Indole and pyrroloypyridine derivatives as gpr17 modulators

Abstract

Disclosed is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof. The variables in Formula (I) are defined herein. Compounds of Formula (I) are useful for regulating GPR17 activity and for treating disorders and diseases mediated by GPR17 in humans or non-humans.

Description

[0001] INDOLE AND PYRROLOYPYRIDINE DERIVATIVES AS GPR17 MODULATORS RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No.63 / 532,811, filed on August 15, 2023. The entire contents of the foregoing application are expressly incorporated herein by reference. FIELD OF THE INVENTION The present invention relates to new indole and pyrrolopyridine compounds and their use for treating GPR17 mediated disorders. The present invention also relates to pharmaceutical compositions of the compounds and their use as a medicine, for example, for the treatment of GPR17 mediated disorders. The invention also relates to processes for preparation of said compounds. BACKGROUND OF THE INVENTION GPR17 is a member of a class of membrane receptors called G-protein coupled receptors (GPCRs). These receptors are characterized by a seven transmembrane domain structure with an intracellular region that couples through G proteins to numerous of intracellular signaling pathways. Many GPCRs have been used as targets for pharmaceutical drugs and diagnostics. Effective modulation of the GPR17 activity may have neuroprotective, anti- inflammatory, and anti- ischemic effects and may thus be useful for the treatment of cerebral, cardiac, and renal ischemia, and stroke, and / or for improving the recovery from these events. Pulmonary fibrosis may also be alleviated through suppressing GPR17-mediated inflammation. GPR17 modulators are also thought to be involved in food uptake, insulin and leptin responses and are thus could have a role in obesity treatment. Moreover, there is strong evidence that GPR17 is involved in myelination processes. Myelin is an essential component of a healthy central nervous system (CNS). The failure to form myelin, damage to myelin and / or the failure to repair myelin may cause certain diseases and may also be a secondary consequence of certain diseases. One example of a disease that is primarily a result of damage to myelin is multiple sclerosis (MS). MS affects approximately 400,000 people in the United States and about 2.5 million people worldwide and is approximately three times more likely to occur in women than men. MS is an inflammatory autoimmune disease that arises from an immune attack directed at oligodendrocytes which results in myelin damage and ultimately loss of neuronal axons. The immediate consequence is a collection of acute symptoms that include difficulty in movement, speech, swallowing, dizziness, and fatigue. Symptoms may also include problems with vision, hearing, or balance. The disease can take several forms. One form is associated with relapses and remissions where the acute symptoms resolve over time, and this form is termed relapsing remitting multiple sclerosis (RRMS). Another form of the disease, primary progressive MS (PPMS) is characterized by a failure to resolve symptoms between attacks, and is considered a more severe form of the disease. In most forms of MS, there is a progressive accumulation of symptoms that do not resolve, and this results in an increasing burden of disability. As MS is a CNS disease, it is beneficial for compounds that are useful for treating MS to be brain penetrant (i.e., capable of crossing blood brain barrier (BBB)). However, many compounds targeting GPR17 have low brain penetration, low stability, and / or high efflux. There is clearly a need for a safe and effective drug for the treatment of GPR17 mediated diseases, such as myelination diseases (e.g., MS), preferably for a drug that is suitable for oral administration and has good brain penetration. Additionally the compounds should have excellent GPR17 potency and microsomal stability. BRIEF DESCRIPTION OF THE FIGURES Fig.1: A schematic of plasma and PBS buffer solution including volumes to RED plated and aliquoted to crash plates. SUMMARY OF THE INVENTION Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions comprising the compounds or pharmaceutically acceptable salts thereof, which are useful for treating GPR17 mediated disorders. In some embodiments, the compounds of the present disclosure have improved potency, microsomal stability, and / or brain penetration in comparison to known GPR17 inhibitors. In a first aspect of the disclosure, the compound represented by Formula (I):

[0002] or a pharmaceutically acceptable salt thereof, wherein: X is N or CRx; Rxis H, halo, ORx1, SRx1, C1-3alkyl, C1-3haloalkyl, NRx1Rx1, C(O)Rx1a, cyano, C3-6cycloalkyl, phenyl, 5 to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, or 4 to 6-membered monocyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 Rx2; Rx1is H, C1-3alkyl or C1-3haloalkyl; Rx1ais ORx1, NRx1Rx1, C1-3alkyl or C1-3haloalkyl; each Rx2is independently halo, cyano, C1-4alkyl, C1-4haloalkyl, ORx1, NRx1Rx1, C3-6cycloalkyl; or two Rx2, together with the atoms to which they are attached, form C3-6carbocyclyl or 5 to 6-membered heterocyclyl; Ring A is a 5-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, a 9 to 10-membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected form N, O and S, or a 8 to 10-membered bicyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S; R1, for each occurrence, is independently selected from halo, -CN, C1-7alkyl, – OR1a, -NR1bR1b, -NR1bC(O)R1a, -C(O)NR1bR1b, -SR1a, C3-6cycloalkyl, phenyl, 5 to 6- membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, and 4 to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the C1-7alkyl, C3-6cycloalkyl, phenyl, 5 to 6- membered heteroaryl and 4 to 10-membered heterocyclyl are each optionally substituted with 1 to 3 R10; R1ais H, C1-6alkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, or 4 to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the C1-6alkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl and 4 to 10-membered heterocyclyl are each optionally substituted with 1 to 3 substituents independently selected from halo, C1-3alkyl and C1-3alkoxy; each R1bis independently H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, or 4 to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S; R10, for each occurrence, is independently selected from halo, -CN, -OR1a, - NR1bR1b, -NR1bC(O)R1a, -C(O)NR1bR1b, -SR1a, C1-3alkyl, C3-6cycloalkyl, phenyl and 4 to 6 membered saturated heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, wherein the C3-6cycloalkyl, phenyl and 4 to 6 membered saturated heterocyclyl are each optionally substituted by one or more halo, C1-4alkyl, C1-4haloalkyl, hydroxy, or cyano; R2is H, halo, C1-3alkyl, C1-3haloalkyl, -NR2aR2a, or –OR2a; each R2ais independently C1-3alkyl, C1-3haloalkyl, benzyl, phenyl, 5 to 10- membered heteroaryl, or -CH2-(5 to 10-membered heteroaryl), wherein the 5 to 10- membered heteroaryl contains 1-4 heteroatoms independently selected from N, O and S, and is optionally substituted with C1-3alkyl; R3is H or C1-3alkyl, wherein the C1-3alkyl is optionally substituted by 1 to 3 halo, -OR3a, -C(O)OR3a, or -C(O)NR3aR3a; each R3ais independently H or C1-3alkyl; and n is 0, 1, 2, or 3; provided that: (i) if one of R2and Rxis H, then the other is not H; (ii) if X is N then R2is not H; (iii) when Rxis H and R2is halo, alkyl, or haloalkyl, then Ring A is not

[0003] Another aspect of the disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition is for use in treating a disease or disorder mediated by GPR17. Another aspect of the disclosure is a method of regulating GPR17 activities in a subject in need thereof. The method comprises administrating to the subject in need thereof an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure, or a pharmaceutically acceptable salt thereof. Also included in the disclosure is use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for regulating GPR17 activities in a subject in need thereof. The disclosure also provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in regulating GPR17 activities in a subject in need thereof. Another aspect of the disclosure is a method of treating a subject suffering from a disease or disorder mediated by GPR17. The method comprises administrating to the subject an effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure, or a pharmaceutically acceptable salt thereof. Also included in the disclosure is use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a subject suffering from a disease or disorder mediated by GPR17. The disclosure also provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a subject suffering from a disease or disorder mediated by GPR17. Another aspect of the disclosure is a method of promoting myelination in a subject with a myelin-related disease. The method comprises administrating to the subject an effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the disclosure, or a pharmaceutically acceptable salt thereof. Also included in the disclosure is use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for promoting myelination in a subject with a myelin-related disease. The disclosure also provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in promoting myelination in a subject with a myelin-related disease. DETAILED DESCRIPTION OF THE INVENTION The compounds or pharmaceutically acceptable salts thereof, as described herein, can have activity as GPR17 modulators. In particular, compounds or pharmaceutically acceptable salts thereof, as described herein, can be GPR17 inhibitors. In a first embodiment, the compounds of the disclosure are represented by Formula (I): or a pharmaceutical salt thereof, wherein: X is N or CRx; Rxis H, halo, ORx1, SRx1, C1-3alkyl, C3-6cycloalkyl, 5 to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, or 4 to 6- membered monocyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S; Rx1is H, C1-3alkyl or C1-3haloalkyl; Ring A is a 5-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, a 9 to 10-membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected form N, O and S, or a 9 to 10-membered bicyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S; R1, for each occurrence, is independently selected from halo, -CN, C1-7alkyl, –OR1a, - SR1a, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, and 4 to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the C1-7alkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl and 4 to 10-membered heterocyclyl are each optionally substituted with 1 to 3 R10; R1ais C1-6alkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, or 4 to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the C1-6alkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl and 4 to 10-membered heterocyclyl are each optionally substituted with 1 to 3 substituents independently selected from halo, C1-3alkyl and C1-3alkoxy; R10, for each occurrence, is independently selected from halo, -CN, -OR1a, -SR1a, C1-3alkyl, C3-6cycloalkyl, phenyl and 4 to 6 membered saturated heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S; R2is H, halo, C1-3alkyl, C1-3haloalkyl, or –OR2a; R2ais C1-3alkyl, C1-3haloalkyl, benzyl, phenyl, 5 to 10-membered heteroaryl, or -CH2- (5 to 10-membered heteroaryl), wherein the 5 to 10-membered heteroaryl contains 1-4 heteroatoms independently selected from N, O and S, and is optionally substituted with C1- 3alkyl; R3is H or C1-3alkyl; and n is 0, 1, or 2. In some embodiments, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is CRx; Rxis halo, ORx1, SRx1, C1-3alkyl, C1-3haloalkyl, NRx1Rx1, C(O)Rx1a, cyano, C3-6cycloalkyl, phenyl, 5 to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, or 4 to 6-membered monocyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 Rx2; and R2is halo, C1-3alkyl, C1-3haloalkyl, -NR2aR2a, or –OR2a; and the remainder of the variables are as described for Formula (I) above. In some embodiments, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is H, -CH3, -CH2CHF2, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2CH2OH, -CH2C(O)OH, or -CH2C(O)NHCH3; and the remainder of the variables are as described for Formula (I) above. Alternatively, in some embodiments, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein R3is H; and the remainder of the variables are as described for Formula (I) above. In a second embodiment, the compounds of the disclosure are represented by Formula (I) or a pharmaceutical acceptable salt thereof, wherein X is CRx; and Rxis H, -Cl, or –OCH3; and the remainder of the variables are as described for Formula (I) above. In a third embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (II), or a pharmaceutically acceptable salt thereof, wherein the variables are as described for Formula (I) above. Alternatively, as part of the third embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (IIIa), (IIIa); or a pharmaceutically acceptable salt thereof, wherein the variables are as described for Formula (I) above. In a fourth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of pyrazolyl, dihydropyrrolopyrazolyl, dihydropyrazolooxazolyl, dihydropyrazolooxazinyl, pyrazolopyrazinonyl, pyrazolopyridinyl, triazolyl, imidazolyl, imidazothiazolyl, imidazopyridinyl, triazolopyridinyl, isothiazolyl, thiazolyl, dihydrothiopyranothiazolyl, thiadiazolyl, thiophenyl, isoxazolyl, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzoloxazolyl, pyridylisoxazolyl, benzoisoxazolyl, indazolyl, pyrazolopyridinyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, and pyridylpyrazolyl,, each of which is optionally substituted with 1 to 3 R1; and the remaining variables are as described in the first aspect or the first, second or third embodiment. Alternatively, as part of the fourth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of pyrazolyl, triazolyl, isothiazolyl, thiazolyl, thiadiazolyl, thiophenyl, isoxazolyl, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzoloxazolyl, pyridylisoxazolyl, and pyridylpyrazolyl, each of which is optionally substituted with 1 or 2 R1; and the remaining variables are as described in the first aspect or the first, second or third embodiment. In a fifth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula: each of which is optionally substituted with 1 to 3 R1; and the remainder of the variables are as described in the first aspect or the first, second or third embodiment. Alternatively, as part of the fifth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula: each of which is optionally substituted with 1 or 2 R1; and the remainder of the variables are as described in the first aspect or the first, second or third embodiment. In a sixth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula:

[0004] variables are as described in the fifth embodiment. Alternatively, as part of the sixth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula: and the remainder of the variables are as described in the fifth embodiment. In a seventh embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein: R1, for each occurrence, is independently selected from halo, -CN, C1-7alkyl, –OR1a, - C(O)NR1bR1b, C3-6cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl, wherein the C1-7alkyl is optionally substituted with 1 to 3 R10, and wherein the C3-6cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halo, C1-3alkyl, and C1-3haloalkyl; R1ais H or C1-4alkyl optionally substituted with 1 to 3 halo; each R1bis independently H or C1-3alkyl; R10, for each occurrence, is independently selected from halo, -CN, -OR1a, -SR1a, - NR1bR1b, -C(O)NR1bR1b, -NR1bC(O)C1-3alkyl, C3-6cycloalkyl, phenyl, and 4 to 6 membered saturated heterocyclyl, wherein the C3-6cycloalkyl is optionally substituted by C1-3haloalkyl and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, or sixth embodiment. Alternatively, as part of the seventh embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein: R1, for each occurrence, is independently selected from halo, -CN, C1-7alkyl, –OR1a, C3-6cycloalkyl, and phenyl, wherein the C1-7alkyl is optionally substituted with 1 to 3 R10; R1ais C1-4alkyl optionally substituted with 1 to 3 halo; R10, for each occurrence, is independently selected from halo, -CN, -OR1a, -SR1a, C3- 6cycloalkyl, phenyl, and 4 to 6 membered saturated heterocyclyl; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, or sixth embodiment. In an eighth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R1, for each occurrence, is independently selected from -F, - Cl, -Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2C(CH3)3, - CH2CH(CH3)2, -CH2CH2CH(CH3)2, -(CH2)3CH3, -(CH2)6CH3, -CH2CH2CH2CN, - CH2CH2CN, -CH2CN, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CHF2, -CF3, - CH2CH2CF3, -CH2CF3, -CH2CH2F, -CH2CHF2, -CF2CH3, -CH2CH2Cl, -CH2CH2CH2F, - CH2CH2CHF2, -CH2CHFCH2F, -CH2CF2CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2OCHF2, -CH2CH2OCH2CF3, - CH2CH2CH2OCH2CF3, -CH2CH2CH2OCHF2, -OH, -OCHF2, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, phenyl, -CH2CH2Ph, methylpyrazolyl, oxetan-3-ylmethyl, -CH2SCH3, -C(O)NHCH3, -CH2CH2NHC(O)CH3, - described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh embodiment. Alternatively, as part of the eighth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formulas (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R1, for each occurrence, is independently selected from –Cl, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, - CH2CH2CH(CH3)2,-(CH2)6CH3, -CH2CH2CN, -CH2CN, -CHF2, -CF3, CH2CH2CF3, -CH2CF3, -CH2CH2F, -CH2CHF2, -CF2CH3, -CH2CH2Cl, -CH2CH2CHF2, -OCH3, -OCH2CH3, - CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CF3, -OCHF2, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, phenyl, -CH2CH2Ph, methylpyrazolyl, oxetan-3-ylmethyl, and -CH2SCH3; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, or seventh embodiment. In a ninth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R2is H, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, -N(C1-3alkyl)2, phenyloxy, benzyloxy, -O-pyridinyl, -O-(methylpyrazolyl), -O- thiazolyl, -O-oxazolyl, -O-CH2-pyridinyl, -O-CH2-(methylpyrazolyl), -O-CH2-oxazolyl, or - O-CH2-thiazolyl; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment. Alternatively, as part of the ninth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R2is H, halo, C1-3alkoxy, C1-3haloalkyl, phenyloxy, benzyloxy, -O- pyridinyl, -O-(methylpyrazolyl), -O-thiazolyl, -O-oxazolyl, -O-CH2-pyridinyl, -O-CH2- (methylpyrazolyl), -O-CH2-oxazolyl, or -O-CH2-thiazolyl; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment. Alternatively, as part of the ninth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R2is H, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy-N(C1-3alkyl)2, or benzyloxy; and the remainder of the variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment. In a tenth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R2is H, -F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -

[0005] the remainder of the variables are as described in the ninth embodiment. Alternatively, as part of the tenth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R2is H, Cl, Br, -OCH3, -CHF2, -CF3, the remainder of the variables are as described in the ninth embodiment. Alternatively, as part of the tenth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R2is H, -F, Cl, Br, -CH3, -CH2CH3, - CH2CH2CH3, -OCH3, -OCHF2, -OCF3, -OCH2CH3, -OCH2CH2CH3, -CHF2, -CF3, -N(CH3)2, the remainder of the variables are as described in the ninth embodiment. In some embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein: X is CRx; Rxis H, halo, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, -N(C1-3alkyl)2, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 5 to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected form N, O, and S, wherein the phenyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 or 2 Rx2; each Rx2is independently halo, cyano, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C3-4cycloalkyl, or two Rx2, together with the atoms to which they are attached, form C3-6carbocyclyl or 5 to 6-membered heterocyclyl; and the remainder of the variables are as described above. In some embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Rxis phenyl, pyrrolidinyl, morpholinyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, wherein the pyrazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl are each optionally substituted with 1 or 3 Rx2; and the remainder of the variables are as described above. In some embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein each Rx2is independently -CH3, -CHF2, -CH2CH3, -OCH3, - F,-Cl, -Br, -CN, or cyclopropyl; or two Rx2, together with the atoms to which they are attached, form cyclopentenyl or dihydrofuranyl; and the remainder of the variables are as described above. In some embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein X is CRxand Rxis H, -F, -Cl, -Br, -CH3, -CHF2, -CH2CH3, - the variables are as described above. In an eleventh embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (IIIa), or a pharmaceutically acceptable salt thereof, wherein: Rxis halo or 5-to 6-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O, and S, wherein the 5-to 6-membered monocyclic heteroaryl is optionally substituted with 1 to 2 Rx2; each Rx2is independently halo, C1-3alkyl,or C3-4cycloalkyl, or two Rx2, together with the atoms to which they are attached, form C3-6carbocyclyl; R2is halo, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl; Ring A is a 5-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S; R1for each occurrence, is independently selected from halo, OR1a, C1-3allkyl and C1-3haloalkyl; R1ais C1-3alkyl; and n is 1 or 2; and the remaining variables are as described for Formula (I) in the first aspect or the first embodiment. Alternatively, as part of the eleventh embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III), or a pharmaceutically acceptable salt thereof, wherein: Rxis halo or 5-to 6-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S, wherein the 5-to 6-membered monocyclic heteroaryl is optionally substituted with 1 to 2 Rx2; each Rx2is independently halo, C1-3alkyl,or C3-4cycloalkyl, or two Rx2, together with the atoms to which they are attached, form C3-6carbocyclyl; Ring A is a 5-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S; R1for each occurrence, is independently selected from halo, OR1a, C1-3allkyl and C1-3haloalkyl; R1ais C1-3alkyl; and n is 1 or 2; and the remaining variables are as described for Formula (I) in the first aspect or the first embodiment. Alternatively, as part of the eleventh embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III), or a pharmaceutically acceptable salt thereof, wherein: Rxis H or Cl; Ring A is a 5-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S; R1for each occurrence, is independently selected from halo, OR1a, C1-3allkyl and C1-3haloalkyl; R1ais C1-3alkyl; n is 1 or 2; and the remaining variables are as described for Formula (I) in the first aspect or the first embodiment. In some embodiments, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Rxis pyrazolyl optionally substituted with halo; and the remainder of the variables are as described in the eleventh embodiment. Alternatively, in some embodiments, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Rxis H. In a twelfth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is isoxazolyl, pyrazolyl, or isothiazolyl, each of which is substituted with 1 or 2 R1; and the remainder of the variables are as described in the eleventh embodiment. In a thirteenth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula: and the remainder of the variables are as described in the eleventh embodiment. In a fourteenth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R1, for each occurrence, is independently selected from –Cl, - CH2CH3, -CHF2, -CF3, -CH2CH2Cl and -OCH3; and the remainder of the variables are as described in the eleventh, twelfth, or thirteenth embodiment. In a fifteenth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein ring A is represented by: wherein R100is C1-3haloalkyl and R101is halo; and the remainder of the variables are as described in the eleventh, twelfth, thirteenth, or fourteenth embodiment. In some embodiments, Rxis H. In a sixteenth embodiment, the compounds of the disclosure or a pharmaceutically acceptable salt thereof are represented by Formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein R100is -CHF2 or -CH2CH2Cl, and R101is Br; and the remainder of the variables are as described in the eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment. In a seventeenth embodiment, the compounds of the disclosure are shown below in Table 1 and in the Exemplification. Pharmaceutically acceptable salts thereof and the corresponding neutral form are included in the disclosure. Table 1:

[0006] As used herein, the term “pharmaceutically acceptable salt” refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66:1-19. Compounds of this disclosure with basic groups can form pharmaceutically acceptable salts with pharmaceuticallyacceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of this disclosure with acidic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). The following abbreviations and terms have the indicated meanings throughout: The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy”, “alkylphenyl”, alkylspirocycloalkyl” and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 10 carbon atoms (C1-10alkyl), 1 to 7 carbon atoms (C1-7alkyl), 1 to 6 carbon atoms (C1-6alkyl) (i.e., 1, 2, 3, 4, 5 or 6), alternatively, 1 to 4 carbon atoms (C1-4alkyl) (i.e., 1, 2, 3, or 4), alternatively, 1 to 3 carbon atoms (C1-3 alkyl) (i.e., 1, 2 or 3). Examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and the like. The term “alkoxy”, used alone or as part of a larger moiety, such as haloalkoxy or alkylalkoxy, means a saturated aliphatic straight-chain or branched monovalent radical composed of an alkyl group bonded to oxygen. Unless otherwise specified, an alkoxy group typically has 1 to 6 carbon atoms and an oxygen atom (C1-6alkoxy), alternatively, 1 to 4 carbon atoms and an oxygen atom (C1-3 alkoxy). Examples of alkoxy include methoxy, ethoxy, and the like. The term “halogen” or “halo” means fluorine or fluoro (F), chlorine or chloro (Cl) or bromine or bromo (Br). The term “haloalkyl”, used alone or as part of a large moiety, such as haloalkoxy or alkylhaloalkoxy, means an alkyl group wherein at least one hydrogen substituent is replaced by a halogen group. Unless otherwise specified, a haloalkyl group typically has 1 to 6 carbon atoms (C1-6haloalkyl), alternatively, 1 to 4 carbon atoms (C1-4haloalkyl). Examples include trifluoromethyl, trifluoroethyl, difluoroethyl, and the like. The term “haloalkoxy”, used alone or as part of a larger moiety, such as alkylhaloalkoxy, means an alkoxy group wherein at least one hydrogen substituent is replaced by a halogen. Unless otherwise specified, an haloalkoxy typically has 1 to 6 carbon atoms (C1-6haloalkoxy), alternatively 1 to 4 carbon atoms (C1-4haloalkoxy). Examples include difluoroethoxy and the like. The term “cycloalkyl”, used alone or as part of a larger moiety, such as alkylcycloalkyl, means a saturated aliphatic monocyclic hydrocarbon ring radical. Unless otherwise specified, a cycloalkyl has 3 to 6 ring carbon atoms (C3-6cycloalkyl), alternatively, 3 to 5 ring carbon atoms (C3-5 cycloalkyl), alternatively, 3 to 4 carbon atoms (C3-4 cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, and the like. The term “carbocyclyl”, used alone or as part of a larger moiety, means a fully or partially saturated monocyclic hydrocarbon ring radical. Unless otherwise specified, a carbocyclyl has 3 to 6 ring carbon atoms (C3-6carbocyclyl), alternatively, 3 to 5 ring carbon atoms (C3-5carbocyclyl), alternatively, 3 to 4 carbon atoms (C3-4carbocyclyl). Examples of carbocyclyl include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, and the like. The term “heterocyclyl”, used alone or a part of a larger moiety such as alkylheterocyclyl, refers to a non-aromatic, fully or partially saturated monocyclic or bicyclic (fused, bridged or spiro) ring radical having 1 to 4 ring heteroatoms independently selected from N, O, and S. In some embodiments, the heterocyclyl is a monocyclic ring radical, for example, a 4- to 8-membered monocyclic ring radical. In some embodiments, the heterocyclyl is a bicyclic ring radical, for example a 9- to 10-membered bicyclic ring radical. Exemplary nitrogen containing heterocycles include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like. Exemplary oxygen containing heterocycles include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. Exemplary heterocycles that contain both N and O include morpholinyl and the like. A fused bicyclic ring is a ring system that has two rings each of which are independently selected from a carbocyclyl or a heterocyclyl, wherein the two ring structures share two adjacent ring atoms. A fused ring may have from 9 to 12 ring members. A bridged bicyclic ring is a ring system that has a carbocyclyl or heterocyclyl ring wherein two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably from one to three) atoms selected from C, N, O, or S. A bridged ring may have from 6 to 8 ring members. A spiro ring is a ring system that has two rings each of which are independently selected from a carbocyclyl or a heterocyclyl, wherein the two ring structures having one ring atom in common. A spiro ring may have from 5 to 8 ring members. "Heteroaryl" refers to an aromatic monocyclic or bicyclic ring radical having 1 to 4 ring heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. In some embodiments, the heteroaryl is a monocyclic ring radical, such as 5- to 6-membered monocyclic ring. In some embodiments, the heteroaryl is a bicyclic ring radical, such as 9- to 10-membered bicyclic ring. Examples of 5- to 6-membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and the like. Examples of 9- to 10-membered bicyclic heteroaryls include, but are not limited to, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzoloxazolyl, pyridylisoxazolyl, and pyridylpyrazolyl and the like. The term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl group. To illustrate, monofluoroalkyl is an alkyl substituted with a fluoro substituent, and difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated). If a group is described as “optionally substituted”, the group can be either (1) not substituted or (2) substituted. If a group is described as optionally substituted with up to a particular number of non-hydrogen substituents, that group can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as a cycloalkyl optionally substituted with up to 3 non- hydrogen substituents, then any cycloalkyl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the cycloalkyl has substitutable positions. Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other. When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture. When two or more stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two or more stereoisomers is intended, but not both. The enrichment of one stereoisomer relative to the other is as indicated above. When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center. A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds described herein. Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reagents, and catalysts by known asymmetric synthetic methods. When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers. When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers. In some embodiments, the present disclosure provides methods of regulating or modulating GPR17 activity. In some embodiments, the present disclosure further provides methods of inhibiting GPR17 activity in a subject in need thereof by administering to the subject an effective amount of a compound of the disclosure. In some embodiments, the present disclosure relates to the use of the compound of present disclosure as a medicine, and preferably for use in the treatment of a GPR17 mediated disease or disorder. In some embodiments, the present disclosure provides methods of treating a subject suffering from a disease or disorder mediated by GPR17 by administering to the subject an effective amount of a compound of the disclosure As used herein, a “GPR17 mediated disease or disorder” or a “disease or disorder mediated by GPR17” can be defined as a disease or disorder which is associated with a dysfunction of the GPR17 singling system such as, for example, an overexpression and / or overactivity of GPR17 receptors. The term of “myelination disease or disorder” or “myelin-related disease or disorder” includes demyelination, dysmyelination and hypomyelination disease or disorders. In some embodiments, the disclosure provides methods of treating a subject suffering from a demyelination disease or disorder. As used herein, a “demyelination disease or disorder” is a disease or disorder that causes damage to the protective covering (myelin sheath) that surrounds nerve fibers in the brain, the nerves leading to the eyes (optic nerves) and spinal cord. In some embodiments, the compounds described herein can be used for the treatment of various diseases of the CNS system, such as a CNS disorder associated with myelin loss and an inflammation disorder in CNS. In some embodiments, the compounds described herein have good brain penetration (i.e. are able to pass the blood-brain-barrier). In some embodiments, the compounds described herein have excellent microsomal stability. In some embodiments, the compounds described herein are potent GPR17 inbibitors. In some embodiment, the compounds of the present disclosure can be used in promoting, stimulating and / or accelerating remyelination or myelination in a subject in need thereof. In some embodiments, the compounds of the present disclosure can be used in treating a disease or disorder selected from multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. In some embodiments, the compounds of the present disclosure can be used in treating MS. In some embodiments, MS is a relapsing form of MS. As used herein, a “relapsing form of MS” includes clinically isolated syndrome (CIS), relapsing-remitting disease (RRMS), and active secondary progressive disease. In some embodiments, the compounds described herein can be used for treating MS selected from relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), non-relapsing SPMS, primary progressive MS (PPMS), clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS). CIS is a first episode of neurologic symptoms caused by inflammation and demyelination in the central nervous system. The episode, which by definition must last for at least 24 hours, is characteristic of multiple sclerosis but does not yet meet the criteria for a diagnosis of MS because people who experience a CIS may or may not go on to develop MS. When CIS is accompanied by lesions on a brain MRI (magnetic resonance imaging) that are similar to those seen in MS, the person has a high likelihood of a second episode of neurologic symptoms and diagnosis of relapsing-remitting MS. When CIS is not accompanied by MS-like lesions on a brain MRI, the person has a much lower likelihood of developing MS. RRMS, the most common disease course of MS, is characterized by clearly defined attacks of new or increasing neurologic symptoms. These attacks – also called relapses or exacerbations – are followed by periods of partial or complete recovery (remissions). During remissions, all symptoms may disappear, or some symptoms may continue and become permanent. However, there is no apparent progression of the disease during the periods of remission. RRMS can be further characterized as either active (with relapses and / or evidence of new MRI activity over a specified period of time) or not active, as well as worsening (a confirmed increase in disability following a relapse) or not worsening. SPMS follows an initial relapsing-remitting course. Some people who are diagnosed with RRMS will eventually transition to a secondary progressive course in which there is a progressive worsening of neurologic function (accumulation of disability) over time. SPMS can be further characterized as either active (with relapses and / or evidence of new MRI activity during a specified period of time) or not active, as well as with progression (evidence of disability accumulation over time, with or without relapses or new MRI activity) or without progression. PPMS is characterized by worsening neurologic function (accumulation of disability) from the onset of symptoms, without early relapses or remissions. PPMS can be further characterized as either active (with an occasional relapse and / or evidence of new MRI activity over a specified period of time) or not active, as well as with progression (evidence of disability accumulation over time, with or without relapse or new MRI activity) or without progression. Patients diagnosed with RIS do not present any overt symptoms of MS, but exhibit brain abnormality (e.g., observed by magnetic resonance imaging (MRI)) that are similar to what is seen in patients with MS. Diagnosis of RIS often occurs during a brain scan due to unrelated conditions, such as headache, migraines, head injury, stroke etc. Although there is a strong association between RIS and MS (RIS often indicates the earliest detectable preclinical phase of the disease), patients with RIS may not go on to develop MS. Compounds of the present disclosure can also be useful in the treatment of a disorder or syndrome associated with brain tissue damage, a cerebrovascular disorder, and certain neurodegenerative diseases. Neurodegenerative disorders have been recently associated strongly with a loss of myelination. Accordingly, it is believed that preserved oligodendroglial and myelin functionality is a crucial prerequisite for the prevention of axonal and neuronal degeneration. In some embodiments, the compounds of the present disclosure can used in treating a neurodegenerative disease associated with demyelination and / or impacted myelination, such as amyotropic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer's disease, Huntington Disease or Parkinson's Disease. The compounds of the disclosure or pharmaceutically acceptable salts thereof may be formulated for administration in any convenient way for use in human or veterinary medicine. In some embodiment, the disclosure provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of compound of the disclosure or pharmaceutically acceptable salt thereof that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Dosage forms for the topical or transdermal administration of a compound of this disclosure or pharmaceutically acceptable salts thereof, include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. When the compounds of the disclosure or pharmaceutically acceptable salts thereof are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. The formulations can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The term “effective amount” means an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, an effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day). The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general the route of administration, the time of administration, the rate of excretion of the particular active ingredient being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular active ingredient employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA. The terms a ”treating” or “treatment” of any disease or disorder includes, in one embodiment, to improve the disease or disorder (i.e., arresting or reducing the development of the disease or at least reducing one of the clinical symptoms of the disease). In another embodiment “treating” or “treatment” refers to improve at least one physical parameter, which may or may not be discernible by the subject, in particular a human subject, but which is based on or associated with the disease or disorder to be treated In yet another embodiment, “treating” or treatment” refers to modulating the disease or disorder, either physically (e.g. stabilization of discernible on non-discernible symptom), physiologically (e.g. stabilization of a physiological parameter), or both. In yet another embodiment, “treating” or treatment” refers to delaying the onset or delaying, inhibiting or decreaseing the likelihood of the progression of the disease or disorder. Accordingly, “treating” or treatment” includes any causal treatment of the underlying disease or disorder (i.e. disease modification), as well as any treatment of signs and symptoms of the disease or disorder (whether with or without disease modification), as well as any alleviation or amelioration of the disease or disorder, or its signs and symptoms. The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years. A “subject” or “patient” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In one aspect, the patient is a human. In one aspect, the patient is an adult human. EXEMPLIFICATION Abbreviations Abbreviations and acronyms used herein include the following: AcOH = Acetic Acid Boc2O = Di-tert-butyl dicarbonate DAD = Diode Array Detection DAST = Diethylaminosulfur trifluoride DCM = Dichloromethane DIAD = Diisopropyl azodicarboxylate DIPEA = N,N-Diisopropylethylamine DMAP = 4-Dimethylaminopyridine DMF = Dimethylformamide DMSO = Dimethyl sulfoxide ELSD = Evaporative light scattering detector EA = EtOAc = Ethyl Acetate ESI = Electrospray Ionization EtOH = Ethanol FA = Formic Acid HFIP = Hexafluoro isopropanol HPLC = High-performance liquid chromatography LCMS = Liquid chromatography–mass spectrometry n-BuLi = n-Butyllithium NaHMDS = Sodium bis(trimethylsilyl)amide MeCN = ACN = Acetonitrile MeOH = Methanol NCS = N-Chlorosuccinimide NMR = Nuclear Magnetic Resonance Pd / C = Palladium on carbon PPh3 = Triphenylphosphine RT = Room temperature SCX = Strong Cation Exchange TBAF = Tetrabutylammonium fluoride tBuOK = Potassium tert-Butoxide TEA = Triethylamine TFA = Trifluoroacetic Acid THF = Tetrahydrofuran TLC = Thin Layer Chromatography UPLC = Ultra-performance liquid chromatography dppf = 1,1'-Bis(diphenylphosphino)ferrocene GENERAL METHODS The compounds of the Examples were analyzed or purified according to one of the Purification Methods referred to below unless otherwise described. Where preparative TLC or silica gel chromatography have been used, one skilled in the art may choose any combination of solvents to purify the desired compound. Silica gel column chromatography was performed using 20−40 μM (particle size), 250−400 mesh, or 400− 632 mesh silica gel using either a Teledyne ISCO Combiflash RF or a Grace Reveleris X2 with ELSD purification systems or using pressurized nitrogen (~10-15 psi) to drive solvent through the column (“flash chromatography”). Wherein an SCX column has been used, the eluant conditions are MeOH followed by methanolic ammonia. Except where otherwise noted, reactions were run under an atmosphere of nitrogen. Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum. ANAYTICAL METHODS ESI-MS data (also reported herein as simply MS) were recorded using Waters System (Acquity HPLC and a Micromass ZQ mass spectrometer); all masses reported are the m / z of the protonated parent ions unless recorded otherwise. LC / MS: A sample was dissolved in a suitable solvent such as MeCN, dimethyl sulfoxide (DMSO), or MeOH and was injected directly into the column using an automated sample handler. The analysis used one of the following methods: (1) acidic method (1.5, 2, 3.5, 4, or 7 min runs, see Acidic LCMS section for additional details vide infra: conducted on a Shimadzu 2010 Series, Shimadzu 2020 Series, or Waters Acquity UPLC BEH. (MS ionization: ESI) instrument equipped with a C18 column (2.1 mm × 30 mm, 3.0 mm or 2.1mm × 50 mm, C18, 1.7 μm), eluting with 1.5 mL / 4 L of trifluoroacetic acid (TFA) in water (solvent A) and 0.75 mL / 4 L of TFA in MeCN (solvent B) or (2) basic method (3, 3.5, 7 min runs, see Basic LCMS section for additional details vide infra: conducted on a Shimadzu 2020 Series or Waters Acquity UPLC BEH (MS ionization: ESI) instrument equipped with XBridge Shield RP18, 5um column (2.1 mm × 30 mm, 3.0 mm i.d.) or 2.1 mm × 50 mm, C18, 1.7 μm column, eluting with 2 mL / 4 L NH3·H2O in water (solvent A) and MeCN (solvent B). The disclosure further includes any variant of the present processes, in which the reaction components are used in the form of their salts or optically pure material. Compounds of the disclosure and intermediates can also be converted into each other according to methods generally known to those skilled in the art. SFC analytical separation Instrument: Waters UPC2 analytical SFC (SFC-H). Column: ChiralCel OJ, 150×4.6mm I.D., 3µm. Mobile phase: A for CO2 and B for Ethanol (0.05%DEA). Gradient: B 40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35° C. Wavelength: 220nm. Detectors: Gilson UV / VIS-156 with UV detection at 220 / 254 nm, Gilson 281 automatic collection, utilizing acidic, basic and neutral methods. For mass-directed peak collection, an ACQUITY QDa Mass Detector (Waters Corporation) was employed. Preparative SFC purification Instrument: MG III preparative SFC (SFC-1). Column: ChiralCel OJ, 250×30mm I.D., 5µm. Mobile phase: A for CO2 and B for Ethanol (0.1%NH3H2O). Gradient: B 50%. Flow rate: 40 mL / min. Back pressure: 100 bar. Column temperature: 38° C. Wavelength: 220nm. Cycle time: ~8min. Column: Chiralpak AD-H; 250 mm x 30 mm, 5 mm; 40% (EtOH + 0.1% DEA) / CO2Column: Chiralpak IA; 250 mm x 30 mm, 5 mm; 40% (MeOH + 0.1% DEA) / CO2Column: Chiralpak IB; 250 mm x 30 mm, 5 mm; 40% (EtOH + 0.1% DEA) / CO2 Column: Chiralpak AD-H; 250 mm x 30 mm, 5 mm; 40% (EtOH + 0.1% NH4OH) / CO2 Column: Chiralpak OJ-H; 250 mm x 30 mm, 5 mm; 30% (EtOH + 0.1% NH4OH) / CO2Column: Chiralpak OD; 250 mm x 30 mm, 5 mm; 35% (EtOH + 0.1% NH4OH) / CO21H-NMR 1H nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. The 1H NMR spectra were recorded on a Bruker Avance III HD 500 MHz, Bruker Avance III 500 MHz, Bruker Avance III 400 MHz, Varian-400 VNMRS, or Varian-400 MR. Characteristic chemical shifts ( ^) are given in parts-per-million downfield from tetramethylsilane (for1H-NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, double doublet; dt, double triplet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCl3, deuterochloroform; DMSO-d6, hexadeuterodimethyl sulfoxide; and MeOH- d4, deuteron-methanol. Where appropriate, tautomers may be recorded within the NMR data; and some exchangeable protons may not be visible. Typically, the compounds of Formula (I) can be prepared according to the schemes provided below. The following examples serve to illustrate the invention without limiting the scope thereof. Methods for preparing such compounds are described hereinafter. Preparation of Intermediates: Preparation 1: 1-(2-chloroethyl)-5-(difluoromethyl)-1H-pyrazol-4-amine Step a: To a solution of methyl 4-nitro-1H-pyrazole-5-carboxylate (1.00 g, 584 mmol, 1.0 eq.), compound 1-bromo-2-chloroethane (1.26 g, 8.77 mmol, 1.5 eq.) and K2CO3 (2.42 g, 17.53 mmol, 3.0 eq.) in MeCN (15.0 mL) at 20 °C. The mixture was stirred at 50 °C for 16 hours. The mixture was filtrated and concentrated in vacuum to give the residue, which was purified by column chromatography to give methyl 1-(2-chloroethyl)-4-nitro-1H-pyrazole-5- carboxylate (360.00 mg, 26.37% yield).1H NMR: (500MHz, DMSO) δ: 8.49 (s, 1H), 4.66 (t, J = 5.5 Hz, 2H), 4.04 (t, J = 5.5 Hz, 2H), 3.97 (s, 3H). Step b: To a solution of methyl 1-(2-chloroethyl)-4-nitro-1H-pyrazole-5-carboxylate (160.00 mg, 684.91 μmol, 1.0 eq.) and CaCl2 (76.01 mg, 684.91 μmol, 1.0 eq.) in EtOH (2.0 mL) was added NaBH4(51.82 mg, 1.37 mmol, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with water (20 mL) and extracted with EA (15 mL x 3). The combined organic layers was washed with brine (20 mL), dried over Na2SO4. The filtrate was concentrated in vacuum to give (1-(2-chloroethyl)-4-nitro-1H-pyrazol-5-yl)methanol (86.00 mg, 61.07% yield).1H NMR: (500MHz, DMSO) δ: 8.33 (s, 1H), 5.76 (t, J = 6.0 Hz, 1H), 4.92 (d, J = 6.0 Hz, 2H), 4.62 (t, J = 6.0 Hz, 2H), 4.05 (t, J = 6.0 Hz, 2H). Step c: To a solution of (1-(2-chloroethyl)-4-nitro-1H-pyrazol-5-yl)methanol (86.00 mg, 418.29 μmol, 1.0 eq.) in DCM (10.0 mL) was added MnO2(727.30 mg, 8.37 mmol, 20.0 eq.) at 25 °C. The mixture was stirred at 40 °C for 3 hours. The mixture was filtered and the filtrate was concentrated under vacuum to give 1-(2-chloroethyl)-4-nitro-1H-pyrazole-5- carbaldehyde (60.00 mg, 70.46% yield).1H NMR: (500MHz, DMSO) δ: 10.26 (s, 1H), 8.51 (s, 1H), 4.84 (t, J = 6.0 Hz, 2H), 4.04 (t, J = 6.0 Hz, 2H). Step d: To a solution 1-(2-chloroethyl)-4-nitro-1H-pyrazole-5-carbaldehyde (60.00 mg, 294.72 μmol, 1.0 eq.) in DCM (4.0 mL) was added DAST (95.01 mg, 589.44 μmol, 2.0 eq.) dropwise at 0 °C. The mixture was stirred at 20°C for 16 hours. The mixture was quenched with NaHCO3.aq (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers was washed with brine (20 mL), dried over Na2SO4. The filtrate was concentrated in vacuum to give the residue, which was purified by prep-TLC to give 1-(2-chloroethyl)-5- (difluoromethyl)-4-nitro-1H-pyrazole (45.00 mg, 67.69% yield).1H NMR: (400MHz, DMSO) δ: 8.54 (s, 1H), 7.77-7.50 (m, 1H), 4.73 (t, J = 6.0 Hz, 2H), 4.10 (t, J = 6.0 Hz, 2H). Step e: To a solution of 1-(2-chloroethyl)-5-(difluoromethyl)-4-nitro-1H-pyrazole (35.00 mg, 155.16 μmol, 1.0 eq.) in MeOH (5.0 mL) was added Pd / C (16.51 mg, 15.52 μmol, 10% purity, 0.1 eq.) at 25 °C under H2 (30 Psi). The reaction was stirred at 25 °C for 2 hours. The mixture was filtrated and concentrated in vacuum to give 1-(2-chloroethyl)-5- (difluoromethyl)-1H-pyrazol-4-amine (44.00 mg, crude). LCMS m / z = 195.8 [M+H]+ 1H NMR: (400MHz, DMSO) δ: 7.34-7.06 (m, 1H), 7.05 (s, 1H), 4.48 (s, 2H), 4.34 (t, J = 6.0 Hz, 2H), 3.91 (t, J = 6.0 Hz, 2H). Preparation 2: 5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-amine To a solution of 1-(trifluoromethyl)-1H-pyrazol-4-amine (70 mg, 373.23 μmol, HCl, 1.0 eq.) in ACN (2 mL) was added NCS (49.84 mg, 373.23 μmol, 1.0 eq.) and stirred at 25 °C for 2 hours. The mixture was quenched with saturate aq. Na2SO3(10 mL). The mixture was extracted with EtOAc (50 mL x 2), dried over Na2SO4, filtered and concentrated to give 5- chloro-1-(trifluoromethyl)-1H-pyrazol-4-amine (69 mg, crude). The crude was used in next step without purification. LCMS m / z = 186.1 [M+H]+Preparation 3: 4-amino-1-heptyl-1H-pyrazole-5-carbonitrile Step a: To a solution of 4-nitro-1H-pyrazole-5-carbonitrile (300 mg, 2.17 mmol, 1.0 eq.) and 1-iodoheptane (491.22 mg, 2.17 mmol, 356.21 µL, 1.0 eq.) in MeCN (5 mL) was added K2CO3 (900.82 mg, 6.52 mmol, 3.0 eq.) at 25 °C. The mixture was stirred at 70 °C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography give 1-heptyl-4-nitro-1H-pyrazole-5-carbonitrile (100 mg, 19.48% yield).1H NMR: (400 MHz, MeOD) δ: 8.33 (s, 1H), 4.41 (t, J = 7.2 Hz, 2H), 2.01- 1.93 (m, 2H), 1.37-1.30 (m, 8H), 0.93-0.89 (m, 3H). Step b: To a solution of 1-heptyl-4-nitro-1H-pyrazole-5-carbonitrile (50 mg, 211.62 µmol, 1.0 eq.) in EtOH (5 mL) was added Fe (59.10 mg, 1.06 mmol, 7.52 µL, 5.0 eq.) and NH4Cl (56.60 mg, 1.06 mmol, 5.0 eq.) at 25 °C. The mixture was stirred at 80 °C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 4-amino-1- heptyl-1H-pyrazole-5-carbonitrile (40 mg, 79.07% yield, 86.3% purity). LCMS m / z = 207.3 [M+H]+ 1H NMR: (400 MHz, DMSO) δ: 7.06 (s, 1H), 5.20 (s, 2H), 4.02 (d, J = 6.8 Hz, 2H), 1.75-1.67 (m, 2H), 1.27-1.15 (m, 8H), 0.86-0.82 (m, 3H). Preparation 4: 1-heptyl-5-(trifluoromethyl)-1H-pyrazol-4-amine 1-heptyl-5-(trifluoromethyl)-1H-pyrazol-4-amine was obtained (40 mg, yield 8% over two steps), from 4-nitro-5-(trifluoromethyl)-1H-pyrazole and 1-iodoheptane following a similar procedure to that described in Preparation 3. LCMS m / z = 250.3 [M+H]+Preparation 5: 5-chloro-1-heptyl-1H-pyrazol-4-amine 5-chloro-1-heptyl-1H-pyrazol-4-amine was obtained (60 mg, yield 13% over two steps), from 5-chloro-4-nitro-1H-pyrazole and 1-iodoheptane following a similar procedure to that described in Preparation 3. LCMS m / z = 216.0 [M+H]+ Preparation 6: 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine was obtained (40 mg, yield 16% over two steps), from 5-chloro-4-nitro-1H-pyrazole and 2,2-difluoroethyl trifluoromethanesulfonate following a similar procedure to that described in Preparation 3. LCMS m / z = 182.0 [M+H]+Preparation 7: 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine 1-(2,2-difluoroethyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine was obtained (40 mg, yield 6% over two steps), from 4-nitro-5-(trifluoromethyl)-1H-pyrazole and 2,2-difluoroethyl trifluoromethanesulfonate following a similar procedure to that described in Preparation 3. LCMS m / z = 215.9 [M+H]+Preparation 8: 4-amino-1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carbonitrile 4-amino-1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carbonitrile was obtained (40 mg, yield 10% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and 1,1,1-trifluoro-3- iodopropane following a similar procedure to that described in Preparation 3. LCMS m / z = 204.8 [M+H]+Preparation 9: 4-amino-1-(2-fluoroethyl)-1H-pyrazole-5-carbonitrile 4-amino-1-(2-fluoroethyl)-1H-pyrazole-5-carbonitrile was obtained (58 mg, yield 13% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and 1-fluoro-2-iodoethane following a similar procedure to that described in Preparation 3. LCMS m / z = 155.3 [M+H]+ Preparation 10: 5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-amine 4-amino-1-(2-chloroethyl)-1H-pyrazole-5-carbonitrile was obtained (30 mg, yield 9% over two steps), from 5-chloro-4-nitro-1H-pyrazole and 1-bromo-2-chloroethane following a similar procedure to that described in Preparation 3. LCMS m / z = 180.0 [M+H]+Preparation 11: 4-amino-1-(cyanomethyl)-1H-pyrazole-5-carbonitrile 4-amino-1-(cyanomethyl)-1H-pyrazole-5-carbonitrile was obtained (53 mg, yield 13% over two steps, 85% pure), from 4-nitro-1H-pyrazole-5-carbonitrile and 2-bromoacetonitrile following a similar procedure to that described in Preparation 3. LCMS m / z = 148.0 [M+H]+1H NMR: (400 MHz, DMSO) δ: 7.41 (s, 1H), 5.58 (s, 2H), 5.46 (s, 2H). Preparation 12: 1-(2-chloroethyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine 1-(2-chloroethyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine was obtained (30 mg, yield 5% over two steps), from -nitro-5-(trifluoromethyl)-1H-pyrazole and 1-bromo-2-chloroethane following a similar procedure to that described in Preparation 3. LCMS m / z = 213.9 [M+H]+Preparation 13: 4-amino-1-(cyclopropylmethyl)-1H-pyrazole-5-carbonitrile 4-amino-1-(cyclopropylmethyl)-1H-pyrazole-5-carbonitrile was obtained (120 mg, yield 31% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and (bromomethyl)cyclopropane following a similar procedure to that described in Preparation 3. LCMS m / z = 163.3 [M+H]+ Preparation 14: 4-amino-1-(2-chloroethyl)-1H-pyrazole-5-carbonitrile 4-amino-1-(2-chloroethyl)-1H-pyrazole-5-carbonitrile was obtained (20 mg, yield 2% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and 1-bromo-2-chloroethane following a similar procedure to that described in Preparation 3. LCMS m / z = 170.7 [M+H]+ 1H NMR: (400 MHz, CDCl3) δ: 7.22 (s, 1H), 4.44 (t, J = 6.0 Hz, 2H), 3.88 (t, J = 8.4 Hz, 2H). Preparation 15: 5-chloro-1-cyclopropyl-1H-pyrazol-4-amine To a solution of 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole (30 mg, 159.93 μmol, 1.0 eq.) in EtOH (2 mL) and water (0.5 mL) was added Iron (44.66 mg, 799.64 μmol, 5.0 eq.) and ammonia hydrochloride (25.66 mg, 479.79 μmol, 3.0 eq.). The reaction mixture was stirred in 80 °C for 1 hour. The mixture was filtered and the filtrate was extracted with EtOAc (20 mL X 3). The combined organic layer was washed with brine (30 mL) and dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to give compound 5-chloro-1-cyclopropyl-1H-pyrazol-4-amine (20 mg, 79.35% yield).1HNMR: (400MHz, CDCl3) δ: 7.17 (s, 1H), 3.40-3.34 (m, 1H), 1.18-1.13 (m, 2H), 1.06-1.00 (m, 2H). Preparation 16: 5-chloro-1-(2,2-difluoropropyl)-1H-pyrazol-4-amine Step a: To a solution of compound 2,2-difluoropropan-1-ol (2 g, 20.82 mmol, 1.0 eq.) and TEA (2.74 g, 27.06 mmol, 3.77 mL, 1.3 eq.) in DCM (100 mL) was added trifluoromethanesulfonic anhydride (7.05 g, 24.98 mmol, 4.20 mL, 1.2 eq.) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with H2O (60 mL) and extracted with DCM (60 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2,2-difluoropropyl trifluoromethanesulfonate (3.5 g, crude). Step b: To a solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol, 1.0 eq.) and K2CO3(1.83 g, 13.27 mmol, 3.0 eq.) in MeCN (10 mL) was added 2,2-difluoropropyl trifluoromethanesulfonate (1.01 g, 4.42 mmol, 1.0 eq.) at 25 °C. The reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield 1-(2,2-difluoropropyl)-4-nitro-1H-pyrazole (530 mg, 58.89% yield, 93.9% purity). LCMS m / z = 192.0 [M+H]+ 1H NMR: (400 MHz, CDCl3) δ: 8.26 (s, 1H), 8.12 (s, 1H), 4.51 (t, J = 12.4 Hz, 2H), 1.71-1.61 (m, 3H). Step c: To a solution of 1-(2,2-difluoropropyl)-4-nitro-1H-pyrazole (500 mg, 2.62 mmol, 1.0 eq.), NH4Cl (699.66 mg, 13.08 mmol, 5.0 eq.) in EtOH (6 mL) and water (2 mL) at 25 °C was added Fe (730.50 mg, 13.08 mmol, 5.0 eq.). The reaction mixture was stirred at 80 °C for 1 hours. The mixture was filtered through a celite pad, and the filtrate was concentrated to give 1-(2,2-difluoropropyl)-1H-pyrazol-4-amine (400 mg, crude). Step d: To a solution of 1-(2,2-difluoropropyl)-1H-pyrazol-4-amine (400 mg, 2.48 mmol, 1.0 eq.) in DCM (3 mL) was added TEA (753.50 mg, 7.45 mmol, 1.04 mL, 3.0 eq.) and Boc2O (541.72 mg, 2.48 mmol, 570.23 μL, 1.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield tert-butyl (1-(2,2- difluoropropyl)-1H-pyrazol-4-yl)carbamate (550 mg, 83.82% yield, 98.8% purity). LCMS m / z = 262.0 [M+H]+ 1H NMR (400 MHz, CDCl3) δ: 7.73 (s, 1H), 7.41 (s, 1H), 6.28 (s, 1H), 4.38 (t, J = 12.0 Hz, 2H), 1.61-1.46 (m, 12H). Step e: To a solution of tert-butyl (1-(2,2-difluoropropyl)-1H-pyrazol-4-yl)carbamate (150 mg, 574.12 μmol, 1.0 eq.) and NCS (114.99 mg, 861.19 μmol, 1.5 eq.) in DCM (3 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield tert-butyl (5-chloro-1-(2,2-difluoropropyl)-1H-pyrazol-4- yl)carbamate (120 mg, 69.88% yield, 98.9% purity). LCMS m / z = 295.9 [M+H]+ 1H NMR (400 MHz, CDCl3) δ: 7.95 (s, 1H), 6.05 (s, 1H), 4.43 (t, J = 11.2 Hz, 2H), 1.67-1.52 (m, 12H). Step f: Tert-butyl (5-chloro-1-(2,2-difluoropropyl)-1H-pyrazol-4-yl)carbamate (100 mg, 338.17 μmol, 1.0 eq.) was dissolved in HCl (2 M, 169.08 μL, EtOAc) at 25 °C. The reaction mixture was stirred at 25 °C for 30 min. The mixture was concentrated to give the compound 5-chloro-1-(2,2-difluoropropyl)-1H-pyrazol-4-amine (60 mg, crude) as a white solid. LCMS m / z = 195.9 [M+H]+Preparation 17: 5-(difluoromethyl)-1-methyl-1H-pyrazol-4-amine Step a: To a solution of compound methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (200.00 mg, 1.08 mmol, 1.0 eq.) and CaCl2 (119.89 mg, 1.08 mmol, 1.0 eq.) in EtOH (2 mL) was added NaBH4(81.74 mg, 2.16 mmol, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with water (20 mL) and extracted with EA (15 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4. The filtrate was concentrated in vacuum to give compound (1-methyl-4-nitro-1H-pyrazol-5- yl)methanol (130.00 mg, 76.59% yield).1H NMR: (500MHz, DMSO) δ: 8.22 (s, 1H), 5.63 (t, J = 6.0 Hz, 1H), 4.86 (d, J = 6.0 Hz, 1H), 3.92 (s, 3H). Step b: To a solution of compound (1-methyl-4-nitro-1H-pyrazol-5-yl)methanol (130.00 mg, 827.36 μmol, 1.0 eq.) in DCM (10 mL) was added MnO2(1.44 g, 16.55 mmol, 20.0 eq.) at 25 °C. The mixture was stirred at 40 °C for 3 hours. The mixture was filtered and the filtrate was concentrated under vacuum to give compound 1-methyl-4-nitro-1H-pyrazole-5-carbaldehyde (120.00 mg, 93.51% yield).1H NMR: (500MHz, DMSO) δ: 10.24 (s, 1H), 8.40 (s, 1H), 4.09 (s, 3H). Step c: To a solution compound 1-methyl-4-nitro-1H-pyrazole-5-carbaldehyde (120.00 mg, 773.64 μmol, 1.0 eq.) in DCM (5 mL) was added DAST (249.40 mg, 1.55 mmol, 2.0 eq.) dropwise at 0 °C. The mixture was stirred at 20°C for 2 hours. The mixture was quenched with NaHCO3.aq (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4. The filtrate was concentrated in vacuum to give the residue, which was purified by column chromatography to give compound 5-(difluoromethyl)-1-methyl-4-nitro-1H-pyrazole (90.00 mg, 65.68% yield.).1H NMR: (400MHz, DMSO) δ: 8.41 (s, 1H), 7.72-7.46 (m, 1H), 4.07-4.06 (m, 3H). Step d: To a solution of compound 5-(difluoromethyl)-1-methyl-4-nitro-1H-pyrazole (45.00 mg, 254.08 μmol, 1.0 eq.) in MeOH (3.0 mL) was added Pd / C (27.04 mg, 25.41 μmol, 10% purity, 0.1 eq.) at 25 °C under H2(15 Psi). The reaction was stirred at 25 °C for 2 hours. The mixture was filtrated and concentrated in vacuum to give compound 5-(difluoromethyl)-1- methyl-1H-pyrazol-4-amine (30.00 mg, crude). LCMS m / z = 148.2 [M+H]+Preparation 18: 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine Step a. To a 500-mL round-bottom flask was added 1-(difluoromethyl)pyrazol-4-amine (6.30 g, 47.3 mmol). The starting material was dissolved in DCM (240 mL) and the flask was thoroughly purged with N2. Triethylamine (10.06 g, 99.40 mmol, 13.85 mL) was then added, and the solution was stirred for approximately 5 minutes before addition of Boc2O (11.36 g, 52.07 mmol, 11.96 mL) by syringe. The resulting reaction mixture stirred at rt for 4 days, after which time it was directly concentrated under reduced pressure. The crude product was purified by silica gel chromatography to provide tert-butyl (1-(difluoromethyl)-1H-pyrazol-4- yl)carbamate (8.65 g, 37.1 mmol, 78.4% yield). LCMS m / z = 234.1 [M+H]+Step b. A 30-mL scintillation vial containing tert-butyl (1-(difluoromethyl)-1H-pyrazol-4- yl)carbamate (1.77 g, 7.59 mmol) dissolved in MeCN (19 mL) was cooled to 0 °C in an ice bath and placed under N2 atmosphere. Next, NCS (3.04 g, 22.8 mmol) was added slowly portion-wise over ~ 1 min. The vial was removed from the ice bath and allowed to stir at rt for 2 h. The reaction mixture was then directly concentrated under reduced pressure to afford the crude product, which was purified by column chromatography to provide tert-butyl (5-chloro- 1-(difluoromethyl)-1H-pyrazol-4-yl)carbamate (1.59 g, 5.94 mmol, 78.3% yield). LCMS m / z = 268.0 [M+H]+ Step c. To a 30-mL scintillation vial containing tert-butyl (5-chloro-1-(difluoromethyl)-1H- pyrazol-4-yl)carbamate (1.14 g, 4.26 mmol) was added HFIP (21.3 mL) followed by TFA (0.67 mL, 8.72 mmol). Stirring continued at rt for 2 h, after which time the reaction was directly concentrated under reduced pressure to afford 5-chloro-1-(difluoromethyl)-1H-pyrazol-4- amine. The material was used without further purification assuming quantitative yield. LCMS m / z = 168.0 [M+H]+Preparation 19: 5-chloro-1-cyclobutyl-1H-pyrazol-4-amine Step a. To a solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol) and bromocyclobutane (597 mg, 4.42 mmol) in DMF (8.84 mL) was added Cs2CO3(2.16 g, 6.63 mmol). The solution was then heated to 60 °C for 16 hours, and then cooled to room temperature. The solution was diluted with brine and EtOAc, and the organics were extracted 3 times, and subsequently dried with Na2SO4. The organics were concentrated and purified via column chromatography to yield 1-cyclobutyl-4-nitro-1H-pyrazole (739 mg, 2.67 mmol, 60% yield). LCMS m / z = 168.0 [M+H]+ 1H NMR: (400 MHz, CDCl3) δ: 8.19 (s, 1H), 8.11 (s, 1H), 4.87- 4.73 (m, 1H), 2.64-2.51 (m, 4H), 2.04-1.82 (m, 2H) Step b: To a solution of 1-cyclobutyl-4-nitro-1H-pyrazole (330 mg, 1.97 mmol) in THF (4 mL) at – 78 °C was added NaHMDS (1 M, 2.17 mmol, 2.17 mL) dropwise. The solution was stirred at this temperature for 30 minutes, before NCS (395 mg, 2.96 mmol) was added. The solution was stirred for a further 30 mins, before the reaction was quenched with an aqueous saturated solution of ammonium chloride. The mixture was extracted with EtOAc, dried with sodium sulfate, and then concentrated. The resulting residue was purified via column chromatography to give 5-chloro-1-cyclobutyl-4-nitro-1H-pyrazole (180 mg, 0.89 mmol, 45% yield).1H NMR: (400 MHz, CDCl3) δ: 8.09 (s, 1H), 4.92-4.76 (m, 1H), 2.68-2.50 (m, 2H), 2.44-2.27 (m, 2H) 1.94-1.70 (m, 2H) . Step c: To a solution of 5-chloro-1-cyclobutyl-4-nitro-1H-pyrazole (180 mg, 0.89 mmol) and ammonium hydrochloride (239 mg, 4.46 mmol) in EtOH (5.4 mL) and water (3.6 mL) was added iron powder (499 mg, 8.93 mmol) and the resulting solution was heated to 70 °C for 2 hours. The solution was then cooled to room temperature, and concentrated. The residue was redissolved in water and the organics were extracted with EtOAc. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The resulting residue was purified via column chromatography to give 5-chloro-1-cyclobutyl-1H-pyrazol-4-amine (153 mg, 0.39 mmol, 44% yield). LCMS m / z = 171.9 [M+H]+ 1H NMR: (500 MHz, CDCl3) δ: 7.56 (s, 1H), 4.83 (t, J = 8.39 Hz, 1H), 2.66 (td, J = 9.69, 2.29 Hz, 2H), 2.50-2.35 (m, 2H), 1.80-1.97 (m,2 H). Preparation 20: 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile was obtained (53 mg, yield 18.3% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and iodoethane following a similar procedure to that described in Preparation 3. LCMS m / z = 137.4 [M+H]+ 1H NMR: (400 MHz, DMSO) δ: 7.05 (s, 1H), 5.20 (s, 2H), 4.10-4.04 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H). Preparation 21: 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile 4-amino-1-(oxetan-3-ylmethyl)-1H-pyrazole-5-carbonitrile was obtained (80 mg, 20.6% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and 3-(bromomethyl)oxetane following a similar procedure to that described in Preparation 3. LCMS m / z =179.0 [M+H]+Preparation 22: 4-amino-1-isopropyl-1H-pyrazole-5-carbonitrile 4-amino-1-isopropyl-1H-pyrazole-5-carbonitrile was obtained (50 mg, 14.7% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and 2-iodopropane following a similar procedure to that described in Preparation 3. LCMS m / z = 150.8 [M+H]+ 1H NMR: (400 MHz, DMSO) δ: 7.06 (s, 1H), 5.18 (s, 2H), 4.51-4.40 (m, 1H), 1.37 (d, J = 6.8 Hz, 6H). Preparation 23: 5-chloro-1-(cyclopropylmethyl)-1H-pyrazol-4-amine 5-chloro-1-(cyclopropylmethyl)-1H-pyrazol-4-amine was obtained (38 mg, yield 5.4% over two steps), from 5-chloro-4-nitro-1H-pyrazole and (bromomethyl)cyclopropane following a similar procedure to that described in Preparation 3. LCMS m / z = 150.8 [M+H]+ 1H NMR: (400 MHz, DMSO) δ: 7.06 (s, 1H), 3.84 (d, J = 7.2 Hz, 2H), 1.22-1.10 (m, 1H), 0.49-0.43 (m, 2H), 0.33-0.29 (m, 2H). Preparation 24: 1-(cyclopropylmethyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine 1-(cyclopropylmethyl)-5-(trifluoromethyl)-1H-pyrazol-4-amine was obtained (20 mg, yield 5.9% over two steps), from 4-nitro-5-(trifluoromethyl)-1H-pyrazole and (bromomethyl)cyclopropane following a similar procedure to that described in Preparation 3. LCMS m / z = 205.7 [M+H]+Preparation 25: 4-amino-1-propyl-1H-pyrazole-5-carbonitrile 4-amino-1-propyl-1H-pyrazole-5-carbonitrile was obtained (123 mg crude over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and 1-iodopropane following a similar procedure to that described in Preparation 3. LCMS m / z = 151.3 [M+H]+Preparation 26: 4-amino-1-(2-cyclopropylethyl)-1H-pyrazole-5-carbonitrile 4-amino-1-(2-cyclopropylethyl)-1H-pyrazole-5-carbonitrile was obtained (40 mg, yield 13.9% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and (2- iodoethyl)cyclopropane following a similar procedure to that described in Preparation 3. LCMS m / z = 176.8 [M+H]+Preparation 27: 4-amino-1-(cyclobutylmethyl)-1H-pyrazole-5-carbonitrile 4-amino-1-(cyclobutylmethyl)-1H-pyrazole-5-carbonitrile was obtained (50 mg crude over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and (bromomethyl)cyclobutane following a similar procedure to that described in Preparation 3. LCMS m / z = 177.1 [M+H]+Preparation 28: 6,7-dichloro-1H-indole-3-sulfonyl chloride Step a: To a solution of compound 1,2-dichloro-3-nitrobenzene (8.0 g, 41.67 mmol) in THF (300 mL) was added vinylmagnesium bromide (1 M, 167 mL) slowly at -78 °C and the mixture was stirred at -78 °C for 4 h under N2atmosphere. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by column chromatography to give 6,7-dichloro-1H-indole (4.98 g, 26.8 mmol, 64.2% yield).1H NMR (400MHz, DMSO): δ 11.65 (br s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 2.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 2.0, 2.8 Hz, 1H). Step b: To a solution of 6,7-dichloro-1H-indole (4.98 g, 26.8 mmol) in MeCN (100 mL) was added sulfurochloridic acid (15.60 g, 133.8 mmol, 8.90 mL) slowly at 0 °C and the mixture was stirred at 20 °C for 2 h under N2 atmosphere. The reaction mixture was added to ice water dropwise and stirred at 20 °C for 0.5 h. The mixture was filtered, washed with water (300 mL x 2) to give the filter cake, which was concentrated to give 6,7-dichloro-1H-indole- 3-sulfonyl chloride (4.76 g, 15.3 mmol, 57.2% yield).1H NMR (400MHz, CDCl3) δ: 9.39 (br s, 1H), 8.04 (d, J = 3.2 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H). Preparation 29: 7-bromo-6-chloro-1H-indole-3-sulfonyl chloride Step a: To a 30-mL scintillation vial containing a solution of 7-bromo-6-chloro-1H-indole (1.50 g, 6.51 mmol) in acetonitrile (13.0 mL) at 0 °C was added sulfurochloridic acid (2.73 g, 23.4 mmol, 1.56 mL) dropwise. The solution was kept in the ice bath for 1 h, removed, and then stirred at 20 °C for 2 days. The reaction mixture was then poured into ice water and extracted three times with EtOAc. The combined organics were dried over sodium sulfate and concentrated under vacuum to provide 7-bromo-6-chloro-1H-indole-3-sulfonyl chloride which was used without further purification assuming quantitative yield (2.14 g). LCMS m / z = 327.7 [M+H]+Preparation 30: 4-amino-1-(2-methoxyethyl)-1H-pyrazole-5-carbonitrile 4-amino-1-(2-methoxyethyl)-1H-pyrazole-5-carbonitrile was obtained (87 mg crude, yield 14.1% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and 1-bromo-2- methoxyethane following a similar procedure to that described in Preparation 3. LCMS m / z = 167.2 [M+H]+Preparation 31: 4-amino-1-(2,2-difluoroethyl)-1H-pyrazole-5-carbonitrile 4-amino-1-(2,2-difluoroethyl)-1H-pyrazole-5-carbonitrile was obtained (38.0 mg crude, 10.0% over two steps), from 4-nitro-1H-pyrazole-5-carbonitrile and 1,1-difluoro-2- iodoethane following a similar procedure to that described in Preparation 3. LCMS m / z = 173.0 [M+H]+ Preparation 32: 5-chloro-1-(2,3-difluoropropyl)-1H-pyrazol-4-amine Step a: To a solution of 4-nitro-1H-pyrazole-5-carbonitrile (2.0 g, 17.7 mmol, 1.0 eq.) and 3- chloropropane-1,2-diol (2.93 g, 26.5 mmol, 1.5 eq.) in DMF (100 mL) was added K2CO3(4.89 g, 35.4 mmol, 2.0 eq.) and KI (293.6 mg, 1.77 mmol, 0.1 eq.) at 20 °C. The mixture was stirred at 90 °C for 2 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (20 mL x 3). The combined organics were evaporated under vacuum and thhe residue was purified by column chromatography to give 3-(4-nitro-1H-pyrazol-1-yl)propane-1,2-diol (1.0 g, 30.2% yield).1H NMR (400MHz, CDCl3) δ: 8.25 (s, 1H), 8.11 (s, 1H), 4.83-4.80 (m, 1H), 4.56-4.43 (m, 1H), 4.36-4.25 (m, 2H), 4.21-4.15 (m, 1H), 3.77-3.70 (m, 1H), 3.66-3.61 (m, 1H). Step b: To a solution of 3-(4-nitro-1H-pyrazol-1-yl)propane-1,2-diol (400 mg, 2.14 mmol, 1.0 eq.) in DCM (3 mL) was added DAST (861 mg, 5.34 mmol, 706 μL, 2.5 eq.) dropwise at 0 °C. The mixture was stirred at 20 °C for 3 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 until pH = 8 and extracted with DCM (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield 1-(2,3-difluoropropyl)-4-nitro-1H-pyrazole (100 mg, 23.5% yield, 96% purity).1H NMR (400MHz, CDCl3) δ: 8.24 (s, 1H), 8.12 (s, 1H), 5.18-4.98 (m, 1H), 4.85-4.55 (m, 2H), 4.55-4.44 (m, 2H). Step c: To a solution of 1-(2,3-difluoropropyl)-4-nitro-1H-pyrazole (100 mg, 523.2 μmol, 1.0 eq.) in EtOH (3 mL) and H2O (1 mL) at 25 ° was added NH4Cl (139.9 mg, 2.6 mmol, 5.0 eq.) and Fe (146.1 mg, 2.62 mmol, 5.0 eq.). The reaction mixture was stirred at 80 °C for 1 hour. The mixture was filtered through a celite pad, and the filtrate was concentrated to give 1-(2,3- difluoropropyl)-1H-pyrazol-4-amine (80 mg, crude). LCMS m / z = 162.2 [M+H]+ Step d: To a solution of 1-(2,3-difluoropropyl)-1H-pyrazol-4-amine (80 mg, 496.4 μmol, 1.0 eq.) in DCM (3 mL) was added TEA (150.7 mg, 1.49 mmol, 207.6 μL, 3.0 eq.) and Boc2O (108.3 mg, 496.4 μmol, 114.1 μL, 1.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to give a residue which was purified by column chromatography to yield tert-butyl (1-(2,3-difluoropropyl)-1H-pyrazol-4-yl)carbamate (50 mg, 37.0% yield over 2 steps) as a white solid. LCMS m / z = 262.1 [M+H]+Step e: NCS (38.3 mg, 287.1 μmol, 1.5 eq.) was added to a solution of tert-butyl (1-(2,3- difluoropropyl)-1H-pyrazol-4-yl)carbamate (50 mg, 191.4 μmol, 1.0 eq.) in MeCN (3 mL) at 25 °C. The reaction mixture was stirred at 40 °C for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield tert-butyl (5-chloro-1-(2,3-difluoropropyl)-1H-pyrazol-4- yl)carbamate (35 mg, 59.5% yield, 96.2% purity). LCMS m / z = 296.1 [M+H]+Step f: To a solution of tert-butyl (5-chloro-1-(2,3-difluoropropyl)-1H-pyrazol-4- yl)carbamate (35 mg, 118.4 μmol, 1.0 eq.) in HFIP (2 mL) was added TFA (13.5 mg, 118.4 μmol, 9.1 μL, 3.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under vacuum to give 5-chloro-1-(2,3-difluoropropyl)-1H- pyrazol-4-amine (20 mg, crude), which was used directly in the next step without purification. Preparation 33: 2-(4-amino-5-chloro-1H-pyrazol-1-yl)acetonitrile 2-(4-amino-5-chloro-1H-pyrazol-1-yl)acetonitrile was obtained (24 mg, yield 4.3% over four steps) from 4-nitro-1H-pyrazole and 2-bromoacetonitrile following a similar procedure to that described in Preparation 19. LCMS m / z = 157.1 [M+H]+ Preparation 34: 3-(4-amino-5-chloro-1H-pyrazol-1-yl)propanenitrile 3-(4-amino-5-chloro-1H-pyrazol-1-yl)propanenitrile was obtained (50 mg, yield 32.5% over four steps) from 4-nitro-1H-pyrazole and 3-bromopropanenitrile following a similar procedure to that described in Preparation 19. LCMS m / z = 171.2 [M+H]+Preparation 35: 5-chloro-1-isopentyl-1H-pyrazol-4-amine 5-chloro-1-isopentyl-1H-pyrazol-4-amine was obtained (30 mg, yield 16.2% over four steps) from 4-nitro-1H-pyrazole and 1-bromo-3-methylbutane following a similar procedure to that described in Preparation 19. LCMS m / z = 188.0 [M+H]+Preparation 36: 5-chloro-1-phenethyl-1H-pyrazol-4-amine 5-chloro-1-phenethyl-1H-pyrazol-4-amine was obtained (30 mg, yield 12.4% over four steps) from 4-nitro-1H-pyrazole and 1-bromo-3-methylbutane following a similar procedure to that described in Preparation 19. LCMS m / z = 222.0 [M+H]+ Preparation 37: 6-chloro-7-(difluoromethoxy)-1H-indole-3-sulfonyl chloride Step a: To a solution of 1-chloro-2-(difluoromethoxy)-3-nitrobenzene (200 mg, 894.6 μmol, 1.0 eq.) in THF (6 mL) was added vinylmagnesium bromide (1 M, 3.58 mmol, 3.58 mL, 4.0 eq.) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 3 hours. The reaction mixture was diluted with aq. NH4Cl (50 mL) and extracted with EtOAc (40 mL x 3) dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield the 6-chloro-7-(difluoromethoxy)-1H-indole (50 mg, 25.68% yield).1H NMR: (400MHz, CDCl3) δ: 8.50 (s, 1H), 7.47 (d, J = 3.2 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.83-6.44 (m, 2H). Step b: To a mixture of 6-chloro-7-(difluoromethoxy)-1H-indole (20 mg, 91.91 μmol, 1.0 eq.) in MeCN (1 mL) was added sulfurochloridic acid (182.07 mg, 1.56 mmol, 103.86 μL, 17.0 eq.) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 6-chloro-7-(difluoromethoxy)-1H-indole-3-sulfonyl chloride (25 mg, 86.1% yield).1H NMR: (400MHz, CDCl3) δ: 8.04 (d, J = 3.2 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 6.90-6.52 (m, 1H). Preparation 38: 7-chloro-6-(dimethylamino)-1H-indole-3-sulfonyl chloride Step a: To a solution of N,N-dimethyl-3-nitroaniline (2.00 g, 12.04 mmol, 1.0 eq.) in DMF (20.0 mL) at 20 °C, a solution of NCS (1.61 g, 12.04 mmol, 1.0 eq.) in DMF (5.0 mL) was added at 20 °C. The mixture was stirred at 75 °C for 3 hours. The mixture was quenched via addition of water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4 then filtered. The filtrate was concentrated in vacuum to give a residue, which was purified by column chromatography to give 2-chloro-N,N-dimethyl-3-nitroaniline (1.10 g, 45.6% yield) as yellow oil. LCMS m / z = 201.0. [M+H]+. Step b: To a solution of 2-chloro-N,N-dimethyl-3-nitroaniline (500.00 mg, 2.49 mmol, 1.0 eq.) in THF (50.0 mL) was added vinylmagnesium bromide (1 M, 9.97 mmol, 4.0 eq.) at -78 °C dropwise under N2. The mixture was stirred at -78 °C for 3 hours. The mixture was quenched with addition of saturated aq. NH4Cl (20 mL) and then extracted with EA (20 mL x 3). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4then filtered. The filtrate was concentrated in vacuum to give a residue, which was purified by column chromatography to give 7-chloro-N,N-dimethyl-1H-indol-6-amine (220.00 mg, 45.4% yield) as yellow oil. LCMS m / z = 195.0. [M+H]+. Step c: To a solution 7-chloro-N,N-dimethyl-1H-indol-6-amine (40.00 mg, 205.49 μmol, 1.0 eq.) in DCM (5.0 mL) was treated with SO3.DMF (141.62 mg, 924.69 μmol, 4.5 eq.) at 20 °C. The mixture was stirred at 20 °C for 2 hours. Subsequently SOCl2(195.57 mg, 1.64 mmol, 8.0 eq.) was added and the mixture was stirred at 20 °C for 1.5 hours. The reaction mixture was hydrolyzed with a saturated solution of NaHCO3 (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4and filtered. The filtrate was concentrated in vacuum to give 7-chloro-6-(dimethylamino)-1H-indole-3- sulfonyl chloride (30.00 mg, crude). The crude product was directly used to the next step. LCMS m / z = 293.0. [M+H]+. Preparation 39: 1-(difluoromethyl)-5-propyl-1H-pyrazol-3-amine Step a: To a solution of 5-propyl-1H-pyrazol-3-amine (100 mg, 618.7 μmol, HCl, 1.0 eq.) in water (6 mL) was added oxone (950.9 mg, 1.55 mmol, 2.5 eq.) at 0 °C. The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield 3-nitro-5-propyl-1H-pyrazole (60 mg, 62.5% yield). LCMS m / z = 156.1. [M+H]+. Step b: To a solution of 3-nitro-5-propyl-1H-pyrazole (60 mg, 386.7 μmol, 1.0 eq.) in MeCN (8 mL) was added sodium 2-chloro-2,2-difluoroacetate (176.9 mg, 1.16 mmol, 3.0 eq.) and K2CO3(160.3 mg, 1.16 mmol, 3.0 eq.) at 20 °C. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield the 1-(difluoromethyl)-3-nitro-5-propyl-1H-pyrazole (20 mg, 25.2% yield).1H NMR: (400MHz, CDCl3) δ: 7.39-7.09 (m, 1H), 6.80 (s, 1H), 2.87 (t, J = 7.6 Hz, 2H), 1.81-1.75 (m, 2H), 1.06 (t, J = 7.6 Hz, 2H). Step c: To a solution of 1-(difluoromethyl)-3-nitro-5-propyl-1H-pyrazole (20 mg, 97.5 μmol, 1.0 eq.) in MeOH (2 mL) was added Pd / C (20.75 mg, 19.50 μmol, 10% purity, 0.2 eq.) (Wet). The mixture was stirred at 25 °C under H2 (15 Psi) for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give 1-(difluoromethyl)-5-propyl-1H- pyrazol-3-amine (12 mg, 70.3% yield). LCMS m / z = 176.2. [M+H]+. Preparation 40: 5-chloro-1-(difluoromethyl)-1H-pyrazol-3-amine Step a: To a solution of 5-chloro-3-nitro-1H-pyrazole (50 mg, 338.9 μmol, 1.0 eq.) in MeCN (6 mL) was added sodium 2-chloro-2,2-difluoroacetate (155.0 mg, 1.02 mmol, 3.0 eq.) and K2CO3 (140.5 mg, 1.02 mmol, 3.0 eq.) at 20 °C. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield the 5-chloro-1-(difluoromethyl)-3-nitro-1H-pyrazole (30 mg, 44.8% yield).1H NMR: (400MHz, CDCl3) δ: 7.43-7.13 (m, 1H), 7.02 (s, 1H). Step b: To a solution of 5-chloro-1-(difluoromethyl)-3-nitro-1H-pyrazole (30 mg, 151.9 μmol, 1.0 eq.) in MeOH (2 mL) was added Pd / C (32.3 mg, 30.38 μmol, 10% purity, 0.2 eq.) (Wet). The mixture was stirred at 25 °C under H2 (15 Psi) for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give 5-chloro-1-(difluoromethyl)-1H- pyrazol-3-amine (20 mg, 78.6% yield). LCMS m / z = 167.9 [M+H]+. Preparation 41: 6-(trifluoromethyl)-1H-indole-3-sulfonyl chloride To solution of 6-(trifluoromethyl)-1H-indole (100 mg, 540.12 μmol, 1.0 eq.) in MeCN (4 mL) was added sulfurochloridic acid (692.30 mg, 5.94 mmol, 394.92 μL, 11.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 1 hour. The reaction was quenched with water (10 mL), extracted with EtOAc (5 mL x 3). The combined organic layer was dried over Na2SO4; filtered and evaporated under vacuum to give 6-(trifluoromethyl)-1H-indole-3-sulfonyl chloride (150 mg, crude).1H NMR: (500MHz, DMSO) δ: 11.48 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.33-7.30 (m, 1H). Preparation 42: 5-chloro-1-(difluoromethyl)-1H-pyrazol-3-amine Step a: To a solution of tert-butyl (1H-pyrazol-4-yl)carbamate (70.00 mg, 382.08 μmol, 1.0 eq.) in MeCN (5.0 mL) was added Cs2CO3 (248.98 mg, 764.16 μmol, 3.0 eq.) and 1-(2- bromoethyl)-1-(trifluoromethyl)cyclopropane (82.92 mg, 382.08 μmol, 1.0 eq.) at 20 °C. The mixture was stirred at 55 °C for 16 hours. The mixture was filtered and concentrated in vacuum to give the residue, which was purified by column chromatography to give tert-butyl (1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazol-4-yl)carbamate (90.00 mg, 73.77% yield). LCMS m / z = 320.2 [M+H]+. Step b: To a solution of tert-butyl (1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazol-4- yl)carbamate (70.00 mg, 219.21 μmol, 1.0 eq.) in MeCN (2.0 mL) was added NCS (58.54 mg, 438.43 μmol, 2.0 eq.) at 20 °C. The mixture was stirred at 50 °C for 10 hours. The mixture was quenched with saturated aq. Na2SO3(20 mL). The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum to give the residue, which was purified by column chromatography to give tert-butyl (5-chloro-1-(2-(1- (trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazol-4-yl)carbamate (40.00 mg, 51.58% yield). LCMS m / z = 354.1 [M+H]+ 1H NMR (400MHz, DMSO) δ: 8.70 (s, 1H), 7.57 (s, 1H), 4.18 (t, J = 7.6 Hz, 2H), 2.02 (t, J = 7.6 Hz, 2H), 1.43 (s, 9H), 0.93-0.89 (m, 2H), 0.70 (s, 2H). Step c: To a solution of tert-butyl (5-chloro-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-1H- pyrazol-4-yl)carbamate (20.00 mg, 56.53 μmol, 1.0 eq.) in HFIP (2.0 mL) was added TFA (32.23 mg, 282.67 μmol, 5.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 2 hours. Solvent was evaporated under vacuum to give 5-chloro-1-(2-(1- (trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazol-4-amine (13.00 mg, 90.66% yield). LCMS m / z = 254.0 [M+H]+. Preparation 43: 4-chloro-5-ethylisoxazol-3-amine Step a: To a solution of 5-ethylisoxazol-3-amine (50.0 mg, 445.9 μmol, 1.0 eq.) in MeCN (2.0 mL) was added NCS (59.54 mg, 445.91 μmol, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The reaction was quenched with saturated aqueous Na2SO3and the mixture was then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was then purified by prep-TLC to give 4-chloro-5-ethylisoxazol-3-amine (35.0 mg, 53.6% yield). LCMS m / z = 147.1 [M+H]+. Preparation 44: 7-chloro-6-methyl-1H-indole-3-sulfonyl chloride Step a: To a solution of 2-chloro-1-methyl-3-nitrobenzene (1 g, 5.83 mmol, 1.0 eq.) in THF (40 mL) was dropwise added vinylmagnesium bromide (1M, 23.31 mL, 4.0 eq.) at -78 °C under N2. The reaction was stirred at -78 °C for 3 hours. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (40 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield 7-chloro-6-methyl-1H-indole (500 mg, 51.56% yield, 99.538% purity).1H NMR (400MHz, DMSO) δ: 11.23 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.32-7.30 (m, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.47-6.45 (m, 1H), 2.42 (s, 3H). Step b: To a solution of 7-chloro-6-methyl-1H-indole (200 mg, 1.21 mmol, 1.0 eq.) in MeCN (8.0 mL) was dropwise added HSO3Cl (1.41 g, 12.08 mmol, 802.70 μL, 10.0 eq.) at 0 °C. The reaction was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield 7-chloro-6-methyl-1H-indole-3-sulfonyl chloride (150 mg, 42.33% yield).1H NMR (400MHz, DMSO) δ: 11.21 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 2.8 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 2.41 (s, 3H). Preparation 45: 6,7-difluoro-1H-indole-3-sulfonyl chloride 6,7-difluoro-1H-indole-3-sulfonyl chloride was obtained (100 mg, yield 5% over two steps), from 1,2-difluoro-3-nitrobenzene following a similar procedure to that described in Preparation 45.1H NMR (400MHz, DMSO) δ: 11.75 (s, 1H), 7.52-7.48 (m, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.08-7.00 (m, 1H). Preparation 46: 6-chloro-7-methyl-1H-indole-3-sulfonyl chloride 6-chloro-7-methyl-1H-indole-3-sulfonyl chloride was obtained (40 mg, yield 1% over two steps), from 1-chloro-2-methyl-3-nitrobenzene following a similar procedure to that described in Preparation 45.1H NMR (400MHz, MeOD) δ: 7.98 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 2.58 (s, 3H). Preparation 47: 6-chloro-7-methoxy-1H-indole-3-sulfonyl chloride 6-chloro-7-methoxy-1H-indole-3-sulfonyl chloride was obtained (30 mg, yield 22% over two steps), from 1-chloro-2-methoxy-3-nitrobenzene following a similar procedure to that described in Preparation 45.1H NMR (400MHz, CDCl3) δ” 11.41 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.31-7.30 (m, 1H), 7.02 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H). Preparation 48: 7-chloro-6-fluoro-1H-indole-3-sulfonyl chloride 7-chloro-6-fluoro-1H-indole-3-sulfonyl chloride was obtained (40 mg, yield 32% over two steps), from 2-chloro-1-fluoro-3-nitrobenzene following a similar procedure to that described in Preparation 45.1H NMR (400MHz, CDCl3) δ: 9.07 (s, 1H), 8.05 (d, J = 3.2 Hz, 1H), 7.94- 7.89 (m, 1H), 7.31-7.28 (m, 1H). Preparation 49: 6-chloro-7-fluoro-1H-indole-3-sulfonyl chloride 6-chloro-7-fluoro-1H-indole-3-sulfonyl chloride was obtained (30 mg, yield 4% over two steps), from 1-chloro-2-fluoro-3-nitrobenzeneene following a similar procedure to that described in Preparation 45.1H NMR (400MHz, CDCl3) δ: 9.13 (br s, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.44-7.39 (m, 1H). Preparation 50: 7-chloro-6-methyl-1H-indole-3-sulfonyl chloride Step a: To a solution of 1-chloro-2-fluoro-3-nitrobenzene (1 g, 5.70 mmol, 1.0 eq.) in DCM (20 mL) was added dimethylamine hydrochloride (929.04 mg, 11.39 mmol, 2.0 eq.) and TEA (1.73 g, 17.09 mmol, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 3 hours. The reaction was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to give 2-chloro-N,N-dimethyl-6-nitroaniline (1 g, 87.50% yield). LCMS m / z = 201.2 [M+H]+.1H NMR (400MHz, CDCl3) δ: 7.56-7.52 (m, 2H), 7.09- 7.04 (m, 1H), 2.85 (s, 6H). Step b: To a stirred solution of 2-chloro-N,N-dimethyl-6-nitroaniline (0.5 g, 2.49 mmol, 1.0 eq.) in THF (50 mL) was added vinylmagnesium bromide (1 M, 9.97 mL, 4.0 eq.) at -78 °C under N2. The mixture was stirred at -78 °C for 4 hours. The mixture was quenched with saturated solution of NH4Cl (80 mL) and extracted with ethyl acetate (100 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromotography to give 6-chloro-N,N- dimethyl-1H-indol-7-amine (260 mg, 53.59% yield).1H NMR (400MHz, CDCl3) δ: 8.55 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.21-7.18 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.54-6.52 (m, 1H), 2.98 (s, 6H). Step c: To a stirred solution of 6-chloro-N,N-dimethyl-1H-indol-7-amine (100 mg, 513.72 μmol, 1.0 eq.) in MeCN (4 mL) was added HSO3Cl (718.30 g, 6.16 mmol, 0.4 mL, 12.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 hours. The mixture was quenched with saturated ice water and extracted with ethyl acetate (20 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography to give 7-chloro-6-methyl-1H-indole-3- sulfonyl chloride (50 mg, 33.20% yield).1H NMR (400MHz, CDCl3) δ: 9.38 (s, 1H), 7.96 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 2.97 (s, 6H). Preparation 51: 5-chloro-1-(3,3-difluoropropyl)-1H-pyrazol-4-amine Step a: To a solution of methyl 3-(4-nitro-1H-pyrazol-1-yl)propanoate (1.0 g, 5.02 mmol, 1.0 eq.) and CaCl2(557.23 mg, 5.02 mmol, 1.0 eq.) in EtOH (10 mL) was added NaBH4(379.91 mg, 10.04 mmol, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. The filtrate was concentrated in vacuum to give 3-(4-nitro-1H-pyrazol-1-yl)propan-1-ol (650 mg, 75.2% yield) as a yellow solid. LCMS m / z = 172.2 [M+H]+ 1H NMR (400 MHz, CDCl3) δ: 8.18 (s, 1H), 8.09 (s, 1H), 4.35 (t, J = 6.4 Hz, 2H), 3.67 (t, J = 5.6 Hz, 2H), 2.17-2.10 (m, 2H). Step b: To a solution of 3-(4-nitro-1H-pyrazol-1-yl)propan-1-ol (2.05 g, 11.98 mmol, 1.0 eq.) in DCM (20 mL) was added Dess-Martin periodinane (7.62 g, 17.97 mmol, 1.5 eq.) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. The filtrate was concentrated in vacuum to give a residue which was purified by column chromatography to give 3-(4-nitro-1H-pyrazol-1-yl)propanal (760 mg, 37.52% yield).1H NMR (400 MHz, CDCl3) δ: 9.81 (s, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 4.48 (t, J = 6.0 Hz, 2H), 3.17 (t, J = 6.0 Hz, 2H). Step c: To a solution of 3-(4-nitro-1H-pyrazol-1-yl)propanal (760 mg, 4.49 mmol, 1.0 eq.) in DCM (10 mL) was added DAST (1.45 g, 8.99 mmol, 1.19 mL, 2.0 eq.) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The mixture was quenched with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. The filtrate was concentrated in vacuum to give a residue which was purified by column chromatography to give 1-(4,4-difluorobutyl)-4-nitro-1H-pyrazole (360 mg, 39.49% yield). LCMS m / z = 237.0 [M+H]+ 1H NMR (400 MHz, DMSO) δ: 8.18 (s, 1H), 8.11 (s, 1H), 6.11-5.81 (m, 1H), 4.37 (t, J = 6.8 Hz, 2H), 2.57-2.47 (m, 2H). Step d: To a solution of 1-(4,4-difluorobutyl)-4-nitro-1H-pyrazole (360 mg, 1.88 mmol, 1.0 eq.) in MeOH (5 mL) was added Pd / C (20.04 mg, 188.35 µmol, 0.1 eq.) at 25 °C. The mixture was stirred at 25 °C under H2(15 Psi) for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 1-(4,4-difluorobutyl)-1H-pyrazol-4-amine (286 mg, 94.23% yield).1H NMR (400 MHz, DMSO) δ: 7.06 (s, 1H), 6.92 (s, 1H), 6.19-5.88 (m, 1H), 4.07 (t, J = 7.2 Hz, 2H), 3.82 (s, 2H), 2.33-2.23 (m, 2H). Step e: To a solution of 1-(4,4-difluorobutyl)-1H-pyrazol-4-amine (286 mg, 1.77 mmol, 1.0 eq.) in DCM (5 mL) was added TEA (359.17 mg, 3.55 mmol, 494.72 µL, 2.0 eq.) and Boc2O (464.79 mg, 2.13 mmol, 489.25 µL, 1.2 eq.) at 25 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue and then purified by column chromatography to give tert-butyl (1-(4,4-difluorobutyl)-1H-pyrazol- 4-yl)carbamate (370 mg, 71.12% yield, 89.12% purity). LCMS m / z = 262.2 [M+H]+ 1H NMR (400 MHz, DMSO) δ: 9.13 (s, 1H), 7.69 (s, 1H), 7.30 (s, 1H), 6.21-5.91 (m, 1H), 4.18 (t, J = 7.2 Hz, 2H), 2.39-2.28 (m, 2H), 1.44 (s, 9H). Step f: To a solution of tert-butyl (1-(4,4-difluorobutyl)-1H-pyrazol-4-yl)carbamate (150 mg, 574.12 µmol, 1.0 eq.) in MeCN (5 mL) was added NCS (229.99 mg, 1.72 mmol, 3.0 eq.) at 25 °C. The mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert- butyl (5-chloro-1-(4,4-difluorobutyl)-1H-pyrazol-4-yl)carbamate (50 mg, 28.45% yield). LCMS m / z = 296.1 [M+H]+ 1H NMR (400 MHz, DMSO) δ: 8.72 (s, 1H), 7.59 (s, 1H), 6.29- 5.98 (m, 1H), 4.22 (t, J = 7.2 Hz, 2H), 2.39-2.29 (m, 2H), 1.43 (s, 9H). Step g: To a solution of tert-butyl (5-chloro-1-(4,4-difluorobutyl)-1H-pyrazol-4-yl)carbamate (50 mg, 169.08 µmol, 1.0 eq.) in HFIP (2 mL) was added TFA (19.28 mg, 169.08 µmol, 12.95 µL, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuum to give 5-chloro-1-(4,4-difluorobutyl)-1H-pyrazol-4-amine (33 mg, 99.78% yield), which was used without further purification. LCMS m / z = 196.2 [M+H]+ Preparation 52: 6-chloro-N-(4-chloro-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide To a solution of 5-methylisothiazol-3-amine (50.00 mg, 331.94 µmol, 1.0 eq.) in MeCN (2.0 mL) was added N-chlorosuccinamide (44.32 mg, 331.94 µmol, 1.0 eq.) 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was filtered under vacuum and the filter cake was evaporated under vacuum to give 4-chloro-5-methylisothiazol-3-amine (37.00 mg, 75.00% yield). LCMS m / z = 149.1 [M+H]+. Preparation 53: 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride Step a: To a solution of 1H-indole-6-carbaldehyde (500 mg, 3.44 mmol, 1.0 eq.) in THF (4 mL) was added sodium hydride (151.54 mg, 3.79 mmol, 60% purity, 1.1 eq.) at 0 °C. The reaction was stirred at 0 °C for 30 min. To the reaction was then added benzenesulfonyl chloride (669.21 mg, 3.79 mmol, 483.53 μL, 1.1 eq.) at 0 °C. The reaction was stirred at 20 °C for 14 hours. The reaction was quenched with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (30 mL x 3). The combined organic layer was dried over Na2SO4; filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to give 1-(phenylsulfonyl)-1H-indole-6- carbaldehyde (550 mg, 55.96% yield). LCMS m / z = 286.1 [M+H]+ 1H NMR (400 MHz, CDCl3) δ: 10.10 (br s, 1H), 8.51 (s, 1H), 7.95-7.92 (m, 2H), 7.82-7.78 (m, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.51-7.47 (m, 2H), 6.76 (d, J = 3.6 Hz, 1H). Step b: To a solution of 1-(phenylsulfonyl)-1H-indole-6-carbaldehyde (550 mg, 1.93 mmol, 1.0 eq.) in DCM (10 mL) was added DAST (1.55 g, 9.64 mmol, 1.27 mL, 5.0 eq.) at 0 °C. The reaction was stirred at 20 °C for 14 hours. The reaction was quenched with saturated NaHCO3 till pH > 7, extracted with DCM (10 mL x 3). The combined organic layer was dried over Na2SO4, filtered; evaporated under vacuum. The residue was purified by column chromatography to give 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole (300 mg, 50.64% yield).1H NMR (400 MHz, CDCl3) δ: 8.17 (s, 1H), 7.91-7.88 (m, 2H), 7.67 (d, J = 4.0 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.58-7.55 (m, 1H), 7.50-7.45 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 6.92-6.63 (m, 2H). Step c: To a solution of 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole (100 mg, 325.40 μmol, 1.0 eq.) in MeCN (1 mL) was slowly added sulfurochloridic acid (189.58 mg, 1.63 mmol, 108.14 μL, 5.0 eq.) at 0 °C. The reaction mixture was stirred at 25 °C for 14 hours. It was then slowly poured with stirring into ice-water (5 mL). The reaction was extracted with EtOAc (10 mL x 3). The combined organic layer was dried over Na2SO4; filtered and evaporated under vacuum. The residue was purified by column chromatography to give 6- (difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride (100 mg, 75.73% yield).1H NMR (400 MHz, CDCl3) δ: 8.46 (s, 1H), 8.21 (m, 1H), 8.09-8.02 (m, 3H), 7.75-7.70 (m, 1H), 7.64-7.59 (m, 3H), 6.96-6.67 (m, 1H). Preparation 54: 7-chloro-6-methoxy-1H-indole-3-sulfonyl chloride 7-chloro-6-methoxy-1H-indole-3-sulfonyl chloride was obtained (70 mg, yield 14% over two steps), from 2-chloro-1-methoxy-3-nitrobenzene following a similar procedure to that described in Preparation 45.1H NMR (400MHz, CDCl3) δ: = 8.93 (s, 1H), 7.97 (d, J = 3.2 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 4.02 (s, 3H). The following examples below were purified using the following prep-HPLC method unless otherwise noted. Prep-HPLC-A: Welch Xtimate C18150 x 25 mm, 5 ^m; 30-72% MeCN / H2O (10 mm NH4HCO3); Prep-HPLC-B: Phenomenex Luna C18150 x 25 mm, 10 ^m; 54-84% MeCN / H2O (0.05%(NH4HCO3)-ACN); Prep-HPLC-C: Waters Sunfire OBD 100 x 50 mm, 5 mm; 5-75% MeCN / H2O (+ 0.1% TFA). Prep-HPLC-D: Phenomenex Synergi C18150 x 30 mm, 4 mm; 49-69% MeCN / H2O (0.05%(NH4HCO3)-ACN); Prep-HPLC-E: Waters Oxbridge C18 150 x 25 mm, 10 um; 25-60% MeCN / H2O (0.05%(NH4HCO3)-ACN); Prep-HPLC-F: Boston Prime C18150 x 30 mm, 15mm; 10-40% MeCN / H2O ((NH3H2O+NH4HCO3)-ACN); Prep-HPLC-G: Boston Green ODS 150 x 30 mm, 5um; 30-60% MeCN / H2O (0.05%(NH4HCO3)-ACN); Prep-HPLC-H: Phenomenex Gemini-NX 150 x 30 mm, 5um; 25- 55% MeCN / H2O (0.05%(NH4HCO3)-ACN); Prep-HPLC-I: Waters SunFire C18 19 x 100, 5um; 35-65% MeOH / H2O. Prep-HPLC-J: YMC-Triart Prep C18150 x 40 mm, 7 ^M; 40-60% MeCN / H2O. Prep-HPLC-K: Waters XSelect CSH C18 30 x 100 mm, 5 uM; 5-30% MeCN / H2O (0.05%(NH4HCO3)-ACN). Preparation 55: 5-bromo-1-(difluoromethyl)-1H-pyrazol-4-amine Step a: To a solution of tert-butyl (1-(difluoromethyl)-1H-pyrazol-4-yl)carbamate (270 mg, 1.16 mmol, 1.0 eq.) in MeCN (2 mL) was added NBS (206.06 mg, 1.16 mmol, 1.0 eq.) at 20 °C. The reaction was stirred at 20 °C for 3 hours. TLC showed the reaction was complete. The combined reaction mixture was quenched with saturated aq. Na2SO3(aq.) (5 mL) then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude, which was purified by column chromatography to give tert-butyl (5-bromo-1- (difluoromethyl)-1H-pyrazol-4-yl)carbamate (260 mg, 56.63% yield, 78.70% purity). LCMS m / z = 313.9 [M+H]+ 1H NMR (400 MHz, CDCl3) δ: 8.14 (s, 1H), 7.32-7.02 (m, 1H), 6.17 (s, 1H), 1.53 (s, 9H). Step b: To a solution of tert-butyl (5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)carbamate (100 mg, 320.40 μmol, 1.0 eq.) in DCM (3 mL) was added TFA (595.60 mg, 5.22 mmol, 16.3 eq.) at 20 °C. The reaction was stirred at 20 °C for 3 hours. TLC showed the reaction was complete. The mixture was concentrated under vacuum to afford 5-bromo-1- (difluoromethyl)-1H-pyrazol-4-amine. The material was used without further purification assuming quantitative yield. LCMS m / z = 211.8 [M+H]+Preparation 56: 6-chloro-7-(thiazol-4-yl)-1H-indole-3-sulfonyl chloride Step a: To a solution of 4-(tributylstannyl)thiazole (184.80 mg, 801.77 μmol, 1.5 eq.) in toluene (5 mL) was added KF (93.16 mg, 1.60 mmol, 3.0 eq.), cataCXium A-Pd-G2 (35.74 mg, 53.45 μmol, 0.1 eq.) and 7-bromo-6-chloro-1H-indole (200 mg, 534.51 μmol, 1.0 eq.) at 20 °C under N2. The reaction was stirred at 100 °C for 16 hours. LCMS showed that the desired product was detected. The mixture was quenched with saturated aq. KF (5 mL) and diluted with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography to give 4-(6- chloro-1H-indol-7-yl)thiazole (100 mg, 79.71% yield). LCMS m / z = 235.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 9.19 (d, J = 1.6 Hz, 1H), 8.11 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 3.2 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 3.2 Hz, 1H). Step b: To a solution of 4-(6-chloro-1H-indol-7-yl)thiazole (50 mg, 213.03 μmol, 1.0 eq.) in MeCN (2 mL) was added dropwise sulfurochloridic acid (124.12 mg, 1.07 mmol, 70.80 μL, 5.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 hour. TLC showed the reactant was consumed completely. Then the mixture was added POCl3 (163.32 mg, 1.07 mmol, 99.29 μL, 5.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 hour. TLC showed the starting material was consumed completely and one new spot was detected. The mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (10 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 6- chloro-7-(thiazol-4-yl)-1H-indole-3-sulfonyl chloride. The material was used without further purification assuming quantitative yield. LCMS m / z = 332.9 [M+H]+Preparation 57: 6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole-3-sulfonyl chloride Step a: To a solution of 2-(2-chloro-6-nitrophenyl)-2H-1,2,3-triazole (1 g, 4.45 mmol, 1.0 eq.) in THF (60 mL) was added bromo(vinyl)magnesium (1 M, 17.81 mmol, 17.81 mL, 4.0 eq.) at -78 °C under N2. The reaction was stirred at -78 °C for 2 hours. TLC showed a new main spot was observed. The reaction was slowly quenched with saturate aq.NH4Cl (40 mL) at 0 °C about 10 min. The reaction was extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (40 mL x 3), dried over Na2SO4; filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to give 6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole (460 mg, 47.25% yield).1H NMR (400 MHz, DMSO) δ: 11.19 (s, 1H), 8.22 (s, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.62 (s, 1H). Step b: To a solution of 6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole (100 mg, 457.37 μmol, 1.0 eq.) in MeCN (3 mL) was added sulfurochloridic acid (133.24 mg, 1.14 mmol, 76.00 μL, 2.5 eq.) at 0 °C. The reaction was stirred at 0 °C for 2 hours. LCMS showed the reaction was complete. To the reaction was added POCl3(280.52 mg, 1.83 mmol, 170.53 μL, 4.0 eq.) at 0 °C. The reaction was stirred at 70 °C for 14 hours. LCMS showed the reaction was complete. The reaction was quenched with ice water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was dried over Na2SO4; filtered and the filtrate was evaporated under vacuum to give 6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole-3-sulfonyl chloride. The material was used without further purification assuming quantitative yield. Preparation 58: 6-chloro-7-(pyridin-2-yl)-1H-indole-3-sulfonyl chloride Step a: To a solution of 7-bromo-6-chloro-1H-indole (100 mg, 433.86 μmol, 1.0 eq.) in dioxane (5 mL) was added PdCl2(PPh3)2 (30.45 mg, 43.39 μmol, 0.1 eq.) at 20 °C. To the reaction was then added 2-(tributylstannyl)pyridine (191.67 mg, 520.63 μmol, 168.57 μL) at 20 °C under N2. The reaction was stirred at 100 °C for 16 hours. LCMS showed the desired mass was detected. The mixture was quenched with saturated aq. KF (10 mL) and diluted with water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography to give 6-chloro-7-(pyridin-2- yl)-1H-indole. The material was used without further purification assuming quantitative yield. LCMS m / z = 229.1 [M+H]+ 1H NMR (400 MHz, CDCl3) δ: 8.71 (d, J = 4.0 Hz, 2H), 8.43 (d, J = 8.0 Hz, 2H), 7.88-7.83 (m, 2H), 7.36-7.32 (m, 2H). Step b: To a solution of 6-chloro-7-(pyridin-2-yl)-1H-indole (50 mg, 218.65 μmol, 1.0 eq.) in MeCN (2 mL) was added dropwise sulfurochloridic acid (254.78 mg, 2.19 mmol, 145.34 μL, 10.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 hour. TLC showed the starting material was consumed completely and one new spot was detected. The mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (10 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 6- chloro-7-(pyridin-2-yl)-1H-indole-3-sulfonyl chloride. The material was used without further purification assuming quantitative yield. LCMS m / z = 326.9 [M+H]+Preparation 59: 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride Step a: To a solution of 1-chloro-2-fluoro-3-nitrobenzene (500 mg, 2.85 mmol, 1.0 eq.) and 1H-pyrazole (290.85 mg, 4.27 mmol, 1.5 eq.) in MeCN (20 mL) was added K2CO3 (1.18 g, 8.54 mmol, 3.0 eq.). The mixture was stirred at 25 °C for 12 hours. LCMS showed the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 1-(2- chloro-6-nitrophenyl)-1H-pyrazole (580 mg, 91.06% yield). LCMS m / z = 223.8 [M+H]+ 1H NMR (MeOD) δ: 8.02-7.95 (m, 3H), 7.76-7.70 (m, 2H), 6.60-6.58 (m, 1H). Step b: To a solution of 1-(2-chloro-6-nitrophenyl)-1H-pyrazole (250 mg, 1.12 mmol, 1.0 eq.) in THF (10 mL) was added bromo(vinyl)magnesium (1 M, 4.47 mmol, 4.47 mL, 4.0 eq.) at -78 °C under N2. The mixture was stirred at -78 °C for 2 hours. LCMS showed desired product was obtained. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 6-chloro-7-(1H-pyrazol-1-yl)-1H- indole (60 mg, 24.66% yield). LCMS m / z = 217.8 [M+H]+ 1H NMR (MeOD) δ: 7.97 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 3.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.63-6.61 (m, 1H), 6.56 (d, J = 3.2 Hz, 1H). Step c: To a solution of 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole (50.00 mg, 229.72 µmol, 1.0 eq.) in MeCN (10 mL) was added HSO3Cl (267.68 mg, 2.30 mmol, 152.70 μL, 10.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 hour. LCMS showed desired product was obtained. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (50 mg, 68.84% yield).1H NMR (MeOD) δ: 8.22 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.01-7.98 (m, 1H), 7.93-7.87 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H). Preparation 60: 6-chloro-7-(4-chloro-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride Step a: To a solution of 1-chloro-2-fluoro-3-nitrobenzene (1 g, 5.70 mmol, 1.0 eq.) and 4- chloro-1H-pyrazole (876.03 mg, 8.54 mmol, 1.5 eq.) in MeCN (40 mL) was added K2CO3 (2.36 g, 17.09 mmol, 3.0 eq.) at 20 °C. The reaction was stirred at 60 °C for 14 hours. LCMS showed the reaction was complete. The reaction was filtered, and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to give 4- chloro-1-(2-chloro-6-nitrophenyl)-1H-pyrazole (1.4 g, 95.23% yield) as a white solid.1H NMR (400 MHz, DMSO) δ: 8.57 (s, 1H), 8.16-8.10 (m, 2H), 7.93 (s, 1H), 7.86-7.81 (m, 1H). Step b: To a solution of 4-chloro-1-(2-chloro-6-nitrophenyl)-1H-pyrazole (1 g, 3.88 mmol, 1.0 eq.) in THF (60 mL) was added bromo(vinyl)magnesium (1 M, 15.50 mmol, 15.50 mL, 4.0 eq.) at -78 °C under N2. The reaction was stirred at -78 °C for 2 hours. TLC showed a new main spot was observed. The reaction was slowly quenched with saturate aq.NH4Cl (40 mL) at 0 °C about 10 min. The reaction was extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (40 mL x 3), dried over Na2SO4; filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to give 6-chloro-7-(4-chloro-1H-pyrazol-1-yl)-1H-indole (500 mg, 51.18% yield).1H NMR (400 MHz, DMSO) δ: 11.20 (s, 1H), 8.41 (s, 1H), 7.95 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.39-7.37 (m, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.60-6.58 (m, 1H). Step c: To a solution of 6-chloro-7-(4-chloro-1H-pyrazol-1-yl)-1H-indole (50 mg, 198.33 μmol, 1.0 eq.) in MeCN (3 mL) was added sulfurochloridic acid (57.78 mg, 495.84 μmol, 32.96 μL, 2.5 eq.) at 0 °C. The reaction was stirred at 0 °C for 2 hours. LCMS showed the reaction was complete. To the reaction was added POCl3 (121.64 mg, 793.34 μmol, 73.95 μL, 4.0 eq.) at 0 °C. The reaction was stirred at 60 °C for 14 hours. LCMS showed the reaction was complete. The reaction was quenched with ice water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was dried over Na2SO4; filtered and the filtrate was evaporated under vacuum to give 6-chloro-7-(4-chloro-1H-pyrazol-1-yl)-1H- indole-3-sulfonyl chloride LCMS m / z = 349.7 [M+H]+. The material was used without further purification assuming quantitative yield. Preparation 61: 6-chloro-7-(4-ethyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride 6-chloro-7-(4-ethyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride was obtained (40 mg, yield 16.6% yield over three steps), from 1-chloro-2-fluoro-3-nitrobenzene and 4-ethyl-1H- pyrazole following a similar procedure to that described in Preparation 60. Preparation 62: 7-(4-bromo-1H-pyrazol-1-yl)-6-chloro-1H-indole-3-sulfonyl chloride 6-chloro-7-(4-ethyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride was obtained (100 mg, yield 16.9% yield over three steps), from 1-chloro-2-fluoro-3-nitrobenzene and 4-bromo-1H- pyrazole following a similar procedure to that described in Preparation 60. Preparation 63: 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole and 6- chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)-1H-indole Step a: To a solution of 1-chloro-2-fluoro-3-nitrobenzene (1 g, 9.25 mmol, 1.0 eq.) in MeCN (10 mL) was added K2CO3 (2.56 g, 18.49 mmol, 2.0 eq.) and 2,4,5,6- tetrahydrocyclopenta[c]pyrazole (1.62 g, 9.25 mmol, 1.0 eq.) at 20 °C. Then the mixture was stirred at 20 °C for 16 hours. LCMS showed that the reaction was complete. The reaction was quenched with water (10 mL) and extracted with EtOAc (20 mL x 3) and washed with brine (20 mL), dried over Na2SO4, filtered. The filtrate was concentrated in vacuum to give the crude, which was purified by column chromatography to give 1-(2-chloro-6-nitrophenyl)- 1,4,5,6-tetrahydrocyclopenta[c]pyrazole and 2-(2-chloro-6-nitrophenyl)-2,4,5,6- tetrahydrocyclopenta[c]pyrazole as a mixture (1.6g, 65.57% yield). LCMS m / z = 263.8 [M+H]+ 1H NMR (400 MHz, CDCl3) δ: 7.80-7.73 (m, 2H), 7.50-7.35 (m, 2H), 2.80-2.74 (m, 4H), 2.48-2.43 (m, 2H). Step b: To a mixture of 1-(2-chloro-6-nitrophenyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole and 2-(2-chloro-6-nitrophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole as a mixture (800.00 mg, 3.04 mmol, 1.0 eq.) in THF (10 mL) was carefully added bromo(vinyl)magnesium (1 M, 12.14 mmol, 12.14 mL, 4.0 eq.) at -60 °C under N2. Then the mixture was stirred at -60 °C for 3 hours. LCMS showed that the reaction was complete. The mixture was quenched with saturated aq. NH4Cl (aq.) (10 mL) then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude, which was purified by column chromatography to give 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole (200 mg, 25.42% yield) LCMS m / z = 258.0 [M+H]+ 1H NMR (400 MHz, DMSO) δ: 11.04 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.33 (t, J = 2.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.56 (dd, J = 2.8, 2.0 Hz, 1H), 2.70-2.63 (m, 2H), 2.58-2.50 (m, 4H) and 6-chloro-7-(5,6- dihydrocyclopenta[c]pyrazol-2(4H)-yl)-1H-indole (200 mg, 25.42% yield) LCMS m / z = 258.0 [M+H]+ 1H NMR (400 MHz, DMSO) δ: 10.97 (s, 1H), 7.68 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.32 (t, J = 2.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.55 (dd, J = 2.8, 2.0 Hz, 1H), 2.77-2.69 (m, 4H), 2.46-2.41 (m, 2H). General methods General Method A: To a solution of aniline (1 eq.) in DCM (0.05M) was added sulfonyl chloride (1.0 eq.) and pyridine (3.0 eq.) at 20 °C. The reaction was stirred at 20 °C until reaction was completed as monitored by TLC or LCMS. The mixture was filtrated and concentrated in vacuum to give the residue, which was purified by the specified HPLC method to give the desired product. General Method B: To a solution of aniline (1 eq.) in pyridine (0.05M) was added sulfonyl chloride (1.0 eq.) at 20 °C. The reaction was stirred at 60 °C for 1 hour. The mixture was filtrated and concentrated in vacuum to give the residue, which was purified by the specified HPLC method to give the desired product. General Method C: To a solution of aniline (1 eq.) in pyridine (0.1M) was added sulfonyl chloride (1.0 eq.) at 20 °C. The reaction was stirred at 20 °C overnight. The mixture was filtrated and concentrated in vacuum to give the residue, which was purified by the specified HPLC method to give the desired product. General Method D: To a solution of aniline (1 eq.) in pyridine (0.1 M) was added the aryl sulfonyl chloride at 20 °C. A catalytic amount of DMAP was added and the reaction mixture was heated at 60 °C overnight. The reaction mixture was then quenched with water and extracted three times with DCM. The combined organics were dried and concentrated and the crude product was then purified by the specified HPLC method to give the desired product. General Method E: To a solution of aniline (1 eq.) in pyridine (0.1 M) was added sulfonyl chloride (1 eq.) and the resulting mixture was heated to 100 °C for 16 h. Then the solution was cooled to room temperature, and concentrated. The resulting residue was purified via the specified reverse phase HPLC method to yield the desired product. General Method F: To a solution of sulfonyl chloride (1 eq) in DCM (0.1 M) was added aniline (1 eq) followed by DIPEA (3 eq). The mixture was stirred at room temperature for 16 hours, and was then concentrated. The resulting residue was purified via the specified reverse phase method to yield the desired product. General Method G: Sulfonyl chloride (1.0 eq.) was added to a solution of aniline (1.1 eq.) in dry pyridine (0.15 M). The reaction mixture was stirred at 60 °C for 24 hours. The solvent was then evaporated in vacuo and the residue was purified via the specified reverse phase HPLC method to yield the desired product. General Method H: Sulfonyl chloride (1.0 eq.), aniline (2.0 eq.), and DMAP (0.1 eq.) were combined followed by addition of DCM and pyridine (1:1 mixture, 0.2M). The mixture was heated to 65 °C for 16 hours. The reaction was then evaporated in vacuo and the residue was purified via the specified reverse phase HPLC method to yield the desired product. EXEMPLIFICATION Examples 1-94 The title compounds were prepared from the appropriate sulfonyl chloride and the appropriate aniline (RNH2) using the specified general method.

[0007] Example 95: N-(5-cyano-1-ethyl-1H-pyrazol-4-yl)-6-(difluoromethyl)-1H-indole-3- sulfonamide Step a: To a solution of 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile (33.55 mg, 246.41 μmol, 1.0 eq.) in pyridine (8 mL) was added 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3- sulfonyl chloride (Preparation 53) (100 mg, 246.41 μmol, 1.0 eq.). The reaction was stirred at 50 °C for 14 hours. The solvent was evaporated under vacuum, and the residue was purified by column chromatography to give N-(5-cyano-1-ethyl-1H-pyrazol-4-yl)-6-(difluoromethyl)- 1-(phenylsulfonyl)-1H-indole-3-sulfonamide (70 mg, 56.20% yield). LCMS m / z = 506.2 [M+H]+Step b: To a solution of N-(5-cyano-1-ethyl-1H-pyrazol-4-yl)-6-(difluoromethyl)-1- (phenylsulfonyl)-1H-indole-3-sulfonamide (70 mg, 138.47 μmol, 1.0 eq.) in THF (5 mL) was added TBAF (1 M, 415.42 μL, 3.0 eq.) at 20 °C. The reaction was stirred at 60 °C for 14 hours. The reaction was quenched with water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was dried over Na2SO4; filtered. The filtrate was evaporated under vacuum. The residue was purified by column chromatography to give N-(5-cyano-1- ethyl-1H-pyrazol-4-yl)-6-(difluoromethyl)-1H-indole-3-sulfonamide (27.5 mg, 53.29% yield). LCMS m / z = 366.0 [M+H]+ 1H NMR (400 MHz, DMSO) ^: 12.34 (br s, 1H), 10.22 (br s, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.71-7.68 (m, 2H), 7.35-6.98 (m, 3H), 4.16-4.10 (m, 2H), 1.25 (d, J = 7.2 Hz, 3H). Example 96: N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(difluoromethyl)-1H- indole-3-slfonamide Step a: To solution of 6-(difluoromethyl)-1H-indole-3-sulfonyl chloride (Preparation 53) (50 mg, 123.21 μmol, 1.0 eq.) in DCM (3 mL) was added 5-chloro-1-(trifluoromethyl)-1H- pyrazol-4-amine (Preparation 2) (22.86 mg, 123.21 μmol, 1.0 eq.), pyridine (29.24 mg, 369.62 μmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated to a residue which was purified by column chromatography to give compound N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(difluoromethyl)-1- (phenylsulfonyl)-1H-indole-3-sulfonamide (40 mg, 58.51% yield). LCMS m / z = 554.9 [M+H]+Step b: To a solution of N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-6- (difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (40 mg, 72.09 μmol, 1.0 eq.) in THF (2 mL) was added TBAF (1 M, 360.43 μmol, 360.43 μL, 5.0 eq.) at 25 °C. The reaction was stirred at 60 °C for 12 hours. The reaction was quenched with water (10 mL), extracted with EtOAc (5 mL x 3). The combined organic layer was dried over Na2SO4; filtered and evaporated under vacuum. The residue was purified by column chromatography to give N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(difluoromethyl)-1H-indole-3- sulfonamide (11.5 mg, 38.47% yield). LCMS m / z = 414.9 [M+H]+ 1H NMR (400MHz, MeOD) δ: 7.83-7.74 (m, 3H), 7.67 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.00-6.71 (m, 1H). Example 97: N-(5-cyano-1-ethyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)-1H-indole-3- sulfonamide Step a: To a solution of 6-(trifluoromethyl)-1H-indole (200 mg, 1.08 mmol, 1.0 eq.) in DCM (8 mL) was added NaOH (133.94 mg, 3.35 mmol, 3.1 eq.) and tetrabutylammonium hydrogensulfate (110.03 mg, 324.07 μmol, 0.3 eq.) at 0 °C. To the reaction was then slowly added benzenesulfonyl chloride (209.87 mg, 1.19 mmol, 151.64 μL, 1.1 eq.) at 0 °C. The reaction was stirred at 0 °C for 1 hour. The reaction was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to give 1- (phenylsulfonyl)-6-(trifluoromethyl)-1H-indole (320 mg, 91.06% yield).1H NMR (400 MHz, CDCl3) ^: 8.30 (s, 1H), 7.92-7.89 (m, 2H), 7.72 (d, J = 3.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.61-7.56 (m, 1H), 7.51-7.47 (m, 3H), 6.74 (d, J = 3.6 Hz, 1H). Step b: To a solution of 1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole (100 mg, 307.40 μmol, 1.0 eq.) in MeCN (1 mL) was slowly added sulfurochloridic acid (179.10 mg, 1.54 mmol, 102.17 μL, 5.0 eq.) at 0 °C. The reaction mixture was stirred at 25 °C for 14 hours. The reaction was slowly added into ice-water (10 mL). The reaction was extracted with EtOAc (10 mL x 3). The combined organic layer was dried over Na2SO4; filtered and evaporated under vacuum. The residue was purified by column chromatography to give 1- (phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-3-sulfonyl chloride (100 mg, 76.76% yield).1H NMR (400 MHz, CDCl3) ^: 8.50 (s, 1H), 8.33 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.05-8.02 (m, 2H), 7.76-7.72 (m, 2H), 7.65-7.61 (m, 2H). Step c: To a solution of 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile (93.38 mg, 220.34 μmol, 1.0 eq.) in pyridine (5 mL) was added 1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-3- sulfonyl chloride (30 mg, 220.34 μmol, 1.0 eq.). The reaction was stirred at 50 °C for 14 hours. Solvent was evaporated under vacuum. The residue was purified by prep-HPLC (Column: Boston Green ODS 150 x 30mm x 5μm, water (FA)-ACN, Gradient Time (min): 10, Flow Rate (ml / min): 60) to give N-(5-cyano-1-ethyl-1H-pyrazol-4-yl)-1- (phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide (20 mg, 17.34% yield). LCMS m / z = 524.2 [M+H]+Step d: To a solution of N-(5-cyano-1-ethyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-6- (trifluoromethyl)-1H-indole-3-sulfonamide (20 mg, 38.20 μmol, 1.0 eq.) in THF (3 mL) was added TBAF (1 M, 38.20 μL, 1.0 eq.) at 20 °C. The reaction was stirred at 60 °C for 14 hours. The reaction was quenched with water (10 mL), extracted with EtOAc (15 mL x 3). The combined organic layer was dried over Na2SO4; filtered and evaporated under vacuum. The residue was purified by prep-TLC to give N-(5-cyano-1-ethyl-1H-pyrazol-4-yl)-6- (trifluoromethyl)-1H-indole-3-sulfonamide (7 mg, 47.80% yield). LCMS m / z = 383.9 [M+H]+ 1H NMR (400MHz, DMSO) ^: 12.47 (br s, 1H), 10.27 (br s, 1H), 8.13 (s, 1H), 7.84 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.36 (s, 1H), 4.16-4.10 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H). Example 98: 6-chloro-N-(4-ethyl-5-methylisoxazol-3-yl)-1H-indole-3-sulfonamide Step a: To a solution of tert-butyl (5-methylisoxazol-3-yl)carbamate (800 mg, 4.04 mmol, 1.0 eq.) in THF (20.0 mL) was added n-BuLi (2.5 M, 3.55 mL, 2.2 eq.) dropwise at -78 °C under N2,the mixture was stirred -78 °C for 1 hour. Iodoethane (944.20 mg, 6.05 mmol, 1.5 eq.) was added to the mixture. The mixture was stirred at 25 °C for 16 hours. The reaction was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4 then filtered. The filtrate was concentrated in vacuum to give a residue which was purified by prep-HPLC-A (Mobile Phase: 37% to 77% MeCN / H2O; 25 ml / min) to give tert-butyl (4-ethyl-5-methylisoxazol-3-yl)carbamate (150 mg, 87.9% yield).1H NMR (500MHz, DMSO) δ: 9.30 (s, 1H), 2.33-2.29 (m, 2H), 2.29 (s, 3H), 1.44 (s, 9H), 1.00 (t, J = 7.5 Hz, 3H). Step b: To a solution of tert-butyl (4-ethyl-5-methylisoxazol-3-yl)carbamate (70 mg, 309.36 μmol, 1.0 eq.) in HFIP (2 mL) was added TFA (70.55 mg, 618.73 μmol, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The reaction was then concentrated under vacuum to give 4-ethyl-5-methylisoxazol-3-amine (35 mg, crude). The crude was used directly to next step. LCMS m / z = 127.1 [M+H]+. Step c: To a solution of 4-ethyl-5-methylisoxazol-3-amine (20 mg, 158.53 μmol, 1.0 eq.) in THF (2.0 mL) was added 6-chloro-1H-indole-3-sulfonyl chloride (39.65 mg, 158.53 μmol, 1.0 eq.) at 20 °C. t-BuOK (1 M, 0.35 mL, 2.2 eq.) was added in the mixture dropwise at 0 °C. The reaction was stirred at 0 °C for 1 hour. The mixture was filtered and concentrated in vacuum to give a residue which was purified by prep-HPLC (FA) (Column: Welch Xtimate C18150 x 25mm x 5um); Mobile Phase: from 35% to 55% of water (FA)-ACN; Flow Rate (ml / min): 25) to give 6-chloro-N-(4-ethyl-5-methylisoxazol-3-yl)-1H-indole-3-sulfonamide (5.0 mg, 9.3% yield). LCMS m / z = 340.0 [M+H]+.1H NMR (400MHz, MeOD) δ: 7.90 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.18 (dd, J = 8.0, 2.0 Hz, 1H), 2.31-2.24 (m, 2H), 2.21 (s, 3H), 0.92 (t, J = 7.6 Hz, 3H). Example 99: 6-chloro-N-(4-chloro-5-methylisoxazol-3-yl)-1H-indole-3-sulfonamide To solution of 6-chloro-1H-indole-3-sulfonyl chloride (50 mg, 199.92 μmol, 1.0 eq.) in pyridine (1.0 mL) was added 4-chloro-5-methylisoxazol-3-amine (26.5 mg, 199.92 μmol, 1.0 eq.) at 25 °C. The mixture was stirred at 80 °C for 16 hours. The mixture was then concentrated to a residue which was purified by prep-HPLC-A (38%-58% MeCN / H2O; 25 ml / min) to give 6-chloro-N-(4-chloro-5-methylisoxazol-3-yl)-1H-indole-3-sulfonamide (20 mg, 27.4% yield). LCMS m / z = 345.9 [M+H]+.1H NMR (400MHz, MeOD) δ: 7.92-7.87 (m, 2H), 7.46 (d, J = 1.6 Hz, 1H), 7.18-7.15 (m, 1H), 2.25 (s, 3H). Example 100: 6-chloro-N-(5-(1,1-difluoroethyl)isoxazol-3-yl)-1H-indole-3-sulfonamide To solution of 6-chloro-1H-indole-3-sulfonyl chloride (50 mg, 199.92 μmol, 1.0 eq.) in pyridine (1.0 mL) was added 5-(1,1-difluoroethyl)isoxazol-3-amine (29.6 mg, 199.92 μmol, 1.0 eq.) at 25 °C. The mixture was stirred at 80 °C for 16 hours. The mixture was then concentrated to a residue which was purified by prep-HPLC-A (28%-58% MeCN / H2O; 25 ml / min) to give 6-chloro-N-(5-(1,1-difluoroethyl)isoxazol-3-yl)-1H-indole-3-sulfonamide (11 mg, 14.78% yield). LCMS m / z = 361.9 [M+H]+.1HNMR (400MHz, MeOD) δ: 7.98 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.23-7.19 (m, 1H), 6.65 (s, 1H), 1.99-1.89 (m, 3H). Example 101: 6-chloro-N-(4-chloro-5-ethylisoxazol-3-yl)-1H-indole-3-sulfonamide To a solution of 4-chloro-5-ethylisoxazol-3-amine (Preparation 43) (15.0 mg, 102.34 μmol, 1.0 eq.), and 6-chloro-1H-indole-3-sulfonyl chloride (25.6 mg, 102.34 μmol, 1.0 eq.) in CH2Cl2 (2.0 mL) was added pyridine (24.28 mg, 307.01 μmol, 3.0 eq.) at 25 °C. The mixture was stirred at 20 °C for 4 hours. The solvent was then evaporated under vacuum to give a residue which was purified by prep-HPLC-A (35%-65% of MeCN / H2O; 25 ml / min) to give 6-chloro- N-(4-chloro-5-ethylisoxazol-3-yl)-1H-indole-3-sulfonamide (2.1 mg, 5.7% yield). LCMS m / z = 360.0 [M+H]+.1H NMR (500MHz, MeOD) δ: 7.96 (s, 1H), 7.86 (d, J = 8.5 HIz, 1H), 7.49 (s, 1H), 7.19 (dd, J = 9.0, 1.5 Hz, 1H), 2.70-2.65 (m, 2H), 1.18 (t, J = 7.5 Hz, 3H). The following compounds were synthesized in a library format using the following procedure: The amine component (1.1 eq.) was dissolved in dry pyridine (0.5 mL) and 6-chloro-1H- indole-3-sulfonyl chloride (1 eq.) was added and stirred for 5 minutes. The reaction mixture was sealed and stirred at 80 °C for 16 hours. The mixture was cooled to ambient temperature, and the solvent was evaporated under reduce pressure. The residue was dissolved in DMSO (0.5 mL) The solution was filtered, analysed by LCMS, and transferred for HPLC purification. The purification was performed using Agilent 1260 Infinity systems equipped with DAD and mass-detector. Waters Sunfire C18 OBD Prep Column, 100 A, 5 µm, 19 mm × 100 mm with SunFire C18 Prep Guard Cartridge, 100 A, 10 µm, 19 mm × 10 mm was used. Deionized Water (phase A) and HPLC-grade Methanol or Acetonitrile (phase B) were used as an eluent. In some cases, ammonia or TFA was used as an additive to improve the separation of the products. In these cases, free bases and TFA salts of the products were formed respectively. Example 137: 6-chloro-N-(5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)-1H- indole-3-sulfonamide Step a: To a solution of 1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-amine (100.0 mg, 558.2 μmol, 1.0 eq.) in DCM (4.0 mL) was added TEA (169.5 mg, 1.6 mmol, 3.0 eq.) and (Boc)2O (182.7 mg, 837.3 μmol, 1.5 eq.) at 20 °C. The mixture was stirred at 20 °C for 4 hours. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum to give the residue, which was purified by prep-TLC to give tert-butyl (1-(3,3,3- trifluoropropyl)-1H-pyrazol-4-yl)carbamate (110.0 mg, 70.6% yield.). LCMS m / z = 280.2 [M+H]+.1H NMR (500MHz, DMSO) δ: 9.16 (s, 1H), 7.73 (s, 1H), 7.30 (s, 1H), 4.28 (t, J = 7.0 Hz, 2H), 2.84-2.50 (m, 2H), 1.44 (s, 9H). Step b: To a solution of tert-butyl (1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)carbamate 2 (50.0 mg, 179.1 μmol, 1.0 eq.) in MeCN (2 mL) was added NCS (23.9 mg, 179.1 μmol, 1.0 eq.) 25 °C. The mixture was stirred at 60 °C for 16 hours. The mixture was quenched with saturated Na2SO3 aq.(3 mL) and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuum to give the residue, which was purified by prep-TLC to give tert- butyl (5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl)carbamate (50.0 mg, 89.0% yield). LCMS m / z = 314.0 [M+H]+. Step c: To a solution of tert-butyl (5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazol-4- yl)carbamate (50.0 mg, 159.39 μmol, 1.0 eq.) was added a solution of HCl in dioxane (4 M, 796.9 μL, 3.19 mmol, 20.0 eq.), at 20 °C. The mixture was stirred at 20 °C for 2 hours. Solvent was evaporated under vacuum to give 5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazol- 4-amine (30.0 mg, 88.1% yield) which was used without further purification. LCMS m / z = 213.9 [M+H]+. Step d: To a solution of 6-chloro-1H-indole-3-sulfonyl chloride (35.13 mg, 140.5 μmol, 1.0 eq.) and 5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-amine (30.00 mg, 140.5 μmol, 1.0 eq.) in DCM (2.0 mL) was added pyridine (33.33 mg, 421.4 μmol, 3.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 2 hours. Solvent was evaporated under vacuum to give the residue, which was purified by prep-HPLC (FA) (Column: Welch Xtimate C18150 x 25mm x 5um); Mobile Phase: from 35% to 65% of water (FA)-ACN; Flow Rate (ml / min): 25) to give the title compound (26.70 mg, 44.5% yield). LCMS m / z = 427.0 [M+H]+.1H NMR (500MHz, MeOD) δ: 7.64-7.61 (m, 2H), 7.48 (d, J = 1.5 Hz, 1H), 7.37 (s, 1H), 7.15 (dd, J = 8.5, 2.0 Hz 1H), 4.24 (t, J = 7.0 Hz, 2H), 2.64-2.56 (m, 2H). Example 138: N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-indole-3- sulfonamide Step a: To solution of 6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride (50 mg, 129.59 µmol, 1.0 eq.) in DCM (3 mL) was added 5-chloro-1-(2-chloroethyl)-1H-pyrazol-4- amine (23.33 mg, 129.59 µmol, 1.0 eq.), Pyridine (30.75 mg, 388.76 µmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated to a residue which was purified by column chromatography to give N-(5-chloro-1-(2-chloroethyl)-1H- pyrazol-4-yl)-6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (30 mg, 43.73% yield).1HNMR: (400MHz, CDCl3) δ: 7.93 (s, 1H), 7.91-7.89 (m, 1H), 7.64-7.60 (m, 1H), 7.53-7.45 (m, 5H), 6.92-6.89 (m, 1H), 6.58 (s, 1H), 4.28-4.25 (m, 2H), 3.87 (s, 3H), 3.76- 3.72 (m, 2H). Step b: To a solution of N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-6-methoxy-1- (phenylsulfonyl)-1H-indole-3-sulfonamide (30 mg, 56.67 µmol, 1.0 eq.) in MeOH (2 mL) was added K2CO3 (31.33 mg, 226.66 µmol, 4.0 eq.) at 25°C. The reaction was stirred at 60 °C for 12 hours. The reaction was evaporated under vacuum. The residue was purified by prep-HPLC ((Column: Welch Xtimate C18150x25mmx5um, water (FA)-ACN as a mobile phase, from 30% to 50%, Gradient Time (min): 12, Flow Rate (ml / min): 25)) to give N-(5- chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-indole-3-sulfonamide (15.3 mg, 63.75% yield, 91.9% purity). LCMS m / z = 432.9 [M+H]+;1H NMR: (400MHz, MeOD) δ: 7.53 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.34 (s, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.83-6.79 (m, 1H), 4.31-4.28 (m, 2H), 3.83 (s, 3H), 3.80-3.76 (m, 2H). Example 139: N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-methoxy-1H-indole-3- sulfonamide Step a: To solution of 6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride (100 mg, 259.17 µmol, 1.0 eq.) in DCM (3 mL) was added 5-chloro-1-(trifluoromethyl)-1H-pyrazol-4- amine (48.09 mg, 259.17 µmol, 1.0 eq.), Pyridine (61.50 mg, 777.52 µmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated to a residue which was purified by column chromatography to give N-(5-chloro-1-(trifluoromethyl)-1H- pyrazol-4-yl)-6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (40 mg, 28.85% yield). LCMS m / z = 535.1 [M+H]+. Step b: To a solution of N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-methoxy-1- (phenylsulfonyl)-1H-indole-3-sulfonamide (20.00 mg, 37.39 µmol, 1.0 eq.) in THF (3 mL) was added TBAF (1 M, 186.95 µmol, 5.0 eq., 186.95 uL) at 25°C. The reaction was stirred at 60 °C for 12 hours. The reaction was quenched with water (10 mL), extracted with EtOAc (5 mL x 3). The combined organic layer was dried over Na2SO4; filtered and evaporated under vacuum. The residue was purified by prep-HPLC ((Column: Welch Xtimate C18 150*25mm*5um, water (FA)-ACN as a mobile phase, from 35% to 65%, Gradient Time (min): 11, Flow Rate (ml / min): 50)) to give N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4- yl)-6-methoxy-1H-indole-3-sulfonamide (2.1 mg, 14.23% yield). LCMS m / z = 394.9 [M+H]+1H NMR: (400MHz, MeOD) δ: 7.70 (s, 1H), 7.57 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.84-6.80 (m, 1H), 3.83 (s, 3H). Example 140: 6-chloro-N-(5-chloro-1-phenyl-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide Step a: To a solution of 4-nitro-1H-pyrazole (1 g, 8.84 mmol, 1.0 eq.) and iodobenzene (3.61 g, 17.69 mmol, 1.98 mL, 2.0 eq.) in DMF (20 mL) was added CuI (168.43 mg, 884.37 µmol, 0.1 eq.) and K2CO3(2.44 g, 17.69 mmol, 2.0 eq.) at 20 °C under N2. The reaction mixture was stirred at 110 °C for 14 hours. LCMS showed material was consumed completely and one main peak was detected. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 4-nitro-1-phenyl-1H- pyrazole (900 mg, 53.80% yield). LCMS m / z = 190.1 [M+H]+ 1H NMR: (400 MHz, CDCl3) δ : 8.64 (s, 1H), 8.28 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.57-7.52 (m, 2H), 7.47-7.43 (m, 1H). Step b: To a solution of 4-nitro-1-phenyl-1H-pyrazole (300 mg, 1.59 mmol, 1.0 eq.) in EtOH (3 mL) and water (1 mL) was added Fe (442.85 mg, 7.93 mmol, 56.34 µL, 5.0 eq.) and NH4Cl (424.15 mg, 7.93 mmol, 5.0 eq.) at 20 °C. The reaction mixture was stirred at 70 °C for 2 hours. LCMS showed material was consumed completely and one main peak was detected. The mixture was filtered and concentrated. The residue was purified by column chromatography to give 1-phenyl-1H-pyrazol-4-amine (100 mg, 39.61% yield). LCMS m / z = 160.1 [M+H]+. Step c: To a stirred solution of 1-phenyl-1H-pyrazol-4-amine (190 mg, 1.19 mmol, 1.0 eq.) in DCM (3 mL) was added Boc2O (1.30 g, 5.97 mmol, 1.37 mL, 5.0 eq.) and TEA (603.88 mg, 5.97 mmol, 831.79 µL, 5.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. LCMS showed material was consumed completely and one main peak was detected. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography to give tert-butyl (1-phenyl-1H-pyrazol-4-yl)carbamate (200 mg, 64.62% yield). LCMS m / z = 260.1 [M+H]+. Step d: To a stirred solution of tert-butyl (1-phenyl-1H-pyrazol-4-yl)carbamate (50 mg, 192.82 µmol, 1.0 eq.) in MeCN (1 mL) was added NCS (38.62 mg, 289.24 µmol, 1.5 eq.) at 20 °C. The reaction mixture was stirred at 40 °C for 2 hours. LCMS showed material was consumed completely and one main peak was detected. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography to give tert-butyl (5-chloro-1-phenyl-1H-pyrazol-4-yl)carbamate (10 mg, 17.65% yield). LCMS m / z = 294.1 [M+H]+ 1H NMR: (400 MHz, CDCl3) δ : 8.09 (br s, 1H), 7.58-7.55 (m, 2H), 7.51- 7.46 (m, 2H), 7.43-7.39 (m, 1H), 6.20-6.03 (m, 1H), 1.55 (s, 9H). Step e: To a stirred solution of tert-butyl (5-chloro-1-phenyl-1H-pyrazol-4-yl)carbamate (50 mg, 170.21 µmol, 1.0 eq.) in HFIP (2 mL) was added TFA (19.41 mg, 170.21 µmol, 13.03 µL, 1.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 6 hours. The reaction mixture was concentrated under reduced pressure to give 5-chloro-1-phenyl-1H-pyrazol-4-amine (30 mg, 91.02% yield). LCMS m / z = 194.0 [M+H]+. Step f: To a solution of 5-chloro-1-phenyl-1H-pyrazol-4-amine (30 mg, 154.93 µmol, 1.0 eq.) and 6-chloro-1H-indole-3-sulfonyl chloride (20.00 mg, 79.97 µmol, 5.16e-1 eq.) in DCM (3 mL) was added Pyridine (12.26 mg, 154.93 µmol, 12.53 µL, 1.0 eq.) at 20 °C. The reaction was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (Column: Water x bridge 150 x 25mm x 10um; Condition: water (NH4HCO3) - ACN; Begin B: 29; End B: 59; Gradient Time (min): 10; 100 % B Hold Time (min): 3; Flow Rate (mL / min): 30) to give compound of 6-chloro-N-(5-chloro-1-phenyl-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide (12.4 mg, 19.65% yield). LCMS m / z = 406.9 [M+H]+ 1H NMR: (400 MHz, MeOD) δ : 7.75 (s, 1H), 7.60-7.57 (m, 2H), 7.51-7.44 (m, 4H), 7.31-7.27 (m, 2H), 7.14 (dd, J = 8.8, 2 Hz, 1H). Example 141: 6-chloro-N-(5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H-indole- 3-sulfonamide Step a: To a solution of 4-nitro-1H-pyrazole (1 g, 8.84 mmol, 1.0 eq.) and K2CO3 (3.67 g, 26.53 mmol, 3.0 eq.) in DMF (20 mL) was added compound 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.05 g, 8.84 mmol, 1.27 mL, 1.0 eq.) at 25 °C. The reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was diluted with H2O (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (40 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield the 4-nitro-1-(2,2,2- trifluoroethyl)-1H-pyrazole (1.7 g, 96.55% yield). LCMS m / z = 196.0 [M+H]+ 1H NMR: (400 MHz, DMSO) δ: 8.30 (s, 1H), 8.16 (s, 1H), 4.81-4.74 (m, 2H). Step b: To a solution of 4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (200 mg, 1.03 mmol, 1.0 eq.), NH4Cl (274.18 mg, 5.13 mmol, 5.0 eq.) and Fe (286.26 mg, 5.13 mmol, 5.0 eq.) in EtOH (3 mL) and H2O (1 mL) at 25 °C. The reaction mixture was stirred at 80 °C for 1 hour. The mixture was filtered through a celite pad, and the filtrate was concentrated to give 1- (2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (150 mg, crude). Step c: To a solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (150 mg, 908.45 µmol, 1.0 eq.) in DCM (3 mL) was added TEA (275.78 mg, 2.73 mmol, 379.86 µL, 3.0 eq.) and Boc2O (237.92 mg, 1.09 mmol, 250.44 uL, 1.2 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography to yield the tert-butyl (1-(2,2,2-trifluoroethyl)-1H- pyrazol-4-yl)carbamate (240 mg, 97.57% yield). LCMS m / z = 266.0 [M+H]+ 1H NMR: (400 MHz, CDCl3) δ: 7.80 (s, 1H), 7.42 (s, 1H), 6.32 (s, 1H), 4.66-4.59 (m, 2H), 1.47 (s, 6H). Step d: To a solution of tert-butyl (1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)carbamate (200 mg, 754.06 µmol, 1.0 eq.) and NCS (151.03 mg, 1.13 mmol, 1.5 eq.) in MeCN (3 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield the tert-butyl (5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)carbamate (150 mg, 66.07% yield). LCMS m / z = 299.9 [M+H]+ 1H NMR: (400 MHz, CDCl3) δ: 7.99 (s, 1H), 6.05 (s, 1H), 4.71-4.64 (m, 2H), 1.53 (s, 9H). Step e: To a solution of tert-butyl (5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)carbamate (50 mg, 157.84 µmol, 1.0 eq.) in HCl / EtOAc (2 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to give the 5-chloro-1- (2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (30 mg, crude). LCMS m / z = 200.1 [M+H]+Step f: A solution of 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-amine (30 mg, 150.33 µmol, 1.0 eq.) and 6-chloro-1H-indole-3-sulfonyl chloride (37.60 mg, 150.33 µmol, 1.0 eq.) in DCM (2 mL) was added Pyridine (59.46 mg, 751.65 µmol, 60.79 µL, 5.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. Solvent was evaporated under vacuum. The residue was purified by prep-HPLC (Waters xbridge 150 x 25mm x 10um, water (NH4HCO3)-ACN as a mobile phase, from 27% to 57%, Gradient Time (min): 10, Flow Rate (ml / min): 30) to give the 6-chloro-N-(5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1H- indole-3-sulfonamide (11.23 mg, 18.06% yield). LCMS m / z = 412.8 [M+H]+ 1H NMR: (400 MHz, MeOD) δ: 7.65-7.62 (m, 2H), 7.48-7.44 (m, 2H), 7.14 (dd, J = 8.4, 1.6 Hz, 1H), 4.79- 4.74 (m, 2H). Example 142: 6-chloro-N-(4,5-dimethylisothiazol-3-yl)-1H-indole-3-sulfonamide Step a: To a solution of 5-methylisothiazol-3-amine (40.00 mg, 265.55 µmol, 1.0 eq.) in MeCN (2.0 mL) was added N-iodosuccinamide (59.74 mg, 265.55 µmol, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was quenched with saturated Na2SO3(aq). The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum to give the residue, which was purified by prep-TLC to give 4-iodo-5- methylisothiazol-3-amine (40.00 mg, 62.75% yield). LCMS m / z = 241.0 [M+H]+ 1H NMR: (500MHz, DMSO) δ: 6.02-6.00 (m, 2H), 2.36 (s, 3H). Step b: To a solution of 4-iodo-5-methylisothiazol-3-amine (27.00 mg, 112.47 µmol, 1.0 eq.) in dioxane (2 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (56.48 mg, 224.94 µmol, 2.0 eq.), K2CO3 (46.63 mg, 337.41 µmol, 3.0 eq.), Pd(dppf)Cl2 (8.23 mg, 11.25 µmol, 0.1 eq.) and water (0.4 mL) at 25 °C under N2. The mixture was stirred at 90 °C for 16 hours. Solvent was concentrated in vacuum to give the residue, which was purified by prep-TLC to give 4,5-dimethylisothiazol-3-amine (17.00 mg, 86.03% yield). LCMS m / z = 129.3 [M+H]+. Step c: To a solution of 4,5-dimethylisothiazol-3-amine (13.00 mg, 101.41 µmol, 1.0 eq.) in THF (2.0 mL) was added 6-chloro-1H-indole-3-sulfonyl chloride (25.36 mg, 101.41 µmol, 1.0 eq.) at 20 °C. t-BuOK (1 M, 223.10 µL, 2.2 eq.) was added in the mixture dropwise at 0 °C. The mixture was stirred at 20 °C for 16 hours. Solvent was evaporated under vacuum to give the residue, which was purified by prep-HPLC (NH4HCO3) (Column: Boston Prime C18 150 x 30mm x 5um); Mobile Phase: from 10% to 40% of water (NH3H2O+NH4HCO3)-ACN; Flow Rate (ml / min): 25) to give 6-chloro-N-(4,5-dimethylisothiazol-3-yl)-1H-indole-3- sulfonamide (1.6 mg, 4.62% yield). LCMS m / z = 349.9 [M+H]+ 1H NMR: (500MHz, MeOD) δ: 7.88 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 8.5, 2.0 Hz, 1H), 2.32 (s, 3H), 1.95 (s, 3H). Example 143: 6-chloro-N-(4-chloro-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide To a solution of 4-chloro-5-methylisothiazol-3-amine (Preparation 52) (15.00 mg, 101.41 µmol, 1.0 eq.) in THF (2.0 mL) was added 6-chloro-1H-indole-3-sulfonyl chloride (25.36 mg, 101.41 µmol, 1.0 eq.) at 20 °C. t-BuOK (1 M, 223.10 µL, 2.2 eq.) was added in the mixture dropwise at 0 °C. The mixture was stirred at 20 °C for 16 h. Solvent was evaporated under vacuum to give the residue, which was purified by prep-HPLC (NH4HCO3) (Column: Boston Prime C18150 x 30mm x 5um); Mobile Phase: from 13% to 43% of water (NH3H2O+NH4HCO3)-ACN; Flow Rate (ml / min): 25) to give 6-chloro-N-(4-chloro-5- methylisothiazol-3-yl)-1H-indole-3-sulfonamide (3.10 mg, 8.44% yield). LCMS m / z = 361.9 [M+H]+ 1H NMR: (400MHz, MeOD) δ: 7.95-7.86 (m, 2H), 7.44 (s, 1H), 7.16-7.12 (m, 1H), 2.35 (s, 3H). Example 144: 6-chloro-N-(3-methoxyisothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3- sulfonamide Step a: A mixture of 6-chloro-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.31 mmol, 1.0 eq.) in sulfurochloridic acid (3.51 g, 30.09 mmol, 2 mL) was stirred at 20 °C. The reaction was stirred at 90 °C for 14 hours. The reaction was quenched with ice-water (60 mL), filtered and washed with water (60 mL). The filter cake was evaporated under vacuum to give 6-chloro- 1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride (250 mg, 75.96% yield). LCMS m / z = 251.0 [M+H]+. Step b: To solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride (50 mg, 199.13 µmol, 1.0 eq.) in DCM (2 mL) was added 3-methoxyisothiazol-4-amine (33.18 mg, 199.13 µmol, 1.0 eq.HCl), Pyridine (47.25 mg, 597.40 µmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated to a residue which was purified by prep-HPLC( (Column: Welch Xtimate C18150*25mm*5um, water(FA)-ACN as a mobile phase, from 25% to 55%, Gradient Time(min): 11, Flow Rate (ml / min): 25 ) ) to give 6- chloro-N-(3-methoxyisothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide (41.8 mg, 60.88% yield). LCMS m / z = 344.8 [M+H]+ 1H NMR: (400MHz, MeOD) δ: 8.42 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H). Example 145: 6-chloro-N-(3-ethoxyisothiazol-4-yl)-1H-indole-3-sulfonamide Step a: To a solution of isothiazol-3-ol (500.00 mg, 4.94 mmol, 1.0 eq.) in DMF (10.0 mL), was added iodoethane (925.36 mg, 3.91 mmol, 1.2 eq.) and Cs2CO3 (3.22 g, 9.89 mmol, 2.0 eq.) at 25 °C and stirred at 25 °C for 16 hours. The mixture was added water (30 mL) and extracted with EA (30 mL x 3). The combined organic layers was washed with brine (50 mL x 3), dried over Na2SO4. The filtrate was concentrated under vacuum to give the residue, which was purified by column chromatography to give 3-ethoxyisothiazole (260.00 mg, 40.71% yield).1H NMR: (400MHz, DMSO) δ: 8.86 (d, J = 4.8 Hz, 1H), 6.74 (d, J = 4.8 Hz, 1H), 4.36-4.29 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H). Step b: To a solution of 3-ethoxyisothiazole (100.00 mg, 774.11 µmol, 1.0 eq.) in H2SO4 (2.0 mL) was added HNO3 (2.83 g, 44.85 mmol, 58 eq.) at 0 °C. The mixture was stirred at 55 °C for 16 hours. The solution was poured over ice and neutralized with aqueous NaOH (1.0 M) to pH =7. The solid was extracted twice with ethyl acetate (20 mL x 3), combined organic layers washed once with brine (50 mL) then dried over Na2SO4. Filtered and concentrated under reduced pressure to give the 3-ethoxy-4-nitroisothiazole (20.00 mg, 14.83% yield).1H NMR: (400MHz, DMSO) δ: 9.98 (s, 1H), 4.50-4.44 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H). Step c: To a solution of 3-ethoxy-4-nitroisothiazole (20.00 mg, 114.83 µmol, 1.0 eq.) in EtOH (3.0 mL) and water (1 mL) was added Fe (64.13 mg, 1.15 mmol, 10.0 eq.) and NH4Cl (30.71 mg, 574.13 µmol, 5.0 eq.) at 25 °C under N2. The mixture was stirred at 70 °C for 2 hours. The mixture was filtered and concentrated in vacuum. Then the residue was dissolved in water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was dried over Na2SO4, filtered in vacuum to give 3-ethoxyisothiazol-4-amine (10.00 mg, 60.40% yield). LCMS m / z = 144.8 [M+H]+. Step d: To a solution of 3-ethoxyisothiazol-4-amine (10.00 mg, 69.35 µmol, 1.0 eq.) and 6- chloro-1H-indole-3-sulfonyl chloride (17.34 mg, 69.35 µmol, 1.0 eq.) in DCM (2 mL) was added pyridine (16.46 mg, 208.05 µmol, 3.0 eq.) at 20 °C and stirred at 20 °C for 16 hours. The mixture was filtrated and concentrated in vacuum to give the residue. Solvent was evaporated under vacuum to give the residue, which was purified by prep-HPLC (FA) (Column: Welch Xtimate C18150 x 25mm x 5um)); Mobile Phase: from 30% to 60% of water (FA)-ACN; Flow Rate (ml / min): 25) to give 6-chloro-N-(3-ethoxyisothiazol-4-yl)-1H- indole-3-sulfonamide (6.6 mg, 26.60% yield). LCMS m / z = 358.0 [M+H]+;1H NMR: (400MHz, MeOD) δ: 8.42 (s, 1H), 7.74 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.17 (dd, J = 8.8, 1.6 Hz, 1H), 4.03-3.97 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H). Example 146: 6-chloro-N-(5-chloro-3-methoxyisothiazol-4-yl)-1H-indole-3-sulfonamide Step a: To a solution of 3-methoxyisothiazol-4-amine (15 mg, 115.24 µmol, 1.0 eq.) in MeCN (2 mL) was added NCS (15.39 mg, 115.24 µmol, 1.0 eq.) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with saturated Na2SO3 (20 mL). The organic layers was washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated to give 5-chloro-3-methoxyisothiazol-4-amine (18 mg, crude). LCMS m / z = 165.1 [M+H]+. Step b: To solution of 5-chloro-3-methoxyisothiazol-4-amine (28 mg, 111.95 µmol, 1.0 eq.) in DCM (2 mL) was added 6-chloro-1H-indole-3-sulfonyl chloride (18.43 mg, 111.95 µmol, 1.0 eq.), Pyridine (26.57 mg, 335.86 µmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated to a residue which was purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 22% to 52%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to give 6-chloro-N-(5- chloro-3-methoxyisothiazol-4-yl)-1H-indole-3-sulfonamide (1.2 mg, 2.83% yield). LCMS m / z = 378.9 [M+H]+;1H NMR: (400MHz, MeOD) δ: 8.00 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.27-7.23 (m, 1H), 3.56 (s, 3H). Example 147: 6-chloro-N-(3-chloroisothiazol-4-yl)-1H-indole-3-sulfonamide Step a: To a solution of 3-chloroisothiazole (200.00 mg, 1.67 mmol, 1.0 eq.) in H2SO4 (3 mL) was added HNO3(4.24 g, 67.27 mmol, 40.2 eq.) at 0 °C. The mixture was stirred at 55 °C for 16 hours. The solution was poured over ice and neutralized with aqueous NaOH (1 M) to pH =7. The solid was extracted twice with ethyl acetate (20 mL x 3), combined organic layers washed once with brine (50 mL) then dried over Na2SO4. Filtered and concentrated under reduced pressure to give the 3-chloro-4-nitroisothiazole (90.00 mg, 32.70% yield).1H NMR: (400MHz, DMSO) δ: 10.09 (s, 1H). Step b: To a solution of 3-chloro-4-nitroisothiazole (90.00 mg, 546.88 µmol, 1.0 eq.) in EtOH (3 mL) and water (1 mL) was added Fe (305.40 mg, 5.47 mmol, 10.0 eq.) and NH4Cl (146.27 mg, 2.73 mmol, 5.0 eq.) at 25 °C under N2. The mixture was stirred at 70 °C for 2 hours. The mixture was filtered and concentrated in vacuum. Then the residue was dissolved in water (20mL) and extracted with EA (20mL x 3). The combined organic layer was dried over Na2SO4, filtered in vacuum to give 3-chloroisothiazol-4-amine (45.00 mg, 61.14% yield, 70% purity).1H NMR: (400MHz, DMSO) δ: 7.62 (s, 1H), 5.14 (s, 2H). Step c: To a solution of 3-chloroisothiazol-4-amine (20.00 mg, 148.60 µmol, 1.0 eq.) and 6- chloro-1H-indole-3-sulfonyl chloride (37.17 mg, 148.60 µmol 1.0 eq.) in DCM (2.0 mL) was added pyridine (35.26 mg, 445.81 µmol, 3.0 eq.) at 25 °C and stirred at 20 °C for 16 hours. The mixture was filtrated and concentrated in vacuum to give the residue, Solvent was evaporated under vacuum to give the residue, which was purified by prep-HPLC (FA) (Column: Welch Xtimate C18150 x 25mm x 5um)); Mobile Phase: from 55% to 85% of water (FA)-ACN; Flow Rate (ml / min): 25) to give 6-chloro-N-(3-chloroisothiazol-4-yl)-1H- indole-3-sulfonamide (16.1 mg, 31.11% yield). LCMS m / z = 347.9 [M+H]+ 1H NMR: (500MHz, MeOD) δ: 8.64 (s, 1H), 7.77 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.16 (dd, J = 8.5, 2.0 Hz, 1H). Example 148: 6-chloro-N-(4-chlorothiazol-5-yl)-1H-indole-3-sulfonamide Step a: To a solution of tert-butyl thiazol-5-ylcarbamate (150 mg, 749.04 µmol, 1.0 eq.) and NCS (150.03 mg, 1.12 mmol, 1.5 eq.) in MeCN (3 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield the tert-butyl (4-chlorothiazol-5-yl)carbamate (100 mg, 56.17% yield). LCMS m / z = 235.0 [M+H]+ 1H NMR: (400 MHz, CDCl3) δ: 8.32 (s, 1H), 7.02 (s, 1H), 1.55 (s, 9H). Step b: To a solution of tert-butyl (4-chlorothiazol-5-yl)carbamate (100 mg, 426.07 µmol, 1.0 eq.) in HFIP (3 mL) was added TFA (48.58 mg, 426.07 µmol, 32.63 µL, 1.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (Welch Xtimate C18150 x 25mm x 10um, water (NH3H2O)-ACN as a mobile phase, from 5% to 35%, Gradient Time (min): 10, Flow Rate (ml / min): 30) to give the 4-chlorothiazol-5-amine (12 mg, 13.39% yield, 64% purity). Step c: A solution of 4-chlorothiazol-5-amine (12 mg, 89.16 µmol, 1.0 eq.) and 6-chloro-1H- indole-3-sulfonyl chloride (22.30 mg, 89.16 µmol, 1.0 eq.) in DCM (2 mL) was added Pyridine (28.21 mg, 356.65 µmol, 28.85 µL, 3.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. Solvent was evaporated under vacuum. The residue was purified by prep-HPLC (Welch Xtimate C18150 x 25mm x 5um, water (NH3H2O)-ACN as a mobile phase, from 1% to 30%, Gradient Time (min): 10, Flow Rate (ml / min): 30) to give the 6- chloro-N-(4-chlorothiazol-5-yl)-1H-indole-3-sulfonamide (9.6 mg, 30.60% yield). LCMS m / z = 347.7 [M+H]+ 1H NMR: (400 MHz, MeOD) δ: 8.57 (s, 1H), 7.76-7.72 (m, 2H), 7.49 (s, 1H), 7.17 (dd, J = 8.4, 2.0 Hz, 1H). Example 149: 6-chloro-7-methoxy-N-(3-methoxyisothiazol-4-yl)-1H-indole-3- sulfonamide Step a: To a solution of 1-chloro-2-methoxy-3-nitrobenzene (500 mg, 2.67 mmol, 1.0 eq.) in THF (20.0 mL) was dropwise added vinyl magnesium bromide (1 M, 10.66 mL, 4.0 eq.) at - 78 °C under N2. The reaction was stirred at -78 °C for 3 hours. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl. (50 mL) and extracted with EtOAc (40 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield the 6-chloro-7- methoxy-1H-indole (85 mg, 16.50% yield, 93.968% purity). LCMS m / z = 182.0 [M+H]+ 1H NMR: (400MHz, CDCl3) δ: 7.33-7.30 (m, 1H), 7.23-7.20 (m, 1H), 7.14-7.11 (m, 1H), 7.10- 7.07 (m, 1H), 4.03 (s, 3H). Step b: To a solution of 6-chloro-7-methoxy-1H-indole (80 mg, 440.48 µmol, 1.0 eq.) in MeCN (3.0 mL) was dropwise added HSO3Cl (513.27 mg, 4.40 mmol, 292.79 µL, 10.0 eq.) at 0 °C. The reaction was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield the 6-chloro-7-methoxy-1H-indole-3-sulfonyl chloride (30 mg, 7.70% yield).1H NMR: (400MHz, CDCl3) δ: 11.41 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.31- 7.30 (m, 1H), 7.02 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H). Step c: To a solution of 6-chloro-7-methoxy-1H-indole-3-sulfonyl chloride (30.00 mg, 107.09 µmol, 1.0 eq.) and 3-methoxyisothiazol-4-amine (13.94 mg, 107.09 µmol, 1.0 eq.) in DCM (2.0 mL) was added pyridine (25.41 mg, 321.28 µmol, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 16 hours. The mixture was filtrated and concentrated in vacuum to give the residue, which was purified by prep-HPLC (NH4HCO3) (Column: Boston Prime C18 150 x 30mm x 5um)); Mobile Phase: from 2% to 32% of water (NH3H2O+NH4HCO3)- ACN; Flow Rate (ml / min): 25) to give 6-chloro-7-methoxy-N-(3-methoxyisothiazol-4-yl)- 1H-indole-3-sulfonamide (8.40 mg, 20.98% yield). LCMS m / z = 373.9 [M+H]+ 1H NMR: (400MHz, MeOD) δ: 8.35 (s, 1H), 7.75 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.67 (s, 3H). Example 150: 6-chloro-N-(4-methoxyisothiazol-3-yl)-1H-indole-3-sulfonamide Step a: To a solution of 4-hydroxyisothiazole-3-carboxylic acid (100 mg, 689.01 µmol, 1.0 eq.) in MeOH (5.00 mL) and THF (5.00 mL) was added diazomethyl(trimethyl)silane (2 M, 1.38 mmol, 689.01 µL, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was evaporated under vacuum. The mixture was diluted with AcOH and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give methyl 4-hydroxyisothiazole-3-carboxylate (30 mg, 27.36% yield). LCMS m / z = 160.1 [M+H]+Step b: To a solution of methyl 4-hydroxyisothiazole-3-carboxylate (30 mg, 188.49 µmol, 1.0 eq.) in ACN (5 mL) was added MeI (52.85 mg, 376.97 µmol, 2.0 eq.) and K2CO3 (78.15 mg, 565.46 µmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was evaporated under vacuum to give the residue. The residue was purified by column chromatography to give methyl 4-methoxyisothiazole-3-carboxylate (30 mg, 91.90% yield). LCMS m / z = 174.1 [M+H]+. Step c: To a mixture of methyl 4-methoxyisothiazole-3-carboxylate (30 mg, 173.22 µmol, 1.0 eq.) in MeOH (2 mL) and water (2 mL) was added lithium hydroxide (14.55 mg, 346.44 µmol, 2.0 eq.) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was diluted with saturated HCl aq. till pH = 7. The mixture was concentrated in vacuo to give the residue which was re-crystallized from water, dried by lyophilization to give 4-methoxyisothiazole-3-carboxylic acid (27 mg, crude). LCMS m / z = 160.0 [M+H]+. Step d: To a solution of 4-methoxyisothiazole-3-carboxylic acid (27 mg, 169.64 µmol, 1.0 eq.) in t-BuOH (2 mL) was added TEA (51.50 mg, 508.91 µmol, 3.0 eq.) and diphenyl phosphorazidate (70.03 mg, 254.46 µmol, 1.5 eq.) at 20 °C. The mixture was warmed and stirred at 90 °C for 16 hours. The mixture was concentrated in vacuo to give the residue, which was purified by column chromatography to give tert-butyl (4-methoxyisothiazol-3- yl)carbamate (10 mg, 25.60% yield). LCMS m / z = 231.1 [M+H]+. Step e: To a solution of tert-butyl (4-methoxyisothiazol-3-yl)carbamate (10 mg, 43.42 µmol, 1.0 eq.) in HCl / EtOAc (2 mL) was stirred under 25 °C for 6 hours. Solvent was evaporated under vacuum to give 4-methoxyisothiazol-3-amine (10 mg, crude) as white solid. LCMS m / z = 231.1 [M+H]+. Step f: To solution of 6-chloro-1H-indole-3-sulfonyl chloride (20 mg, 79.97 µmol, 1.0 eq.) in DCM (3 mL) was added 4-methoxyisothiazol-3-amine (10.41 mg, 79.97 µmol, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated to a residue which was purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 28% to 58%, Gradient Time (min): 11, Flow Rate (ml / min): 25) to give 6-chloro-N-(4-methoxyisothiazol-3-yl)-1H-indole-3-sulfonamide (1.4 mg, 5.09% yield). LCMS m / z = 343.9 [M+H]+ 1H NMR:(400MHz, MeOD) δ: 7.96 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.18-7.15 (m, 1H), 3.76 (s, 3H). Example 151: 6-chloro-N-(5-chloro-1-(3,3-difluoropropyl)-1H-pyrazol-4-yl)-1H-indole- 3-sulfonamide Step h: To a solution of 5-chloro-1-(4,4-difluorobutyl)-1H-pyrazol-4-amine (Preparation 51) (33 mg, 168.71 µmol, 1.0 eq.) and 6-chloro-1H-indole-3-sulfonyl chloride (42.20 mg, 168.71 µmol, 1.0 eq.) in DCM (2 mL) was added pyridine (40.04 mg, 506.14 µmol, 40.94 µL, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (Column: Phenomenex luna C18150 x 25mm x 10um, water (NH3H2O+NH4HCO3)- ACN as a mobile phase, from 32% to 62%, Gradient Time (min): 15, Flow Rate (ml / min): 25) to give 6-chloro-N-(5-chloro-1-(3,3-difluoropropyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide (5.7 mg, 8.20% yield). LCMS m / z = 408.9 [M+H]+ 1H NMR (400 MHz, MeOD) ^: 7.65 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.35 (s, 1H), 7.15-7.11 (m, 1H), 5.96-5.67 (m, 1H), 4.14 (t, J = 6.8 Hz, 2H), 2.24-2.14 (m, 2H). Example 152: 6-chloro-N-(5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-yl)-1H- indole-3-sulfonamide Step a: To a solution of 4-nitro-1H-pyrazole (1.0 g, 8.84 mmol, 1.0 eq.) and 2-bromoethan-1- ol (1.22 g, 9.73 mmol, 689.54 μL, 1.1 eq.) in DMF (15 mL) was added K2CO3(3.67 g, 26.53 mmol, 3.0 eq.). The mixture was stirred at 70 °C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield 2-(4-nitro-1H-pyrazol-1-yl)ethan-1-ol (1.0 g, 71.96% yield).1H NMR (400 MHz, MeOD) δ: 8.55 (s, 1H), 8.13 (s, 1H), 4.27 (t, J = 5.2 Hz, 2H), 3.91 (t, J = 4.8 Hz, 2H). Step b: To a solution of yield 2-(4-nitro-1H-pyrazol-1-yl)ethan-1-ol (500 mg, 3.18 mmol, 1.0 eq.) and CuI (303.02 mg, 1.59 mmol, 0.5 eq.) in MeCN (10 mL) was added a solution of 2,2- difluoro-2-(fluorosulfonyl)acetic acid (850.05 mg, 4.77 mmol, 493.35 μL, 1.5 eq.) in MeCN (10 mL) dropwise at 55 °C over a period of 30 min under N2. The reaction mixture was stirred at 55 °C for another 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield 1-(2-(difluoromethoxy)ethyl)- 4-nitro-1H-pyrazole (120 mg, 18.21% yield).1H NMR (400 MHz, MeOD) δ: 8.58 (s, 1H), 8.14 (s, 1H), 6.55-6.17 (m, 1H), 4.46 (t, J = 5.2 Hz, 2H), 4.26 (t, J = 5.2 Hz, 2H). Step c: To a solution of 1-(2-(difluoromethoxy)ethyl)-4-nitro-1H-pyrazole (120 mg, 579.33 μmol, 1.0 eq.) in EtOH (3 mL) and water (1 mL) was added Fe (161.78 mg, 2.90 mmol, 20.58 μL, 5.0 eq.) and NH4Cl (154.95 mg, 2.90 mmol, 5.0 eq.) at 20 °C. The reaction mixture was stirred at 80 °C for 2 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give 1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-amine (150 mg, crude), which was used without purification. LCMS m / z = 178.3 [M+H]+Step d: To a solution of 1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-amine (150 mg, 846.73 μmol, 1.0 eq.) in DCM (2 mL) was added Boc2O (277.19 mg, 1.27 mmol, 291.78 μL) and TEA (257.04 mg, 2.54 mmol, 354.05 μL, 3.0 eq.) at 20 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to yield tert- butyl (1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-yl)carbamate (100 mg, 41.04% yield). LCMS m / z = 278.1 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 7.68 (s, 1H), 7.40 (s, 1H), 6.52- 6.13 (m, 1H), 4.31 (t, J = 5.2 Hz, 2H), 4.16 (t, J = 5.2 Hz, 2H), 1.49 (s, 9H). Step e: To a solution of tert-butyl (1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-yl)carbamate (100 mg, 360.66 μmol, 1.0 eq.) in MeCN (5 mL) was added NCS (96.32 mg, 721.33 μmol, 2.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl (5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4- yl)carbamate (30 mg, 24.62% yield, 92.27% purity). LCMS m / z = 312.1 [M+H]+Step f: To a solution of tert-butyl (5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4- yl)carbamate (30 mg, 96.24 μmol, 1.0 eq.) in HFIP (3 mL) was added TFA (10.97 mg, 96.24 μmol, 7.37 μL, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 5-chloro-1-(2- (difluoromethoxy)ethyl)-1H-pyrazol-4-amine (20 mg, 98.21% yield). The crude compound was used in the next step without further purification. LCMS m / z = 212.2 [M+H]+Step g: To a solution of 5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-amine (20 mg, 94.52 μmol, 1.0 eq.) in DCM (2 mL) was added 6-chloro-1H-indole-3-sulfonyl chloride (23.64 mg, 94.52 μmol, 1.0 eq.), and Pyridine (22.43 mg, 283.56 μmol, 22.93 μL, 3.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure and the obtained residue was purified by prep- HPLC (Column: Phenomenex luna C18150 x 25mm x 10um, water (NH4HCO3)-ACN as a mobile phase, from 28% to 58%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to give 6-chloro-N-(5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide (8.1 mg, 19.76% yield). LCMS m / z = 426.8 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 7.65-7.62 (m, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.34 (s, 1H), 7.17-7.13 (m, 1H), 6.43- 6.05 (m, 1H), 4.23 (t, J = 5.2 Hz, 2H), 4.08 (t, J = 5.2 Hz, 2H). Example 153: 6-chloro-N-(5-chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)- 1H-indole-3-sulfonamide Step a: To a solution of 4-nitro-1H-pyrazole (500.00 mg, 4.42 mmol, 1.0 eq.), 2-(2,2,2- trifluoroethoxy)ethan-1-ol (637.15 mg, 4.42 mmol, 1.0 eq.) and PPh3 (1.16 g, 4.42 mmol, 1.0 eq.) in THF (20 mL) was added DIAD (894.13 mg, 4.42 mmol, 1.0 eq.) slowly at 20 °C. The mixture was stirred at 20 °C for 16 hours. The mixture was quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuum to give the residue, which was purified by column chromatography to give 4-nitro-1-(2-(2,2,2- trifluoroethoxy)ethyl)-1H-pyrazole (40.00 mg, 37.83% yield). LCMS m / z = 240.0 [M+H]+Step b: To a solution of 4-nitro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole (250.00 mg, 1.05 mmol, 1.0 eq.) in MeOH (10.0 mL) was added Pd / C (111.25 mg, 104.54 μmol, 10%purity, 0.1 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture filtered and concentrated in vacuum to give 1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4- amine (200.00 mg, 91.74% yield) which was used without purification. LCMS m / z = 210.0 [M+H]+ 1H NMR (500MHz, DMSO) ^: 7.02 (s, 1H), 6.91 (s, 1H), 4.01 (t, J = 5.5 Hz, 2H), 4.02-3.86 (m, 2H), 3.85 (t, J = 5.5 Hz, 2H). Step c: To a solution of 1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-amine (40.00 mg, 191.23 μmol, 1.0 eq.) in DCM (4 mL) was added TEA (58.05mg, 573.30 μmol, 3.0 eq.) and (Boc)2O (83.47 mg, 382.47 μmol, 2.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 16 hours. The mixture was added to water (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuum to give the residue, which was purified by prep-TLC to give tert-butyl (1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)carbamate (50.00 mg, 84.54% yield). LCMS m / z = 309.9 [M+H]+Step d: To a solution of give tert-butyl (1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4- yl)carbamate (40.00 mg, 129.33 μmol, 1.0 eq.) in MeCN (2.0 mL) was added NCS (103.62 mg, 775.99 μmol, 6.0 eq.) at 20 °C. The mixture was stirred at 60 °C for 9 hours. The mixture was concentrated in vacuum to give the residue, which was purified by prep-TLC to provide tert-butyl (5-chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)carbamate (25.00 mg, 56.24% yield). LCMS m / z = 343.9 [M+H]+Step e: To a solution of tert-butyl (5-chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4- yl)carbamate (10.00 mg, 29.09 μmol, 1.0 eq.) in DCM (0.2 mL) was added TFA (0.02 mL) at 20 °C. The reaction was stirred at 20 °C for 3 hours. The reaction mixture was concentrated and used directly in the next step. Step f: To a solution of 6-chloro-1H-indole-3-sulfonyl chloride (7.19 mg, 28.73 μmol, 1.0 eq.) in DCM (2.0 mL) was added crude 5-chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H- pyrazol-4-amine (7.00 mg, 28.73 μmol, 1.0 eq.) and pyridine (22.73 mg, 287.34 μmol, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 16 hours. The mixture was filtered and concentrated in vacuum to give the residue, which was purified by prep-HPLC (NH4HCO3) (Column: Boston Prime C18150 x 30mm x 5um)); Mobile Phase: from 15% to 45% of water (NH3H2O+NH4HCO3)-ACN; Flow Rate (ml / min): 25) to give 6-chloro-N-(5-chloro-1-(2- (2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide (4.30 mg, 32.73% yield.). LCMS m / z = 456.9 [M+H]+ 1H NMR (400MHz, MeOD) ^: 7.65-7.61 (m, 2H), 7.48 (d, J = 1.6 Hz, 1H), 7.34 (s, 1H), 7.15 (dd, J = 8.4, 2.0 Hz, 1H), 4.17 (t, J = 5.2 Hz, 2H), 3.84 (t, J = 5.6 Hz, 2H), 3.80-3.75 (m, 2H). Example 154: 6-chloro-N-(5-chloro-1-isopentyl-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide To a solution of 5-chloro-1-isopentyl-1H-pyrazol-4-amine (Preparation 35) (30 mg, 159.86 µmol, 1.0 eq.) in DCM (3 mL) was added Pyridine (37.93 mg, 479.57 µmol, 38.9 µL, 1.0 eq.) and 6-chloro-1H-indole-3-sulfonyl chloride (15.00 mg, 59.98 µmol, 0.38 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-TLC to give 6-chloro-N-(5- chloro-1-isopentyl-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide (8.6 mg, 13.41% yield). LCMS m / z = 402.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 7.67 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 2 Hz, 1H), 7.34 (s, 1H), 7.11 (dd, J = 8.4, 1.6 Hz, 1H), 3.97 (t, J = 7.2 Hz, 2H), 1.52-1.46 (m, 2H), 1.39-1.30 (m, 1H), 0.87 (d, J = 6.4 Hz, 6H). Example 155: 7-bromo-6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-1H- indole-3-sulfonamide To a solution of 5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-amine (Preparation 10) (36.01 mg, 0.20 mmol) in pyridine (1.00 mL, 0.2 M) was added 7-bromo-6-chloro-1H-indole-3-sulfonyl chloride (Preparation 29; 65.8 mg, 0.20 mmol) and a crystal of DMAP (cat.). The reaction mixture was heated at 90 °C for 16 h, cooled to rt, and quenched with water. The mixture was extracted three times with DCM, dried over sodium sulfate, and concentrated under reduced pressure to afford a residue which was purified by column chromatography. The title compound, 7-bromo-6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide, was obtained (28.5 mg, 95.0% yield). LCMS m / z = 472.8 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 7.67 (s, 1H), 7.62 (d, J = 8.51 Hz, 1H), 7.42 (s, 1H), 7.29 (d, J = 8.51 Hz, 1H), 4.30 (t, J = 5.75 Hz, 2H), 3.80 (t, J = 6.00 Hz, 2H).

[0008] Example 156: 7-bromo-6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1H- indole-3-sulfonamide To a scintillation vial containing 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (Preparation 18) (713.7 mg, 4.26 mmol, 2 eq.) was added 7-bromo-6-chloro-1H-indole-3- sulfonyl chloride (Preparation 29) (700.0 mg, 2.13 mmol, 1 eq) and a crystal of DMAP (cat.). The contents were dissolved in pyridine (25.0 mL, 0.1 M) and heated at 55 ° C for 16 h. After this time, the reaction mixture was diluted with water and extracted twice with DCM and once with EtOAc. The combined organics were dried over sodium sulfate and concentrated under vacuum to provide the crude product as a brown oil. The crude residue was purified by silica gel chromatography to provide 7-bromo-6-chloro-N-(5-chloro-1-(difluoromethyl)-1H- pyrazol-4-yl)-1H-indole-3-sulfonamide (583.7 mg, 59.6% yield). LCMS m / z = 459.0 [M-H]-1H NMR (400 MHz, MeOD) δ: 7.74 (s, 1H), 7.63 (s, 1H), 7.61 (d, J = 8.51 Hz, 1H), 7.30 (d, J = 8.51 Hz, 1H), 7.53-7.22 (m, 1 H). Example 157: 6-chloro-N-(5-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide To a solution of 6-chloro-1H-indole-3-sulfonyl chloride (40.00 mg, 220.30 μmol, 1.0 eq.) in Pyridine (2 mL) was added 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazol-4-amine (Preparation 6) (27.55 mg, 110.15 μmol, 0.5 eq.) at 25 °C. The reaction was stirred at 60 °C for 1 hour. The mixture was concentrated in vacuum to give the residue. The residue was purified by prep-HPLC (Column: Phenomenex C18150 x 25mm x 10um, water (FA)-ACN as a mobile phase, Gradient Time (min): 10, Flow Rate (ml / min): 25) to give 6-chloro-N-(5-chloro-1- (2,2-difluoroethyl)-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide (16.9 mg, 19.22% yield). LCMS m / z = 394.9 [M+H]+.1H NMR: (400MHz, DMSO) ^: 9.55 (s, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.28 (s, 1H), 7.20-7.17 (m, 1H), 6.41-6.11 (m, 1H), 4.53-4.40 (m, 2H). Example 158: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide To a scintillation vial containing tert-butyl (5-chloro-1-(difluoromethyl)-1H-pyrazol-4- yl)carbamate (864.9 mg, 3.23 mmol, 2.0 eq.) was added HFIP (16.2 mL, 0.1 M) followed by TFA (0.25 mL, 3.23 mmol, 2.0 eq.). The reaction mixture was stirred at rt for 2 h, changing from bright yellow to orange as the reaction progressed. The reaction mixture was then directly concentrated under reduced pressure to provide 5-chloro-1-(difluoromethyl)-1H- pyrazol-4-amine as a thick red oil, which was used without purification assuming quantitative yield. To the vial containing the pyrazole was then added 6-chloro-1H-indole-3-sulfonyl chloride (404.0 mg, 1.62 mmol.1.0 eq.). The reactants were dissolved in pyridine (8.0 mL) and DMAP (19.7 mg, 0.162 mmol, 0.10 eq.) was then added. The reaction mixture was stirred at 75 °C for approximately 18 h, after which time it was diluted with water and extracted twice with DCM and then once with EtOAc. The combined organics were dried over sodium sulfate and concentrated under reduced pressure to afford the crude product as a brown oil. The crude residue was purified by silica gel chromatography to provide the title compound as a brown oil (503.3 mg). The product was further purified by two rounds of prep-HPLC (Column: Waters XSelect CSH Prep C185um OBD 30 x 100 mm); Mobile Phase: 5% to 55% of water (NH4OH)- MeCN; Flow Rate (ml / min): 50) to provide 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H- pyrazol-4-yl)-1H-indole-3-sulfonamide (163.8 mg, 26.6% yield). LCMS m / z = 380.8 [M+H]+.1H NMR (400 MHz, MeOD) δ: 7.70 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.51-7.22 (m, 2H), 7.18-7.14 (m, 1H). Example 159: 6-chloro-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide 6-Chloro-1H-indole-3-sulfonyl chloride (39 mg, 1.0 equiv.) was added to the solution of 1- methyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride (35 mg, 1.1 eq) in dry Pyridine (1 mL). The reaction mixture was stirred at 60 °C for 24 h. Then the solvent was evaporated in vacuo and the residue was dissolved in DMSO (0.5 mL) and subjected to prep. HPLC (Waters SunFire C1819*1005 mkm column; gradient mixture H2O-MeOH as a mobile phase) to 6-chloro-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide (27.3 mg, 46% yield). LCMS m / z = 379.0 [M+H]+.1H NMR: (500 MHz, DMSO) δ: 12.06 (br s, 1H), 9.61 (s, 1H), 7.82 (s, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.14 (s, 1H), 3.83 (s, 3H). Example 160: 6-chloro-N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-indole-3- sulfonamide To solution of 6-chloro-1H-indole-3-sulfonyl chloride (90 mg, 359.85 μmol, 1.0 eq.) in DCM (3 mL) was added 5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-amine (Preparation 2) (66.77 mg, 359.85 μmol, 1.0 eq.), Pyridine (85.39 mg, 1.08 mmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated to a residue which was purified by prep-HPLC(Column: YMC-Triart Prep C18150*40mm*7um, water(FA)-ACN as a mobile phase, from 40% to 60%, Gradient Time(min): 15, Flow Rate (ml / min): 50 ) to give 6-chloro-N-(5-chloro-1-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide (27.4 mg, 19.07% yield). LCMS m / z = 399.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 7.74 (d, J = 6.0 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 0.8 Hz, 1H), 7.18-7.14 (m, 1H). Example 161: 6,7-dichloro-N-(3-methoxyisothiazol-4-yl)-1H-indole-3-sulfonamide To a solution of 6,7-dichloro-1H-indole-3-sulfonyl chloride (Preperation 28) (15.00 mg, 52.72 μmol, 1.0 eq.) and 3-methoxyisothiazol-4-amine (6.86 mg, 52.72 μmol, 1.0 eq.) in DCM (2.0 mL) was added pyridine (12.51 mg, 158.15 μmol, 3.0 eq.) at 20 °C. The reaction was stirred at 20 °C for 4 hours. The mixture was filtrated and concentrated in vacuum to give the residue, which was purified by prep-HPLC (NH4HCO3) (Column: Boston Prime C18 150 x 30mm x 5um)); Mobile Phase: from 10% to 40% of water (NH3H2O+NH4HCO3)- ACN; Flow Rate (ml / min): 25) to give 6,7-dichloro-N-(3-methoxyisothiazol-4-yl)-1H-indole- 3-sulfonamide (8.40 mg, 20.98% yield). LCMS m / z = 377.9 [M+H]+ 1H NMR: (400MHz, MeOD) δ: 8.38 (s, 1H), 7.82 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H). Example 162: 6-chloro-N-(5-propylthiazol-2-yl)-1H-indole-3-sulfonamide To a scintillation vial containing 5-propylthiazol-2-amine (34.1 mg, 240.0 μmol, 1.2 eq.) was added 6-chloro-1H-indole-3-sulfonyl chloride (50.0 mg, 200.0 μmol, 1.0 eq.) and a crystal of DMAP (cat.). The contents were dissolved in pyridine (2.0 mL, 0.1 M) and stirred at 50 °C for approximately 72 h. After this time, the reaction mixture was quenched with water and extracted with EtOAc. The organics were dried over sodium sulfate and concentrated under vacuum to provide the crude product as a brown oil. The crude product was purified by prep- HPLC (Column: Waters XSelect CSH Prep C185um OBD 30 x 100 mm); Mobile Phase: from 5% to 55% of water (NH4HCO3)-MeCN; Flow Rate (ml / min): 50) to provide 6-chloro- N-(5-propylthiazol-2-yl)-1H-indole-3-sulfonamide (16.0 mg, 22.5% yield) as a white solid. LCMS m / z = 356.0 [M+H]+ 1H NMR (600 MHz, DMSO) δ: 12.24 (br s, 1H), 11.81 (br s, 1H), 7.87 (s, 1H), 7.72 (d, J = 8.39 Hz, 1H), 7.50 (d, J = 1.91 Hz, 1H), 7.17 (dd, J = 8.39, 1.91 Hz, 1H), 6.90 (s, 1H), 2.52-2.48 (m, 2H), 1.51 (m, 2H) 0.88 (t, J = 7.25 Hz, 3H). Example 163: 6-chloro-N-(5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4-yl)- 1H-indole-3-sulfonamide Step a: To a solution of tert-butyl (1H-pyrazol-4-yl)carbamate (200 mg, 1.09 mmol, 1.0 eq.) in MeCN (3 mL) was added cesium carbonate (711 mg, 2.18 mmol, 2 eq.) at 25 °C. The mixture was allowed to stir at this temperature for 15 minutes, then 1-bromo-3- (trifluoromethyl)cyclobutane (244 mg, 1.20 mmol, 1.1 eq) was added. The mixture was allowed to stir at 50 °C for 72 hours. The mixture was concentrated to a residue which was redissolved in ethyl acetate, washed with 10mL citric acid, 10mL water, then 10mL brine. The organics were then dried with sodium sulfate, filtered, and concentrated to a residue. The residue was further purified by column chromatography to afford tert-butyl tert-butyl (1-(3- (trifluoromethyl)cyclobutyl)-1H-pyrazol-4-yl)carbamate (85mg, 26% yield). LCMS m / z = 306.1 [M+H]+. Step b: To a solution of tert-butyl (1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4- yl)carbamate (85 mg, 275.1 µmol, 1.0 eq.) in MeCN (2 mL) was added N-chlorosuccinimide (36 mg, 206.4 µmol, 1.0 eq.) at 25 °C. The mixture was allowed to stir at 70 °C for 8 hours. The mixture was concentrated to a residue which was redissolved in dichloromethane, washed with 10mL NaOH (1 M), 10mL water, then 10mL brine. The organics were then dried with sodium sulfate, filtered, and concentrated to a residue. The residue was further purified by column chromatography to afford tert-butyl (5-chloro-1-(3- (trifluoromethyl)cyclobutyl)-1H-pyrazol-4-yl)carbamate (65mg, 70% yield). LCMS m / z = 340.1 [M+H]+. Step c: To a solution of tert-butyl (5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4- yl)carbamate (84 mg, 275.1 µmol, 1.0 eq.) in HFIP (3 mL) was added TFA (69.11 mg, 606.06 µmol, 46.41 µL, 3.0 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 18 hours. The mixture was concentrated to give a residue. The residue was redissolved in ethyl acetate and washed with 10mL saturated sodium bicarbonate solution, 10mL of water, and then 10mL of brine. The organic layer was concentrated to give the 5-chloro-1-(3- (trifluoromethyl)cyclobutyl)-1H-pyrazol-4-amine (43 mg, 88.83% yield). LCMS m / z = 240.1 [M+H]+. Step d: A solution of 5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-4-amine (43.25 mg, 180.48 µmol, 1.0 eq.) and 6-chloro-1H-indole-3-sulfonyl chloride (45.14 mg, 180.48 µmol, 1.0 eq.) in DCM (2 mL) was added Pyridine (2 mL) at 30 °C. The reaction mixture was stirred at 30 °C for 18 hours. Solvent was evaporated under vacuum. The residue was purified by prep-HPLC (Waters Sunfire OBD 100 x 50 mm, 5 mm; 5-75% MeCN / H2O (+ 0.1% TFA)) to give the 6-chloro-N-(5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazol- 4-yl)-1H-indole-3-sulfonamide (38mg mg, 46.45% yield) as an off-white solid. LCMS m / z = 453.1 [M+H]+;1H NMR (600 MHz, DMSO) δ: 7.76 (br d, J=4.20 Hz, 1 H), 7.49 (br s, 1 H), 7.37 (s, 1 H), 7.29 - 7.24 (m, 1 H), 7.09 – 6.98 (m, 1 H), 4.84 - 4.64 (m, 1 H), 3.04 – 2.95 (m, 1 H), 2.48 - 2.41 (m, 4 H). Example 164: 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-7-(pyridazin-3- yl)-1H-indole-3-sulfonamide Step a: To a solution of 7-bromo-6-chloro-1H-indole (93.66 mg, 406.36 μmol, 1.5 eq.) in toluene (5 mL) was added 3-(tributylstannyl)pyridazine (100.00 mg, 270.91 μmol, 1.0 eq.), cateCXium A-Pd-G2 (18.11 mg, 27.09 μmol, 0.1 eq.) and KF (47.22 mg, 812.72 μmol, 3.0 eq.) at 20 °C under N2. The mixture was stirred at 110 °C for 16 h. TLC showed the starting material was consumed and a new spot was observed. The mixture was filtered and concentrated under vacuum to give the residue, which was purified by column chromatography to give 6-chloro-7-(pyridazin-3-yl)-1H-indole (35.00 mg, 56.251% yield). LCMS m / z = 230.2 [M+H]+Step b: To a solution 6-chloro-7-(pyridazin-3-yl)-1H-indole (35.00 mg, 152.40 μmol, 1.0 eq.) in MeCN (3 mL) was added HSO3Cl (53.27 mg, 457.19 μmol, 3.0 eq.) dropwise at 0 °C and stirred at 20 °C for 1 h. TLC showed the staring material was consumed and a new spot was observed. Then POCl3(116.84 mg, 761.98 μmol, 5.0 eq.) was added to the mixture slowly at 0 °C. The mixture was stirred at 60 °C for 16 h. TLC showed the staring material was consumed and a new spot was observed. It was then slowly poured with stirring into ice- water (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-chloro-7-(pyridazin-3-yl)-1H-indole-3- sulfonyl chloride (30.00 mg, 59.99% purity). LCMS m / z = 327.9 [M+H]+Step c: To a solution of 6-chloro-7-(pyridazin-3-yl)-1H-indole-3-sulfonyl chloride (50 mg, 152.36 μmol, 1.0 eq.) in DCM (2 mL) was added pyridine (24.10 mg, 304.72 μmol, 24.65 μL, 2.0 eq.) and 5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-amine (27.43 mg, 152.36 μmol, 1.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 16 hours. LCMS showed that the desired product was detected. The mixture was concentrated under vacuum to give the crude, which was purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um, water (FA)- ACN as a mobile phase, from 32% to 62%, Gradient Time (min): 11, Flow Rate (ml / min): 25) to give 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-7-(pyridazin-3-yl)-1H- indole-3-sulfonamide (2.1 mg, 2.91% yield, 99.49% purity). LCMS m / z = 471.1 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 9.30 (dd, J = 4.8, 1.6 Hz, 1H), 8.06 (dd, J = 8.8, 1.6 Hz, 1H), 7.91 (dd, J = 8.8, 5.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.42-7.37 (m, 2H), 4.32 (t, J = 5.6 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H). Example 165: N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-1H-indole-3- sulfonamide To a solution of 5-bromo-1-(difluoromethyl)-1H-pyrazol-4-amine (Preparation 55) (30 mg, 141.51 μmol, 1.0 eq.) in DCM (2 mL) was added pyridine (22.39 mg, 283.03 μmol, 22.89 μL, 2.0 eq.) and 6-chloro-1H-indole-3-sulfonyl chloride (35.39 mg, 141.51 μmol, 1.0 eq.) at 20 °C. The reaction was stirred at 20 °C for 16 hours. LCMS showed that the desired product was detected. The mixture was concentrated under vacuum to give the crude, which was purified by prep-HPLC (Column: Boston Green ODS 150*30mm*5um, water (FA)-ACN as a mobile phase, from 40% to 70%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-1H-indole-3-sulfonamide (24.33 mg, 40.39% yield). LCMS m / z = 425.0 [M+H]+ 1H NMR (500 MHz, MeOD) δ : 7.68 (s, 1H), 7.63-7.60 (m, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.48-7.22 (m, 1H), 7.15 (dd, J = 8.5, 1.5 Hz, 1H). Example 166: N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(thiazol-4- yl)-1H-indole-3-sulfonamide To a solution of 5-bromo-1-(difluoromethyl)-1H-pyrazol-4-amine (Preparation 55) (31.81 mg, 150.05 μmol, 1.0 eq.) in DCM (2 mL) was added pyridine (22.39 mg, 283.03 μmol, 22.89 μL, 2.0 eq.) and 6-chloro-7-(thiazol-4-yl)-1H-indole-3-sulfonyl chloride (Preparation 56) (50 mg, 150.05 μmol, 1.0 eq.) at 20 °C. The reaction was stirred at 20 °C for 16 hours. LCMS showed that the desired product was detected. The mixture was concentrated under vacuum to give the crude, which was purified by prep-HPLC (Column: Welch Xtimate C18 150*25mm*5um, water (FA)-ACN as a mobile phase, from 40% to 70%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4- yl)-6-chloro-7-(thiazol-4-yl)-1H-indole-3-sulfonamide (5.6 mg, 7.20% yield, 98.16% purity). LCMS m / z = 508.1 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 9.22 (d, J = 1.6 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.98-7.22 (m, 5H). Example 167: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(thiazol-4-yl)- 1H-indole-3-sulfonamide To a solution of 6-chloro-7-(thiazol-4-yl)-1H-indole-3-sulfonyl chloride (Preparation 56) (60.00 mg, 180.06 μmol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (30.17 mg, 180.06 μmol, 1.0 eq.) in DCM (3.0 mL) was added pyridine (42.73 mg, 540.19 μmol, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 2 hours. LCMS showed the starting material was consumed and one peak with desired mass was detected. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex luna C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 36% to 66%, Gradient Time (min): 10, Flow Rate (ml / min): 30) to afford 6-chloro-N-(5-chloro-1- (difluoromethyl)-1H-pyrazol-4-yl)-7-(thiazol-4-yl)-1H-indole-3-sulfonamide (10.83 mg, 12.95% yield, 100% purity). LCMS m / z = 463.8 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 9.22 (d, J = 1.6 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.71-7.67 (m, 2H), 7.62 (s, 1H), 7.53-7.23 (m, 2H). Example 168: N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(2H-1,2,3- triazol-2-yl)-1H-indole-3-sulfonamide To a solution of 6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole-3-sulfonyl chloride (Preparation 57) (50 mg, 157.65 μmol, 1.0 eq.) in DCM (4 mL) was added pyridine (24.94 mg, 315.31 μmol, 25.50 μL, 2.0 eq.) and 5-bromo-1-(difluoromethyl)-1H-pyrazol-4-amine (Preparation 55) (33.42mg, 157.65 μmol, 1.0 eq.) at 20 °C. The reaction was stirred at 20 °C for 16 hours. LCMS showed the desired mass was detected. The mixture was concentrated under vacuum to give the crude, which was purified by prep-HPLC (Column: Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 45% to 65%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4- yl)-6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole-3-sulfonamide (5.53 mg, 6.92% yield, 97.25% purity). LCMS m / z = 494.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.10 (s, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.71-7.68 (m, 2H), 7.54-7.24 (m, 2H). Example 169: 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-7-(2H-1,2,3- triazol-2-yl)-1H-indole-3-sulfonamide To a solution of 6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole-3-sulfonyl chloride (Preparation 57) (60.00 mg, 189.18 μmol, 1.0 eq.) and 5-chloro-1-(2-chloroethyl)-1H- pyrazol-4-amine (34.06 mg, 189.18 μmol, 1.0 eq.) in DCM (2.0 mL) was added pyridine (44.89 mg, 567.55 μmol, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (Phenomenex luna C18150*25mm*10um, water (FA)-ACN as a mobile phase, from 27% to 57%, Gradient Time (min): 8, Flow Rate (ml / min): 30) to afford 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-7-(2H- 1,2,3-triazol-2-yl)-1H-indole-3-sulfonamide (23.5 mg, 26.96% yield). LCMS m / z = 461.7 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.10 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 4.32 (t, J = 6.0 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H). Example 170: N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(pyridin-2- yl)-1H-indole-3-sulfonamide To a solution of 6-chloro-7-(pyridin-2-yl)-1H-indole-3-sulfonyl chloride (Preparation 58) (50 mg, 152.82 μmol, 1.0 eq.) in DCM (3 mL) was added pyridine ((24.18 mg, 305.64 μmol, 24.72 μL, 2.0 eq.) and 5-bromo-1-(difluoromethyl)-1H-pyrazol-4-amine (Preparation 55) (32.40 mg, 152.82 μmol, 1.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 16 hours. LCMS showed that the desired mass was detected. The mixture was concentrated under vacuum to give the crude, which was purified by prep-HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as a mobile phase, from 45% to 65%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4- yl)-6-chloro-7-(pyridin-2-yl)-1H-indole-3-sulfonamide (7.12 mg, 9.14% yield). LCMS m / z = 504.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.75 (d, J = 4.4 Hz, 1H), 8.04 (t, J = 7.6, 1.6 Hz, 1H), 7.76 (t, J = 7.6 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H), 7.56-7.54 (m, 1H), 7.41-7.34 (m, 2H). Example 171: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(pyridin-2- yl)-1H-indole-3-sulfonamide To a solution of 6-chloro-7-(pyridin-2-yl)-1H-indole-3-sulfonyl chloride (Preparation 58) (40 mg, 122.25 μmol, 1.0 eq.) in DCM (4 mL) was added 5-chloro-1-(difluoromethyl)-1H- pyrazol-4-amine (20.48 mg, 122.25 μmol, 1.0 eq.) and pyridine (29.01 mg, 366.76 μmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was complete. The mixture was concentrated to give a residue which was purified by prep-HPLC (Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 35% to 55%, Gradient Time (min): 12, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1- (difluoromethyl)-1H-pyrazol-4-yl)-7-(pyridin-2-yl)-1H-indole-3-sulfonamide (3.36 mg, 6.00% yield). LCMS m / z = 458.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.74-8.72 (m, 1H), 8.04-8.00 (m, 1H), 7.76-7.72 (m, 2H), 7.64 (d, J = 11.2 Hz, 2H), 7.54-7.51 (m, 1H), 7.51- 7.24 (m, 2H). Example 172: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(pyridin-2- yl)-1H-indole-3-sulfonamide Step a: To a solution of 7-bromo-6-chloro-1H-indole (150 mg, 650.79 μmol, 1.0 eq.) and 5- methyl-2-(tributylstannyl)pyridine (248.71 mg, 650.79 μmol, 1.0 eq.) in dioxane (3 mL) was added PdCl2(PPh3)2 (45.68 mg, 65.08 μmol, 0.1 eq.). The mixture was degassed with N2 for 3 times and it was stirred at 100 °C for 16 hours. LCMS indicated that the reaction was complete. The reaction was quenched with CsF (50 mg) in water (10 mL), extracted with EtOAc (50 mL x 3). The mixture was filtered and concentrated. The residue was purified by column chromatography to give 6-chloro-7-(5-methylpyridin-2-yl)-1H-indole (40 mg, 25.32% yield). LCMS m / z = 242.9 [M+H]+Step b: To solution of 6-chloro-7-(5-methylpyridin-2-yl)-1H-indole (40 mg, 164.81 μmol, 1.0 eq.) in MeCN (2 mL) was added sulfurochloridic acid (192.04 mg, 1.65 mmol, 10.0 eq.) at 0 °C. The mixture was stirred at 25 °C for 30 min. TLC showed the reaction was complete. The reaction was quenched with water (10 mL), extracted with EtOAc (50 mL x 3). The combined organic layer was dried over Na2SO4; filtered and evaporated under vacuum to give 6-chloro-7-(5-methylpyridin-2-yl)-1H-indole-3-sulfonyl. The material was used without further purification assuming quantitative yield. Step c: To a solution of 6-chloro-7-(5-methylpyridin-2-yl)-1H-indole-3-sulfonyl (50 mg, 146.54 μmol, 1.0 eq.) in DCM (3 mL) was added 5-chloro-1-(difluoromethyl)-1H-pyrazol-4- amine (24.55 mg, 146.54 μmol, 1.0 eq.) and pyridine (34.77 mg, 439.61 μmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was complete. The mixture was concentrated to give a residue, which was purified by prep- HPLC (Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 38% to 58%, Gradient Time (min): 11, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1- (difluoromethyl)-1H-pyrazol-4-yl)-7-(5-methylpyridin-2-yl)-1H-indole-3-sulfonamide (5.46 mg, 7.20% yield). LCMS m / z = 472.1 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.56 (d, J = 1.6 Hz, 1H), 7.85-7.83 (m, 1H), 7.72 (d, J = 6.8 Hz, 1H), 7.65-7.61 (m, 3H), 7.51-7.27 (m, 2H), 2.47 (s, 3H). Example 173: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(1H-pyrazol- 1-yl)-1H-indole-3-sulfonamide To a solution of 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (50 mg, 158.15 µmol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (39.74 mg, 237.22 µmol, 1.5 eq.) in DCM (2 mL) was added pyridine (37.53 mg, 474.44 µmol, 38.37 µL, 3.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 1 hour. LCMS showed desired product was obtained. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5um, water (NH3H2O+NH4HCO3)-ACN as a mobile phase, from 29% to 59%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1- (difluoromethyl)-1H-pyrazol-4-yl)-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonamide (2.8 mg, 3.93% yield). LCMS m / z = 446.9 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.06 (d, J = 2.8 Hz, 1H), 7.88 (d, J = 1.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.54- 7.24 (m, 2H), 6.65-6.63 (m, 1H). Example 174: 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-7-(1H-pyrazol-1- yl)-1H-indole-3-sulfonamide To a solution of 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (50 mg, 158.15 μmol, 1.0 eq.) in DCM (2 mL) was added pyridine (25.02 mg, 316.29 μmol, 25.58 μL, 2.0 eq.) and 5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-amine (28.47 mg, 158.15 μmol, 1.0 eq.) at 20 °C. The reaction was stirred at 20 °C for 16 hours. LCMS showed that the desired mass was detected. The mixture was concentrated under vacuum to give the crude, which was purified by prep-HPLC (Boston Green ODS 150*30mm*5um, water (FA)- ACN as a mobile phase, from 45% to 65%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazol-4-yl)-7-(1H-pyrazol-1-yl)- 1H-indole-3-sulfonamide (18.2 mg, 24.90% yield). LCMS m / z = 461.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.04 (d, J = 2.4 Hz, 1H), 7.88 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.64 (t, J = 2.4 Hz, 1H), 4.32 (t, J = 5.6 Hz, 2H), 3.81 (t, J = 5.6 Hz, 2H). Example 175: N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(1H-pyrazol- 1-yl)-1H-indole-3-sulfonamide To a solution of 5-bromo-1-(difluoromethyl)-1H-pyrazol-4-amine (Preparation 55) (30 mg, 141.51 μmol, 1.0 eq.) in DCM (2 mL) was added pyridine (22.39 mg, 283.03 μmol, 22.89 μL, 2.0 eq.) and 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (44.74 mg, 141.51 μmol, 1.85 eq.) at 20 °C. The reaction was stirred at 20 °C for 16 hours. LCMS showed that the desired product was detected. The mixture was concentrated under vacuum to give the crude, which was purified by prep-HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as a mobile phase, from 40% to 70%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4- yl)-6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonamide (10.32 mg, 14.83% yield). LCMS m / z = 492.9 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.05 (d, J = 2.5 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.67 (s, 2H), 7.51-7.27 (m, 2H), 6.64 (t, J = 2.0 Hz, 1H). Example 176: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4- methoxypyridin-2-yl)-1H-indole-3-sulfonamide Step a: To a solution of 7-bromo-6-chloro-1H-indole (130.25 mg, 565.0 μmol, 1.5 eq.) in toluene (5 mL) was added 4-methoxy-2-(tributylstannyl)pyridine (150.00 mg, 376.72 μmol, 1.0 eq.), cataCXium A-Pd-G2 (25.19 mg, 37.67 μmol, 0.1 eq.) and KF (65.66 mg, 1.13 mmol, 3.0 eq.) at 25 °C under N2. The mixture was stirred at 110 °C for 16 h. TLC showed the starting material was consumed and a new spot was observed. The mixture was filtered and concentrated under vacuum to give the residue, which was purified by column chromatography to give 6-chloro-7-(4-methoxypyridin-2-yl)-1H-indole (50.00 mg, 51.30% yield). LCMS m / z = 259.2 [M+H]+Step b: To a solution of 6-chloro-7-(4-methoxypyridin-2-yl)-1H-indole (50.00 mg, 193.27 μmol, 1.0 eq.) in MeCN (5 mL) was added HSO3Cl (67.56 mg, 579.82 μmol, 3.0 eq.) dropwise at 0 °C and stirred at 20 °C for 1 h. TLC showed the staring material was consumed and a new spot was observed. To the reaction was then slowly added POCl3(148.17 mg, 966.36 μmol, 5.0 eq.) at 0 °C. The mixture was stirred at 60 °C for 16 h. TLC showed the staring material was consumed and a new spot was observed. It was then slowly poured into the stirring ice-water (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-chloro-7-(4- methoxypyridin-2-yl)-1H-indole-3-sulfonyl chloride (40.00 mg, 57.94% purity).The material was used without further purification assuming quantitative yield. LCMS m / z = 356.9 [M+H]+Step c: To a solution of 6-chloro-7-(4-methoxypyridin-2-yl)-1H-indole-3-sulfonyl chloride (40.00 mg, 111.98 μmol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (18.76 mg, 111.98 μmol 1.0 eq.) in DCM (4 mL) was added pyridine (26.57 mg, 335.94 μmol, 3.0 eq.) at 20 °C. The mixture was stirred at 20 °C for 2 h. LCMS showed the starting material was consumed and the desired Mass was observed. Solvent was evaporated under vacuum to give the residue, which was purified by prep-HPLC (Welch Xtimate C18 150*30mm*5um, water (FA)-ACN as a mobile phase, from 20% to 50%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H- pyrazol-4-yl)-7-(4-methoxypyridin-2-yl)-1H-indole-3-sulfonamide (25.72 mg, 46.67% yield). LCMS m / z = 488.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.54 (d, J = 6.0 Hz, 1H), 7.76- 7.62 (m, 3H), 7.54-7.24 (m, 3H), 7.14 (d, J = 3.2 Hz, 1H), 3.97 (s, 3H). Example 177: N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(4-chloro- 1H-pyrazol-1-yl)-1H-indole-3-sulfonamide To a solution of 5-bromo-1-(difluoromethyl)-1H-pyrazol-4-amine (Preparation 55) (40 mg, 114.09 μmol, 1.0 eq.) in DCM (2 mL) was added pyridine (18.05 mg, 228.18 μmol, 18.45 μL, 2.0 eq.) and 6-chloro-7-(4-chloro-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 60) (24.19 mg, 114.09 μmol, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed that the desired mass was detected. The mixture was concentrated under vacuum to give the crude, which was purified by prep-HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as a mobile phase, from 40% to 70%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford N-(5-bromo-1-(difluoromethyl)- 1H-pyrazol-4-yl)-6-chloro-7-(4-chloro-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide (5.3 mg, 8.70% yield). LCMS m / z = 526.9 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.19 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 4.8 Hz, 2H), 7.54-7.25 (m, 2H). Example 178: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4-chloro-1H- pyrazol-1-yl)-1H-indole-3-sulfonamide To a solution of 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (30 mg, 179.06 μmol, 1.57 eq.) and 6-chloro-7-(4-chloro-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 60) (40 mg, 114.09 μmol, 1.0 eq.) in DCM (3 mL) was added pyridine (27.07 mg, 342.26 μmol, 27.68 μL, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 1 hour. LCMS showed desired mass was obtained and the starting material was consumed complete. Solvent was evaporated under vacuum. The residue was purified by prep-HPLC (Welch Ultimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 35% to 65%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H- pyrazol-4-yl)-7-(4-chloro-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide (10.59 mg, 17.91% yield). LCMS m / z = 481.1 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.18 (s, 1H), 7.86 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.54-7.24 (m, 2H). Example 179: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4- (difluoromethyl)-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide Step a: To a solution of 1H-pyrazole-4-carbaldehyde (200 mg, 2.08 mmol, 1.0 eq.) in DCM (5 mL) was added TEA (631.86 mg, 6.24 mmol, 870.34 ^L, 3.0 eq.), Boc2O (263.25 mg, 1.38 mmol, 1.5 eq.) and DMAP (22.49 mg, 184.11 ^mol, 0.2 eq.) at 20 °C. The reaction mixture was stirred at 20 °C for 12 hours. TLC showed a new main spot was observed. Solvent was evaporated under vacuum. The residue was purified by column chromatography to yield tert-butyl 4-formyl-1H-pyrazole-1-carboxylate (130 mg, 31.76% yield).1H NMR (400 MHz, CDCl3) δ: 9.97 (s, 1H), 8.62 (s, 1H), 8.14 (s, 1H), 1.69 (s, 9H). Step b: To a solution of butyl 4-formyl-1H-pyrazole-1-carboxylate (130 mg, 662.58 μmol, 1.0 eq.) in DCM (3 mL) was added DAST (427.20 mg, 2.65 mmol, 350.17 ^L, 4.0 eq.) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. LCMS showed the starting material was consumed and one peak with desired mass was detected. The reaction mixture was quenched with saturated aq.NaHCO3 (20 mL) and extracted with DCM (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give tert-butyl 4-(difluoromethyl)-1H- pyrazole-1-carboxylate (60 mg, 41.50% yield).1H NMR (400 MHz, MeOD) δ: 8.46 (s, 1H), 7.93 (s, 1H), 6.86 (t, J = 56.0 Hz, 1H), 1.66 (s, 9H). Step c: To a solution of tert-butyl 4-(difluoromethyl)-1H-pyrazole-1-carboxylate (60 mg, 274.98 μmol, 1.0 eq.) in HCl / Dioxane (2M, 3 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material was consumed and one peak with desired mass was detected. The mixture was concentrated to give the 4-(difluoromethyl)-1H- pyrazole. The product was used directly for next step as crude. Step d: A solution of 1-chloro-2-fluoro-3-nitrobenzene (500 mg, 2.85 mmol, 1.0 eq.), 4- (difluoromethyl)-1H-pyrazole (403.61 mg, 3.42 mmol, 1.2 eq.) and Cs2CO3 (2.78 g, 8.54 mmol, 3.0 eq.) in DMF (2 mL) was stirred at 25 °C for 12 hours. LCMS showed the starting material was consumed and one peak with desired mass was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 1-(2-chloro-6-nitrophenyl)-4-(difluoromethyl)-1H-pyrazole (660 mg, 84.58% yield). LCMS m / z = 274.1 [M+H]+ 1H NMR (400 MHz, CDCl3) δ: 7.96-7.88 (m, 3H), 7.83 (t, J = 8.4 Hz, 1H), 7.64-7.59 (m, 1H), 6.83 (t, J = 56.4 Hz, 1H). Step e: To a solution of 1-(2-chloro-6-nitrophenyl)-4-(difluoromethyl)-1H-pyrazole (660 mg, 2.41 mmol, 1.0 eq.) in THF (15.0 mL) was dropwise added bromo(vinyl)magnesium (1M, 9.65 mL, 4.0 eq.) at -78 °C under N2. The reaction was stirred at -78 °C for 3 hours. TLC showed the starting material was consumed completely. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 6-chloro-7-(4-(difluoromethyl)-1H- pyrazol-1-yl)-1H-indole (290 mg, 44.92% yield). LCMS m / z = 267.9 [M+H]+ 1H NMR (400 MHz, CDCl3) δ: 9.23 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.86 (t, J = 56.8 Hz, 1H), 6.60 (s, 1H). Step f: To a solution of 6-chloro-7-(4-(difluoromethyl)-1H-pyrazol-1-yl)-1H-indole (100 mg, 373.61 μmol, 1.0 eq.) in MeCN (4 mL) was added HSO3Cl (108.84 mg, 934.02 μmol, 62.09 μL, 2.5 eq.) at 0 °C. The mixture was stirred at 0 °C for 2 hours. LCMS showed the starting material was consumed and one peak with desired mass was detected. Then POCl3(229.14 mg, 1.49 mmol, 139.30 μL, 4.0 eq.) was added and stirred at 70 °C for 12 hours. LCMS showed the starting material was consumed and one peak with desired mass was detected. The reaction mixture was quenched with the stirring ice water (20 mL) and extracted with EtOAc (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-chloro-7-(4-(difluoromethyl)-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride. The product was used directly for next step as crude. Step g: To a solution of 6-chloro-7-(4-(difluoromethyl)-1H-pyrazol-1-yl)-1H-indole-3- sulfonyl chloride (40.00 mg, 109.24 μmol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H- pyrazol-4-amine (18.30 mg, 109.24 μmol, 1.0 eq.) in DCM (2.0 mL) was added pyridine (25.92 mg, 327.72 μmol, 3.0 eq.) at 25 °C. The reaction was stirred at 25 °C for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated to give a residue. The residue was purified by prep-HPLC (Welch Ultimate C18150*25mm*7um, water (FA)- ACN as a mobile phase, from 35% to 65%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4- (difluoromethyl)-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide (18.96 mg, 34.90% yield). LCMS m / z = 497.1 [M+H]+ 1H NMR (400 MHz, MeOD) δ: .35 (s, 1H), 8.06 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.54-7.24 (m, 2H), 6.97 (t, J = 56.0 Hz, 1H). Example 180: 6-chloro-N-(3-methoxyisothiazol-4-yl)-7-(1H-pyrazol-1-yl)-1H-indole-3- sulfonamide To a solution of 6-chloro-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (40.00 mg, 126.52 μmol, 1.0 eq.) and 3-methoxyisothiazol-4-amine (21.08 mg, 126.52 μmol 1.06 eq.) in DCM (2 mL) was added pyridine (30.02 mg, 379.55 μmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 4 h. LCMS showed the starting material was consumed and the desired Mass was observed. Solvent was evaporated under vacuum to give the residue, which was purified by prep-HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as a mobile phase, from 35% to 65%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford 6-chloro-N-(3-methoxyisothiazol-4-yl)-7-(1H-pyrazol-1-yl)-1H-indole-3-sulfonamide (20.40 mg, 39.02% yield). LCMS m / z = 409.9 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 8.38 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.87-7.84 (m, 2H), 7.77 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 8.64-6.62 (m, 1H), 3.71 (s, 3H). Example 181: N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(4-ethyl-1H- pyrazol-1-yl)-1H-indole-3-sulfonamide To solution of 6-chloro-7-(4-ethyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 61) (70 mg, 203.36 μmol, 1.0 eq.) in DCM (4 mL) was added 5-bromo-1- (difluoromethyl)-1H-pyrazol-4-amine (Preparation 55) (43.11 mg, 203.36 μmol, 1.0 eq.) and pyridine (48.26 mg, 610.08 μmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was complete. The mixture was concentrated to give a residue, which was purified by prep-HPLC (Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 47% to 77%, Gradient Time (min): 11, Flow Rate (ml / min): 25) to afford N-(5-bromo-1-(difluoromethyl)-1H-pyrazol-4-yl)-6-chloro-7-(4-ethyl- 1H-pyrazol-1-yl)-1H-indole-3-sulfonamide (14.64 mg, 13.85% yield). LCMS m / z = 519.9 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 7.84 (s, 1H), 7.73 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 2H), 7.54-7.24 (m, 2H), 2.69-2.62 (m, 2H), 1.30 (t, J = 7.6 Hz, 3H). Example 182: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4-ethyl-1H- pyrazol-1-yl)-1H-indole-3-sulfonamide To solution of 6-chloro-7-(4-ethyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 61) (40 mg, 116.21 μmol, 1.0 eq.) in DCM (4 mL) was added 5-chloro-1- (difluoromethyl)-1H-pyrazol-4-amine (19.47 mg, 116.21 μmol, 1.0 eq.) and pyridine (27.58 mg, 348.62 μmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed the reaction was complete. The mixture was concentrated to give a residue, which was purified by prep-HPLC (Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 42% to 72%, Gradient Time (min): 11, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4-ethyl-1H-pyrazol-1-yl)-1H- indole-3-sulfonamide (2.22 mg, 3.86% yield). LCMS m / z = 475.1 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 7.84 (s, 1H), 7.74-7.71 (m, 2H), 7.68 (s, 1H), 7.64 (s, 1H), 7.51-7.27 (m, 2H), 2.68-2.62 (m, 2H), 1.30 (t, J = 8.0 Hz, 3H). Example 183: 7-(4-bromo-1H-pyrazol-1-yl)-6-chloro-N-(5-chloro-1-(difluoromethyl)- 1H-pyrazol-4-yl)-1H-indole-3-sulfonamide To a solution of 7-(4-bromo-1H-pyrazol-1-yl)-6-chloro-1H-indole-3-sulfonyl chloride (Preparation 62) (100.00 mg, 253.13 μmol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H- pyrazol-4-amine (45.00 mg, 268.59 μmol 1.06 eq.) in DCM (2.0 mL) was added pyridine (60.07 mg, 759.38 μmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 4 h. LCMS showed the starting material consumed and desire mass observed. Solvent was evaporated under vacuum to give the residue, which was purified by column chromatography to give crude compound. The crude product was purified by prep-HPLC (Boston Prime C18 150*30mm*5um, water (NH3H2O+NH4HCO3)-ACN as a mobile phase, from 15% to 45%, Gradient Time (min): 12, Flow Rate (ml / min): 25) to afford 7-(4-bromo-1H-pyrazol-1-yl)-6- chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indole-3-sulfonamide (5.32 mg, 17.73% yield). LCMS m / z = 525.0 [M+H]+ 1H NMR (400 MHz, DMSO) δ: 12.21 (s, 1H), 10.02 (s, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.92-7.63 (m, 4H), 7.44 (d, J = 8.4 Hz, 1H). Example 184: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(4- cyclopropyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonamide Step a: To a solution of 1-chloro-2-fluoro-3-nitrobenzene (400.00 mg, 2.28 mmol, 1.0 eq.) in MeCN (10 mL) was added K2CO3 (944.75 mg, 6.84 mmol, 3.0 eq.) and 4-cyclopropyl-1H- pyrazole (295.69 mg, 2.73 mmol, 1.2 eq.) at 25 °C. The mixture was stirred at 60 °C for 16 h. TLC showed the starting material was consumed and a new spot was observed. The mixture was filtered and concentrated in vacuum to give the residue, which was purified by column chromatography to give 1-(2-chloro-6-nitrophenyl)-4-cyclopropyl-1H-pyrazole (570.00 mg, 94.87% yield.1H NMR (400 MHz, CDCl3) δ: 7.81 (dd, J1= 8.0 Hz, J2= 1.2 Hz, 1H), 7.76 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.53-7.49 (m, 3H), 1.83-1.76 (m, 1H), 0.95-0.90 (m, 2H), 0.65-0.60 (m, 2H). Step b: To a solution of 1-(2-chloro-6-nitrophenyl)-4-cyclopropyl-1H-pyrazole (270.00 mg, 1.02 mmol, 1.0 eq.) in THF (40 mL) was added bromo(vinyl)magnesium (1 M, 5.12 mmol, 5.0 eq.) at -78 °C under N2. The mixture was stirred at -78 °C for 3 h. TLC showed the starting material was consumed completely and a new spot was observed. The reaction mixture was quenched with saturated aq.NH4Cl (50 mL) and extracted with EtOAc (40 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 6-chloro-7-(4-cyclopropyl-1H- pyrazol-1-yl)-1H-indole (100.00 mg, 37.89% yield). LCMS m / z = 258.0 [M+H]+Step c: To a solution of 6-chloro-7-(4-cyclopropyl-1H-pyrazol-1-yl)-1H-indole (100.00 mg, 388.02 μmol, 1.0 eq.) in MeCN (4 mL) was added NBS (69.06 mg, 388.02 μmol, 1.0 eq.) and stirred at 25 °C for 2 h. TLC showed the staring material was consumed and a new spot was observed. The mixture was quenched with saturated aq.Na2SO3 (30 mL). The mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the residue, which was purified by column chromatography to give 3-bromo-6-chloro-7-(4-cyclopropyl-1H-pyrazol- 1-yl)-1H-indole (12.00 mg, 91.87% purity). LCMS m / z = 336.0 [M+H]+Step d: To a solution of 3-bromo-6-chloro-7-(4-cyclopropyl-1H-pyrazol-1-yl)-1H-indole (120.00 mg, 356.49 μmol, 1.0 eq.) and phenylmethanethiol (90.00 mg, 724.62 μmol, 2.03 eq.) in dioxane (5 mL) was added DIEA (138.22 mg, 1.07 mmol, 3.0 eq.) and Pd(t-Bu3P)2 (27.33 mg, 53.47 μmol, 0.15 eq.) at 25 °C under N2. The mixture was stirred at 80 °C for 16 h. TLC showed the starting material was consumed and a new spot was observed. The mixture was diluted with water (50 mL), extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude was purified by column chromatography to give the crude product, which was purified by prep-HPLC (Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 60% to 90%, Gradient Time (min): 12, Flow Rate (ml / min): 25) to 3-(benzylthio)-6-chloro-7-(4-cyclopropyl-1H-pyrazol-1-yl)-1H-indole (120.00 mg, 88.60% yield). LCMS m / z = 379.9 [M+H]+Step e: To a solution 3-(benzylthio)-6-chloro-7-(4-cyclopropyl-1H-pyrazol-1-yl)-1H-indole (70.00 mg, 184.26 μmol, 1.0 eq.) in AcOH (1.5 mL) was added water (0.2 mL) and NCS (73.81 mg, 552.77 μmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 1 h. TLC showed the starting material was consumed and a new spot was observed. The reaction mixture was then diluted with water (30 mL) and extracted with EA (30 mL x 3). The organic layer was washed with saturated aq.NaHCO3 (30 mL) and dried over Na2SO4; filtered and concentrated in vacuum to give 6-chloro-7-(4-cyclopropyl-1H-pyrazol-1-yl)-1H- indole-3-sulfonyl chloride (50.00 mg, 76.18% yield), which was used directly without further purification. Step f: To a solution of 6-chloro-7-(4-cyclopropyl-1H-pyrazol-1-yl)-1H-indole-3-sulfonyl chloride (40.00 mg, 112.29 μmol, 1.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4- amine (18.81 mg, 112.29 μmol 1.06 eq.) in DCM (2 mL) was added pyridine (26.65 mg, 336.86 μmol, 3.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed and the desired Mass was observed. Solvent was evaporated under vacuum to give the residue, which was purified by prep-HPLC (Welch Xtimate C18150*25mm*5um, water (FA)-ACN as a mobile phase, from 40% to 70%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1- (difluoromethyl)-1H-pyrazol-4-yl)-7-(4-cyclopropyl-1H-pyrazol-1-yl)-1H-indole-3- sulfonamide (19.59 mg, 35.61% yield). LCMS m / z = 487.1 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 7.80 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.67 (s, 1H), 7.64 (s, 1H), 7.54- 7.25 (m, 2H), 1.89-1.83 (m, 1H), 0.97-0.92 (m ,2H), 0.67-0.63 (m, 2H). Example 185: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(5,6- dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole-3-sulfonamide Step a: To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole (Preparation 63) (50.00 mg, 194.01 μmol, 1.0 eq.) in MeCN (2 mL) was added dropwise sulfurochloridic acid (226.07 mg, 1.94 mmol, 128.96 μL, 10.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 hour. TLC showed reactant 1 was consumed completely. Then was added POCl3 (118.99 mg, 776.04 μmol, 72.34 μL, 4.0 eq.) at 0 °C. The reaction mixture was stirred at 60 °C for 16 hours. TLC showed material was consumed completely and one new spot was detected. The mixture was quenched with saturated ice water and extracted with ethyl acetate (20 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)- yl)-1H-indole-3-sulfonyl chloride (50mg, 72.3% yield). The product was used directly for next step as crude. Step b: To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole-3- sulfonyl chloride (50 mg, 140.36 μmol, 1.0 eq.) in DCM (2 mL) was added pyridine (22.20 mg, 280.72 μmol, 22.70 μL, 2.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (23.52 mg, 140.36 μmol, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed that the desired product was detected. The mixture was concentrated under vacuum to give the crude, which was purified by prep-HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as a mobile phase, from 50% to 80%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H- pyrazol-4-yl)-7-(5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole-3-sulfonamide (15.83 mg, 22.97% yield). LCMS m / z = 487.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ: 7.75 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 12.8 Hz, 2H), 7.54-7.24 (m, 3H), 2.79-2.75 (m, 2H), 2.68-2.60 (m, 4H). Example 186: 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl)-7-(5,6- dihydrocyclopenta[c]pyrazol-1(4H)-yl)-1H-indole-3-sulfonamide Step a: To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)-1H-indole (Preparation 63) (50.00 mg, 194.01 μmol, 1.0 eq.) in MeCN (2 mL) was added dropwise sulfurochloridic acid (113.03 mg, 970.05 μmol, 64.48 μL, 5.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 1 hour. TLC showed the reactant was consumed completely. Then was added POCl3 (118.99 mg, 776.04 μmol, 72.34 μL, 4.0 eq.) at 0 °C. The reaction mixture was stirred at 60 °C for 16 hours. TLC showed material was consumed completely and one new spot was detected. The mixture was quenched with saturated ice water and extracted with ethyl acetate (20 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)- yl)-1H-indole-3-sulfonyl chloride (50mg, 72.3% yield). The product was used directly for next step as crude. Step b: To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)-1H-indole-3- sulfonyl chloride (50 mg, 140.36 μmol, 1.0 eq.) in DCM (2 mL) was added pyridine (22.20 mg, 280.72 μmol, 22.70 μL, 2.0 eq.) and 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (23.52 mg, 140.36 μmol, 1.0 eq.) at 25 °C. The mixture was stirred at 25 °C for 16 hours. LCMS showed the desired product was detected. The mixture was concentrated under vacuum to give the crude, which was purified by prep-HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as a mobile phase, from 50% to 80%, Gradient Time (min): 10, Flow Rate (ml / min): 25) to afford 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H- pyrazol-4-yl)-7-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)-1H-indole-3-sulfonamide (18.04 mg, 26.37% yield). LCMS m / z = 487.1 [M+H]+ 1H NMR (400 MHz, CDCl3) δ: 10.42 (s, 1H), 7.96 (s, 1H), 7.72-7.69 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.20- 6.90 (m, 1H), 6.21 (s, 1H), 2.86 (t, J = 7.2 Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H), 2.56-2.49 (m, 2H). The following compounds were made as described for the examples above:

[0009] 1. GPR17 cAMP HTRF assay A stably expressing GPR17-1321N1 clonal cell line was generated using lentivirus to introduce full length GPR17 expression and evaluate cAMP activity using a cAMP HTRF assay. GPR17-1321N1 and wt-1321N1 cells were cultured in DMEM with 10% FBS, 1% glutamax and 1% Penicillin-Streptomycin, supplemented with 5 µg / ml of puromycin for the GPR17-1321N1 line. Stock concentration of compounds were serially diluted to 10 point, 3- fold dilution in DMSO.40 nl of compounds in DMSO and reference controls (BIO-1948681 and DMSO) were dispensed into white 384 well plates. Cells were prepared in OptiMEM with 0.5 mM IBMX at a density of 7x105cells / ml.10 µl volume of the diluted cells was added into the compound treated plates for a final density of 7000 cells / well and incubated for 15 min at room temperature.10 µl of OptiMEM with MDL29951 agonist and Forskolin, final concentration of MDL29951 at EC80 of agonist activity with 5 µM for Forskolin, was added to plates. Incubate plate at room temperature for 15 min. Following stimulation treatment, cAMP levels were measured using cAMP Gs dynamic kit HTRF (Cisbio / Perkin Elmer). Dispensed 10 µl of 1x cAMP-d2 (acceptor reagent) diluted in lysis buffer, followed by 10 µl of 1x of Anti-cAMP cryptate (Eu-donor reagent) diluted in lysis buffer and incubate for 1 hr at room temperature. The plate was read at 665nm and 615nm wavelengths on the PHERAstar (BMG Labtech) and the HTRF ratio was calculated from 665nm / 615nm. Activity was normalized to the following equation, with 0% activity control and 100% control on the same plate. % Activity = (well data – 0% activity) / (100% activity – 0% activity) x 100 Percent activity vs compound concentration was plotted and fit to a 4-parameter logistic model to obtain IC50values. The data is presented in the table below.

[0010] “++++” = IC50< 100 nM; “+++” = IC50 >= 100 nM and <= 500 nM; “++” = IC50 >500 nM and < 10,000 nM; “+” = IC50 >= 10,000 nM 2. MDR1-MDCK assay procedure ^ Human MDR1 transfected MDCK cells (NIH cell line in-licensed from Absorption Systems) were used in the assay. ^ The compounds were tested at 1 µM concentration prepared in transport buffer (Hank’s balanced salt solution with HEPES) ^ MDR1-MDCK cell were cultured for 7 days in 96 well transwell insert plates (Corning). Insert plates were washed before the assay and TEER (Trans epithelial electric resistance) was measured. ^ These plates were loaded with test compound solution 85 µL for A-B transport and 260 µL for B-A transport in the respective donor compartment. The volume of receiver buffer (Transport buffer supplemented with 1% BSA) in the respective receiver compartment was 250 and 75 µL. ^ 10 µL samples was taken from donor compartment (T=0 timepoint) ^ Assay plates were incubated for 120 minutes. ^ At 120 minutes (T=120 timepoint) samples from respective donor (10uL) and receiver (50 µL) compartments was taken. ^ After addition of 40 µL transport buffer with BSA to donor samples, crash solution (Acetonitrile with internal standard, 110 µL) was added to all samples. ^ After centrifugation 50 µL supernatant was transferred to separate plate and mixed with 50 µL water. ^ Samples were analyzed using LC-MS / MS coupled with high throughput injection system. ^ Analyte / internal standard area ratios were used for apparent permeability (Papp), efflux ratio and mass recovery estimation based on equations below. Papp = (dCr / dt) x Vr / (A x CE) Mass balance = 100 x ((Vrx Crfinal) + (Vdx Cdfinal)) / (Vdx CE) Where: dCr / dt is the cumulative concentration in the receiver compartment versus time in ^M s-1Vr is the volume of the receiver compartment in cm3Vdis the volume of the donor compartment in cm3A is the area of the insert (0.143 cm2for 96-well insert) CE is the estimated experimental concentration (Time = 0) of the dosing solution Crfinalis the concentration of the receiver at the end of the incubation period Cdfinalis the concentration of the donor at the end of the incubation period. The efflux ratio for the tested compounds is shown in the table below.

[0011] Ratio < 5; “+++” = Ratio >= 5 and <= 20; “++” = Ratio > 20 and <= 100; “+” = Ratio > 100 3. Kp,uu Brain Penetration Assay Generic Study Protocol for in vivo PK Studies (non-GLP) In vivo For the brain-to-plasma partition coefficient (Kp) evaluation, a dosing solution was intravenously infused into animals at a constant flow rate for 4 to 24 h. Blood samples were serially collected during infusion, and CSF and brain samples were harvested at the end of infusion. For characterization of PK properties, a dosing solution was administered to animals via oral gavage or parenteral routes. Blood samples were collected after administration. Other biological samples, including tissue, bile, urine, and feces, can be collected during or at the end of the study if necessary. All the animal experiments were conducted in accordance with the internally approved animal protocols. Bioanalysis Tissue samples were typically homogenized in phosphate buffer saline (PBS) using a bead ruptor. CSF samples were typically diluted with 8% BSA in PBS to prevent from non- specific binding. Artificial CSF (aCSF) is used as the surrogate matrix. Dosing solutions were spiked into plasma for analysis when needed. Calibration curves were prepared by spiking the analyte(s) into blank matrices, which were processed together with plasma, tissue homogenate and / or CSF samples by protein precipitation using a proper organic solvent (e.g. acetonitrile and methanol) containing generic analogue internal standards (e.g. verapamil, chrysin and glyburide). Matrix matching was used when analyzing multiple matrices in the same run. Samples above the upper limit of quantitation (ULOQ) needed to be diluted into the calibration range using either a pre- extraction or post-extraction dilution approach. Processed samples were analyzed by LC-MS / MS using a proper method performing within the acceptable sensitivity, selectivity, precision and accuracy. For an analytical run to be accepted, over 75% of the calibration standards in the dual calibration curves needed to be within 20% of the nominal concentrations. Compound- or study-specific bioanalytical methods that deviate from the typical procedure might be used when necessary, which will be documented in a study specific protocol included in the data upload. PK Plasma concentrations were analyzed by non-compartmental analysis (NCA) using a “Linear up log down” fitting to generate basic PK parameters that include but are not limited to volume of distribution (Vd), maximal concentration (Cmax), time to reach maximal concentration (Tmax), area under the curve (AUC), half-life (t1 / 2), clearance (CL) and bioavailability (F). The PK parameters were normalized to the adjusted dose when dosing solution analysis was conducted. Brain concentrations were compared against plasma concentrations at the corresponding timepoint for the calculation of partition coefficient (Kp). Unbound drug partition coefficient (Kpuu), defined as the ratio of unbound drug partition across the blood-brain barrier, was calculated using the equation below: Cb: measured total drug concentration in brain Fub: unbound drug fraction in brain Cp: measured total drug concentration in plasma Fup: unbound drug fraction in plasma Compound- or study-specific PK analysis that deviates from the typical procedure might be used when necessary, which will be documented in a study specific protocol included in the data upload. Determination of Fraction Unbound (Fu): The unbound fraction of the test compound was determined based on the protocols described below. 1) Dilute initial 10mM test article to 125μM by adding 5μL to a total volume of 395μL solvent solution (100% acetonitrile) in a 1mL 96-well plate (Waters 186002481 Milford, MA). Ensure that the compounds are in solution. 2) Thaw frozen (rat, human, mouse, dog, and / or monkey) plasma (BIOIVT, Westbury, NY) in and warm the PBS buffer in a warm (37°C) water bath. • Dilute the 125uM test article solutions by adding 8μL to a final volume of 992μL of plasma to make a final concentration of 1μM in a 2mL 96 well plate (Costar 3961). Mix thoroughly. • This spiked plasma solution is shown in figure 1. 3) Prepare a chilled ‘crash’ solution of internal standard in a solvent solution. • Pipette 200μL of 25ng / mL solution of internal standard, CPDPX (8-Cyclopentyl- 1,3-dipropylxanthine, Sigma-Aldrich, C101) in 1:1 acetonitrile / methanol solvent solution into a 1mL 96-well plate. • Chill on ice or refrigerate at 4°C. • This solution becomes the ‘Crash’ plate in figure 1. 4) From remaining spiked plasma, remove 50μL (T=0h) of each plasma sample and place into a crash plate which contains 200μL. To matrix match, add 50μL of blank buffer to the crashed sample (similar to PPB samples). Maintain remaining spiked plasma at 37˚C for 4h time point 5) Transfer 500μL of the warmed PBS buffer to the white side of the RED device (Thermo Scientific, Rockford IL, baseplate cat# 89811, insert cat# 89810) and 300 μL of the spiked plasma to the corresponding red ring side of the RED device. 6) Cover all the RED device plates with a lid and transfer them to a 37˚C incubator with 5% CO2 environment and shake at 200 rpm for 4 hours. 7) Reaction Termination after 4 hours: • Add 50μL of sample (plasma or buffer sample) and 50μL of the opposite blank matrix (add blank buffer to the plasma samples and blank plasma to the buffer samples) to crash plates (same as above) to the crash plate containing 200μL. Mix crash plate thoroughly. • From remaining spiked plasma, remove 50μL (T=4h) of each plasma sample and place into a crash plate. To matrix match, add 50μL of blank buffer to the crashed sample (similar to the protein binding samples). • Centrifuge crash plate at 3900rpm for 10 minutes at 4˚C (Eppendorf Centrifuge 5810R, Hamburg, Germany) 8) Sample preparation of LC / MS / MS: • Transfer 30μL of supernatant from the crash plates to 384-well plates containing 120μL of 0.1 formic acid in 90:10 water:acetonitrile using the PPB 96 to 384 pretty method on the Tecan. Inject into the LC / MS. • Volumes and diluent composition may be adjusted based on instrument (LC- MS / MS) sensitivity and test article sensitivity, solubility, and polarity to ensure adequate signal and retention of test articles within the linear limitation of the instrument. 9) Standard Curve • Prepare standard curve of pooled test articles treated in a similar fashion as the reaction samples using plasma and buffer. 10) Data processing and analysis Multiquant will be chosen application used to process the data for PPB. Equations: Equation 1. Calculation of %Free (% PPBunb) % Free = (PAR of buffer side / PAR of plasma side)*100 PAR – Peak area ratio (PAR) Fu = % Free / 100 Fu = fraction unbound Equation 2. Final calculation using dilution factor (D) This dilution factor formula is used only if tissue or plasma is diluted. The Kp,uu,brainvalues are shown in the table below. “++” = Kp,uu,brain >0.1 and <= 0.5 “+++” = Kp,uu,brain> 0.5

Claims

CLAIMS What is claimed is:

1. A compound represented by the following formula (I):or a pharmaceutically acceptable salt thereof, wherein: X is N or CRx; Rxis H, halo, ORx1, SRx1, C1-3alkyl, C1-3haloalkyl, NRx1Rx1, C(O)Rx1a, cyano, C3-6cycloalkyl, phenyl, 5 to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, or 4 to 6-membered monocyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 Rx2; Rx1is H, C1-3alkyl or C1-3haloalkyl; Rx1ais ORx1, NRx1Rx1, C1-3alkyl or C1-3haloalkyl; each Rx2is independently halo, cyano, C1-4alkyl, C1-4haloalkyl, ORx1, NRx1Rx1, C3-6cycloalkyl; or two Rx2, together with the atoms to which they are attached, form C3-6carbocyclyl or 5 to 6-membered heterocyclyl; Ring A is a 5-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, a 9 to 10-membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected form N, O and S, or a 8 to 10-membered bicyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S; R1, for each occurrence, is independently selected from halo, -CN, C1-7alkyl, - OR1a, -NR1bR1b, -NR1bC(O)R1a, -C(O)NR1bR1b, -SR1a, C3-6cycloalkyl, phenyl, 5 to 6- membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, and 4 to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the C1-7alkyl, C3-6cycloalkyl, phenyl, 5 to 6- membered heteroaryl and 4 to 10-membered heterocyclyl are each optionally substituted with 1 to 3 R10;R1ais H, C1-6alkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, or 4 to 10- membered heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the C1-6alkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl and 4 to 10-membered heterocyclyl are each optionally substituted with 1 to 3 substituents independently selected from halo, C1-3alkyl and C1-3alkoxy; each R1bis independently H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, or 4 to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S; R10, for each occurrence, is independently selected from halo, -CN, -OR1a, - NR1bR1b, -NR1bC(O)R1a, -C(O)NR1bR1b, -SR1a, C1-3alkyl, C3-6cycloalkyl, phenyl and 4 to 6 membered saturated heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S, wherein the C3-6cycloalkyl, phenyl and 4 to 6 membered saturated heterocyclyl are each optionally substituted by one or more halo, C1-4alkyl, C1-4haloalkyl, hydroxy, or cyano; R2is H, halo, C1-3alkyl, C1-3haloalkyl, -NR2aR2a, or –OR2a; each R2ais independently C1-3alkyl, C1-3haloalkyl, benzyl, phenyl, 5 to 10- membered heteroaryl, or -CH2-(5 to 10-membered heteroaryl), wherein the 5 to 10- membered heteroaryl contains 1-4 heteroatoms independently selected from N, O and S, and is optionally substituted with C1-3alkyl; R3is H or C1-3alkyl, wherein the C1-3alkyl is optionally substituted by 1 to 3 halo, -OR3a, -C(O)OR3a, or -C(O)NR3aR3a; each R3ais independently H or C1-3alkyl; and n is 0, 1, 2, or 3; provided that: (i) if one of R2and Rxis H, then the other is not H; (ii) if X is N then R2is not H; (iii) when Rxis H and R2is halo, alkyl, or haloalkyl, then Ring A is not2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is N or CRx; Rxis H, halo, ORx1, SRx1, C1-3alkyl, C3-6cycloalkyl, 5 to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, or 4 to 6-membered monocyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S; Rx1is H, C1-3alkyl or C1-3haloalkyl; Ring A is a 5-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, a 9 to 10-membered bicyclic heteroaryl containing 1-4 heteroatoms independently selected form N, O and S, or a 9 to 10-membered bicyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S; R1, for each occurrence, is independently selected from halo, -CN, C1-7alkyl, – OR1a, -SR1a, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, and 4 to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the C1-7alkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl and 4 to 10-membered heterocyclyl are each optionally substituted with 1 to 3 R10;R1ais C1-6alkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, or 4 to 10-membered heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the C1-6alkyl, C3-6cycloalkyl, phenyl, 5 to 6-membered heteroaryl and 4 to 10-membered heterocyclyl are each optionally substituted with 1 to 3 substituents independently selected from halo, C1-3alkyl and C1-3alkoxy; R10, for each occurrence, is independently selected from halo, -CN, -OR1a, - SR1a, C1-3alkyl, C3-6cycloalkyl, phenyl and 4 to 6 membered saturated heterocyclyl containing 1-2 heteroatoms independently selected from N, O and S; R2is H, halo, C1-3alkyl, C1-3haloalkyl, or –OR2a; R2ais C1-3alkyl, C1-3haloalkyl, benzyl, phenyl, 5 to 10-membered heteroaryl, or -CH2-(5 to 10-membered heteroaryl), wherein the 5 to 10-membered heteroaryl contains 1-4 heteroatoms independently selected from N, O and S, and is optionally substituted with C1-3alkyl; R3is H or C1-3alkyl; and n is 0, 1, or 2.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is CRx; Rxis halo, ORx1, SRx1, C1-3alkyl, C1-3haloalkyl, NRx1Rx1, C(O)Rx1a, cyano, C3-6cycloalkyl, phenyl, 5 to 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, or 4 to 6-membered monocyclic heterocyclyl containing 1-4 heteroatoms independently selected form N, O and S, wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 Rx2; and R2is halo, C1-3alkyl, C1-3haloalkyl, -NR2aR2a, or –OR2a.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3is H, -CH3, -CH2CHF2, -CH2CH2OH, -CH2CH2OCH3, - CH2CH2CH2OH, -CH2C(O)OH, or -CH2C(O)NHCH3.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R3is H.

6. The compound of any one of claims 1, 2, 4, or 5, or a pharmaceutically acceptable salt thereof, wherein X is CRx; and Rxis H, -Cl or –OCH3.

7. The compound of any one of claims 1, 2, or 5, wherein the compound is represented by formula (II):or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1 to 6, wherein the compound is represented by formula (IIIa):or a pharmaceutically acceptable salt thereof, 9. The compound of any one of claims 1 to 8, or pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of pyrazolyl, dihydropyrrolopyrazolyl, dihydropyrazolooxazolyl, dihydropyrazolooxazinyl, pyrazolopyrazinonyl, pyrazolopyridinyl, triazolyl, imidazolyl, imidazothiazolyl, imidazopyridinyl, triazolopyridinyl, isothiazolyl, thiazolyl, dihydrothiopyranothiazolyl, thiadiazolyl, thiophenyl, isoxazolyl, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzoloxazolyl, pyridylisoxazolyl, benzoisoxazolyl, indazolyl, pyrazolopyridinyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, and pyridylpyrazolyl, each of which is optionally substituted with 1 to 3 R1.

10. The compound of any one of claims 1 to 8, or pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of pyrazolyl, triazolyl, isothiazolyl, thiazolyl, thiadiazolyl, thiophenyl, isoxazolyl, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzoloxazolyl, pyridylisoxazolyl, and pyridylpyrazolyl, each of which is optionally substituted with 1 or 2 R1.

11. The compound of any one of claims 1 to 9, or pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula:

12. The compound of any one of claims 1 to 10, or pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula:

13. The compound of claim 11, or pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula:

14. The compound of claim 12, or pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula:.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein: R1, for each occurrence, is independently selected from halo, -CN, C1-7alkyl, – OR1a, -C(O)NR1bR1b, C3-6cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl, wherein the C1-7alkyl is optionally substituted with 1 to 3 R10, and wherein the C3-6cycloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 groups independently selected from halo, C1-3alkyl, and C1-3haloalkyl; R1ais H or C1-4alkyl optionally substituted with 1 to 3 halo; each R1bis independently H or C1-3alkyl; R10, for each occurrence, is independently selected from halo, -CN, -OR1a, - SR1a, -NR1bR1b, -C(O)NR1bR1b, -NR1bC(O)C1-3alkyl, C3-6cycloalkyl, phenyl, and 4 to 6 membered saturated heterocyclyl, wherein the C3-6cycloalkyl is optionally substituted by C1-3haloalkyl.

16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein: R1, for each occurrence, is independently selected from halo, -CN, C1-7alkyl, – OR1a, C3-6cycloalkyl, and phenyl, wherein the C1-7alkyl is optionally substituted with 1 to 3 R10; R1ais C1-4alkyl optionally substituted with 1 to 3 halo; R10, for each occurrence, is independently selected from halo, -CN, -OR1a, - SR1a, C3-6cycloalkyl, phenyl, and 4 to 6 membered saturated heterocyclyl.

17. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R1, for each occurrence, is independently selected from -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2C(CH3)3, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -(CH2)3CH3, -(CH2)6CH3, -CH2CH2CH2CN, -CH2CH2CN, - CH2CN, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CHF2, -CF3, - CH2CH2CF3, -CH2CF3, -CH2CH2F, -CH2CHF2, -CF2CH3, -CH2CH2Cl, - CH2CH2CH2F, -CH2CH2CHF2, -CH2CHFCH2F, -CH2CF2CH3, -OCH3, -OCH2CH3, - OCH(CH3)2, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2OCHF2, - CH2CH2OCH2CF3, -CH2CH2CH2OCH2CF3, -CH2CH2CH2OCHF2, -OH, -OCHF2, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, phenyl, -CH2CH2Ph, methylpyrazolyl, oxetan-3-ylmethyl, -CH2SCH3, -C(O)NHCH3,18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R1, for each occurrence, is independently selected from -Cl, -CN, - CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH(CH3)2, -(CH2)6CH3, - CH2CH2CN, -CH2CN, -CHF2, -CF3, -CH2CH2CF3, -CH2CF3, -CH2CH2F, -CH2CHF2, -CF2CH3, -CH2CH2Cl, -CH2CH2CHF2, -OCH3, -OCH2CH3, -CH2OCH3, - CH2CH2OCH3, -CH2CH2OCH2CF3, -OCHF2, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, phenyl, -CH2CH2Ph, methylpyrazolyl, oxetan-3-ylmethyl, and -CH2SCH3.

19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R2is H, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, - N(C1-3alkyl)2, phenyloxy, benzyloxy, -O-pyridinyl, -O-(methylpyrazolyl), -O- thiazolyl, -O-oxazolyl, -O-CH2-pyridinyl, -O-CH2-(methylpyrazolyl), -O-CH2- oxazolyl, or -O-CH2-thiazolyl.

20. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R2is H, halo, C1-3alkoxy, C1-3haloalkyl, phenyloxy, benzyloxy, -O- pyridinyl, -O-(methylpyrazolyl), -O-thiazolyl, -O-oxazolyl, -O-CH2-pyridinyl, -O- CH2-(methylpyrazolyl), -O-CH2-oxazolyl, or -O-CH2-thiazolyl.

21. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R2is H, halo, C1-3alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy- N(C1-3alkyl)2, or benzyloxy.

22. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein: R2is H, -F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCHF2, -OCF3, - ,23.

24. The compound claim 19, or a pharmaceutically acceptable salt thereof, wherein: R2is H, -F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCHF2, -OCF3, -25. The compound of any one of claims 1 to 5 or 8 to 24, or a pharmaceutically acceptable salt thereof, wherein: X is CRx; Rxis H, halo, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C1-3haloalkoxy, -N(C1-3alkyl)2, phenyl, 5 to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and 5 to 6-membered heterocyclyl containing 1-2 heteroatoms independently selected form N, O, and S, wherein the phenyl, heteroaryl, and heterocyclyl are each optionally substituted with 1 or 2 Rx2;each Rx2is independently halo, cyano, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, C3- 4cycloalkyl, or two Rx2, together with the atoms to which they are attached, form C3-6carbocyclyl or 5 to 6-membered heterocyclyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein: Rxis phenyl, pyrrolidinyl, morpholinyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, wherein the pyrazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl are each optionally substituted with 1 or 3 Rx2.

27. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein: each Rx2is independently -CH3, -CHF2, -CH2CH3, -OCH3, -F,-Cl, -Br, -CN, or cyclopropyl; or two Rx2, together with the atoms to which they are attached, form cyclopentenyl or dihydrofuranyl.

28. The compound of any one of claims 1 to 5 or 8 to 27, or a pharmaceutically acceptable salt thereof, wherein X is CRxand Rxis H, -F, -Cl, -Br, -CH3, -CHF2, -, , , , , , , , , , ,29. The compound of claim 1, wherein the compound is represented by formula (IIIa):or a pharmaceutically acceptable salt thereof, wherein: Rxis halo or 5-to 6-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O, and S, wherein the 5-to 6-membered monocyclic heteroaryl is optionally substituted with 1 to 2 Rx2; each Rx2is independently halo, C1-3alkyl,or C3-4cycloalkyl, or two Rx2, together with the atoms to which they are attached, form C3-6ccarbocyclyl; R2is halo, C1-3alkyl, C1-3alkoxy, or C1-3haloalkyl; Ring A is a 5-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S; R1for each occurrence, is independently selected from halo, OR1a, C1-3allkyl and C1-3haloalkyl; R1ais C1-3alkyl; and n is 1 or 2.

30. The compound of claim 1, wherein the compound is represented by formula (III):or a pharmaceutically acceptable salt thereof, wherein: Rxis halo or 5-to 6-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S, wherein the 5-to 6-membered monocyclic heteroaryl is optionally substituted with 1 to 2 Rx2; each Rx2is independently halo, C1-3alkyl,or C3-4cycloalkyl, or two Rx2, together with the atoms to which they are attached, form C3-6carbocyclyl; Ring A is a 5-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S; R1for each occurrence, is independently selected from halo, OR1a, C1-3allkyl and C1-3haloalkyl; R1ais C1-3alkyl; and n is 1 or 2.

31. The compound of claim 29 or 30, wherein Rxis pyrazolyl optionally substituted with halo.

32. The compound of claim 1, wherein the compound is represented by formula (III):or a pharmaceutically acceptable salt thereof, wherein: Rxis H or Cl; Ring A is a 5-membered monocyclic heteroaryl containing 1-2 heteroatoms independently selected from N, O and S;R1for each occurrence, is independently selected from halo, OR1a, C1-3allkyl and C1-3haloalkyl; R1ais C1-3alkyl; and n is 1 or 2.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein Rxis H.

34. The compound of any one of claims 29 to 33, or a pharmaceutically acceptable salt thereof, wherein ring A is isoxazolyl, pyrazolyl, or isothiazolyl, each of which is substituted with 1 or 2 R1.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein ring A is represented by:

36. The compound of any one of claims 29 to 35, or a pharmaceutically acceptable salt thereof, wherein R1, for each occurrence, is independently selected from -Br, –Cl, - CH2CH3, -CHF2, -CF3, -CH2CH2Cl and -OCH3.

37. The compound of any one of claims 29 to 35, or a pharmaceutically acceptable salt thereof, wherein R1, for each occurrence, is independently selected from –Cl, - CH2CH3, -CHF2, -CF3, -CH2CH2Cl and -OCH3.

38. The compound of any one of claims 29 to 33, or a pharmaceutically acceptable salt thereof, wherein ring A is represented by:wherein R100is C1-3haloalkyl and R101is halo.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R100is -CHF2or -CH2CH2Cl, and R101is Br.

40. The compound of claim 1, wherein the compound is any one of the compounds in Table 1.

41. A compound, wherein the compound is selected from the compounds in Table 1.

42. A pharmaceutical composition comprising a compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

43. A method of regulating GPR17 activity in a subject in need thereof, comprising the step of administrating to the subject in need thereof an effective amount of a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 42.

44. A method of treating a subject suffering from a disease or disorder mediated by GPR17, comprising administrating to the subject an effective amount of a compound of any one of claims 1 to 41, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 42.

45. The method of claim 44, wherein the disease or disorder is selected from a disease or disorder resulting from direct damage to myelin sheaths, a demyelinating disorder, a CNS disorder associated with myelin loss and an inflammation disorder in CNS.

46. The method of claim 45, wherein the disease of disorder is selected from multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

47. The method of claim 46, wherein the disease of disorder is selected from multiple sclerosis.

48. A method of promoting myelination in a subject with a myelin-related disease or disorder comprising administering to the subject an effective amount of a compound of any one of claims 1 to 41, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 42.

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