Indole and pyrrolopyridine derivatives as GPR17 modifiers

Abstract

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

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 532,811, filed on 15 August 2023. The entire contents of the aforementioned application are expressly incorporated herein by reference.

[0002] This invention relates to novel indole and pyrrolopyridine compounds, and their use for treating GPR17-mediated disorders. The invention also relates to pharmaceutical compositions of these compounds, and their use as pharmaceuticals, for example, for the treatment of GPR17-mediated disorders. Furthermore, the invention relates to processes for the preparation of the above compounds. [Background technology]

[0003] 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 that has an intracellular region that binds to numerous intracellular signaling pathways via G proteins. Many GPCRs are used as pharmaceutical and diagnostic targets.

[0004] Effective modulation of GPR17 activity may have neuroprotective, anti-inflammatory, and anti-ischemic effects, and therefore may be useful in the treatment of cerebral ischemia, cardiac ischemia, and renal ischemia, as well as stroke, and / or in improving recovery from these events. Pulmonary fibrosis can also be alleviated by suppressing GPR17-mediated inflammation. GPR17 modifiers are also thought to be involved in food uptake, insulin and leptin responses, and therefore may play a role in the treatment of obesity.

[0005] Furthermore, there is strong evidence that GPR17 is involved in the myelin formation process. Myelin is an essential component of a healthy central nervous system (CNS). Myelin failure, myelin damage, and / or myelin repair failure can cause certain diseases, or be a secondary consequence of certain diseases. One example of a disease that is primarily a result of myelin damage is multiple sclerosis (MS). MS affects approximately 400,000 people in the United States and about 2.5 million people worldwide, and is about three times more common in women than in men. MS is an inflammatory autoimmune disease resulting from an immune attack targeting oligodendrocytes, leading to myelin damage and ultimately loss of neuronal axons. The immediate consequences are a set of acute symptoms, including difficulty with movement, speech, and swallowing, dizziness, and fatigue. Symptoms may also include problems with vision, hearing, or balance. The disease can take several forms. One form involves relapses and remissions, in which the acute symptoms resolve over time. This form is called relapsing-remitting multiple sclerosis (RRMS). Another form of the disease, primary progressive MS (PPMS), is characterized by symptoms not resolving 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, which leads to an increasing burden of disability. Since MS is a CNS disease, it is beneficial that compounds useful in treating MS are brain-permeable (i.e., can cross the blood-brain barrier (BBB)). However, many compounds that target GPR17 have low brain permeability, low stability, and / or high efflux.

[0006] There is a clear need for safe and effective drugs for the treatment of GPR17-mediated diseases such as myelin formation disorders (e.g., MS), preferably drugs suitable for oral administration and with good brain permeability. Furthermore, the compounds should possess excellent GPR17 efficacy and microsomal stability. [Brief explanation of the drawing]

[0007] [Figure 1]Schematic diagram of plasma and PBS buffer solution, including the volume of cultured RED and the volume aliquoted into the crush plate. Summary of the Invention

[0008] Provided herein are compounds or pharmaceutically acceptable salts thereof, and compositions comprising the compounds or pharmaceutically acceptable salts thereof, useful for treating GPR17-mediated disorders. In some embodiments, the compounds of the present disclosure have improved potency, microsomal stability, and / or brain permeability compared to known GPR17 inhibitors.

[0009] In a first aspect of the present disclosure, there is provided a compound represented by formula (I): Chemical Formula or a pharmaceutically acceptable salt thereof, wherein in the formula: X is N or CR x , R x is H, halo, OR x1 , SR x1 , C 1~3 alkyl, C 1~3 haloalkyl, NR x1 R x1 , C(O)R x1a , cyano, C 3~6 cycloalkyl, phenyl, 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, or 4- to 6-membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O and S, wherein phenyl, 5- to 6-membered monocyclic heteroaryl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 R x2 , R x1 is H, C 1~3 alkyl, or C 1~3 haloalkyl, R x1a is OR x1 , NR x1 R x1 , C1~3 Alkyl, or C 1~3 It is a haloalkyl, Each R x2 These are independently: halo, cyano, and C. 1~4 Alkyl, C 1~4 Haloalkyl, OR x1 , NR x1 R x1 , C 3~6 Is it cycloalkyl? or two R's x2 Together with the atoms to which they are bonded, C 3~6 They form carbocyclils or 5-6 member heterocyclils. Ring A is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, a 9 to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, or an 8 to 10-membered bicyclic heterocycline having 1 to 4 heteroatoms independently selected from N, O, and S. R 1 Each instance is independently represented as Halo, -CN, C 1~7 Alkyl, -OR 1a , -NR 1b R 1b , -NR 1b C(O)R 1a -C(O)NR 1b R 1b , -SR 1a , C 3~6 Selected from cycloalkyls, phenyls, 5-6 membered heteroaryls having 1-3 heteroatoms independently selected from N, O, and S, and 4-10 membered heterocyclines having 1-4 heteroatoms independently selected from N, O, and S, C 1~7 Alkyl, C 3~6 Cycloalkyls, phenyls, 5-6 membered heteroaryls, and 4-10 membered heterocyclines each have 1-3 R groups. 10 It is arbitrarily replaced with, R 1a H, C 1~6 Alkyl, C 3~6A cycloalkyl, a phenyl, a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, or a 4-10 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S, C 1~6 Alkyl, C 3~6 Cycloalkyls, phenyls, 5-6 membered heteroaryls, and 4-10 membered heterocyclines are each independently halos and C 1~3 Alkyl and C 1~3 It is optionally substituted with 1 to 3 substituents selected from alkoxys. Each R 1b H and C are independent of each other. 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 A cycloalkyl, a phenyl, a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, or a 4-10 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S, R 10 Each instance is independently determined as: Halo, -CN, -OR 1a , -NR 1b R 1b , -NR 1b C(O)R 1a -C(O)NR 1b R 1b , -SR 1a , C 1~3 Alkyl, C 3~6 Selected from cycloalkyls, phenyls, and 4-6 member saturated heterocyclines having 1-2 heteroatoms independently selected from N, O, and S, C 3~6 Cycloalkyls, phenyls, and 4-6 member saturated heterocyclines each contain one or more halos, C 1~4 Alkyl, C 1~4 They are optionally substituted with haloalkyl, hydroxy, or cyano, R 2 H, Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -NR 2a R 2a , or -OR 2a And, Each R 2a is independently C 1~3 alkyl, C 1~3 haloalkyl, benzyl, phenyl, 5- to 10-membered heteroaryl, or -CH2-(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl contains 1 to 4 heteroatoms independently selected from N, O and S, and is optionally substituted with C 1~3 alkyl, R 3 is H or C 1~3 alkyl, wherein C 1~3 alkyl is optionally substituted with 1 to 3 halo groups, -OR 3a , -C(O)OR 3a , or -C(O)NR 3a R 3a each R 3a is independently H or C 1~3 alkyl, n is 0, 1, 2 or 3, provided that, (i) when one of R 2 and R x is H, the other is not H, (ii) when X is N, R 2 is not H, (iii) when R x is H and R 2 is halo, alkyl or haloalkyl, ring A is

Chemical Formula

Chemical Formula

[0010] ​Another aspect of the present disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the present disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition is for use in the treatment of a disease or disorder mediated by GPR17.

[0011] Another aspect of the present disclosure is a method for controlling GRP17 activity in a subject where such control is required. This method involves administering an effective amount of a pharmaceutical composition to a subject requiring such control, comprising an effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier or excipient and the compound of the present disclosure or a pharmaceutically acceptable salt thereof. The present disclosure also includes the use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof for the manufacture of a pharmacopoeia for controlling GRP17 activity in a subject where such control is required. The present disclosure also provides the compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in controlling GRP17 activity in a subject where such control is required.

[0012] Another aspect of the Disclosure is a method for treating a subject suffering from a GPR17-mediated disease or disorder. The method involves administering to a subject an effective amount of a pharmaceutical composition comprising an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier or excipient and the compound of the Disclosure or a pharmaceutically acceptable salt thereof. The Disclosure also includes the use of the compound of the Disclosure or a pharmaceutically acceptable salt thereof for the manufacture of a pharmacopoeia for treating a subject suffering from a GPR17-mediated disease or disorder. The Disclosure also provides the compound of the Disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of a subject suffering from a GPR17-mediated disease or disorder.

[0013] Another aspect of the present disclosure is a method of promoting myelination in a subject having a myelin-related disease. The method comprises administering to the subject an effective amount of a compound of the present 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 present disclosure or a pharmaceutically acceptable salt thereof. The present disclosure also includes the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for promoting myelination in a subject having a myelin-related disease. The present disclosure also provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in promoting myelination in a subject having a myelin-related disease. Mode for Carrying Out the Invention

[0014] The compound described in the present specification or a pharmaceutically acceptable salt thereof may have activity as a GPR17 modulator. In particular, the compound described in the present specification or a pharmaceutically acceptable salt thereof may be a GPR17 inhibitor.

[0015] In a first embodiment, the compound of the present disclosure has formula (I): Chemical formula represented by, or a pharmaceutically acceptable salt thereof, wherein: X is N or CR x , and R x is H, halo, OR x1 , SR x1 C 1~3 alkyl, C 3~6 cycloalkyl, 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, or 4- to 6-membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O and S, R x1 is H, C 1~3 alkyl, or C 1~3 haloalkyl, Ring A is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, a 9 to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, or a 9 to 10-membered bicyclic heterocycline having 1 to 4 heteroatoms independently selected from N, O, and S. R 1 Each instance is independently represented as Halo, -CN, C 1~7 Alkyl, -OR 1a , -SR 1a , C 3~6 Selected from cycloalkyls, phenyls, 5-6 membered heteroaryls having 1-3 heteroatoms independently selected from N, O, and S, and 4-10 membered heterocyclines having 1-4 heteroatoms independently selected from N, O, and S, C 1~7 Alkyl, C 3~6 Cycloalkyls, phenyls, 5-6 membered heteroaryls, and 4-10 membered heterocyclines each have 1-3 R groups. 10 It is arbitrarily replaced with, R 1a C 1~6 Alkyl, C 3~6 A cycloalkyl, a phenyl, a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, or a 4-10 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S, C 1~6 Alkyl, C 3~6 Cycloalkyls, phenyls, 5-6 membered heteroaryls, and 4-10 membered heterocyclines are each independently halos and C 1~3 Alkyl and C 1~3 It is optionally substituted with 1 to 3 substituents selected from alkoxys. R 10 Each instance is independently determined as: Halo, -CN, -OR 1a , -SR 1a , C 1~3 Alkyl, C 3~6 Selected from cycloalkyls, phenyls, and 4-6 member saturated heterocyclines having 1-2 heteroatoms independently selected from N, O, and S, R 2 H, Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, or -OR 2a And, R 2a C 1~3 Alkyl, C 1~3 Haloalkyl, benzyl, phenyl, 5-10 membered heteroaryl, or -CH2-(5-10 membered heteroaryl), where the 5-10 membered heteroaryl independently contains 1-4 heteroatoms selected from N, O, and S, and C 1~3 It is optionally substituted with alkyl, R 3 is H or C 1~3 It is alkyl, n is 0, 1, or 2.

[0016] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are represented by formula (I) or pharmaceutically acceptable salts thereof, where, X is CR x And, R x Hello, OR x1 , SR x1 , C 1~3 Alkyl, C 1~3 Haloalkyl, NR x1 R x1 , C(O)R x1a , cyano, C 3~6 A cycloalkyl, a phenyl, a 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, or a 4-6 member monocyclic heterocyclil having 1-4 heteroatoms independently selected from N, O, and S, wherein the phenyl, the 5-6 member monocyclic heteroaryl, and the 4-6 member monocyclic heterocyclil each have 1-3 R x2 It is arbitrarily replaced with, R 2 Hello, C 1~3 Alkyl, C 1~3 Haloalkyl, -NR 2a R 2a , or -OR 2aThe remaining variables are as explained in equation (I) above.

[0017] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are represented by formula (I) or a pharmaceutically acceptable salt thereof, where R 3 The molecules are H, -CH3, -CH2CHF2, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2CH2OH, -CH2C(O)OH, or -CH2C(O)NHCH3, and the remaining variables are as described for equation (I) above.

[0018] Alternatively, in some embodiments, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I) or a pharmaceutically acceptable salt thereof, where R 3 is H, and the remaining variables are as explained in equation (I) above.

[0019] In a second embodiment, the compound of the present disclosure is represented by formula (I) or a pharmaceutically acceptable salt thereof, where X is CR x And R x is H, -Cl, or -OCH3, and the remaining variables are as described for equation (I) above.

[0020] In a third embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is of formula (II), [ka] The compound or a pharmaceutically acceptable salt thereof is represented by the formula (I) above, with the variables as described above. Alternatively, as part of a third embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by the formula (IIIa), [ka] It is represented by or a pharmaceutically acceptable salt thereof, with the variables as described for formula (I) above.

[0021] In the fourth embodiment, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are represented by formula (I), (II), or (IIIa), or pharmaceutically acceptable salts thereof, wherein ring A is from the group consisting of pyrazolyl, dihydropyrrolopyrazolyl, dihydropyrazolooxazolyl, dihydropyrazolooxazinyl, pyrazolopyradinyl, pyrazolopyridinyl, pyrazolyl, imidazolyl, imidazothiazolyl, imidazopyridinyl, triazolopyridinyl, isothiazolyl, thiazolyl, dihydrothiopyranothiazolyl, thiadiazolyl, thiophenyl, isoxazolyl, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzolooxazolyl, pyridylisoxazolyl, benzoisoxazolyl, indazolyl, pyrazolopyridinyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, and pyridylpyrazolyl (each of which has 1 to 3 R 1 The compounds are selected from (which are optionally substituted with ), and the remaining variables are as described in the first embodiment or the first, second, or third embodiment. Alternatively, as part of a fourth embodiment, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein ring A is from the group consisting of pyrazolyl, triazolyl, isothiazolyl, thiazolyl, thiadiazolyl, thiophenyl, isoxazolyl, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzolooxazolyl, pyridylisoxazolyl, and pyridylpyrazolyl (each of which has 1 or 2 R 1 The variables are selected from (which are arbitrarily substituted by) and the remaining variables are as described in the first embodiment or the first, second, or third embodiment.

[0022] In the fifth embodiment, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein ring A is given by the following formula: [ka] [ka] Represented by, each of these, has 1 to 3 R 1 The following substitutions are made as appropriate, and the remaining variables are as described in the first embodiment or the first, second, or third embodiment. Alternatively, as part of a fifth embodiment, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are represented by formula (I), (II), or (IIIa), or are pharmaceutically acceptable salts thereof, where ring A is given by the following formula: [ka] Represented by, each of these is represented by 1 or 2 R 1 The variables are arbitrarily substituted, and the remaining variables are as described in the first embodiment or the first, second, or third embodiment.

[0023] In the sixth embodiment, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, wherein ring A is given by the following formula: [ka] [ka] [ka] It is represented by the formula (I), (II), or (IIIa), with the remaining variables as described in the fifth embodiment. Alternatively, as part of the sixth embodiment, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are represented by formula (I), (II), or (IIIa), or pharmaceutically acceptable salts thereof, where ring A is given by the following formula: [ka] This is expressed by the same expression, and the remaining variables are as described in the fifth embodiment.

[0024] In the seventh embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, where, R 1 Each instance is independently represented as Halo, -CN, C 1~7 Alkyl, -OR 1a -C(O)NR 1b R 1b , C 3~6 Selected from cycloalkyls, phenyls, and 5-6 membered monocyclic heteroaryls, C 1~7 Alkyl groups consist of 1 to 3 R groups. 10 It is arbitrarily replaced with C 3~6 Cycloalkyls, phenyls, and 5-6 membered monocyclic heteroaryls are each independently halo and C. 1~3 Alkyl and C 1~3 It is optionally substituted with 1 to 3 groups selected from haloalkyl groups. R 1a C is optionally replaced by H, or 1 to 3 halos. 1~4 It is alkyl, Each R 1b H or C 1~3 It is alkyl, R 10 Each instance is independently determined as: Halo, -CN, -OR 1a , -SR 1a , -NR 1b R 1b -C(O)NR 1b R 1b , -NR 1b C(O)C 1~3 Alkyl, C 3~6 Selected from cycloalkyls, phenyls, and 4-6 member saturated heterocyclines, C 3~6 Cycloalkyl is C 1~3 They are optionally substituted with haloalkyl groups. The remaining variables are as described in the first embodiment or in the first, second, third, fourth, fifth, or sixth embodiments. Alternatively, as part of the seventh embodiment, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are represented by formula (I), (II), or (IIIa), or pharmaceutically acceptable salts thereof, where, R 1 Each instance is independently represented as Halo, -CN, C 1~7 Alkyl, -OR 1a , C 3~6 Selected from cycloalkyl and phenyl, C 1~7 Alkyl groups consist of 1 to 3 R groups. 10 It is arbitrarily replaced with, R 1a C is arbitrarily replaced by 1 to 3 halos. 1~4 It is alkyl, R 10 Each instance is independently determined as: Halo, -CN, -OR 1a , -SR 1a , C 3~6 Selected from cycloalkyls, phenyls, and 4-6 member saturated heterocyclines, The remaining variables are as described in the first embodiment or in the first, second, third, fourth, fifth, or sixth embodiment.

[0025] In the eighth embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, where R 1are, independently for each occurrence, -CH2CN, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CHF2, -CF3, -CH2CH2CF3, -CH2CF3, -CH2CH2F, -CH2CHF2, -CF2CH3, -CH2CH2Cl, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CHFCH2F, -CH 2CF2CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2OCHF2, -CH2CH2OCH2CF3, -CH2CH2CH2OCH2CF3, -CH2CH2CH2OCHF2, -OH, -OCHF2, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, phenyl, -CH2CH2Ph, methylpyrazolyl, oxetane-3-ylmethyl, -CH2SCH3, -C(O)NHCH3, -CH2CH2NHC(O)CH3, -CH2CH2NCH3C(O)CH3, -CH2CH2C(O)NHCH3, [ka] A compound is selected from the above, and the remaining variables are as described in the first embodiment, or in the first, second, third, fourth, fifth, sixth, or seventh embodiment. Alternatively, as part of the eighth embodiment, a compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, where R 1Each instance is independent of the following: -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, -CH2O The compounds are selected from CH3, -CH2CH2OCH3, -CH2CH2OCH2CF3, -OCHF2, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, phenyl, -CH2CH2Ph, methylpyrazolyl, oxetane-3-ylmethyl, and -CH2SCH3, the remaining variables being as described in the first embodiment or in the first, second, third, fourth, fifth, sixth, or seventh embodiments.

[0026] In the ninth embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, where R 2 H, Halo, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Haloalkoxy, -N(C) 1~3 Alkyl)2, phenyloxy, benzyloxy, -O-pyridinyl, -O-(methylpyrazolyl), -O-thiazolyl, -O-oxazolyl, -O-CH2-pyridinyl, -O-CH2-(methylpyrazolyl), -O-CH2-oxazolyl, or -O-CH2-thiazolyl, the remainder of the variables as described in the first embodiment, or in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment. Alternatively, as part of the ninth embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, where R 2 H, Halo, C 1~3 Alkoxy, C 1~3The compounds are haloalkyl, phenyloxy, benzyloxy, -O-pyridinyl, -O-(methylpyrazolyl), -O-thiazolyl, -O-oxazolyl, -O-CH2-pyridinyl, -O-CH2-(methylpyrazolyl), -O-CH2-oxazolyl, or -O-CH2-thiazolyl, the remaining variables being as described in the first embodiment or in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment. Alternatively, as part of the ninth embodiment, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are represented by formula (I), (II), or (IIIa), or pharmaceutically acceptable salts thereof, where R 2 H, Halo, C 1~3 Alkyl, C 1~3 Alkoxy, C 1~3 Haloalkyl, C 1~3 Haloalkoxy-N(C) 1~3 The alkyl)2, or benzyloxy, the remaining variables are as described in the first embodiment, or in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0027] In the tenth embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, where R 2 is H, -F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCHF2, -OCF3, -OCH2CH3, -OCH2CH2CH3, -CHF2, -CF3, -N(CH3)2, [ka] The remaining variables are as described in the ninth embodiment. Alternatively, as part of the tenth embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, where R 2 are H, Cl, Br, -OCH3, -CHF2, -CF3, [ka] The remaining variables are as described in the ninth embodiment. Alternatively, as part of the tenth embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (I), (II), or (IIIa), or a pharmaceutically acceptable salt thereof, where R 2 is H, -F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCHF2, -OCF3, -OCH2CH3, -OCH2CH2CH3, -CHF2, -CF3, -N(CH3)2, or [ka] The remaining variables are as described in the ninth embodiment.

[0028] In some embodiments, the compounds of the disclosed herein or pharmaceutically acceptable salts thereof are represented by formula (I), (II), or (IIIa), or pharmaceutically acceptable salts thereof, where, X is CR x And, R x H, Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Haloalkoxy, -N(C) 1~3 Alkyl)2, phenyl, 5-6 membered heteroaryls having 1-3 heteroatoms independently selected from N, O, and S, and 5-6 membered heterocyclines having 1-2 heteroatoms independently selected from N, O, and S, wherein phenyl, heteroaryl, and heterocycline each have 1 or 2 R x2 It is arbitrarily replaced with, Each R x2 These are independently: halo, cyano, and C. 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 3~4 Is it cycloalkyl? or two R's x2Together with the atoms to which they are bonded, C 3~6 It forms carbocyclils or 5-6 member heterocyclils, and the remaining variables are as described above.

[0029] In some embodiments, the compounds of the disclosed herein or pharmaceutically acceptable salts thereof are represented by formula (I), (II), or (IIIa), or pharmaceutically acceptable salts thereof, where R x These are phenyl, pyrrolidinyl, morpholinyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyridinyl, and pyrimidinyl, where pyrazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyridinyl, and pyrimidinyl each have 1 or 3 R x2 The variables have been arbitrarily replaced, and the remaining variables are as described above.

[0030] In some embodiments, the compounds of the disclosed herein or pharmaceutically acceptable salts thereof are represented by formula (I), (II), or (IIIa), or pharmaceutically acceptable salts thereof, where each R x2 These are independently -CH3, -CHF2, -CH2CH3, -OCH3, -F, -Cl, -Br, -CN, or cyclopropyl, or two R x2 These, together with the atoms to which they are bonded, form cyclopentenyl or dihydrofuranyl, and the remaining variables are as described above.

[0031] In some embodiments, the compounds of the disclosed herein or pharmaceutically acceptable salts thereof are represented by formula (I), (II), or (IIIa), or pharmaceutically acceptable salts thereof, where X is CR x And R x is H, -F, -Cl, -Br, -CH3, -CHF2, -CH2CH3, -CH(CH3)2, -OCH3, -OCHF2, -OCH2CF3, -N(CH3)2, [ka] The remaining variables are as described above.

[0032] In the eleventh embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is of formula (IIIa), [ka] It is represented by or a pharmaceutically acceptable salt thereof, in the formula, R x A halo is a 5-6 member monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, O, and S, and a 5-6 member monocyclic heteroaryl has 1-2 R x2 It is arbitrarily replaced with, Each R x2 It is independently, Halo, C 1~3 Alkyl, or C 3~4 Is it cycloalkyl? or two R's x2 Together with the atoms to which they are bonded, C 3~6 Forms carbocyclyl, R 2 Hello, C 1~3 Alkyl, C 1~3 Alkoxy, or C 1~3 It is a haloalkyl, Ring A is a 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. R 1 Each appearance is independent of the halo, OR 1a , C 1~3 Alkyl and C 1~3 Selected from haloalkyl groups, R 1a C 1~3 It is alkyl, n is either 1 or 2. The remaining variables are as described for formula (I) in the first aspect or first embodiment. Alternatively, as part of the eleventh embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is formula (III), [ka] It is represented by or a pharmaceutically acceptable salt thereof, in the formula, R x A halo is a 5-6 member monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, O, and S, and a 5-6 member monocyclic heteroaryl has 1-2 R x2 It is arbitrarily replaced with, Each R x2 It is independently, Halo, C 1~3 Alkyl, or C 3~4 Is it cycloalkyl? or two R's x2 Together with the atoms to which they are bonded, C 3~6 Forms carbocyclyl, Ring A is a 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. R 1 Each appearance is independent of the halo, OR 1a , C 1~3 Alkyl and C 1~3 Selected from haloalkyl groups, R 1a C 1~3 It is alkyl, n is either 1 or 2. The remaining variables are as described for formula (I) in the first aspect or first embodiment.

[0033] Alternatively, as part of the eleventh embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is of formula (III), [ka] It is represented by or a pharmaceutically acceptable salt thereof, in the formula, R x is either H or Cl, Ring A is a 5-membered monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, O, and S. R 1 Each appearance is independent of the halo, OR 1a , C 1~3 Alkyl and C 1~3 Selected from haloalkyl groups, R 1a C 1~3 It is alkyl, n is either 1 or 2. The remaining variables are as described for formula (I) in the first aspect or first embodiment.

[0034] In some embodiments, the compounds of the disclosed herein or pharmaceutically acceptable salts thereof are represented by formula (III) or (IIIa), or pharmaceutically acceptable salts thereof, where R x R is a pyrazolyl optionally substituted with a halo, and the remaining variables are as described in the 11th embodiment. Alternatively, in some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are represented by formula (III) or (IIIa), or are pharmaceutically acceptable salts thereof, where R x H is H.

[0035] In the twelfth embodiment, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are represented by formula (III) or (IIIa), or pharmaceutically acceptable salts thereof, wherein ring A is isoxazolyl, pyrazolyl, or isothiazolyl, each of which has 1 or 2 R 1 It is replaced with, and the rest of the variables are as described in the 11th embodiment.

[0036] In the thirteenth embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein ring A is given by the following formula: [ka] This is expressed as follows, and the remaining variables are as described in the 11th embodiment.

[0037] In the fourteenth embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, where R 1 Each instance is independently selected from -Cl, -CH2CH3, -CHF2, -CF3, -CH2CH2Cl, and -OCH3, and the remaining variables are as described in the 11th, 12th, or 13th embodiment.

[0038] In the 15th embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is represented by formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, wherein ring A is: [ka] It is expressed by, in the formula, R 100 C 1~3 It is a haloalkyl, R 101 is halo, and the remaining variables are as described in the 11th, 12th, 13th, or 14th embodiment. In some embodiments, R x H is H.

[0039] In the sixteenth embodiment, the compound of the Disclosure or a pharmaceutically acceptable salt thereof is represented by formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, where R 100 is -CHF2 or -CH2CH2Cl, and R 101 is Br, and the remaining variables are as described in the 11th, 12th, 13th, 14th, or 15th embodiment.

[0040] In the 17th embodiment, the compounds of the Disclosure are shown in Table 1 and the Examples below. Their pharmaceutically acceptable salts and corresponding neutral forms are included in the Disclosure. [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 Table 1-67 Table 1-68 Table 1-69 Table 1-70 [Table 1-71] [Table 1-72] [Table 1-73] [Table 1-74] [Table 1-75] [Table 1-76] [Table 1-77] [Table 1-78]

[0041] As used herein, the term “pharmaceutically acceptable salt” means a pharmaceutically acceptable salt that, within the bounds of appropriate medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, and allergic reactions, and is commensurate with a reasonable benefit / risk ratio.

[0042] Pharmaceutically acceptable salts are known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in J. Pharm. Sci. (1977) 66:1-19. Compounds of the present disclosure having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of the present disclosure having an acidic group can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0043] The following abbreviations and terms have the meanings indicated throughout the text.

[0044] The term "alkyl," used alone or as part of larger terms such as "alkoxy," "alkylphenyl," or "alkylspirocycloalkyl," refers to a saturated aliphatic linear or branched monovalent hydrocarbon radical. Unless otherwise specified, alkyl groups typically consist of 1 to 10 carbon atoms (C). 1~10 Alkyl), 1 to 7 carbon atoms (C 1~7 Alkyl), 1 to 6 carbon atoms (C 1~6 Alkyl) (i.e., 1, 2, 3, 4, 5, or 6), or 1 to 4 carbon atoms (C) 1~4 Alkyl) (i.e., 1, 2, 3, or 4), or 1 to 3 carbon atoms (C) 1~3 It has alkyl groups (i.e., 1, 2, or 3). Examples include methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

[0045] The term “alkoxy,” used alone or as part of a larger group such as a haloalkoxy or alkylalkoxy, refers to a saturated aliphatic linear or branched monovalent radical composed of an alkyl group bonded to an oxygen atom. Unless otherwise specified, an alkoxy group typically consists of 1 to 6 carbon atoms and 1 oxygen atom (C). 1~6 Alkyl(alkoxy), or 1 to 4 carbon atoms and 1 oxygen atom (C) 1~3 It contains an alkoxy compound. Examples of alkoxy compounds include methoxy and ethoxy.

[0046] The term "halogen" or "halo" refers to fluorine or fluoro(F), chlorine or chloro(Cl), or bromine or bromo(Br).

[0047] The term “haloalkyl,” used alone or as part of a larger group such as a haloalkoxy or alkylhaloalkoxy, refers to an alkyl group in which at least one hydrogen substituent is replaced by a halogen group. Unless otherwise specified, haloalkyl groups typically consist of 1 to 6 carbon atoms (C 1~6 Haloalkyl, or 1 to 4 carbon atoms (C 1~4 It has a haloalkyl group. Examples include trifluoromethyl, trifluoroethyl, and difluoroethyl.

[0048] When used alone or as part of a larger group such as alkylhaloalkoxy, the term “haloalkoxy” refers to an alkoxy group in which at least one hydrogen substituent is replaced by a halogen. Unless otherwise specified, haloalkoxy typically consists of 1 to 6 carbon atoms (C) 1~6 Haloalkoxy, or 1 to 4 carbon atoms (C 1~4 It has a haloalkoxy. Examples include difluoroethoxy.

[0049] When used alone or as part of a larger group such as alkylcycloalkyl, the term “cycloalkyl” refers to a saturated aliphatic monocyclic hydrocarbon ring radical. Unless otherwise specified, cycloalkyl refers to a ring radical consisting of 3 to 6 carbon atoms (C3-6 cycloalkyl), or 3 to 5 carbon atoms (C3-5 cycloalkyl), or 3 to 4 carbon atoms (C3-4 cycloalkyl). 3~4 It contains a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl and cyclobutyl.

[0050] When used alone or as part of a larger term, the term "carbocyryl" refers to a fully or partially saturated monocyclic hydrocarbon ring radical. Unless otherwise specified, a carbocyryl is defined as a ring radical consisting of 3-6 carbon atoms (C3-6 carbocyryl), 3-5 carbon atoms (C3-5 carbocyryl), or 3-4 carbon atoms (C3-5 carbocyryl). 3~4 It contains carbocyclyl. Examples of carbocyclyl include cyclopropyl, cyclobutyl, cyclopentenyl, and cyclohexenyl.

[0051] The term “heterocyclyl,” used alone or as part of a larger part such as an alkyl heterocyclyl, refers to a non-aromatic, fully or partially saturated monocyclic or bicyclic (condensed, bridging, or spiro) ring radical having 1 to 4 ring heteroatoms independently selected from N, O, or S. In some embodiments, the heterocyclyl is a monocyclic ring radical, e.g., a 4- to 8-membered monocyclic ring radical. In some embodiments, the heterocyclyl is a bicyclic ring radical, e.g., a 9- to 10-membered bicyclic ring radical. Exemplary nitrogen-containing heterocycles include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. Exemplary oxygen-containing heterocycles include oxetanyl, tetrahydrofuranil, and tetrahydropyranil. Exemplary heterocycles containing both N and O include morpholinyl.

[0052] A fused bicyclic ring is a ring system having two rings, each independently selected from either a carbocyclyl or heterocyclyl, where the two ring structures share two adjacent ring atoms. A fused ring can have 9 to 12 ring members.

[0053] A bridging bicyclic ring is a ring system having a carbocykyl or heterocyclyl ring, where two non-adjacent atoms of the ring are linked (bridled) by one or more (preferably 1 to 3) atoms selected from C, N, O, or S. A bridging ring system may have 6 to 8 ring members.

[0054] A spiro ring is a ring system consisting of two rings, each independently selected from either a carbocyclyl or heterocyclyl ring, with the two rings sharing one ring atom. Spiro rings can have 5 to 8 members.

[0055] A "heteroaryl" refers to an aromatic monocyclic or bicyclic ring radical having 1 to 4 ring heteroatoms independently selected from O, N, and S, where N may be oxidized (e.g., N(O)) or quaternized, and S may optionally be oxidized to sulfoxides and sulfones. In some embodiments, the heteroaryl is a monocyclic ring radical, such as a 5-6 member monocyclic ring. In some embodiments, the heteroaryl is a bicyclic ring radical, such as a 9-10 member bicyclic ring. Examples of 5-6 member monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridadinyl. Examples of 9-10 membered bicyclic heteroaryls include, but are not limited to, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzoloxazolyl, pyridylisoxazolyl, and pyridylpyrazolyl.

[0056] The term "substituted" refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent, regardless of whether the term "optionally" precedes it. Therefore, for example, a substituted alkyl is an alkyl group that has at least one non-hydrogen substituent in place of a hydrogen substituent. For example, a monofluoroalkyl group is an alkyl group substituted with a fluoro substituent, and a difluoroalkyl group is an alkyl group substituted with two fluoro substituents. It should be noted that when there are two or more substitutions on a substituent, (unless otherwise specified) each non-hydrogen substituent may be identical or different.

[0057] If a group is described as "optionally substituted," that group may be either (1) unsubstituted or (2) substituted. If a group is described as being optionally substituted with a certain number of non-hydrogen substituents, that group may be either (1) unsubstituted or (2) substituted with the lesser of that certain number of non-hydrogen substituents or the maximum number of substituted positions on the substituent. For example, if a group is described as a cycloalkyl that is optionally substituted with up to three non-hydrogen substituents, any cycloalkyl with fewer than three substituted positions will only be optionally substituted with the same number of non-hydrogen substituents as the cycloalkyl has substituted positions.

[0058] Compounds containing one or more chiral centers can exist in various stereoisomeric forms; that is, each chiral center may have an R configuration, an S configuration, or a mixture of both. Stereoisomers are compounds that differ only in their spatial configuration. Stereoisomers include all diastereomer and enantiomer forms of a compound. Enantiomers are stereoisomers that are mirror images of each other and cannot be superimposed. Diastereomers are stereoisomers that contain two or more chiral centers that are neither identical nor mirror images of each other.

[0059] If the stereochemical configuration at the chiral centers of a compound having one or more chiral centers is represented by its chemical name (e.g., if the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., if the configuration is indicated by a "wedge" bond), then the enrichment of the indicated configuration over the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%.

[0060] "Enrichment of the indicated configuration with respect to the opposite configuration" is expressed in mole percent and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center(s) by the total number of all compounds in the mixture having the same or opposite stereochemical configurations.

[0061] When two or more stereoisomers are represented by a chemical name or structure, and the names or structures are connected by "or," one or the other of the two or more stereoisomers is intended, but not both. The enrichment of one stereoisomer with respect to the other is as described above.

[0062] If a disclosed compound having a chiral center is represented by a structure that does not indicate the composition at the chiral center, that structure means that it encompasses compounds having an S composition at the chiral center, compounds having an R composition at the chiral center, or compounds having a mixture of R and S compositions at the chiral center. If a disclosed compound having a chiral center is represented by its chemical name without indicating the composition at the chiral center with "S" or "R", that chemical name means that it encompasses compounds having an S composition at the chiral center, compounds having an R composition at the chiral center, or compounds having a mixture of R and S compositions at the chiral center.

[0063] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. This instruction encompasses all enantiomerically pure mixtures, enantiomerically enriched mixtures, diastereomerically pure mixtures, diastereomerically enriched mixtures, and racemic mixtures, as well as diastereomeric mixtures of the compounds described herein.

[0064] Enantiomer and diastereomer mixtures can be separated into their enantiomer or stereoisomer components by known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of 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 synthesis methods.

[0065] When a compound is specified by a name or structure that indicates a single enantiomer, unless otherwise specified, the compound is optically pure (also referred to as "enantiomerically pure") by at least 60%, 70%, 80%, 90%, 99%, or 99.9%. Optical purity is calculated by dividing the weight of the mixture of the named or represented enantiomers by the total weight of the mixture of both enantiomers.

[0066] If the stereochemistry of a disclosed compound is named or represented by its structure, and that named or represented structure encompasses two or more stereoisomers (for example, as in the case of a diastereomer pair), it should be understood that, unless otherwise specified, it may contain one of the encompassed stereoisomers or any mixture of the contained stereoisomers. It should also be understood that the stereoisomer purity of the named or represented stereoisomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight. In this case, the stereoisomer purity is determined by dividing the total weight of the mixture of stereoisomers encompassed in the name or structure by the total weight of the mixture of all stereoisomers.

[0067] In some embodiments, the Disclosure provides methods for controlling or modulating GPR17 activity. In some embodiments, the Disclosure further provides methods for inhibiting GPR17 activity in a subject requiring inhibition of GPR17 activity by administering an effective amount of the Compound of the Disclosure to said subject. In some embodiments, the Disclosure relates to the use of the Compound of the Disclosure as a pharmaceutical, preferably for use in the treatment of a GPR17-mediated disease or disorder. In some embodiments, the Disclosure provides methods for treating a subject suffering from a GPR17-mediated disease or disorder by administering an effective amount of the Compound of the Disclosure to said subject.

[0068] As used herein, “GPR17-mediated disease or disorder” or “disease or disorder mediated by GPR17” may be defined as a disease or disorder associated with dysfunction of the GPR17 signaling pathway, such as overexpression and / or overactivity of the GPR17 receptor.

[0069] The terms “myelin formation disorder” or “myelin-related disorder” include demyelination, myelin sheathing disorders, and myelin formation disorders. In some embodiments, the Disclosure provides methods for treating subjects suffering from demyelinating disorders. As used herein, “desylenesis disorder” is a disorder or condition that causes damage to the protective sheath (myelin sheath) surrounding nerve fibers in the brain that lead to the eyes (optic nerves) and spinal cord.

[0070] In some embodiments, the compounds described herein can be used to treat a variety of CNS disorders, including CNS disorders associated with myelin loss and inflammatory disorders in the CNS.

[0071] In some embodiments, the compounds described herein have good brain permeability (i.e., they can cross 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 inhibitors.

[0072] In some embodiments, the compounds of the present disclosure can be used to promote, stimulate, and / or accelerate remyelination or myelin formation in patients who require it.

[0073] In some embodiments, the compounds of the Disclosure may be used to treat 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 Disclosure may be used to treat MS. In some embodiments, MS is relapsing MS.

[0074] As used herein, “relapsing MS” includes clinical isolation syndrome (CIS), relapsing-remitting disease (RRMS), and active secondary progressive disease.

[0075] In some embodiments, the compounds described herein may be used to treat MS selected from relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), non-relapsing SPMS, primary progressive MS (PPMS), clinical isolation syndrome (CIS), and radioactivity separation syndrome (RIS).

[0076] CIS is the initial symptom of neurological symptoms caused by inflammation and demyelination in the central nervous system. By definition, the onset of these symptoms must last for at least 24 hours and is characteristic of multiple sclerosis. However, since some people who have experienced CIS may or may not develop MS, it does not yet meet the diagnostic criteria for MS. If CIS is accompanied by lesions similar to those seen in MS on brain MRI (magnetic resonance imaging), there is a high probability that neurological symptoms will reappear and the patient will be diagnosed with relapsing-remitting MS. If brain MRI does not show MS-like lesions in CIS, the likelihood of that person developing MS is much lower.

[0077] RRMS is the most common disease course of MS and is characterized by well-defined episodes of new or worsening neurological symptoms. These episodes (also called relapses or exacerbations) are followed by periods of partial or complete recovery (remission). During remission, all symptoms may disappear, or some symptoms may persist and become permanent. However, there is no apparent progression of the disease during remission. RRMS can further be characterized as active (with evidence of relapses and / or new MRI activity over a specific period) or inactive, and worsening (with confirmed increase in disability after relapse) or not worsening.

[0078] SPMS follows an initial relapsing-remitting course. Some individuals diagnosed with RRMS eventually progress to a secondary progressive course, experiencing a progressive deterioration of neurological function (accumulation of impairment) over time. SPMS can further be characterized as either active (with evidence of relapse and / or new MRI activity during a specified period) or inactive, and as progressive (with evidence of accumulation of impairment over time, regardless of relapse or new MRI activity) or not progressive.

[0079] PPMS is characterized by a progression of neurological function (accumulation of impairment) from the onset of symptoms without early relapse or remission. PPMS can be further characterized as active (with occasional relapses and / or evidence of new MRI activity over a specific period) or inactive, and as progressive (with evidence of accumulation of impairment over time, regardless of relapse or new MRI activity) or non-progressive.

[0080] Patients diagnosed with RIS do not exhibit any obvious symptoms of MS, but show brain abnormalities similar to those seen in MS patients (e.g., observed on magnetic resonance imaging (MRI)). RIS is often diagnosed during brain scans for unrelated conditions such as headache, migraine, head injury, or stroke. While there is a strong correlation between RIS and MS (RIS often represents the earliest detectable preclinical stage of the disease), RIS patients may not develop MS.

[0081] The compounds of this disclosure may also be useful in the treatment of disorders or syndromes associated with brain tissue injury, cerebrovascular disorders, and certain neurodegenerative diseases. Neurodegenerative disorders have recently been strongly associated with the loss of myelin formation. Therefore, maintaining the functionality of oligodendroglia and myelin is considered an important requirement for preventing axonal and neuronal degeneration. In some embodiments, the compounds of this disclosure can be used in the treatment of neurodegenerative diseases associated with demyelination and / or affected myelin formation, such as muscular dystrophy (ALS), multiple system atrophy (MSA), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0082] The compounds of this disclosure or pharmaceutically acceptable salts thereof may be formulated for administration by any convenient means for use in human medicine or veterinary medicine. In some embodiments, this disclosure provides pharmaceutical compositions comprising the compounds described herein (e.g., the compounds of formula (I) or pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable carrier or excipient.

[0083] The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or dosage form suitable for use in contact with human and animal tissues, within the bounds of appropriate medical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit-to-risk ratio.

[0084] "Pharmacopoeia-acceptable excipients" and "pharmacopoeia-acceptable carriers" refer to substances that can be included in the compositions of the present disclosure without causing any significantly harmful toxic effects to the subject, and which may be used to aid in the formulation and / or administration of activators to a subject, and / or absorption by the subject. Non-limiting examples of pharmacopoeia-acceptable excipients include water, NaCl, ordinary physiological saline, Ringer's lactate solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates, e.g., lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants. Such preparations may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or aromatics, which do not react harmfully with or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutically acceptable excipients are suitable for use with the disclosed compound.

[0085] This formulation can conveniently be provided in single dosage forms and can be prepared by any method well known in the field of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. The amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect.

[0086] Dosage forms for topical or transdermal administration of the compounds of this disclosure or pharmaceutically acceptable salts thereof include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, or inhalants. The active compound may be mixed with a pharmaceutically acceptable carrier and, if necessary, with any preservatives, buffers, or sprays under sterile conditions.

[0087] When the compounds of this disclosure or pharmaceutically acceptable salts thereof are administered to humans and animals as pharmaceuticals, they can be given by themselves or, for example, in combination with a pharmaceutically acceptable carrier as a pharmaceutical composition containing 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient.

[0088] The preparation can be administered topically, orally, percutaneously, rectally, vaginally, parenterally, intranasally, intrapulmonaryly, intraocularly, intramuscularly, intraarterially, intrathecally, intraarticularly, intradermally, intraperitoneally, subcutaneously, subepidermally, or by inhalation.

[0089] The actual dosage levels of the active ingredient in the pharmaceutical compositions of this disclosure may be varied to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response for a particular patient, composition, and mode of administration without harming the patient.

[0090] The term "effective dose" means the amount administered to a subject or patient that, when administered, produces a beneficial or desired outcome, including a clinical outcome, such as inhibiting, suppressing, or reducing the symptoms of the condition being treated in the subject compared to a control. For example, an effective dose can be administered in unit dosage forms (e.g., 0.1 mg to about 50 g per day, or 1 mg to about 5 g per day). The exact amount of compound or a pharmaceutically acceptable salt administered to produce an "effective dose" in a subject will depend on the mode of administration, the type and severity of the disease or condition, as well as the characteristics of the subject, such as the common route of administration, the time of administration, the elimination rate of the specific active ingredient used, the duration of treatment, other drugs, compounds, and / or substances used in combination with the specific active ingredient used, the age, sex, weight, condition, overall health, and medical history of the patient being treated, and other factors well known in the medical field. A physician or veterinarian with ordinary skill in the art can easily determine and prescribe the effective dose of the required pharmaceutical composition. For example, a physician or veterinarian may start with a dose of the compound of the present disclosure used in a pharmaceutical composition at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0091] The terms “administer,” “give delivery,” and “give delivery,” as used herein, refer to methods that may be used to enable the delivery of a composition to a desired site of action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, percutaneous, and rectal administration. Administration techniques that may be employed in conjunction with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA.

[0092] The terms “to treat” or “to cure” any disease or disorder include, in one embodiment, improving the disease or disorder (i.e., preventing or inhibiting the onset of the disease, or reducing at least one of the clinical symptoms of the disease). In another embodiment, “to treat” or “to cure” means improving at least one physical parameter that is based on or related to the disease or disorder to be treated, whether the subject, in particular a human subject, may or may not be recognizable. In yet another embodiment, “to treat” or “to cure” means modulating the disease or disorder either physically (e.g., recognizable stabilization in an unrecognizable symptom), physiologically (e.g., stabilization of a physiological parameter), or both. In yet another embodiment, “to treat” or “to cure” means delaying the onset of the disease or disorder, or delaying, inhibiting, or reducing the likelihood of the disease or disorder progressing. Therefore, “to treat” or “treatment” includes any causal treatment of the underlying disease or disorder (i.e., relief of the disease), any treatment of the signs and symptoms of the disease or disorder (whether or not the disease is regulated), and any relief or improvement of the disease or disorder, or its signs and symptoms.

[0093] The specific mode of administration and regimen will be selected by the attending physician, taking into account the details of the case (e.g., the patient, the disease, the disease state involved, the specific treatment, and whether the treatment is prophylactic). Treatment may involve administration once or multiple times a day, or less than once a day (e.g., once a week or once a month), over a period of several days to several months, or even several years.

[0094] The "subject" or "patient" is a mammal requiring medical treatment, preferably a human, but may also be an animal requiring veterinary treatment, such as a companion animal (e.g., a dog or cat), livestock (e.g., a cow, sheep, pig, or horse), or laboratory animal (e.g., a rat, mouse, or guinea pig). In one embodiment, the patient is a human. In another embodiment, the patient is an adult human. [Examples]

[0095] Abbreviation Abbreviations and acronyms used herein include the following: Acetic acid (ACOH) Boc2O = Di-tert-butyl dicarbonate DAD = Diode Array Detection DAST = Diethylaminosulfur trifluoride DCM = Dichloromethane DIAD = Diisopropyl azodicarboxylate DIPEA = N,N-diisopyruethylamine DMAP = 4-dimethylaminopyridine DMF = Dimethylformamide DMSO = Dimethyl sulfoxide ELSD = Evaporative Light Scattering Detector EA = HCl = ethyl acetate ESI = Electrospray Ionization EtOH = Ethanol FA = Formic Acid HFIP = Hexafluoroisopropanol 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 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 Calculation UPLC = Ultra-high-performance liquid chromatography dppf=1,1'-bis(diphenylphosphin)ferrocene

[0096] General method Unless otherwise stated, the compounds in the examples were purified by analysis or one of the purification methods mentioned below.

[0097] When using preparative TLC or silica gel chromatography, those skilled in the art can select any combination of solvents to purify the desired compound. Silica gel column chromatography uses 20-40 μM (particle size), 250-400 mesh, or 400-632 mesh silica gel with either a Teledyne ISCO Combiflash RF or Grace Reveleris X2 with an ELSD purification system, or passes the solvent through the column using pressurized nitrogen (approximately 10-15 psi) ("flash chromatography").

[0098] When an SCX column is used, the eluent conditions are MeOH followed by methanolic ammonia.

[0099] All reactions were carried out under a nitrogen atmosphere unless otherwise specified. Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum.

[0100] Analysis method ESI-MS data (also reported simply as MS herein) are recorded using a Waters System (Acquity HPLC and Micromass ZQ mass spectrometer), and all reported masses are in m / z for protonated parent ions unless otherwise recorded.

[0101] LC / MS: Samples were dissolved in a suitable solvent such as MeCN, dimethyl sulfoxide (DMSO), or MeOH, and injected directly into the column using an automated sample handler. Analysis was performed using one of the following methods: (1) Acidic method (runs of 1.5, 2, 3.5, 4, or 7 minutes; see the Acidic LCMS section below for additional details): performed using a Waters Acquity UPLC BEH (MS ionization: ESI) instrument equipped with a Shimadzu 2010 series, Shimadzu 2020 series, or C18 column (2.1 mm × 30 mm, 3.0 mm, or 2.1 mm × 50 mm, C18, 1.7 μm), eluted with 1.5 mL / 4 L of trifluoroacetic acid (TFA) and 0.75 mL / 4 L of TFA / MeCN (solvent B) in water (solvent A); or (2) Basic method (runs of 3, 3.5, or 7 minutes; see the Basic LCMS section below for additional details): Shimadzu 2020 series or XBridge Shield The procedure was performed using a Waters Acquity UPLC BEH (MS ionization: ESI) instrument equipped with an RP18, 5 μm column (2.1 mm × 30 mm, inner diameter 3.0 mm) or a 2.1 mm × 50 mm, C18, 1.7 μm column, and elution was performed with 2 mL / 4 L NH3H2O ​​in water (solvent A) and MeCN (solvent B).

[0102] This disclosure further includes any modifications of the process in which the reactants are used in the form of their salts or optically pure substances. The compounds and intermediates of this disclosure can also be interconverted according to methods commonly known to those skilled in the art.

[0103] SFC analysis separation Instrument: Waters UPC2 analytical SFC (SFC-H). Column: ChiralCel OJ, 150 × 4.6 mm I.D., 3 μm. Mobile phase: CO2 in A, ethanol (0.05% DEA) in B. Gradient: B 40%. Flow rate: 2.5 mL / min. Back pressure: 100 bar. Column temperature: 35°C, Wavelength: 220 nm.

[0104] Detectors: Gilson UV / VIS-156 for UV detection at 220 / 254 nm, and Gilson 281 automated acquisition using acidic, basic, and neutral methods. ACQUITY QDa Mass Detector (Waters Corporation) is used for mass-directional peak acquisition.

[0105] Preparative SFC purification Instrument: MG III preparative SFC (SFC-1). Column: ChiralCel OJ, 250×30mm ID, 5μm. Mobile phase: CO2 in A, ethanol (0.1% NH3H2O) in B. Gradient: B 50%. Flow rate: 40mL / min. Back pressure: 100bar. Column temperature: 38℃, wavelength: 220nm. Cycle time: approximately 8 minutes.

[0106] Column: Chiralpak AD-H; 250mm x 30mm, 5mm; 40% (EtOH + 0.1% DEA) / CO2 Column: Chiralpak IA; 250mm x 30mm, 5mm; 40% (MeOH + 0.1% DEA) / CO2 Column: Chiralpak IB; 250mm x 30mm, 5mm; 40% (EtOH + 0.1% DEA) / CO2 Column: Chiralpak AD-H; 250mm x 30mm, 5mm; 40% (EtOH + 0.1% NH4OH) / CO2 Column: Chiralpak OJ-H; 250mm x 30mm, 5mm; 30% (EtOH + 0.1% NH4OH) / CO2 Column: Chiralpak OD; 250mm x 30mm, 5mm; 35% (EtOH + 0.1% NH4OH) / CO2

[0107] 1 H-NMR 1 The ¹H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structure in all cases. ¹H NMR spectra were recorded on Bruker Avance III HD 500 MHz, Bruker Avance III 500 MHz, Bruker Avance III 400 MHz, Varian-400V NMRS, or Varian-400MR. Characteristic chemical shifts (δ) are shown in parts per million from tetramethylsilane to low field, using conventional abbreviations for the names of the main peaks: e.g., s (singular), d (double), t (tripular), q (quadruple), dd (double double), dt (triple double), m (multiple), br (broad). 1 (For H-NMR). The following abbreviations are commonly used for solvents: CDCl3, deuterated chloroform; DMSO-d6, hexadeutate dimethyl sulfoxide; and MeOH-d4, deuterated methanol. If necessary, tautomers may be recorded in the NMR data, and some interchangeable protons may not be visible.

[0108] Typically, compounds of formula (I) can be prepared according to the scheme provided below. The following examples illustrate the present invention without limiting its scope. A method for preparing such compounds will now be described.

[0109] Preparation of intermediates: Preparation 1: 1-(2-chloroethyl)-5-(difluoromethyl)-1H-pyrazole-4-amine [ka] Step a: 4-nitro-1H-pyrazole-5-carboxylate methyl (1.00 g, 584 mmol, 1.0 equivalent), compound 1-bromo-2-chloroethane (1.26 g, 8.77 mmol, 1.5 equivalents), and K2CO3 (2.42 g, 17.53 mmol, 3.0 equivalents) were dissolved in MeCN (15.0 mL) at 20°C. The mixture was stirred at 50°C for 16 hours. The mixture was filtered and concentrated under vacuum to obtain the residue, which was purified by column chromatography to obtain 1-(2-chloroethyl)-4-nitro-1H-pyrazole-5-carboxylate methyl (360.00 mg, yield 26.37%). 1 H 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).

[0110] Step b: To a solution of methyl 1-(2-chloroethyl)-4-nitro-1H-pyrazole-5-carboxylate (160.00 mg, 684.91 μmol, 1.0 equivalent) and CaCl2 (76.01 mg, 684.91 μmol, 1.0 equivalent) in EtOH (2.0 mL), NaBH4 (51.82 mg, 1.37 mmol, 2.0 equivalent) was added 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) and dried over Na2SO4. The filtrate was concentrated under vacuum to obtain (1-(2-chloroethyl)-4-nitro-1H-pyrazole-5-yl)methanol (86.00 mg, yield 61.07%). 1 H 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).

[0111] Step c: To a solution of (1-(2-chloroethyl)-4-nitro-1H-pyrazole-5-yl)methanol (86.00 mg, 418.29 μmol, 1.0 equivalent) in DCM (10.0 mL), MnO2 (727.30 mg, 8.37 mmol, 20.0 equivalents) was added 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 obtain 1-(2-chloroethyl)-4-nitro-1H-pyrazole-5-carbaldehyde (60.00 mg, yield 70.46%). 1 H 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).

[0112] Step d: To a solution of 1-(2-chloroethyl)-4-nitro-1H-pyrazole-5-carboaldehyde (60.00 mg, 294.72 μmol, 1.0 equivalent) in DCM (4.0 mL), DAST (95.01 mg, 589.44 μmol, 2.0 equivalents) was added dropwise at 0°C. The mixture was stirred at 20°C for 16 hours. The mixture was quenched with aqueous NaHCO3 solution (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 under vacuum to obtain a residue, which was purified by preparative TLC to obtain 1-(2-chloroethyl)-5-(difluoromethyl)-4-nitro-1H-pyrazole (45.00 mg, yield 67.69%). 1 H 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).

[0113] Step e: To a solution of 1-(2-chloroethyl)-5-(difluoromethyl)-4-nitro-1H-pyrazole (35.00 mg, 155.16 μmol, 1.0 equivalent) in MeOH (5.0 mL), Pd / C (16.51 mg, 15.52 μmol, 10% purity, 0.1 equivalent) was added under H2 (30 Psi) at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was filtered and concentrated under vacuum to obtain 1-(2-chloroethyl)-5-(difluoromethyl)-1H-pyrazole-4-amine (44.00 mg, crude). LCMS m / z = 195.8 [M+H] + 1 H 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).

[0114] Preparation 2: 5-Chloro-1-(trifluoromethyl)-1H-pyrazole-4-amine [ka] To a solution of 1-(trifluoromethyl)-1H-pyrazole-4-amine (70 mg, 373.23 μmol, HCl, 1.0 equivalent) in ACN (2 mL), NCS (49.84 mg, 373.23 μmol, 1.0 equivalent) was added and the mixture was stirred at 25°C for 2 hours. The mixture was quenched with saturated Na₂SO₃ aqueous solution (10 mL). The mixture was extracted with RINKAN (50 mL x 2), dried over Na₂SO₄, filtered, and concentrated to obtain 5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-amine (69 mg, crude). The crude product was used in the next step without purification. LCMS m / z = 186.1 [M+H] +

[0115] Preparation 3: 4-amino-1-heptyl-1H-pyrazole-5-carbonitrile [ka] Step a: To a solution of 4-nitro-1H-pyrazole-5-carbonitrile (300 mg, 2.17 mmol, 1.0 equivalent) and 1-iodoheptane (491.22 mg, 2.17 mmol, 356.21 μL, 1.0 equivalent) in MeCN (5 mL), K2CO3 (900.82 mg, 6.52 mmol, 3.0 equivalent) was added 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  (10 mL × 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 1-heptyl-4-nitro-1H-pyrazole-5-carbonitrile (100 mg, yield 19.48%). 1 H 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).

[0116] Step b: To a solution of 1-heptyl-4-nitro-1H-pyrazole-5-carbonitrile (50 mg, 211.62 μmol, 1.0 equivalent) in EtOH (5 mL), Fe (59.10 mg, 1.06 mmol, 7.52 μL, 5.0 equivalent) and NH4Cl (56.60 mg, 1.06 mmol, 5.0 equivalent) were added at 25°C. The mixture was stirred at 80°C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain 4-amino-1-heptyl-1H-pyrazole-5-carbonitrile (40 mg, yield 79.07%, purity 86.3%). LCMS m / z = 207.3 [M+H] + 1 H 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).

[0117] Preparation 4: 1-Heptyl-5-(trifluoromethyl)-1H-pyrazole-4-amine [ka] 1-heptyl-5-(trifluoromethyl)-1H-pyrazole-4-amine (40 mg, 8% yield in 2 steps) was obtained from 4-nitro-5-(trifluoromethyl)-1H-pyrazole and 1-iodoheptane using the same procedure as described in Preparation 3. LCMS m / z = 250.3 [M+H] +

[0118] Preparation 5: 5-Chloro-1-heptyl-1H-pyrazole-4-amine [ka] 5-chloro-1-heptyl-1H-pyrazole-4-amine (60 mg, 13% yield in 2 steps) was obtained from 5-chloro-4-nitro-1H-pyrazole and 1-iodoheptane using the same procedure as described in Preparation 3. LCMS m / z = 216.0 [M+H] +

[0119] Preparation 6: 5-Chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-amine [ka] 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-amine (40 mg, 16% yield in 2 steps) was obtained from 5-chloro-4-nitro-1H-pyrazole and 2,2-difluoroethyltrifluoromethanesulfonic acid using the same procedure as described in Preparation 3. LCMS m / z = 182.0 [M+H] +

[0120] Preparation 7: 5-Chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-amine [ka] 1-(2,2-difluoroethyl)-5-(trifluoromethyl)-1H-pyrazole-4-amine (40 mg, 6% yield in 2 steps) was obtained from 4-nitro-5-(trifluoromethyl)-1H-pyrazole and 2,2-difluoroethyltrifluoromethanesulfonic acid using the same procedure as described in Preparation 3. LCMS m / z = 215.9 [M+H] +

[0121] Preparation 8: 4-amino-1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carbonitrile [ka] 4-amino-1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carbonitrile (40 mg, 10% yield in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and 1,1,1-trifluoro-3-iodopropane using the same procedure as described in Preparation 3. LCMS m / z = 204.8 [M+H] +

[0122] Preparation 9: 4-amino-1-(2-fluoroethyl)-1H-pyrazole-5-carbonitrile [ka] 4-amino-1-(2-fluoroethyl)-1H-pyrazole-5-carbonitrile (58 mg, 13% yield in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and 1-fluoro-2-iodoethane using the same procedure as described in Preparation 3. LCMS m / z = 155.3 [M+H] +

[0123] Preparation 10: 5-Chloro-1-(2-chloroethyl)-1H-pyrazole-4-amine [ka] 4-amino-1-(2-chloroethyl)-1H-pyrazole-5-carbonitrile (30 mg, 9% yield in 2 steps) was obtained from 5-chloro-4-nitro-1H-pyrazole and 1-bromo-2-chloroethane using the same procedure as described in Preparation 3. LCMS m / z = 180.0 [M+H] +

[0124] Preparation 11: 4-amino-1-(cyanomethyl)-1H-pyrazole-5-carbonitrile [ka] 4-amino-1-(cyanomethyl)-1H-pyrazole-5-carbonitrile (53 mg, 13% yield in 2 steps, 85% purity) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and 2-bromoacetonitrile using the same procedure as described in Preparation 3. LCMS m / z = 148.0 [M+H] + 1 H NMR: (400 MHz, DMSO) δ: 7.41 (s, 1H), 5.58 (s, 2H), 5.46 (s, 2H).

[0125] Preparation 12: 1-(2-chloroethyl)-5-(trifluoromethyl)-1H-pyrazole-4-amine [ka] 1-(2-chloroethyl)-5-(trifluoromethyl)-1H-pyrazole-4-amine (30 mg, 5% yield in 2 steps) was obtained from nitro-5-(trifluoromethyl)-1H-pyrazole and 1-bromo-2-chloroethane using the same procedure as described in Preparation 3. LCMS m / z = 213.9 [M+H] +

[0126] Preparation 13: 4-amino-1-(chloropropylmethyl)-1H-pyrazole-5-carbonitrile [ka] 4-amino-1-(chloropropylmethyl)-1H-pyrazole-5-carbonitrile (120 mg, 31% yield in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and (bromomethyl)cyclopropane using the same procedure as described in Preparation 3. LCMS m / z = 163.3 [M+H] +

[0127] Preparation 14: 4-amino-1-(2-chloroethyl)-1H-pyrazole-5-carbonitrile [ka] 4-amino-1-(2-chloroethyl)-1H-pyrazole-5-carbonitrile (20 mg, 2% yield in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and 1-bromo-2-chloroethane using the same procedure as described in Preparation 3. LCMS m / z = 170.7 [M+H] + 1 H 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).

[0128] Preparation 15: 5-Chloro-1-cyclopropyl-1H-pyrazole-4-amine [ka] To a solution of 5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole (30 mg, 159.93 μmol, 1.0 equivalent) in EtOH (2 mL) and water (0.5 mL), iron (44.66 mg, 799.64 μmol, 5.0 equivalents) and ammonium hydrochloride (25.66 mg, 479.79 μmol, 3.0 equivalents) were added. The reaction mixture was stirred at 80°C for 1 hour. The mixture was filtered, and the filtrate was extracted with  (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under vacuum. The residue was purified by column chromatography to obtain compound 5-chloro-1-cyclopropyl-1H-pyrazole-4-amine (20 mg, yield 79.35%). 1 HNMR: (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).

[0129] Preparation 16: 5-Chloro-1-(2,2-difluoropropyl)-1H-pyrazole-4-amine [ka] Step a: To a solution of compound 2,2-difluoropropan-1-ol (2 g, 20.82 mmol, 1.0 equivalent) and TEA (2.74 g, 27.06 mmol, 3.77 mL, 1.3 equivalents) in DCM (100 mL), trifluoromethanesulfonic anhydride (7.05 g, 24.98 mmol, 4.20 mL, 1.2 equivalents) was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with H2O (60 mL), extracted with DCM (60 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2,2-difluoropropyltrifluoromethanesulfonic acid (3.5 g, crude).

[0130] Step b: 2,2-difluoropropyltrifluoromethanesulfonic acid (1.01 g, 4.42 mmol, 1.0 equivalent) was added at 25°C to a solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol, 1.0 equivalent) and K2CO3 (1.83 g, 13.27 mmol, 3.0 equivalent) in MeCN (10 mL). The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was diluted with H2O (20 mL), extracted with siRNA (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 1-(2,2-difluoropropyl)-4-nitro-1H-pyrazole (530 mg, yield 58.89%, purity 93.9%). LCMS m / z = 192.0 [M+H] + 1 H 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).

[0131] Step c: To a solution of 1-(2,2-difluoropropyl)-4-nitro-1H-pyrazole (500 mg, 2.62 mmol, 1.0 equivalent) and NH4Cl (699.66 mg, 13.08 mmol, 5.0 equivalents) in EtOH (6 mL) and water (2 mL) at 25°C, Fe (730.50 mg, 13.08 mmol, 5.0 equivalents) was added. 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 obtain 1-(2,2-difluoropropyl)-1H-pyrazole-4-amine (400 mg, crude).

[0132] Step d: To a solution of 1-(2,2-difluoropropyl)-1H-pyrazole-4-amine (400 mg, 2.48 mmol, 1.0 equivalent) in DCM (3 mL), TEA (753.50 mg, 7.45 mmol, 1.04 mL, 3.0 equivalent) and Boc2O (541.72 mg, 2.48 mmol, 570.23 μL, 1.0 equivalent) were added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (20 mL), extracted with DCM (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce (1-(2,2-difluoropropyl)-1H-pyrazole-4-yl)carbamate tert-butyl (550 mg, yield 83.82%, purity 98.8%). LCMS m / z = 262.0 [M+H] + 1 H 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).

[0133] Step e: (1-(2,2-difluoropropyl)-1H-pyrazole-4-yl)carbamate tert-butyl (150 mg, 574.12 μmol, 1.0 equivalent) and NCS (114.99 mg, 861.19 μmol, 1.5 equivalents) were dissolved 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), extracted with ELISA (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce (5-chloro-1-(2,2-difluoropropyl)-1H-pyrazole-4-yl)carbamate tert-butyl (120 mg, yield 69.88%, purity 98.9%). LCMS m / z = 295.9 [M+H] + 1 H 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).

[0134] Step f: Tert-butyl (5-chloro-1-(2,2-difluoropropyl)-1H-pyrazole-4-yl)carbamate (100 mg, 338.17 μmol, 1.0 equivalent) was dissolved in HCl (2 M, 169.08 μL, ethylethanol) at 25°C. The reaction mixture was stirred at 25°C for 30 minutes. The mixture was concentrated to obtain compound 5-chloro-1-(2,2-difluoropropyl)-1H-pyrazole-4-amine (60 mg, crude) as a white solid. LCMS m / z = 195.9 [M+H] +

[0135] Preparation 17: 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-amine [ka] Step a: To a solution of compound 1-methyl-4-nitro-1H-pyrazole-5-carboxylate methyl (200.00 mg, 1.08 mmol, 1.0 equivalent) and CaCl2 (119.89 mg, 1.08 mmol, 1.0 equivalent) in EtOH (2 mL), NaBH4 (81.74 mg, 2.16 mmol, 2.0 equivalent) was added 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) and dried over Na2SO4. The filtrate was concentrated under vacuum to obtain the mixture (1-methyl-4-nitro-1H-pyrazole-5-yl)methanol (130.00 mg, yield 76.59%). 1 H 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).

[0136] Step b: To a solution of compound (1-methyl-4-nitro-1H-pyrazole-5-yl)methanol (130.00 mg, 827.36 μmol, 1.0 equivalent) in DCM (10 mL), MnO2 (1.44 g, 16.55 mmol, 20.0 equivalents) was added 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 obtain compound 1-methyl-4-nitro-1H-pyrazole-5-carboaldehyde (120.00 mg, yield 93.51%). 1 H NMR: (500MHz, DMSO) δ: 10.24 (s, 1H), 8.40 (s, 1H), 4.09 (s, 3H).

[0137] Step c: To a solution of compound 1-methyl-4-nitro-1H-pyrazole-5-carboaldehyde (120.00 mg, 773.64 μmol, 1.0 equivalent) in DCM (5 mL), DAST (249.40 mg, 1.55 mmol, 2.0 equivalents) was added dropwise at 0°C. The mixture was stirred at 20°C for 2 hours. The mixture was quenched with aqueous NaHCO3 solution (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 under vacuum to obtain the residue, which was purified by column chromatography to obtain compound 5-(difluoromethyl)-1-methyl-4-nitro-1H-pyrazole (90.00 mg, yield 65.68%). 1 H NMR: (400MHz, DMSO) δ: 8.41 (s, 1H), 7.72-7.46 (m, 1H), 4.07-4.06 (m, 3H).

[0138] Step d: To a solution of compound 5-(difluoromethyl)-1-methyl-4-nitro-1H-pyrazole (45.00 mg, 254.08 μmol, 1.0 equivalent) in MeOH (3.0 mL), Pd / C (27.04 mg, 25.41 μmol, 10% purity, 0.1 equivalent) was added under H2 (15 Psi) at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was filtered and concentrated under vacuum to obtain compound 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-amine (30.00 mg, crude). LCMS m / z = 148.2 [M+H] +

[0139] Preparation 18: 5-Chloro-1-(difluoromethyl)1H-pyrazole-4-amine [ka] Step a. 1-(difluoromethyl)pyrazole-4-amine (6.30 g, 47.3 mmol) was added to a 500 mL round-bottom flask. The starting material was dissolved in DCM (240 mL), and the flask was completely purged with N2. Then, triethylamine (10.06 g, 99.40 mmol, 13.85 mL) was added, and the solution was stirred for approximately 5 minutes. After that, Boc2O (11.36 g, 52.07 mmol, 11.96 mL) was added by syringe. The resulting reaction mixture was stirred at room temperature for 4 days, and then concentrated directly under reduced pressure. The crude product was purified by silica gel chromatography to supply tert-butyl (1-(difluoromethyl)-1H-pyrazole-4-yl)carbamate (8.65 g, 37.1 mmol, yield 78.4%). LCMS m / z = 234.1 [M+H] +

[0140] Step b. A 30 mL scintillation vial containing tert-butyl (1-(difluoromethyl)-1H-pyrazole-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 an N2 atmosphere. Next, NCS (3.04 g, 22.8 mmol) was slowly added in small portions over approximately 1 minute. The vial was removed from the ice bath and stirred at room temperature for 2 hours. The reaction mixture was then concentrated directly under reduced pressure to obtain the crude product, which was purified by column chromatography to supply tert-butyl (5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)carbamate (1.59 g, 5.94 mmol, yield 78.3%). LCMS m / z = 268.0 [M+H] +

[0141] Step c. To a 30 mL scintillation vial containing tert-butyl (5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)carbamemate (1.14 g, 4.26 mmol), HFIP (21.3 mL) was added, followed by TFA (0.67 mL, 8.72 mmol). Stirring was continued at room temperature for 2 hours, after which the reaction product was directly concentrated under reduced pressure to obtain 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine. The material was used without further purification, assuming a quantitative yield. LCMS m / z = 168.0 [M+H] +

[0142] Preparation 19: 5-Chloro-1-cyclobutyl-1H-pyrazole-4-amine [ka] Step a. 4-nitro-1H-pyrazole (500 mg, 4.42 mmol) and bromocyclobutane (597 mg, 4.42 mmol) were dissolved in DMF (8.84 mL) and Cs2CO3 (2.16 g, 6.63 mmol) was added. The solution was then heated to 60°C for 16 hours and then cooled to room temperature. The solution was diluted with brine and siRNA, and the organic matter was extracted three times. The solution was then dried over Na2SO4. The organic matter was concentrated and purified by column chromatography to produce 1-cyclobutyl-4-nitro-1H-pyrazole (739 mg, 2.67 mmol, 60% yield). LCMS m / z = 168.0 [M+H] + 1 H 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)

[0143] Step b: To a solution of 1-cyclobutyl-4-nitro-1H-pyrazole (330 mg, 1.97 mmol) in THF (4 mL) at -78°C, NaHMDS (1 M, 2.17 mmol, 2.17 mL) was added dropwise. The solution was stirred at this temperature for 30 minutes, after which NCS (395 mg, 2.96 mmol) was added. The solution was stirred for another 30 minutes, and the reaction product was quenched with a saturated aqueous solution of ammonium chloride. The mixture was extracted with siRNA, dried over sodium sulfate, and then concentrated. The resulting residue was purified by column chromatography to obtain 5-chloro-1-cyclobutyl-4-nitro-1H-pyrazole (180 mg, 0.89 mmol, 45% yield). 1 H 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).

[0144] 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), iron powder (499 mg, 8.93 mmol) was added, and the resulting solution was heated at 70°C for 2 hours. The solution was then cooled to room temperature and concentrated. The residue was dissolved again in water, and organic matter was extracted with RINKAN. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to obtain 5-chloro-1-cyclobutyl-1H-pyrazole-4-amine (153 mg, 0.39 mmol, yield 44%). LCMS m / z = 171.9 [M+H] + 1 H 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).

[0145] Preparation 20: 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile [ka] 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile (53 mg, 18.3% yield in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and iodoethane using the same procedure as described in Preparation 3. LCMS m / z = 137.4 [M+H] + 1 H 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).

[0146] Preparation 21: 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile [ka] 4-amino-1-(oxetane-3-ylmethyl)-1H-pyrazole-5-carbonitrile (80 mg, 20.6% yield in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and 3-(bromomethyl)oxetane using the same procedure as described in Preparation 3. LCMS m / z = 179.0 [M+H] +

[0147] Preparation 22: 4-amino-1-isopropyl-1H-pyrazole-5-carbonitrile [ka] 4-amino-1-isopropyl-1H-pyrazole-5-carbonitrile (50 mg, 14.7% yield in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and 2-iodopropane using the same procedure as described in Preparation 3. LCMS m / z = 150.8 [M+H] + 1 H 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).

[0148] Preparation 23: 5-Chloro-1-(cyclopropylmethyl)-1H-pyrazole-4-amine [ka] 5-chloro-1-(chloropropylmethyl)-1H-pyrazole-4-amine (38 mg, 5.4% yield in 2 steps) was obtained from 5-chloro-4-nitro-1H-pyrazole and (bromomethyl)cyclopropane using the same procedure as described in Preparation 3. LCMS m / z = 150.8 [M+H] + 1 H 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).

[0149] Preparation 24: 1-(cyclopropylmethyl)-5-(trifluoromethyl)-1H-pyrazole-4-amine [ka] 1-(cyclopropylmethyl)-5-(trifluoromethyl)-1H-pyrazole-4-amine (20 mg, 5.9% yield in 2 steps) was obtained from 4-nitro-5-(trifluoromethyl)-1H-pyrazole and (bromomethyl)cyclopropane using the same procedure as described in Preparation 3. LCMS m / z = 205.7 [M+H] +

[0150] Preparation 25: 4-amino-1-propyl-1H-pyrazole-5-carbonitrile [ka] 4-amino-1-propyl-1H-pyrazole-5-carbonitrile (123 mg of crude product in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and 1-iodopropane using the same procedure as described in Preparation 3. LCMS m / z = 151.3 [M+H] +

[0151] Preparation 26: 4-amino-1-(2-cyclopropylethyl)-1H-pyrazole-5-carbonitrile [ka] 4-amino-1-(2-cyclopropylethyl)-1H-pyrazole-5-carbonitrile (40 mg, 13.9% yield in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and (2-iodoethyl)cyclopropane using the same procedure as described in Preparation 3. LCMS m / z = 176.8 [M+H] +

[0152] Preparation 27: 4-amino-1-(cyclobutylmethyl)-1H-pyrazole-5-carbonitrile [ka] Following the same procedure as described in Preparation 3, 4-amino-1-(chlorobutylmethyl)-1H-pyrazole-5-carbonitrile (50 mg of crude product in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and (bromomethyl)cyclobutane. LCMS m / z = 177.1 [M+H] +

[0153] Preparation 28: 6,7-Dichloro-1H-indole-3-sulfonyl chloride [ka] Step a: To a solution of compound 1,2-dichloro-3-nitrobenzene (8.0 g, 41.67 mmol) in THF (300 mL), magnesium vinyl bromide (1 M, 167 mL) was slowly added at -78°C, and the mixture was stirred at -78°C for 4 hours under an N2 atmosphere. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution and extracted with siRNA (200 mL x 3). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to obtain a residue, which was purified by column chromatography to obtain 6,7-dichloro-1H-indole (4.98 g, 26.8 mmol, yield 64.2%). 1 H 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).

[0154] Step b: To a solution of 6,7-dichloro-1H-indole (4.98 g, 26.8 mmol) in MeCN (100 mL), sulfonic chloride (15.60 g, 133.8 mmol, 8.90 mL) was slowly added at 0°C, and the mixture was stirred at 20°C for 2 hours under an N2 atmosphere. The reaction mixture was added dropwise to ice water and stirred at 20°C for 0.5 hours. The mixture was filtered and washed with water (300 mL x 2) to obtain a filter cake, which was concentrated to obtain 6,7-dichloro-1H-indole-3-sulfonyl chloride (4.76 g, 15.3 mmol, yield 57.2%). 1 H 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).

[0155] Preparation 29: 7-Bromo-6-chloro-1H-indole-3-sulfonyl chloride [ka] Step a: 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 dropwise to sulfonic acid chloride (2.73 g, 23.4 mmol, 1.56 mL). The solution was kept in an ice bath for 1 hour, removed, and then stirred at 20°C for 2 days. Next, the reaction mixture was poured into ice water and extracted three times with dimethyl phosphate. The combined organic matter was dried over sodium sulfate and concentrated under vacuum to supply 7-bromo-6-chloro-1H-indole-3-sulfonyl chloride, which was used without further purification, based on an estimated quantitative yield (2.14 g). LCMS m / z = 327.7 [M+H] +

[0156] Preparation 30: 4-amino-1-(2-methoxyethyl)-1H-pyrazole-5-carbonitrile [ka] Following the same procedure as described in Preparation 3, 4-amino-1-(2-methoxyethyl)-1H-pyrazole-5-carbonitrile (87 mg crude product, 14.1% yield in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and 1-bromo-2-methoxyethane. LCMS m / z = 167.2 [M+H] +

[0157] Preparation 31: 4-amino-1-(2,2-difluoroethyl)-1H-pyrazole-5-carbonitrile [ka] Following the same procedure as described in Preparation 3, 4-amino-1-(2,2-difluoroethyl)-1H-pyrazole-5-carbonitrile (38.0 mg crude product, 10.0% in 2 steps) was obtained from 4-nitro-1H-pyrazole-5-carbonitrile and 1,1-difluoro-2-iodoethane. LCMS m / z = 173.0 [M+H] +

[0158] Preparation 32: 5-Chloro-1-(2,3-difluoropropyl)-1H-pyrazole-4-amine [ka] Step a: To a solution of 4-nitro-1H-pyrazole-5-carbonitrile (2.0 g, 17.7 mmol, 1.0 equivalent) and 3-chloropropane-1,2-diol (2.93 g, 26.5 mmol, 1.5 equivalent) in DMF (100 mL), K2CO3 (4.89 g, 35.4 mmol, 2.0 equivalent) and KI (293.6 mg, 1.77 mmol, 0.1 equivalent) were added at 20°C. The mixture was stirred at 90°C for 2 hours. The reaction product was quenched with water (20 mL) and extracted with siRNA (10 mL x 3). The combined organic layer was washed with brine (20 mL x 3). The combined organic substances were evaporated under vacuum, and the residue was purified by column chromatography to obtain 3-(4-nitro-1H-pyrazole-1-yl)propan-1,2-diol (1.0 g, yield 30.2%).1 H 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).

[0159] Step b: To a solution of 3-(4-nitro-1H-pyrazole-1-yl)propan-1,2-diol (400 mg, 2.14 mmol, 1.0 equivalent) in DCM (3 mL), DAST (861 mg, 5.34 mmol, 706 μL, 2.5 equivalents) was added dropwise at 0°C. The mixture was stirred at 20°C for 3 hours. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution until the pH was 8, 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 produce 1-(2,3-difluoropropyl)-4-nitro-1H-pyrazole (100 mg, yield 23.5%, purity 96%). 1 H 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).

[0160] Step c: 100 mg, 523.2 μmol, 1.0 equivalent of 1-(2,3-difluoropropyl)-4-nitro-1H-pyrazole (100 mg, 523.2 μmol, 1.0 equivalent) was dissolved in EtOH (3 mL) and H2O (1 mL) at 25°C. NH4Cl (139.9 mg, 2.6 mmol, 5.0 equivalents) and Fe (146.1 mg, 2.62 mmol, 5.0 equivalents) were added. 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 obtain 1-(2,3-difluoropropyl)-1H-pyrazole-4-amine (80 mg, crude). LCMS m / z = 162.2 [M+H] +

[0161] Step d: To a solution of 1-(2,3-difluoropropyl)-1H-pyrazole-4-amine (80 mg, 496.4 μmol, 1.0 equivalent) in DCM (3 mL), TEA (150.7 mg, 1.49 mmol, 207.6 μL, 3.0 equivalents) and Boc2O (108.3 mg, 496.4 μmol, 114.1 μL, 1.0 equivalent) were added at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated to obtain a residue, which was purified by column chromatography to produce (1-(2,3-difluoropropyl)-1H-pyrazole-4-yl)carbamate tert-butyl (50 mg, 37.0% yield in 2 steps) as a white solid. LCMS m / z = 262.1 [M+H] +

[0162] Step e: NCS (38.3 mg, 287.1 μmol, 1.5 equivalents) was added at 25°C to a solution of (1-(2,3-difluoropropyl)-1H-pyrazole-4-yl)carbamate tert-butyl (50 mg, 191.4 μmol, 1.0 equivalent) in MeCN (3 mL). The reaction mixture was stirred at 40°C for 1 hour. The reaction mixture was diluted with H2O (20 mL), extracted with ELISA (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce (5-chloro-1-(2,3-difluoropropyl)-1H-pyrazole-4-yl)carbamate tert-butyl (35 mg, yield 59.5%, purity 96.2%). LCMS m / z = 296.1 [M+H] +

[0163] Step f: To a solution of tert-butyl (5-chloro-1-(2,3-difluoropropyl)-1H-pyrazole-4-yl)carbamate (35 mg, 118.4 μmol, 1.0 equivalent) in HFIP (2 mL), TFA (13.5 mg, 118.4 μmol, 9.1 μL, 3.0 equivalent) was added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain 5-chloro-1-(2,3-difluoropropyl)-1H-pyrazole-4-amine (20 mg, crude), which was used directly in the next step without purification.

[0164] Preparation 33: 2-(4-amino-5-chloro-1H-pyrazole-1-yl)acetonitrile [ka] 2-(4-amino-5-chloro-1H-pyrazole-1-yl)acetonitrile (24 mg, 4.3% yield in 4 steps) was obtained from 4-nitro-1H-pyrazole and 2-bromoacetonitrile using the same procedure as described in Preparation 19. LCMS m / z = 157.1 [M+H] +

[0165] Preparation 34: 3-(4-amino-5-chloro-1H-pyrazole-1-yl)propanenitrile [ka] 3-(4-amino-5-chloro-1H-pyrazole-1-yl)propanenitrile (50 mg, 32.5% yield in 4 steps) was obtained from 4-nitro-1H-pyrazole and 3-bromopropanenitrile using the same procedure as described in Preparation 19. LCMS m / z = 171.2 [M+H] +

[0166] Preparation 35: 5-Chloro-1-isopentyl-1H-pyrazole-4-amine [ka] 5-chloro-1-isopentyl-1H-pyrazole-4-amine (30 mg, 16.2% yield in 4 steps) was obtained from 4-nitro-1H-pyrazole and 1-bromo-3-methylbutane using a procedure similar to that described in Preparation 19. LCMS m / z = 188.0 [M+H] +

[0167] Preparation 36: 5-Chloro-1-phenethyl-1H-pyrazole-4-amine [ka] 5-chloro-1-phenethyl-1H-pyrazole-4-amine (30 mg, 12.4% yield in 4 steps) was obtained from 4-nitro-1H-pyrazole and 1-bromo-3-methylbutane using a procedure similar to that described in Preparation 19. LCMS m / z = 222.0 [M+H] +

[0168] Preparation 37: 6-Chloro-7-(difluoromethoxy)-1H-indole-3-sulfonyl chloride [ka] Step a: To a solution of 1-chloro-2-(difluoromethoxy)-3-nitrobenzene (200 mg, 894.6 μmol, 1.0 equivalent) in THF (6 mL), magnesium vinyl bromide (1 M, 3.58 mmol, 3.58 mL, 4.0 equivalents) was added under N2 at -78°C. The reaction mixture was stirred at -78°C for 3 hours. The reaction mixture was diluted with aqueous NH4Cl solution (50 mL), extracted with  (40 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 6-chloro-7-(difluoromethoxy)-1H-indole (50 mg, yield 25.68%). 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).

[0169] Step b: To a mixture of 6-chloro-7-(difluoromethoxy)-1H-indole (20 mg, 91.91 μmol, 1.0 equivalent) in MeCN (1 mL), sulfonic chloride (182.07 mg, 1.56 mmol, 103.86 μL, 17.0 equivalents) was added all at once 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  (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 6-chloro-7-(difluoromethoxy)-1H-indole-3-sulfonyl chloride (25 mg, yield 86.1%). 1 H 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).

[0170] Preparation 38: 7-Chloro-6-(dimethylamino)-1H-indole-3-sulfonyl chloride [ka] Step a: To a solution of N,N-dimethyl-3-nitroaniline (2.00 g, 12.04 mmol, 1.0 equivalent) in DMF (20.0 mL) at 20°C, a solution of NCS (1.61 g, 12.04 mmol, 1.0 equivalent) in DMF (5.0 mL) was added at 20°C. The mixture was stirred at 75°C for 3 hours. Water (30 mL) was added to the mixture to quench it, and it was extracted with siRNA (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and then filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by column chromatography to obtain 2-chloro-N,N-dimethyl-3-nitroaniline (1.10 g, yield 45.6%) as a yellow oil. LCMS m / z = 201.0. [M+H] + .

[0171] Step b: To a solution of 2-chloro-N,N-dimethyl-3-nitroaniline (500.00 mg, 2.49 mmol, 1.0 equivalent) in THF (50.0 mL), magnesium vinyl bromide (1 M, 9.97 mmol, 4.0 equivalents) was added dropwise at -78°C under N2. The mixture was stirred at -78°C for 3 hours. The mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and then extracted with EA (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and then filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by column chromatography to obtain 7-chloro-N,N-dimethyl-1H-indole-6-amine (220.00 mg, yield 45.4%) as a yellow oil. LCMS m / z = 195.0. [M+H] + .

[0172] Step c: A solution of 7-chloro-N,N-dimethyl-1H-indole-6-amine (40.00 mg, 205.49 μmol, 1.0 equivalent) in DCM (5.0 mL) was treated with SO3.DMF (141.62 mg, 924.69 μmol, 4.5 equivalents) at 20°C. The mixture was stirred at 20°C for 2 hours. Subsequently, SOCl2 (195.57 mg, 1.64 mmol, 8.0 equivalents) 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 Na2SO4 and filtered. The filtrate was concentrated under vacuum to obtain 7-chloro-6-(dimethylamino)-1H-indole-3-sulfonyl chloride (30.00 mg, crude). The crude product was used directly in the next step. LCMS m / z = 293.0. [M+H] + .

[0173] Preparation 39: 1-(difluoromethyl)-5-propyl-1H-pyrazole-3-amine [ka] Step a: To a solution of 5-propyl-1H-pyrazole-3-amine (100 mg, 618.7 μmol, HCl, 1.0 equivalent) in water (6 mL), Oxone (950.9 mg, 1.55 mmol, 2.5 equivalents) was added 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  (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 3-nitro-5-propyl-1H-pyrazole (60 mg, yield 62.5%). LCMS m / z = 156.1. [M+H] + .

[0174] Step b: To a solution of 3-nitro-5-propyl-1H-pyrazole (60 mg, 386.7 μmol, 1.0 equivalent) in MeCN (8 mL), sodium 2-chloro-2,2-difluoroacetate (176.9 mg, 1.16 mmol, 3.0 equivalents) and K2CO3 (160.3 mg, 1.16 mmol, 3.0 equivalents) were added 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  (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 1-(difluoromethyl)-3-nitro-5-propyl-1H-pyrazole (20 mg, yield 25.2%). 1 H 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).

[0175] Step c: To a solution of 1-(difluoromethyl)-3-nitro-5-propyl-1H-pyrazole (20 mg, 97.5 μmol, 1.0 equivalent) in MeOH (2 mL), Pd / C (20.75 mg, 19.50 μmol, 10% purity, 0.2 equivalents) (wet) was added. The mixture was stirred at 25°C for 4 hours under H2 (15 Psi). The mixture was filtered, and the filtrate was concentrated under vacuum to obtain 1-(difluoromethyl)-5-propyl-1H-pyrazole-3-amine (12 mg, yield 70.3%). LCMS m / z = 176.2. [M+H] + .

[0176] Preparation 40: 5-Chloro-1-(difluoromethyl)-1H-pyrazole-3-amine [ka] Step a: To a solution of 5-chloro-3-nitro-1H-pyrazole (50 mg, 338.9 μmol, 1.0 equivalent) in MeCN (6 mL), sodium 2-chloro-2,2-difluoroacetate (155.0 mg, 1.02 mmol, 3.0 equivalents) and K2CO3 (140.5 mg, 1.02 mmol, 3.0 equivalents) were added 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  (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 5-chloro-1-(difluoromethyl)-3-nitro-1H-pyrazole (30 mg, yield 44.8%). 1 H NMR: (400MHz, CDCl3) δ: 7.43-7.13 (m, 1H), 7.02 (s, 1H).

[0177] Step b: To a solution of 5-chloro-1-(difluoromethyl)-3-nitro-1H-pyrazole (30 mg, 151.9 μmol, 1.0 equivalent) in MeOH (2 mL), Pd / C (32.3 mg, 30.38 μmol, 10% purity, 0.2 equivalents) (wet) was added. The mixture was stirred at 25°C for 4 hours under H2 (15 Psi). The mixture was filtered, and the filtrate was concentrated under vacuum to obtain 5-chloro-1-(difluoromethyl)-1H-pyrazole-3-amine (20 mg, yield 78.6%). LCMS m / z = 167.9 [M+H] + .

[0178] Preparation 41: 6-(trifluoromethyl)-1H-indole-3-sulfonyl chloride [ka] To a solution of 6-(trifluoromethyl)-1H-indole (100 mg, 540.12 μmol, 1.0 equivalent) in MeCN (4 mL), sulfonic chloride (692.30 mg, 5.94 mmol, 394.92 μL, 11.0 equivalents) was added at 25°C. The mixture was stirred at 25°C for 1 hour. The reaction product was quenched with water (10 mL) and extracted with  (5 mL x 3). The combined organic layer was dried over Na₂SO₄, filtered, and evaporated under vacuum to obtain 6-(trifluoromethyl)-1H-indole-3-sulfonyl chloride (150 mg, crude). 1 H 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).

[0179] Preparation 42: 5-Chloro-1-(difluoromethyl)-1H-pyrazole-3-amine [ka] Step a: To a solution of (1H-pyrazole-4-yl)carbamate tert-butyl (70.00 mg, 382.08 μmol, 1.0 equivalent) in MeCN (5.0 mL), Cs2CO3 (248.98 mg, 764.16 μmol, 3.0 equivalent) and 1-(2-bromoethyl)-1-(trifluoromethyl)cyclopropane (82.92 mg, 382.08 μmol, 1.0 equivalent) were added at 20°C. The mixture was stirred at 55°C for 16 hours. The mixture was filtered and concentrated under vacuum to obtain the residue, which was purified by column chromatography to obtain (1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (90.00 mg, yield 73.77%). LCMS m / z = 320.2 [M+H] + .

[0180] Step b: To a solution of (1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (70.00 mg, 219.21 μmol, 1.0 equivalent) in MeCN (2.0 mL), NCS (58.54 mg, 438.43 μmol, 2.0 equivalent) was added at 20°C. The mixture was stirred at 50°C for 10 hours. The mixture was quenched with saturated Na2SO3 aqueous solution (20 mL). The mixture was extracted with ELISA (20 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. This residue was purified by column chromatography to obtain (5-chloro-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (40.00 mg, yield 51.58%). LCMS m / z = 354.1 [M+H] + 1 H 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).

[0181] Step c: To a solution of tert-butyl (5-chloro-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazole-4-yl)carbamate (20.00 mg, 56.53 μmol, 1.0 equivalent) in HFIP (2.0 mL), TFA (32.23 mg, 282.67 μmol, 5.0 equivalent) was added at 20°C. The mixture was stirred at 20°C for 2 hours. The solvent was evaporated under vacuum to obtain 5-chloro-1-(2-(1-(trifluoromethyl)cyclopropyl)ethyl)-1H-pyrazole-4-amine (13.00 mg, yield 90.66%). LCMS m / z = 254.0 [M+H] + .

[0182] Preparation 43: 4-Chloro-5-ethylisoxazole-3-amine [ka] Step a: To a solution of 5-ethylisoxazole-3-amine (50.0 mg, 445.9 μmol, 1.0 equivalent) in MeCN (2.0 mL), NCS (59.54 mg, 445.91 μmol, 1.0 equivalent) was added at 25°C. The mixture was stirred at 25°C for 16 hours. The reaction product was quenched with saturated Na₂SO₃ aqueous solution, and the mixture was then extracted with  (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain a residue, which was then purified by preparative TLC to obtain 4-chloro-5-ethylisoxazole-3-amine (35.0 mg, yield 53.6%). LCMS m / z = 147.1 [M+H] + .

[0183] Preparation 44: 7-Chloro-6-methyl-1H-indole-3-sulfonyl chloride [ka] Step a: To a solution of 2-chloro-1-methyl-3-nitrobenzene (1 g, 5.83 mmol, 1.0 equivalent) in THF (40 mL), magnesium vinyl bromide (1 M, 23.31 mL, 4.0 equivalents) was added dropwise under N2 at -78°C. The reaction mixture was stirred at -78°C for 3 hours. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (50 mL), extracted with ₹ (40 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 7-chloro-6-methyl-1H-indole (500 mg, yield 51.56%, purity 99.538%). 1 H 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).

[0184] Step b: To a solution of 7-chloro-6-methyl-1H-indole (200 mg, 1.21 mmol, 1.0 equivalent) in MeCN (8.0 mL), HSO3Cl (1.41 g, 12.08 mmol, 802.70 μL, 10.0 equivalent) was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (20 mL), extracted with siRNA (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 7-chloro-6-methyl-1H-indole-3-sulfonyl chloride (150 mg, yield 42.33%). 1 H 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).

[0185] Preparation 45: 6,7-difluoro-1H-indole-3-sulfonyl chloride [ka] 6,7-difluoro-1H-indole-3-sulfonyl chloride (100 mg, 5% yield in 2 steps) was obtained from 1,2-difluoro-3-nitrobenzene following the same procedure as described in Preparation 45. 1 H 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).

[0186] Preparation 46: 6-Chloro-7-methyl-1H-indole-3-sulfonyl chloride [ka] 6-chloro-7-methyl-1H-indole-3-sulfonyl chloride (40 mg, 1% yield in 2 steps) was obtained from 1-chloro-2-methyl-3-nitrobenzene following a procedure similar to that described in Preparation 45. 1 H 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).

[0187] Preparation 47: 6-Chloro-7-methoxy-1H-indole-3-sulfonyl chloride [ka] 6-chloro-7-methoxy-1H-indole-3-sulfonyl chloride (30 mg, 22% yield in 2 steps) was obtained from 1-chloro-2-methoxy-3-nitrobenzene following a procedure similar to that described in Preparation 45. 1 H 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).

[0188] Preparation 48: 7-Chloro-6-fluoro-1H-indole-3-sulfonyl chloride [ka] 7-chloro-6-fluoro-1H-indole-3-sulfonyl chloride (40 mg, 32% yield in 2 steps) was obtained from 2-chloro-1-fluoro-3-nitrobenzene following the same procedure as described in Preparation 45. 1 H 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).

[0189] Preparation 49: 6-Chloro-7-fluoro-1H-indole-3-sulfonyl chloride [ka] 6-chloro-7-fluoro-1H-indole-3-sulfonyl chloride (30 mg, 4% yield in 2 steps) was obtained from 1-chloro-2-fluoro-3-nitrobenzene following the same procedure as described in Preparation 45. 1 H 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).

[0190] Preparation 50: 7-Chloro-6-methyl-1H-indole-3-sulfonyl chloride [ka] Step a: To a solution of 1-chloro-2-fluoro-3-nitrobenzene (1 g, 5.70 mmol, 1.0 equivalent) in DCM (20 mL), dimethylamine hydrochloride (929.04 mg, 11.39 mmol, 2.0 equivalents) and TEA (1.73 g, 17.09 mmol, 3.0 equivalents) were added at 25°C. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered, and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to obtain 2-chloro-N,N-dimethyl-6-nitroaniline (1 g, yield 87.50%). LCMS m / z = 201.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 7.56-7.52 (m, 2H), 7.09-7.04 (m, 1H), 2.85 (s, 6H).

[0191] Step b: To a stirred solution of 2-chloro-N,N-dimethyl-6-nitroaniline (0.5 g, 2.49 mmol, 1.0 equivalent) in THF (50 mL), magnesium vinyl bromide (1 M, 9.97 mL, 4.0 equivalents) was added under N2 conditions at -78 °C. The mixture was stirred at -78 °C for 4 hours. The mixture was quenched with a saturated solution of NH4Cl (80 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography to obtain 6-chloro-N,N-dimethyl-1H-indole-7-amine (260 mg, yield 53.59%). 1 H 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).

[0192] Step c: To a stirred solution of 6-chloro-N,N-dimethyl-1H-indole-7-amine (100 mg, 513.72 μmol, 1.0 equivalent) in MeCN (4 mL), HSO3Cl (718.30 g, 6.16 mmol, 0.4 mL, 12.0 equivalents) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was quenched with saturated ice water, extracted with ethyl acetate (20 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography to obtain 7-chloro-6-methyl-1H-indole-3-sulfonyl chloride (50 mg, yield 33.20%). 1 H 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).

[0193] Preparation 51: 5-Chloro-1-(3,3-difluoropropyl)-1H-pyrazole-4-amine [ka] Step a: To a solution of methyl 3-(4-nitro-1H-pyrazole-1-yl)propanoate (1.0 g, 5.02 mmol, 1.0 equivalent) and CaCl2 (557.23 mg, 5.02 mmol, 1.0 equivalent) in EtOH (10 mL), NaBH4 (379.91 mg, 10.04 mmol, 2.0 equivalents) was added 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 layer was washed with brine (20 mL) and dried over Na2SO4. The filtrate was concentrated under vacuum to obtain 3-(4-nitro-1H-pyrazole-1-yl)propan-1-ol (650 mg, yield 75.2%) as a yellow solid. LCMS m / z = 172.2 [M+H] + 1 H 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).

[0194] Step b: To a solution of 3-(4-nitro-1H-pyrazole-1-yl)propan-1-ol (2.05 g, 11.98 mmol, 1.0 equivalent) in DCM (20 mL), Dess-Martin periodinane (7.62 g, 17.97 mmol, 1.5 equivalent) was added 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 under vacuum to obtain the residue, which was purified by column chromatography to obtain 3-(4-nitro-1H-pyrazole-1-yl)propanal (760 mg, yield 37.52%). 1 H 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).

[0195] Step c: To a solution of 3-(4-nitro-1H-pyrazole-1-yl)propanal (760 mg, 4.49 mmol, 1.0 equivalent) in DCM (10 mL), DAST (1.45 g, 8.99 mmol, 1.19 mL, 2.0 equivalents) was added 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 layer was washed with brine (20 mL) and dried over Na2SO4. The filtrate was concentrated under vacuum to obtain the residue, which was purified by column chromatography to obtain 1-(4,4-difluorobutyl)-4-nitro-1H-pyrazole (360 mg, yield 39.49%). LCMS m / z = 237.0 [M+H] + 1 H 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).

[0196] Step d: To a solution of 1-(4,4-difluorobutyl)-4-nitro-1H-pyrazole (360 mg, 1.88 mmol, 1.0 equivalent) in MeOH (5 mL), Pd / C (20.04 mg, 188.35 μmol, 0.1 equivalent) was added at 25°C. The mixture was stirred under H2 (15 Psi) at 25°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain 1-(4,4-difluorobutyl)-1H-pyrazole-4-amine (286 mg, yield 94.23%). 1 H 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).

[0197] Step e: To a solution of 1-(4,4-difluorobutyl)-1H-pyrazole-4-amine (286 mg, 1.77 mmol, 1.0 equivalent) in DCM (5 mL), TEA (359.17 mg, 3.55 mmol, 494.72 μL, 2.0 equivalents) and Boc2O (464.79 mg, 2.13 mmol, 489.25 μL, 1.2 equivalents) were added at 25°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was then purified by column chromatography to obtain (1-(4,4-difluorobutyl)-1H-pyrazole-4-yl)carbamate tert-butyl (370 mg, yield 71.12%, purity 89.12%). LCMS m / z = 262.2 [M+H] + 1 H 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).

[0198] Step f: To a solution of (1-(4,4-difluorobutyl)-1H-pyrazole-4-yl)carbamate tert-butyl (150 mg, 574.12 μmol, 1.0 equivalent) in MeCN (5 mL), NCS (229.99 mg, 1.72 mmol, 3.0 equivalents) was added 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 RINKAN (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain (5-chloro-1-(4,4-difluorobutyl)-1H-pyrazole-4-yl)carbamate tert-butyl (50 mg, yield 28.45%). 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).

[0199] Step g: To a solution of tert-butyl (5-chloro-1-(4,4-difluorobutyl)-1H-pyrazole-4-yl)carbamate (50 mg, 169.08 μmol, 1.0 equivalent) in HFIP (2 mL), TFA (19.28 mg, 169.08 μmol, 12.95 μL, 1.0 equivalent) was added at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under vacuum to obtain 5-chloro-1-(4,4-difluorobutyl)-1H-pyrazole-4-amine (33 mg, 99.78% yield), which was used without further purification. LCMS m / z = 196.2 [M+H] +

[0200] Preparation 52: 6-Chloro-N-(4-Chloro-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide [ka] 5-methylisothiazole-3-amine (50.00 mg, 331.94 μmol, 1.0 equivalent) was dissolved in MeCN (2.0 mL) and N-chlorosuccinamide (44.32 mg, 331.94 μmol, 1.0 equivalent) was added at 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 obtain 4-chloro-5-methylisothiazole-3-amine (37.00 mg, yield 75.00%). LCMS m / z = 149.1 [M + H] + .

[0201] Preparation 53: 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride [ka] Step a: Sodium hydride (151.54 mg, 3.79 mmol, 60% purity, 1.1 equivalents) was added at 0°C to a solution of 1H-indole-6-carbaldehyde (500 mg, 3.44 mmol, 1.0 equivalent) in THF (4 mL). The reaction mixture was stirred at 0°C for 30 minutes. Next, benzenesulfonyl chloride (669.21 mg, 3.79 mmol, 483.53 μL, 1.1 equivalents) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 20°C for 14 hours. The reaction mixture was quenched with water (20 mL) and extracted with RINKAN (20 mL x 3). The combined organic layers were washed with brine (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to obtain 1-(phenylsulfonyl)-1H-indole-6-carbaldehyde (550 mg, yield 55.96%). LCMS m / z = 286.1 [M+H] + 1 H 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).

[0202] Step b: To a solution of 1-(phenylsulfonyl)-1H-indole-6-carbaldehyde (550 mg, 1.93 mmol, 1.0 equivalent) in DCM (10 mL), DAST (1.55 g, 9.64 mmol, 1.27 mL, 5.0 equivalents) was added at 0°C. The reaction mixture was stirred at 20°C for 14 hours. The reaction mixture was quenched with saturated NaHCO3 until pH > 7 and extracted with DCM (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 obtain 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole (300 mg, yield 50.64%). 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).

[0203] Step c: To a solution of 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole (100 mg, 325.40 μmol, 1.0 equivalent) in MeCN (1 mL), sulfonic chloride (189.58 mg, 1.63 mmol, 108.14 μL, 5.0 equivalents) was slowly added at 0°C. The reaction mixture was stirred at 25°C for 14 hours. Then, while stirring, it was slowly poured into ice water (5 mL). The reaction was extracted with  (10 mL × 3). The combined organic layer was dried over Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by column chromatography to obtain 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride (100 mg, yield 75.73%). 1 H 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).

[0204] Preparation 54: 7-Chloro-6-methoxy-1H-indole-3-sulfonyl chloride [ka] 7-chloro-6-methoxy-1H-indole-3-sulfonyl chloride (70 mg, 14% yield in 2 steps) was obtained from 2-chloro-1-methoxy-3-nitrobenzene following a procedure similar 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)。

[0205] Unless otherwise specified, the following examples were purified using the following preparative HPLC methods: Preparative HPLC-A: Welch Xtimate C18 150×25mm, 5μm; 30~72% MeCN / H2O (10mm NH4HCO3); Preparative HPLC-B: Phenomenex Luna C18 150×25mm, 10μm; 54~84% MeCN / H2O (0.05% (NH4HCO3)-ACN); Preparative HPLC-C: Waters Sunfire OBD 100×50mm, 5mm; 5~75% MeCN / H2O (+0.1% TFA). Preparative HPLC-D: Phenomenex Synergi C18 150×30mm, 4mm; 49-69% MeCN / H2O (0.05% (NH4HCO3)-ACN); Preparative HPLC-E: Waters Oxbridge C18 150×25mm, 10um; 25-60% MeCN / H2O (0.05% (NH4HCO3)-ACN); Preparative HPLC-F: Boston Prime C18 150×30mm, 15mm; 10-40% MeCN / H2O ((NH3H2O+NH4HCO3)-ACN); Preparative HPLC-G: Boston Green ODS 150×30mm, 5um; 30-60% MeCN / H2O (0.05% (NH4HCO3)-ACN); Preparative HPLC-H: Phenomenex Gemini-NX Preparative HPLC-I: Waters SunFire C18 19×100, 5um; 25-55% MeCN / H2O (0.05% (NH4HCO3)-ACN); Preparative HPLC-J: YMC-Triart Prep C18 150×40mm, 7μM; 40-60% MeCN / H2O; Preparative HPLC-K: Waters XSelect CSH C18 30×100mm, 5uM; 5-30% MeCN / H2O (0.05% (NH4HCO3)-ACN).

[0206] Preparation 55: 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-amine [ka] Step a: To a solution of (1-(difluoromethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (270 mg, 1.16 mmol, 1.0 equivalent) in MeCN (2 mL), NBS (206.06 mg, 1.16 mmol, 1.0 equivalent) was added at 20°C. The reaction mixture was stirred at 20°C for 3 hours. TLC indicated that the reaction was complete. The combined reaction mixture was quenched with saturated Na2SO3 aqueous solution (water) (5 mL) and then extracted with RINKAN (10 mL × 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain (5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (260 mg, yield 56.63%, purity 78.70%). LCMS m / z = 313.9 [M+H] + 1 H NMR (400 MHz, CDCl3) δ: 8.14 (s, 1H), 7.32-7.02 (m, 1H), 6.17 (s, 1H), 1.53 (s, 9H).

[0207] Step b: To a solution of tert-butyl (5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)carbamate (100 mg, 320.40 μmol, 1.0 equivalent) in DCM (3 mL), TFA (595.60 mg, 5.22 mmol, 16.3 equivalents) was added at 20°C. The reaction mixture was stirred at 20°C for 3 hours. TLC indicated that the reaction was complete. The mixture was concentrated under vacuum to obtain 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-amine. The material was used without further purification, assuming a quantitative yield. LCMS m / z = 211.8 [M+H] +

[0208] Preparation 56: 6-Chloro-7-(thiazole-4-yl)-1H-indole-3-sulfonyl chloride [ka] Step a: To a solution of 4-(tributylstannyl)thiazole (184.80 mg, 801.77 μmol, 1.5 equivalents) in toluene (5 mL), KF (93.16 mg, 1.60 mmol, 3.0 equivalents), cataCXium A-Pd-G2 (35.74 mg, 53.45 μmol, 0.1 equivalent), and 7-bromo-6-chloro-1H-indole (200 mg, 534.51 μmol, 1.0 equivalent) were added at 20 °C under N2. The reaction mixture was stirred at 100 °C for 16 hours. LC-MS indicated the detection of the desired product. The mixture was quenched with saturated aqueous KF (5 mL), diluted with water (20 mL), and extracted with  (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 4-(6-chloro-1H-indole-7-yl)thiazole (100 mg, yield 79.71%). LCMS m / z = 235.0 [M+H] + 1 H 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).

[0209] Step b: To a solution of 4-(6-chloro-1H-indole-7-yl)thiazole (50 mg, 213.03 μmol, 1.0 equivalent) in MeCN (2 mL), sulfonic chloride (124.12 mg, 1.07 mmol, 70.80 μL, 5.0 equivalents) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. TLC showed that the reactants were completely consumed. Next, POCl3 (163.32 mg, 1.07 mmol, 99.29 μL, 5.0 equivalents) was added to the mixture at 0°C. The mixture was stirred at 0°C for 1 hour. TLC showed that the starting materials were completely consumed and one new spot was detected. The mixture was quenched with ice water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6-chloro-7-(thiazole-4-yl)-1H-indole-3-sulfonyl chloride. The material was used without further purification, assuming a quantitative yield. LCMS m / z = 332.9 [M+H] +

[0210] Preparation 57: 6-Chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole-3-sulfonyl chloride [ka] Step a: To a solution of 2-(2-chloro-6-nitrophenyl)-2H-1,2,3-triazole (1 g, 4.45 mmol, 1.0 equivalent) in THF (60 mL), bromo(vinyl)magnesium (1 M, 17.81 mmol, 17.81 mL, 4.0 equivalents) was added under N2 at -78°C. The reaction mixture was stirred at -78°C for 2 hours. TLC showed that a new main spot was observed. The reaction mixture was slowly quenched with saturated NH4Cl aqueous solution (40 mL) at 0°C for about 10 minutes. The reaction mixture was extracted with RINKAN (20 mL x 3). The combined organic layers were 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 obtain 6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole (460 mg, yield 47.25%).1 H 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).

[0211] 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 equivalent) in MeCN (3 mL), sulfonic chloride (133.24 mg, 1.14 mmol, 76.00 μL, 2.5 equivalents) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. LC-MS indicated that the reaction was complete. POCl3 (280.52 mg, 1.83 mmol, 170.53 μL, 4.0 equivalents) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 70°C for 14 hours. LC-MS indicated that the reaction was complete. The reaction mixture was quenched with ice water (10 mL) and extracted with RINKAN (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was evaporated under vacuum to obtain 6-chloro-7-(2H-1,2,3-triazol-2-yl)-1H-indole-3-sulfonyl chloride. The material was used without further purification, assuming a quantitative yield.

[0212] Preparation 58: 6-Chloro-7-(pyridine-2-yl)-1H-indole-3-sulfonyl chloride [ka] Step a: To a solution of 7-bromo-6-chloro-1H-indole (100 mg, 433.86 μmol, 1.0 equivalent) in dioxane (5 mL), PdCl2(PPh3)2 (30.45 mg, 43.39 μmol, 0.1 equivalent) was added at 20°C. Then, 2-(tributylstannyl)pyridine (191.67 mg, 520.63 μmol, 168.57 μL) was added to the reaction mixture at 20°C under N2. The reaction mixture was stirred at 100°C for 16 hours. LC-MS showed that the desired mass was detected. The mixture was quenched with saturated KF aqueous solution (10 mL), diluted with water (20 mL), and extracted with RINKAN (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography to obtain 6-chloro-7-(pyridine-2-yl)-1H-indole. The material was used without further purification, assuming a quantitative yield. LCMS m / z = 229.1 [M+H] + 1 H 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).

[0213] Step b: To a solution of 6-chloro-7-(pyridine-2-yl)-1H-indole (50 mg, 218.65 μmol, 1.0 equivalent) in MeCN (2 mL), sulfonic chloride (254.78 mg, 2.19 mmol, 145.34 μL, 10.0 equivalent) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. TLC showed that the starting material had been completely consumed and one new spot was detected. The mixture was quenched with ice water (10 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6-chloro-7-(pyridine-2-yl)-1H-indole-3-sulfonyl chloride. The material was used without further purification, assuming a quantitative yield. LCMS m / z = 326.9 [M+H] +

[0214] Preparation 59: 6-Chloro-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride [ka] Step a: 1-chloro-2-fluoro-3-nitrobenzene (500 mg, 2.85 mmol, 1.0 equivalent) and 1H-pyrazole (290.85 mg, 4.27 mmol, 1.5 equivalents) were dissolved in MeCN (20 mL), to which K2CO3 (1.18 g, 8.54 mmol, 3.0 equivalents) was added. The mixture was stirred at 25°C for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 1-(2-chloro-6-nitrophenyl)-1H-pyrazole (580 mg, yield 91.06%). LC-MS m / z = 223.8 [M+H] + 1 H NMR (MeOD) δ: 8.02-7.95 (m, 3H), 7.76-7.70 (m, 2H), 6.60-6.58 (m, 1H).

[0215] Step b: To a solution of 1-(2-chloro-6-nitrophenyl)-1H-pyrazole (250 mg, 1.12 mmol, 1.0 equivalent) in THF (10 mL), bromo(vinyl)magnesium (1 M, 4.47 mmol, 4.47 mL, 4.0 equivalent) was added under N2 at -78°C. The mixture was stirred at -78°C for 2 hours. LC-MS showed that the desired product was obtained. The reaction mixture was diluted with H2O (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 6-chloro-7-(1H-pyrazole-1-yl)-1H-indole (60 mg, yield 24.66%). LC-MS 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).

[0216] Step c: To a solution of 6-chloro-7-(1H-pyrazole-1-yl)-1H-indole (50.00 mg, 229.72 μmol, 1.0 equivalent) in MeCN (10 mL), HSO3Cl (267.68 mg, 2.30 mmol, 152.70 μL, 10.0 equivalent) was added at 0°C. The mixture was stirred at 0°C for 1 hour. LC-MS showed that the desired product was obtained. The reaction mixture was diluted with H2O (20 mL) and extracted with Âx (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 6-chloro-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (50 mg, yield 68.84%). 1 H 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).

[0217] Preparation 60: 6-Chloro-7-(4-Chloro-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride [ka] Step a: To a solution of 1-chloro-2-fluoro-3-nitrobenzene (1 g, 5.70 mmol, 1.0 equivalent) and 4-chloro-1H-pyrazole (876.03 mg, 8.54 mmol, 1.5 equivalent) in MeCN (40 mL), K2CO3 (2.36 g, 17.09 mmol, 3.0 equivalent) was added at 20°C. The reaction mixture was stirred at 60°C for 14 hours. LC-MS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to obtain 4-chloro-1-(2-chloro-6-nitrophenyl)-1H-pyrazole (1.4 g, yield 95.23%) as a white solid. 1 H 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).

[0218] Step b: To a solution of 4-chloro-1-(2-chloro-6-nitrophenyl)-1H-pyrazole (1 g, 3.88 mmol, 1.0 equivalent) in THF (60 mL), bromo(vinyl)magnesium (1 M, 15.50 mmol, 15.50 mL, 4.0 equivalents) was added under N2 at -78°C. The reaction mixture was stirred at -78°C for 2 hours. TLC showed that a new main spot was observed. The reaction mixture was slowly quenched with saturated NH4Cl aqueous solution (40 mL) at 0°C for about 10 minutes. The reaction mixture was extracted with RINKAN (20 mL x 3). The combined organic layers were 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 obtain 6-chloro-7-(4-chloro-1H-pyrazole-1-yl)-1H-indole (500 mg, yield 51.18%). 1 H 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).

[0219] Step c: To a solution of 6-chloro-7-(4-chloro-1H-pyrazole-1-yl)-1H-indole (50 mg, 198.33 μmol, 1.0 equivalent) in MeCN (3 mL), sulfonic chloride (57.78 mg, 495.84 μmol, 32.96 μL, 2.5 equivalents) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. LC-MS indicated that the reaction was complete. POCl3 (121.64 mg, 793.34 μmol, 73.95 μL, 4.0 equivalents) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 60°C for 14 hours. LC-MS indicated that the reaction was complete. The reaction mixture was quenched with ice water (10 mL) and extracted with RINKAN (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was evaporated under vacuum to obtain 6-chloro-7-(4-chloro-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride. LCMS m / z = 349.7 [M+H] + The materials were used without further purification, assuming a quantitative yield.

[0220] Preparation 61: 6-Chloro-7-(4-ethyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride [ka] 6-chloro-7-(4-ethyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (40 mg, 16.6% yield in 3 steps) was obtained from 1-chloro-2-fluoro-3-nitrobenzene and 4-ethyl-1H-pyrazole using a procedure similar to that described in Preparation 60.

[0221] Preparation 62: 7-(4-bromo-1H-pyrazole-1-yl)-6-chloro-1H-indole-3-sulfonyl chloride [ka] 6-chloro-7-(4-ethyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (100 mg, 16.9% yield in 3 steps) was obtained from 1-chloro-2-fluoro-3-nitrobenzene and 4-bromo-1H-pyrazole using a procedure similar to that described in Preparation 60.

[0222] Preparation 63: 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazole-1(4H)-yl)-1H-indole and 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazole-2(4H)-yl)-1H-indole [ka] Step a: To a solution of 1-chloro-2-fluoro-3-nitrobenzene (1 g, 9.25 mmol, 1.0 equivalent) in MeCN (10 mL), K2CO3 (2.56 g, 18.49 mmol, 2.0 equivalent) and 2,4,5,6-tetrahydrocyclopenta[c]pyrazole (1.62 g, 9.25 mmol, 1.0 equivalent) were added at 20°C. The mixture was then stirred at 20°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction was quenched with water (10 mL), extracted with siRNA (20 mL x 3), washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain a crude product, which was purified by column chromatography to obtain 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 (1.6 g, yield 65.57%). LCMS m / z = 263.8 [M+H] + 1 H 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).

[0223] 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 (800.00 mg, 3.04 mmol, 1.0 equivalent) in THF (10 mL), bromo(vinyl)magnesium (1 M, 12.14 mmol, 12.14 mL, 4.0 equivalents) was carefully added under N2 at -60°C. The mixture was stirred at -60°C for 3 hours. LC-MS indicated that the reaction was complete. The mixture was quenched with saturated NH4Cl aqueous solution (water) (10 mL) and then extracted with ELISA (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was then purified by column chromatography to obtain 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazole-1(4H)-yl)-1H-indole (200 mg, yield 25.42%) (LCMS m / z = 258.0 [M+H]). + 1 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]pyrazole-2(4H)-yl)-1H-indole (200 mg, yield 25.42%) (LCMS m / z = 258.0 [M+H]) + 1 H 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)) were obtained.

[0224] General method General Method A: To a solution of aniline (1 equivalent) in DCM (0.05 M), sulfonyl chloride (1.0 equivalent) and pyridine (3.0 equivalents) were added at 20°C. The reaction was stirred at 20°C while monitoring the reaction by TLC or LC-MS until completion. The mixture was filtered and concentrated under vacuum to obtain the residue, which was purified by the specified HPLC method to obtain the desired product.

[0225] General method B: To a solution of aniline (1 equivalent) in pyridine (0.05 M), sulfonyl chloride (1.0 equivalent) was added at 20°C. The reaction mixture was stirred at 60°C for 1 hour. The mixture was filtered and concentrated under vacuum to obtain the residue, which was purified by the specified HPLC method to obtain the desired product.

[0226] General method C: To a solution of aniline (1 equivalent) in pyridine (0.1 M), sulfonyl chloride (1.0 equivalent) was added at 20°C. The reaction mixture was stirred overnight at 20°C. The mixture was filtered and concentrated under vacuum to obtain the residue, which was purified by the specified HPLC method to obtain the desired product.

[0227] General method D: A solution of aniline (1 equivalent) in pyridine (0.1 M) was prepared by adding aryl sulfonyl chloride at 20°C. A catalytic amount of DMAP was added, and the reaction mixture was heated overnight at 60°C. The reaction mixture was then quenched with water and extracted three times with DCM. The combined organic matter was dried and concentrated, and the crude product was then purified by the specified HPLC method to obtain the desired product.

[0228] General method E: To a solution of aniline (1 equivalent) in pyridine (0.1 M), sulfonyl chloride (1 equivalent) was added, and the resulting mixture was heated at 100°C for 16 hours. The solution was then cooled to room temperature and concentrated. The resulting residue was purified by the specified reverse-phase HPLC method to obtain the desired product.

[0229] General method F: Aniline (1 equivalent) and then DIPEA (3 equivalents) were added to a solution of sulfonyl chloride (1 equivalent) in DCM (0.1 M). The mixture was stirred at room temperature for 16 hours and then concentrated. The resulting residue was purified via the specified reverse-phase method to obtain the desired product.

[0230] General method G: Sulfonyl chloride (1.0 equivalent) was added to a solution of aniline (1.1 equivalents) in dry pyridine (0.15 M). The reaction mixture was stirred at 60°C for 24 hours. The solvent was then evaporated under vacuum, and the residue was purified by the specified reverse-phase HPLC method to obtain the desired product.

[0231] In the general method, sulfonyl chloride (1.0 equivalent), aniline (2.0 equivalents), and DMAP (0.1 equivalent) were combined, and then DCM and pyridine (1:1 mixture, 0.2 M) were added. The mixture was heated at 65°C for 16 hours. The reaction products were then evaporated under vacuum, and the residue was purified by the specified reverse-phase HPLC method to obtain the desired product.

[0232] Examples 1-94 The title compound was prepared from suitable sulfonyl chloride and suitable aniline (RNH2) using the specified general method. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 Table 2-39 Table 2-40

[0233] Example 95: N-(5-cyano-1-ethyl-1H-pyrazole-4-yl)-6-(difluoromethyl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile (33.55 mg, 246.41 μmol, 1.0 equivalent) in pyridine (8 mL), 6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride (Preparation 53) (100 mg, 246.41 μmol, 1.0 equivalent) was added. The reaction mixture was stirred at 50°C for 14 hours. The solvent was evaporated under vacuum, and the residue was purified by column chromatography to obtain N-(5-cyano-1-ethyl-1H-pyrazole-4-yl)-6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (70 mg, yield 56.20%). LCMS m / z = 506.2 [M + H] +

[0234] Step b: To a solution of N-(5-cyano-1-ethyl-1H-pyrazole-4-yl)-6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (70 mg, 138.47 μmol, 1.0 equivalent) in THF (5 mL), TBAF (1 M, 415.42 μL, 3.0 equivalents) was added at 20 °C. The reaction mixture was stirred at 60 °C for 14 hours. The reaction mixture was quenched with water (10 mL) and extracted with ELISA (10 mL x 3). The combined organic layer was dried over Na₂SO₄ and filtered. The filtrate was evaporated under vacuum. The residue was purified by column chromatography to obtain N-(5-cyano-1-ethyl-1H-pyrazole-4-yl)-6-(difluoromethyl)-1H-indole-3-sulfonamide (27.5 mg, yield 53.29%). LCMS m / z = 366.0 [M+H] + 1H NMR (400 MHz, DMSO) δ: 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).

[0235] Example 96: N-(5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-(difluoromethyl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 6-(difluoromethyl)-1H-indole-3-sulfonyl chloride (Preparation 53) (50 mg, 123.21 μmol, 1.0 equivalent) in DCM (3 mL), 5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-amine (Preparation 2) (22.86 mg, 123.21 μmol, 1.0 equivalent) and pyridine (29.24 mg, 369.62 μmol, 3.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated into a residue and purified by column chromatography to obtain compound N-(5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (40 mg, yield 58.51%). LCMS m / z = 554.9 [M+H] +

[0236] Step b: To a solution of N-(5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (40 mg, 72.09 μmol, 1.0 equivalent) in THF (2 mL), TBAF (1 M, 360.43 μmol, 360.43 μL, 5.0 equivalents) was added at 25 °C. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was quenched with water (10 mL) and extracted with HCl (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 obtain N-(5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-(difluoromethyl)-1H-indole-3-sulfonamide (11.5 mg, yield 38.47%). LCMS m / z = 414.9 [M+H] + 1 H 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).

[0237] Example 97: N-(5-cyano-1-ethyl-1H-pyrazole-4-yl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 6-(trifluoromethyl)-1H-indole (200 mg, 1.08 mmol, 1.0 equivalent) in DCM (8 mL), NaOH (133.94 mg, 3.35 mmol, 3.1 equivalents) and tetrabutylammonium bisulfate (110.03 mg, 324.07 μmol, 0.3 equivalents) were added at 0°C. Then, benzenesulfonyl chloride (209.87 mg, 1.19 mmol, 151.64 μL, 1.1 equivalents) was slowly added to the reaction product at 0°C. The reaction product was stirred at 0°C for 1 hour. The reaction product was filtered, and the filtrate was evaporated under vacuum. The residue was purified by column chromatography to obtain 1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole (320 mg, yield 91.06%). 1 H NMR (400 MHz, CDCl3) δ: 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).

[0238] Step b: To a solution of 1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole (100 mg, 307.40 μmol, 1.0 equivalent) in MeCN (1 mL), sulfonic chloride (179.10 mg, 1.54 mmol, 102.17 μL, 5.0 equivalents) was slowly added at 0°C. The reaction mixture was stirred at 25°C for 14 hours. The reaction product was slowly added to ice water (10 mL). The reaction was extracted with RINKAN (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 obtain 1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-3-sulfonyl chloride (100 mg, yield 76.76%). 1H NMR (400 MHz, CDCl3) δ: 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).

[0239] Step c: 1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-3-sulfonyl chloride (30 mg, 220.34 μmol, 1.0 equivalent) was added to a solution of 4-amino-1-ethyl-1H-pyrazole-5-carbonitrile (93.38 mg, 220.34 μmol, 1.0 equivalent) in pyridine (5 mL). The reaction mixture was stirred at 50 °C for 14 hours. The solvent was evaporated under vacuum. The residue was purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm, water (FA)-ACN, gradient time (min): 10, flow rate (ml / min): 60) to obtain N-(5-cyano-1-ethyl-1H-pyrazole-4-yl)-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide (20 mg, yield 17.34%). LCMS m / z = 524.2 [M+H] +

[0240] Step d: To a solution of N-(5-cyano-1-ethyl-1H-pyrazole-4-yl)-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide (20 mg, 38.20 μmol, 1.0 equivalent) in THF (3 mL), TBAF (1 M, 38.20 μL, 1.0 equivalent) was added at 20 °C. The reaction mixture was stirred at 60 °C for 14 hours. The reaction mixture was quenched with water (10 mL) and extracted with Âxa (15 mL x 3). The combined organic layer was dried over Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by preparative TLC to obtain N-(5-cyano-1-ethyl-1H-pyrazole-4-yl)-6-(trifluoromethyl)-1H-indole-3-sulfonamide (7 mg, yield 47.80%). LCMS m / z = 383.9 [M+H] + 1H NMR (400MHz, DMSO) δ: 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).

[0241] Example 98: 6-Chloro-N-(4-ethyl-5-methylisoxazol-3-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of tert-butyl (5-methylisoxazole-3-yl)carbamate (800 mg, 4.04 mmol, 1.0 equivalent) in THF (20.0 mL), n-BuLi (2.5 M, 3.55 mL, 2.2 equivalents) was added dropwise under N2 conditions at -78°C, and the mixture was stirred at -78°C for 1 hour. Iodoethane (944.20 mg, 6.05 mmol, 1.5 equivalents) was added to the mixture. The mixture was stirred at 25°C for 16 hours. The reaction product was diluted with water (20 mL) and extracted with  (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and then filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC-A (mobile phase: 37%~77% MeCN / H2O; 25 ml / min) to obtain (4-ethyl-5-methylisoxazole-3-yl)carbamate tert-butyl (150 mg, yield 87.9%). 1 H 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).

[0242] Step b: To a solution of tert-butyl (4-ethyl-5-methylisoxazole-3-yl)carbamate (70 mg, 309.36 μmol, 1.0 equivalent) in HFIP (2 mL), TFA (70.55 mg, 618.73 μmol, 2.0 equivalents) was added at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction product was then concentrated under vacuum to obtain 4-ethyl-5-methylisoxazole-3-amine (35 mg, crude). The crude product was used directly in the next step. LCMS m / z = 127.1 [M+H] + .

[0243] Step c: To a solution of 4-ethyl-5-methylisoxazole-3-amine (20 mg, 158.53 μmol, 1.0 equivalent) in THF (2.0 mL), 6-chloro-1H-indole-3-sulfonyl chloride (39.65 mg, 158.53 μmol, 1.0 equivalent) was added at 20°C. t-BuOK (1 M, 0.35 mL, 2.2 equivalents) was added dropwise to the mixture at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was filtered and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (FA) (column: Welch Xtimate C18 150×25mm×5um; mobile phase: 35%~55% water (FA)-ACN; flow rate (ml / min): 25) to obtain 6-chloro-N-(4-ethyl-5-methylisoxazole-3-yl)-1H-indole-3-sulfonamide (5.0 mg, yield 9.3%). LCMS m / z = 340.0 [M+H] + . 1 H 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).

[0244] Example 99: 6-Chloro-N-(4-Chloro-5-methylisoxazol-3-yl)-1H-indole-3-sulfonamide [ka] 6-chloro-1H-indole-3-sulfonyl chloride (50 mg, 199.92 μmol, 1.0 equivalent) was dissolved in pyridine (1.0 mL), to which 4-chloro-5-methylisoxazole-3-amine (26.5 mg, 199.92 μmol, 1.0 equivalent) was added at 25°C. The mixture was stirred at 80°C for 16 hours. The mixture was then concentrated to the residue and purified by preparative HPLC-A (38%~58% MeCN / H2O; 25 ml / min) to obtain 6-chloro-N-(4-chloro-5-methylisoxazole-3-yl)-1H-indole-3-sulfonamide (20 mg, yield 27.4%). LCMS m / z = 345.9 [M+H] + . 1 H 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).

[0245] Example 100: 6-Chloro-N-(5-(1,1-difluoroethyl)isoxazole-3-yl)-1H-indole-3-sulfonamide [ka] 6-chloro-1H-indole-3-sulfonyl chloride (50 mg, 199.92 μmol, 1.0 equivalent) was dissolved in pyridine (1.0 mL), to which 5-(1,1-difluoroethyl)isoxazole-3-amine (29.6 mg, 199.92 μmol, 1.0 equivalent) was added at 25°C. The mixture was stirred at 80°C for 16 hours. The mixture was then concentrated to the residue and purified by preparative HPLC-A (28%~58% MeCN / H2O; 25 ml / min) to obtain 6-chloro-N-(5-(1,1-difluoroethyl)isoxazole-3-yl)-1H-indole-3-sulfonamide (11 mg, yield 14.78%). 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).

[0246] Example 101: 6-Chloro-N-(4-Chloro-5-ethylisoxazol-3-yl)-1H-indole-3-sulfonamide [ka] 4-chloro-5-ethylisoxazole-3-amine (Preparation 43) (15.0 mg, 102.34 μmol, 1.0 equivalent) and 6-chloro-1H-indole-3-sulfonyl chloride (25.6 mg, 102.34 μmol, 1.0 equivalent) were dissolved in CH2Cl2 (2.0 mL), to which pyridine (24.28 mg, 307.01 μmol, 3.0 equivalent) was added at 25°C. The mixture was stirred at 20°C for 4 hours. The solvent was then evaporated under vacuum to obtain residues, which were purified by preparative HPLC-A (35%~65% MeCN / H2O; 25 ml / min) to obtain 6-chloro-N-(4-chloro-5-ethylisoxazole-3-yl)-1H-indole-3-sulfonamide (2.1 mg, yield 5.7%). LCMS m / z = 360.0 [M+H] + . 1 H 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).

[0247] The following compounds were synthesized in library form using the following procedure.

[0248] The amine component (1.1 equivalents) was dissolved in dry pyridine (0.5 mL), 6-chloro-1H-indole-3-sulfonyl chloride (1 equivalent) was added, and the mixture was 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 reduced pressure. The residue was dissolved in DMSO (0.5 mL). The solution was filtered, analyzed by LC-MS, and transferred for HPLC purification. Purification was performed using an Agilent 1260 Infinity system equipped with DAD and a mass detector. A Waters Sunfire C18 OBD preparative column, 100A, 5 μm, 19 mm × 100 mm and a Sunfire C18 preparative guard cartridge, 100A, 10 μm, 19 mm × 10 mm were used. Deionized water (phase A) and HPLC-grade methanol or acetonitrile (phase B) were used as eluents. In some cases, ammonia or TFA was used as an additive to improve product separation. In these cases, the free base and TFA salt of the product were formed, respectively. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9]

[0249] Example 137: 6-Chloro-N-(5-Chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-amine (100.0 mg, 558.2 μmol, 1.0 equivalent) in DCM (4.0 mL), TEA (169.5 mg, 1.6 mmol, 3.0 equivalents) and (Boc)2O (182.7 mg, 837.3 μmol, 1.5 equivalents) were added at 20°C. The mixture was stirred at 20°C for 4 hours. Water (30 mL) was added, and the mixture was extracted with  (30 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was purified by preparative TLC to obtain (1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-yl)carbamate tert-butyl (110.0 mg, yield 70.6%). LCMS m / z = 280.2 [M+H] + . 1 H 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).

[0250] Step b: To a solution of (1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-yl)carbamate tert-butyl 2 (50.0 mg, 179.1 μmol, 1.0 equivalent) in MeCN (2 mL), NCS (23.9 mg, 179.1 μmol, 1.0 equivalent) was added at 25 °C. The mixture was stirred at 60 °C for 16 hours. The reaction product was quenched with saturated Na2SO3 aqueous solution (3 mL), and the mixture was extracted with  (20 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was purified by preparative TLC to obtain (5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-yl)carbamate tert-butyl (50.0 mg, yield 89.0%). LCMS m / z = 314.0 [M+H] + .

[0251] Step c: To a solution of tert-butyl (5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-yl)carbamate (50.0 mg, 159.39 μmol, 1.0 equivalent), a solution in HCl dioxane (4 M, 796.9 μL, 3.19 mmol, 20.0 equivalents) was added at 20°C. The mixture was stirred at 20°C for 2 hours. The solvent was evaporated under vacuum to obtain 5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-amine (30.0 mg, yield 88.1%), which was used without further purification. LCMS m / z = 213.9 [M+H] + .

[0252] Step d: Pyridine (33.33 mg, 421.4 μmol, 3.0 equivalents) was added at 20°C to a solution of 6-chloro-1H-indole-3-sulfonyl chloride (35.13 mg, 140.5 μmol, 1.0 equivalent) and 5-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-amine (30.00 mg, 140.5 μmol, 1.0 equivalent) in DCM (2.0 mL). The mixture was stirred at 20°C for 2 hours. The solvent was evaporated under vacuum to obtain the residue, which was purified by preparative HPLC (FA) (column: Welch Xtimate C18 150 × 25 mm × 5 μm); mobile phase: 35%~65% water (FA)-ACN; flow rate (ml / min): 25) to obtain the title compound (26.70 mg, yield 44.5%). LCMS m / z = 427.0 [M+H] + . 1 H 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).

[0253] Example 138: N-(5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-6-methoxy-1H-indole-3-sulfonamide [ka] Step a: To a solution of 6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride (50 mg, 129.59 μmol, 1.0 equivalent) in DCM (3 mL), 5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-amine (23.33 mg, 129.59 μmol, 1.0 equivalent) and pyridine (30.75 mg, 388.76 μmol, 3.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated into a residue and purified by column chromatography to obtain N-(5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (30 mg, yield 43.73%). 1 HNMR: (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).

[0254] Step b: To a solution of N-(5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (30 mg, 56.67 μmol, 1.0 equivalent) in MeOH (2 mL), K2CO3 (31.33 mg, 226.66 μmol, 4.0 equivalents) was added at 25 °C. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was evaporated under vacuum. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25mm×5um, mobile phase: water (FA)-ACN, 30%~50%, gradient time (min): 12, flow rate (ml / min): 25) to obtain N-(5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-6-methoxy-1H-indole-3-sulfonamide (15.3 mg, yield 63.75%, purity 91.9%). 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).

[0255] Example 139: N-(5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-methoxy-1H-indole-3-sulfonamide [ka] Step a: To a solution of 6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonyl chloride (100 mg, 259.17 μmol, 1.0 equivalent) in DCM (3 mL), 5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-amine (48.09 mg, 259.17 μmol, 1.0 equivalent) and pyridine (61.50 mg, 777.52 μmol, 3.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated into a residue and purified by column chromatography to obtain N-(5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (40 mg, yield 28.85%). LCMS m / z = 535.1 [M+H] + .

[0256] Step b: To a solution of N-(5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-methoxy-1-(phenylsulfonyl)-1H-indole-3-sulfonamide (20.00 mg, 37.39 μmol, 1.0 equivalent) in THF (3 mL), TBAF (1 M, 186.95 μmol, 5.0 equivalents, 186.95 μL) was added at 25 °C. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was quenched with water (10 mL) and extracted with  (5 mL x 3). The combined organic layer was dried over Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, mobile phase: water (FA)-ACN, 35%~65%, gradient time (min): 11, flow rate (ml / min): 50) to obtain N-(5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-yl)-6-methoxy-1H-indole-3-sulfonamide (2.1 mg, yield 14.23%). LCMS m / z = 394.9 [M+H] + 1 H 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).

[0257] Example 140: 6-Chloro-N-(5-Chloro-1-phenyl-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 4-nitro-1H-pyrazole (1 g, 8.84 mmol, 1.0 equivalent) and iodobenzene (3.61 g, 17.69 mmol, 1.98 mL, 2.0 equivalents) in DMF (20 mL), CuI (168.43 mg, 884.37 μmol, 0.1 equivalent) and K2CO3 (2.44 g, 17.69 mmol, 2.0 equivalent) were added under N2 at 20 °C. The reaction mixture was stirred at 110 °C for 14 hours. LC-MS indicated complete consumption of the material, with one major peak detected. The reaction mixture was diluted with H2O (20 mL) and extracted with SiO2 (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 obtain the residue. The residue was purified by column chromatography to obtain 4-nitro-1-phenyl-1H-pyrazole (900 mg, yield 53.80%). LCMS m / z = 190.1 [M+H] + 1 H 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).

[0258] Step b: To a solution of 4-nitro-1-phenyl-1H-pyrazole (300 mg, 1.59 mmol, 1.0 equivalent) in EtOH (3 mL) and water (1 mL), Fe (442.85 mg, 7.93 mmol, 56.34 μL, 5.0 equivalent) and NH4Cl (424.15 mg, 7.93 mmol, 5.0 equivalent) were added at 20°C. The reaction mixture was stirred at 70°C for 2 hours. LC-MS indicated complete consumption of the material, with one major peak detected. The mixture was filtered and concentrated. The residue was purified by column chromatography to obtain 1-phenyl-1H-pyrazole-4-amine (100 mg, yield 39.61%). LC-MS m / z = 160.1 [M+H] + .

[0259] Step c: To a solution of 1-phenyl-1H-pyrazole-4-amine (190 mg, 1.19 mmol, 1.0 equivalent) in DCM (3 mL), Boc2O (1.30 g, 5.97 mmol, 1.37 mL, 5.0 equivalent) and TEA (603.88 mg, 5.97 mmol, 831.79 μL, 5.0 equivalent) were added at 25°C. The reaction mixture was stirred at 25°C for 12 hours. LC-MS indicated complete consumption of the material, with one major peak detected. The mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography to obtain tert-butyl (1-phenyl-1H-pyrazole-4-yl)carbamate (200 mg, yield 64.62%). LC-MS m / z = 260.1 [M+H] + .

[0260] Step d: To a stirred solution of (1-phenyl-1H-pyrazole-4-yl)carbamate tert-butyl (50 mg, 192.82 μmol, 1.0 equivalent) in MeCN (1 mL), NCS (38.62 mg, 289.24 μmol, 1.5 equivalents) was added at 20°C. The reaction mixture was stirred at 40°C for 2 hours. LC-MS indicated complete consumption of the material, with one major peak detected. The mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography to obtain (5-chloro-1-phenyl-1H-pyrazole-4-yl)carbamate tert-butyl (10 mg, yield 17.65%). LC-MS m / z = 294.1 [M+H] + 1 H 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).

[0261] Step e: To a stirred solution of tert-butyl (5-chloro-1-phenyl-1H-pyrazole-4-yl)carbamate (50 mg, 170.21 μmol, 1.0 equivalent) in HFIP (2 mL), TFA (19.41 mg, 170.21 μmol, 13.03 μL, 1.0 equivalent) was added at 20°C. This mixture was stirred at 20°C for 6 hours. The reaction mixture was concentrated under reduced pressure to obtain 5-chloro-1-phenyl-1H-pyrazole-4-amine (30 mg, yield 91.02%). LCMS m / z = 194.0 [M+H] + .

[0262] Step f: To a solution of 5-chloro-1-phenyl-1H-pyrazole-4-amine (30 mg, 154.93 μmol, 1.0 equivalent) and 6-chloro-1H-indole-3-sulfonyl chloride (20.00 mg, 79.97 μmol, 5.16 e-1 equivalent) in DCM (3 mL), pyridine (12.26 mg, 154.93 μmol, 12.53 μL, 1.0 equivalent) was added at 20°C. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Water × bridge 150 × 25 mm × 10 μm; conditions: water (NH4HCO3)-ACN; start B: 29; end B: 59; gradient time (min): 10; 100% B retention time (min): 3; flow rate (mL / min): 30) to obtain the compound 6-chloro-N-(5-chloro-1-phenyl-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (12.4 mg, yield 19.65%). LCMS m / z = 406.9 [M+H] + 1 H 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).

[0263] Example 141: 6-Chloro-N-(5-Chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] Step a: Compound 2,2,2-trifluoroethyltrifluoromethanesulfonic acid (2.05 g, 8.84 mmol, 1.0 equivalent) was added at 25°C to a solution of 4-nitro-1H-pyrazole (1 g, 8.84 mmol, 1.0 equivalent) and K2CO3 (3.67 g, 26.53 mmol, 3.0 equivalent) in DMF (20 mL). The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was diluted with H2O (60 mL) and extracted with siRNA (50 mL x 3). The combined organic layer was washed with brine (40 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (1.7 g, yield 96.55%). LCMS m / z = 196.0 [M+H] + 1 H NMR: (400 MHz, DMSO) δ: 8.30 (s, 1H), 8.16 (s, 1H), 4.81-4.74 (m, 2H).

[0264] Step b: 4-Nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (200 mg, 1.03 mmol, 1.0 equivalent), NH4Cl (274.18 mg, 5.13 mmol, 5.0 equivalents), and Fe (286.26 mg, 5.13 mmol, 5.0 equivalents) were dissolved 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 obtain 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-amine (150 mg, crude).

[0265] Step c: To a solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-amine (150 mg, 908.45 μmol, 1.0 equivalent) in DCM (3 mL), TEA (275.78 mg, 2.73 mmol, 379.86 μL, 3.0 equivalents) and Boc2O (237.92 mg, 1.09 mmol, 250.44 μL, 1.2 equivalents) were added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated to obtain a residue. The residue was purified by column chromatography to produce (1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (240 mg, yield 97.57%). LCMS m / z = 266.0 [M+H] + 1 H 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).

[0266] Step d: (1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (200 mg, 754.06 μmol, 1.0 equivalent) and NCS (151.03 mg, 1.13 mmol, 1.5 equivalents) were dissolved 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), extracted with  (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce (5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (150 mg, yield 66.07%). LCMS m / z = 299.9 [M+H] + 1 H NMR: (400 MHz, CDCl3) δ: 7.99 (s, 1H), 6.05 (s, 1H), 4.71-4.64 (m, 2H), 1.53 (s, 9H).

[0267] Step e: (5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (50 mg, 157.84 μmol, 1.0 equivalent) was dissolved in HCl / Â (2 mL) at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated to obtain 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-amine (30 mg, crude). LCMS m / z = 200.1 [M+H] +

[0268] Step f: To a solution of 5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-amine (30 mg, 150.33 μmol, 1.0 equivalent) and 6-chloro-1H-indole-3-sulfonyl chloride (37.60 mg, 150.33 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (59.46 mg, 751.65 μmol, 60.79 μL, 5.0 equivalent) was added at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The solvent was evaporated under vacuum. The residue was purified by preparative HPLC (Waters xbridge 150x25mmx10um, water (NH4HCO3)-ACN as mobile phase, 27%~57%, gradient time (min): 10, flow rate (ml / min): 30) to obtain 6-chloro-N-(5-chloro-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (11.23 mg, yield 18.06%). LCMS m / z = 412.8 [M+H] + 1 H 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).

[0269] Example 142: 6-Chloro-N-(4,5-dimethylisothiazol-3-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 5-methylisothiazole-3-amine (40.00 mg, 265.55 μmol, 1.0 equivalent) in MeCN (2.0 mL), N-iodosquinamide (59.74 mg, 265.55 μmol, 1.0 equivalent) was added at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was quenched with saturated Na₂SO₃ (water). The mixture was extracted with  (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue, which was purified by preparative TLC to obtain 4-iodo-5-methylisothiazole-3-amine (40.00 mg, yield 62.75%). LCMS m / z = 241.0 [M+H] + 1 H NMR: (500MHz, DMSO) δ: 6.02-6.00 (m, 2H), 2.36 (s, 3H).

[0270] Step b: To a solution of 4-iodo-5-methylisothiazole-3-amine (27.00 mg, 112.47 μmol, 1.0 equivalent) in dioxane (2 mL), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (56.48 mg, 224.94 μmol, 2.0 equivalent), K2CO3 (46.63 mg, 337.41 μmol, 3.0 equivalent), Pd(dppf)Cl2 (8.23 mg, 11.25 μmol, 0.1 equivalent), and water (0.4 mL) were added at 25°C under N2. The mixture was stirred at 90°C for 16 hours. The solvent was concentrated under vacuum to obtain a residue, which was purified by preparative TLC to obtain 4,5-dimethylisothiazole-3-amine (17.00 mg, yield 86.03%). LCMS m / z = 129.3 [M+H] + .

[0271] Step c: To a solution of 4,5-dimethylisothiazole-3-amine (13.00 mg, 101.41 μmol, 1.0 equivalent) in THF (2.0 mL), 6-chloro-1H-indole-3-sulfonyl chloride (25.36 mg, 101.41 μmol, 1.0 equivalent) was added at 20°C. t-BuOK (1 M, 223.10 μL, 2.2 equivalents) was added dropwise to the mixture at 0°C. The mixture was stirred at 20°C for 16 hours. The solvent was evaporated under vacuum to obtain a residue, which was purified by preparative HPLC (NH4HCO3) (column: Boston Prime C18 150×30mm×5um); mobile phase: 10%~40% water (NH3H2O+NH4HCO3)-ACN; flow rate (ml / min): 25) to obtain 6-chloro-N-(4,5-dimethylisothiazole-3-yl)-1H-indole-3-sulfonamide (1.6 mg, yield 4.62%). LCMS m / z = 349.9 [M+H] + 1 H 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).

[0272] Example 143: 6-Chloro-N-(4-Chloro-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide [ka] To a solution of 4-chloro-5-methylisothiazole-3-amine (Preparation 52) (15.00 mg, 101.41 μmol, 1.0 equivalent) in THF (2.0 mL), 6-chloro-1H-indole-3-sulfonyl chloride (25.36 mg, 101.41 μmol, 1.0 equivalent) was added at 20°C. t-BuOK (1 M, 223.10 μL, 2.2 equivalents) was added dropwise to the mixture at 0°C. The mixture was stirred at 20°C for 16 hours. The solvent was evaporated under vacuum to obtain a residue, which was purified by preparative HPLC (NH4HCO3) (column: Boston Prime C18 150x30mmx5um); mobile phase: 13%~43% water (NH3H2O+NH4HCO3)-ACN; flow rate (ml / min): 25) to obtain 6-chloro-N-(4-chloro-5-methylisothiazol-3-yl)-1H-indole-3-sulfonamide (3.10 mg, yield 8.44%). LCMS m / z = 361.9 [M+H] + 1 H NMR: (400MHz, MeOD) δ: 7.95-7.86 (m, 2H), 7.44 (s, 1H), 7.16-7.12 (m, 1H), 2.35 (s, 3H).

[0273] Example 144: 6-Chloro-N-(3-methoxyisothiazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide [ka] Step a: The mixture of 6-chloro-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.31 mmol, 1.0 equivalent) in sulfonic chloride (3.51 g, 30.09 mmol, 2 mL) was stirred at 20°C. The reaction mixture was stirred at 90°C for 14 hours. The reaction mixture was quenched with ice water (60 mL), filtered, and washed with water (60 mL). The filtered cake was evaporated under vacuum to obtain 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride (250 mg, yield 75.96%). LCMS m / z = 251.0 [M+H] + .

[0274] Step b: To a solution of 6-chloro-1H-pyrrolo[2,3-b]pyridine-3-sulfonyl chloride (50 mg, 199.13 μmol, 1.0 equivalent) in DCM (2 mL), 3-methoxyisothiazole-4-amine (33.18 mg, 199.13 μmol, 1.0 eq. HCl) and pyridine (47.25 mg, 597.40 μmol, 3.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 12 hours. The mixture was concentrated to the residue and purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, mobile phase: water (FA)-ACN, 25% to 55%, gradient time (min): 11, flow rate (ml / min): 25) to obtain 6-chloro-N-(3-methoxyisothiazole-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-sulfonamide (41.8 mg, yield 60.88%). LCMS m / z = 344.8 [M+H] + 1 H 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).

[0275] Example 145: 6-Chloro-N-(3-ethoxyisothiazol-4-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of isothiazole-3-ol (500.00 mg, 4.94 mmol, 1.0 equivalent) in DMF (10.0 mL), iodoethane (925.36 mg, 3.91 mmol, 1.2 equivalents) and Cs2CO3 (3.22 g, 9.89 mmol, 2.0 equivalents) were added at 25°C and the mixture was stirred at 25°C for 16 hours. Water (30 mL) was added to the mixture and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and dried over Na2SO4. The filtrate was concentrated under vacuum to obtain a residue, which was purified by column chromatography to obtain 3-ethoxyisothiazole (260.00 mg, yield 40.71%). 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).

[0276] Step b: To a solution of 3-ethoxyisothiazole (100.00 mg, 774.11 μmol, 1.0 equivalent) in H2SO4 (2.0 mL), HNO3 (2.83 g, 44.85 mmol, 58 equivalents) was added at 0°C. The mixture was stirred at 55°C for 16 hours. The solution was poured onto ice and neutralized to pH=7 with aqueous NaOH solution (1.0 M). The solid was extracted twice with ethyl acetate (20 mL x 3), the combined organic phase was washed once with brine (50 mL), and then dried over Na2SO4. The solution was filtered and concentrated under reduced pressure to obtain 3-ethoxy-4-nitroisothiazole (20.00 mg, yield 14.83%). 1 H NMR: (400MHz, DMSO) δ: 9.98 (s, 1H), 4.50-4.44 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0277] Step c: To a solution of 3-ethoxy-4-nitroisothiazole (20.00 mg, 114.83 μmol, 1.0 equivalent) in EtOH (3.0 mL) and water (1 mL), Fe (64.13 mg, 1.15 mmol, 10.0 equivalents) and NH4Cl (30.71 mg, 574.13 μmol, 5.0 equivalents) were added at 25°C under N2. The mixture was stirred at 70°C for 2 hours. The mixture was filtered and concentrated under vacuum. The residue was then dissolved in water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was dried over Na2SO4 and filtered under vacuum to obtain 3-ethoxyisothiazole-4-amine (10.00 mg, yield 60.40%). LCMS m / z = 144.8 [M+H] + .

[0278] Step d: To a solution of 3-ethoxyisothiazole-4-amine (10.00 mg, 69.35 μmol, 1.0 equivalent) and 6-chloro-1H-indole-3-sulfonyl chloride (17.34 mg, 69.35 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (16.46 mg, 208.05 μmol, 3.0 equivalent) was added at 20°C and stirred at 20°C for 16 hours. The mixture was filtered and concentrated under vacuum to obtain the residue. The solvent was evaporated under vacuum to obtain a residue, which was purified by preparative HPLC (FA) (column: Welch Xtimate C18 150x25mmx5um); mobile phase: 30%~60% water (FA)-ACN; flow rate (ml / min): 25) to obtain 6-chloro-N-(3-ethoxyisothiazole-4-yl)-1H-indole-3-sulfonamide (6.6 mg, yield 26.60%). LCMS m / z = 358.0 [M+H] + ; 1 H 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).

[0279] Example 146: 6-Chloro-N-(5-Chloro-3-methoxyisothiazole-4-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 3-methoxyisothiazole-4-amine (15 mg, 115.24 μmol, 1.0 equivalent) in MeCN (2 mL), NCS (15.39 mg, 115.24 μmol, 1.0 equivalent) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was quenched with saturated Na₂SO₃ aqueous solution (20 mL). The organic layer was washed with brine (10 mL x 2), dried over Na₂SO₄, filtered, and concentrated to obtain 5-chloro-3-methoxyisothiazole-4-amine (18 mg, crude). LCMS m / z = 165.1 [M+H] + .

[0280] Step b: To a solution of 5-chloro-3-methoxyisothiazole-4-amine (28 mg, 111.95 μmol, 1.0 equivalent) in DCM (2 mL), 6-chloro-1H-indole-3-sulfonyl chloride (18.43 mg, 111.95 μmol, 1.0 equivalent) and pyridine (26.57 mg, 335.86 μmol, 3.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated to the residue and purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, mobile phase: water (FA)-ACN, 22%~52%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-3-methoxyisothiazole-4-yl)-1H-indole-3-sulfonamide (1.2 mg, yield 2.83%). LCMS m / z = 378.9 [M+H] + ; 1 H 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).

[0281] Example 147: 6-Chloro-N-(3-chloroisothiazol-4-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 3-chloroisothiazole (200.00 mg, 1.67 mmol, 1.0 equivalent) in H2SO4 (3 mL), HNO3 (4.24 g, 67.27 mmol, 40.2 equivalents) was added at 0°C. The mixture was stirred at 55°C for 16 hours. The solution was poured onto ice and neutralized to pH=7 with aqueous NaOH solution (1 M). The solid was extracted twice with ethyl acetate (20 mL x 3), the combined organic phase was washed once with brine (50 mL), and then dried over Na2SO4. The mixture was filtered and concentrated under reduced pressure to obtain 3-chloro-4-nitroisothiazole (90.00 mg, yield 32.70%). 1 H NMR: (400MHz, DMSO) δ: 10.09 (s, 1H).

[0282] Step b: To a solution of 3-chloro-4-nitroisothiazole (90.00 mg, 546.88 μmol, 1.0 equivalent) in EtOH (3 mL) and water (1 mL), Fe (305.40 mg, 5.47 mmol, 10.0 equivalents) and NH4Cl (146.27 mg, 2.73 mmol, 5.0 equivalents) were added at 25°C under N2. The mixture was stirred at 70°C for 2 hours. The mixture was filtered and concentrated under vacuum. The residue was then dissolved in water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was dried over Na2SO4 and filtered under vacuum to obtain 3-chloroisothiazole-4-amine (45.00 mg, yield 61.14%, purity 70%). 1 H NMR: (400MHz, DMSO) δ: 7.62 (s, 1H), 5.14 (s, 2H).

[0283] Step c: To a solution of 3-chloroisothiazole-4-amine (20.00 mg, 148.60 μmol, 1.0 equivalent) and 6-chloro-1H-indole-3-sulfonyl chloride (37.17 mg, 148.60 μmol, 1.0 equivalent) in DCM (2.0 mL), pyridine (35.26 mg, 445.81 μmol, 3.0 equivalent) was added at 25°C and the mixture was stirred at 20°C for 16 hours. The mixture was filtered, concentrated under vacuum to obtain the residue, and the solvent was evaporated under vacuum to obtain the residue. This residue was purified by preparative HPLC (FA) (column: Welch Xtimate C18 150x25mmx5um); mobile phase: 55%~85% water (FA)-ACN; flow rate (ml / min): 25) to obtain 6-chloro-N-(3-chloroisothiazole-4-yl)-1H-indole-3-sulfonamide (16.1 mg, yield 31.11%). LCMS m / z = 347.9 [M+H] + 1 H 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).

[0284] Example 148: 6-Chloro-N-(4-chlorothiazole-5-yl)-1H-indole-3-sulfonamide [ka] Step a: Dissolve tert-butyl thiazole-5-ylcarbamate (150 mg, 749.04 μmol, 1.0 equivalent) and NCS (150.03 mg, 1.12 mmol, 1.5 equivalents) in MeCN (3 mL) at 25°C. Stir the reaction mixture at 25°C for 2 hours. Dilute the reaction mixture with H2O (30 mL), extract with  (20 mL x 3), dry over Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Purify the residue by column chromatography to produce (4-chlorothiazole-5-yl)carbamate tert-butyl (100 mg, yield 56.17%). 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).

[0285] Step b: To a solution of tert-butyl (4-chlorothiazole-5-yl)carbamate (100 mg, 426.07 μmol, 1.0 equivalent) in HFIP (3 mL), TFA (48.58 mg, 426.07 μmol, 32.63 μL, 1.0 equivalent) was added at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated to obtain the residue. The residue was purified by preparative HPLC (Welch Xtimate C18 150x25 mmx10 μm, water (NH3H2O)-ACN as mobile phase, 5%~35%, gradient time (min): 10, flow rate (ml / min): 30) to obtain 4-chlorothiazole-5-amine (12 mg, yield 13.39%, purity 64%).

[0286] Step c: To a solution of 4-chlorothiazole-5-amine (12 mg, 89.16 μmol, 1.0 equivalent) and 6-chloro-1H-indole-3-sulfonyl chloride (22.30 mg, 89.16 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (28.21 mg, 356.65 μmol, 28.85 μL, 3.0 equivalent) was added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The solvent was evaporated under vacuum. The residue was purified by preparative HPLC (Welch Xtimate C18 150x25mmx5um, water (NH3H2O)-ACN as mobile phase, 1%~30%, gradient time (min): 10, flow rate (ml / min): 30) to obtain 6-chloro-N-(4-chlorothiazole-5-yl)-1H-indole-3-sulfonamide (9.6 mg, yield 30.60%). LCMS m / z = 347.7 [M+H] + 1 H 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).

[0287] Example 149: 6-Chloro-7-methoxy-N-(3-methoxyisothiazole-4-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 1-chloro-2-methoxy-3-nitrobenzene (500 mg, 2.67 mmol, 1.0 equivalent) in THF (20.0 mL), magnesium vinyl bromide (1 M, 10.66 mL, 4.0 equivalents) was added dropwise under N2 at -78°C. The reaction mixture was stirred at -78°C for 3 hours. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (50 mL), extracted with  (40 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 6-chloro-7-methoxy-1H-indole (85 mg, yield 16.50%, purity 93.968%). LCMS m / z = 182.0 [M+H] + 1 H 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).

[0288] Step b: To a solution of 6-chloro-7-methoxy-1H-indole (80 mg, 440.48 μmol, 1.0 equivalent) in MeCN (3.0 mL), HSO3Cl (513.27 mg, 4.40 mmol, 292.79 μL, 10.0 equivalents) was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (20 mL), extracted with Âxy (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 6-chloro-7-methoxy-1H-indole-3-sulfonyl chloride (30 mg, yield 7.70%). 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).

[0289] Step c: To a solution of 6-chloro-7-methoxy-1H-indole-3-sulfonyl chloride (30.00 mg, 107.09 μmol, 1.0 equivalent) and 3-methoxyisothiazole-4-amine (13.94 mg, 107.09 μmol, 1.0 equivalent) in DCM (2.0 mL), pyridine (25.41 mg, 321.28 μmol, 3.0 equivalent) was added at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The mixture was filtered and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (NH4HCO3) (column: Boston Prime C18 150x30mmx5um); mobile phase: 2%~32% water (NH3H2O+NH4HCO3)-ACN; flow rate (ml / min): 25) to obtain 6-chloro-7-methoxy-N-(3-methoxyisothiazole-4-yl)-1H-indole-3-sulfonamide (8.40 mg, yield 20.98%). LCMS m / z = 373.9 [M+H] + 1 H 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).

[0290] Example 150: 6-Chloro-N-(4-methoxyisothiazole-3-yl)-1H-indole-3-sulfonamide [ka] Step a: Diazomethyl(trimethyl)silane (2M, 1.38 mmol, 689.01 μL, 2.0 equivalents) was added at 25°C to a solution of 4-hydroxyisothiazole-3-carboxylic acid (100 mg, 689.01 μmol, 1.0 equivalent) in MeOH (5.00 mL) and THF (5.00 mL). 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  (50 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to obtain methyl 4-hydroxyisothiazole-3-carboxylic acid (30 mg, yield 27.36%). LCMS m / z = 160.1 [M+H] +

[0291] Step b: To a solution of 4-hydroxyisothiazole-3-methyl carboxylate (30 mg, 188.49 μmol, 1.0 equivalent) in ACN (5 mL), MeI (52.85 mg, 376.97 μmol, 2.0 equivalents) and K2CO3 (78.15 mg, 565.46 μmol, 3.0 equivalents) were added at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was evaporated under vacuum to obtain the residue. The residue was purified by column chromatography to obtain 4-methoxyisothiazole-3-methyl carboxylate (30 mg, yield 91.90%). LCMS m / z = 174.1 [M+H] + .

[0292] Step c: To a mixture of methyl 4-methoxyisothiazole-3-carboxylate (30 mg, 173.22 μmol, 1.0 equivalent) in MeOH (2 mL) and water (2 mL), lithium hydroxide (14.55 mg, 346.44 μmol, 2.0 equivalents) was added all at once at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was diluted to pH=7 with saturated aqueous HCl. The mixture was concentrated under vacuum to obtain a residue, which was recrystallized from water and dried by freeze-drying to obtain 4-methoxyisothiazole-3-carboxylic acid (27 mg, crude). LCMS m / z = 160.0 [M+H] + .

[0293] Step d: To a solution of 4-methoxyisothiazole-3-carboxylic acid (27 mg, 169.64 μmol, 1.0 equivalent) in t-BuOH (2 mL), TEA (51.50 mg, 508.91 μmol, 3.0 equivalents) and diphenyl phosphate azide (70.03 mg, 254.46 μmol, 1.5 equivalents) were added at 20°C. The mixture was heated and stirred at 90°C for 16 hours. The mixture was concentrated under vacuum to obtain a residue, which was purified by column chromatography to obtain tert-butyl (4-methoxyisothiazole-3-yl)carbamate (10 mg, yield 25.60%). LCMS m / z = 231.1 [M+H] + .

[0294] Step e: (4-methoxyisothiazole-3-yl)carbamate tert-butyl (10 mg, 43.42 μmol, 1.0 equivalent) was dissolved in HCl / Â (2 mL) and stirred at 25°C for 6 hours. The solvent was evaporated under vacuum to obtain 4-methoxyisothiazole-3-amine (10 mg, crude) as a white solid. LCMS m / z = 231.1 [M+H] + .

[0295] Step f: 4-methoxyisothiazole-3-amine (10.41 mg, 79.97 μmol, 1.0 equivalent) was added at 25°C to a solution of 6-chloro-1H-indole-3-sulfonyl chloride (20 mg, 79.97 μmol, 1.0 equivalent) in DCM (3 mL). The mixture was stirred at 25°C for 16 hours. The mixture was concentrated to the residue and purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 μm, mobile phase: water (FA)-ACN, 28%~58%, gradient time (min): 11, flow rate (ml / min): 25) to obtain 6-chloro-N-(4-methoxyisothiazole-3-yl)-1H-indole-3-sulfonamide (1.4 mg, yield 5.09%). 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).

[0296] Example 151: 6-Chloro-N-(5-Chloro-1-(3,3-difluoropropyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] Step h: To a solution of 5-chloro-1-(4,4-difluorobutyl)-1H-pyrazole-4-amine (Preparation 51) (33 mg, 168.71 μmol, 1.0 equivalent) and 6-chloro-1H-indole-3-sulfonyl chloride (42.20 mg, 168.71 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (40.04 mg, 506.14 μmol, 40.94 μL, 3.0 equivalent) was added at 25°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150×25mm×10um, mobile phase: water (NH3H2O+NH4HCO3)-ACN, 32%~62%, gradient time (min): 15, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(3,3-difluoropropyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (5.7 mg, yield 8.20%). LCMS m / z = 408.9 [M+H] + 1 H NMR (400 MHz, MeOD) δ: 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).

[0297] Example 152: 6-Chloro-N-(5-Chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 4-nitro-1H-pyrazole (1.0 g, 8.84 mmol, 1.0 equivalent) and 2-bromoethane-1-ol (1.22 g, 9.73 mmol, 689.54 μL, 1.1 equivalents) in DMF (15 mL), K2CO3 (3.67 g, 26.53 mmol, 3.0 equivalents) was added. The mixture was stirred at 70°C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 2-(4-nitro-1H-pyrazole-1-yl)ethane-1-ol (1.0 g, yield 71.96%). 1 H 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).

[0298] Step b: To a solution of 2-(4-nitro-1H-pyrazole-1-yl)ethane-1-ol (500 mg, 3.18 mmol, 1.0 equivalent) and CuI (303.02 mg, 1.59 mmol, 0.5 equivalent) in MeCN (10 mL), a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (850.05 mg, 4.77 mmol, 493.35 μL, 1.5 equivalent) in MeCN (10 mL) was added dropwise under N2 over 30 minutes at 55°C. The reaction mixture was stirred for a further 2 hours at 55°C. The reaction mixture was diluted with H2O (20 mL) and extracted with  (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to produce 1-(2-(difluoromethoxy)ethyl)-4-nitro-1H-pyrazole (120 mg, yield 18.21%). 1 H 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).

[0299] Step c: To a solution of 1-(2-(difluoromethoxy)ethyl)-4-nitro-1H-pyrazole (120 mg, 579.33 μmol, 1.0 equivalent) in EtOH (3 mL) and water (1 mL), Fe (161.78 mg, 2.90 mmol, 20.58 μL, 5.0 equivalents) and NH4Cl (154.95 mg, 2.90 mmol, 5.0 equivalents) were added 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 obtain 1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-amine (150 mg, crude), which was used without purification. LCMS m / z = 178.3 [M+H] +

[0300] Step d: To a solution of 1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-amine (150 mg, 846.73 μmol, 1.0 equivalent) in DCM (2 mL), Boc2O (277.19 mg, 1.27 mmol, 291.78 μL) and TEA (257.04 mg, 2.54 mmol, 354.05 μL, 3.0 equivalent) were added 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 obtain the residue. The residue was purified by column chromatography to produce (1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (100 mg, yield 41.04%). LCMS m / z = 278.1 [M+H] + 1 H 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).

[0301] Step e: To a solution of (1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (100 mg, 360.66 μmol, 1.0 equivalent) in MeCN (5 mL), NCS (96.32 mg, 721.33 μmol, 2.0 equivalents) was added at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain (5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (30 mg, yield 24.62%, purity 92.27%). LCMS m / z = 312.1 [M+H] +

[0302] Step f: To a solution of tert-butyl (5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-yl)carbamate (30 mg, 96.24 μmol, 1.0 equivalent) in HFIP (3 mL), TFA (10.97 mg, 96.24 μmol, 7.37 μL, 1.0 equivalent) was added at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-amine (20 mg, yield 98.21%). The crude compound was used in the next step without further purification. LCMS m / z = 212.2 [M+H] +

[0303] Step g: To a solution of 5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-amine (20 mg, 94.52 μmol, 1.0 equivalent) in DCM (2 mL), 6-chloro-1H-indole-3-sulfonyl chloride (23.64 mg, 94.52 μmol, 1.0 equivalent) and pyridine (22.43 mg, 283.56 μmol, 22.93 μL, 3.0 equivalent) were added at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150x25mmx10um, mobile phase: water (NH4HCO3)-ACN, 28%~58%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(2-(difluoromethoxy)ethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (8.1 mg, yield 19.76%). LCMS m / z = 426.8 [M+H] + 1 H 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).

[0304] Example 153: 6-Chloro-N-(5-Chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] Step a: DIAD (894.13 mg, 4.42 mmol, 1.0 equivalent) was slowly added at 20°C to a solution of 4-nitro-1H-pyrazole (500.00 mg, 4.42 mmol, 1.0 equivalent), 2-(2,2,2-trifluoroethoxy)ethane-1-ol (637.15 mg, 4.42 mmol, 1.0 equivalent), and PPh3 (1.16 g, 4.42 mmol, 1.0 equivalent) in THF (20 mL). 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 layer was washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by column chromatography to obtain 4-nitro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole (40.00 mg, yield 37.83%). LCMS m / z = 240.0 [M+H] +

[0305] 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 equivalent) in MeOH (10.0 mL), Pd / C (111.25 mg, 104.54 μmol, 10% purity, 0.1 equivalent) was added at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was filtered and concentrated under vacuum to obtain 1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole-4-amine (200.00 mg, yield 91.74%), which was used without purification. LCMS m / z = 210.0 [M+H] + 1H NMR (500MHz, DMSO) δ: 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).

[0306] Step c: To a solution of 1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole-4-amine (40.00 mg, 191.23 μmol, 1.0 equivalent) in DCM (4 mL), TEA (58.05 mg, 573.30 μmol, 3.0 equivalents) and (Boc)2O (83.47 mg, 382.47 μmol, 2.0 equivalents) were added 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 layer was washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain a residue, which was purified by preparative TLC to obtain (1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (50.00 mg, yield 84.54%). LCMS m / z = 309.9 [M+H] +

[0307] Step d: To a solution of (1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (40.00 mg, 129.33 μmol, 1.0 equivalent) in MeCN (2.0 mL), NCS (103.62 mg, 775.99 μmol, 6.0 equivalent) was added at 20°C. The mixture was stirred at 60°C for 9 hours. The mixture was concentrated under vacuum to obtain a residue, which was purified by preparative TLC to supply (5-chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole-4-yl)carbamate tert-butyl (25.00 mg, yield 56.24%). LCMS m / z = 343.9 [M+H] +

[0308] Step e: To a solution of tert-butyl (5-chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole-4-yl)carbamate (10.00 mg, 29.09 μmol, 1.0 equivalent) in DCM (0.2 mL), TFA (0.02 mL) was added at 20°C. The reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was concentrated and used directly in the next step.

[0309] Step f: To a solution of 6-chloro-1H-indole-3-sulfonyl chloride (7.19 mg, 28.73 μmol, 1.0 equivalent) in DCM (2.0 mL), crude 5-chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole-4-amine (7.00 mg, 28.73 μmol, 1.0 equivalent) and pyridine (22.73 mg, 287.34 μmol, 3.0 equivalents) were added at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The mixture was filtered and concentrated under vacuum to obtain the residue, which was purified by preparative HPLC (NH4HCO3) (column: Boston Prime C18 150x30mmx5um); mobile phase: 15%~45% water (NH3H2O+NH4HCO3)-ACN; flow rate (ml / min): 25 to obtain 6-chloro-N-(5-chloro-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (4.30 mg, yield 32.73%). LCMS m / z = 456.9 [M+H] + 1 H NMR (400MHz, MeOD) δ: 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).

[0310] Example 154: 6-Chloro-N-(5-Chloro-1-isopentyl-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] To a solution of 5-chloro-1-isopentyl-1H-pyrazole-4-amine (Preparation 35) (30 mg, 159.86 μmol, 1.0 equivalent) in DCM (3 mL), pyridine (37.93 mg, 479.57 μmol, 38.9 μL, 1.0 equivalent) and 6-chloro-1H-indole-3-sulfonyl chloride (15.00 mg, 59.98 μmol, 0.38 equivalents) were added at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative TLC to obtain 6-chloro-N-(5-chloro-1-isopentyl-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (8.6 mg, yield 13.41%). LCMS m / z = 402.0 [M+H] + 1 H 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).

[0311] Example 155: 7-Bromo-6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] To a solution of 5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-amine (Preparation 10) (36.01 mg, 0.20 mmol) in pyridine (1.00 mL, 0.2 M), 7-bromo-6-chloro-1H-indole-3-sulfonyl chloride (Preparation 29; 65.8 mg, 0.20 mmol) and DMAP crystals (catalyst) were added. The reaction mixture was heated at 90°C for 16 hours, cooled to room temperature, and quenched with water. The mixture was extracted three times with DCM, dried over sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography. The title compound, 7-bromo-6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (28.5 mg, yield 95.0%), was obtained. LCMS m / z = 472.8 [M+H] + 1 H 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).

[0312] Example 156: 7-Bromo-6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] A scintillation vial containing 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (Preparation 18) (713.7 mg, 4.26 mmol, 2 equivalents) was mixed with 7-bromo-6-chloro-1H-indole-3-sulfonyl chloride (Preparation 29) (700.0 mg, 2.13 mmol, 1 equivalent) and DMAP crystals (catalyst). The contents were dissolved in pyridine (25.0 mL, 0.1 M) and heated at 55°C for 16 hours. The reaction mixture was then diluted with water and extracted twice with DCM and once with ethyl acetate. The combined organic matter was dried over sodium sulfate and concentrated under vacuum to supply the crude product as brown oil. The crude residue was purified by silica gel chromatography to supply 7-bromo-6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (583.7 mg, yield 59.6%). LCMS m / z = 459.0 [MH] - 1 H 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, 1H).

[0313] Example 157: 6-Chloro-N-(5-Chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] To a solution of 6-chloro-1H-indole-3-sulfonyl chloride (40.00 mg, 220.30 μmol, 1.0 equivalent) in pyridine (2 mL), 5-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-amine (Preparation 6) (27.55 mg, 110.15 μmol, 0.5 equivalent) was added at 25°C. The reaction mixture was stirred at 60°C for 1 hour. The mixture was concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex C18 150x25mmx10um, mobile phase: water (FA)-ACN, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (16.9 mg, yield 19.22%). LCMS m / z = 394.9 [M+H] + . 1 H NMR: (400MHz, DMSO) δ: 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).

[0314] Example 158: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] A scintillation vial containing tert-butyl (5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)carbamate (864.9 mg, 3.23 mmol, 2.0 equivalents) was mixed with HFIP (16.2 mL, 0.1 M), followed by TFA (0.25 mL, 3.23 mmol, 2.0 equivalents). The reaction mixture was stirred at room temperature for 2 hours, and as the reaction progressed, it changed from bright yellow to orange. The reaction mixture was then directly concentrated under reduced pressure to supply 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine as a concentrated red oil, which was used without purification, assuming a quantitative yield.

[0315] Next, 6-chloro-1H-indole-3-sulfonyl chloride (404.0 mg, 1.62 mmol, 1.0 equivalent) was added to the vial containing pyrazole. The reaction mixture was dissolved in pyridine (8.0 mL), and then DMAP (19.7 mg, 0.162 mmol, 0.10 equivalent) was added. The reaction mixture was stirred at 75°C for approximately 18 hours, then diluted with water and extracted twice with DCM, followed by once with Âxy. The combined organic matter was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product as brown oil. The crude residue was purified by silica gel chromatography to supply the title compound as brown oil (503.3 mg).

[0316] The product was further purified by two-cycle preparative HPLC (column: Waters XSelect CSH Prep C18 5um OBD 30×100mm; mobile phase: 5%~55% water (NH4OH)-MeCN; flow rate (ml / min): 50) to supply 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (163.8 mg, yield 26.6%). LCMS m / z = 380.8 [M+H] + . 1 H 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).

[0317] Example 159: 6-Chloro-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] 6-chloro-1H-indole-3-sulfonyl chloride (39 mg, 1.0 equivalent) was added to a solution of 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-amine hydrochloride (35 mg, 1.1 equivalents) in dry pyridine (1 mL). The reaction mixture was stirred at 60°C for 24 hours. The solvent was then evaporated under vacuum, and the residue was dissolved in DMSO (0.5 mL). The mixture was subjected to preparative HPLC (Waters SunFire C18 19*100 5 mkm column; gradient mixture H2O-MeOH as mobile phase) to obtain 6-chloro-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (27.3 mg, 46% yield). LCMS m / z = 379.0 [M+H] + . 1 H 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).

[0318] Example 160: 6-Chloro-N-(5-Chloro-1-(trifluoromethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] To a solution of 6-chloro-1H-indole-3-sulfonyl chloride (90 mg, 359.85 μmol, 1.0 equivalent) in DCM (3 mL), 5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-amine (Preparation 2) (66.77 mg, 359.85 μmol, 1.0 equivalent) and pyridine (85.39 mg, 1.08 mmol, 3.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated to obtain a residue, which was purified by preparative HPLC (column: YMC-Triart Prep C18 150*40mm*7um, mobile phase: water (FA)-ACN, 40%~60%, gradient time (min): 15, flow rate (ml / min): 50) to obtain 6-chloro-N-(5-chloro-1-(trifluoromethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (27.4 mg, yield 19.07%). LCMS m / z = 399.0 [M+H] + 1 H 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).

[0319] Example 161: 6,7-Dichloro-N-(3-methoxyisothiazole-4-yl)-1H-indole-3-sulfonamide [ka] Pyridine (12.51 mg, 158.15 μmol, 3.0 equivalents) was added at 20°C to a solution of 6,7-dichloro-1H-indole-3-sulfonyl chloride (Preparation 28) (15.00 mg, 52.72 μmol, 1.0 equivalent) and 3-methoxyisothiazole-4-amine (6.86 mg, 52.72 μmol, 1.0 equivalent) in DCM (2.0 mL). The reaction mixture was stirred at 20°C for 4 hours. The mixture was filtered and concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (NH4HCO3) (column: Boston Prime C18 150x30mmx5um); mobile phase: 10%~40% water (NH3H2O+NH4HCO3)-ACN; flow rate (ml / min): 25) to obtain 6,7-dichloro-N-(3-methoxyisothiazole-4-yl)-1H-indole-3-sulfonamide (8.40 mg, yield 20.98%). LCMS m / z = 377.9 [M+H] + 1 H 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).

[0320] Example 162: 6-Chloro-N-(5-propylthiazole-2-yl)-1H-indole-3-sulfonamide [ka] A scintillation vial containing 5-propylthiazole-2-amine (34.1 mg, 240.0 μmol, 1.2 equivalents) was mixed with 6-chloro-1H-indole-3-sulfonyl chloride (50.0 mg, 200.0 μmol, 1.0 equivalent) and DMAP crystals (catalyst). The contents were dissolved in pyridine (2.0 mL, 0.1 M) and stirred at 50°C for approximately 72 hours. The reaction mixture was then quenched with water and extracted with Â. The organic matter was dried over sodium sulfate and concentrated under vacuum to supply the crude product as brown oil. The crude product was purified by preparative HPLC (column: Waters XSelect CSH Prep C18 5um OBD 30x100mm; mobile phase: 5%~55% water (NH4HCO3)-MeCN; flow rate (ml / min): 50) to obtain 6-chloro-N-(5-propylthiazole-2-yl)-1H-indole-3-sulfonamide (16.0 mg, yield 22.5%) as a white solid. LCMS m / z = 356.0 [M+H] + 1 H 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).

[0321] Example 163: 6-Chloro-N-(5-Chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of tert-butyl (1H-pyrazole-4-yl)carbamate (200 mg, 1.09 mmol, 1.0 equivalent) in MeCN (3 mL), cesium carbonate (711 mg, 2.18 mmol, 2 equivalents) was added at 25°C. The mixture was stirred at this temperature for 15 minutes, and then 1-bromo-3-(trifluoromethyl)cyclobutane (244 mg, 1.20 mmol, 1.1 equivalents) was added. The mixture was stirred at 50°C for 72 hours. The mixture was concentrated into a residue, which was then dissolved again in ethyl acetate and washed with 10 mL of citric acid, 10 mL of water, and then 10 mL of brine. The organic matter was then dried over sodium sulfate, filtered, and concentrated into a residue. The residue was further purified by column chromatography to obtain tert-butyl (1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-4-yl)carbamate (85 mg, 26% yield). LCMS m / z = 306.1 [M+H] + .

[0322] Step b: To a solution of (1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-4-yl)carbamate tert-butyl (85 mg, 275.1 μmol, 1.0 equivalent) in MeCN (2 mL), N-chlorosuccinimide (36 mg, 206.4 μmol, 1.0 equivalent) was added at 25 °C. The mixture was stirred at 70 °C for 8 hours. The mixture was concentrated into a residue, which was redissolved in dichloromethane and washed with 10 mL of NaOH (1 M), 10 mL of water, and then 10 mL of brine. The organic matter was then dried over sodium sulfate, filtered, and concentrated into a residue. The residue was further purified by column chromatography to obtain (5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-4-yl)carbamate tert-butyl (65 mg, 70% yield). LCMS m / z = 340.1 [M+H] + .

[0323] Step c: To a solution of tert-butyl (5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-4-yl)carbamate (84 mg, 275.1 μmol, 1.0 equivalent) in HFIP (3 mL), TFA (69.11 mg, 606.06 μmol, 46.41 μL, 3.0 equivalents) was added at 25°C. The reaction mixture was stirred at 25°C for 18 hours. The mixture was concentrated to obtain the residue. The residue was again dissolved in ethyl acetate and washed with 10 mL of saturated sodium bicarbonate solution, 10 mL of water, and then 10 mL of brine. The organic layer was concentrated to obtain 5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-4-amine (43 mg, yield 88.83%). LCMS m / z = 240.1 [M+H] + .

[0324] Step d: Pyridine (2 mL) was added at 30°C to a solution of 5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-4-amine (43.25 mg, 180.48 μmol, 1.0 equivalent) and 6-chloro-1H-indole-3-sulfonyl chloride (45.14 mg, 180.48 μmol, 1.0 equivalent) in DCM (2 mL). The reaction mixture was stirred at 30°C for 18 hours. The solvent was evaporated under vacuum. The residue was purified by preparative HPLC (Waters Sunfire OBD 100x50mm, 5mm; 5-75% MeCN / H2O (+0.1% TFA)) to obtain 6-chloro-N-(5-chloro-1-(3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (38 mg, yield 46.45%) as a grayish-white solid. LCMS m / z = 453.1 [M+H] + ; 1 H 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).

[0325] Example 164: 6-Chloro-N-(5-Chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-7-(pyridazine-3-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 7-bromo-6-chloro-1H-indole (93.66 mg, 406.36 μmol, 1.5 equivalents) in toluene (5 mL), 3-(tributylstannyl)pyridazine (100.00 mg, 270.91 μmol, 1.0 equivalent), cateCXium A-Pd-G2 (18.11 mg, 27.09 μmol, 0.1 equivalent), and KF (47.22 mg, 812.72 μmol, 3.0 equivalents) were added at 20°C under N2. The mixture was stirred at 110°C for 16 hours. TLC showed that the starting material had been consumed and new spots were observed. The mixture was filtered and concentrated under vacuum to obtain the residue, which was purified by column chromatography to obtain 6-chloro-7-(pyridazin-3-yl)-1H-indole (35.00 mg, yield 56.251%). LCMS m / z = 230.2 [M+H] +

[0326] Step b: To a solution of 6-chloro-7-(pyridazin-3-yl)-1H-indole (35.00 mg, 152.40 μmol, 1.0 equivalent) in MeCN (3 mL), HSO3Cl (53.27 mg, 457.19 μmol, 3.0 equivalents) was added dropwise at 0°C and the mixture was stirred at 20°C for 1 hour. TLC showed that the starting material had been consumed and new spots were observed. Next, POCl3 (116.84 mg, 761.98 μmol, 5.0 equivalents) was slowly added to the mixture at 0°C. The mixture was stirred at 60°C for 16 hours. TLC showed that the starting material had been consumed and new spots were observed. Next, the solution was slowly poured into ice water (20 mL) while stirring, extracted with siRNA (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 6-chloro-7-(pyridazin-3-yl)-1H-indole-3-sulfonyl chloride (30.00 mg, purity 59.99%). LCMS m / z = 327.9 [M+H] +

[0327] Step c: To a solution of 6-chloro-7-(pyridazin-3-yl)-1H-indole-3-sulfonyl chloride (50 mg, 152.36 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (24.10 mg, 304.72 μmol, 24.65 μL, 2.0 equivalent) and 5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-amine (27.43 mg, 152.36 μmol, 1.0 equivalent) were added at 20°C. The mixture was stirred at 20°C for 16 hours. LC-MS showed that the desired product was detected. The mixture was concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, mobile phase: water (FA)-ACN, 32%~62%, gradient time (min): 11, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-7-(pyridazin-3-yl)-1H-indole-3-sulfonamide (2.1 mg, yield 2.91%, purity 99.49%). 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).

[0328] Example 165: N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-1H-indole-3-sulfonamide [ka] To a solution of 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-amine (Preparation 55) (30 mg, 141.51 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (22.39 mg, 283.03 μmol, 22.89 μL, 2.0 equivalent) and 6-chloro-1H-indole-3-sulfonyl chloride (35.39 mg, 141.51 μmol, 1.0 equivalent) were added at 20°C. The reaction mixture was stirred at 20°C for 16 hours. LC-MS confirmed the detection of the desired product. The mixture was concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5um, mobile phase: water (FA)-ACN, 40%~70%, gradient time (min): 10, flow rate (ml / min): 25) to obtain N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-1H-indole-3-sulfonamide (24.33 mg, yield 40.39%). LCMS m / z = 425.0 [M+H] + 1 H 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).

[0329] Example 166: N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(thiazole-4-yl)-1H-indole-3-sulfonamide [ka] To a solution of 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-amine (Preparation 55) (31.81 mg, 150.05 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (22.39 mg, 283.03 μmol, 22.89 μL, 2.0 equivalent) and 6-chloro-7-(thiazole-4-yl)-1H-indole-3-sulfonyl chloride (Preparation 56) (50 mg, 150.05 μmol, 1.0 equivalent) were added at 20°C. The reaction mixture was stirred at 20°C for 16 hours. LC-MS confirmed the detection of the desired product. The mixture was concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, mobile phase: water (FA)-ACN, 40%~70%, gradient time (min): 10, flow rate (ml / min): 25) to obtain N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(thiazole-4-yl)-1H-indole-3-sulfonamide (5.6 mg, yield 7.20%, purity 98.16%). LCMS m / z = 508.1 [M+H] + 1 H 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).

[0330] Example 167: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(thiazole-4-yl)-1H-indole-3-sulfonamide [ka] 6-Chloro-7-(thiazole-4-yl)-1H-indole-3-sulfonyl chloride (Preparation 56) (60.00 mg, 180.06 μmol, 1.0 equivalent) and 5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (30.17 mg, 180.06 μmol, 1.0 equivalent) were dissolved in DCM (3.0 mL), to which pyridine (42.73 mg, 540.19 μmol, 3.0 equivalents) was added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. LC-MS indicated that the starting materials had been consumed, and one peak representing the desired mass was detected. The mixture was concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*5um, mobile phase: water (FA)-ACN, 36%~66%, gradient time (min): 10, flow rate (ml / min): 30) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(thiazole-4-yl)-1H-indole-3-sulfonamide (10.83 mg, yield 12.95%, purity 100%). LCMS m / z = 463.8 [M+H] + 1 H 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).

[0331] Example 168: N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(2H-1,2,3-triazole-2-yl)-1H-indole-3-sulfonamide [ka] 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 equivalent) in DCM (4 mL), pyridine (24.94 mg, 315.31 μmol, 25.50 μL, 2.0 equivalent) and 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-amine (Preparation 55) (33.42 mg, 157.65 μmol, 1.0 equivalent) were added at 20°C. The reaction mixture was stirred at 20°C for 16 hours. LC-MS showed that the desired mass was detected. The mixture was concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, mobile phase: water (FA)-ACN, 45%~65%, gradient time (min): 10, flow rate (ml / min): 25) to obtain N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(2H-1,2,3-triazole-2-yl)-1H-indole-3-sulfonamide (5.53 mg, yield 6.92%, purity 97.25%). LCMS m / z = 494.0 [M+H] + 1 H 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).

[0332] Example 169: 6-Chloro-N-(5-Chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-7-(2H-1,2,3-triazole-2-yl)-1H-indole-3-sulfonamide [ka] 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 equivalent) and 5-Chloro-1-(2-chloroethyl)-1H-pyrazole-4-amine (34.06 mg, 189.18 μmol, 1.0 equivalent) were dissolved in 2.0 mL of DCM, to which pyridine (44.89 mg, 567.55 μmol, 3.0 equivalents) was added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated to obtain the residue. The residue was purified by preparative HPLC (Phenomenex luna C18 150*25mm*10um, water (FA)-ACN as mobile phase, 27%~57%, gradient time (min): 8, flow rate (ml / min): 30) to obtain 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-7-(2H-1,2,3-triazole-2-yl)-1H-indole-3-sulfonamide (23.5 mg, yield 26.96%). LCMS m / z = 461.7 [M+H] + 1 H 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).

[0333] Example 170: N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(pyridine-2-yl)-1H-indole-3-sulfonamide [ka] To a solution of 6-chloro-7-(pyridine-2-yl)-1H-indole-3-sulfonyl chloride (Preparation 58) (50 mg, 152.82 μmol, 1.0 equivalent) in DCM (3 mL), pyridine (24.18 mg, 305.64 μmol, 24.72 μL, 2.0 equivalent) and 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-amine (Preparation 55) (32.40 mg, 152.82 μmol, 1.0 equivalent) were added at 20°C. The mixture was stirred at 20°C for 16 hours. LC-MS showed that the desired mass was detected. The mixture was concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as mobile phase, 45%~65%, gradient time (min): 10, flow rate (ml / min): 25) to obtain N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(pyridine-2-yl)-1H-indole-3-sulfonamide (7.12 mg, yield 9.14%). LCMS m / z = 504.0 [M+H] + 1 H 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).

[0334] Example 171: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(pyridine-2-yl)-1H-indole-3-sulfonamide [ka] To a solution of 6-chloro-7-(pyridine-2-yl)-1H-indole-3-sulfonyl chloride (Preparation 58) (40 mg, 122.25 μmol, 1.0 equivalent) in DCM (4 mL), 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (20.48 mg, 122.25 μmol, 1.0 equivalent) and pyridine (29.01 mg, 366.76 μmol, 3.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated to obtain a residue, which was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5um, water (FA)-ACN as mobile phase, 35%~55%, gradient time (min): 12, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(pyridazin-2-yl)-1H-indole-3-sulfonamide (3.36 mg, yield 6.00%). LCMS m / z = 458.0 [M+H] + 1 H 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).

[0335] Example 172: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(pyridine-2-yl)-1H-indole-3-sulfonamide [ka] Step a: PdCl2(PPh3)2 (45.68 mg, 65.08 μmol, 0.1 equivalent) was added to a solution of 7-bromo-6-chloro-1H-indole (150 mg, 650.79 μmol, 1.0 equivalent) and 5-methyl-2-(tributylstannyl)pyridine (248.71 mg, 650.79 μmol, 1.0 equivalent) in dioxane (3 mL). The mixture was degassed three times with N2 and stirred at 100°C for 16 hours. LC-MS indicated that the reaction was complete. The reaction product was quenched with CsF (50 mg) in water (10 mL) and extracted with  (50 mL x 3). The mixture was filtered and concentrated. The residue was purified by column chromatography to obtain 6-chloro-7-(5-methylpyridine-2-yl)-1H-indole (40 mg, yield 25.32%). LCMS m / z = 242.9 [M+H] +

[0336] Step b: To a solution of 6-chloro-7-(5-methylpyridine-2-yl)-1H-indole (40 mg, 164.81 μmol, 1.0 equivalent) in MeCN (2 mL), sulfonic chloride (192.04 mg, 1.65 mmol, 10.0 equivalent) was added at 0°C. The mixture was stirred at 25°C for 30 minutes. TLC indicated that the reaction was complete. The reaction product was quenched with water (10 mL) and extracted with Âxa (50 mL x 3). The combined organic layer was dried over Na₂SO₄, filtered, and evaporated under vacuum to obtain 6-chloro-7-(5-methylpyridine-2-yl)-1H-indole-3-sulfonyl. The material was used without further purification, assuming a quantitative yield.

[0337] Step c: To a solution of 6-chloro-7-(5-methylpyridine-2-yl)-1H-indole-3-sulfonyl (50 mg, 146.54 μmol, 1.0 equivalent) in DCM (3 mL), 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (24.55 mg, 146.54 μmol, 1.0 equivalent) and pyridine (34.77 mg, 439.61 μmol, 3.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated to obtain a residue, which was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5um, water (FA)-ACN as mobile phase, 38%~58%, gradient time (min): 11, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(5-methylpyridine-2-yl)-1H-indole-3-sulfonamide (5.46 mg, yield 7.20%). LCMS m / z = 472.1 [M+H] + 1 H 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).

[0338] Example 173: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonamide [ka] 6-chloro-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (50 mg, 158.15 μmol, 1.0 equivalent) and 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (39.74 mg, 237.22 μmol, 1.5 equivalents) were dissolved in 2 mL of DCM, to which pyridine (37.53 mg, 474.44 μmol, 38.37 μL, 3.0 equivalents) was added at 20°C. The mixture was stirred at 20°C for 1 hour. LC-MS showed that the desired product was obtained. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5um, water (NH3H2O+NH4HCO3)-ACN as mobile phase, 29%~59%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonamide (2.8 mg, yield 3.93%). LCMS m / z = 446.9 [M+H] + 1 H 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).

[0339] Example 174: 6-Chloro-N-(5-Chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonamide [ka] To a solution of 6-chloro-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (50 mg, 158.15 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (25.02 mg, 316.29 μmol, 25.58 μL, 2.0 equivalent) and 5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-amine (28.47 mg, 158.15 μmol, 1.0 equivalent) were added at 20°C. The reaction mixture was stirred at 20°C for 16 hours. LC-MS showed that the desired mass was detected. The mixture was concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as mobile phase, 45%~65%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(2-chloroethyl)-1H-pyrazole-4-yl)-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonamide (18.2 mg, yield 24.90%). LCMS m / z = 461.0 [M+H] + 1 H 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).

[0340] Example 175: N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonamide [ka] To a solution of 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-amine (Preparation 55) (30 mg, 141.51 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (22.39 mg, 283.03 μmol, 22.89 μL, 2.0 equivalent) and 6-chloro-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (44.74 mg, 141.51 μmol, 1.85 equivalent) were added at 20°C. The reaction mixture was stirred at 20°C for 16 hours. LC-MS confirmed the detection of the desired product. The mixture was concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as mobile phase, 40%~70%, gradient time (min): 10, flow rate (ml / min): 25) to obtain N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonamide (10.32 mg, yield 14.83%). LCMS m / z = 492.9 [M+H] + 1 H 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).

[0341] Example 176: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(4-methoxypyridine-2-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 7-bromo-6-chloro-1H-indole (130.25 mg, 565.0 μmol, 1.5 equivalents) in toluene (5 mL), 4-methoxy-2-(tributylstannyl)pyridine (150.00 mg, 376.72 μmol, 1.0 equivalent), cataCXium A-Pd-G2 (25.19 mg, 37.67 μmol, 0.1 equivalent), and KF (65.66 mg, 1.13 mmol, 3.0 equivalents) were added at 25°C under N2. The mixture was stirred at 110°C for 16 hours. TLC showed that the starting material had been consumed and new spots were observed. The mixture was filtered and concentrated under vacuum to obtain the residue, which was purified by column chromatography to obtain 6-chloro-7-(4-methoxypyridine-2-yl)-1H-indole (50.00 mg, yield 51.30%). LCMS m / z = 259.2 [M+H] +

[0342] Step b: To a solution of 6-chloro-7-(4-methoxypyridine-2-yl)-1H-indole (50.00 mg, 193.27 μmol, 1.0 equivalent) in MeCN (5 mL), HSO3Cl (67.56 mg, 579.82 μmol, 3.0 equivalents) was added dropwise at 0°C and the mixture was stirred at 20°C for 1 hour. TLC showed that the starting material had been consumed and new spots were observed. Next, POCl3 (148.17 mg, 966.36 μmol, 5.0 equivalents) was slowly added to the reactant at 0°C. The mixture was stirred at 60°C for 16 hours. TLC showed that the starting material had been consumed and new spots were observed. Next, the mixture was slowly poured into 20 mL of stirred ice water, extracted with siRNA (20 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 6-chloro-7-(4-methoxypyridine-2-yl)-1H-indole-3-sulfonyl chloride (40.00 mg, purity 57.94%). The material was used without further purification, assuming a quantitative yield. LCMS m / z = 356.9 [M+H] +

[0343] Step c: Pyridine (26.57 mg, 335.94 μmol, 3.0 equivalents) was added at 20°C to a solution of 6-chloro-7-(4-methoxypyridine-2-yl)-1H-indole-3-sulfonyl chloride (40.00 mg, 111.98 μmol, 1.0 equivalent) and 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (18.76 mg, 111.98 μmol, 1.0 equivalent) in DCM (4 mL). The mixture was stirred at 20°C for 2 hours. LC-MS showed that the starting materials were consumed and the desired mass was observed. The solvent was concentrated under vacuum to obtain a residue, which was purified by preparative HPLC (Welch Xtimate C18 150*30mm*5um, water (FA)-ACN as mobile phase, 20%~50%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(4-methoxypyridine-2-yl)-1H-indole-3-sulfonamide (25.72 mg, yield 46.67%). LCMS m / z = 488.0 [M+H] + 1 H 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).

[0344] Example 177: N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(4-chloro-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide [ka] To a solution of 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-amine (Preparation 55) (40 mg, 114.09 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (18.05 mg, 228.18 μmol, 18.45 μL, 2.0 equivalent) and 6-chloro-7-(4-chloro-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 60) (24.19 mg, 114.09 μmol, 1.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. LC-MS showed that the desired mass was detected. The mixture was concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as mobile phase, 40%~70%, gradient time (min): 10, flow rate (ml / min): 25) to obtain N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(4-chloro-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide (5.3 mg, yield 8.70%). LCMS m / z = 526.9 [M+H] + 1 H 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).

[0345] Example 178: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(4-Chloro-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide [ka] Pyridine (27.07 mg, 342.26 μmol, 27.68 μL, 3.0 equivalents) was added at 25°C to a solution of 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (30 mg, 179.06 μmol, 1.57 equivalents) and 6-chloro-7-(4-chloro-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 60) (40 mg, 114.09 μmol, 1.0 equivalent) in DCM (3 mL). The reaction mixture was stirred at 25°C for 1 hour. LC-MS yielded the desired mass, indicating that the starting materials were completely consumed. The solvent was evaporated under vacuum. The residue was purified by preparative HPLC (Welch Ultimate C18 150*25mm*5um, water (FA)-ACN as mobile phase, 35%~65%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(4-chloro-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide (10.59 mg, yield 17.91%). LCMS m / z = 481.1 [M+H] + 1 H 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).

[0346] Example 179: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(4-(difluoromethyl)-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 1H-pyrazole-4-carbaldehyde (200 mg, 2.08 mmol, 1.0 equivalent) in DCM (5 mL), TEA (631.86 mg, 6.24 mmol, 870.34 μL, 3.0 equivalents), Boc2O (263.25 mg, 1.38 mmol, 1.5 equivalents), and DMAP (22.49 mg, 184.11 μmol, 0.2 equivalents) were added at 20°C. The reaction mixture was stirred at 20°C for 12 hours. TLC showed the observation of a new main spot. The solvent was evaporated under vacuum. The residue was purified by column chromatography to produce 4-formyl-1H-pyrazole-1-carboxylate tert-butyl (130 mg, yield 31.76%). 1 H NMR (400 MHz, CDCl3) δ: 9.97 (s, 1H), 8.62 (s, 1H), 8.14 (s, 1H), 1.69 (s, 9H).

[0347] Step b: To a solution of 4-formyl-1H-pyrazole-1-carboxylate butyl (130 mg, 662.58 μmol, 1.0 equivalent) in DCM (3 mL), DAST (427.20 mg, 2.65 mmol, 350.17 μL, 4.0 equivalents) was added at 0°C. The reaction mixture was stirred at 25°C for 12 hours. LC-MS indicated that the starting material had been consumed, and one peak with the desired mass was detected. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (20 mL), extracted with DCM (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 4-(difluoromethyl)-1H-pyrazole-1-carboxylate tert-butyl (60 mg, yield 41.50%). 1 H 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).

[0348] Step c: 4-(difluoromethyl)-1H-pyrazole-1-carboxylate tert-butyl (60 mg, 274.98 μmol, 1.0 equivalent) was dissolved in HCl / dioxane (2 M, 3 mL) at 25°C. The reaction mixture was stirred at 25°C for 2 hours. LC-MS indicated that the starting material had been consumed and one peak of the desired mass was detected. The mixture was concentrated to obtain 4-(difluoromethyl)-1H-pyrazole. The product was used directly as the crude product for the next step.

[0349] Step d: A solution of 1-chloro-2-fluoro-3-nitrobenzene (500 mg, 2.85 mmol, 1.0 equivalent), 4-(difluoromethyl)-1H-pyrazole (403.61 mg, 3.42 mmol, 1.2 equivalents), and Cs2CO3 (2.78 g, 8.54 mmol, 3.0 equivalents) in DMF (2 mL) was stirred at 25°C for 12 hours. LC-MS indicated that the starting materials had been consumed and one peak of the desired mass was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 1-(2-chloro-6-nitrophenyl)-4-(difluoromethyl)-1H-pyrazole (660 mg, yield 84.58%). LCMS m / z = 274.1 [M+H] + 1 H 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).

[0350] Step e: To a solution of 1-(2-chloro-6-nitrophenyl)-4-(difluoromethyl)-1H-pyrazole (660 mg, 2.41 mmol, 1.0 equivalent) in THF (15.0 mL), bromo(vinyl)magnesium (1 M, 9.65 mL, 4.0 equivalents) was added dropwise under N2 at -78°C. The reaction mixture was stirred at -78°C for 3 hours. TLC showed that the starting material was completely consumed. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (20 mL), extracted with siRNA (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 6-chloro-7-(4-(difluoromethyl)-1H-pyrazole-1-yl)-1H-indole (290 mg, yield 44.92%). LCMS m / z = 267.9 [M+H] + 1 H 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).

[0351] Step f: HSO3Cl (108.84 mg, 934.02 μmol, 62.09 μL, 2.5 equivalents) was added at 0°C to a solution of 6-chloro-7-(4-(difluoromethyl)-1H-pyrazole-1-yl)-1H-indole (100 mg, 373.61 μmol, 1.0 equivalent) in MeCN (4 mL). The mixture was stirred at 0°C for 2 hours. LC-MS indicated that the starting material had been consumed and one peak at the desired mass was detected. Next, POCl3 (229.14 mg, 1.49 mmol, 139.30 μL, 4.0 equivalents) was added and the mixture was stirred at 70°C for 12 hours. LC-MS indicated that the starting material had been consumed and one peak at the desired mass was detected. The reaction mixture was quenched with 20 mL of stirred ice water, extracted with 20 mL x 3 of toluene, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 6-chloro-7-(4-(difluoromethyl)-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride. The product was used directly as the crude product in the next step.

[0352] Step g: Pyridine (25.92 mg, 327.72 μmol, 3.0 equivalents) was added at 25°C to a solution of 6-chloro-7-(4-(difluoromethyl)-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (40.00 mg, 109.24 μmol, 1.0 equivalent) and 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (18.30 mg, 109.24 μmol, 1.0 equivalent) in DCM (2.0 mL). The reaction mixture was stirred at 25°C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated to obtain the residue. The residue was purified by preparative HPLC (Welch Ultimate C18 150*25mm*7um, water (FA)-ACN as mobile phase, 35%~65%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(4-(difluoromethyl)-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide (18.96 mg, yield 34.90%). 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).

[0353] Example 180: 6-Chloro-N-(3-methoxyisothiazole-4-yl)-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonamide [ka] Pyridine (30.02 mg, 379.55 μmol, 3.0 equivalents) was added at 25°C to a solution of 6-chloro-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 59) (40.00 mg, 126.52 μmol, 1.0 equivalent) and 3-methoxyisothiazole-4-amine (21.08 mg, 126.52 μmol, 1.06 equivalents) in DCM (2 mL). The mixture was stirred at 25°C for 4 hours. LC-MS showed that the starting materials were consumed and the desired mass was observed. The solvent was evaporated under vacuum to obtain the crude product, which was then purified by preparative HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as mobile phase, 35%~65%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(3-methoxyisothiazole-4-yl)-7-(1H-pyrazole-1-yl)-1H-indole-3-sulfonamide (20.40 mg, yield 39.02%). LCMS m / z = 409.9 [M+H] + 1 H 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).

[0354] Example 181: N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(4-ethyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide [ka] To a solution of 6-chloro-7-(4-ethyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 61) (70 mg, 203.36 μmol, 1.0 equivalent) in DCM (4 mL), 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-amine (Preparation 55) (43.11 mg, 203.36 μmol, 1.0 equivalent) and pyridine (48.26 mg, 610.08 μmol, 3.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated to obtain a residue, which was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5um, water (FA)-ACN as mobile phase, 47%~77%, gradient time (min): 11, flow rate (ml / min): 25) to obtain N-(5-bromo-1-(difluoromethyl)-1H-pyrazole-4-yl)-6-chloro-7-(4-ethyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide (14.64 mg, yield 13.85%). LCMS m / z = 519.9 [M+H] + 1 H 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).

[0355] Example 182: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(4-ethyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide [ka] To a solution of 6-chloro-7-(4-ethyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (Preparation 61) (40 mg, 116.21 μmol, 1.0 equivalent) in DCM (4 mL), 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (19.47 mg, 116.21 μmol, 1.0 equivalent) and pyridine (27.58 mg, 348.62 μmol, 3.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated to obtain a residue, which was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5um, water (FA)-ACN as mobile phase, 42%~72%, gradient time (min): 11, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(4-ethyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide (2.22 mg, yield 3.86%). LCMS m / z = 475.1 [M+H] + 1 H 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).

[0356] Example 183: 7-(4-bromo-1H-pyrazole-1-yl)-6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide [ka] Pyridine (60.07 mg, 759.38 μmol, 3.0 equivalents) was added at 25°C to a solution of 7-(4-bromo-1H-pyrazole-1-yl)-6-chloro-1H-indole-3-sulfonyl chloride (Preparation 62) (100.00 mg, 253.13 μmol, 1.0 equivalent) and 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (45.00 mg, 268.59 μmol, 1.06 equivalents) in DCM (2.0 mL). The mixture was stirred at 25°C for 4 hours. LC-MS showed that the starting materials had been consumed and the desired mass was observed. The solvent was evaporated under vacuum to obtain the residue, which was purified by column chromatography to obtain the crude compound. The crude product was purified by preparative HPLC (Boston Prime C18 150*30mm*5um, water (NH3H2O+NH4HCO3)-ACN as mobile phase, 15%~45%, gradient time (min): 12, flow rate (ml / min): 25) to obtain 7-(4-bromo-1H-pyrazole-1-yl)-6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-1H-indole-3-sulfonamide (5.32 mg, yield 17.73%). LCMS m / z = 525.0 [M+H] + 1 H 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).

[0357] Example 184: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(4-cyclopropyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 1-chloro-2-fluoro-3-nitrobenzene (400.00 mg, 2.28 mmol, 1.0 equivalent) in MeCN (10 mL), K2CO3 (944.75 mg, 6.84 mmol, 3.0 equivalents) and 4-cyclopropyl-1H-pyrazole (295.69 mg, 2.73 mmol, 1.2 equivalents) were added at 25°C. The mixture was stirred at 60°C for 16 hours. TLC showed that the starting material had been consumed and new spots were observed. The mixture was filtered and concentrated under vacuum to obtain the residue, which was purified by column chromatography to obtain 1-(2-chloro-6-nitrophenyl)-4-cyclopropyl-1H-pyrazole (570.00 mg, yield 94.87%). 1 H 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).

[0358] Step b: To a solution of 1-(2-chloro-6-nitrophenyl)-4-cyclopropyl-1H-pyrazole (270.00 mg, 1.02 mmol, 1.0 equivalent) in THF (40 mL), bromo(vinyl)magnesium (1 M, 5.12 mmol, 5.0 equivalent) was added under N2 at -78°C. The mixture was stirred at -78°C for 3 hours. TLC showed that the starting material had been completely consumed and new spots were observed. The reaction mixture was quenched with saturated NH4Cl aqueous solution (50 mL), extracted with siRNA (40 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to obtain 6-chloro-7-(4-cyclopropyl-1H-pyrazole-1-yl)-1H-indole (100.00 mg, yield 37.89%). LCMS m / z = 258.0 [M+H] +

[0359] Step c: To a solution of 6-chloro-7-(4-cyclopropyl-1H-pyrazole-1-yl)-1H-indole (100.00 mg, 388.02 μmol, 1.0 equivalent) in MeCN (4 mL), NBS (69.06 mg, 388.02 μmol, 1.0 equivalent) was added and the mixture was stirred at 25°C for 2 hours. TLC showed that the starting material had been consumed and new spots were observed. The mixture was quenched with saturated Na2SO3 aqueous solution (30 mL). The mixture was extracted with RINKAN (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified by column chromatography to obtain 3-bromo-6-chloro-7-(4-cyclopropyl-1H-pyrazole-1-yl)-1H-indole (12.00 mg, purity 91.87%). LCMS m / z = 336.0 [M+H] +

[0360] Step d: To a solution of 3-bromo-6-chloro-7-(4-cyclopropyl-1H-pyrazole-1-yl)-1H-indole (120.00 mg, 356.49 μmol, 1.0 equivalent) and phenylmethanethiol (90.00 mg, 724.62 μmol, 2.03 equivalents) in dioxane (5 mL), DIEA (138.22 mg, 1.07 mmol, 3.0 equivalents) and Pd(t-Bu3P)2 (27.33 mg, 53.47 μmol, 0.15 equivalents) were added at 25°C under N2. The mixture was stirred at 80°C for 16 hours. TLC showed that the starting material had been consumed and new spots were observed. The mixture was diluted with water (50 mL) and extracted with SiO2 (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography to obtain the crude product, which was then purified by preparative HPLC (Welch Xtimate C18 150*25 mm*5 μm, water (FA)-ACN as mobile phase, 60%~90%, gradient time (min): 12, flow rate (ml / min): 25) to obtain 3-(benzylthio)-6-chloro-7-(4-cyclopropyl-1H-pyrazole-1-yl)-1H-indole (120.00 mg, yield 88.60%). LCMS m / z = 379.9 [M+H] +

[0361] Step e: To a solution of 3-(benzylthio)-6-chloro-7-(4-cyclopropyl-1H-pyrazole-1-yl)-1H-indole (70.00 mg, 184.26 μmol, 1.0 equivalent) in AcOH (1.5 mL), water (0.2 mL) and NCS (73.81 mg, 552.77 μmol, 3.0 equivalents) were added at 25°C. The mixture was stirred at 25°C for 1 hour. TLC showed that the starting material had been consumed and new spots were 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 aqueous NaHCO3 (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain 6-chloro-7-(4-cyclopropyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (50.00 mg, yield 76.18%), which was used directly without further purification.

[0362] Step f: Pyridine (26.65 mg, 336.86 μmol, 3.0 equivalents) was added at 25°C to a solution of 6-chloro-7-(4-cyclopropyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonyl chloride (40.00 mg, 112.29 μmol, 1.0 equivalent) and 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (18.81 mg, 112.29 μmol, 1.06 equivalents) in DCM (2 mL). The mixture was stirred at 25°C for 16 hours. LC-MS showed that the starting materials were consumed and the desired mass was observed. The solvent was evaporated under vacuum to obtain a residue, which was purified by preparative HPLC (Welch Xtimate C18 150*25mm*5um, water (FA)-ACN as mobile phase, 40%~70%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(4-cyclopropyl-1H-pyrazole-1-yl)-1H-indole-3-sulfonamide (19.59 mg, yield 35.61%). 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).

[0363] Example 185: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(5,6-dihydrocyclopenta[c]pyrazole-1(4H)-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazole-1(4H)-yl)-1H-indole (Preparation 63) (50.00 mg, 194.01 μmol, 1.0 equivalent) in MeCN (2 mL), sulfonic chloride (226.07 mg, 1.94 mmol, 128.96 μL, 10.0 equivalent) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. TLC showed that reactant 1 was completely consumed. Then, POCl3 (118.99 mg, 776.04 μmol, 72.34 μL, 4.0 equivalent) was added at 0°C. The reaction mixture was stirred at 60°C for 16 hours. TLC showed that the material was completely consumed and one new spot was detected. The mixture was quenched with saturated ice water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazole-1(4H)-yl)-1H-indole-3-sulfonyl chloride (50 mg, yield 72.3%). The product was used directly as the crude product in the next step.

[0364] Step b: To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazole-1(4H)-yl)-1H-indole-3-sulfonyl chloride (50 mg, 140.36 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (22.20 mg, 280.72 μmol, 22.70 μL, 2.0 equivalent) and 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (23.52 mg, 140.36 μmol, 1.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. LC-MS showed that the desired product was detected. The mixture was concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as mobile phase, 50%~80%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(5,6-dihydrocyclopenta[c]pyrazole-1(4H)-yl)-1H-indole-3-sulfonamide (15.83 mg, yield 22.97%). LCMS m / z = 487.0 [M+H] + 1 H 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).

[0365] Example 186: 6-Chloro-N-(5-Chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(5,6-dihydrocyclopenta[c]pyrazole-1(4H)-yl)-1H-indole-3-sulfonamide [ka] Step a: To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazole-2(4H)-yl)-1H-indole (Preparation 63) (50.00 mg, 194.01 μmol, 1.0 equivalent) in MeCN (2 mL), sulfonic chloride (113.03 mg, 970.05 μmol, 64.48 μL, 5.0 equivalents) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. TLC showed that the reactants were completely consumed. Next, POCl3 (118.99 mg, 776.04 μmol, 72.34 μL, 4.0 equivalents) was added at 0°C. The reaction mixture was stirred at 60°C for 16 hours. TLC showed that the materials were completely consumed and one new spot was detected. The mixture was quenched with saturated ice water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazole-2(4H)-yl)-1H-indole-3-sulfonyl chloride (50 mg, yield 72.3%). The product was used directly as the crude product in the next step.

[0366] Step b: To a solution of 6-chloro-7-(5,6-dihydrocyclopenta[c]pyrazole-2(4H)-yl)-1H-indole-3-sulfonyl chloride (50 mg, 140.36 μmol, 1.0 equivalent) in DCM (2 mL), pyridine (22.20 mg, 280.72 μmol, 22.70 μL, 2.0 equivalent) and 5-chloro-1-(difluoromethyl)-1H-pyrazole-4-amine (23.52 mg, 140.36 μmol, 1.0 equivalent) were added at 25°C. The mixture was stirred at 25°C for 16 hours. LC-MS showed that the desired product was detected. The mixture was concentrated under vacuum to obtain a crude product, which was purified by preparative HPLC (Boston Green ODS 150*30mm*5um, water (FA)-ACN as mobile phase, 50%~80%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-chloro-N-(5-chloro-1-(difluoromethyl)-1H-pyrazole-4-yl)-7-(5,6-dihydrocyclopenta[c]pyrazole-2(4H)-yl)-1H-indole-3-sulfonamide (18.04 mg, yield 26.37%). LCMS m / z = 487.1 [M+H] + 1 H 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).

[0367] As described in the above examples, the following compounds were prepared. [Table 4-1] [Table 4-2] [Table 4-3] Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 Table 4-19 Table 4-20 Table 4-21 Table 4-22 Table 4-23 Table 4-24 Table 4-25 Table 4-26 Table 4-27 Table 4-28 Table 4-29 Table 4-30 Table 4-31 Table 4-32 Table 4-33 Table 4-34 Table 4-35 Table 4-36 Table 4-37 Table 4-38 Table 4-39 Table 4-40 Table 4-41 Table 4-42 Table 4-43 Table 4-44 Table 4-45 Table 4-46 Table 4-47 Table 4-48 Table 4-49 Table 4-50 Table 4-51 Table 4-52 Table 4-53

[0368] 1. GPR17 cAMP HTRF assay Stable GPR17-1321N1 clonal cell lines were generated using lentivirus, full-length GPR17 expression was introduced, and cAMP activity was evaluated using a cAMP HTRF assay. GPR17-1321N1 cells and wt-1321N1 cells were cultured in DMEM containing 10% FBS, 1% glutamax, and 1% penicillin-streptomycin, supplemented with 5 μg / ml puromycin for the GPR17-1321N1 cell line. Stock concentrations of the compound were serially diluted up to 10-point, or 3-fold, dilutions in DMSO. 40 nl of the compound in DMSO and reference controls (BIO-1948681 and DMSO) were dispensed into white 384-well plates. Cells were divided into 7 × 10⁶ wells. 5 Cells were prepared in OptiMEM containing 0.5 mM IBMX at a density of cells / ml. 10 μl of diluted cells were added to a compound-treated plate to a final density of 7000 cells / well, and incubated at room temperature for 15 minutes. 10 μl of OptiMEM containing the MDL29951 agonist and forskolin (for forskolin, the final concentration of MDL29951 at EC80 with 5 μM agonist activity) was added to the plate. The plate was incubated at room temperature for 15 minutes. After stimulation, cAMP levels were measured using the cAMP Gs Dynamic Kit HTRF (Cisbio / Perkin Elmer). 10 μl of 1× cAMP-d2 (acceptor reagent) diluted in lysis buffer, followed by 10 μl of 1× anti-cAMP cryptotate (Eu-donor reagent) diluted in lysis buffer, were dispensed and incubated at room temperature for 1 hour. The plate was read at wavelengths of 665 nm and 615 nm using PHERAstar (BMG Labtech), and the HTRF ratio was calculated from 665 nm / 615 nm. Using 0% activity control and 100% activity control on the same plate, the activity was normalized to the following formula. % activity = (well data - 0% activity) / (100% activity - 0% activity) x 100

[0369] The activity percentage versus compound concentration was plotted and fitted to a 4-parameter logistic model to determine IC. 50The values ​​were obtained. The data is shown in the table below. [Table 5-1] [Table 5-2] [Table 5-3]

[0370] 2. MDR1-MDCK assay procedure Human MDR1-transfected MDCK cells (an NIH cell line licensed from Absorption Systems) were used in the assay. The compounds were tested at a 1 μM concentration prepared with a transport buffer (Hanks equilibrium salt solution containing HEPES). MDR1-MDCK cells were cultured for 7 days in a 96-well transwell insert plate (Corning). The insert plate was washed before the assay and TEER (transepithelial electrical resistance) was measured. These plates were loaded with 85 μL of the test compound solution for AB transport and 260 μL for BA transport in each donor compartment. The volumes of receiver buffer (transport buffer supplemented with 1% BSA) in each receiver compartment were 250 μL and 75 μL, respectively. • A 10 μL sample was collected from the donor compartment (at time T=0). The assay plate was incubated for 120 minutes. Samples were collected from each donor (10 μL) and receiver (50 μL) compartment at 120 minutes (T=120). After adding 40 μL of transport buffer containing BSA to the donor sample, crush solution (acetonitrile containing internal standard, 110 μL) was added to all samples. After centrifugation, 50 μL of the supernatant was transferred to another plate and mixed with 50 μL of water. • Samples were analyzed using an LC-MS / MS integrated with a high-throughput injection system. The test substance / internal standard area ratio is used to estimate apparent permeability (Papp) and efflux ratio based on the following formula. P app = (dC r / dt) x V r / (A x C E ) Material balance = 100 x ((V r xC r final )+(V d xC d final )) / (V d xC E ) During the ceremony, dC r / dt is μMs -1 This is the cumulative concentration within the receiver compartment over time in units of , V r is, cm 3 This is the volume of the receiver compartment in units. V d is, cm 3 This is the volume of the donor compartment in units. A is the area of ​​the insert (0.143 cm² for a 96-well insert). 2 ) C E This is the estimated experimental concentration of the administered solution (time = 0), C r final This is the concentration of the receiver at the end of the incubation period. C d final This represents the donor concentration at the end of the incubation period.

[0371] The leachate ratios of the tested compounds are shown in the table below. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0372] 3.K p,uu Brain osmosis assay General research protocols (non-GLP) for in vivo PK studies In Vivo To evaluate the distribution coefficient (Kp) from brain to plasma, the administration solution was intravenously infused into animals at a constant flow rate for 4–24 hours. Blood samples were collected continuously during infusion, and CSF and brain samples were collected at the end of the infusion.

[0373] To evaluate the properties of the PK, the administration solution was given to animals via forced oral administration or parenteral routes. Blood samples were collected after administration. Other biological samples, such as tissue, bile, urine, and feces, may be collected during or at the end of the study as needed.

[0374] All animal experiments were conducted in accordance with internally approved animal protocols.

[0375] bioanalysis Tissue samples were typically homogenized in phosphate-buffered saline (PBS) using a bead raptor.

[0376] To prevent nonspecific binding, CSF samples were typically diluted with 8% BSA in PBS. Artificial CSF (aCSF) was used as a surrogate matrix.

[0377] If necessary, the administered solution was spiked into the plasma for analysis.

[0378] Calibration curves were created by spiking samples into a blank matrix, which was processed together with plasma, tissue, homogenate, and / or CSF samples by protein precipitation in a suitable organic solvent (e.g., acetonitrile and methanol) containing common analog internal standards (e.g., verapamil, chrysin, glybrid). Matrix matching was used when analyzing multiple matrices in the same run. Samples exceeding the upper limit of quantification (ULOQ) had to be diluted to the calibration range using a pre-extraction or post-extraction dilution approach.

[0379] The processed samples were analyzed by LC-MS / MS using appropriate methods performed within acceptable sensitivity, selectivity, precision, and accuracy. For the analysis to be approved, at least 75% of the calibration curves of the dual calibration curve must be within 20% of the nominal concentration.

[0380] Where necessary, compounds or study-specific bioanalytical methods that deviate from typical procedures may be used, which will be documented in the study-specific protocol included in the data upload.

[0381] PK Plasma concentrations were analyzed by non-compartmental analysis (NCA) using linear up-log-down fitting to generate fundamental PK parameters, including but not limited to volume of distribution (Vd), maximum concentration (Cmax), time to maximum concentration (Tmax), area under the curve (AUC), half-life (t1 / 2), clearance (CL), and bioavailability (F). When drug solution analysis was performed, PK parameters were normalized to the adjusted dose.

[0382] To calculate the distribution coefficient (Kp), brain concentration was compared with plasma concentration at the corresponding time point.

[0383] The unbound drug partition coefficient (Kpuu), defined as the ratio of unbound drug distribution across the blood-brain barrier, was calculated using the following equation.

number

[0384] Determination of the unbound fraction (Fu): The unbound fraction of the test compound was determined based on the protocol described below. 1) Dilute the initial 10 mM test substance to 125 μM by adding 5 μL to a total volume of 395 μL of solvent solution (100% acetonitrile) in a 1 mL 96-well plate (Waters 186002481 Milford, MA). Confirm that the compound is present in the solution. 2) Thaw frozen (rat, human, mouse, dog, and / or monkey) plasma (BIOIVT, Westbury, NY) in a warm water bath (37°C) and warm the PBS buffer. Dilute the 125 μM test substance solution by adding 8 μL to a final volume of 992 μL of plasma in a 2 mL 96-well plate (Costar 3961) to a final concentration of 1 μM. Mix thoroughly. This spike plasma solution is shown in Figure 1. 3) Prepare a cooled "crush" solution of the internal standard in a solvent solution. • Pipette 200 μL of a 25 ng / mL solution of the internal standard, CPDPX (8-cyclopentyl-1,3-dipropylxanthine, Sigma-Aldrich, C101), in a 1:1 acetonitrile / methanol solvent solution into a 1 mL 96-well plate. • Chill on ice or store in the refrigerator at 4°C. The solution will become the "crush" plate shown in Figure 1. 4) Take 50 μL (T=0h) of each plasma sample from the remaining spike plasma and place it in a crush plate containing 200 μL. To match the matrix, add 50 μL of blank buffer to the crush sample (same as the PPB sample). Maintain the remaining spike plasma at 37°C for 4 hours. 5) Transfer 500 μL of warmed PBS buffer to the white side of the RED device (Thermo Scientific, Rockford IL, baseplate cat#89811, insert cat#89810), and transfer 300 μL of spiked plasma to the corresponding red ring side of the RED device. 6) Cover all RED device plates with lids and transfer them to a 37°C incubator in a 5% CO2 environment, shaking at 200 rpm for 4 hours. 7) Reaction ends after 4 hours: Add 50 μL of sample (plasma or buffer sample) and 50 μL of the opposite blank matrix (add blank buffer to the plasma sample and blank plasma to the buffer sample) to a crush plate (same as above), and then add it to a crush plate containing 200 μL. Mix the crush plate thoroughly. • Take 50 μL (T=4h) of each plasma sample from the remaining spike plasma and place it in a crush plate. To match the matrix, add 50 μL of blank buffer to the crushed sample (same as for the protein-bound sample). • Centrifuge the crushed plate at 3900 rpm for 10 minutes at 4°C (Eppendorf Centrifuge 5810R, Hamburg, Germany) 8) Sample preparation for LC / MS / MS: Using Tecan's PPB96-384 pretty method, 30 μL of supernatant from the crush plate is injected into an LC / MS containing 120 μL of 0.1 formic acid in 90:10 water:acetonitrile. The volume and diluent composition are adjusted based on the sensitivity of the instrument (LC-MS / MS) and the sensitivity, solubility, and polarity of the test substance, ensuring appropriate signal and retention of the test substance within the instrument's linear limitations. 9) Standard curve • Create a standard curve for pooled test substances processed in the same manner as the reaction samples, using plasma and buffer. 10) Data processing and analysis Select Multiquant as the application used to process PPB data. equation: Equation 1. Calculation of %Free(%PPBunb) %Free = (PAR on buffer side / PAR on plasma side) * 100 PAR - Peak Area Ratio (PAR) Fu=%Free / 100 Fu = uncombined fraction Equation 2. Final calculation using the dilution factor (D) This dilution formula is used only when tissue or plasma is being diluted.

[0385] K p,uu,脳 The values ​​are shown in the table below. [Table 7]

Claims

1. The compound represented by the following formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, X is N or CR ｘ And, R ｘ represents H, halo, OR ｘ１ , SR ｘ１ , C １～３ alkyl, C １～３ haloalkyl, NR ｘ１ R ｘ１ , C(O)R ｘ１ａ , cyano, C ３～６ cycloalkyl, phenyl, 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms each independently selected from N, O and S, or 4- to 6-membered monocyclic heterocyclyl having 1 to 4 heteroatoms each independently selected from N, O and S; said phenyl, said 5- to 6-membered monocyclic heteroaryl and said 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 R ｘ２ groups, R ｘ１ H, C １～３ Alkyl, or C １～３ It is a haloalkyl, R ｘ１ａ is OR ｘ１ NR ｘ１ R ｘ１ , C １～３ Alkyl, or C １～３ It is a haloalkyl, Each R ｘ２ These are independently: Halo, Cyano, C １～４ Alkyl, C １～４ Haloalkyl, OR ｘ１ NR ｘ１ R ｘ１ , C ３～６ Is it cycloalkyl? or two R's ｘ２ Together with the atoms to which they are bonded, C ３～６ They form carbocyclils or 5-6 member heterocyclils. Ring A is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, a 9 to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, or an 8 to 10-membered bicyclic heterocycline having 1 to 4 heteroatoms independently selected from N, O, and S. R １ Each instance is independently represented as Halo, -CN, C １～７ Alkyl, -OR １ａ , -NR １ｂ R １ｂ , -NR １ｂ C(O)R １ａ , -C(O)NR １ｂ R １ｂ ,-SR １ａ , C ３～６ Selected from cycloalkyls, phenyls, 5-6 membered heteroaryls having 1-3 heteroatoms independently selected from N, O, and S, and 4-10 membered heterocyclines having 1-4 heteroatoms independently selected from N, O, and S, the C １～７ alkyl, the C ３～６ The cycloalkyl, the phenyl, the 5-6 membered heteroaryl, and the 4-10 membered heterocyclyl each have 1-3 R １０ It is arbitrarily replaced with, R １ａ H, C １～６ Alkyl, C ３～６ A cycloalkyl, a phenyl, a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, or a 4-10 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S, wherein the C １～６ alkyl, the C ３～６ The cycloalkyl group, the phenyl group, the 5-6 membered heteroaryl group, and the 4-10 membered heterocyclil group are each independently a halo, C １～３ Alkyl and C １～３ It is optionally substituted with 1 to 3 substituents selected from alkoxys. Each R １ｂ H and C are independent of each other. １～４ Alkyl, C １～４ Haloalkyl, C ３～６ A cycloalkyl, a phenyl, a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, or a 4-10 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S. R １０ Each occurrence is independently represented as Halo, -CN, -OR １ａ , -NR １ｂ R １ｂ , -NR １ｂ C(O)R １ａ , -C(O)NR １ｂ R １ｂ ,-SR １ａ , C １～３ Alkyl, C ３～６ Selected from cycloalkyls, phenyls, and 4-6 member saturated heterocyclines having 1-2 heteroatoms independently selected from N, O, and S, the C ３～６ Each of the cycloalkyl, phenyl, and 4-6 member saturated heterocyclyl is a halo, C １～４ Alkyl, C １～４ They are optionally substituted with haloalkyl, hydroxy, or cyano compounds. R ２ H, Halo, C １～３ Alkyl, C １～３ Haloalkyl, -NR ２ａ R ２ａ , or -OR ２ａ And, Each R ２ａ Independently, C １～３ Alkyl, C １～３ Haloalkyl, benzyl, phenyl, 5-10 member heteroaryl, or -CH ２ - (5-10 member heteroaryl), where the 5-10 member heteroaryl independently contains 1-4 heteroatoms selected from N, O, and S, and C １～３ It is optionally substituted with alkyl, R ３ is H or C １～３ Alkyl, and the C １～３ Alkyl groups consist of 1 to 3 halos, -OR ３ａ , -C(O)OR ３ａ , or -C(O)NR ３ａ R ３ａ It is arbitrarily replaced by Each R ３ａ H or C １～３ It is alkyl, n is 0, 1, 2, or 3. however, (i) R ２ and R ｘ when one of them is H, the other is not H, (ii) If X is N, R ２ It is not H. (iii) R ｘ H is R ２ If is halo, alkyl, or haloalkyl, then ring A is 【Chemistry 2】 Not, and (iv) The compound is 【Transformation 3】 isn't it, The aforementioned compound or a pharmaceutically acceptable salt thereof.

2. X is N or CR ｘ And, R ｘ is H, halo, OR ｘ１ , SR ｘ１ , C １～３ alkyl, C ３～６ cycloalkyl, 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S, or 4- to 6-membered monocyclic heterocyclyl having 1 to 4 heteroatoms independently selected from N, O and S, R ｘ１ H, C １～３ Alkyl, or C １～３ It is a haloalkyl, Ring A is a 5-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, a 9 to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, or a 9 to 10-membered bicyclic heterocycline having 1 to 4 heteroatoms independently selected from N, O, and S. R １ Each instance is independently represented as Halo, -CN, C １～７ Alkyl, -OR １ａ ,-SR １ａ , C ３～６ Selected from cycloalkyls, phenyls, 5-6 membered heteroaryls having 1-3 heteroatoms independently selected from N, O, and S, and 4-10 membered heterocyclines having 1-4 heteroatoms independently selected from N, O, and S, the C １～７ alkyl, the C ３～６ The cycloalkyl, the phenyl, the 5-6 membered heteroaryl, and the 4-10 membered heterocyclyl each have 1-3 R １０ It is arbitrarily replaced with, R １ａ C １～６ Alkyl, C ３～６ A cycloalkyl, a phenyl, a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, or a 4-10 membered heterocyclyl having 1-4 heteroatoms independently selected from N, O, and S, wherein the C １～６ alkyl, the C ３～６ The cycloalkyl group, the phenyl group, the 5-6 membered heteroaryl group, and the 4-10 membered heterocyclil group are each independently a halo, C １～３ Alkyl and C １～３ It is optionally substituted with 1 to 3 substituents selected from alkoxys. R １０ Each occurrence is independently represented as Halo, -CN, -OR １ａ ,-SR １ａ , C １～３ Alkyl, C ３～６ Selected from cycloalkyls, phenyls, and 4-6 member saturated heterocyclines having 1-2 heteroatoms independently selected from N, O, and S, R ２ H, Halo, C １～３ Alkyl, C １～３ Haloalkyl, or -OR ２ａ And, R ２ａ C １～３ Alkyl, C １～３ Haloalkyl, benzyl, phenyl, 5-10 member heteroaryl, or -CH ２ - (5-10 member heteroaryl), where the 5-10 member heteroaryl independently contains 1-4 heteroatoms selected from N, O, and S, and C １～３ It is optionally substituted with alkyl, R ３ is H or C １～３ It is alkyl, n is 0, 1, or 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. X is CR ｘ And, R ｘ Hello, OR ｘ１ , SR ｘ１ , C １～３ Alkyl, C １～３ Haloalkyl, NR ｘ１ R ｘ１ , C(O)R ｘ１ａ , cyano, C ３～６ The cycloalkyl, phenyl, a 5-6 member monocyclic heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, or a 4-6 member monocyclic heterocyclil having 1-4 heteroatoms independently selected from N, O, and S, wherein the phenyl, the 5-6 member monocyclic heteroaryl, and the 4-6 member monocyclic heterocyclil each have 1-3 R ｘ２ It is arbitrarily replaced with, R ２ Hello, C １～３ Alkyl, C １～３ Haloalkyl, -NR ２ａ R ２ａ , or -OR ２ａ That is, The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R ３ H, -CH ３ ien-CH ２ CHF ２ ien-CH ２ CH ２ OH, -CH ２ CH ２ OCH ３ ien-CH ２ CH ２ CH ２ OH, -CH ２ C(O)OH, or -CH ２ C(O)NHCH ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

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

6. X is CR ｘ And R ｘ is H, -Cl, or -OCH ３ The compound according to any one of claims 1, 2, 4, or 5, or a pharmaceutically acceptable salt thereof.

7. The aforementioned compound is given by formula (II): 【Chemistry 4】 The compound according to any one of claims 1, 2, or 5, or a pharmaceutically acceptable salt thereof, represented by or a pharmaceutically acceptable salt thereof.

8. The aforementioned compound is given by formula (IIIa): 【Transformation 5】 The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, represented by or a pharmaceutically acceptable salt thereof.

9. Ring A is selected from the group consisting of pyrazolyl, dihydropyrrolopyrazolyl, dihydropyrazolooxazolyl, dihydropyrazolooxazinyl, pyrazopyrazinonyl, pyrazolopyridinyl, triazolyl, imidazolyl, imidazothiazolyl, imidazopyridinyl, triazolopyridinyl, isothiazolyl, thiazolyl, dihydrothiopyranothiazolyl, thiadiazolyl, thiophenyl, isoxazolyl, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzolooxazolyl, pyridylisoxazolyl, benzoisoxazolyl, indazolyl, pyrazolopyridinyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, and pyridylpyrazolyl, each of which has 1 to 3 R １ A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is optionally substituted with.

10. Ring A is selected from the group consisting of pyrazolyl, triazolyl, isothiazolyl, thiazolyl, thiadiazolyl, thiophenyl, isoxazolyl, dihydropyranoisoxazolyl, tetrahydrobenzoisoxazolyl, tetrahydrobenzolooxazolyl, pyridylisoxazolyl, and pyridylpyrazolyl, each of which has one or two R １ A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is optionally substituted with.

11. Ring A is given by the following equation: 【Chemistry 6-1】 【Chemistry 6-2】 These are represented by , and each of these has 1 to 3 R １ A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, optionally substituted with.

12. Ring A is given by the following equation: 【Transformation 7】 These are represented by , and each of these has one or two R １ A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, which is optionally substituted with.

13. Ring A is given by the following equation: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 The compound according to claim 11, or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

14. Ring A is given by the following equation: 【Chemistry 9】 The compound according to claim 12, or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

15. R １ Each instance is independently represented as Halo, -CN, C １～７ Alkyl, -OR １ａ , -C(O)NR １ｂ R １ｂ , C ３～６ Selected from cycloalkyl, phenyl, and 5-6 membered monocyclic heteroaryls, the C １～７ Alkyl groups consist of 1 to 3 R groups. １０ It is arbitrarily replaced by the C ３～６ The cycloalkyl, the phenyl, and the 5-6 membered monocyclic heteroaryl are each independently a halo, C １～３ Alkyl and C １～３ It is optionally substituted with 1 to 3 groups selected from haloalkyl groups. R １ａ C is optionally replaced by H or 1 to 3 halos. １～４ It is alkyl, Each R １ｂ H or C １～３ It is alkyl, R １０ Each occurrence is independently represented as Halo, -CN, -OR １ａ ,-SR １ａ , -NR １ｂ R １ｂ , -C(O)NR １ｂ R １ｂ , -NR １ｂ C(O)C １～３ Alkyl, C ３～６ Selected from cycloalkyl, phenyl, and 4-6 member saturated heterocyclyl, the C ３～６ Cycloalkyl is C １～３ Optionally substituted with a haloalkyl group, A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. R １ Each instance is independently represented as Halo, -CN, C １～７ Alkyl, -OR １ａ , C ３～６ Selected from cycloalkyl and phenyl, the C １～７ Alkyl groups consist of 1 to 3 R groups. １０ It is arbitrarily replaced with, R １ａ C is arbitrarily substituted with 1 to 3 halos. １～４ It is alkyl, R １０ Each occurrence is independently represented as Halo, -CN, -OR １ａ ,-SR １ａ , C ３～６ Selected from cycloalkyls, phenyls, and 4-6 member saturated heterocyclines, A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

17. R １ is independently, each occurrence, -F, -Cl, -Br, -CN, -CH ３ , -CH ２ CH ３ , -CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ C(CH ３ ) ３ , -CH ２ CH(CH ３ ) ２ , -CH ２ CH ２ CH(CH ３ ) ２ , -(CH ２ ) ３ CH ３ , -(CH ２ ) ６ CH ３ , -CH ２ CH ２ CH ２ CN, -CH ２ CH ２ CN, -CH ２ CN, -CH ２ CH ２ NH ２ , -CH ２ CH ２ NHCH ３ , -CH ２ CH ２ N(CH ３ ) ２ , -CHF ２ , -CF ３ , -CH ２ CH ２ CF ３ , -CH ２ CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CF ２ CH ３ , -CH ２ CH ２ Cl, -CH ２ CH ２ CH ２ F, -CH ２ CH ２ CHF ２ ien-CH ２ CHFCH ２ F, -CH ２ CF ２ CH ３ , -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ ien-CH ２ OCH ３ ien-CH ２ CH ２ OCH ３ ien-CH ２ CH ２ CH ２ OCH ３ ien-CH ２ CH ２ OCHF ２ ien-CH ２ CH ２ OCH ２ CF ３ ien-CH ２ CH ２ CH ２ OCH ２ CF ３ ien-CH ２ CH ２ CH ２ OCHF ２ , -OH, -OCHF ２ Cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, phenyl, -CH ２ CH ２ Ph, methylpyrazolyl, oxetane-3-ylmethyl, -CH ２ SCH ３ , -C(O)NHCH ３ ien-CH ２ CH ２ NHC(O)CH ３ ien-CH ２ CH ２ NCH ３ C(O)CH ３ ien-CH ２ CH ２ C(O)NHCH ３ , 【Chemistry 10】 A compound according to any one of claims 1 to 15, selected from, or a pharmaceutically acceptable salt thereof.

18. R １ Each instance is independently represented as -Cl, -CN, and -CH. ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -CH(CH ３ ) ２ ien-CH ２ CH ２ CH (CH ３ ) ２ ,-(CH ２ ) ６ CH ３ ien-CH ２ CH ２ CN, -CH ２ CN, -CHF ２ , -CF ３ ien-CH ２ CH ２ CF ３ ien-CH ２ CF ３ ien-CH ２ CH ２ F, -CH ２ CHF ２ , -CF ２ CH ３ ien-CH ２ CH ２ Cl, -CH ２ CH ２ CHF ２ , -OCH ３ , -OCH ２ CH ３ ien-CH ２ OCH ３ ien-CH ２ CH ２ OCH ３ ien-CH ２ CH ２ OCH ２ CF ３ , -OCHF ２ Cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, phenyl, -CH ２ CH ２ Ph, methylpyrazolyl, oxetane-3-ylmethyl, and -CH ２ SCH ３ A compound according to any one of claims 1 to 16, selected from, or a pharmaceutically acceptable salt thereof.

19. R ２ H, Halo, C １～３ Alkyl, C １～３ Alkoxy, C １～３ Haloalkyl, C １～３ Haloalkoxy, -N(C) １～３ Alkyl) ２ phenyloxy, benzyloxy, -O-pyridinyl, -O-(methylpyrazolyl), -O-thiazolyl, -O-oxazolyl, -O-CH ２ -pyridinyl, -O-CH ２ -(methylpyrazolyl),-O-CH ２ -Oxazolyl, or -O-CH ２ - A compound according to any one of claims 1 to 17, which is thiazolyl, or a pharmaceutically acceptable salt thereof.

20. R ２ H, Halo, C １～３ Alkoxy, C １～３ Haloalkyl, phenyloxy, benzyloxy, -O-pyridinyl, -O-(methylpyrazolyl), -O-thiazolyl, -O-oxazolyl, -O-CH ２ -pyridinyl, -O-CH ２ -(methylpyrazolyl),-O-CH ２ -Oxazolyl, or -O-CH ２ - A compound according to any one of claims 1 to 17, which is thiazolyl, or a pharmaceutically acceptable salt thereof.

21. R ２ H, Halo, C １～３ Alkyl, C １～３ Alkoxy, C １～３ Haloalkyl, C １～３ Haloalkoxy-N(C) １～３ Alkyl) ２ The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, which is benzyloxy.

22. R ２ は、H、-F、C-、Br、-CH ３ 、-CH ２ CH ３ 、-CH ２ CH ２ CH ３ ,-OCH ３ 、-OCHF ２ 、-OCF ３ ,-OCH ２ CH ３ ,-OCH ２ CH ２ CH ３ 、-CHF ２ 、-CF ３ 、-N(CH ３ ) ２ 、 【Chemistry 11】 The compound according to claim 19, or a pharmaceutically acceptable salt thereof.

23. R ２ は、H、Cl、Brr、-OCH ３ 、-CHF ２ 、-CF ３ 、 【Chemistry 12】 The compound according to claim 20, or a pharmaceutically acceptable salt thereof.

24. R ２ は、H、-F、C-、Br、-CH ３ 、-CH ２ CH ３ 、-CH ２ CH ２ CH ３ ,-OCH ３ 、-OCHF ２ 、-OCF ３ ,-OCH ２ CH ３ ,-OCH ２ CH ２ CH ３ 、-CHF ２ 、-CF ３ 、-N(CH ３ ) ２ 、or 【Chemistry 13】 The compound according to claim 19, or a pharmaceutically acceptable salt thereof.

25. X is CR ｘ And, R ｘ H, Halo, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C １～３ Haloalkoxy, -N(C) １～３ Alkyl) ２ , phenyl, a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, and a 5-6 membered heterocyclil having 1-2 heteroatoms independently selected from N, O, and S, wherein each of the phenyl, the heteroaryl, and the heterocyclil has 1 or 2 R ｘ２ It is arbitrarily replaced with, Each R ｘ２ These are independently: Halo, Cyano, C １～３ Alkyl, C １～３ Haloalkyl, C １～３ Alkoxy, C ３～４ Is it cycloalkyl? or two R's ｘ２ Together with the atoms to which they are bonded, C ３～６ They form carbocyclines or heterocyclines with 5-6 members. A compound according to any one of claims 1 to 5 or 8 to 24, or a pharmaceutically acceptable salt thereof.

26. R ｘ These are phenyl, pyrrolidinyl, morpholinyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyridinyl, and pyrimidinyl, and each of the pyrazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyridinyl, and pyrimidinyl has 1 or 3 R ｘ２ It is arbitrarily replaced by The compound according to claim 25, or a pharmaceutically acceptable salt thereof.

27. Each R ｘ２ It is independently, -CH ３ ,-CHF ２ ien-CH ２ CH ３ , -OCH ３ , -F, -Cl, -Br, -CN, or cyclopropyl, or two R's ｘ２ These, together with the atoms to which they are bonded, form cyclopentenyl or dihydrofuranyl. The compound according to claim 25, or a pharmaceutically acceptable salt thereof.

28. X is CR ｘ And R ｘ These are H, -F, -Cl, -Br, -CH ３ ,-CHF ２ ien-CH ２ CH ３ , -CH(CH ３ ) ２ , -OCH ３ , -OCHF ２ , -OCH ２ CF ３ , -N(CH ３ ) ２ , 【Chemistry 14】 A compound according to any one of claims 1 to 5 or 8 to 27, or a pharmaceutically acceptable salt thereof.

29. The aforementioned compound is of formula (IIIa): 【Chemistry 15】 It is represented by or a pharmaceutically acceptable salt thereof, in the formula, R ｘ is a halo, or a 5-6 member monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, O, and S, wherein the 5-6 member monocyclic heteroaryl has 1-2 R ｘ２ It is arbitrarily replaced with, Each R ｘ２ It is independent, Haro, C １～３ Alkyl, or C ３～４ Is it cycloalkyl? or two R's ｘ２ Together with the atoms to which they are bonded, C ３～６ Forms carbocyclyl, R ２ Hello, C １～３ Alkyl, C １～３ Alkoxy, or C １～３ It is a haloalkyl, Ring A is a five-membered monocyclic heteroaryl having one or two heteroatoms independently selected from N, O, and S. R １ Each appearance is independent of the other, halo, OR １ａ , C １～３ Alkyl and C １～３ Selected from haloalkyl groups, R １ａ C １～３ It is alkyl, n is either 1 or 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

30. The aforementioned compound is of formula (III): 【Chemistry 16】 It is represented by or a pharmaceutically acceptable salt thereof, in the formula, R ｘ is a halo, or a 5-6 member monocyclic heteroaryl having 1-2 heteroatoms independently selected from N, O, and S, wherein the 5-6 member monocyclic heteroaryl has 1-2 R ｘ２ It is arbitrarily replaced with, Each R ｘ２ It is independent, Haro, C １～３ Alkyl, or C ３～４ Is it cycloalkyl? or two R's ｘ２ Together with the atoms to which they are bonded, C ３～６ Forms carbocyclyl, Ring A is a five-membered monocyclic heteroaryl having one or two heteroatoms independently selected from N, O, and S. R １ Each appearance is independent of the other, halo, OR １ａ , C １～３ Alkyl and C １～３ Selected from haloalkyl groups, R １ａ C １～３ It is alkyl, n is either 1 or 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

31. R ｘ The compound according to claim 29 or 30, wherein is a pyrazolyl optionally substituted with a halo.

32. The aforementioned compound is of formula (III): 【Chemistry 17】 It is represented by or a pharmaceutically acceptable salt thereof, in the formula, R ｘ is either H or Cl, Ring A is a five-membered monocyclic heteroaryl having one or two heteroatoms independently selected from N, O, and S. R １ Each appearance is independent of the other, halo, OR １ａ , C １～３ Alkyl and C １～３ Selected from haloalkyl groups, R １ａ C １～３ It is alkyl, n is either 1 or 2. The compound according to claim 1.

33. R ｘ The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein is H.

34. Ring A is isoxazolyl, pyrazolyl, or isothiazolyl, each of which has one or two R １ A compound according to any one of claims 29 to 33, or a pharmaceutically acceptable salt thereof, substituted with.

35. Ring A is, [Chemistry 18] The compound according to claim 34, or a pharmaceutically acceptable salt thereof, as represented by [the specified formula].

36. R １ Each instance is independently represented by -Br, -Cl, and -CH. ２ CH ３ ,-CHF ２ , -CF ３ ien-CH ２ CH ２ Cl and -OCH ３ A compound according to any one of claims 29 to 35, selected from, or a pharmaceutically acceptable salt thereof.

37. R １ Each instance of these is independently represented by -Cl and -CH. ２ CH ３ ,-CHF ２ , -CF ３ ien-CH ２ CH ２ Cl and -OCH ３ A compound according to any one of claims 29 to 35, selected from, or a pharmaceutically acceptable salt thereof.

38. Ring A is, 【Chemistry 19】 It is expressed by, where R １００ is C １～３ It is a haloalkyl, R １０１ The compound according to any one of claims 29 to 33, or a pharmaceutically acceptable salt thereof, wherein is a halo.

39. R １００ is, -CHF ２ or -CH ２ CH ２ Cl and R １０１ The compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein is Br.

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

41. A compound selected from the compounds in Table 1.

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

43. A method for controlling GPR17 activity in a subject requiring such control, comprising administering an effective amount of a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 42, to the subject requiring such control.

44. A method for treating a subject suffering from a disease or disorder mediated by GRP17, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 42.

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

46. The method according to claim 45, wherein the disease or disorder is selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

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

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

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