 2.05 (m, 2H), 2.03 – 1.85 (m, 2H), 1.79 – 1.67 (m, 1H), 1.23 (s, 9H). LC-MS(ESI): m / z [M+H] + = 460.2.

[0290] Chiral analysis method: Column: CHIRALPAK IF-3 4.6 250 mm 5 μm; Mobile phase: A is MtBE (0.1% DEA) and B is MeOH:DCM = 1:1; Gradient: Mobile phase A: Mobile phase B = 50:50 (v / v); HPLC equipment: HPLC-Agilent; Column temperature: 35℃.

[0291] Chiral preparative HPLC conditions: CHIRALPAK IF-3 20 250 mm 5 μm; Mobile phase: A is MtBE (0.1% DEA) and B is MeOH:DCM = 1:1; Gradient: Mobile phase A: Mobile phase B = 50:50 (v / v); Flow rate: 20 mL / min; Wavelength: UV 220 nm; Preparative HPLC equipment: Preparative HPLC-Gilson; Column temperature: 25℃.

[0292] Example 92: 5-((5-(3-(5-ethyloxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: (2-O-Butyl)carbamate tert-butyl ester Ethyl magnesium bromide (46 mL, 137.6 mmol) was added to a solution of tert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (10 g, 45.8 mmol) in THF (100 mL) over 15 min at 0 °C. The reaction was stirred at room temperature for 45 min. The reaction was quenched with NH4Cl solution (100 mL) and extracted with EA (3 × 80 mL). The combined organic layers were washed with brine and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography by elution with PE and EA (100:0 to 90:10) to yield the product (9 g, 95% yield).

[0293] Step 2: 1-Aminobut-2-one hydrochloride tert-butyl (2-oxobutyl)carbamate (9 g, 48.1 mmol) was added to HCl (4 M, 60 mL) in dioxane and the resulting solution was stirred at room temperature for 2 h. The reaction was concentrated under vacuum to give the crude product (5 g, 84.7%).

[0294] Step 3: 3-(methoxycarbonyl)cyclopentane-1-carboxylic acid NaOH (4.2 g, 107.5 mmol) was added to a solution of dimethyl cyclopentane-1,3-dicarboxylate (20 g, 107.5 mmol) in MeOH (200 mL). The resulting solution was stirred at room temperature for 12 h. The mixture was acidified with aqueous HCl (2 M) to pH < 8. The resulting mixture was extracted with EA (3 × 80 mL), and the organic layers were combined, dried over Na₂SO₄, and then concentrated under vacuum to give the product (12.8 g, 68.8%). LCMS (ESI) m / z [MH]- = 171.

[0295] Step 4: Methyl 3-((2-oxobutyl)carbamoyl)cyclopentane-1-carboxylate Add 3-(methoxycarbonyl)cyclopentane-1-carboxylic acid (9.08 g, 52.8 mmol), HATU (24 g, 63.3 mmol), and DIEA (17 g, 132 mmol) to a solution of 1-aminobutyric acid-2-one hydrochloride (6.5 g, 52.8 mmol) in DMF (150 mL). Stir the resulting solution overnight at room temperature. Quench the reaction with H₂O (300 mL) and extract with EA (3 × 80 mL). Wash the combined organic layers with brine, dry to Na₂SO₄, and concentrate under vacuum. Purify the residue by silica gel column chromatography with PE:EA (100:0 to 60:40) to give the product (8 g, 63.5%). LCMS (ESI) m / z [M+H] + = 242.

[0296] Step 5: Methyl 3-(5-ethyloxazol-2-yl)cyclopentane-1-carboxylate Methyl 3-((2-oxobutyl)carbamoyl)cyclopentane-1-carboxylate (6.9 g, 28.6 mmol) was dissolved in POCl3 (30 mL) and stirred at 60 °C for 1 h. The resulting mixture was concentrated under vacuum. H2O (100 mL) was added and the mixture was adjusted to pH = 8 with aqueous Na2CO3 solution (2 M). The resulting solution was extracted with DCM (2 × 80 mL). The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated under vacuum. The residue was purified by column chromatography on silica gel using PE:EA (100:0 to 62:38) elution to give the product (3.6 g, 57.1%). LCMS (ESI) m / z [M+H] + = 224.

[0297] Step 6: 3-(3-(5-ethyloxazol-2-yl)cyclopentyl)-3-oxopropionitrile n-Buli (2.5 M, 11.7 mL, 29.3 mmol) was added to a solution of CH3CN (1.2 g, 29.3 mmol) in THF (70 mL) at -78 °C, and the mixture was stirred at this temperature for 1 h under a N2 atmosphere. Methyl 3-(5-ethyloxazol-2-yl)cyclopentane-1-carboxylate (3.3 g, 14.6 mmol) was added at -78 °C, and the mixture was stirred further for another hour. The reaction was quenched with NH4Cl solution (80 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using PE:EA (100:0 to 60:40) elution to give the product (2 g, 58.3% yield). LCMS (ESI) m / z [M+H] + = 233.

[0298] Step 7: 5-(3-(5-ethyloxazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine Hydrazine hydrate (379 mg, 7.58 mmol) and TsOH (50 mg) were added to a solution of 3-(3-(5-ethyloxazol-2-yl)cyclopentyl)-3-oxopropionitrile (1.6 g, 6.89 mmol) in EtOH (80 mL). The resulting solution was stirred at 90 °C for 1 h. The reaction was concentrated under vacuum. The residue was purified by column chromatography on silica gel by elution with DCM:MeOH (100:0 to 90:10) to give the product (769.3 mg, 45.5%). 1 H NMR (500 MHz, chloroform-) d ) δ6.63 (dt, J = 18.1, 1.5 Hz, 1H), 5.49 (d, J = 3.5 Hz, 1H), 4.74 (s, 2H), 3.43(tdd, J = 13.5, 7.6, 5.5 Hz, 1H), 3.33 – 3.23 (m, 1H), 2.66 (qd, J = 7.6, 1.5 Hz,2H), 2.54 – 2.38 (m, 1H), 2.30 – 2.18 (m, 1H), 2.17 – 2.08 (m, 1H), 2.11 –2.00 (m, 2H), 1.85 – 1.73 (m, 1H), 1.26 (t, J= 7.5 Hz, 3H). LCMS (ESI) m / z [M+H] + = 247.

[0299] Step 8: 5-((5-(3-(5-ethyloxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3- Dihydrobenzo[d]isothiazol 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 6. 1 H NMR (500 MHz, DMSO- d 6) δ12.04 (s, 1H), 8.73 (s, 1H), 8.22 (d, J = 26.7 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 6.71 (s, 1H), 5.86 (d, J = 11.3 Hz, 1H), 4.41 (s, 2H), 3.29 –3.15 (m, 2H), 2.67 – 2.61 (m, 2H), 2.48 – 2.41 (m, 1H), 2.22 – 2.06 (m, 2H),2.02 – 1.85 (m, 2H), 1.79 – 1.68 (m, 1H), 1.17 (td, J = 7.5, 4.2 Hz, 3H). LC-MS(ESI): m / z [M+H] + = 432.2.

[0300] Example 93: 4-Fluoro-5-((5-(3-(5-(hydroxymethyl)oxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: Methyl 3-((2,3-dihydroxypropyl)carbamoyl)cyclopentane-1-carboxylate HATU (30 g, 78.9 mmol), 3-aminopropyl-1,2-diol (6 g, 65.9 mmol), and DIEA (21 g, 162 mmol) were added to a solution of 3-methoxycarbonyl)cyclopentane-1-carboxylic acid (11.3 g, 65.7 mmol) in DMF (60 mL). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with H2O (100 mL) and extracted with 3 × 80 mL EA. The combined organic layers were washed with brine, concentrated under vacuum, and the residue was purified by silica gel column chromatography by elution with PE:EA (100:0 to 60:40) to give the product (10 g, 95% yield). LCMS (ESI) m / z [MH] - = 246.

[0301] Step 2: 3-((3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)carbamoyl)cyclopentane- Methyl 1-formate TBSCl (4.3 g, 28.6 mmol) and imidazole (8.3 g, 122 mmol) were added to a solution of methyl 3-((2,3-dihydroxypropyl)carbamoyl)cyclopentane-1-carboxylate (10 g, 40.8 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE:EA (100:0 to 70:30) elution to give the product (5 g, 36% yield). LCMS (ESI) m / z [M+H] + = 360.

[0302] Step 3: 3-((3-((tert-butyldimethylsilyl)oxy)-2-oxopropyl)carbamoyl)cyclopentane Methyl alkyl-1-carboxylate DMP (11.8 g, 27.8 mmol) was added to a solution of methyl 3-((3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)carbamoyl)cyclopentane-1-carboxylate (5 g, 13.8 mmol) in DCM (60 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE:EA (100:0 to 70:30) elution to give the product (3 g, 61%). LCMS (ESI) m / z [M+H] + =358.

[0303] Step 3: 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)cyclopentane-1-carboxylic acid Methyl ester A solution of methyl 3-((3-((tert-butyldimethylsilyl)oxy)-2-oxopropyl)carbamoyl)cyclopentane-1-carboxylate (3 g, 8.3 mmol) in ACN (58 mL) was supplemented with a solution of C2Cl6 (5.75 g, 52.8 mmol) in ACN (45 mL), TEA (5 g, 49 mmol), and PPh3 (6.37 g, 24.3 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with H2O (100 mL) and extracted with EA (3 × 80 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography with PE:EA (100:0 to 60:40) to give the product (1.8 g, 65.5%). LCMS (ESI) m / z [M+1] + =340.

[0304] Step 4: 3-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)cyclopentyl)-3- Oxypropionitrile n-BuLi (2.5 M) (4.23 mL, 10.6 mmol) was added to a solution of CH3CN (435 mg, 10.6 mmol) in THF (90 mL) at -78 °C and stirred for 1 h under N2 atmosphere. A solution of methyl 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)cyclopentane-1-carboxylate (1.8 g, 5.3 mmol) was added to the solution at -78 °C and stirred for another hour. The reaction was quenched with NH4Cl aqueous solution (80 mL) and extracted with 3 × 50 mL LEtOAc. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE:EA (100:0 to 60:40) elution to give the product (1.1 g, 61%). LCMS (ESI) m / z [M+H] + = 349.

[0305] Step 5: 5-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)cyclopentyl)-1H- Pyrazole-3-amine To a solution of 3-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)cyclopentyl)-3-oxopropionitrile (1.1 g, 3.16 mmol) in EtOH (20 mL), NH₂NH₂H₂O (174 mg, 3.48 mmol) and TsOH (50 mg) were added. The resulting mixture was stirred at 90 °C for 1 h. The reaction was concentrated under vacuum, and the residue was purified by silica gel column chromatography by elution with DCM:MeOH (100:0 to 90:10) to give the product (723 mg, 65.7%). ¹H NMR (300 MHz, DMSO-) d 6) δ 11.12 (s, 1H), 6.96 (d, J = 2.1 Hz, 1H), 5.20 (d, J = 2.2 Hz, 1H), 4.65 (d, J = 2.2 Hz, 2H), 3.34 – 3.25 (m, 2H), 3.14 –2.92 (m, 1H), 2.38 (m, J = 12.6, 7.0 Hz, 1H), 2.05 (m, J = 13.3, 6.2 Hz, 2H),1.97 – 1.89 (m, 1H), 1.87 – 1.76 (m, 1H), 1.76 – 1.61 (m, 1H), 1.31 – 1.09(m, 1H), 0.86 (d, J = 2.3 Hz, 9H), 0.06 (d, J = 2.1 Hz, 6H). LCMS (ESI) m / z [M+H] + = 363.

[0306] Step 4: 5-((5-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)cyclopentanyl) 1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium-1,1-dioxide A mixture of 5-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine (50 mg, 0.138 mmol), 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (44 mg, 0.165 mmol), Brettephos Pd G3 (13 mg, 0.014 mmol), and K2CO3 (57 mg, 0.414 mmol) in t-BuOH (10 mL) was stirred in a sealed tube at 110 °C for 3 h under N2 atmosphere. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EtOAc (1:4) elution to give the product (40 mg, 53%). LC-MS (ESI): m / z [M+H] + = 548.2.

[0307] Step 5: 4-Fluoro-5-((5-(3-(5-(hydroxymethyl)oxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)- 2,3-Dihydrobenzo[d]isothiazolium 1,1-dioxide TFA (1 mL) was added to a solution of 5-((5-(3-(5-((((tert-butyldimethylsilyl)oxy)methyl)oxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (40 mg, 0.073 mmol) in DCM (4 mL). The solution was stirred at room temperature for 4 h. The solution was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and then NH3 (7 M, 1 mL) in MeOH was added. After stirring at room temperature for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18: RD-CO-095 column, eluted with 20%–60% water (containing 0.1% FA) in acetonitrile) to give the product (15 mg, 47%). 1 H NMR (500 MHz, DMSO-) d 6) δ 12.06 (s, 1H), 8.76 (s, 1H), 8.28 (t, J = 8.0 Hz, 1H),7.71 (s, 1H), 7.48 (d, J= 8.6 Hz, 1H), 6.90 (s, 1H), 5.85 (s, 1H), 5.35-5.27(m, 1H), 4.50-4.37 (m, 4H), 3.44 – 3.36 (m, 1H), 3.26 – 3.16 (m, 1H), 2.48 –2.42 (m, 1H), 2.17 – 2.07 (m, 2H), 2.03 – 1.96 (m, 1H), 1.95-1.84 (m, 1H), 1.80-1.70 (m, 1H). LC-MS (ESI): m / z [M+H] + = 434.38.

[0308] Example 94: 5-((5-(3-(4-(tert-butyl)oxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: cis-1-(3,3-dimethyl-2-oxobutyl)3-methylcyclopentane-1,3-dicarboxylate A solution of cis-3-(methoxycarbonyl)cyclopentane-1-carboxylic acid (5 g, 29 mmol) in DMF (60 mL) was mixed with 1-chloro-3,3-dimethylbutanone (5 g, 37.7 mmol) and K₂CO₃ (11.25 g, 81.2 mmol) and stirred at room temperature for 2 h. The reaction was quenched with H₂O (100 mL) and extracted with 3 × 80 mL EA. The combined organic layers were washed with brine and concentrated under vacuum. The residue was purified by silica gel column chromatography with PE:EA (100:0 to 60:40) elution to give the product (6.2 g, 80%). LCMS (ESI): m / z [M+H] + = 271.

[0309] Step 2: Methyl cis-3-(4-(tert-butyl)oxazol-2-yl)cyclopentane-1-carboxylate AcONH4 (11 g, 183 mmol) was added to a solution of cis-1-(3,3-dimethyl-2-oxobutyl)-3-methylcyclopentane-1,3-dicarboxylate (5 g, 18.5 mmol) in AcOH (200 mL) after microwave incubation at 100 °C for 1.5 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE:EA (100:0 to 60:40) elution to give the product (2 g, 44%). LCMS (ESI): m / z [M+H] + = 252.

[0310] Step 3: 3-(3-(4-(tert-butyl)oxazol-2-yl)cyclopentyl)-3-oxopropionitrile n-BuLi (2.5 M) (11 mL, 27.4 mmol) was added to a solution of CH3CN (1.5 g, 36.5 mmol) in THF (70 mL) at -78 °C and stirred for 1 h under N2 atmosphere. A solution of methyl 3-(4-(tert-butyl)oxazol-2-yl)cyclopentane-1-carboxylate (2.3 g, 9.2 mmol) in THF (30 mL) was added to the solution at -78 °C and stirred for another hour. The reaction was quenched with NH4Cl solution (80 mL) and extracted with 3 × 50 mL EtOAc. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (PE:EA) (100:0 to 60:40) to give the product (1 g, 43.4%). LCMS (ESI): m / z [M+H] + = 261.

[0311] Step 4: 5-(3-(4-(tert-butyl)oxazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine Hydrazine hydrate (211 mg, 4.2 mmol) and TsOH (50 mg) were added to a solution of 3-(3-(4-(tert-butyl)oxazol-2-yl)cyclopentyl)-3-oxopropionitrile (1 g, 3.8 mmol) in EtOH (15 mL). The mixture was stirred at 90 °C for 1 h. The reaction was concentrated under vacuum. The residue was purified by silica gel column chromatography by elution with DCM:MeOH (100:0 to 90:10) to give the product (546 mg, 50%). 1 H NMR (300 MHz, DMSO- d 6) δ 11.17 (s,1H), 7.62 (s, 1H), 5.22 (d, J = 5.4 Hz, 1H), 4.45 (s, 2H), 3.33 – 3.25 (m, 1H), 3.15 – 2.87 (m, 1H), 2.36 (m, J = 12.1, 7.2 Hz, 1H), 2.10 – 2.00 (m, 2H), 1.98– 1.89 (m, 1H), 1.82 (m, J= 12.3, 10.5 Hz, 1H), 1.74 – 1.62 (m, 1H), 1.20 (s, 9H). LCMS (ESI): m / z [M+H] + = 275.

[0312] Step 5: 5-((5-(3-(4-(tert-butyl)oxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro- 2,3-Dihydrobenzo[d]isothiazolium 1,1-dioxide BrettPhos Pd G3 (9 mg, 0.01 mmol) and K2CO3 (42 mg, 0.3 mmol) were added to a mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (26 mg, 0.1 mmol) and 5-(3-(4-(tert-butyl)oxazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine (27 mg, 0.1 mmol) in t-BuOH (3 mL). The reaction mixture was stirred at 110 °C for 4 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18: RD-CO-058 column, eluted with 34%–49% water (containing 0.1% FA) in acetonitrile to give the product (11.14 mg, 24%). 1 H NMR (500 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 7.69 – 7.64 (m, 2H), 7.48 (d, J =8.6, 1H), 5.85 (s, 1H), 4.41 (s, 2H), 3.24 – 3.15 (m, 1H), 2.49 – 2.41 (m, 1H), 2.26 – 1.64 (m, 6H), 1.20 – 1.19 (m, 9H). LC-MS (ESI): m / z [M+H] + = 460.3.

[0313] Example 95: 5-((5-(3-(5-(tert-butyl)thiazolyl-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: Methyl cis-3-((3,3-dimethyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylate H₂SO₄ (15.2 g, 11.7578 mmol, 1 equivalent) was added dropwise to a stirred solution of cis-3-((3,3-dimethyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylic acid (20 g, 7.839 mmol) in MeOH (50 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction was quenched by adding saturated NH₄Cl (aqueous solution) (100 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 150 mL). The residue was purified by silica gel column chromatography with elution of DCM / MeOH (10:1) to give the product (20 g, 98.8%). LC-MS (ESI): m / z [M+H] + = 270.2.

[0314] Step 2: Methyl cis-3-(5-(tert-butyl)thiazolyl-2-yl)cyclopentane-1-carboxylate Lawson's reagent (7.1 mg, 0.572 mmol, 1.5 equivalence) was added fractionally to a stirred mixture of methyl cis-3-((3,3-dimethyl-2-oxobutyl)carbamoyl)cyclopentane-1-carboxylate in toluene (500 mL) at room temperature. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The reaction was quenched by adding saturated NH4Cl (100 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 150 mL). The residue was purified by silica gel column chromatography with elution of DCM / MeOH (10:1) to give a crude product, which was further purified by reversed-phase rapid chromatography under the following conditions (20 g, 0.3717 mmol, 97.2% yield): Column: XBridge Shield RP18 OBD column 19 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 5% B to 30% B over 9 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.9. LC-MS (ESI): m / z [M+H] + = 268.39.

[0315] Step 3: 3-(3-(5-(tert-butyl)thiazolyl-2-yl)cyclopentyl)-3-oxopropionitrile n-BuLi (7.50 g, 1.4972 mmol, 2.0 equivalent) was added dropwise to a stirred mixture of CH3CN (5.68 g, 1.4972 mmol, 2.0 equivalent) in THF (150 mL) at -78 °C. The resulting mixture was stirred at -78 °C for 1 h under a nitrogen atmosphere. Cis-methyl-3-(5-(tert-butyl)thiazolyl-2-yl)cyclopentane-1-carboxylate (20 g, 0.7487 mmol, 1.0 equivalent) in THF (150 mL) was added to the above mixture at -78 °C. The resulting mixture was stirred at -78 °C for 1 h under a nitrogen atmosphere. The reaction was then stirred at room temperature for 1 h. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (100 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 150 mL). The residue was purified by silica gel column chromatography with elution of DCM / MeOH (10:1) to obtain the crude product, which was further purified by reversed-phase rapid chromatography under the following conditions (15 g, 0.44 mmol, 81.0% yield): Column: XBridge Shield RP18 OBD column 19 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 5% B to 30% B over 9 min; Wavelength: 254 nm / 220 nm; RT1 (min): 8.9. LC-MS (ESI): m / z [M+H] + = 277.40.

[0316] Step 4: 5-(3-(5-(tert-butyl)thiazolyl-2-yl)cyclopentyl)-1H-pyrazole-3-amine PTSA (0.90 g, 0.071 mmol, 0.1 equivalent, 100%) was added fractionally to a stirred solution of 3-(3-(5-(tert-butyl)thiazolyl-2-yl)cyclopentyl)-3-oxopropionitrile (10.0 g, 0.724 mmol, 1.0 equivalent, 100%) and NH₂NH₂H₂O (2.5 g, 0.796 mmol, 1.1 equivalent) in EtOH (250 mL). The resulting mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by reversed-phase rapid chromatography under the following conditions: column: Xselect CSH C18 OBD column, 30 150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B over 10 min; Wavelength: 254 nm; RT1 (min): 9. This produced 1306.6 mg, 0.814 mmol, 91.9% yield. 1 H NMR (400 MHz, DMSO- d 6) δ10.37 (s, 1H), 9.85-9.75 (m, 1H), 9.27-9.17 (m, 1H), 8.83 (s, 1H), 8.11-8.01(m, 1H), 7.92 (s, 1H), 7.54-7.44 (m, 1H), 7.35-7.25 (m, 1H), 7.18-7.08 (m, 1H), 2.99-2.89 (m, 2H), 2.71-2.61 (m, 2H). LC-MS (ESI): m / z [M+H] + = 291.43.

[0317] Step 5: 5-((5-(3-(5-(tert-butyl)thiazolyl-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro- 2,3-Dihydrobenzo[d]isothiazolium 1,1-dioxide BrettPhos Pd G3 (9 mg, 0.01 mmol) and K2CO3 (42 mg, 0.3 mmol) were added to a mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (26 mg, 0.1 mmol) and 5-(3-(5-(tert-butyl)thiazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine (29 mg, 0.1 mmol) in t-BuOH (3 mL). The reaction mixture was stirred at 110 °C for 4 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18: RD-CO-058 column, eluted with 34%–49% water (containing 0.1% FA) in acetonitrile) to give the product (12.09 mg, 25%). 1 H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.27 – 8.19 (m, 1H), 7.70 (s, 1H), 7.48 (d, J= 8.6 Hz, 1H),7.39 (s, 1H), 5.87 (s, 1H), 4.41 (s, 2H), 3.66 – 3.60 (m, 1H), 3.37 – 3.27(m, 1H), 2.33 – 2.06 (m, 4H), 1.97 – 1.70 (m, 2H), 1.34 (s, 9H). LC-MS (ESI): m / z [M+H] + = 476.3.

[0318] Example 96: cis-5-((5-(3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: cis-3-(2-neovalerhydrazide-1-carbonyl)cyclopentane-1-carboxylic acid In a 500-mL round-bottom flask, cis-3-oxa-bicyclo[3.2.1]octane-2,4-dione (15.0 g, 107.42 mmol), neopentanoylhydrazide (24.82 g, 214.29 mmol), TEA (21.64 g, 214.29 mmol), and THF (300 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give cis-3-(2-neovaleranoylhydrazide-1-carbonyl)cyclopentane-1-carboxylic acid (23.0 g, 83.85%). LC-MS (ESI): m / z [M+H] + = 257.2.

[0319] Step 2: Methyl cis-3-(2-neovalerhydrazide-1-carbonyl)cyclopentane-1-carboxylate In a 250-mL round-bottom flask, cis-3-(2-neovalerhydrazide-1-carbonyl)cyclopentane-1-carboxylic acid (23.0 g, 89.84 mmol), H₂SO₄ (8.8 g, 89.84 mmol), and MeOH (100 mL) were added at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was neutralized to pH 7 with aqueous Na₂CO₃ and extracted with 300 mL of EtOAc. The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (100:0 to 50:50) elution to give the product (15.1 g, 62.25%). LC-MS (ESI): m / z [M+H]+ = 271.2.

[0320] Step 3: Methyl cis-3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)cyclopentane-1-carboxylate Methyl cis-3-(2-neovalerhydrazide-1-carbonyl)cyclopentane-1-carboxylate (15.0 g, 55.56 mmol), DIEA (21.50 g, 166.67 mmol), TsCl (31.83 g, 166.67 mmol), and CH3CN (150 mL) were added to a 500 mL round-bottom flask at room temperature. The resulting mixture was stirred at 70 °C for 2 h. The mixture was extracted with EtOAc (400 mL). The combined organic layers were washed with brine (2 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (100:0–30:70) elution to give methyl cis-3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)cyclopentane-1-carboxylate (6.0 g, 42.86%). LC-MS (ESI): m / z [M+H] + = 253.2.

[0321] Step 4: 3-(3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)cyclopentyl)-3-oxopropionitrile n-BuLi (18.10 mL, 45.24 mmol) was added dropwise to CH3CN (1.85 g, 45.24 mmol) under a nitrogen atmosphere at -78 °C. The resulting mixture was stirred at -78 °C for 30 min. A solution of cis-3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)cyclopentane-1-carboxylate (5.70 g, 22.62 mmol) in 20 mL THF was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 2 h. The reaction was quenched at 0 °C with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (400 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (100:0–70:30) elution to obtain the product (5.0 g, 84.69%). LC-MS (ESI): m / z [M+H] + = 262.2.

[0322] Step 5: 5-(3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine At room temperature, NH₂NH₂·H₂O (0.84 g, 16.86 mmol) and PTSA (160.0 mg) were added to a solution of 3-(3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)cyclopentyl)-3-oxopropionitrile (4.0 g, 15.33 mmol) in EtOH (60 mL). The resulting mixture was stirred at 90 °C for 1 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with DCM / MeOH (100:0–95:5) to give the product (2.016 g, 47.83%). 1 H NMR (500 MHz, DMSO- d 6) δ 11.06 (s, 1H), 5.22 (d, J = 17.6 Hz, 1H), 4.52 (s, 2H), 3.16 – 3.02 (m, 1H), 2.41 (dt, J = 12.5, 1H), 2.25 – 1.80 (m,5H), 1.78 – 1.64 (m, 1H), 1.34 (d, J = 2.0 Hz, 9H). LC-MS (ESI): m / z [M+H] + =276.4.

[0323] Step 6: cis-5-((5-(3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)cyclopentyl)-1H-pyrazole-3- (amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 6. 1 H NMR (500 MHz, DMSO- d 6) δ11.69 (s, 1H), 8.04 (t, J = 8.8 Hz, 1H), 7.92 (s, 1H), 6.85 (t, J = 6.1 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 5.69 (s, 1H), 5.00 (s, 1H), 4.72 (s, 2H), 4.33 (s,1H), 3.03 (t, J = 8.5 Hz, 1H), 2.99 (s, 3H), 2.92 (d, J = 6.2 Hz, 2H), 2.44 (dd, J= 14.0, 7.3 Hz, 1H), 2.06 – 1.97 (m, 1H), 1.92 (d, J = 21.6 Hz, 1H), 1.72 (t, J =10.3 Hz, 2H), 1.60 (s, 1H), 1.02 (s, 6H). LC-MS (ESI): m / z [M+H] + = 459.2.

[0324] Example 97: trans-5-((5-(3-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 96. 1 H NMR (500 MHz, DMSO- d 6) δ12.05 (s, 1H), 8.74 (s, 1H), 8.26 (t, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J =8.6 Hz, 1H), 5.88 (s, 1H), 4.41 (d, J = 5.0 Hz, 2H), 3.58 (p, J = 7.7 Hz, 1H),3.31 – 3.22 (m, 1H), 2.33 (dt, J = 13.3, 7.3 Hz, 1H), 2.27 – 2.14 (m, 1H), 2.14 – 2.06 (m, 1H), 1.99 – 1.91 (m, 1H), 1.79 – 1.71 (m, 1H), 1.35 (s, 6H). LC-MS(ESI): m / z [M+H] + = 459.2.

[0325] Example 98: 5-((5-(3-(1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: (3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)cyclopent-2-ene-1- 1H-pyrazole-5-yl)carbamate benzyl ester FA (10 mL) was added to a stirred solution of (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (1 g, 0.086 mmol), and the solution was stirred at 75 °C for 10 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (1:1) elution to give the product (500 mg, 56.8%). LC-MS (ESI): m / z [M+H] + = 410.3.

[0326] Step 2: (3-(3-(1-(tert-butyl)-1H-pyrazol-3-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)amino benzyl carbamate Pd(dppf)Cl2 (110.5 mg, 0.122 mmol) and K3PO4 (775.9 mg, 3.66 mmol) were added to a solution of (3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (500 mg, 1.22 mmol) and 3-bromo-1-(tert-butyl)-1H-pyrazol (369.7 mg, 1.83 mmol) in dioxane / H2O (10:2 mL). The reaction mixture was stirred at 100 °C for 6 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with PE / EA (1:4) elution to give the product (400 mg, 80.8%). LC-MS (ESI): m / z [M+H] + = 406.3.

[0327] Step 3: 5-(3-(1-(tert-butyl)-1H-pyrazole-3-yl)cyclopentyl)-1H-pyrazole-3-amine (3-(3-(1-(tert-butyl)-1H-pyrazol-3-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)benzyl carbamate (500 mg, 1.23 mmol) was dissolved in MeOH (10 mL), and Pd / C (10% on carbon, 200 mg) was added. The reaction mixture was stirred at room temperature for 2 hours at 1 atm H2. The resulting mixture was filtered, the filtrate was concentrated, and dried under vacuum to give the product (200 mg, 58.6%). LC-MS (ESI): m / z [M+H] + = 274.3.

[0328] Step 3: 5-((5-(3-(1-(tert-butyl)-1H-pyrazole-3-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4- Fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide A solution of 5-(3-(1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)-1H-pyrazol-3-amine (50 mg, 0.183 mmol), 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (48.5 mg, 0.183 mmol), Brettphos G3 Pd (16.3 mg, 0.018 mmol), and K2CO3 (75.8 mg, 0.549 mmol) in t-BuOH (10 mL) was stirred at 110 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution using EA to give 50 mg of product. The residue of 50 mg 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 (22.6 mg, 26.9%). ¹H NMR (500 MHz, DMSO-) d 6) δ = δ12.02 (s, 1H), 8.71 (d, J =2.3 Hz, 1H), 8.32 – 8.21 (m, 1H), 7.78 – 7.55 (m, 2H), 7.47 (d, J = 8.6 Hz,1H), 6.08-6.05 (m, 1H), 5.85 (d, J = 4.0 Hz, 1H), 4.41 (d, J = 5.0 Hz, 2H), 3.28– 3.23 (m, 1H), 3.21 – 3.16 (m, 1H), 2.42 – 2.34 (m, 1H), 2.20 – 1.95 (m,3H), 1.84 – 1.66 (m, 3H), 1.48 (s, 9H). LC-MS (ESI): m / z [M+H] + = 459.2.

[0329] Example 99: 5-((5-(3-(1-(tert-butyl)-1H-pyrazol-4-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 98. 1H NMR (500 MHz, DMSO- d 6) δ =11.99 (s, 1H), 8.71 (s, 1H), 8.25 (s, 0H), 7.69 (t, J = 5.1 Hz, 0H), 7.61 (d, J =8.0 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.31 (s, 1H), 5.84 (s, 1H), 4.40 (d, J =5.0 Hz, 2H), 3.28 – 2.99 (m, 1H), 2.42 – 2.34 (m, 0H), 2.21 – 1.93 (m, 1H), 1.82 – 1.56 (m, 1H), 1.48 (d, J = 2.2 Hz, 4H). LC-MS (ESI): m / z [M+H] + = 459.2.

[0330] Example 100: 5-((5-(3-(3-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 98. 1 H NMR (500 MHz, DMSO- d 6) δ12.11 (brs, 1H), 12.03 (s, 1H), 8.72 (d, J = 2.7 Hz, 2H), 8.26 (s, 1H), 7.69(t, J = 5.2 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 5.85 (d, J = 10.0 Hz, 2H), 4.40 (d, J = 5.2 Hz, 2H), 3.19 – 3.13 (m, 1H), 2.41 – 2.33 (m, 2H), 2.17 – 2.08 (m, 2H), 1.83 – 1.64 (m, 3H), 1.23 (s, 9H). LC-MS (ESI): m / z [M+H] + = 459.2.

[0331] Example 101: 4-Fluoro-5-((5-(3-(5-(2-hydroxypropane-2-yl)-1H-pyrazol-3-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: 3-(3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazole-3-yl)cyclopent-1-ene- methyl 1-yl)-1H-pyrazole-5-carboxylate Pd(dppf)Cl2 (146 mg, 0.2 mmol), K2CO3 (828 mg, 6 mmol), and H2O (2 mL) were added to a mixture of (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole-5-yl)carbamate (930 mg, 2 mmol) and methyl 3-bromo-1H-pyrazole-5-carboxylate (410 mg, 2 mmol) in dioxane (20 mL). The reaction mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography with PE / EA (4:1) elution to give the product (740 mg, 80%). LC-MS (ESI): m / z [M+H] + = 464.3.

[0332] Step 2: 3-(3-(5-(((benzyloxy)carbonyl)amino)-1H-pyrazol-3-yl)cyclopent-1-en-1-yl)-1H-pyrazol Methyl 5-azole carboxylate A mixture of methyl 3-(3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopent-1-en-1-yl)-1H-pyrazol-5-carboxylate (740 mg, 1.6 mmol) in formic acid (7 mL) was stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography with PE / EA (2:1) elution to give the product (407 mg, 62%). LC-MS (ESI): m / z [M+H] + = 408.3.

[0333] Step 3: (3-(3-(5-(2-hydroxypropane-2-yl)-1H-pyrazol-3-yl)cyclopent-2-en-1-yl)-1H-pyrazol Benzyl 5-azolyl carbamate CH3MgBr (5 mL, 1 N) was slowly added to a mixture of methyl 3-(3-(5-((((benzyloxy)carbonyl)amino)-1H-pyrazol-3-yl)cyclopent-1-en-1-yl)-1H-pyrazol-5-carboxylate (407 mg, 1 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The mixture was quenched with water and extracted with DCM. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography with DCM / MeOH (20:1) elution to give the product (244 mg, 60%). LC-MS (ESI): m / z [M+H] + = 408.3.

[0334] Step 4: 2-(3-(3-(5-amino-1H-pyrazol-3-yl)cyclopentyl)-1H-pyrazol-5-yl)prop-2-ol Pd / C (120 mg, 0.5 M) was added to a mixture of (3-(3-(5-(2-hydroxypropan-2-yl)-1H-pyrazol-3-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (244 mg, 0.6 mmol) and H2O (1 mL) in THF (4 mL). The reaction was stirred at room temperature under H2 for 12 h. The mixture was filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with DCM / MeOH (10:1) elution to give the product (130 mg, 79%). LC-MS (ESI): m / z [M+H] + = 276.2.

[0335] Step 5: 4-Fluoro-5-((5-(3-(5-(2-hydroxypropane-2-yl)-1H-pyrazol-3-yl)cyclopentyl)-1H-pyrazol (Azol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide BrettPhos Pd G3 (9 mg, 0.01 mmol) and K2CO3 (42 mg, 0.3 mmol) were added to a mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (26 mg, 0.1 mmol) and 2-(3-(3-(5-amino-1H-pyrazol-3-yl)cyclopentyl)-1H-pyrazol-5-yl)prop-2-ol (27 mg, 0.1 mmol) in t-BuOH (3 mL). The reaction mixture was stirred at 110 °C for 4 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18: RD-CO-058 column, eluted with 34%–49% water (containing 0.1% FA) in acetonitrile to give the product (10.09 mg, 10%). 1 H NMR (500 MHz, DMSO) δ 12.28 –11.92 (m, 2H), 8.72 (s, 1H), 8.26 (s, 1H), 7.69 (s, 1H), 7.48 (d, J = 8.6 Hz,1H), 5.96 (s, 1H), 5.84 (s, 1H), 4.93 (s, 1H), 4.41 (d, J = 3.5 Hz, 2H), 3.28– 3.11 (m, 2H), 2.43 – 2.34 (m, 1H), 2.17 – 1.69 (m, 5H), 1.40 (s, 6H). LC-MS(ESI): m / z [M+H] + = 461.3.

[0336] Example 102: 4-Fluoro-5-((5-(3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: 1-(4-bromo-1H-pyrazol-1-yl)-2-methylprop-2-ol Cs₂CO₃ (17 g, 53 mmol) was added to a solution of 4-bromo-1H-pyrazole (5 g, 35.1 mmol) in MeCN (200 mL), followed by dropwise addition of a solution of 2,2-dimethylethylene oxide (3.5 mL, 371 mmol) in MeCN (10 mL) in an ice bath. The mixture was stirred at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated, and the residue was purified by rapid column chromatography with 0–20% EtOAc / heptane elution to obtain the product (6.58 g, 86%). LC-MS (ESI): m / z [M+H] + = 219.2.

[0337] Step 2: 4-Fluoro-5-((5-(3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)cyclopentyl)-1H-pyrazol (Azol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 98. ¹H NMR (500 MHz, DMSO-) d 6) δ =12.00 (s, 1H), 8.71 (s, 1H), 8.26 (s, 1H), 7.69 (s, 1H), 7.47 (d, J = 7.8 Hz,2H), 7.30 (s, 1H), 5.83 (s, 1H), 4.64 (s, 1H), 4.40 (d, J = 4.8 Hz, 2H), 3.94(s, 2H), 3.22-3.12 (m, 1H), 3.10-3.00 (m, 1H), 2.38 (dd, J = 12.1, 6.4 Hz, 1H), 2.10 (s, 3H), 1.83 – 1.71 (m, 1H), 1.70 – 1.52 (m, 2H), 1.03 (s, 6H). LC-MS(ESI): m / z [M+H] + = 475.2.

[0338] Example 103: 5-((5-(3-(5-(tert-butyl)-1 H -imidazol-2-yl)cyclopentyl)-1 H -pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide Step 1: 5-(tert-butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -Imidazole and 4-(tert-butyl))-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -imidazol At 0℃, towards 5-(tert-butyl)-1 H Imidazole (1.0 g, 8.05 mmol) was dissolved in THF (15 mL) and NaH (60% dispersion in mineral oil, 386 mg, 9.66 mmol) was added. The mixture was stirred for 30 min, then SEMCl (1.41 g, 8.46 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The resulting mixture was quenched with saturated NH4Cl aqueous solution, extracted with EA, dried over Na2SO4, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 1:1–1:9) to give product A (1.07 g, 52%) and product B (500 mg, 24%). LC-MS (ESI): m / z [M+H] + = 439.1.Product A: 1 H NMR (500 MHz, DMSO- d 6) δ = 7.66 (d, J = 1.2, 1H), 6.93 (d, J = 1.3,1H), 5.28 (s, 2H), 3.55 – 3.47 (m, 2H), 1.24 (s, 9H), 0.92 – 0.81 (m, 2H), -0.00 (s, 9H). LC-MS (ESI): m / z [M+H] + = 255.2. Product B: 1 H NMR (500 MHz, DMSO- d 6) δ =7.67 (s, 1H), 6.68 (s, 1H), 5.41 (s, 2H), 3.53 – 3.48 (m, 2H), 1.33 (s, 9H), 0.90 – 0.85 (m, 12H), -0.00 (s, 9H). LC-MS (ESI): m / z [M+H] + = 255.2.

[0339] Step 2: 2-Bromo-5-(tert-butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -imidazol 5-(tert-butyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 Hβ-Imidazole (255 mg, 1 mmol) was dissolved in THF (10 mL) and cooled to -60 °C under nitrogen. n-BuLi (2.5 M, 0.44 mL, 1.1 mmol in hexane) was added dropwise, and the mixture was stirred at -60 °C for 1 hour. CBr4 (322 mg, 1 mmol) was added to THF (3 mL), and the reaction mixture was warmed to room temperature and stirred for 20 minutes. The resulting mixture was quenched with aqueous NH4Cl solution, extracted with EA, dried over Na2SO4, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 5:1) to give the product (130 mg, 39%). 1 H NMR (500 MHz, DMSO- d 6) δ = 7.19 (s, 1H), 5.24 (s, 2H), 3.56(t, J = 7.9, 2H), 1.22 (s, 9H), 0.87 (t, J = 7.9, 2H), -0.00 (s, 9H). LC-MS (ESI): m / z [M+H] + = 333.5.

[0340] Step 3: 5-((5-(3-(5-(tert-butyl)-1) H -imidazol-2-yl)cyclopentyl)-1 H -pyrazole-3-yl)amino)-4- 2,3-Dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 76. 1 H NMR (500 MHz, DMSO- d 6) δ =12.45 (s, 1H), 8.72 (s, 1H), 8.22 (t, J = 7.8, 1H), 8.18 (s, 1H), 7.69 (s, 1H),7.47 (d, J = 8.6, 1H), 6.55 (s, 1H), 5.86 (s, 1H), 4.41 (s, 2H), 3.20 (m, 2H), 2.42 – 2.33 (m, 1H), 2.11 – 1.98 (m, 2H), 1.90 (m, 2H), 1.80 – 1.70 (m, 1H), 1.22 (s, 9H). LC-MS (ESI): m / z [M+H] + = 459.35.

[0341] Example 104: 5-((5-(3-(5-(tert-butyl)tetrahydrofuran-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: 2-Bromo-5-(tert-butyl)furan NBS (1.96 g, 11 mmol) was added to a solution of 2-(tert-butyl)furan (1.24 g, 10 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 16 h. The mixture was diluted with H2O (50 mL) and extracted with EA (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0–30%) as elution to give the product (560 mg, 27.6%). LC-MS (ESI): m / z [M+H] + = 203.

[0342] Step 2: (1-(tert-butyl)-3-(3-(5-(tert-butyl)furan-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole- 5-yl) benzyl carbamate Add (1-(tert-butyl)furan (110 mg, 0.54 mmol) to a mixture of dioxane (10 mL) and H₂O (2 mL) to (278 mg, 0.6 mmol) benzyl carbamate, Pd(dppf)Cl₂ (43.8 mg, 0.05 mmol), and K₃PO₄ (286 mg, 1.35 mmol). Stir the mixture at 90 °C for 16 h under a nitrogen atmosphere. Concentrate the mixture under vacuum. Purify the residue by silica gel column chromatography with EA / PE (0–30%) to give the product (80 mg, 32%). LC-MS (ESI): m / z [M+H] + = 462.3.

[0343] Step 3: 1-(tert-butyl)-3-(3-(5-(tert-butyl)tetrahydrofuran-2-yl)cyclopentyl)-1H-pyrazole-5-amine Pd / C (10 mg) was added to a solution of (1-(tert-butyl)-3-(3-(5-(tert-butyl)furan-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (80 mg, 17.3 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 5 h under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under vacuum to give (53 mg, crude product), which was used for the next step without further purification. LC-MS (ESI): m / z [M+H] + = 334.3.

[0344] Step 4: 5-((1-(tert-butyl)-3-(3-(5-(tert-butyl)tetrahydrofuran-2-yl)cyclopentyl)-1H-pyrazole-5- (4-(4-methoxybenzyl)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide A mixture of 5-bromo-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (49 mg, 0.13 mmol), 1-(tert-butyl)-3-(3-(5-(tert-butyl)tetrahydrofuran-2-yl)cyclopentyl)-1H-pyrazole-5-amine (53 mg, 0.16 mmol), Pd2dba3 (14.6 mg, 0.016 mmol), and Xantphos (18.5 mg, 0.032 mmol) in dioxane (10 mL) was stirred at 100 °C for 16 h under N2 atmosphere. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with EA / PE (0-80%) elution to give the product (50 mg, 61.7%). LC-MS (ESI): m / z [M+H] + = 639.3.

[0345] Step 5: 5-((5-(3-(5-(tert-butyl)tetrahydrofuran-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4- Fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide TfOH (0.5 mL) was added to a solution of 5-((1-(tert-butyl)-3-(3-(5-(tert-butyl)tetrahydrofuran-2-yl)cyclopentyl)-1H-pyrazole-5-yl)amino)-4-fluoro-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (50 mg, 0.078 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (50 mL) and washed with saturated NaHCO3 (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the product (1.9 mg, 0.05%). LC-MS (ESI): m / z [M+H] + = 463.2.

[0346] Example 105: 4-Fluoro-5-((5-(3-(2-isopropyloxazol-5-yl)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide Step 1: 2-Bromo-5-iodoxazole TMMMgCl·LiCl (1M solution in THF) (37.43 mL, 37.43 mmol) was added dropwise to a stirred solution of 2-bromooxazole (5 g, 34.03 mmol) in dry THF (60 mL) at -60 °C. The reaction mixture was stirred at -60 °C for 1 h. Then, I₂ (9.5, 37.43 mmol) was added dropwise to THF (20 mL). The reaction mixture was slowly warmed to room temperature and then quenched with saturated Na₂S₂O₅ solution (50 mL). The aqueous layer was extracted with EA (2 × 50 mL), and the combined organic layers were dried over Na₂SO₄. The solvent was evaporated under reduced pressure, and the remaining residue was purified by rapid silica gel column chromatography with PA / EA (0% to 20%) to give the product (5 g, 53.9%). LC-MS (ESI): m / z [M+H] + = 273.8.

[0347] Step 2: (3-(3-(2-bromooxazol-5-yl)cyclopent-2-en-1-yl)-1-(tert-butyl)-1H-pyrazol-5-yl)amino benzyl carbamate To (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)cyclopent-2-en-1-yl)-1H β-pyrazole-5-yl)carbamate (450 mg, 0.97 mmol) and 2-bromo-5-iodoxazole (400 mg, 1.45 mmol) were reacted in a solution of dioxane (20 mL) and H₂O (2 mL) with Pd(PPh₃)₄ (112 mg, 0.097 mmol) and Na₂CO₃ (310 mg, 2.91 mmol). The reaction mixture was stirred at 60 °C for 16 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 3:1) to give the product (276 mg, 59%). LC-MS (ESI): m / z [M+H] + = 485.2.

[0348] Step 3: (1-(tert-butyl)-3-(3-(2-(prop-1-en-2-yl)oxazol-5-yl)cyclopent-2-en-1-yl)-1 H - pyrazole-5-yl) benzyl carbamate A solution of (3-(3-(2-bromooxazol-5-yl)cyclopent-2-en-1-yl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (100 mg, 0.207 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxacyclopentaborane (42 mg, 0.248 mmol) in dioxane (5 mL) and H₂O (0.5 mL) was mixed with Pd(dppf)Cl₂ (15 mg, 0.02 mmol) and Na₂CO₃ (66 mg, 0.621 mmol). The reaction mixture was stirred at 100 °C for 2 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 3:1) to give the product (73 mg, 79%). LC-MS (ESI): m / z [M+H] + = 447.0.

[0349] Step 4: 1-(tert-butyl)-3-(3-(2-isopropyloxazol-5-yl)cyclopent-2-en-1-yl)-1H-pyrazole-5-amine Pd / C (10%, 30 mg on carbon) was added to a solution of (1-(tert-butyl)-3-(3-(2-(prop-1-en-2-yl)oxazol-5-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (73 mg, 0.164 mmol) in THF (10 mL), and the reaction mixture was stirred at room temperature for 3 hours at 1 atm hydrogen. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure and dried under vacuum to give the product (50 mg, 96%). LC-MS (ESI): m / z [M+H] + =316.6.

[0350] Step 5: 4-Fluoro-5-((5-(3-(2-isopropyloxazol-5-yl)cyclopentyl)-1 H -pyrazole-3-yl)amino)-2, 3-Dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ =12.03 (s, 1H), 8.72 (d, J = 1.8, 1H), 8.26 (t, J = 7.6, 1H), 7.69 (s, 1H), 7.47(d, J = 8.6, 1H), 6.75 (d, J = 0.8, 1H), 5.84 (s, 1H), 4.40 (d, J = 4.3, 2H), 3.29– 3.24 (m, 1H), 3.24 – 3.15 (m, 1H), 3.00 (m, 1H), 2.45 – 2.38 (m, 1H), 2.15– 2.00 (m, 2H), 1.86 – 1.64 (m, 3H), 1.24 (d, J = 6.9, 6H). LC-MS (ESI): m / z [M+H] + = 446.27.

[0351] Example 106: 5-((5-(3-(2-cyclopropyloxazol-5-yl)cyclopentyl)-1 H -pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide Step 1: (1-(tert-butyl)-3-(3-(2-cyclopropyloxazol-5-yl)cyclopent-2-en-1-yl)-1H-pyrazole-5- Benzyl carbamate (3-(3-(2-bromooxazol-5-yl)cyclopent-2-en-1-yl)-1-(tert-butyl)-1 H β-pyrazole-5-yl)carbamate (100 mg, 0.207 mmol) and cyclopropylboronic acid (89 mg, 1.035 mmol) were reacted in a solution of dioxane (5 mL) and H₂O (0.5 mL) with Pd(dppf)Cl₂ (15 mg, 0.02 mmol) and Cs₂CO₃ (202 mg, 0.621 mmol). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The resulting mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 3:1) to give the product (20 mg, 22%). LC-MS (ESI): m / z [M+H] + = 447.0.

[0352] Step 2: 5-((5-(3-(2-cyclopropyloxazol-5-yl)cyclopentyl)-1 H -pyrazol-3-yl)amino)-4-fluoro-2, 3-Dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ =12.02 (s, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 7.69 (t, J = 5.0, 1H), 7.47 (d, J =8.6, 1H), 6.70 (s, 1H), 5.84 (s, 1H), 4.40 (d, J = 4.9, 2H), 3.28 – 3.23 (m,1H), 3.18 (m, 1H), 2.43 – 2.34 (m, 1H), 2.15 – 1.99 (m, 3H), 1.82 – 1.63 (m,3H), 1.00 – 0.95 (m, 2H), 0.89 – 0.84 (m, 2H). LC-MS (ESI): m / z [M+H] + = 444.33.

[0353] Example 107: cis-5-((5-(3-(5-(tert-butyl)furan-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: 1-(tert-butyl)-3-(3-(5-(tert-butyl)furan-2-yl)cyclopentyl)-1H-pyrazole-5-amine Pd / C (10 mg) was added to a solution of (1-(tert-butyl)-3-(3-(5-(tert-butyl)furan-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (80 mg, 17.3 mmol) in THF / EA (5 mL / 5 mL). The mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under vacuum to give (62 mg, crude product), which was used for the next step without further purification. LC-MS (ESI): m / z [M+H] + = 330.3.

[0354] Step 2: cis-5-((5-(3-(5-(tert-butyl)furan-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)- 4-Fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 104. 1 H NMR (500 MHz, DMSO- d 6) δ 12.02 (s, 1H), 8.71 (s, 1H), 8.30.-8.19 (m, 1H), 7.69 (t, J =5 Hz, 1H), 7.47(d, J =10 Hz, 1H), 5.95 (d, J =5 Hz, 1H), 5.89 (d, J =5 Hz, 1H), 5.83 (s, 1H), 4.40(d, J =5 Hz, 2H), 3.25-3.11 (m, 2H). 2.43-2.34 (m, 1H), 2.14-1.99 (m, 2H), 1.83-1.64 (m, 3H), 1.21 (s, 9H). LC-MS (ESI): m / z [M+H] + = 459.2.

[0355] Example 108: trans-5-((5-(3-(5-(tert-butyl)furan-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 107. 1 H NMR (500 MHz, DMSO- d 6) δ12.00 (s, 1H), 8.72 (s, 1H), 8.32.-8.19 (m, 1H), 7.69 (t, J =5 Hz, 1H), 7.47(d, J =10 Hz, 1H), 5.99 (d, J =5 Hz, 1H), 5.89 (d, J =5 Hz, 1H), 5.85 (s, 1H), 4.40(d, J =5 Hz, 2H), 3.33-3.18 (m, 2H), 2.20-2.05 (m, 3H), 2.03-1.94 (m, 1H), 1.79-1.65 (m, 2H), 1.22 (s, 9H). LC-MS (ESI): m / z [M+H] + = 459.2.

[0356] Example 109: 4-Fluoro-5-((5-(3-(5-isopropyloxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound in racemic form was synthesized in a procedure similar to that in Example 18 and separated by chiral HPLC to obtain: Enantiomer 1 (Example 109a, 99.67% ee); retention time: 4.06 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.04 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 7.69 (t, J = 5.2 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 1.2 Hz, 1H), 5.85 (d, J = 12.6 Hz, 1H), 4.40(d, J = 5.2 Hz, 2H), 3.24 - 3.13 (m, 1H), 2.98 - 2.89 (m, 1H), 2.48 - 2.41 (m,1H), 2.18 - 1.85 (m, 5H), 1.78 - 1.69 (m, 1H), 1.19 (dd, J= 6.8, 5.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 446.3.

[0357] Enantiomer 2 (Example 109b, 93.05% ee); retention time: 4.20 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.04 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 7.69 (t, J = 5.2 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 1.2 Hz, 1H), 5.85 (d, J = 12.6 Hz, 1H), 4.40(d, J = 5.2 Hz, 2H), 3.24 - 3.13 (m, 1H), 2.98 - 2.89 (m, 1H), 2.48 - 2.41 (m,1H), 2.18 - 1.85 (m, 5H), 1.78 - 1.69 (m, 1H), 1.19 (dd, J = 6.8, 5.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 446.3.

[0358] Enantiomer 3 (Example 109c, 94.11% ee); retention time: 4.89 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.04 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 7.69 (t, J = 5.2 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 1.2 Hz, 1H), 5.85 (d, J = 12.6 Hz, 1H), 4.40(d, J= 5.2 Hz, 2H), 3.24 - 3.13 (m, 1H), 2.98 - 2.89 (m, 1H), 2.48 - 2.41 (m,1H), 2.18 - 1.85 (m, 5H), 1.78 - 1.69 (m, 1H), 1.19 (dd, J = 6.8, 5.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 446.3.

[0359] Enantiomer 4 (Example 109d, 99.09% ee); retention time: 6.12 min. 1 H NMR (500 MHz, DMSO- d 6) δ 12.04 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 7.69 (t, J = 5.2 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 1.2 Hz, 1H), 5.85 (d, J = 12.6 Hz, 1H), 4.40(d, J = 5.2 Hz, 2H), 3.24 - 3.13 (m, 1H), 2.98 - 2.89 (m, 1H), 2.48 - 2.41 (m,1H), 2.18 - 1.85 (m, 5H), 1.78 - 1.69 (m, 1H), 1.19 (dd, J = 6.8, 5.0 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 446.3.

[0360] Chiral analysis method: Column: CHIRALPAK IA 4.6 250 mm 5 μm; Mobile phase: A is MtBE (0.1% 2MNH3MeOH) and B is DCM:MeOH=50:50; Gradient: Mobile phase A:Mobile phase B = 80:20 (v / v); HPLC equipment: HPLC-Agilent; Column temperature: 35℃.

[0361] Chiral preparative HPLC conditions: CHIRALPAK IA 20 250 mm 5 μm; Mobile phase: A is MtBE and B is MeOH:DCM=50:50; Gradient: Mobile phase A:Mobile phase B = 80:20 (v / v); Flow rate: 20 mL / min; Wavelength: UV 220nm; Preparative HPLC equipment: Preparative HPLC-Gilson; Column temperature: 25℃.

[0362] Example 110: 4-Fluoro-5-((5-(3-(5-(2-hydroxypropane-2-yl)oxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: (5-(3-oxocyclopentyl)-1H-pyrazole-3-yl)benzyl carbamate (1-(tert-butyl)-5-(3-oxocyclopentyl)-1H-pyrazole-3-yl)benzyl carbamate (10.00 g, 28.17 mmol) and formic acid (50 mL) were added to a 250-mL round-bottom flask at room temperature. The resulting mixture was stirred at 75 °C for 2 h. The mixture was concentrated under reduced pressure to give (5-(3-oxocyclopentyl)-1H-pyrazole-3-yl)benzyl carbamate (5.0 g, 59.36%). LC-MS (ESI): m / z [M+H] + = 300.3.

[0363] Step 2: 3-(((benzyloxy)carbonyl)amino)-5-(3-oxocyclopentyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester Add (5-(3-oxocyclopentyl)-1H-pyrazol-3-yl)benzyl carbamate (6.00 g, 20.07 mmol), Boc₂O (6.56 g, 30.10 mmol), Et₃N (2.08 g, 60.20 mmol), and DCM (60 mL) to a 500 mL round-bottom flask at room temperature. Stir the resulting mixture at room temperature for 5 h. Extract the mixture with DCM (200 mL). Wash the combined organic layers with brine (2 × 200 mL) and dry over anhydrous Na₂SO₄. Filter and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (100:0–90:10) elution to give tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-(3-oxocyclopentyl)-1H-pyrazole-1-carboxylic acid (7.00 g, 87.43%). LC-MS (ESI): m / z [M+H] + = 400.2.

[0364] Step 3: 3-(((benzyloxy)carbonyl)amino)-5-(3-(((trifluoromethyl)sulfonyl)oxy)cyclopent-2-ene- 1-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester In a 250-mL three-necked round-bottom flask purged and maintained with nitrogen inert gas, tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-(3-oxocyclopentyl)-1H-pyrazole-1-carboxylic acid (5.00 g, 12.53 mmol) in 100 mL of THF was added dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h. PhN(Tf)₂ (6.43 g, 18.80 mmol) in 20 mL of THF was added dropwise at -78 °C. The resulting mixture was stirred from -78 °C to room temperature for 4 h. The reaction was quenched at 0 °C with saturated NH₄Cl (aqueous solution). The resulting mixture was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (100:0–95:5) elution to give tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-(3-((((trifluoromethyl)sulfonyl)oxy)cyclopent-2-en-1-yl)-1H-pyrazol-1-carboxylic acid (4.00 g, 60.11%). LC-MS (ESI): m / z [M+H] + = 532.2.

[0365] Step 4: 3-(((benzyloxy)carbonyl)amino)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxanepentaneboron) tert-butyl alkyl-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole-1-carboxylate At room temperature, tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-(3-((((trifluoromethyl)sulfonyl)oxy)cyclopent-2-en-1-yl)-1H-pyrazole-1-carboxylic acid (4.00 g, 7.53 mmol), B2Pin2 (3.84 g, 15.07 mmol), Pd(dppf)Cl2 (607.5 mg, 0.75 mmol), KOAc (2.21 g, 22.59 mmol), and dioxane (50 mL) were added to a 250-mL round-bottom flask. The resulting mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (100:0–97:3) elution to give tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole-1-carboxylic acid (3.4 g, 88.51%). LC-MS (ESI): m / z [M+H] + = 510.4.

[0366] Step 5: 2-(3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)-1H-pyrazole-5-yl) ring Methyl pent-1-en-1-yl)oxazol-5-carboxylate At room temperature, tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole-1-carboxylate (2.40 g, 4.72 mmol), ethyl 2-bromooxazol-5-carboxylate (1.24 g, 5.66 mmol), Pd(dppf)Cl2 (380.7 mg, 0.47 mmol), K3PO4 (3.00 g, 14.16 mmol), and dioxane / H2O (5 / 1) (30 mL) were added to a 100-mL round-bottom flask. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (100:0–90:10) elution to give methyl 2-(3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)-1H-pyrazol-5-yl)cyclopent-1-en-1-yl)oxazol-5-carboxylate (1.30 g, 54.27%). LC-MS (ESI): m / z [M+H] + = 509.4.

[0367] Step 6: 3-Amino-5-(3-(5-(2-hydroxypropane-2-yl)oxazol-2-yl)cyclopent-2-en-1-yl)-1H-pyridine tert-butyl 1-azole carboxylate Methyl 2-(3-(3-((((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)-1H-pyrazol-5-yl)cyclopent-1-en-1-yl)oxazol-5-carboxylate (600.0 mg, 1.18 mmol) was added dropwise to 10 mL of THF in a 100-mL three-necked round-bottom flask purged and maintained with nitrogen. MeMgBr (1.97 mL, 5.91 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched at 0 °C with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (100:0–50:50) elution to give tert-butyl 3-amino-5-(3-(5-(2-hydroxypropan-2-yl)oxazol-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole-1-carboxylic acid (300.0 mg, 67.91%). LC-MS (ESI): m / z [M+H] + =375.4.

[0368] Step 7: 3-Amino-5-(3-(5-(2-hydroxypropane-2-yl)oxazol-2-yl)cyclopentyl)-1H-pyrazole-1-methyl tert-butyl ester 3-Amino-5-(3-(5-(2-hydroxypropan-2-yl)oxazol-2-yl)cyclopent-2-en-1-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (300.0 mg, 0.80 mmol), Pd / C (300.0 mg), and THF (10 mL) were added to a 100-mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature under H2 atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EtOAc (100:0–20:80) elution to give 3-amino-5-(3-(5-(2-hydroxypropan-2-yl)oxazol-2-yl)cyclopentyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (150.0 mg, 49.73%). LC-MS (ESI): m / z [M+H] + = 377.4.

[0369] Step 8: 2-(2-(3-(3-amino-1H-pyrazol-5-yl)cyclopentyl)oxazol-5-yl)prop-2-ol 3-Amino-5-((1S,3R)-3-(5-(2-hydroxypropane-2-yl)oxazol-2-yl)cyclopentyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (220.0 mg, 0.59 mmol), SiO2 (220.0 mg), and toluene (10 mL) were added to a 100-mL round-bottom flask at room temperature. The resulting mixture was stirred at 100 °C for 15 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM / MeOH (100:0–92:8) elution to give the product (90.0 mg, 55.73%). 1 ¹H NMR (300 MHz, chloroform-d) δ 6.80 (d, J = 9.9 Hz, 1H), 5.51 (s, 1H), 3.72(s, 2H), 3.43 (d, J = 6.6 Hz, 2H), 3.33 (s, 1H), 2.49 (dt, J = 13.6 Hz, 1H), 2.14(ddd, J = 32.1 Hz, 3H), 1.82 (s, 1H), 1.46 (s, 6H). LC-MS (ESI): m / z [M+H] + =277.3.

[0370] Step 9: 4-Fluoro-5-((5-(3-(5-(2-hydroxypropane-2-yl)oxazol-2-yl)cyclopentyl)-1H-pyrazole-3- (amino)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 6. 1 H NMR (500 MHz, DMSO- d 6) δ 12.05 (s, 1H), 8.73 (d, J = 2.6 Hz, 1H), 8.26 (s, 1H), 7.69 (t, J = 5.1 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 6.79 (s, 1H), 5.84 (s, 1H), 5.23 (s, 1H), 4.40 (d, J =5.0 Hz, 2H), 3.41 – 3.34 (m, 1H), 3.20 (ddd, J = 17.5, 10.1, 7.3 Hz, 1H), 2.45(dd, J= 13.5, 6.2 Hz, 1H), 2.17 – 2.06 (m, 2H), 2.03 – 1.94 (m, 1H), 1.90 (dt, J = 12.3, 10.2 Hz, 1H), 1.75 (ddd, J = 12.7, 10.5, 5.6 Hz, 1H), 1.42 (s, 6H). LC-MS (ESI): m / z [M+H] + = 462.3.

[0371] Example 111: 5-((5-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: (4,4-Dimethyl-3-oxopentane-2-yl)tert-butyl carbamate n-BuLi (45.26 mL, 113.15 mmol) was added dropwise to a solution of (1-(methoxy(methyl)amino)-1-oxopropane-2-yl)carbamate tert-butyl ester (10.50 g, 45.26 mmol) in Et₂O (150 mL) at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 2 h. The reaction was quenched at 0 °C with saturated NH₄Cl (aqueous solution) and then extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with PE / EA (100:0–90:10) elution to give the product (1.8 g, 17.37%). LC-MS (ESI): m / z [M+H] + = 230.3.

[0372] Step 2: 4-Amino-2,2-dimethylpentan-3-one chloride (4,4-Dimethyl-3-oxopentane-2-yl)tert-butyl carbamate (1.8 g, 13.95 mmol) and HCl-dioxane (4 M, 20 mL) were added to a 250 mL round-bottom flask at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give the product (1.0 g, 98.62% yield). LC-MS (ESI): m / z [M+H] + =130.3.

[0373] Step 3: cis-3-((4,4-dimethyl-3-oxopent-2-yl)carbamoyl)cyclopentane-1-carboxylic acid 4-Amino-2,2-dimethylpentan-3-one (1.0 g, 7.75 mmol) and TEA (1.57 g, 15.5 mmol) were added to a solution of (1R,5S)-3-oxabicyclo[3.2.1]octane-2,4-dione (1.09 g, 7.75 mmol) in THF (30 mL). The resulting mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure to give the product (2.0 g, 95.91%). LC-MS (ESI): m / z [M+H] + = 270.3.

[0374] Step 4: cis-3-((4,4-dimethyl-3-oxopentane-2-yl)carbamoyl)cyclopentane-1-carboxylic acid ester 2.05 g (7.62 mmol) of cis-3-((4,4-dimethyl-3-oxopent-2-yl)carbamoyl)cyclopentane-1-carboxylic acid was dissolved in MeOH (50 mL) and H₂SO₄ (1.49 g, 15.24 mmol) was added. The resulting mixture was stirred at room temperature for 3 h. The mixture was neutralized to pH 7 with aqueous Na₂CO₃ and extracted with 150 mL of EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using PE / EtOAc (100:0–70:30) elution to give the product (1.90 g, 88% yield). LC-MS (ESI): m / z [M+H] + = 284.3.

[0375] Step 5: Methyl cis-3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentane-1-carboxylate Methyl cis-3-((4,4-dimethyl-3-oxopentane-2-yl)carbamoyl)cyclopentane-1-carboxylate (1.90 g, 6.71 mmol) was added to POCl3 (40 mL). The resulting mixture was stirred at 60 °C for 5 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (100:0–40:60) elution to give the product (1.60 g, 89.93%). LC-MS (ESI): m / z [M+H] + = 266.2.

[0376] Step 6: 3-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-3-oxopropionitrile CH3CN (496.1 mg, 12.1 mmol) in 20 mL of THF was placed in a 100-mL three-necked round-bottom flask purged with nitrogen. Then, n-BuLi (4.84 mL, 12.1 mmol) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 30 min, and then added dropwise at -78 °C to a solution of methyl cis-3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentane-1-carboxylate (1.60 g, 6.04 mmol) in 50 mL of THF. The resulting mixture was stirred at -78 °C for 2 h. The reaction was quenched at 0 °C with saturated NH4Cl (aqueous solution). The resulting mixture was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / EA (100:0–60:40) elution to give the product (0.92 g, 55.61% yield). LC-MS (ESI): m / z [M+H] + = 275.3.

[0377] Step 7: 5-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine Hydrazine hydrate (180.5 mg, 3.61 mmol) and TsOH (50 mg) were added to a solution of 3-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-3-oxopropionitrile (900.0 mg, 3.28 mmol) in EtOH (20 mL). The resulting mixture was stirred at 90 °C for 1 h. The reaction was concentrated under vacuum, and the residue was purified by silica gel column chromatography with PE:EA (100:0 to 80:20) to give the product (844.6 mg, 89.28% yield). 1 H NMR (300MHz, DMSO- d 6) δ 5.19 (s, 1H), 3.21 (p, J = 8.1 Hz, 1H), 3.10 – 2.94 (m, 1H), 2.39 – 2.24 (m, 1H), 2.10 (s, 4H), 2.08 – 1.85 (m, 3H), 1.88 – 1.59 (m, 1H), 1.27 (s, 9H). LC-MS (ESI): m / z [M+H] + = 289.3.

[0378] Step 8: 5-((5-(3-(5-(tert-butyl)-4-methyloxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino 1,1-dioxide of 4-fluoro-2,3-dihydrobenzo[d]isothiazolium The title compound was synthesized in a procedure similar to that of Example 6. 1 H NMR (500 MHz, DMSO- d 6) δ 12.03(s, 1H), 8.72 (s, 1H), 8.26 (t, J =5 Hz, 1H), 7.69 (d, J =5 Hz, 1H), 7.47 (d, J =10Hz, 1H), 5.84 (s, 1H), 4.40 (d, J =5 Hz, 2H), 3.30-3.12 (m, 2H), 2.46-2.38 (m,1H), 2.18-2.03 (m, 5H), 1.99-1.82 (m, 2H), 1.77-1.69 (m, 1H), 1.27 (s, 9H). LC-MS (ESI): m / z [M+H] + = 474.2.

[0379] Example 112: 4-Fluoro-5-((5-(3-(5-(1-methylcyclopropyl)oxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: Trimethyl((1-methylcyclopropyl)ethynyl)silane n-BuLi (2.5 M) (29 mL, 72.4 mmol) was added to a solution of (cyclopropylethynyl)trimethylsilane (10 g, 72.4 mmol) in diethyl ether (80 mL) at room temperature and stirred overnight. Dimethyl sulfate (24.5 g, 194 mmol) was added at -10 °C. The reaction was stirred at room temperature for 1 h. The reaction was quenched with NH4Cl:NH3H2O ​​= 1:3 (125 mL) and stirred at room temperature for 1 h. The resulting solution was extracted with 2 × 150 mL of Et2O. The combined organic layers were washed with 5% HCl solution, NaHCO3 solution, and water. The reaction was concentrated under reduced pressure at 0 °C to give the crude product (11 g, 95%).

[0380] Step 2: Methyl 3-cyanocyclopentane-1-carboxylate TEA (10.6 g, 105 mmol) and TFAA (16.2 g, 77.2 mmol) were added to a solution of methyl 3-carbamoylcyclopentane-1-carboxylate (6 g, 35 mmol) in THF (150 mL), and the mixture was stirred at room temperature for 3 h. The reaction was concentrated under vacuum. The crude product was purified by silica gel column chromatography with PE:EA (100:0 to 77:23) to give the product (4.6 g, 85.8%).

[0381] Step 3: Methyl 3-(5-(1-methylcyclopropyl)oxazol-2-yl)cyclopentane-1-carboxylate Ph3PAuNTf2 (723 mg, 0.979 mmol) and 8-methylquinoline 1-oxide (4.05 g, 25.46 mmol) were added to a solution of methyl 3-cyanocyclopentane-1-carboxylate (3 g, 19.59 mmol) in trimethyl((1-methylcyclopropyl)ethynyl)silane (9 g, 58.77 mmol). The resulting mixture was stirred at 60 °C for 4 h under a nitrogen atmosphere. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography using PE:EA (100:0 to 92:8) elution to give the product (5 g, 95%). LCMS (ESI) m / z [M+H] + = 250.

[0382] Step 4: 3-(3-(5-(1-methylcyclopropyl)oxazol-2-yl)cyclopentyl)-3-oxopropionitrile n-Buli (2.5 M) (3.2 mL, 1.6 mmol) was added to a solution of CH3CN (330 mg, 1.6 mmol) in THF (30 mL) at -78 °C and stirred for 1 h under N2 atmosphere. Methyl 3-(5-(1-methylcyclopropyl)oxazol-2-yl)cyclopentane-1-carboxylate (1 g, 0.8 mmol) was added at -78 °C and stirred for another hour. The reaction was quenched with NH4Cl solution (40 mL) and extracted with 3 × 30 mL EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography with PE:EA (100:0 to 60:40) elution to give the product (540 mg, 52.4%). LCMS (ESI) m / z [M+H] + = 259.

[0383] Step 5: 5-(3-(5-(1-methylcyclopropyl)oxazol-2-yl)cyclopentyl)-1H-pyrazole-3-amine A solution of 3-(3-(5-(1-methylcyclopropyl)oxazol-2-yl)cyclopentyl)-3-oxopropionitrile (500 mg, 1.93 mmol) in EtOH (10 mL) was added to a solution of 3-(3-(5-(1-methylcyclopropyl)oxazol-2-yl)cyclopentyl)-3-oxopropionitrile (500 mg, 1.93 mmol) and stirred at 90 °C for 1 h. The reaction was concentrated under vacuum, and the residue was purified by silica gel column chromatography by elution with DCM:MeOH (100:0 to 94:6) to give the product (468 mg, 88.8%). 1 H NMR (300 MHz, DMSO- d 6) δ 6.69 (s, 1H), 5.21 (d, J = 7.8 Hz, 2H), 3.27 – 2.94 (m, 5H), 2.42 – 2.23 (m,2H), 2.14 – 1.59 (m, 13H), 1.35 (s, 3H), 0.91 (q, J = 4.0 Hz, 2H), 0.79 – 0.70(m, 2H). LCMS (ESI) m / z [M+H] + = 273.

[0384] Step 6: 4-Fluoro-5-((5-(3-(5-(1-methylcyclopropyl)oxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl) (amino)-2,3-dihydrobenzo[d]isothiazol 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 6. 1 H NMR (500 MHz, DMSO- d 6) δ =12.04 (s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 7.69 (s, 1H), 7.48 (d, J = 8.6 Hz,1H), 6.70 (s, 1H), 5.83 (s, 1H), 4.41 (s, 2H), 3.24-3.14 (m, 2H), 2.46 – 2.38(m, 1H), 2.16 – 2.02 (m, 2H), 2.01 – 1.83 (m, 2H), 1.77 – 1.67 (m, 1H), 1.34 (s, 3H), 0.91 (q, J = 4.1 Hz, 2H), 0.75 (q, J = 4.1 Hz, 2H). LC-MS (ESI): m / z [M+H]+ = 458.2.

[0385] Example 113: 5-(tert-butyl)-2-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[] d Isothiazol-5-yl)amino)-1 H methyl pyrazol-5-yl)cyclopentyl)oxazol-4-carboxylate Step 1: Ethyl 2-bromo-5-(tert-butyl)oxazol-4-carboxylate LiHMDS (1.0 M, 11.2 mL, 11.2 mmol in THF) was added to a solution of ethyl 5-(tert-butyl)oxazol-4-carboxylate (2.0 g, 10.15 mmol) in 50 mL of THF at -60 °C under nitrogen atmosphere. The mixture was stirred at -60 °C for 1 hour, followed by the addition of CBr4 (3.37 g, 10.15 mmol) in 15 mL of THF at -60 °C. The reaction mixture was then warmed to room temperature and stirred for another 30 minutes. The resulting mixture was quenched with a saturated aqueous NH4Cl solution, extracted with EA, dried over Na2SO4, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 5:1) to give the product (1.4 g, 50%). LC-MS (ESI): m / z [M+H] + = 276.0.

[0386] Step 2: 5-(tert-butyl)-2-(3-(1-(tert-butyl)-5-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]) Ethyl isothiazol-5-yl)amino)-1H-pyrazole-3-yl)cyclopentyl)oxazol-4-carboxylate The title compound was synthesized using a procedure similar to that in Example 1. LC-MS (ESI): m / z [M+H] + = 588.3.

[0387] Step 3: 5-(tert-butyl)-2-(3-(5-((4-fluoro-2-formyl-1,1-dioxide-2,3-dihydrobenzo[d]iso) Thiazol-5-yl)amino)-1H-pyrazole-3-yl)cyclopentyl)oxazol-4-carboxylic acid ethyl ester Ethyl 5-(tert-butyl)-2-(3-(1-(tert-butyl)-5-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazole-3-yl)cyclopentyl)oxazol-4-carboxylate (72 mg, 0.122 mmol) was dissolved in formic acid (10 mL) and stirred at 75 °C for 4 h. The solution was concentrated under vacuum to give the crude product, which was used directly in the next step without further purification. LC-MS (ESI): m / z [M+H] + = 560.3.

[0388] Step 4: 5-(tert-butyl)-2-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[ d Isothiazine-5- (amino)-1 H methyl pyrazol-5-yl)cyclopentyl)oxazol-4-carboxylate K₂CO₃ (34 mg, 0.25 mmol) was added to a solution of ethyl 5-(tert-butyl)-2-(3-(5-((4-fluoro-2-formyl-1,1-dioxy-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazole-3-yl)cyclopentyl)oxazol-4-carboxylate (70 mg, crude) in MeOH (10 mL), and the mixture was stirred at room temperature for 1 h. The mixture was filtered and concentrated, and the residue was purified by column chromatography on silica gel (100% EA) to give the product (20 mg, 32%). 1 H NMR (500 MHz, DMSO-) d 6) δ = 12.05 (d, J = 8.4, 1H), 8.73 (d, J = 5.7, 1H), 8.25 (d, J =7.7, 1H), 7.69 (s, 1H), 7.47 (d, J = 8.6, 1H), 5.85 (d, J = 16.4, 1H), 4.40 (d, J =2.4, 2H), 3.79 (d, J = 5.3, 3H), 3.49 – 3.38 (m, 1H), 3.24 – 3.18 (m, 1H), 2.45(m, 1H), 2.35 – 2.15 (m, 1H), 2.15 – 2.03 (m, 2H), 1.97 – 1.87 (m, 1H), 1.79– 1.68 (m, 1H), 1.38 (d, J = 7.1, 9H). LC-MS (ESI): m / z [M+H] + = 518.41.

[0389] Example 114: 5-(tert-butyl)-2-(3-(3-((4-fluoro-1,1-dioxide-2,3-dihydrobenzo[] d Isothiazol-5-yl)amino)-1 H ethyl pyrazol-5-yl)cyclopentyl)oxazol-4-carboxylate In step 4 of Example 113 (column chromatography on silica gel, eluted with 100% EA), the title compound was separated.1 HNMR (500 MHz, DMSO- d 6) δ = 12.05 (d, J = 10.3, 1H), 8.73 (d, J = 5.9, 1H), 8.26(s, 1H), 7.69 (s, 1H), 7.47 (m, 1H), 5.86 (d, J = 13.6, 1H), 4.41 (s, 2H), 4.27(m, 2H), 3.49 – 3.38 (m, 1H), 3.25 – 3.16 (m, 1H), 2.48 – 2.43 (m, 1H), 2.35– 2.16 (m, 1H), 2.15 – 2.01 (m, 2H), 2.00 – 1.86 (m, 1H), 1.75 (m, 1H), 1.38(d, J = 6.8, 9H), 1.28 (m, 3H). LC-MS (ESI): m / z [M+H] + = 532.40.

[0390] Example 115: 2-(3-(3-((4-fluoro-1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl-5-yl)amino)-1H-pyrazole-5-yl)cyclopentyl)-5-isopropyloxazol-4-carboxylic acid ethyl ester The title compound was synthesized in a procedure similar to that of Example 114. 1 H NMR (500 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.73 (d, J = 6.0 Hz, 1H), 8.30 (d, J = 46.7 Hz, 1H), 7.69 (s, 1H), 7.47 (dd, J = 8.6, 3.2 Hz, 1H), 5.86 (d, J = 15.3 Hz, 1H), 4.41 (s, 2H), 4.31 –4.18 (m, 2H), 3.66 (tt, J= 13.9, 6.9 Hz, 1H), 3.54 – 3.43 (m, 1H), 3.28 – 3.17(m, 1H), 2.49 – 2.43 (m, 1H), 2.25 – 2.09 (m, 2H), 2.08 – 1.87 (m, 2H), 1.81– 1.65 (m, 1H), 1.28 (td, J = 7.1, 3.8 Hz, 3H), 1.23 (dd, J = 10.3, 4.3 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 519.2.

[0391] Example 116: 5-((5-(3-(5-cyclopropyloxazol-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 9. 1 H NMR (500 MHz, DMSO) δ 12.03(s, 1H), 8.73 (s, 1H), 8.26 (s, 1H), 7.69 (t, J = 5.0 Hz, 1H), 7.47 (d, J = 8.6Hz, 1H), 6.70 (d, J = 0.6 Hz, 1H), 5.83 (s, 1H), 4.40 (d, J = 5.1 Hz, 2H), 3.29(s, 1H), 3.23 – 3.14 (m, 1H), 2.46 – 2.38 (m, 1H), 2.15 – 2.05 (m, 2H), 2.00 – 1.84 (m, 3H), 1.77 – 1.69 (m, 1H), 0.92 – 0.86 (m, 2H), 0.71 – 0.66 (m, 2H). LC-MS (ESI): m / z [M+H] + = 444.3.

[0392] Example 117: 5-((3-(3-(4-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.08(s, 1H), 8.73 (s, 1H), 8.50-8.41 (m, 1H), 8.32-8.22 (m, 1H), 7.69 (d, J =5 Hz, 1H), 7.48 (d, J =10 Hz, 1H), 7.42-7.24 (m, 2H), 5.88 (s, 1H), 4.40 (d, J =5 Hz,2H), 3.48-3.38 (m, 1H), 3.27-3.19 (m, 1H), 2.45-2.35 (m, 1H), 2.29-2.06 (m,2H), 2.01-1.80 (m, 3H), 1.28 (s, 9H). LC-MS (ESI): m / z [M+H] + = 470.2.

[0393] Example 118: 5-((3-(3-(6-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazole-5-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.08(s, 1H), 8.74 (s, 1H), 8.31-8.21 (m, 1H), 7.77-7.56 (m, 2H), 7.47 (d, J =10 Hz,1H), 7.32-7.03 (m, 2H), 5.87 (s, 1H), 4.41 (s, 2H), 3.44-3.17 (m, 2H), 2.45-2.38 (m, 1H), 2.30-2.03 (m, 2H), 2.01-1.78 (m, 3H), 1.33 (s, 9H). LC-MS (ESI): m / z [M+H] + = 470.2.

[0394] Example 119: 5-((3-(3-(5-(tert-butyl)pyridin-2-yl)cyclopentyl)-1H-pyrazol-5-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.06 (s, 1H), 8.72 (d, J =5 Hz, 1H), 8.56 (d, J =5 Hz, 1H), 8.33-8.22 (m, 1 H), 7.75-7.66 (m, 2H), 7.48 (d, J =10 Hz, 1H), 7.23 (d, J =10 Hz, 1H), 5.87 (s, 1H), 4.41(d, J =5 Hz, 2H), 3.30-3.18 (m, 2H), 2.42-2.33 (m, 1H), 2.22-2.02 (m, 2H), 1.98-1.76 (m, 3H), 1.30 (s, 9H). LC-MS (ESI): m / z [M+H] + = 470.2.

[0395] Example 120: 4-Fluoro-5-((5-(3-(6-methylpyridin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.11(s, 1H), 8.75 (s, 1H), 8.47-8.16 (m, 2H), 7.94-7.62 (m, 3H), 7.48 (d, J=10 Hz,1H), 5.91 (s, 1H), 4.41 (s, 2H), 3.49-3.25 (m, 2H), 2.69 (s, 3H), 2.57-2.54(m, 1H), 2.33-2.15 (m, 2H), 2.02-1.84 (m, 3H). LC-MS (ESI): m / z [M+H] + = 427.1.

[0396] Example 121: 4-Fluoro-5-((5-(3-(6-methoxypyridin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.05(s, 1H), 8.73 (s, 1H), 8.25 (t, J =5 Hz, 1H), 7.74-7.65 (m, 1H), 7.60 (t, J =10Hz, 1H), 7.48 (d, J =10 Hz, 1H), 6.88 (d, J =10 Hz, 1H), 6.62 (d, J =10 Hz, 1H),5.87 (s, 1H), 4.41 (s, 2H), 3.84 (s, 3H), 3.44-3.16 (m, 2H), 2.44-2.34 (m,1H), 2.27-2.01 (m, 2H), 1.99-1.72 (m, 3H). LC-MS (ESI): m / z [M+H] + = 444.1.

[0397] Example 122: 4-Fluoro-5-((5-(3-(4-isopropylpyridin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound (90 mg) was synthesized in a procedure similar to that in Example 4. 1 H NMR (500 MHz, DMSO- d6)δ 12.07 (s, 1H), 8.73 (s, 1H), 8.41 (d, J = 7.7 Hz, 1H), 8.28 (t, J = 7.7 Hz,1H), 7.69 (s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.17 (s, 1H), 7.09 (dd, J = 5.1, 1.4Hz, 1H), 5.87 (s, 1H), 4.41 (d, J = 4.4 Hz, 2H), 3.25-3.16 (m, 1H), 2.90-2.82(m, 1H), 2.57-2.54 (m, 1H), 2.40-2.35 (m, 1H), 2.20-2.05 (m, 2H), 2.00-1.90(m, 2H), 1.89 – 1.77 (m, 1H), 1.20 (d, J = 6.9 Hz, 6H). LC-MS (ESI): m / z [M+H] + =456.34.

[0398] Example 123: 5-((5-(3-(4-(tert-butyl)-6-methylpyridin-2-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 2. 1 H NMR (500 MHz, DMSO- d 6) δ 12.18(s, 1H), 8.72 (s, 1H), 8.33-8.22 (m, 1H), 7.69 (t, J =5 Hz, 1H), 7.48 (d, J =10Hz, 1H), 7.07 (s, 2H), 5.88 (s, 1H), 4.41 (d, J =5 Hz, 2H), 3.30-3.18 (m, 2H), 2.44 (s, 3H), 2.40-2.32 (m, 1H), 2.18-2.02 (m, 2H), 1.98-1.78 (m, 3H), 1.25(s, 9H). LC-MS (ESI): m / z [M+H]+ = 484.2.

[0399] Example 124: 4-Fluoro-5-((5-(3-(4-methylpyrimidin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: (1-(tert-butyl)-3-(3-(4-methylpyrimidin-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl) benzyl carbamate Pd(dppf)Cl2 (146 mg, 0.2 mmol), K2CO3 (828 mg, 6 mmol), and H2O (2 mL) were added to a mixture of (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (930 mg, 2 mmol) and 2-chloro-4-methylpyrimidine (256 mg, 2 mmol) in dioxane (20 mL). The reaction mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography with PE / EA (4:1) elution to give the product (265 mg, 25%). LC-MS (ESI): m / z [M+H] + = 432.3.

[0400] Step 2: (5-(3-(4-methylpyrimidin-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-3-yl)benzyl carbamate ester A mixture of (1-(tert-butyl)-3-(3-(4-methylpyrimidin-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (265 mg, 0.5 mmol) in formic acid (3 mL) was stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography with PE / EA (2:1) elution to give the product (125 mg, 66%). LC-MS (ESI): m / z [M+H] + = 376.2.

[0401] Step 3: 5-(3-(4-methylpyrimidin-2-yl)cyclopentyl)-1H-pyrazole-3-amine Pd / C (63 mg, 0.5 M) was added to a mixture of (5-(3-(4-methylpyrimidin-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-3-yl)carbamate (125 mg, 0.33 mmol) and H2O (1 mL) in THF (4 mL). The reaction was stirred at room temperature under H2 for 12 h. The mixture was filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with DCM / MeOH (10:1) elution to give the product (36 mg, 44%). LC-MS (ESI): m / z [M+H] + = 244.2.

[0402] Step 4: 4-Fluoro-5-((5-(3-(4-methylpyrimidin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3- Dihydrobenzo[d]isothiazol 1,1-dioxide BrettPhos Pd G3 (9 mg, 0.01 mmol) and K2CO3 (42 mg, 0.3 mmol) were added to a mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (26 mg, 0.1 mmol) and 5-(3-(4-methylpyrimidin-2-yl)cyclopentyl)-1H-pyrazole-3-amine (24 mg, 0.1 mmol) in t-BuOH (3 mL). The reaction mixture was stirred at 110 °C for 4 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18: RD-CO-058 column, eluted with 34%–49% water (containing 0.1% FA) in acetonitrile to give the product (6.79 mg, 16%). 1 H NMR (500 MHz, DMSO- d6) δ 12.04 (s, 1H), 8.72 (s,1H), 8.58 (d, J = 5.1 Hz, 1H), 8.28 (t, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.48(d, J = 8.6 Hz, 1H), 7.20 (d, J = 5.1 Hz, 1H), 5.86 (s, 1H), 4.41 (s, 2H), 3.44 (dt, J = 16.1, 8.2 Hz, 1H), 3.27 – 3.19 (m, 1H), 2.48 – 2.38 (m, 4H), 2.11 – 1.95 (m, 4H), 1.87 – 1.76 (m, 1H). LC-MS (ESI): m / z [M+H] + = 429.3.

[0403] Example 125: 5-((5-(3-(4-ethylpyrimidin-2-yl)cyclopentyl)-1 H -pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ =12.04 (s, 1H), 8.72 (d, J = 4.7, 1H), 8.61 (d, J = 5.1, 1H), 8.27 (s, 1H), 7.69(t, J = 5.0, 1H), 7.48 (d, J = 8.5, 1H), 7.21 (d, J = 5.1, 1H), 5.87 (d, J = 8.6,1H), 4.41 (d, J = 5.0, 2H), 3.58 – 3.41 (m, 1H), 3.28 – 3.18 (m, 1H), 2.71 (m,2H), 2.47 – 2.31 (m, 1H), 2.24 – 2.09 (m, 2H), 2.09 – 1.91 (m, 2H), 1.87 –1.73 (m, 1H), 1.22 (m, 3H). LC-MS (ESI): m / z [M+H]+ = 443.3.

[0404] Example 126: 4-Fluoro-5-((5-(3-(4-isopropylpyrimidin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ12.04 (s, 1H), 8.72 (s, 1H), 8.62 (d, J = 4.9 Hz, 1H), 8.27 (s, 1H), 7.69 (s,1H), 7.48 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 5.87 (d, J = 10.0 Hz, 1H),4.41 (s, 2H), 3.59 – 3.43 (m, 1H), 3.27 – 3.15 (m, 1H), 3.00 – 2.88 (m, 1H),2.45 (dd, J = 12.7, 6.6 Hz, 1H), 2.25 – 1.95 (m, 4H), 1.82 (dd, J = 26.1, 16.8Hz, 1H), 1.23 (d, J = 6.7 Hz, 6H). LC-MS (ESI): m / z [M+H] + = 457.2.

[0405] Example 127: cis-5-((5-(3-(4-(tert-butyl)pyrimidin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. ¹H NMR (500 MHz, DMSO-) d 6) δ =12.04 (s, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.63 (d, J= 5.3 Hz, 1H), 8.26 (s, 1H), 7.69 (t, J = 5.2 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 5.3 Hz, 1H), 5.85(s, 1H), 4.40 (d, J = 5.1 Hz, 2H), 3.51-3.43 (m, 2H), 3.25 – 3.19 (m, 1H), 2.47– 2.42 (m, 1H), 2.20 – 1.94 (m, 5H), 1.88 – 1.76 (m, 1H), 1.30 (s, 9H). LC-MS(ESI): m / z [M+H]+ = 471.2.

[0406] Example 128: 5-((5-(3-(5-(tert-butyl)pyridin-3-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.06(s, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.31-8.22 (m, 1H), 7.73(s, 1H), 7.69 (t, J =5 Hz, 1H), 7.48 (d, J =10 Hz, 1H), 5.89 (s, 1H), 4.41 (d, J =5Hz, 2H), 3.29-3.15 (m, 2H), 2.46-2.39 (m, 1H), 2.24-2.12 (m, 2H), 1.95-1.71(m, 3H), 1.31 (s, 9H). LC-MS (ESI): m / z [M+H] + = 470.2.

[0407] Example 129: 5-((5-(3-(2-(tert-butyl)pyridin-4-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.08(s, 1H), 8.74 (s, 1H), 8.53 (s, 1H), 8.13 (s, 1H), 7.38-7.32 (m, 4H), 5.90(s, 1H), 4.41 (s, 2H), 3.30-3.21 (m, 2H), 2.48-2.42 (m, 1H), 2.26-2.14 (m, 2H), 1.95-1.72 (m, 3H), 1.36 (s, 9H). LC-MS (ESI): m / z [M+H] + = 470.2.

[0408] Example 130: 5-((5-(3-(6-(tert-butyl)pyrimidin-4-yl)cyclopentyl)-1 H -pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[ d Isothiazole 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ = 12.04 (d, J = 8.9, 1H), 9.03 (m, 1H), 8.73 (s, 1H), 8.28 (d, J = 7.0, 1H), 7.69(s, 1H), 7.48 (d, J = 8.6, 1H), 7.43 (s, 1H), 5.88 (s, 1H), 4.41 (d, J = 4.4,2H), 3.43 (m, 1H), 3.23 (m, 1H), 2.45 – 2.23 (m, 1H), 2.23 – 2.08 (m, 2H),2.08 – 1.72 (m, 3H), 1.31 (d, J = 5.1, 9H). LC-MS (ESI): m / z [M+H] + = 471.35.

[0409] Example 131: 5-((5-(3-(5-(tert-butyl)pyridazin-3-yl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide The title compound was synthesized in a procedure similar to that of Example 1. 1 H NMR (500 MHz, DMSO- d 6) δ 12.08(s, 1H), 9.20 (s, 1H), 8.74 (s, 1H), 8.28 (t, J =5 Hz, 1H), 7.69 (t, J =5 Hz,1H), 7.54-7.45 (m, 2H), 5.89 (s, 1H), 4.41 (d, J =5 Hz, 2H), 3.62-3.47 (m, 1H), 3.30-3.24 (m, 1H), 2.49-2.44 (m, 1H), 2.34-2.13 (m, 2H), 2.07-1.83 (m, 3H), 1.31 (s, 9H). LC-MS (ESI): m / z [M+H] + = 470.2.

[0410] Example 132: 5-((5-(3-(3-(tert-butyl)phenyl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide Step 1: (1-(tert-butyl)-3-(3-(3-(tert-butyl)phenyl)cyclopent-2-en-1-yl)-1H-pyrazole-5-yl) benzyl carbamate Pd(dppf)Cl2 (146 mg, 0.2 mmol), K2CO3 (828 mg, 6 mmol), and H2O (2 mL) were added to a mixture of (1-(tert-butyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (930 mg, 2 mmol) and 1-bromo-3-(tert-butyl)benzene (426 mg, 2 mmol) in dioxane (20 mL). The reaction mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography with PE / EA (4:1) elution to give the product (472 mg, 50%). LC-MS (ESI): m / z [M+H]+ = 472.3.

[0411] Step 2: (3-(3-(3-(tert-butyl)phenyl)cyclopent-2-en-1-yl)-1H-pyrazole-5-yl)carbamate A mixture of (1-(tert-butyl)-3-(3-(3-(tert-butyl)phenyl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (472 mg, 1 mmol) in formic acid (4 mL) was stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography with PE / EA (2:1) elution to give the product (332 mg, 80%). LC-MS (ESI): m / z [M+H] + = 416.3.

[0412] Step 3: 5-(3-(3-(tert-butyl)phenyl)cyclopentyl)-1H-pyrazole-3-amine Pd / C (104 mg, 0.5 M) was added to a mixture of (3-(3-(3-(tert-butyl)phenyl)cyclopent-2-en-1-yl)-1H-pyrazol-5-yl)carbamate (104 mg, 0.25 mmol) and H2O (1 mL) in THF (4 mL). The reaction was stirred at room temperature under H2 for 12 h. The mixture was filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with DCM / MeOH (10:1) elution to give the product (28 mg, 39%). LC-MS (ESI): m / z [M+H] + = 284.2.

[0413] Step 4: 5-((5-(3-(3-(tert-butyl)phenyl)cyclopentyl)-1H-pyrazole-3-yl)amino)-4-fluoro-2,3-di Hydrobenzo[d]isothiazolium 1,1-dioxide BrettPhos Pd G3 (9 mg, 0.01 mmol) and K2CO3 (42 mg, 0.3 mmol) were added to a mixture of 5-bromo-4-fluoro-2,3-dihydrobenzo[d]isothiazolium 1,1-dioxide (26 mg, 0.1 mmol) and 5-(3-(3-(tert-butyl)phenyl)cyclopentyl)-1H-pyrazole-3-amine (28 mg, 0.1 mmol) in t-BuOH (3 mL). The reaction mixture was stirred at 110 °C for 4 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire C18: RD-CO-058 column, eluted with 34%–49% wa...

Claims

1. A compound of formula (I) Formula (I) Or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, wherein: m can be 0, 1, 2, 3 or 4, provided that the valence theory is satisfied; n can be 0, 1, 2, 3, 4 or 5, provided that the valence theory is satisfied; It can be a single bond or a double bond independently; Ring A is selected from heteroaryl rings and aryl rings; X 1 It is a single bond or O; X 2 X 3 X 4 and X 5 Each is independently selected from N and C; R 1 Each of the following is independently selected from halogens, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -CN, and -OH, wherein each of the -C1-C8 alkyl, C3-C8 cycloalkyl, or 3- to 8-membered heterocyclic groups is optionally selected from at least one of the following: halogens, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -OH, -C6-C 12 Substitution with aryl, 5- to 12-membered heteroaryl, and oxo (=O) substituents; R 5 Selected from -SO2R 5a and -SO2NR 5a R 5b , where R 5a and R 5b Each is independently selected from hydrogen and -C1-C3 alkyl groups; R 6 Selected from hydrogen, -C1-C3 alkyl, and -C3-C8 cycloalkyl; or R 5 and R 6 Together with the atoms to which they are attached, they form 5- to 12-membered rings, the rings comprising S(=O)₂ or S(=O), and 0-2 additional heteroatoms independently selected from nitrogen and oxygen as one or more ring members; the rings are optionally substituents R. 5c replace; R 5c Each is independently selected from halogens, -C1-C8 alkyl groups, -C3-C8 cycloalkyl groups, 3- to 8-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, and oxy-group (=O); Ring B is selected from 5- to 7-membered heterocyclic groups, phenyl groups, and 5- to 7-membered heteroaryl groups; R 2 Each is independently selected from halogens, -C1-C8 alkyl groups, -C2-C8 alkenyl groups, -C2-C8 alkynyl groups, -C3-C8 cycloalkyl groups, 3- to 8-membered heterocyclic groups, and -C6-C... 12 aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 2a -CN, -C(O)R 2a -CO2R 2a -NR 2a R 2b -NR 2a COR 2b , and -NR 2a CO2R 2b The -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally selected independently from at least one of the following: halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 2c -C1-C8 alkyl-OR 2c -C(O)R 2c -CO2R 2c -NR 2c R 2d -NR 2c COR 2d , and -NR 2c CO2R 2d Substituents of the substituents; R 2a R 2b R 2c and R 2d Each is independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, C6-C 12 aryl, and 5- to 12-membered heteroaryl, wherein the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally selected from at least one group selected from halogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Substitution with aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OH, and -C1-C8 alkoxy groups; R 7 Selected from hydrogen, -C1-C3 alkyl, and -C3-C8 cycloalkyl; or Adjacent R 2 and R 7 Together with the atoms to which they are attached, they form 3- to 12-membered rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur as one or more ring members; the rings are optionally substituents R. 7a replace; R 7a Each is independently selected from halogens, -C1-C8 alkyl groups, -C3-C8 cycloalkyl groups, 3- to 8-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, and oxy-group (=O); R 3 and R 4 Each is independently selected from hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, and -C(O)R 3a Each of the -C1-C8 alkyl and C3-C8 cycloalkyl groups is optionally selected independently from at least one halogen, oxo group (=O), -CN, -OR. 3b and -NR 3b R 3c Substituents; and R 3a R 3b and R 3c Each is independently selected from hydrogen, -C1-C8 alkyl, and C3-C8 cycloalkyl; wherein each of the -C1-C8 alkyl and C3-C8 cycloalkyl is optionally substituted by at least one substituent independently selected from halogen, -C1-C8 alkyl, C3-C8 cycloalkyl, oxo (=O), -CN, -OH, and -C1-C8 alkoxy.

2. The compound of claim 1, wherein ring A is a 6-membered heteroaryl ring, and X 2 X 3 X 4 and X 5 Three of them are N; preferably, ring A is a 6-membered heteroaryl ring, and X 2 X 3 X 4 and X 5 Two of them are N; more preferably, ring A is a 6-membered heteroaryl ring, and X 2 X 3 X 4 and X 5 One of them is N; even more preferably, ring A is a 6-membered heteroaryl ring, and X 2 It is N.

3. The compound of claim 1, wherein the compound is selected from (IIa), (IIb), (IIc), and (IId): Preferably, the compound is selected from (IIIa), (IIIb), (IIIc), and (IIId): 。 4. The compound as claimed in any one of the preceding claims, wherein m can be 0, 1, 2, 3 or 4, provided that the valence theory is satisfied; R 1 Each of the following groups is independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, -CN, and -OH, wherein methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, ... Each of cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3- to 8-membered heterocyclic groups is optionally selected independently from at least one of -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, -OH, -C6-C 12 Substitution with aryl, 5- to 12-membered heteroaryl, and oxo (=O) substituents; Preferably, m is 0, 1, 2, 3 or 4, provided that the valence theory is satisfied; R 1 Each of the following groups is independently selected from -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, 3- to 8-membered heterocyclic groups, -CN, and -OH, wherein each of the methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, or 3- to 8-membered heterocyclic groups is optionally selected from at least one group independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, 3- to 8-membered heterocyclic groups, -OH, -C6-C 12 Substitution with aryl, 5- to 12-membered heteroaryl, and oxo (=O) groups; More preferably, m is 0 or 1, provided that the valence theory is satisfied; R 1 Each of the following is independently selected from -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, -CN, and -OH; wherein the methyl group is replaced by -OH. Even more preferably, m is 0 or 1, provided that valence theory is satisfied; R 1 It is -F or CH2OH.

5. The compound as claimed in any one of the preceding claims, wherein R 5 Selected from -SO2R 5a and -SO2NR 5a R 5b , where R 5a and R 5b Each is independently selected from hydrogen, methyl, ethyl, and propyl (n-propyl or isopropyl); Preferably, R 5 Selected from -SO2R 5a and -SO2NR 5a R 5b , where R 5a and R 5b Each is independently selected from hydrogen and methyl; More preferably, R 5 Selected from -SO2R 5a and -SO2NR 5a R 5b , where R 5a and R 5b Each is hydrogen; Even more preferably, R 5 It is -SO2NH2.

6. The compound as claimed in any one of the preceding claims, wherein R 6 Selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; Preferably, R 6 Selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, and cyclopentyl; More preferably, R 6 Selected from hydrogen, methyl, ethyl, and cyclopropyl; Even more preferably, R 6 It is hydrogen.

7. The compound according to any one of claims 1 to 4, wherein Adjacent R 5 and R 6 Together with the atoms to which they are attached, they form 3- to 12-membered rings, the rings comprising S(=O)₂ or S(=O), and 0-2 additional heteroatoms independently selected from nitrogen and oxygen as one or more ring members; the rings are optionally substituents R. 5c replace; R 5c Each group is independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, and -C6-C. 12 Aryl, 5- to 12-membered heteroaryl, and oxy-group (=O); Preferably, adjacent R 5 and R 6 Together with the atoms to which they are attached, they form 4-, 5-, 6-, or 7-membered rings, the rings comprising S(=O)₂ or S(=O), and 0-2 additional heteroatoms independently selected from nitrogen and oxygen as one or more ring members; the rings are optionally substituents R. 5c replace; R 5c Each is independently selected from -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, and oxy-group (=O); More preferably, adjacent R 5 and R 6 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the ring comprising S(=O)₂ or S(=O), and 0-1 additional nitrogen atoms as ring members; the ring is optionally substituented by at least one R. 5c replace; R 5c Each is independently selected from -F, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, 3- to 8-membered heterocyclic groups, 5- to 12-membered heteroaryl groups, and oxo groups (=O); Even more preferably, adjacent R 5 and R 6 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, which contains S(=O)2 or S(=O) and an additional 0-1 nitrogen atoms as ring members; the ring is optionally substituted with methyl groups.

8. The compound as claimed in any one of the preceding claims, wherein Ring B is selected from 5- or 6-membered heterocyclic groups, phenyl groups, and 5- or 6-membered heteroaryl groups; Preferably, ring B is selected from 5-membered heterocyclic groups, 5-membered heteroaryl groups, 6-membered heteroaryl groups, and phenyl groups; wherein the 5-membered heterocyclic group, 5-membered heteroaryl group, or 6-membered heteroaryl group comprises 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur as one or more ring members; More preferably, ring B is selected from a 5-membered heterocyclic group comprising 1-2 heteroatoms independently selected from oxygen and nitrogen as one or more ring members, a 5-membered heteroaryl group comprising 1-3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur as one or more ring members, a 6-membered heteroaryl group comprising 1-2 nitrogen atoms as one or more ring members, and phenyl. Even more preferably, ring B is selected from furanyl, pyridinyl, oxazolyl, pyrimidinyl, pyridazinyl, pyrazolyl, thiazolyl, oxadiazolyl, phenyl, tetrahydrofuranyl, imidazolyl, triazolyl, pyrroleyl, pyrrolidinyl, imidazolyl, isothiazolyl, and isoxazolyl.

9. The compound as claimed in any one of the preceding claims, wherein n can be 0, 1, 2, 3, 4 or 5, provided that the valence theory is satisfied; R 2 Each group is independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 2a -CN, -C(O)R 2a -CO2R 2a -NR 2a R 2b -NR 2a COR 2b , and -NR 2a CO2R 2b The methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally selected independently from at least one of the following: -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 2c -C1-C8 alkyl-OR 2c -C(O)R 2c -CO2R 2c -NR 2c R 2d -NR 2c COR 2d , and -NR 2c CO2R 2d Substituents of the substituents; R 2a R 2b R 2c and R 2d Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, C6-C 12 aryl, and 5- to 12-membered heteroaryl, wherein the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally selected independently from at least one of the following: -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, C6-C 12 Substituents of aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, and octoxy; Preferably, n is 0, 1, 2, 3, 4 or 5, provided that the valence theory is satisfied; R 2 Each is independently selected from -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), -C2-C8 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo (=O), -OR 2a -CN, -C(O)R 2a -CO2R 2a -NR 2a R 2b -NR 2a COR 2b , and -NR 2a CO2R 2b The methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), -C2-C8 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally selected independently from at least one group selected from -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, 3- to 8-membered heterocyclic groups, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 2c -C1-C8 alkyl-OR 2c -C(O)R 2c -CO2R 2c -NR 2c R 2d -NR 2c COR 2d , and -NR 2c CO2R 2d Substituents of the substituents; R 2a R 2b R 2c and R 2d Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, 3- to 8-membered heterocyclic groups, C6-C 12 aryl, and 5- to 12-membered heteroaryl, wherein the methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally selected independently from at least one of -F, -Cl, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, C6-C 12 Substitution of aryl, oxo (=O), -CN, -OH, methoxy, and ethoxy groups; More preferably, n is 0, 1, 2, 3, 4 or 5, provided that the valence theory is satisfied; R 2 Each is independently selected from -Cl, methyl, ethyl, isopropyl, tert-butyl, vinyl, cyclopropyl, cyclobutyl, phenyl, oxo (=O), -OR 2a and -CO2R 2a The methyl, ethyl, isopropyl, tert-butyl, vinyl, cyclopropyl, cyclobutyl, or phenyl group is optionally selected from at least one group independently of -F, methyl, -C1-C8 alkyl, or -OR. 2c and -OR 2c Substituents of the substituents; R 2a and R 2c Each is independently selected from hydrogen, methyl, and ethyl; Even more preferably, n is 0, 1, 2, 3, 4 or 5, provided that the valence theory is satisfied; R 2 Each of the following groups is independently selected from -Cl, methyl, ethyl, isopropyl, tert-butyl, vinyl, cyclopropyl, cyclobutyl, phenyl, oxo (=O), CF3, methoxy, -OH, -CH2OCH3, CH2OH, -CO2CH3, and -CO2CH2CH3, wherein each of the ethyl, isopropyl, tert-butyl, vinyl, or cyclopropyl groups is optionally substituted by at least one substituent independently selected from methyl, -CH2OH, and -OH.

10. The compound as claimed in any one of the preceding claims, wherein R 7 Selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; Preferably, R 7 Selected from hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, and cyclopentyl; More preferably, R 7 Selected from hydrogen, methyl, ethyl, and cyclopropyl; Even more preferably, R 7 It is hydrogen.

11. The compound according to any one of claims 1 to 9, wherein n can be 2, 3, 4, or 5, provided that valence theory is satisfied; adjacent R 2 and R 7 Together with the atoms to which they are attached, they form 5-, 6-, 7-, 8-, or 9-membered rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, and optionally oxidized sulfur as one or more ring members; the rings are optionally substituents R. 7a replace; R 7a Each group is independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic groups, and -C6-C. 12 Aryl, 5- to 12-membered heteroaryl, and oxy-group (=O); Preferably, n is 2, 3, 4, or 5, provided that valence theory is satisfied; adjacent R 2 and R 7 Together with the atoms to which they are attached, they form 5-, 6-, 7-, 8-, or 9-membered rings, the rings comprising 0-3 heteroatoms independently selected from nitrogen and oxygen as one or more ring members; the rings are optionally substituents R. 7a replace; R 7a Each is independently selected from -F, -Cl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Aryl and oxy (=O); More preferably, n is 2, 3, or 4, provided that valence theory is satisfied; adjacent R 2 and R 7 Together with the atoms to which they are attached, they form a 5- or 6-membered ring, the ring containing 0-1 heteroatoms selected from nitrogen and oxygen atoms as ring members; the ring is optionally substituented by at least one R. 7a replace; R 7a Each is independently selected from -F, methyl, ethyl, cyclopropyl, cyclobutyl, -C6-C 12 Aryl and oxy (=O); Even more preferably, n is 2, provided that valence theory is satisfied; adjacent R 2 and R 7 Together with the atoms to which they are attached, they form cyclopentyl, cyclohexyl, ethylene oxide, tetrahydrofuranyl, phenyl, or pyridyl groups; wherein the cyclopentyl, cyclohexyl, ethylene oxide, or tetrahydrofuranyl groups are optionally substituted with two methyl substituents.

12. The compound as claimed in any one of the preceding claims, wherein R 3 and R 4 Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -C(O)R 3a The methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl group is optionally selected from at least one group independently from -F, -Cl, -Br, -I, -CN, or -OR. 3b and -NR 3b R 3c Substituents of the substituents; R 3a R 3b and R 3c Each of the following is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; wherein the methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl Each of the groups is optionally substituted by at least one substituent independently selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxo (=O), -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, and octyloxy; Preferably, R 3 and R 4 Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, and -C(O)R. 3a The methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), cyclopropyl, cyclobutyl, or cyclopentyl group is optionally selected independently from at least one group chosen from -F and -NR. 3b R 3c Substituents of the substituents; R 3a R 3b and R 3c Each is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; More preferably, R 3 and R 4 Each is independently selected from hydrogen, methyl, and -C(O)R 3a ;R 3a Selected from hydrogen, methyl, and ethyl; Even more preferably, R 3 and R 4 Each is hydrogen on its own.

13. The compound as claimed in any of the preceding claims, wherein Partially selected from , , , , , , , , , , , , , , , , and .

14. The compound as claimed in any of the preceding claims, wherein... Partially selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , and .

15. The compound of any one of the preceding claims, wherein the compound is selected from... 。 16. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer, or prodrug thereof, and at least one pharmaceutically acceptable carrier or excipient.

17. A method of treating cancer, the method comprising administering to a subject in need a compound as described in any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer thereof, or prodrug thereof.

18. A method of treating cancer using the compound, pharmaceutically acceptable salt, or stereoisomer, tautomer, or prodrug as claimed in any one of claims 1 to 15.

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