Inhibitors of RNA helicase DHX9 and uses thereof

Abstract

Compounds of formula (I), or pharma- ceutically acceptable salts thereof, are provided which are useful for inhibiting DHX9 and treating various DHX9-mediated conditions or diseases, such as cancer. TIFF2025508382000400.tif3669

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 309,917, filed February 14, 2022. The entire contents of the foregoing application are expressly incorporated herein by reference.

[0002] The present disclosure relates to inhibitors of RNA helicase DHX9 and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, and their use in the treatment of disease. [Background technology]

[0003] DHX9, also known as RNA helicase A (RHA) or nuclear DNA helicase II (NDH II), is a DExH-box RNA helicase that shuttles between the nucleus and cytoplasm and can drive cycles of 3' to 5' directional movement using all four NTPs. Functionally, DHX9 can bind to, unwind, or degrade dsDNA / RNA, ssDNA / RNA, DNA:RNA hybrids (such as R-loops), circular RNA, and DNA / RNA G-quadruplexes. Therefore, DHX9 plays a regulatory role in various RNA- and DNA-related cellular processes, such as transcription, translation, RNA splicing, editing, RNA transport and processing, microRNA production, and maintaining genome stability (Pan et al., 2021, Current Protein & Peptide Science (22), 29-40).

[0004] Due to its regulatory role in processes such as transcription and maintaining genome stability, DHX9 has been shown to be a master regulator in various cancer types (Gulliver et al., 2020, Future Science OA(2), FSO650). DHX9 has been shown to be involved in regulating genes associated with sustained growth signaling, growth suppressor evasion, apoptosis evasion, angiogenesis, and metastasis, all hallmarks of cancer. Specifically, microsatellite-unstable cancers, such as microsatellite-instability (MSI) colorectal cancer, and tumors with mismatch repair (MMR) deficiency, exhibit a strong dependency on DHX9.

[0005] In addition to its role in cancer, DHX9 has been implicated in other diseases involving gene replication, translation, or regulation, including viral infections and autoimmune diseases.

[0006] Thus, there is a need for DHX9 inhibitors as potential therapeutic agents for treating diseases or disorders that respond to DHX9 inhibition. Summary of the Invention

[0007] The present disclosure provides compounds that are DHX9 inhibitors. In a first aspect, the present disclosure provides a compound having formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: X is a halo; Y is O or NR y and R y But H or C 1-4 is alkyl, R 1 But C 1-4 Alkyl or C 3-6 is cycloalkyl, C 1-4 Alkyl or C 3-6 each cycloalkyl is optionally and independently substituted with 1 to 3 halo or —OH; Ring A is C 3-6 cycloalkyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl; m is 0 to 3; n is 0 or 2, Each R 2 But independently, C 1-4 Alkyl, C 3-6 Cycloalkyl, halo, OR 2a , Cyano, -NR 2b R 2c , -SO2R 2a , -C(O)R 2d , and -C(O)NR 2b R 2c Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl is 1 to 4 R 2e or two R 2 together form oxo, R 2a But H, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 Alkoxy C 1-4 is alkyl, R 2d But H, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 2a , phenyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 8-membered bicyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, 1-4 The alkyl is optionally substituted with 1 to 3 halo, and the 5-6 membered monocyclic heteroaryl is substituted with 1 to 3 C 1-4 Alkyl, C 1-4 optionally substituted with haloalkyl, or phenyl; R 2b and R 2c However, independently, H, C 1-4 Alkyl, C 3-6 selected from cycloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl;1-4 Alkyl is halo and C 1-3 optionally substituted with 1 to 3 substituents independently selected from alkoxy, or R 2b and R 2c together with the nitrogen to which they are attached form a 4- to 6-membered monocyclic heterocyclyl or a 6- to 10-membered bicyclic heterocyclyl, and each of the 4- to 6-membered monocyclic heterocyclyl or the 6- to 10-membered bicyclic heterocyclyl is selected from the group consisting of 1 to 3 R 2d is optionally replaced by Each R 2e However, independently, halo, cyano, NR 2b R 2c , OR 2a phenyl, and 4- to 6-membered monocyclic heterocyclyl; Z is a bond, -CH2-, -O-, or -OC 1-4 Alkylene-*, -C 1-4 Alkylene-O-*, -C(O)-, -C(O)O-*, -OC(O)-*, -S(O)2-, -S(O)2N(Z a )-*,-N(Z a )S(O)2-*, -N(Z a )-, -N(Z a )-C 1-4 Alkylene-*, -C 1-4 Alkylene-N(Z a )-*, -C(O)N(Z a )-*, -N(Za)C(O)-*, or -C(O)N(Z a )-C 1-3 alkylene-*, where * is R 3 indicates the point of attachment to Z a But H or C 1-4 is alkyl, R 3 But C 3-6 cycloalkyl, 7-10 membered bicyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl; 3-6cycloalkyl, 7-10 membered bicyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl, each optionally and independently, being represented by 1 to 4 R 4 is replaced by Each R 4 But independently, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, Halo, OR 4a , Cyano, -NR 4b R 4c , -C(O)R 4a , -C(O)OR 4a , -C(O)NR 4b R 4c , -NR 4b C(O)R 4a , -NR 4b C(O)OR 4a , -NR 4b SO2R 4a , -SR 4a , -S(O)R 4a , -SO2R 4a , SO2NR 4b R 4c , -P(O)R 4b R 4c , phenyl, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered monocyclic heterocyclyl, and 6- to 10-membered bicyclic heterocyclyl; 1-4 Alkyl, C 2-4 Alkenyl, or C 2-4 Alkynyl is one to four R 4d and phenyl, 5-6 membered monocyclic heteroaryl, 4-6 membered monocyclic heterocyclyl, and 6-10 membered bicyclic heterocyclyl are each optionally substituted by 1-3 R 4e and optionally further substituted by one or two oxo, or two R 4 together form oxo, R 4a But H, 1 to 4 R 4d C optionally replaced with 1-4 Alkyl, -NR 4bR 4c , C 3-6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl; 3-6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, each optionally and independently, 1 to 3 R 4e is replaced by R 4b and R 4c are each independently selected from H, phenyl, 4- to 6-membered monocyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 1 to 4 R 4d C optionally replaced with 1-4 alkyl, or R 4b and R 4c together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic heterocyclyl; Each R 4d But independently, halo, OR 4f , -C(O)C 1-4 Alkyl, -C(O)NR 4b R 4c , -C(O)C 1-4 Haloalkyl, -C(O)OR 4f , -NR 4b R 4c , phenyl, and 5- to 6-membered monocyclic heteroaryl, each of which is selected from 1 to 3 R 4g is optionally replaced by Each R 4e But independently, Halo, C 1-4 Alkyl, cyano, OR 4f , -NR 4b R 4c , -C(O)H, -C(O)R 4h , -SO2C 1-3 Alkyl, and -C(O)NR 4b R 4c Selected from C 1-4 Alkyl, halo, -SO2C 1-3 Alkyl and -C(O)NR 4b R 4c , and -C(O)NR 4b R4c or optionally substituted with 1 to 3 substituents independently selected from 4e together form oxo, R 4f But H, C 1-4 Alkyl, C 1-4 haloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, wherein phenyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 halo; Each R 4g But independently, halo, OR 4f , C 1-4 Alkyl, C 1-4 Haloalkyl, halo, cyano, -NR 4b R 4c , -C(O)H, and -C(O)OR 4f is selected from Each R 4h But independently, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkoxy, or -N(R 4b )2.

[0008] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

[0009] In yet another aspect, the present disclosure provides a method for treating a disease or disorder responsive to inhibition of DHX9 in a subject, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for treating cancer.

[0010] Another aspect of the present disclosure relates to the use of at least one compound as described herein or its pharmaceutically acceptable salt for the manufacture of a medicament for treating a disease or disorder that responds to the inhibition of DHX9.Also provided is a compound as described herein or its pharmaceutically acceptable salt for use in treating a disease or disorder that responds to the inhibition of DHX9. [Brief explanation of the drawings]

[0011] [Figure 1a] 1 shows tumor volume over time for an in vivo efficacy study of the compound of Example 31 in LS411N xenografts. [Figure 1b] 1 shows tumor volume over time for an in vivo efficacy study of the compound of Example 31 in LS411N xenografts. [Figure 1c] 1 shows the percentage of tumor volume change over time for an in vivo efficacy study of the compound of Example 31 in LS411N xenografts. [Figure 2] 1 shows the percentage of body weight change over time for an in vivo efficacy study of the compound of Example 31 in LS411N xenografts. [Figure 3a] 1 shows tumor volume over time during and after dosing in an in vivo efficacy study of the compound of Example 31 in LS411N xenografts. [Figure 3b] 1 shows the percentage of tumor volume change over time during and after the 28 day dosing period of an in vivo efficacy study of the compound of Example 31 in LS411N xenografts. [Figure 4] 1 shows the antiproliferative activity of 290 DHX9 inhibitor compounds described herein in CRC-MSI (LS411N) cells versus CRC-MSS (NCI-H747) cells. [Figure 5a] 1 shows a 10-day proliferation screen of the compound of Example 18 in a panel of different cancer cell lines. [Figure 5b] 1 shows the proliferation EC50 of the compound of Example 18 in MSI versus MSS cell lines as represented by colon, endometrial, and hematopoietic cancers. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful for treating diseases or disorders mediated by DHX9 function / activity. In some embodiments, the compounds of the present disclosure are DHX9 inhibitors.

[0013] Compounds and Compositions In a first embodiment, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are as defined below: X is a halo; Y is O or NR y and R y But H or C 1-4 is alkyl, R 1 But C 1-4 Alkyl or C 3-6 is cycloalkyl, C 1-4 Alkyl or C 3-6 each cycloalkyl is optionally and independently substituted with 1 to 3 halo; Ring A is C 3-6 cycloalkyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl; m is 0 to 3; n is 0 or 1, Each R 2 But independently, C 1-4 Alkyl, C 3-6 Cycloalkyl, halo, OR 2a , Cyano, -NR 2b R 2c , -SO2R 2a , -C(O)R 2d , and -C(O)NR 2b R 2c Selected from C 1-4 Alkyl and C 3-6 Cycloalkyl is 1 to 4 R 2e or two R 2 together form oxo, R 2a But H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4Alkoxy C 1-4 is alkyl, R 2d But H, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 2a , phenyl, 4- to 6-membered monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, 1-4 the alkyl is optionally substituted with 1 to 3 halo; R 2b and R 2c However, independently, H, C 1-4 Alkyl, C 3-6 cycloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl, or R 2b and R 2c together with the nitrogen to which they are attached form a 4- to 6-membered monocyclic heterocyclyl or a 6- to 10-membered bicyclic heterocyclyl, and each of the 4- to 6-membered monocyclic heterocyclyl or the 6- to 10-membered bicyclic heterocyclyl is selected from the group consisting of 1 to 3 R 2d is optionally replaced by Each R 2e However, independently, halo, cyano, NR 2b R 2c , OR 2a phenyl, and 4- to 6-membered monocyclic heterocyclyl; Z is a bond, -CH2-, -O-, or -OC 1-4 Alkylene-*, -C 1-4 Alkylene-O-*, -C(O)-, -C(O)O-*, -OC(O)-*, -S(O)2-, -S(O)2N(Z a )-*,-N(Z a )S(O)2-*, -N(Z a )-, -N(Z a )-C 1-4 Alkylene-*, -C 1-4 Alkylene-N(Z a )-*, -C(O)N(Z a )-* or -C(O)N(Z a )-C 1-3 alkylene-*, where * is R 3 indicates the point of attachment to Z a But H or C 1-4 is alkyl, R 3 But C 3-6 cycloalkyl, 7-10 membered bicyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl; 3-6 cycloalkyl, 7-10 membered bicyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl, each optionally and independently, being represented by 1 to 4 R 4 is replaced by Each R 4 But independently, C 1-4 Alkyl, Halo, OR 4a , Cyano, -NR 4b R 4c , -C(O)R 4a , -C(O)OR 4a , -C(O)NR 4b R 4c , -NR 4b C(O)R 4a , -NR 4b C(O)OR 4a , -SR 4a , -SO2R 4a , -SO2NR 4b R 4c , -P(O)R 4b R 4c , phenyl, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered monocyclic heterocyclyl, and 6- to 10-membered bicyclic heterocyclyl; 1-4 Alkyl is 1 to 4 R 4d and phenyl, 5-6 membered monocyclic heteroaryl, 4-6 membered monocyclic heterocyclyl, and 6-10 membered bicyclic heterocyclyl are each optionally substituted by 1-3 R 4e or two R 4 together form oxo, R 4a But H, 1 to 4 R 4dC optionally replaced with 1-4 Alkyl, C 3-6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl; 3-6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, each optionally and independently, 1 to 3 R 4e is replaced by R 4b and R 4c are each independently selected from H, phenyl, 4- to 6-membered monocyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 1 to 4 R 4d C optionally replaced with 1-4 alkyl, Each R 4d But independently, halo, OR 4f , -C(O)C 1-4 Alkyl, -C(O)NR 4b R 4c , -C(O)C 1-4 haloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl, wherein phenyl and 5- to 6-membered monocyclic heteroaryl are each selected from 1 to 3 R 4g is optionally replaced by Each R 4e are independently halo, C optionally substituted with 1 to 3 halo 1-4 Alkyl, cyano, OR 4f , -NR 4b R 4c , -C(O)H, -C(O)C 1-4 Alkyl, -C 1-4 Alkylene-C(O)NR 4b R 4c , and -C(O)NR 4b R 4c or two R 4e together form oxo, R 4f But H, C 1-4 Alkyl, C 1-4haloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, wherein phenyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 halo; Each R 4g But independently, halo, OR 4f , C 1-4 Alkyl, halo, cyano, -NR 4b R 4c , -C(O)H, and -C(O)OR 4f In some embodiments, Y is O.

[0014] In a second embodiment, for a compound of Formula (I) as described in the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, X is Cl, Br, or F, and the remaining variables are as described in the first aspect or first embodiment.

[0015] In a third embodiment, for a compound of Formula (I) as described in the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, X is Cl or Br, and the remaining variables are as described in the first aspect or first embodiment.

[0016] In a fourth embodiment, for a compound of Formula (I) as described in the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, X is Cl, and the remaining variables are as described in the first aspect or first embodiment.

[0017] In a fifth embodiment, for compounds of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, Ring A is selected from the group consisting of phenyl, thiophenyl, pyrrolyl, pyrazoyl, furanyl, isothiazolyl, thiazoyl, imidazoyl, cyclobutyl, benzofuranyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, imidazo[1,2-a]pyridin-6- ... 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, 2 yl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2-oxo-2,3-dihydro-1H-imidazolyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, 5-oxo-5H-thiazolo[3,2-a]pyridinyl, thieno[3, 2-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, benzothiophenyl, thieno[3,2-d]pyrimidinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-b]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, 1-oxo-1,2-dihydropyrrolo[1,2 [α]pyrazinyl, pyrrolo[2,1-f][1,2,4]triazinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl, and the remainder of the variables are as described in the first aspect, or the first, second, third, or fourth embodiment.In an alternative fifth embodiment, Ring A is selected from the group consisting of phenyl, thiophenyl, pyrrolyl, pyrazoyl, furanyl, isothiazolyl, thiazoyl, imidazoyl, cyclobutyl, benzofuranyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, imidazo[1,2-a]pyridin-6-yl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2-oxo-2,3-dihydro-1H-imidazolyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, 5-oxo-5H-thiazolo[3,2-a]pyridinyl, thieno[3,2-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3 [-c]pyridinyl, benzothiophenyl, thieno[3,2-d]pyrimidinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-b]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, 1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazinyl, pyrrolo[2,1-f][1,2,4]triazinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl, and the remainder of the variables are as described in the first aspect, or the first, second, third, or fourth embodiment.

[0018] In a sixth embodiment, for the compounds of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, ring A is of the following formula: [ka] Each of them is represented by 0 to 2 R 2 and 0 to 1 ZR 3 and the remaining variables are as described in the first aspect, or the first, second, third, or fourth embodiment. In an alternative sixth embodiment, ring A is substituted with: [ka] and each of them contains 0 to 2 R 2 and 0 to 1 ZR 3 and the remaining variables are as described in the first aspect, or the first, second, third, or fourth embodiment.

[0019] In a seventh embodiment, for the compounds of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, ring A is of the following formula: [ka] [ka] and the remaining variables are as described in the first aspect, or the first, second, third, or fourth embodiment. In an alternative seventh embodiment, ring A is represented by: [ka] [ka] and the remaining variables are as described in the first aspect, or the first, second, third, or fourth embodiment.

[0020] In an eighth embodiment, for compounds of Formula (I) as described in the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, Ring A is phenyl, thiophenyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, and imidazolyl, and the remaining variables are as described in the first aspect, or first, second, third, or fourth embodiment.

[0021] In a ninth embodiment, for compounds of Formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, Ring A is [ka] and each of them is 0 to 1 R 2 and one R 3and the remaining variables are as described in the first, second, third, or fourth embodiment.

[0022] In a tenth embodiment, for the compounds of Formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, Ring A is [ka] and the remaining variables are as described in the first aspect, or the first, second, third, or fourth embodiment.

[0023] In an eleventh embodiment, for compounds of formula (I) described in the first aspect or first embodiment, R 2 is -OCH3, cyclopropyl, -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH(OH)CH3, -C(CH3)2OH, -CH2OCH3, -CH2OH, -CH2CF3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CN, -CH2CHF2, -CH2NH2, -N(CH3)2, -SO2CH3, cyano, halo, -C(O)OH, -C(O)N(CH3)2, and -C(O)NHCH3, or a group having the following structural formula: [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment, or any alternative embodiment therein. In an alternative eleventh embodiment, R 2 is -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH(OH)CH3, -CH2OCH3, -CH2OH, -CH2CF3, -CH2CH2OH, -CH2C H2CH2OH, -CH2CN, -CH2CHF2, -CH2NH2, -N(CH3)2, cyano, halo, -C(O)OH, -C(O)N(CH3)2, -C(O)NHCH3, [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment, or any alternative embodiment therein.

[0024] In a twelfth embodiment, for compounds of Formula (I) as described in the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, n is 1, and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, eighth, or eleventh embodiment, or any alternative embodiment therein.

[0025] In a thirteenth embodiment, for compounds of formula (I) as described in the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, n is 1, Z is a bond, and the remaining variables are as described in the first aspect or first, second, third, fourth, fifth, sixth, seventh, eighth, eleventh, or twelfth embodiment.

[0026] In a fourteenth embodiment, for compounds of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, n is 1 and Z is -CH2-, -CH(CH3)-, -O-, -N(H)-, -N(C 1-4 alkyl)-, or -C(O)NH-*, where * is R 3 and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, eleventh, or twelfth embodiment.

[0027] In a fifteenth embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 3is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrazinyl, thiophenyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octanyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-1 H-pyrazolyl, benzamidazolyl, indazolyl, indoyl, imidazolidinyl, azetidinyl, 2,3-dihydrobenzofuranyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1H-indenyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, spiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, and 2-oxaspiro[3.3]heptanyl, each of which is selected from 1 to 3 R 4 and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or any alternative embodiment therein. In an alternative fifteenth embodiment, R 3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrazinyl, thiophenyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octanyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3- dihydro-1H-pyrazolyl, benzamidazolyl, indazolyl, indoyl, 2,3-dihydrobenzofuranyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1H-indenyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, spiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, and 2-oxaspiro[3.3]heptanyl, each of which is selected from the group consisting of 1 to 3 R 4and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or any alternative embodiment therein. In some embodiments, R 3 is 1 to 2 R 4 In some embodiments, R 3 is one R 4 In some embodiments, R 3 is non-substituted.

[0028] In a sixteenth embodiment, for compounds of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, Z is -CH2- and R 3 is thiophenyl, pyrrolyl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is selected from the group consisting of 1 to 2 R 4 and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or any alternative embodiment therein.

[0029] In a seventeenth embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 3 has the following structural formula: [ka] Each of them is represented by 1 to 3 R 4 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, or any alternative embodiment therein. In an alternative seventh embodiment, R 3 teeth, [ka] and each of them contains 1 to 3 R 4 and the remaining variables are as described in the first, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, or any alternative embodiment therein. In some embodiments, R 3 is 1 to 2 R 4 In some embodiments, R 3 is one R 4 In some embodiments, R 3 is non-substituted.

[0030] In an eighteenth embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 3 has the following structural formula: [ka] [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, or any alternative embodiment therein. In an alternative eighteenth embodiment, R 3 teeth, [ka] [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, or any alternative embodiment therein.

[0031] In a nineteenth embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 3 is phenyl or 5-6 membered monocyclic heteroaryl, each of which is 4 and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or any alternative embodiment therein.

[0032] In a twentieth embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 3 is phenyl, pyrazolyl, pyridyl, and pyrimidyl, each of which is selected from the group consisting of 1 to 2 R 4 and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or any alternative embodiment therein.

[0033] In a twenty-first embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 3 teeth, [ka] and each of them contains 1 to 2 R 4and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or any alternative embodiment therein.

[0034] In a twenty-second embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 3 has the following structural formula: [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or any alternative embodiment therein. In an alternative twenty-second embodiment, R 3 teeth, [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment, or any alternative embodiment therein.

[0035] In a twenty-third embodiment, for a compound of formula (I) according to the first embodiment or the first embodiment, or a pharmaceutically acceptable salt thereof, R 4 is C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OR 4a , -CN, -NH2, -NR 4b R 4c , halo, -C(O)R 4a , -NHC(O)R 4a , -NHC(O)OR 4a , -NR 4b SO2R 4a , -SR 4a, -S(O)R 4a , -SO2R 4a , -SO2NR 4b R 4c , -P(O)R 4b R 4c , -C(O)OC 1-4 R is selected from alkyl, benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl, 6- to 10-membered bicyclic heterocyclyl, and 4- to 6-membered monocyclic heterocyclyl; 4 C represented by 1-3 Alkyl, C 2-4 Alkenyl, or C 2-4 Alkynyl is a group consisting of halo, phenyl, and one to two R 4g and 1 to 2 R 4g 4-6 membered monocyclic heterocyclyl optionally substituted with -C(O)NR 4b R 4c , -C(O)R 4a , and OR 4f and R 4 Each of the benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl, 6- to 10-membered bicyclic heterocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by the formula (I) can be substituted with 1 to 3 R 4e and optionally substituted by one or two oxo, or two R 4 together form oxo and R 4a is H, 1 to 4 R 4d C optionally replaced with 1-4 Alkyl, -NR 4b R 4c , C 3-6 cycloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, and the phenyl, 4- to 6-membered monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl are each independently selected from 1 to 3 R 4e and each R 4b are independently H or C 1-4 alkyl, and R 4c is H, 1 to 4 R 4dC optionally replaced with 1-4 alkyl, 4- to 6-membered monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, and each R 4d are independently halo, -OR 4f , C 3-6 Cycloalkyl, -C(O)OH, -NR 4b R 4c , phenyl, and 5-6 membered monocyclic heteroaryl, wherein phenyl and 5-6 membered monocyclic heteroaryl are each selected from C 1-3 Alkyl, C 1-3 optionally substituted with 1 to 3 substituents independently selected from haloalkyl, halo, CN, and OH; 4e are independently halo, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, -C(O)R 4h , -SO2C 1-3 Alkyl, -C 1-3 Alkyl SO2C 1-3 Alkyl, -C(O)N(C 1-3 alkyl)2, and cyano, or two R 4e together form oxo and R 4f is H, C 1-4 alkyl, phenyl, or 5-6 membered monocyclic heteroaryl, wherein phenyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 halo; and each R 4g independently, C 1-3 alkyl or halo, and each R 4h independently, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkoxy or -N(R 4b )2, and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment, or any alternative embodiment therein. In an alternative twenty-third embodiment, R 4is C 1-3 Alkyl, -OR 4a , -CN, -NH2, halo, -C(O)R 4a , -NHC(O)R 4a , -NHC(O)OR 4a , -SR 4a , -SO2R 4a , -SO2NR 4b R 4c , -P(O)R 4b R 4c , -C(O)OC 1-4 alkyl, benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl, and 4- to 6-membered monocyclic heterocyclyl; R 4 C represented by 1-3 Alkyl, halo, OR 4f , -C(O)NR 4b R 4c , phenyl, and 5-6 membered monocyclic heteroaryl; R 4 Each of the benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl, and 4- to 6-membered monocyclic heteroaryl represented by the formula 4e or two R 4 together form oxo and R 4a is H, 1 to 4 R 4d C optionally replaced with 1-4 Alkyl, -NR 4b R 4c , phenyl, or 5- to 6-membered monocyclic heteroaryl, and the phenyl and 5- to 6-membered monocyclic heteroaryl are each selected from the group consisting of 1 to 3 R 4e is optionally replaced by R 4b is H or C 1-4 alkyl, and R 4c is H, 1 to 4 R 4d C optionally replaced with 1-4 alkyl, 4- to 6-membered monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, and each R 4d independently, C 1-3selected from alkyl, halo, phenyl, and 5-6 membered monocyclic heteroaryl, wherein phenyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 substituents independently selected from halo, CN, and OH; and each R 4e independently, halo, C 1-4 Alkyl, -C(O)C 1-3 Alkyl, -C(O)N(C 1-3 alkyl)2, and cyano, or two R 4e together form oxo, R 4f is H, C 1-4 alkyl, phenyl, or 5-6 membered monocyclic heteroaryl, wherein phenyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 halo, and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment, or any alternative embodiment therein.

[0036] In a twenty-fourth embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 4 has the following structural formula: [ka] Each of them is represented by 1 to 3 R 4e and optionally further substituted with 1 or 2 oxo, and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment, or any alternative embodiment therein. In an alternative twenty-fourth embodiment, R 4 teeth, [ka] and each of them contains 1 to 3 R 4e and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment, or any alternative embodiment therein.

[0037] In a twenty-fifth embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 4 has the following structural formula: [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment, or any alternative embodiment therein. In an alternative twenty-fifth embodiment, R 4 teeth, [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment, or any alternative embodiment therein.

[0038] In a twenty-sixth embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, each R 4eare independently -F, -CH3, -CF3, -CH2CHF2, -CH2CF3, -CH2SO2CH3, -OH, -OCH3, -SO2CH3, -C(O)CH3, -C(O)cyclopropyl, -C(O)cyclobutyl, -C(O)cyclopentyl, -C(O)CH(CH3)2, -C(O)C(CH3)3-C(O)N(CH3)2, -C(O)OCH3, or cyano; and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiment, or any alternative embodiment therein. In an alternative twenty-sixth embodiment, R 4e is —CH3, —C(O)CH3, —C(O)CH(CH3)2—C(O)N(CH3)2, or cyano, and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiment, or any alternative embodiment therein.

[0039] In a twenty-seventh embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 4 -OR 4a and R 4a is 1 to 3 R 4d C optionally replaced with 1-3 Alkyl or 1 to 3 R 4e and each R is a 4- to 6-membered monocyclic heterocyclyl optionally substituted with 4d independently, halo, C 1-2 alkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, provided that 2 or 3 R 4d If there is R 4d one of R is phenyl or 5-6 membered monocyclic heteroaryl, and the other R 4dare each independently halo or C 1-2 alkyl, and R 4d The phenyl and 5-6 membered monocyclic heteroaryl represented by 1-3 Alkyl, C 1-3 optionally substituted with 1 to 3 substituents independently selected from haloalkyl and halo, and each R 4e independently, C 1-4 Alkyl, C 1-4 Haloalkyl, -SO2C 1-3 Alkyl, or -C(O)C 3-6 is cycloalkyl, and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment, or any alternative embodiment therein. In an alternative twenty-seventh embodiment, R 4 -OR 4a and R 4a is 1 to 3 R 4d C replaced with 1-3 alkyl, and R 4d one of R is phenyl or 5-6 membered monocyclic heteroaryl, and the other R 4d each independently represents halo or C 1-2 alkyl, and R 4d are each optionally substituted with 1 to 3 halo, and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment, or any alternative embodiment therein.

[0040] In a twenty-eighth embodiment, for a compound of formula (I) according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, R 4are -CH3, CH2OH, -CHF2, -CF3, -CH(CF3)OH, -CH2OCH3, -CH2CN, -CH2CF3, -CH2CH2OH, -CH2C(O)N(CH3)2, -C≡CC(CH3)2OH, -OH, -OCH3, -OCH2CH3, -OCH2CH2OCH3, -OCH(CH3)2, -OCF3, -OCHF2, -OCH2CF3, -O-cyclopropyl, -O-cyclobutyl, -OC(CH3)3, -OC(CH3)2CH2OH, -OCH(CH3)C(O)OH, -OC(CH3)2C(O)OH, -OCH(CH3)CH2OH , -OCH2CH2N(CH3)2, -CN, -NH2, -NHCH3, halo, -C(O)H, -C(O)CH(CH3)2, -C(O)OCH3, -C(O)Ot-butyl, -N(CH3)SO2CH3, -NHC(O)CH3, -NHC(O)cyclopropyl, -NHC(O)OC (CH3)3, -C(O)CH3, -C(O)OH, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NC(CH3)3, -SCH3, -S(O)CH3, -SO2CH3, -SO2N(CH3)2, -P(O)(CH3)2, phenyl or R 4 has the following structural formula: [ka] [ka] [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment, or any alternative embodiment therein. In an alternative twenty-eighth embodiment, R 4is -CH3, CH2OH, -CHF2, -CF3, -CH(CF3)OH, -CH2OCH3, -CH2CN, -CH2CF3, -CH2CH2OH, -CH2C(O)N(CH3)2, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -CN, -NH2, -NHR 4c , halo, -C(O)H, -C(O)CH(CH3)2, -C(O)OCH3, -C(O)Ot-butyl, -NHC(O)CH3, -NHC(O)cyclopropyl, -NHC(O)OC(CH3)3, -C(O)CH3, -C(O)OH, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NC(CH3)3, -SCH3, -SO2CH3, -SO2N(CH3)2, -P(O)(CH3)2, phenyl, [ka] and the remaining variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment, or any alternative embodiment therein.

[0041] In a twenty-ninth embodiment, the compound of the present disclosure has formula (IIA), (IIB), or (IIC): [ka] or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1, and the variables X, R shown in formula (IIA), (IIB), or (IIC) are 1 , R 2 , and R 3 is as described in the first aspect, or the first, second, third, fourth, eleventh, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment, or any alternative embodiment therein.

[0042] In a thirtieth embodiment, the compound of the present disclosure has formula (IIIA) or (IIIB): [ka] or a pharmaceutically acceptable salt thereof, and the variables X, R shown in formula (IIIA) or (IIIB) 1 , R 2 , and R 3 is as described in the first aspect, or the first, second, third, fourth, eleventh, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment, or any alternative embodiment therein.

[0043] In a thirty-first embodiment, the compound of the present disclosure has formula (IVA), (IVB), (IVC), or (IVD): [ka] or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1, and the variables X, R shown in formula (IVA), (IVB), (IVC), or (IVD) are 1 , R 2 , and R 3 is as described in the first aspect, or the first, second, third, fourth, eleventh, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, or twenty-eighth embodiment, or any alternative embodiment therein.

[0044] In a thirty-second embodiment, for a compound of Formula (I), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IVA), (IVB), (IVC), or (IVD), or a pharmaceutically acceptable salt thereof, R 1is -CH3 or -CH2CH3, and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, or thirty-first embodiment, or any alternative embodiment therein.

[0045] In a thirty-third embodiment, for a compound of Formula (I), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IVA), (IVB), (IVC), or (IVD), or a pharmaceutically acceptable salt thereof, R 1 is -CH3, and the remainder of the variables are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, or thirty-first embodiment, or any alternative embodiment therein.

[0046] In a thirty-fourth embodiment, the compound of the present disclosure has formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is Cl or Br; R 1 is -CH3 or -CH2CH3, Ring A is selected from phenyl, thiophenyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, and imidazolyl; m is 0 or 1; Each R 2 But independently, C 1-3 Alkyl and -C(O)R 2d Selected from C 1-3 The alkyl is R2g is optionally replaced by R 2d is a 4- to 6-membered monocyclic heterocyclyl; R 2g is cyano or OH, R 3 is phenyl or 5- to 6-membered monocyclic heteroaryl, and the phenyl or 5- to 6-membered monocyclic heteroaryl is each optionally and independently selected from one or two R 4 is replaced by Each R 4 But independently, Halo, C 1-4 Alkyl, -O-benzyl, -OC 1-3 alkyl, cyano, -NH2, and 4-6 membered monocyclic heterocyclyl, and benzyl is selected from 1-3 halo or C 1-3 Optionally substituted with haloalkyl.

[0047] In an alternative thirty-fourth embodiment, for compounds of Formula (V) or pharmaceutically acceptable salts thereof, the definitions of the variables are as follows: X is Cl or Br; R 1 is -CH3 or -CH2CH3, Ring A is selected from phenyl, thiophenyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, and imidazolyl; m is 0 or 1; Each R 2 But independently, C 1-3 Alkyl and -C(O)R 2d Selected from C 1-3 The alkyl is R 2g is optionally replaced by R 2d is a 4- to 6-membered monocyclic heterocyclyl; R 2g is cyano or OH, R 3 is phenyl or 5- to 6-membered monocyclic heteroaryl, and the phenyl or 5- to 6-membered monocyclic heteroaryl is each optionally and independently selected from one or two R 4 is replaced by Each R 4 But independently, C 1-4 and selected from alkyl, -O-benzyl, cyano, -NH2, and 4-6 membered monocyclic heterocyclyl, wherein benzyl is optionally substituted with halo.

[0048] In a thirty-fifth embodiment, for compounds of Formula (V), or pharmaceutically acceptable salts thereof, ring A is [ka] and the remaining variables are as described in the thirty-fourth embodiment or any alternative embodiment described therein.

[0049] In a thirty-sixth embodiment, the compound of the present disclosure has formula (IIB), (IIIA), (IVA), or (IVB): [ka] or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1, and the variables X, R shown in formula (IIIA), (IVA), or (IVB) are 1 , R 2 , and R 3 is as described in the thirty-fourth embodiment or any alternative embodiment described therein.

[0050] In a thirty-seventh embodiment, for a compound of Formula (V), (IIB), (IIIA), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 is phenyl, pyrazolyl, pyridyl, and pyrimidyl, each of which is selected from the group consisting of 1 to 2 R 4 and the remaining variables are as described in the thirty-fourth, thirty-fifth, or thirty-sixth embodiment, or any alternative embodiment therein.

[0051] In a thirty-eighth embodiment, for a compound of Formula (V), (IIB), (IIIA), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 3 has the following structural formula: [ka] Each of them is represented by 1 to 2 R 4 and the remaining variables are as described in the thirty-fourth, thirty-fifth, or thirty-sixth embodiment, or any alternative embodiment therein. In an alternative thirty-eighth embodiment, R 3 teeth, [ka] and the remaining variables are as described in the thirty-fourth, thirty-fifth, or thirty-sixth embodiment, or any alternative embodiment therein.

[0052] In a thirty-ninth embodiment, for a compound of Formula (V), (IIB), (IIIA), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 4 is -F, -OCH(CH3)2, -OC(CH3)3, -CH3, cyano, -NH2, or R 4 has the following structural formula: [ka] and the remaining variables are as described in the thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, or thirty-eighth embodiment, or any alternative embodiment therein. In an alternative thirty-ninth embodiment, R 4 are -CH3, cyano, -NH2, [ka] and the remaining variables are as described in the thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, or thirty-eighth embodiment, or any alternative embodiment therein.

[0053] In a fortieth embodiment, for a compound of Formula (V), (IIB), (IIIA), (IVA), or (IVB), or a pharmaceutically acceptable salt thereof, R 2 are -CH3, -CH2CN, -CH2OH, [ka] and the remaining variables are as described in the thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment, or any alternative embodiment therein.

[0054] In a forty-first embodiment, the present disclosure provides a compound represented by formula (IIB) or (IVB): [ka] or a pharmaceutically acceptable salt thereof, wherein: m is 1, R 1 is -CH3, X is Cl; R 2 is -CH3, R 3 is pyrimidinyl or pyridinyl, each of which is selected from the group consisting of one or two R 4 is optionally replaced by R 4 But, Hello, -OC 1-3 alkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the 4- to 6-membered monocyclic heterocyclyl is selected from the group consisting of 1 or 2 halo or C 1-3 Optionally substituted with haloalkyl.

[0055] In a forty-second embodiment, for compounds of formula (IIB) or (IVB), or pharmaceutically acceptable salts thereof, R 3 has the following structural formula: [ka] and the remaining variables are as described in the forty-first embodiment.

[0056] In a forty-third embodiment, for compounds of formula (IIB) or (IVB), or pharmaceutically acceptable salts thereof, each R 4are independently -F, -OCH(CH3)2, or -OC(CH3)3, or R 4 has the following structural formula: [ka] and the remaining variables are as described in the forty-first or forty-second embodiment.

[0057] In a forty-fourth embodiment, the present disclosure provides a compound described herein (eg, a compound of any one of Examples 1-736), or a pharmaceutically acceptable salt thereof.

[0058] In a forty-fifth embodiment, the present disclosure provides a compound selected from the group consisting of: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-phenyl-1H-imidazole-4-carboxamide, 5-bromo-N-(3-fluoro-5-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide, N-(3-fluoro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrazole-3-carboxamide, 5-bromo-N-(3-fluoro-5-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide, N-(3-fluoro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-2-phenyl-1H-imidazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-phenylfuran-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-phenyl-1H-pyrrole-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-phenyl-1H-imidazole-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-methyl-3-(1H-pyrazol-1-yl)benzamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-phenylthiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-2-phenylcyclobutane-1-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-3'-cyano-[1,1'-biphenyl]-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(pyridin-4-yl)benzamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide, N-(3-iodo-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(pyrazin-2-yl)thiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(2-hydroxy-6-methylphenyl)thiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(2-hydroxyphenyl)-5-methylthiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(2-hydroxyphenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-5-methyl-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methyl-4-(pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methyl-4-(pyridin-2-yl)thiophene-2-carboxamide, 4-(3-(benzyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, 4-(2-(benzyloxy)phenyl)-N-(3-bromo-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, 4-(3-(benzyloxy)pyridin-2-yl)-N-(3-bromo-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, 4-(3-(benzyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(4-cyanopyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-fluoropyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-cyanopyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(2-cyano-6-methylphenyl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-5-methyl-1-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-cyanopyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-cyclohexyl-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(3-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(pyrimidin-2-yl)-1H-pyrazole-4-carboxamide, 1-(2-(benzyloxy)phenyl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(3-cyanophenyl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-cyano-2-methylphenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-morpholinopyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(6-(difluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(6-(difluoromethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(2-formylphenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(1H-pyrazol-1-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyridin-3-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(1-phenylethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyridin-2-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyridin-4-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3-fluorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(oxazol-5-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, 1-(2-(benzyloxy)-5-cyanophenyl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 1-(3-(benzyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((4-fluorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3-chlorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, 4-bromo-N-(3-fluoro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, 4-bromo-N-(3-(ethylsulfonamido)-5-fluorophenyl)thiophene-2-carboxamide, N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide, N-(3-(ethylsulfonamido)-5-fluorophenyl)-4-phenylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-ethyl-5-phenyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, 5-bromo-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxamide, 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 1-(5-(4-acetylpiperazin-1-yl)-3-methylpyridin-2-yl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, 4-(6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperazine-1-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(4-morpholinopyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(2-methylmorpholino)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-morpholinopyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(cyanomethyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(difluoro(phenyl)methoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyano-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, 1-benzyl-N-(3-bromo-5-(methylsulfonamido)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(3-cyano-1H-pyrazol-1-yl)benzamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(2-chloropyridin-4-yl)benzamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazole-4-carboxamide, 4-((1H-pyrrol-2-yl)methyl)-N-(3-bromo-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2-hydroxyphenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2-methoxyphenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluorophenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-phenyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide, 4-(2-(benzyloxy)phenyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-(ethylsulfonamido)-5-fluorophenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-(2-hydroxyphenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2,6-difluorophenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(1H-pyrazol-1-yl)benzamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-3-(1H-pyrazol-1-yl)benzamide, 1-ethyl-N-(3-fluoro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrazole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)-4-phenylthiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamimidamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamidoimidamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, N-(3-bromo-5-(methylsulfonamidoimidamido)phenyl)-5-methyl-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-phenylthiophene-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-phenylfuran-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxypropyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-phenyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-2-ethylimidazo[1,2-a]pyridine-6-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(dimethylamino)-2-ethylimidazo[1,2-a]pyridine-6-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)imidazo[1,2-a]pyridine-6-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)benzofuran-7-carboxamide; tert-butyl 4-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(pyridin-2-yl)isothiazole-5-carboxamide, 5-(2-(benzyloxy)phenyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrazole-3-carboxamide, 3-(2-(benzyloxy)phenyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrazole-5-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(pyridin-2-yl)-1H-pyrazole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(1-phenylethyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-difluoroethyl)-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide, tert-butyl 6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(4-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, 1-(4-(4-acetylpiperazin-1-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(4-isobutyrylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(4-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-2-phenyl-1H-imidazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(2-oxopiperidin-1-yl)-1H-pyrrole-3-carboxamide, 1-(2-(benzyloxy)cyclobutyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(3-(hydroxymethyl)-1H-pyrazol-1-yl)benzamide, N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(2-(hydroxymethyl)phenyl)-1H-pyrazole-4-carboxamide, 1-(3-aminopyridin-2-yl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(phenylamino)-1H-pyrazole-5-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(piperazine-1-carbonyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N2-(3-chloro-5-(methylsulfonamido)phenyl)-N4-phenylthiophene-2,4-dicarboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(phenoxymethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, 1-(3-(benzylamino)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-ethoxypyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-1-methyl-5-(pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2-oxopyrrolidin-1-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyclopropyl-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(pyrimidin-2-yloxy)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3-hydroxybenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3-oxomorpholino)pyridin-2-yl)-1H-pyrazole-4-carboxamide, 5-(aminomethyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(4-methyl-3-oxopiperazin-1-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-(pyridin-3-ylmethoxy)pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyrimidin-5-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((2-fluorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, 1-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(4-methyl-3-oxopiperazin-1-yl)-3-(pyridin-3-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-morpholino-3-(pyridin-3-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyrimidin-2-yloxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-methoxypyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(methylsulfonyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(N,N-dimethylsulfamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(dimethylphosphoryl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-((3-fluorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3-cyanobenzyl)oxy)-5-fluoropyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3-fluorobenzyl)oxy)-6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(thiazol-2-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, 1-(3-((1H-pyrazol-4-yl)methoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoropyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-ethoxypyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)indolizine-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-((3-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-fluoro-6-((3-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide, 3-(3-(benzyloxy)pyridin-2-yl)-N5-(3-chloro-5-(methylsulfonamido)phenyl)-N2-methylthiophene-2,5-dicarboxamide, 3-(3-(benzyloxy)pyridin-2-yl)-N5-(3-chloro-5-(methylsulfonamido)phenyl)-N2,N2-dimethylthiophene-2,5-dicarboxamide, 4-(3-(benzyloxy)pyridin-2-yl)-N-(3-fluoro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(oxazol-5-ylmethoxy)pyridin-2-yl)thiophene-2-carboxamide, 4-(3-(benzyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(pyridin-3-ylmethoxy)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(methylthio)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(methylthio)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(cyclopropanecarboxamido)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(2-(dimethylamino)-2-oxoethyl)pyridin-2-yl)thiophene-2-carboxamide, 2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)-N,N-dimethylnicotinamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-methylpyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-hydroxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorophenoxy)methyl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5'-fluoro-[3,3'-bipyridin]-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)thieno[2,3-c]pyridine-2-carboxamide, 1-(3-((3-bromobenzyl)oxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-ethyl-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-isopropyl-4-(pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(methoxymethyl)-4-(pyridin-2-yl)thiophene-2-carboxamide, 4-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(1-phenyl-1H-1,2,3-triazol-4-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(pyrimidin-2-ylamino)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(methyl(pyrimidin-2-yl)amino)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(pyridin-3-yloxy)pyridin-2-yl)thiophene-2-carboxamide, 4-(2-(benzyloxy)-6-fluorophenyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, 4-bromo-N-(3-chloro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, methyl (5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)prolinate, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(piperidin-4-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(piperazin-1-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-morpholinothiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiophene-2-carboxamide, N-(3-chloro-5-(cyclopropanesulfonamido)phenyl)-5-methyl-1-(5-morpholinopyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-((difluoromethyl)sulfonamido)phenyl)-5-methyl-1-(5-morpholinopyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methyl-1-(5-morpholinopyridin-2-yl)-1H-pyrrole-3-carboxamide, 1-(8-oxabicyclo[3.2.1]octan-3-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-(3-fluorophenyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, 1-(3-((1H-imidazol-2-yl)methoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 1-(3-((1H-pyrazol-5-yl)methoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, 1-(3-((1H-imidazol-4-yl)methoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-((3-fluorobenzyl)oxy)-6-methylphenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorophenoxy)methyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(5-fluoropyridin-3-yl)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorobenzyl)oxy)-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-phenoxycyclopentyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-phenylcyclopentyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-methyl-3-(oxazol-5-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(((5-fluoropyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(pyrimidin-2-yloxy)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(pyridin-3-yloxy)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(3-fluorophenoxy)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(1-methyl-2-oxopiperidin-4-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-(oxazol-5-ylmethoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methyl(tetrahydrofuran-3-yl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(pyrrolidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-morpholinopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(2,2-dimethylmorpholino)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-morpholinopyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-ethyl-5-(5-morpholinopyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-morpholinopyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, 1-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, 5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide, 5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(3-(thiazol-2-ylmethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(3-(thiazol-2-ylmethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-cyclopentyl-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(4-isobutyrylpiperazin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, 4-(6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methyl-1H-pyrrol-1-yl)pyridin-3-yl)-N,N-dimethylpiperazine-1-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(1,1-dioxidothiomorpholino)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-difluoroethyl)-5-(5-fluoropyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(1-hydroxyethyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)thieno[3,2-c]pyridine-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)thieno[3,2-b]pyridine-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-7-methylthieno[3,2-c]pyridine-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dimethoxybenzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)pyrrolo[1,2-b]pyridazine-6-carboxamide, 6-chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)benzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-6-fluorobenzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-fluorobenzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-fluorobenzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-7-fluorobenzo[b]thiophene-2-carboxamide, 5-chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)benzo[b]thiophene-2-carboxamide, 6-chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)indolizine-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methylindolizine-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-7-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-8-(trifluoromethyl)indolizine-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-7-methoxybenzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylindolizine-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-8-fluoroindolizine-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-hydroxycyclobutyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(1-methyl-2-oxopiperidin-4-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-phenethyl-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-cyclopentyl-1H-pyrazole-4-carboxamide, 1-(6-acetamidospiro[3.3]heptan-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-methyl-2-azaspiro[3.3]heptan-6-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl)-1H-pyrazole-4-carboxamide, 1-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-bromo-5-(methylsulfonamido)phenyl-2,4,6-d3)-4-phenylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-dimethylpiperidin-4-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazole-4-carboxamide, 1-(1-acetylpiperidin-4-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, tert-butyl (6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)carbamate, 1-(6-aminospiro[3.3]heptan-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, and 1-(3-fluoro-5-morpholinopyridin-2-yl)-5-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-fluoro-5-morpholinopyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyridin-2-yl)-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-methyl-3-oxopiperazin-1-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-morpholinopyrimidin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5'-fluoro-[3,3'-bipyridin]-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-methyl-2-oxoimidazolidin-1-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-methoxybenzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1,3-dimethylpyrrolo[1,2-a]pyrazine-7-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(4-phenylpiperazine-1-carbonyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(trifluoromethyl)benzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4,5-difluorobenzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4,7-difluorobenzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(trifluoromethyl)benzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyrimidin-5-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methoxybenzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(piperidine-1-carbonyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(morpholine-4-carbonyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)thiophene-2-carboxamide, 4-(3-(2-(azetidin-1-yl)-2-oxoethyl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2-oxooxazolidin-3-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-morpholinopyrazin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(pyrimidin-2-ylmethyl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-5-(4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(2-oxopyrrolidin-1-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxy-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-fluoro-5-(methylsulfonamido)phenyl)-5-methyl-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(4-methylpiperazine-1-carbonyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyridin-3-yloxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(3-(pyridin-3-yloxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(2-(dimethylamino)-2-oxoethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(2-hydroxypropan-2-yl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-6,8-dimethylindolizine-2-carboxamide, N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-5-(2,6-diazaspiro[3.3]heptane-2-carbonyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-8-methylindolizine-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)pyrrolo[1,2-a]pyrazine-7-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-methoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylbenzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-ethoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-ethoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(methoxymethyl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoropyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-ethoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-ethoxypyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-chloropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-methoxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yloxy)-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide, 4-chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)benzo[b]thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(3-fluorophenoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-methoxy-1H-pyrazol-1-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(1-phenethyl-1H-imidazol-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-methoxy-1H-pyrazol-1-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(methoxymethyl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-cyanopyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-chloropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3-fluoroazetidin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-fluoropyridin-2-yl)-5-(methoxymethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-ethoxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-ethoxy-1H-pyrazol-1-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-fluoro-1H-pyrazol-1-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-fluoro-1H-pyrazol-1-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-methoxypyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(methoxymethyl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-methoxypyrimidin-2-yl)thiophene-2-carboxamide, 5-(5-(azetidin-1-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-methoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methyl(tetrahydrofuran-3-yl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methyl(tetrahydrofuran-3-yl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(2-methoxyethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-ethoxypyrimidin-2-yl)thiophene-2-carboxamide, 1-(5-(azetidin-1-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-(cyclopropylmethoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyclopropyl-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide, 1-(5-(azetidin-1-yl)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3-fluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-chloropyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, 5-chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoropyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5,5'-difluoro-[3,3'-bipyridin]-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-1'-methyl-2'-oxo-1',2'-dihydro-[3,4'-bipyridin]-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-1'-methyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridin]-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5,5'-difluoro-[3,3'-bipyridin]-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methylsulfonyl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(cyclopropylmethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, tert-butyl 3-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-(5-fluoropyrimidin-2-yl)-1H-pyrrol-1-yl)azetidine-1-carboxylate, 1-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoropyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-cyclopropyl-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methylthio)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methylsulfinyl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyclopropyl-1-(5-fluoropyrimidin-2-yl)-1H-pyrrole-3-carboxamide, 5-(5-(azetidin-1-yl)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4,4-dimethyl-2,5-dioxo-3-(pyridin-2-yl)imidazolidin-1-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-2'-methyl-[3,3'-bipyridin]-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(oxazol-5-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(oxetan-3-yloxy)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-ethoxypyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(difluoromethoxy)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-methoxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3,5-difluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, 5-chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-ethyl-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide, 1-(5-(5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3-fluoroazetidin-1-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(N-methylmethylsulfonamido)pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-cyclopropyl-5-(5-fluoropyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(2-oxopyrrolidin-1-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyrimidin-2-yl)-1-isopropyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(methylsulfonyl)pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5,5'-difluoro-[3,3'-bipyridin]-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3,4-dimethyl-2,5-dioxo-4-(pyridin-2-yl)imidazolidin-1-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-methylpyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, methyl 4-(6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)piperazine-1-carboxylate, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-((1-methylazetidin-3-yl)oxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide, methyl 4-(6-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methylthiophen-3-yl)-5-methylpyridin-3-yl)piperazine-1-carboxylate, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3,5-difluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3-fluoroazetidin-1-yl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3,5-difluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-1-(3-chloro-5-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(pyrrolidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-chloro-5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-methylpyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-1-(3,5-difluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, 1-(azetidin-3-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-cyano-5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-methoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3-chloro-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(methylamino)pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(2-oxooxazolidin-3-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(2,4,6-trifluorophenyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(3-fluoro-5-methylpyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(2,4,6-trifluorophenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(2-oxooxazolidin-3-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-chloro-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(4-pivaloylpiperazin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-methoxypyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4-(cyclopentanecarbonyl)piperazin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, 1-(5-(7-azabicyclo[2.2.1]heptan-7-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3-methoxyazetidin-1-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(2-cyano-4-fluoro-6-methylphenyl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-methylpyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3-fluoro-5-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methyl-4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4-(cyclobutanecarbonyl)piperazin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(4,4-difluoropiperidin-1-yl)-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-methoxy-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3,5-difluoropyridin-4-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-methylpyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-cyano-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, 1-(3-chloro-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-isopropoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4,4-difluoropiperidin-1-yl)-3-methylpyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-(difluoromethoxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(4-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-chloro-5-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-methoxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-isopropoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyclobutoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-ethoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-methoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(difluoromethoxy)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-(3-fluoroazetidin-1-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-ethoxy-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3-fluorooxetan-3-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyridin-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-methoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, 4-(5-(1-acetylpiperidin-4-yl)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(cyclopropanesulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(propylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, methyl 4-(6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylate, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4-methoxypiperidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-cyano-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-cyclobutoxy-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-(difluoromethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, 4-(5-(tert-butoxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-ethoxy-5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3-fluoro-3-methylazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-cyclobutoxy-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(3-(methylsulfonyl)azetidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3-methoxyazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(3-fluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4,4-dimethyl-1,4-azasilinan-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(3-((methylsulfonyl)methyl)azetidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(4,4-dimethyl-1,4-azasilinan-1-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-isopropoxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoropyrrolidin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoropyrrolidin-1-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((1-(cyclopropanecarbonyl)azetidin-3-yl)oxy)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-isopropoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoropiperidin-1-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(1,1-difluoro-6-azaspiro[2.5]octan-6-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoropiperidin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(1-(2,2-difluoroethyl)piperidin-4-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoropyrrolidin-1-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-((1-methylazetidin-3-yl)oxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyanopyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-isopropoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-ethoxy-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-isopropoxypyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-isopropoxypyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyano-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyanopyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyano-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-isopropoxypyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoropyrrolidin-1-yl)-3-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoropyrrolidin-1-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoropyrrolidin-1-yl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-3-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-((1-hydroxy-2-methylpropan-2-yl)oxy)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-ethyl-4-(3-fluoropyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, 4-(5-(tert-butoxy)-3-fluoropyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(dimethylphosphoryl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3,5-difluoropyridin-2-yl)-5-ethylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-ethyl-4-(5-fluoropyridin-2-yl)thiophene-2-carboxamide, 4-(5-(tert-butoxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(dimethylphosphoryl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, 4-(5-(tert-butoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, 1-(5-(tert-butoxy)-3-fluoropyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, 1-(5-(tert-butoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, 5-(5-(tert-butoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(propylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3,5-difluoropyridin-2-yl)-1H-pyrrole-3-carboxamide, 4-(5-(tert-butoxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)thiophene-2-carboxamide, N-(3-chloro-5-((1-methylethyl)sulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, 5-(5-(tert-butoxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-methylpyridin-2-yl)thiophene-2-carboxamide, N-(3-chloro-5-(N-methylmethylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, 1-(5-(tert-butoxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide, 5-(5-(tert-butoxy)-3-fluoropyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide, 5-(3,5-difluoropyridin-2-yl)-N-(3-fluoro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-3-fluoro-4-(5-isopropoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-3-methyl-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide, 4-(3-fluoro-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-N-(3-fluoro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiazole-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3-fluoro-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-4-(3-fluoro-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-((1-methylazetidin-3-yl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, 4-(5-(azetidin-3-yloxy)-3-fluoropyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1,1-dioxidethiomorpholino)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide, 4-(3-(4-acetylpiperazin-1-yl)-5-fluoropyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(3-methoxypyrrolidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-((methyl)sulfonamido-1,1,1-d3)phenyl)-4-(5-isopropoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, 2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methylthiophen-3-yl)-3,5-difluoropyridine 1-oxide, 4-(5-(azetidin-3-yloxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(3-hydroxy-1-methylazetidin-3-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(2-fluoro-3-(methylsulfonamido)phenyl)-4-(3-(pyridin-3-ylmethoxy)pyridin-2-yl)thiophene-2-carboxamide, 1-(2-(benzyloxy)cyclopentyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(((5-fluoropyridin-3-yl)oxy)methyl)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-fluoro-6-((5-fluoropyridin-3-yl)methoxy)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(dimethylcarbamoyl)-6-((3-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,4-difluoro-6-(oxazol-5-ylmethoxy)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-(oxazol-5-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)thiophene-2-carboxamide, 1-(2-(benzyloxy)phenyl)-N-(3-fluoro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-fluoro-6-(oxazol-5-ylmethoxy)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-((3-fluorobenzyl)oxy)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-1H-pyrazole-4-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-(hydroxymethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-(thiazol-2-ylmethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((2-methylthiazol-4-yl)methoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3,5-dimethylisoxazol-4-yl)methoxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-(pyrimidin-5-ylmethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(2-((5-fluoropyridin-3-yl)methoxy)-4-methylpyridin-3-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((1-methyl-1H-1,2,3-triazol-5-yl)methoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, (E)—N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(2-(2-(5-fluoropyridin-3-yl)vinyl)phenyl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((1-methyl-1H-tetrazol-5-yl)methoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-(2-(5-fluoropyridin-3-yl)ethyl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, (E)—N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-(2-(5-fluoropyridin-3-yl)vinyl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, 4-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methyl-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-(1-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((1S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((1R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((5-ethylpyridin-3-yl)methoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(5-fluoropyridin-3-yl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, (R)—N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(5-fluoropyridin-3-yl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, (S)—N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(5-fluoropyridin-3-yl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-4-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(oxazol-5-ylmethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-(oxazol-5-ylmethoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((3,5-difluorobenzyl)oxy)-2-methylpyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-(pyrimidin-5-ylmethoxy)pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, 5-(3-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methoxy)pyridin-2-yl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide, 5-(3-((3-hydroxybenzyl)oxy)pyridin-2-yl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(3,5-difluorophenyl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, (S)—N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(3,5-difluorophenyl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, (R)—N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(3,5-difluorophenyl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((3,5-difluorobenzyl)oxy)pyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((1-isopropylazetidin-3-yl)oxy)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, (S)—N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((1-methylpyrrolidin-3-yl)oxy)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, (R)—N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((1-methylpyrrolidin-3-yl)oxy)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-difluoroethyl)-5-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((1-(methylsulfonyl)azetidin-3-yl)oxy)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, (R)—N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-((1-methylpyrrolidin-3-yl)oxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, (S)—N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-((1-methylpyrrolidin-3-yl)oxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, 2-((2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methylthiophen-3-yl)pyrimidin-5-yl)oxy)propanoic acid, N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-4-(5-isopropoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-hydroxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, 4-(5-(tert-butoxy)pyrimidin-2-yl)-N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide, 2-((2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methylthiophen-3-yl)pyrimidin-5-yl)oxy)-2-methylpropanoic acid, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-((1-hydroxypropan-2-yl)oxy)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(2-(dimethylamino)ethoxy)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(1-hydroxy-1-(1-methylazetidin-3-yl)ethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-isopropoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-((1-(2,2,2-trifluoroethyl)azetidin-3-yl)oxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, 2-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)-3,5-difluoropyridine 1-oxide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-((1-isopropylazetidin-3-yl)oxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((1-(2,2-difluoroethyl)azetidin-3-yl)oxy)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-difluoroethyl)-5-(5-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-6-methoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoropyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-methoxypyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide; and N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

[0059] The compounds and intermediates described herein may be isolated and used as compounds themselves. Alternatively, if moieties capable of forming salts are present, the compounds or intermediates may be isolated and used as their corresponding salts. As used herein, the term "salt" or "salts" refers to acid addition or base addition salts of the compounds described herein. "Salts" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds described herein and are typically not biologically or otherwise unsuitable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups, or groups similar thereto.

[0060] Pharmaceutically acceptable acid addition salts include those derived from inorganic or organic acids, such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, hydrogensulfate / sulfate, camphorsulfate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurate ... The salts of hydroxybenzoates include methylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, torusylate and trifluoroacetate.

[0061] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0062] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0063] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0064] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I-XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0065] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0066] Salts can be synthesized from compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, or bicarbonate), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where feasible. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa., (1985), and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0067] Isotopically labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples and Preparations, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent. In one embodiment, the present disclosure provides a deuterated compound described herein, or a pharmaceutically acceptable salt thereof.

[0068] Pharmaceutically acceptable solvates in accordance with the present disclosure include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0069] It will be recognized by those skilled in the art that compounds of the present disclosure may contain chiral centers and therefore exist in different stereoisomeric forms. As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that may exist in a given compound of the present disclosure. It is understood that a substituent may be attached to a chiral center of a carbon atom. Thus, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0070] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The terms "racemic" or "rac" are used to indicate a racemic mixture when appropriate. When specifying the stereochemistry of compounds of the present disclosure, single stereoisomers with known relative and absolute configurations of two chiral centers are designated using the conventional RS system (e.g., (1S,2S)). "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated by either R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (right-handed or left-handed) they rotate plane-polarized light at the wavelength of the sodium D line. Alternatively, resolved compounds can be defined by the retention times of each of the corresponding enantiomers / diastereomers via chiral HPLC.

[0071] Certain compounds described herein contain one or more asymmetric centers or axes and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-.

[0072] Unless otherwise specified, the compounds of the present disclosure are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-stereoisomers can be prepared using chiral synthesizers or chiral reagents, or by conventional techniques (e.g., CHIRALPAK, available from DAICEL Corp., using appropriate solvents or solvent mixtures to achieve good resolution). RTM and CHIRALCEL RTM The compounds can be separated using chiral SFC or HPLC chromatography columns such as HPLC or HPLC. When the compounds contain double bonds, the substituents may be in the E or Z configuration. When the compounds contain disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0073] The present disclosure also provides pharmaceutical compositions comprising a compound described herein (e.g., a compound described in any one of the preceding embodiments), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0074] How to use The compounds described herein have DHX9 inhibitory activity.As used herein, "DHX9 inhibitory activity" refers to the ability of a compound or composition to induce detectable reduction in DHX9 activity in vivo or in vitro (for example, at least 10% reduction in DHX9 activity measured by a given assay, such as the bioassay described in Examples and known in the art).

[0075] In certain embodiments, the present disclosure provides a method for treating a disease or disorder responsive to inhibition of DHX9 activity (referred to herein as a "DHX9-mediated disease or disorder") in a subject in need thereof. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to forty-fifth embodiments), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0076] In certain embodiments, the present disclosure provides the use of a compound described herein (e.g., a compound described in any one of the first to forty-fifth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a DHX9-mediated disorder or disease in a subject in need of treatment.

[0077] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first through forty-fifth embodiments) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, for use in treating a DHX9-mediated disorder or disease in a subject in need of treatment.

[0078] In certain embodiments, the DHX9-mediated disease or disorder is selected from cancer, viral infection, and autoimmune disease.

[0079] In some embodiments, the present disclosure provides a method of treating cancer. In some embodiments, the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer. In some embodiments, the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer, and gastric cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is Ewing's sarcoma.

[0080] In some embodiments, the cancer is a microsatellite instability (MSI) cancer. In some embodiments, the cancer is an MSI-high cancer. In other embodiments, the cancer is an MSI-low cancer. MSI is determined by PCR analysis of five different nucleotide repeats, depending on the type of cancer. MSI-low cancers are characterized by instability at only one of the five sites, while MSI-high cancers are characterized by instability at two or more of the five sites (G. Yang et al. Correlations between microsatellite instability and the biological behavior of tumors. Journal of Cancer Research and Clinical Oncology, 2019).

[0081] MSI-high cancers are further characterized by defective mismatch repair (dMMR) (M. Lorenzi, et al., Epidemiology of Microsatellite Instability High (MSI-H) and Deficient Mismatch Repair (dMMR) in Solid Tumors: A Structured Literature Review. Journal of Oncology, Volume 2020, Article ID 1897929). For example, dMMR in colorectal cancer can be determined by MLH1 promoter hypermethylation, which renders MLH1 inactive, accounting for approximately 80-90% of MSI-high colorectal cancers. MSI-high colorectal cancer with inactivated MLH1 is also referred to as sporadic MSI-high colorectal cancer. Alternatively, dMMR can be determined by immunohistochemical mutation status of the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, MSH3, PMS1, and / or PMS2. In MSI-high colorectal cancer, MLH1 and MSH2 are the two most commonly mutated MMR proteins. They are mutated in approximately 10-20% of MSI-high colorectal cancers. MSI-high colorectal cancers with these mutations are also known as Lynch syndrome cancers.

[0082] In some embodiments, the cancer is an MSI cancer and / or has mutations or defects in DNA mismatch repair (MMR) and / or mutations or defects in RNA splicing and the kinetochore complex.

[0083] The compounds described herein, or pharmaceutically acceptable salts thereof, may be used to reduce the expression or activity of DHX9 or otherwise affect the properties and / or behavior of DHX9 in cells.

[0084] One embodiment of the present disclosure includes a method for reducing the expression or activity of DHX9 in a subject or otherwise affecting the properties and / or behavior of DHX9 in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0085] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a mammal.

[0086] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a primate.

[0087] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a human.

[0088] As used herein, the terms "effective amount" and "therapeutically effective amount" can be used interchangeably. This refers to an amount effective to treat or reduce the severity of one or more of the diseases, disorders, or conditions cited herein. In some embodiments, an effective dose can be between 10 μg and 500 mg.

[0089] The compounds and compositions according to the disclosed methods may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the above-cited diseases, disorders or conditions.

[0090] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered parenterally.

[0091] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically, or intranasally.

[0092] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered systemically.

[0093] The compounds of the present disclosure are typically used as pharmaceutical compositions (e.g., a compound of the present disclosure and at least one pharmaceutically acceptable carrier). As used herein, the term "pharmaceutically acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and the like, and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. For purposes of this disclosure, solvates and hydrates are considered to be pharmaceutical compositions comprising a compound of the present disclosure and a solvent (ie, a solvate) or water (ie, a hydrate).

[0094] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., the compound of the present disclosure or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the present disclosure are typically formulated into drug dosage forms to provide a controllable dose of the drug and provide patients with an elegant and easy-to-use product.

[0095] Pharmaceutical compositions (or formulations) for application can be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent inadvertent access to the contents of the package. Additionally, the container has deposited thereon a label describing the contents of the container. The label also includes appropriate warnings.

[0096] Pharmaceutical compositions containing the compounds of the present disclosure will generally be formulated for parenteral or oral administration, or alternatively for use as suppositories.

[0097] For example, the pharmaceutical oral compositions of the present disclosure can be made up in a solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in a liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, and buffers.

[0098] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol, also in the case of tablets; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, if desired; d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) Absorbents, colorants, flavors and sweeteners.

[0099] Tablets may be film coated or enteric coated according to methods known in the art.

[0100] Compositions suitable for oral administration include the compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearin, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0101] Parenteral compositions (e.g., intravenous (IV) formulations) are isotonic aqueous solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure and / or buffers. In addition, they may also contain other therapeutically useful substances. The compositions generally contain about 0.1 to 75%, or about 1 to 50%, of the active ingredient, prepared according to conventional mixing, granulating, or coating methods, respectively.

[0102] The compounds of the present disclosure or pharmaceutical compositions thereof for use in subjects (e.g., humans) are typically administered orally or parenterally in therapeutic doses. When administered intravenously via infusion, the dosage may depend on the infusion rate at which the IV preparation is administered. Generally, the therapeutically effective dosage of the compounds, pharmaceutical compositions, or combinations thereof depends on the subject's species, body weight, age, and individual condition, disorder, or disease, or its severity, being treated. A physician, pharmacist, clinician, or veterinarian skilled in the art can easily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of a disorder or disease.

[0103] The above dosage characteristics can be advantageously demonstrated in vitro and in vivo tests using mammals, such as mice, rats, dogs, monkeys, or their isolated organs, tissues, and preparations. The compounds of the present disclosure can be applied in vitro in the form of solutions, for example, aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, for example, as a suspension, or in aqueous solution. The dosage in vitro is about 10 -3 Molar ~ 10 -9 The concentration may range from molar to molar.

[0104] definition As used herein, "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. This term includes mammals, such as humans. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., a human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0105] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0106] As used herein, the terms "treat," "treating," or "treatment" of any disease, condition, or disorder refer to the management and care of a patient for the purpose of combating the disease, condition, or disorder, and include the administration of compounds of the present disclosure to achieve a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely reducing the severity of the disease, condition, or disorder; ameliorating or ameliorating clinical symptoms, complications, or indicators associated with the disease, condition, or disorder; or delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or disorder; or eliminating the disease, condition, or disorder. In certain embodiments, the effect may be preventing the onset of symptoms or complications of the disease, condition, or disorder.

[0107] As used herein, the term "cancer" has its meaning commonly accepted in the art. The term can broadly refer to abnormal cell growth.

[0108] As used herein, a subject is "in need" of a treatment (in some embodiments, a human) if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0109] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "optionally substituted" refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Specific substituents are described in the definitions and in the compound descriptions and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position.

[0110] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-4 The term "alkyl" refers to an alkyl having 1 to 4 carbon atoms. 1-3 Alkyl" and "C 1-2 The term "alkyl" should be construed accordingly. 1-4 Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy has the same definition as above. When indicated as "optionally substituted," the alkane radical or alkyl moiety can be unsubstituted or substituted with one or more substituents (generally 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0111] As used herein, the term "alkylene" refers to a fully saturated branched or unbranched divalent hydrocarbon radical. The term "C alkylene" refers to an alkylene having from 1 to 4 carbon atoms. The terms "C alkylene" and "C alkylene" should be construed accordingly. Representative examples of "C alkylene" include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, and tert-butylene.

[0112] As used herein, the term “alkoxy” refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., C 1-4 -O-C, where alkyl is as defined herein. 1-4 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. In some embodiments, an alkoxy group has about 1 to 4 carbons, and in some embodiments, about 1 or 2 carbons. 1-2 The term "alkoxy" should be construed accordingly.

[0113] As used herein, "C 1-4 Alkoxy C 1-4 The term "alkyl" refers to a C alkyl group as defined herein. 1-4 refers to an alkyl group, and at least one of the hydrogen atoms is C 1-4 Replaced by alkoxy. C 1-4 Alkoxy C 1-4 The alkyl group is connected through the remainder of the molecule described herein via the alkyl group.

[0114] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx ", where x and xx are integers. For example, "C 1-3 "Alkyl" is an alkyl group having 1 to 3 carbon atoms.

[0115] "Halogen" or "halo" can be fluorine, chlorine, bromine or iodine.

[0116] As used herein, "halo-substituted C" refers to a 1-4 Alkyl" or "C 1-4 The term "haloalkyl" refers to a C 1-4 C refers to an alkyl group in which at least one of the hydrogen atoms is replaced by a halo atom. 1-4 The haloalkyl group is a monohalo-C 1-4 Alkyl, dihalo-C 1-4 Alkyl or perhalo-C 1-4 Alkyl-containing polyhalo-C 1-4 It can be alkyl. Monohalo-C 1-4 Alkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihalo-C 1-4 Alkyl and polyhalo-C 1-4 The alkyl group may have two or more of the same halo atoms or a combination of different halo groups within the alkyl group. Typically, polyhalo-C 1-4 The alkyl group may contain up to 9, 8, 7, 6, 5, 4, 3, or 2 halo groups. 1-4 Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. 1-4 An alkyl group is a C group having all hydrogen atoms replaced by halo atoms. 1-4 Refers to an alkyl group.

[0117] The term "aryl" refers to an aromatic carbocyclic single ring or two fused ring systems containing from 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl.

[0118] The term "heteroaryl" refers to a 5- to 12-membered aromatic radical containing 1 to 4 heteroatoms selected from N, O, and S. In some cases, the nitrogen atom in a heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic." Heteroaryl groups may be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithinyl, oxathianyl, triazinyl, tetrazinyl, and the like. Bicyclic heteroaryl includes groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, indazolyl, benzofuranyl, benzimidazolyl, and imidazo[1,2-a]pyridine.

[0119] The term "carbocyclic ring" or "carbocyclyl" refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring, which may exist as a monocyclic, bicyclic (including fused, spiro, or bridged) or spiro ring. Bicyclic carbocyclyl groups include unsaturated carbocyclic radicals fused to another unsaturated carbocyclic radical, a cycloalkyl, or an aryl, such as, for example, cyclohexyl, cyclohexenyl, 2,3-dihydroindenyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless otherwise specified, carbocyclic rings typically contain 4 to 10 ring members.

[0120] "C 3-6 The term "cycloalkyl" refers to a fully saturated carbocyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0121] The term "heterocycle" or "heterocyclyl" refers to a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. Heterocyclyl groups can be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, but are not limited to, piperdinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and pyrrolidinyl. Bicyclic heterocyclyl groups include, for example, unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, a cycloalkyl, aryl, or heteroaryl ring, such as 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl. In some embodiments, the heterocyclyl group is a 4- to 6-membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is an 8- to 10-membered bicyclic heterocyclyl group.

[0122] As used herein, the term "spiro" ring refers to a two-ring system in which both rings share one common atom. Examples of spiro rings include 5-oxaspiro[2.3]hexane, oxaspiro[2.4]heptanyl, 5-oxaspiro[2.4]heptanyl, 4-oxaspiro[2.4]heptane, 4-oxaspiro[2.5]octanyl, 6-oxaspiro[2.5]octanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[bicyclo[2.1.1]hexane-2,3'-oxetan]-1-yl, oxaspiro[bicyclo[3.2.0]heptane-6,1'-cyclobutan]-7-yl, 2,6-diazaspiro[3.3]heptanyl, and -oxa-6-azaspiro[3.3]heptanyl. ]heptane, 2,2,6-diazaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, 7-azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, 8-azaspiro[4.5]decane, 1,6-diazaspiro[3.3]heptane, 5-azaspiro[2.5]octane, 4,7-diazaspiro[2.5]octane, 5-oxa-2-azaspiro[3.4]octane, 6-oxa-1-azaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, and the like.

[0123] The term "fused" ring refers to two ring systems that share two adjacent ring atoms. Fused heterocycles contain at least one ring atom that is a heteroatom selected from O, N, and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0124] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety joined by two non-adjacent ring atoms (e.g., bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, and bicyclo[3.2.1]octane).

[0125] The phrase "pharmaceutically acceptable" indicates that the substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0126] Unless otherwise specified, the term "compounds of the disclosure" refers to compounds of Formula (I) and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). Where moieties capable of forming salts are present, salts, particularly pharmaceutically acceptable salts, are also included.

[0127] As used herein, the terms "a," "an," "the," and similar terms used in the context of this disclosure (particularly in the context of the claims) should be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") described herein is intended merely to better clarify the invention and does not limit the scope of the claims unless otherwise specified.

[0128] Intermediates and compounds of the present disclosure may exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0129] In one embodiment, the disclosure relates to a compound of formula (I) as defined herein in free form. In another embodiment, the disclosure relates to a compound of formula (I) as defined herein in the form of a salt. In another embodiment, the disclosure relates to a compound of formula (I) as defined herein in the form of an acid addition salt. In a further embodiment, the disclosure relates to a compound of formula (I) as defined herein in the form of a pharmaceutically acceptable salt. In yet another embodiment, the disclosure relates to a compound of formula (I) as defined herein in the form of a pharmaceutically acceptable acid addition salt. In yet a further embodiment, the disclosure relates to any one of the example compounds in free form. In yet a further embodiment, the disclosure relates to any one of the example compounds in the form of a salt. In yet another embodiment, the disclosure relates to any one of the example compounds in the form of an acid addition salt. In yet a further embodiment, the disclosure relates to any one of the example compounds in the form of a pharmaceutically acceptable salt. In yet another embodiment, the disclosure relates to any one of the example compounds in the form of a pharmaceutically acceptable salt.

[0130] The compounds of the present disclosure can be synthesized by synthetic routes that include processes similar to those well known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich, or are readily prepared using methods well known to those skilled in the art (e.g., Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilstein's Handbuch der organischen Chemie, 4, Aufl. Springer-Verlag, Berlin (with supplements) (also available from the Beilstein online database)).

[0131] For illustrative purposes, the reaction schemes shown below provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. While specific starting materials and reagents are shown in the schemes and described below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions.

[0132] Example Abbreviation: PE = petroleum ether EtOAc = EA = ethyl acetate ESI = electrospray ionization MeOH = methanol EtOH = ethanol DCM = dichloromethane DIAD = diisopropyl azodicarboxylate DMF = dimethylformamide DPPA = diphenylphosphoryl azide EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU = hexafluorophosphate azabenzotriazole tetramethyluronium HCl = Hydrochloric acid H2O = Water NBS = N-bromosuccinimide LCMS = Liquid Chromatography Mass Spectrometry HPLC = High Pressure Liquid Chromatography THF = tetrahydrofuran MeCN = ACN = Acetonitrile DMSO = dimethyl sulfoxide PhMe = toluene AcOH = acetic acid CDI = carbonyldiimidazole TFA = trifluoroacetic acid DIPEA = DIEA = diisopropylethylamine TLC = thin layer chromatography N2 = nitrogen KOH = potassium hydroxide NH4HCO3 = ammonium bicarbonate t-BuOH = tert-butanol NH4Cl = ammonium chloride t-BuOK = potassium tert-butoxide NaH = sodium hydride Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Na2SO4 = sodium sulfate K2CO3 = Potassium Carbonate K3PO4 = Potassium phosphate Cs2CO3 = Cesium carbonate NaHCO3 = sodium bicarbonate Pd(OAc)2 = palladium(II) acetate Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0) NaOH = Sodium hydroxide TCFH = N'-tetramethylformamidinium hexafluorophosphate NMI = 1-methylimidazole Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xantphos PdG3 = [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate RuPhos = 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl RuPhos Pd G3 = (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Pd / C = palladium on carbon Pd(dppf)Cl2DCM = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)Cl2 = bis(triphenylphosphine)palladium(II) dichloride STAB = NaBH(AcO)3 = sodium triacetoxyborohydride AlMe3 = Al(CH3)3 = Trimethylaluminum DIAD = diisopropyl azodicarboxylate PEPPSI-IHeptCl = (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-κN)-palladium Er(OTf)3 = erbium(III) triflate Br2 = Bromine KOAc = potassium acetate TEBAc = benzyltriethylammonium chloride B2pin2 = Bis(pinacolato)diboron BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BPO = Benzoyl Peroxide Py = pyridine LiAlH4 = lithium aluminum hydride

[0133] General method 1. 1 The H NMR spectrum was recorded as follows: NMR10 Bruker AVANCE III HD 300MHz NMR16 Bruker AVANCE III HD 300MHz NMR19 Bruker AVANCE III HD 400MHz NMR24 Bruker AVANCE NEO 400MHz NMR30 Bruker AVANCE NEO 400MHz 2. LCMS measurements were performed on a Shimadzu LCMS-2020 using the following conditions: Method A: Mobile phase: A: water (0.05% TFA) B: acetonitrile (0.05% TFA); Gradient phase: 5% B to 100% B in 2.0 min, 100% B in 0.7 min (total run time: 2.8 min); Flow rate: 1.5 mL / min; Column: HALO C18, 3.0 x 30 mm, 2.0 μm; Column temperature: 40 °C; Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI. Method B: Mobile phase: A: water (0.1% FA) B: acetonitrile (0.1% FA); Gradient phase: 5% B to 100% B in 2.0 min, 100% B in 0.7 min (total run time: 2.8 min); Flow rate: 1.5 mL / min; Column: HALO C18, 3.0 x 30 mm, 2.0 μm; Column temperature: 40 °C; Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI. Method C: Mobile phase: A: Water (5 mM NH4HCO3) B: Acetonitrile, Gradient phase: 10% B to 95% B in 2.0 min, 100% B in 0.6 min (total run time: 2.8 min), Flow rate: 1.5 mL / min, Column: Poroshell HPH-C18, 3.0 x 50 mm, 4.0 μm, Column temperature: 40 °C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[0134] Preparation of intermediates The compounds claimed herein were prepared according to the procedures outlined in the following scheme. Compound names were generated using software integrated into ChemDraw. To the extent that there is a discrepancy between the name of a compound and its depicted structure, the depicted chemical structure should be taken as the appropriate compound.

[0135] Intermediate A: N-(3-amino-5-chlorophenyl)methanesulfonamide [ka] Step 1: To a stirred mixture of 1-chloro-3-fluoro-5-nitrobenzene (45 g, 256.35 mmol, 1.00 equiv.), methanesulfonamide (24.38 g, 256.35 mmol, 1.00 equiv.), and CsCO (250.57 g, 769.05 mmol, 3.00 equiv.) in 500 mL of DMSO was added. The resulting solution was stirred at 60 °C for 2 h. After cooling, the mixture was quenched with 1000 mL of water, extracted with 3 × 1000 mL of ethyl acetate, dried over anhydrous NaSO, and concentrated. The residue was purified on a silica gel column eluted with 50% ethyl acetate in petroleum ether to give N-(3-chloro-5-nitrophenyl)methanesulfonamide (41 g, 63.81%) as a pale yellow solid. LCMS (ESI) [M+H] + :249.9

[0136] Step 2: A stirred solution of N-(3-chloro-5-nitrophenyl)methanesulfonamide (41.00 g, 163.57 mmol, 1.00 equiv.), Fe (91.35 g, 1635.75 mmol, 10.00 equiv.), and NHCl (87.50 g, 1635.75 mmol, 10.00 equiv.) in 500 mL of ethanol and 300 mL of water was stirred at 90 °C for 2 h. The resulting mixture was filtered, and the filter cake was washed with 6 × 50 mL of methanol. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with 50% ethyl acetate in petroleum ether to give N-(3-amino-5-chlorophenyl)methanesulfonamide (25.3 g, 70.1%) as a pale yellow solid. LCMS(ESI)[M+H] + :220.01. 1 H NMR(300MHz,DMSO-d6)δ 9.64(s,1H),6.41-6.31(m,3H),5.54(s,2H),2.98(s,3H)

[0137] Intermediate E: N-(3-amino-5-chlorophenyl)propane-1-sulfonamide [ka] 3-Bromo-5-chloroaniline (1 g, 4.843 mmol, 1 equiv.), propane-1-sulfonamide (1.19 g, 9.686 mmol, 2 equiv.), (1S,2S)-N in ACN (10 mL) 1 , N 2 A solution of 2.07 g (14.529 mmol, 3 equiv.), CuI (2.77 g (14.529 mmol, 3 equiv.), and KCO (2.01 g (14.529 mmol, 3 equiv.)) was stirred at 110 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give N-(3-amino-5-chlorophenyl)propane-1-sulfonamide (540 mg, 45% yield) as a yellow solid. LCMS(ESI)[M+H] + :249

[0138] Intermediate H: N-(3-amino-5-chlorophenyl)cyclopropanesulfonamide [ka] Step 1: A solution of 3-chloro-5-nitroaniline (300 mg, 1.738 mmol, 1 equiv.) and cyclopropanesulfonyl chloride (244 mg, 1.738 mmol, 1 equiv.) in pyridine (5 ml) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give N-(3-chloro-5-nitrophenyl)cyclopropanesulfonamide (255 mg, 53% yield) as a white solid. LCMS(ESI)[M+H] + :277

[0139] Step 2: A solution of N-(3-chloro-5-nitrophenyl)cyclopropanesulfonamide (235 mg, 0.849 mmol, 1 equiv.), Fe (474 ​​mg, 8.490 mmol, 10 equiv.), and NHCl (136 mg, 2.547 mmol, 3 equiv.) in ethanol (5 mL) and HO (1 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with ethanol (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give N-(3-amino-5-chlorophenyl)cyclopropanesulfonamide (190 mg, 91% yield) as a white solid. LCMS(ESI)[M+H] + :247

[0140] The following intermediates were prepared using similar experimental procedures for intermediates AE or H. [Table 1]

[0141] Intermediate J: 2-bromo-5-(tert-butoxy)pyrimidine [ka] A mixture of 2-bromopyrimidin-5-ol (2.5 g, 14.3 mmol, 1 equiv.) and Er(OTf) (0.44 g, 0.7 mmol, 0.05 equiv.) in BocO (60 mL) was stirred at 50 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 2-bromo-5-(tert-butoxy)pyrimidine (400 mg, 6% yield) as a yellow oil. This reaction was repeated 13 times to give a total of 2.9 g of the desired product. LCMS (ESI) [M+H]: 231

[0142] Intermediate K: 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate [ka] Step 1: A mixture of 5-methylthiophene-2-carboxylic acid (100 g, 703.383 mmol, 1 equiv.) and Br2 (123.65 g, 773.721 mmol, 1.1 equiv.) in AcOH (1 L) was stirred at 60 °C for 2 h. The product was precipitated by adding water (500 mL) at 0 °C. The precipitated solid was collected by filtration and washed with water to give 4-bromo-5-methylthiophene-2-carboxylic acid (130 g, 84%) as a yellow solid. LCMS (ESI) [M+H]+: 221

[0143] Step 2: A mixture of 4-bromo-5-methylthiophene-2-carboxylic acid (100 g, 452.345 mmol, 1 equiv.) and H2SO4 (100 mL, 1876.211 mmol, 4.15 equiv.) in MeOH (1 L) was stirred at 50 °C overnight. The resulting mixture was concentrated in vacuo. The resulting mixture was diluted with water (200 mL). The aqueous layer was extracted with EtOAc (3 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give methyl 4-bromo-5-methylthiophene-2-carboxylate (80 g, 74% yield) as a pale yellow solid. GCMS: 234. 1 H NMR (300MHz, DMSO-d6) δ 7.70 (s, 1H), 3.82 (s, 3H), 2.43 (s, 3H).

[0144] Step 3: A mixture of 4-bromo-5-methylthiophene-2-carboxylate (80 g, 340.281 mmol, 1 equiv.), bis(pinacolato)diboron (172.82 g, 680.562 mmol, 2 equiv.), Pd(dppf)Cl (12.45 g, 17.014 mmol, 0.05 equiv.), and KOAc (100.19 g, 1020.843 mmol, 3 equiv.) in 1,4-dioxane (800 mL) was stirred at 80 °C overnight under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (15:1) to give methyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (90 g, crude). The crude product was recrystallized from hexane to give methyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (35 g, 36% yield) as a white solid. LCMS (ESI) [M+H] + :283. 1 H NMR(400MHz,DMSO-d6)δ 7.70(s,1H),3.79(s,3H),2.65(s,3H),1.28(s,12H)

[0145] Intermediate L: Methyl 5-methyl-1H-pyrrole-3-carboxylate [ka] Step 1: Tosylmethyl isocyanide (200 g, 1.03 mol, 1 equiv.) was dissolved in 1.5 L of dichloromethane and cooled to 0 °C. Benzyltriethylammonium chloride (46.62 g, 2.05 mol, 2 equiv.), methyl iodide (126.3 mL, 2.05 mol, 2 equiv.), and 1.5 L of 30% aqueous sodium hydroxide solution were added. The mixture was stirred at 0 °C for 3 h. Water (4 L) was added to the reaction mixture, and it was extracted with dichloromethane (1.5 L × 3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (4:1) to give 1-((1-isocyanoethyl)sulfonyl)-4-methylbenzene (167 g, 78.0% yield) as a brown oil. Step 2: A solution of methyl acrylate (138.2 mL, 1.55 mol, 0.97 equiv.) and 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (335 g, 1.60 mol, 1 equiv.) in diethyl ether (3 L) and DMSO (1.5 L) was added dropwise under nitrogen to a stirred suspension of sodium hydride (60% purity) (99.7 g, 2.49 mol, 1.55 equiv.) in diethyl ether (4 L). The resulting suspension was stirred at room temperature for 4 h. The reaction mixture was poured into sodium chloride solution (5 L), the layers were separated, and the aqueous solution was extracted with EA (3 × 5 L). The combined organic layers were washed with water (5 L), dried over Na2SO4, filtered, and evaporated to give a beige solid. The crude product was purified by flash silica chromatography, elution gradient 0-40% ethyl acetate to give methyl 5-methyl-1H-pyrrole-3-carboxylate (105.6 g, 47.4% yield) as a white solid. LCMS (ESI) [M+H] + :140. 1 H NMR(400MHz,DMSO-d6)δ 11.18(s,1H),7.24(dd,J=3.0,1.7Hz,1H),6.10(dt,J=2.7,1.4Hz,1H),3.66(s,3H),2.15(d,J=1.0Hz,3H).

[0146] Intermediate M: 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-3-carboxylate [ka] Step 1: To a stirred solution of methyl 1H-pyrrole-3-carboxylate (100 g, 800 mmol, 1 equiv.) and NaH (60%) (64 g, 1.6 mol, 2 equiv.) in DMF (1 L) was added CHCl (227.2 g, 1.6 mol, 2 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 3 h. The reaction was quenched by adding water (5 L) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 5 L). The combined organic layers were washed with brine (3 × 5 L) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give methyl 1-methylpyrrole-3-carboxylate (95 g, 85.6%) as a white solid. LCMS (ESI) [M+H] + :140

[0147] Step 2: A solution of methyl 1-methylpyrrole-3-carboxylate (95 g, 683.5 mmol, 1 equiv.), B2Pin2 (138.9 g, 546.7 mmol, 0.8 equiv.), di-mu-methoxobis(1,5-cyclooctadiene)diiridium(I) (6.7 g, 10.3 mmol, 0.015 equiv.), and 4,4'-di-tert-butyl-2,2'-bipyridine (5.49 g, 20.5 mmol, 0.03 equiv.) in 1,4-dioxane (1 L) was stirred at 100 °C for 3 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2 / 1) to give the crude product. The crude product was triturated with PE for 12 hours at room temperature and filtered to give 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-3-carboxylate (105 g, 57.8% yield) as a white solid. LCMS (ESI) [M+H] + :266. 1H NMR (300 MHz, chloroform-d) δ 7.37 (d, J = 1.6 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 1.31 (s, 12H).

[0148] The following intermediates were prepared using similar experimental procedures as for intermediate M: [Table 2]

[0149] General scheme The compounds described below can be prepared, for example, through the following general schemes, among other methods known to those skilled in the art.

[0150] General Scheme A: [ka] Carboxylic acid esters, either commercially available or prepared via various means (e.g., Suzuki coupling, Buchwald coupling, alkylation, SNAr, ring condensation, or multi-step synthesis), are hydrolyzed with various reagents (e.g., lithium hydroxide) to generate the carboxylic acid. The carboxylic acid is then coupled with an appropriate reagent (e.g., one of the anilines or other amines described above) using various reagents to provide the desired product.

[0151] General Scheme B: [ka] Carboxylic acid esters, either commercially available or prepared via various means (e.g., Suzuki coupling, Buchwald coupling, alkylation, SNAr, ring condensation, or multi-step synthesis), are reacted with an appropriate reagent (e.g., one of the anilines or other amines described above) in the presence of trimethylaluminum or other suitable reagent to provide the desired product.

[0152] In general, any method can be considered suitable and interchangeable for obtaining the examples shown below. For the examples shown below, one skilled in the art can identify alternative conditions for the individual steps, such as alkylation, hydrolysis, substitution, cross-coupling, or other chemical transformations. [Example]

[0153] Example 1: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-phenyl-1H-imidazole-4-carboxamide [ka] To a mixture of 1-phenyl-1H-imidazole-4-carboxylic acid (70 mg, 0.371 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (81.8 mg, 0.371 mmol) in ACN (1 mL) was added TCFH (103 mg, 0.371 mmol) and NMI (30.4 mg, 0.371 mmol), and the resulting mixture was stirred at room temperature for 2 h. After concentration, the residue was purified by reverse-phase flash chromatography eluting with 60% acetonitrile in water (0.1% NH4HCO3) to give N-(3-chloro-5-methanesulfonamidophenyl)-1-phenyl-1H-imidazole-4-carboxamide (47.2 mg, 32.4%) as a white solid. LCMS [M+H] + :391. 1 H NMR(400MHz,DMSO-d6)δ 10.27(s,1H),10.05(s,1H),8.53-8.44(m,2H),7.83-7.74(m,4H),7.57(dd ,J=8.6,7.2Hz,2H),7.48-7.39(m,1H),6.92(t,J=2.0Hz,1H),3.10(s,3H).

[0154] Examples 2-14 and 321-332 The compounds listed in the table below were prepared using procedures similar to those described in Example 1. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0155] Example 15: N-(3-bromo-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide [ka] Step 1: To a mixture of methyl 4-bromothiophene-2-carboxylate (30 g, 135 mmol), phenylboronic acid (32.9 g, 270 mmol), Pd(dppf)Cl (11.0 g, 13.5 mmol), and KPO (85.8 g, 405 mmol), dioxane (300 mL) and HO (30 mL) were added. The resulting mixture was stirred at 80 °C under a N atmosphere for 2 h. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in petroleum ether to give methyl 4-phenylthiophene-2-carboxylate (27.1 g, 124 mmol) as a pale yellow solid.

[0156] Step 2: To a stirred solution of methyl 4-phenylthiophene-2-carboxylate (26.1 g, 119 mmol) in 260 mL of THF and 260 mL of water, LiOH (24.9 g, 595 mmol) was added. The resulting mixture was stirred at room temperature overnight. It was then concentrated, and the pH value of the residual solution was adjusted to 3 with 1 M HCl (aq). The product precipitated from the solution. After filtration, 4-phenylthiophene-2-carboxylic acid (24.4 g, 119 mmol) was obtained as a white solid.

[0157] Step 3: To a mixture of 4-phenylthiophene-2-carboxylic acid (10.1 g, 49.6 mmol) and N-(3-amino-5-bromophenyl)methanesulfonamide (11 g, 41.4 mmol) in ACN (110 mL) was added TCFH (17.3 g, 62.1 mmol) and NMI (10.1 g, 124 mmol) at room temperature. The resulting mixture was stirred overnight, then concentrated, and the residue was purified by reverse-phase flash chromatography eluting with 60% acetonitrile in water (0.1% FA) to give N-(3-bromo-5-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (11.0519 g, 24.486 mmol) as a pale yellow solid. LCMS (ESI) [MH] - :449. 1 H NMR(300MHz,DMSO-d6)δ 10.46(s,1H),10.09(s,1H),8.49(d,J=1.5Hz,1H),8.23(d,J=1.4Hz,1H), 7.96-7.60(m,4H),7.57-7.24(m,3H),7.11(t,J=1.9Hz,1H),3.08(s,3H).

[0158] Example 16 The compounds listed in the table below were prepared using procedures similar to those described in Example 15. [Table 4]

[0159] Example 17: N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide [ka] Step 1: A mixture of 4-bromothiophene-2-carboxylate (250 g, 1063.37 mmol, 1.00 equiv.) and bis(pinacolato)diboron (810.10 g, 3190.13 mmol, 3.00 equiv.) and Pd(dppf)Cl (38.90 g, 53.17 mmol, 0.05 equiv.) and AcOK (313.09 g, 3190.13 mmol, 3.00 equiv.) in 1500 mL of ethyl 1,4-dioxane was stirred at 80° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with 50% ethyl acetate in petroleum ether to give ethyl 4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (231.02 g, 81.0%) as a yellow solid.

[0160] Step 2: A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (231.00 g, 861.52 mmol, 1.00 equiv.) and 2-bromopyridine (163.34 g, 1033.83 mmol, 1.20 equiv.) and Pd(dppf)Cl (31.52 g, 43.076 mmol, 0.05 equiv.) and KCO (357.20 g, 2584.57 mmol, 3.00 equiv.) in 1000 mL of 1,4-dioxane and 100 mL of water was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with 50% ethyl acetate in petroleum ether to give methyl 4-(pyridin-2-yl)thiophene-2-carboxylate (196.12 g, 103.8%) as a white solid. LCMS (ESI). [M+H] + :219

[0161] Step 3: A mixture of methyl 4-(pyridin-2-yl)thiophene-2-carboxylate (186.00 g, 848.31 mmol, 1.00 equiv.) and LiOH (60.95 g, 2544.924 mmol, 3.00 equiv.) in 1000 mL of ethanol and 100 mL of water was stirred at 60 °C for 1 h. The mixture was adjusted to pH 6 with HCl (aq.). The precipitated solid was collected by filtration and washed with 3 × 100 mL of water. This gave 4-(pyridin-2-yl)thiophene-2-carboxylic acid (133.12 g, 76.4%) as a white solid. LCMS (ESI) [M+H] + :206

[0162] Step 4: A mixture of 4-(pyridin-2-yl)thiophene-2-carboxylic acid (133.12 g, 648.05 mmol, 1.00 equiv.) and N-(3-amino-5-bromophenyl)methanesulfonamide (171.82 g, 648.05 mmol, 1.00 equiv.) and TCFH (272.75 g, 972.08 mmol, 1.50 equiv.) and NMI (159.63 g, 1944.159 mmol, 3 equiv.) in 800 mL of acetonitrile was stirred at room temperature for 2 hours. The residue was purified on a silica gel column eluted with 10% methanol in dichloromethane to give 75 g of the desired product (95% purity). The desired product was purified by trituration with 300 mL of 30% methanol in dichloromethane. This gave N-(3-bromo-5-methanesulfonamidophenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide (54.8097 g, 18.7%) as a white solid. LCMS (ESI) [M+H] + :452. 1H NMR(300MHz,DMSO-d6)δ 10.61(s,1H),10.08(s,1H),8.75(d,J=1.4Hz,1H),8.65(m,J=4.8,1.4Hz,1H),8.52(d,J=1.3Hz,1H),7.92(m,J=2.9,1. 4Hz,2H), 7.84(t,J=1.8Hz,1H),7.75(t,J=1.9Hz,1H),7.36(td,J=5.3,3.1Hz,1H),7.10(t,J=1.8Hz,1H),3.08(s,3H).

[0163] Example 31: N-(3-chloro-5-methanesulfonamidophenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide [ka] Step 1: A solution of methyl 4-bromothiophene-2-carboxylate (150 g, 678.52 mmol, 1.00 equiv.), Pd(dppf)Cl (24.82 g, 33.93 mmol, 0.05 equiv.), AcOK (199.77 g, 2035.55 mmol, 3.00 equiv.), and bis(pinacolato)diboron (206.76 g, 814.22 mmol, 1.2 equiv.) in 1000 mL of dioxane was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was cooled and concentrated. The residue was purified on a silica gel column eluted with 10% ethyl acetate in petroleum ether to give methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (170 g, 92.5%) as a yellow solid.

[0164] Step 2: A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (170 g, 634.02 mmol, 1.00 equiv.), Pd(dppf)Cl (23.20 g, 31.70 mmol, 0.05 equiv.), KCO (262.87 g, 1902.06 mmol, 3.00 equiv.), and 2-bromo-3-methylpyridine (109.07 g, 634.02 mmol, 1.00 equiv.) in 1000 mL of 1,4-dioxane and 200 mL of water was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was cooled and concentrated. The residue was purified by silica gel column chromatography eluting with 50% ethyl acetate in petroleum ether to give methyl 4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (115 g, 77%) as a yellow solid. LCMS (ESI) [M+H]: 234

[0165] Step 3: To a stirred solution of methyl 4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (115 g, 492.95 mmol, 1.00 equiv.), LiOH (118.06 g, 4929.49 mmol, 10.00 equiv.) in 250 mL of ethanol and 250 mL of water was added. The mixture was then stirred at room temperature for 2 hours. The mixture was adjusted to pH 5 with citric acid. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried under vacuum to give 4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (60 g, 54.9%) as a yellow solid. LCMS(ESI)[M+H]+:220

[0166] Step 4: To a stirred solution of 4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (60 g, 273.65 mmol, 1.00 equiv.), TCFH (115.17 g, 410.47 mmol, 1.50 equiv.), and NMI (67.40 g, 820.94 mmol, 3.00 equiv.) in 1000 mL of acetonitrile, N-(3-amino-5-chlorophenyl)methanesulfonamide (50 g, 226.58 mmol, 0.83 equiv.) was added. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated and purified by reverse flash chromatography eluting with 56% acetonitrile in water (0.05% FA) to give N-(3-chloro-5-methanesulfonamidophenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide (49.6634 g, 42.8%) as a white solid. LCMS (ESI) [M+H]: 422. 1 H NMR(300MHz, methanol-d4)δ 8.49-8.41(m,1H),8.21(d,J=1.4Hz,1H),7.99(d,J=1.4Hz,1H),7.85-7.75(m,1H),7.69(t,J=1.9Hz,1 H),7.60(t,J=1.9Hz,1H),7.35(dd,J=7.7,4.9Hz,1H),7.05(t,J=2.0Hz,1H),3.06(s,3H),2.50(s,3H).

[0167] Examples 18-35 and 333-386 The compounds listed in the table below were prepared using procedures similar to those described in Example 17. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] [Table 5-13] [Table 5-14] [Table 5-15]

[0168] Example 36: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide [ka] Step 1: To a stirred solution of 2-fluoropyridine (150 g, 1.54 mol), KOH (260 g, 4.62 mol), and ethyl 1H-pyrazole-4-carboxylate (258.7 g, 1.85 mol) in 3500 mL of DMSO was added. The mixture was then stirred at 100° C. for 2 hours. The mixture was cooled and then quenched with 3000 mL of water. The aqueous layer was extracted with 3×1000 mL of ethyl acetate. The mixture was concentrated and purified on silica gel eluting with 35% ethyl acetate in petroleum ether to give ethyl 1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate (168 g, 49.5%) as a yellow solid. LCMS(ESI)[M+H] + :218

[0169] Step 2: To a stirred solution of ethyl 1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate (168 g, 0.77 mol), LiOH (53 g, 2.32 mol) in 1000 mL of water and 3000 mL of tetrahydrofuran was added, and the mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH 6 with concentrated HCl. The aqueous layer was extracted with 3 x 500 mL of ethyl acetate. This was concentrated and purified by reverse flash chromatography eluting with 50% acetonitrile in water (0.05% FA) to give 1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (116 g, 80.5%) as an off-white solid. LCMS (ESI) [M+H] + :190

[0170] Step 4: To a stirred solution of 1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (95 g, 0.51 mol), TCFH (211 g, 0.75 mol), NMI (246 g, 3.03 mol), and N-(3-amino-5-bromophenyl)methanesulfonamide (134 g, 0.51 mol) in 300 mL of acetonitrile was added. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated and purified by reverse flash chromatography eluting with 50% acetonitrile in water (0.05% FA) to give N-(3-bromo-5-methanesulfonamidophenyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide (51.5 g, 23.6%) as a white solid. LCMS (ESI) [M+H] + :436. 1 H NMR(300MHz,acetone-d6)δ 9.67(s,1H),9.29(d,J=0.9Hz,1H),8.83(s,1H),8.54(dt,J=4.8,1.4Hz,1H),8.26(d,J=0.8Hz,1H),8.13-8.01(m,2H) ),7.99(dt,J=2.5,1.2Hz,1H),7.80(dt,J=2.9,1.4Hz,1H),7.44(h,J=4.7Hz,1H),7.26(t,J=1.9Hz,1H),3.11(s,3H).

[0171] Examples 37 to 49 and 387 The compounds listed in the table below were prepared using procedures similar to those described in Example 36. [Table 6-1] [Table 6-2] [Table 6-3]

[0172] Example 50: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(pyrimidin-2-yl)-1H-pyrazole-4-carboxamide [ka] Step 1: A solution of ethyl 1H-pyrazole-4-carboxylate (500 mg, 3.568 mmol, 1 equiv.) and pyrimidine, 2-bromo- (567.23 mg, 3.568 mmol, 1 equiv.) and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (101.50 mg, 0.714 mmol, 0.2 equiv.) with CuI (67.95 mg, 0.357 mmol, 0.1 equiv.) and K2CO3 (1479.27 mg, 10.704 mmol, 3 equiv.) in toluene (5 mL) was stirred at 110 °C for 2 h under a nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3 × 30 mL). The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1:1) to give ethyl 1-(pyrimidin-2-yl)pyrazole-4-carboxylate (440 mg, 56.52%) as a white solid. LCMS (ESI) [M+H] + :219

[0173] Step 2: A solution of ethyl 1-(pyrimidin-2-yl)pyrazole-4-carboxylate (440 mg, 2.016 mmol, 1 equiv.) and LiOH (144.87 mg, 6.048 mmol, 3 equiv.) in EtOH (4 mL) and HO (1.5 mL) was stirred at 60 °C for 1 h. The mixture was acidified to pH 6 with HCl (aq.). The residue was purified by reverse-phase flash chromatography under the following conditions: column, silica gel, mobile phase, MeCN in water, gradient 0% to 100% in 20 min, detector, UV 254 nm. This afforded 11-(pyrimidin-2-yl)pyrazole-4-carboxylic acid (380 mg, 99.10%) as a white solid. LCMS (ESI) [M+H] + :191

[0174] Step 3: To a stirred solution of 1-(pyrimidin-2-yl)pyrazole-4-carboxylic acid (80 mg, 0.421 mmol, 1 equiv.) and N-(3-amino-5-bromophenyl)methanesulfonamide (111.54 mg, 0.421 mmol, 1 equiv.) in DMSO (4 mL), NMI (103.62 mg, 1.263 mmol, 3 equiv.) and NMI (103.62 mg, 1.263 mmol, 3 equiv.) were added in portions at room temperature. The residue was purified by reverse-phase flash chromatography under the following conditions: column, silica gel, mobile phase, MeCN in water, gradient from 0% to 100% in 20 min, detector, UV at 254 nm. This gave N-(3-bromo-5-methanesulfonamidophenyl)-1-(pyrimidin-2-yl)pyrazole-4-carboxamide (19.3 mg, 10.49%) as a white solid. LCMS (ESI) [M+H] + :436. 1 H NMR(300MHz,DMSO-d6)δ 10.34(s,1H),10.07(s,1H),9.46(s,1H),8.96(d,J=4.8Hz,2H),8.33(s,1H),7.86(t,J=1. 8Hz,1H), 7.69(t,J=1.8Hz,1H),7.59(t,J=4.8Hz,1H),7.09(t,J=1.9Hz,1H),3.08(s,3H).

[0175] Examples 51 to 60 and 388 to 393 The compounds listed in the table below were prepared using procedures similar to those described in Example 50. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

[0176] Example 61: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyridin-3-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide [ka] Step 1: To a mixture of 3-(bromomethyl)pyridine (520 mg, 3.02 mmol), 2-bromopyridin-3-ol (629 mg, 3.62 mmol), and K2CO3 (1.25 g, 9.06 mmol), DMF (5 mL) was added. The resulting mixture was stirred at 60 °C under a N2 atmosphere for 2 hours. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate in petroleum ether to give 2-bromo-3-[(pyridin-3-yl)methoxy]pyridine (550 mg, 68.6%) as a white solid. LCMS [M+H] + :265

[0177] Step 2: To a mixture of 2-bromo-3-[(pyridin-3-yl)methoxy]pyridine (550 mg, 2.07 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (117 mg, 0.828 mmol), ethyl 1H-pyrazole-4-carboxylate (434 mg, 3.10 mmol), CuI (78.8 mg, 0.414 mmol), and K2CO3 (855 mg, 6.20 mmol), ACN (6 mL) was added. The resulting mixture was stirred at 90 °C under a N2 atmosphere for 2 h. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 95% ethyl acetate in petroleum ether to give ethyl 1-{3-[(pyridin-3-yl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylate (450 mg, 66.9%) as a yellow solid. LCMS [M+H] + :325

[0178] Step 3: To a stirred solution of ethyl 1-{3-[(pyridin-3-yl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylate (450 mg, 1.38 mmol) in 4 mL of EtOH and 4 mL of water, LiOH (289 mg, 6.89 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. It was then concentrated, and the pH value of the residual solution was adjusted to 3 with 1 M HCl (aq). The product precipitated from the solution. After filtration, the filter cake was washed with water and dried under vacuum. This afforded 1-{3-[(pyridin-3-yl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylic acid (260 mg, 63.2%) as a white solid. LCMS [M+H] + :297

[0179] Step 4: To a mixture of 1-{3-[(pyridin-3-yl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylic acid (120 mg, 0.405 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (107 mg, 0.485 mmol) in ACN (1 mL) was added TCFH (169 mg, 0.607 mmol) and NMI (99.2 mg, 1.21 mmol) at room temperature for 2 h. After concentration, the residue was purified by reverse-phase flash chromatography eluting with 65% acetonitrile in water (0.1% NH4HCO3) to give N-(3-chloro-5-methanesulfonamidophenyl)-1-{3-[(pyridin-3-yl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxamide (27.0 mg, 13.3%) as a white solid. LCMS[M+H] + :499. 1H NMR(300MHz,DMSO-d6)δ 10.21(s,1H),10.08(s,1H),8.91(d,J=0.7Hz,1H),8.70-8.63(m,1H),8.53(dd,J=4.8,1.7Hz,1H),8.30(d,J=0.7Hz,1H),8.21(dd,J=4.6,1 .3Hz,1H),7.96-7.81(m,2H),7.70(t,J=1.9Hz,1H),7.65-7.53(m,2H),7.47-7.37(m,1H),6.94(t,J=2.0Hz,1H),5.36(s,2H),3.07(s,3H).

[0180] Examples 62 to 70 The compounds listed in the table below were prepared using procedures similar to those described in Example 61. [Table 8-1] [Table 8-2]

[0181] Example 71: 4-Bromo-N-(3-fluoro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide [ka] Step 1: To a stirred solution of methyl 3-amino-5-fluorobenzoate (1 g, 5.91 mmol), HATU (2.92 g, 7.68 mmol), and DIEA (2.28 g, 17.7 mmol) in DMF (10 mL), 4-bromothiophene-2-carboxylic acid (1.34 g, 6.50 mmol) was added. The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford methyl 3-(4-bromothiophene-2-amido)-5-fluorobenzoate (1.28 g, 3.59 mmol) as a yellow solid. LCMS (ESI) [M+H] + :358

[0182] Step 2: To a stirred solution of methyl 3-(4-bromothiophene-2-amido)-5-fluorobenzoate (1.25 g, 3.48 mmol) in EtOH (10 mL) and HO (10 mL) was added LiOH (416 mg, 17.4 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was acidified to pH 5 with citric acid. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried under vacuum to give 3-(4-bromothiophene-2-amido)-5-fluorobenzoic acid (1.02 g, 2.98 mmol) as a white solid. LCMS (ESI) [M+H] + :344

[0183] Step 3: To a stirred solution of 3-(4-bromothiophene-2-amido)-5-fluorobenzoic acid (1 g, 2.906 mmol, 1 equiv.) and DPPA (1.04 g, 3.778 mmol, 1.3 equiv.) in t-BuOH (20 mL), EtN (0.88 g, 8.718 mmol, 3 equiv.) was added at 80 °C for 6 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (2:1) to afford tert-butyl N-[3-(4-bromothiophene-2-amido)-5-fluorophenyl]carbamate (750 mg, 61.53%) as a pale yellow solid. LCMS (ESI) [M+H] + :415

[0184] Step 4: To a stirred solution of tert-butyl N-[3-(4-bromothiophene-2-amido)-5-fluorophenyl]carbamate (700 mg, 1.68 mmol) in DCM (10 mL) was added TFA (1.91 g, 16.8 mmol) dropwise at 0 °C for 1 h. The resulting mixture was concentrated in vacuo. The mixture was basified to pH 9 with NaOH. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-100%) to give N-(3-amino-5-fluorophenyl)-4-bromothiophene-2-carboxamide (513 mg, 1.62 mmol) as a yellow solid. LCMS (ESI) [M+H]+ :315

[0185] Step 5: To a stirred solution of N-(3-amino-5-fluorophenyl)-4-bromothiophene-2-carboxamide (100 mg, 0.317 mmol) in pyridine (5 mL) was added MsCl (39.8 mg, 0.348 mmol) dropwise at 0 °C. The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-100%) to give 4-bromo-N-(3-fluoro-5-methanesulfonamidophenyl)thiophene-2-carboxamide (25.3 mg, 0.0643 mmol) as a white solid. LCMS (ESI) [M+H] + :393. 1 H NMR(300MHz,DMSO-d6)δ 10.52(s,1H),10.12(s,1H),8.11(d,J=1.5Hz,1H),8.05(d,J=1.4Hz,1H) ,7.46(dd,J=10.4,2.1Hz,2H),6.75(dt,J=10.5,2.2Hz,1H),3.08(s,3H).

[0186] Examples 72 to 78 The compounds listed in the table below were prepared using procedures similar to those described in Example 71. [Table 9-1] [Table 9-2]

[0187] Example 79: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-ethyl-5-phenyl-1H-pyrrole-3-carboxamide [ka] Step 1: To a solution of methyl 1H-pyrrole-3-carboxylate (2.0 g, 15.9 mmol) in DMF (20 mL) was added NaH (791 mg, 19.8 mmol, 60% purity) at 0 °C. The mixture was stirred at 0-5 °C for 15 min, and MeI (3.37 g, 23.8 mmol) was added to the above mixture at 0-5 °C. The mixture was stirred at 25 °C for 1.5 h. The mixture was poured into water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (15 mL × 2) and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was pre-purified by column chromatography on silica gel eluted with PE:EA = 100:1 to 5:1. Methyl 1-ethyl-1H-pyrrole-3-carboxylate (1.2 g, 7.83 mmol, 98.3% yield) was obtained as a yellow oil. LCMS: MS(ESI) retention time: 0.654 min, (M+1)+ = 154.0. 1 H NMR (400 MHz, chloroform-d) δ = 7.24 (t, J = 2.0 Hz, 1H) 6.52-6.56 (m, 1H) 6.50 (dd, J = 2.8, 1.6 Hz, 1H) 3.86 (q, J = 7.2 Hz, 2H) 3.72 (s, 3H) 1.37 (t, J = 7.2 Hz, 3H).

[0188] Step 2: To a solution of methyl 1-ethyl-1H-pyrrole-3-carboxylate (1.2 g, 7.83 mmol) in THF (20 mL) was added NBS (1.43 g, 8.06 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (25 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1). Methyl 5-bromo-1-ethyl-1H-pyrrole-3-carboxylate (1.8 g, 7.75 mmol, 99.4% yield) was obtained as a colorless oil. LCMS: MS (ESI) retention time: 0.783 min, (M+1)+ = 233.9. 1H NMR (400 MHz, chloroform-d) δ = 7.37 (d, J = 1.6 Hz, 1H), 6.59 (d, J = 1.6 Hz, 1H), 3.96 (q, J = 7.2 Hz, 2H), 3.75-3.84 (m, 3H), 1.40 (t, J = 7.2 Hz, 3H).

[0189] Step 3: To a solution of methyl 5-bromo-1-ethyl-1H-pyrrole-3-carboxylate (1.8 g, 7.75 mmol) and phenylboronic acid (1.2 g, 9.84 mmol) in MeOH (4 mL) and toluene (30 mL) was added tetrakis(triphenylphosphane)palladium (716 mg, 620 μmol) and 2.0 M aqueous disodium carbonate (7.75 μL, 15.5 mmol). The mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The mixture was poured into water (20 mL), cooled to 25 °C, and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (15 mL × 2) and dried over Na SO . The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The resulting oil was purified by flash chromatography eluting with 5% ethyl acetate / hexane. Compound 4 (1.1 g, 4.79 mmol, 62.1% yield) was obtained as a colorless oil. LCMS: MS(ESI) retention time: 0.830 min, (M+1)+ = 230.0. 1 H NMR (400 MHz, chloroform-d) δ = 7.26-7.40 (m, 6H), 6.50-6.52 (m, 1H), 3.86-3.93 (m, 2H), 3.73-3.79 (m, 3H), 1.26 (t, J = 7.2 Hz, 3H).

[0190] Step 4: To a solution of methyl 1-ethyl-5-phenyl-1H-pyrrole-3-carboxylate (1 g, 3.53 mmol) in THF (10 mL), MeOH (10 mL), and HO (10 mL) was added LiOH—HO (545 mg, 13.0 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was cooled to 25 °C and poured into water (20 mL). The pH of the mixture was adjusted to 3–4 with 1 N HCl. The mixture was extracted with EA (30 mL × 3). The combined organic layers were washed with brine (15 mL × 2) and dried over NaSO. The mixture was filtered, and the filtrate was concentrated in vacuo to give 1-ethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (850 mg, 3.94 mmol, 90.6% yield) as a white solid. LCMS:MS(ESI) retention time: 0.766 min, (M+1)+=216.0. 1 H NMR (400 MHz, methanol-d₄) δ = 7.51 (d, J = 2.0 Hz, 1H) 7.35-7.48 (m, 5H) 6.42-6.55 (m, 1H) 4.01-4.10 (m, 2H) 1.28 (t, J = 7.3 Hz, 3H)

[0191] Step 5: To a solution of 1-ethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (250 mg, 1.16 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (300 mg, 1.35 mmol) in pyridine (5 mL) was added EDCI (667 mg, 3.48 mmol). The mixture was stirred at 25 °C for 15 hours. The mixture was partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was separated and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with 1 N HCl (20 mL × 4) and brine (25 mL × 2), dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150 × 50 mm × 3 μm, mobile phase: [water (0.225% FA)-ACN], B%: 36% × 66%, 10 min) and lyophilized. N-(3-chloro-5-(methylsulfonamido)phenyl)-1-ethyl-5-phenyl-1H-pyrrole-3-carboxamide (286.74 mg, 98.48% purity, 0.675 mmol, 58.2% yield) was obtained as an off-white solid. LCMS: MS (ESI) retention time: 0.920 min, (M+1)+ = 417.9. 1 H NMR(400MHz,DMSO-d6)δ=9.93-10.26(m,1H)9.77(s,1H)7.72(d,J=1.6Hz,2H)7.58-7.66(m,1H)7.34-7. 54(m,5H)6.88(s,1H)6.74(d,J=1.6Hz,1H)4.02(q,J=7.2Hz,2H)2.94-3.12(m,3H)1.25(t,J=7.2Hz,3H)

[0192] Examples 80 to 82 The compounds listed in the table below were prepared using procedures similar to those described in Example 79. [Table 10]

[0193] Example 83: 5-bromo-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide [ka] Step 1: To a stirred solution of methyl 5-bromo-1H-pyrrole-3-carboxylate (500 mg, 2.45 mmol), CHCl (521 mg, 3.67 mmol), and CsCO (2.38 g, 7.35 mmol), DMSO (10 mL) was added. The mixture was then stirred at room temperature for 2 h. The mixture was concentrated and purified by flash chromatography eluting with petroleum ether / EtOAc (0–100%, acidic system) to afford methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (500 mg, 2.29 mmol) as a yellow solid. LCMS (ESI) [M+H] + :217.97

[0194] Step 2: To a stirred solution of methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (500 mg, 2.29 mmol) in EtOH (6 mL) and HO (2 mL) was added LiOH (164 mg, 6.86 mmol). The mixture was then stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0-100%, acidic system) to afford 5-bromo-1-methyl-1H-pyrrole-3-carboxylic acid (453 mg, 2.22 mmol) as an off-white solid. LCMS (ESI) [M+H] + :203.96

[0195] Step 3: To a stirred solution of 5-bromo-1-methyl-1H-pyrrole-3-carboxylic acid (203 mg, 0.994 mmol), TCFH (417 mg, 1.49 mmol), and N-(3-amino-5-chlorophenyl)methanesulfonamide (219 mg, 0.993 mmol) in ACN (10 mL) was added NMI (407 mg, 4.97 mmol). The mixture was then stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0–100%, acidic system) to afford 5-bromo-N-(3-chloro-5-methanesulfonamidophenyl)-1-methyl-1H-pyrrole-3-carboxamide (31.9 mg, 0.0782 mmol) as an off-white solid. LCMS (ESI) [M+H] + :405.95. 1 H NMR(300MHz,DMSO-d6)δ 10.04(s,1H),9.78(s,1H),7.72-7.65(m,2H),7.59(t,J=1.9Hz,1H),6.89(t,J=2.0Hz,1H),6.83(d,J=2.1Hz,1H),3.63(s,3H),3.05(s,3H).

[0196] Example 84: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide [ka] Step 1: To a stirred solution of methyl 5-bromo-1H-pyrrole-3-carboxylate (450 mg, 2.20 mmol) and iodomethane (374 mg, 2.64 mmol) in DMSO (10 mL). The mixture was then stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (380 mg, 1.74 mmol) as a white solid.

[0197] Step 2: To a stirred solution of methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (380 mg, 1.74 mmol) and 3-methyl-2-(tributylstannyl)pyridine (1.99 g, 5.22 mmol) in DMSO (5 mL), CuI (66.2 mg, 348 μmol), Pd(PPh3)4 (402 mg, 348 μmol), PPh3 (684 mg, 2.61 mmol), and LiCl (95.8 mg, 2.26 mmol) were added at 100 °C for 12 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (75 mL), transferred to a separatory funnel, and washed with 10% aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with water (75 mL x 3), brine, and dried over magnesium sulfate. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EA / PE (0–100%) to give ethyl 1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate (346 mg, 1.50 mmol) as a white solid.

[0198] Step 3: To a stirred solution of methyl 1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate (200 mg, 868 μmol) in EtOH (3 mL) and HO (3 mL) was added LiOH (207 mg, 8.68 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was acidified to pH 5 with citric acid. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried under vacuum to give 1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylic acid (150 mg, 693 μmol) as a white solid.

[0199] Step 4: To a stirred solution of 1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylic acid (100 mg, 462 μmol), TCFH (168 mg, 600 μmol), and NMI (113 mg, 1.38 mmol) in ACN (5 mL), N-(3-amino-5-bromophenyl)methanesulfonamide (134 mg, 508 μmol) was added. The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by reverse flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford N-(3-bromo-5-methanesulfonamidophenyl)-1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide (24.8 mg, 53.6 μmol) as a white solid. LCMS (ESI): [M+H] + :463. 1 H NMR(300MHz,DMSO-d6)δ 9.99(s,1H),9.78(s,1H),8.56-8.44(m,1H),7.84(t,J=1.8Hz,1H),7.77(d,J=7.8Hz,1H),7.72-7.64(m,2H),7 .29(dd,J=7.7,4.7Hz,1H),7.03(t,J=1.9Hz,1H),6.91(d,J=1.9Hz,1H),3.69(s,3H),3.06(s,3H),2.40(s,3H).

[0200] Example 85: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxamide [ka] Step 1: To a mixture of methyl 5-methyl-1H-pyrrole-3-carboxylate (210 mg, 1.50 mmol), t-BuOK (252 mg, 2.25 mmol), and 3-bromocyclohex-1-ene (288 mg, 1.79 mmol), NMP (2 mL) was added. The resulting mixture was stirred at room temperature under a N2 atmosphere for 2 hours. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in petroleum ether to give methyl 1-(cyclohex-2-en-1-yl)-5-methyl-1H-pyrrole-3-carboxylate (175 mg, 52.8%) as a pale yellow solid. LCMS[M+H] + :220

[0201] Step 2: To a mixture of methyl 1-(cyclohex-2-en-1-yl)-5-methyl-1H-pyrrole-3-carboxylate (175 mg, 0.798 mmol) and Pd / C (84.9 mg, 0.798 mmol), EtOAc (2 mL) was added. The resulting mixture was stirred at room temperature under an H atmosphere for 2 hours. The reaction mixture was filtered. The reaction mixture was then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in petroleum ether to give methyl 1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxylate (145 mg, 82.1%) as a yellow solid. LCMS [M+H] + :222

[0202] Step 3: To a stirred solution of methyl 1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxylate (145 mg, 0.656 mmol) in 2 mL of THF and 2 mL of water, LiOH (137.7 mg, 3.27 mmol) was added. The resulting mixture was stirred at 50 °C overnight. It was then concentrated, and the pH value of the residual solution was adjusted to 3 with 1 M HCl (aq). The product precipitated from the solution. After filtration, the filter cake was washed with water (2 mL) and dried under vacuum. This afforded 1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxylic acid (60 mg, 43.9%) as a white solid. LCMS [M+H] + :207

[0203] Step 4: To a mixture of 1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxylic acid auxiliary (60 mg, 0.289 mmol) and N-(3-amino-5-bromophenyl)methanesulfonamide (91.7 mg, 0.346 mmol) in ACN (1 mL) was added TCFH (121 mg, 0.433 mmol) and NMI (71.0 mg, 0.867 mmol) at room temperature. The resulting mixture was stirred for 2 hours, then concentrated, and the residue was purified by reverse-phase flash chromatography eluting with 93% acetonitrile in water (0.1% FA) to give N-(3-bromo-5-methanesulfonamidophenyl)-1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxamide (45.6 mg, 34.6%) as a white solid. LCMS [M+H] + :454. 1 H NMR(300MHz,DMSO-d6)δ 9.96(s,1H),9.56(s,1H),7.81(t,J=1.8Hz,1H),7.66(t,J=1.9Hz,1H),7.57(d,J=2.0Hz,1H),7.00(t,J=1.9Hz,1H),6 .34(s,1H),3.87(s,1H),3.05(s,3H),2.26-2.13(m,3H),1.88(dd,J=25.6,12.1Hz,4H),1.51(dd,J=46.0,12.5Hz,6H).

[0204] Example 86: 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide [ka] Step 1: To a solution of 5-bromo-2-fluoropyridine (200 mg, 1.136 mmol, 1 equiv.) and ethyl 1H-pyrazole-4-carboxylate (238.9 mg, 1.705 mmol, 1.50 equiv.) in DMSO (5 mL) was added CsCO (1110.8 mg, 3.409 mmol, 3.00 equiv.) at room temperature. The resulting solution was stirred at 60 °C for 2 h. The reaction was quenched with water. The reaction mixture was diluted with water (50 mL). The resulting solution was extracted with EtOAc (50 × 3 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (42%) to give ethyl 1-(5-bromopyridin-2-yl)pyrazole-4-carboxylate (300 mg, 84.69%) as a yellow solid. LCMS (ESI): [M+H] + :296

[0205] Step 2: To a solution of ethyl 1-(5-bromopyridin-2-yl)pyrazole-4-carboxylate (200 mg, 0.675 mmol, 1 equiv.), 1-(piperazin-1-yl)ethanone (129.8 mg, 1.013 mmol, 1.50 equiv.), Pd(AcO) (15.2 mg, 0.068 mmol, 0.10 equiv.), and BINAP (84.1 mg, 0.135 mmol, 0.20 equiv.) in toluene (5 mL), CsCO (660.2 mg, 2.026 mmol, 3.00 equiv.) was added at room temperature under nitrogen. The resulting solution was stirred at 100 °C for 2 h. The resulting solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (45%) to give ethyl 1-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]pyrazole-4-carboxylate (130 mg, 53.81%) as a yellow solid. LCMS (ESI): [M+H] + :344

[0206] Step 3: To a solution of ethyl 1-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]pyrazole-4-carboxylate (135 mg, 0.393 mmol, 1 equiv.) in THF (2 mL) and HO (2 mL) was added LiOH (47.1 mg, 1.967 mmol, 5.00 equiv.) at room temperature. The resulting solution was stirred at room temperature for 1 h. The residue was purified by flash chromatography on a C18 column gel eluted with ACN / water (0.1% FA) (35%) to afford 1-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]pyrazole-4-carboxylic acid (95 mg, 70.50%) as a white solid. LCMS (ESI): [M+H] + :316

[0207] Step 4: To a solution of 1-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]pyrazole-4-carboxylic acid (95 mg, 0.301 mmol, 1 equiv.), NMI (49.5 mg, 0.603 mmol, 2.00 equiv.), and TCFH (126.8 mg, 0.452 mmol, 1.50 equiv.) in ACN (2 mL) was added at room temperature. The resulting solution was stirred at room temperature for 10 min. N-(3-amino-5-bromophenyl)methanesulfonamide (119.8 mg, 0.452 mmol, 1.50 equiv.) was then added and stirred at room temperature for 1 h. The residue was purified by preparative HPLC under the following conditions: Column: Sunfire prep C18 column, 30 × 150 mm, 5 μm, Mobile phase A: water (0.1% FA), Mobile phase B: ACN, Flow rate: 60 mL / min, Gradient: 33% B to 47% B, 47% B in 7 min, Wavelength: 254 / 220 nm, RT1 (min): 6.28 to give 1-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]-N-(3-bromo-5-methanesulfonamidophenyl)pyrazole-4-carboxamide (19.7 mg, 11.37%) as a white solid. LCMS (ESI): [M+H] + :562. 1 H NMR(300MHz,DMSO-d6)δ 10.24(s,1H),10.06(s,1H),9.28(d,J=0.8Hz,1H),8.33-8.16(m,2H),7.96-7.78(m,2H),7.76-7.54( m,2H),7.08(t,J=1.9Hz,1H),3.62(t,J=5.2Hz,4H),3.25(t,J=5.3Hz,4H),3.07(s,3H),2.07(s,3H).

[0208] Examples 87-94 and 394-423 The compounds listed in the table below were prepared using procedures similar to those described in Example 86. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10] [Table 11-11] [Table 11-12]

[0209] Example 95: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxamide [ka] Step 1: To a stirred solution of methyl 5-bromo-1H-pyrrole-3-carboxylate (600 mg, 2.94 mmol), K2CO3 (812 mg, 5.88 mmol), and 2-bromoacetonitrile (705 mg, 5.88 mmol) in DMSO (10 mL). The mixture was then stirred at room temperature for 4 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford methyl 5-bromo-1-(cyanomethyl)-1H-pyrrole-3-carboxylate (693 mg, 2.85 mmol) as a white solid.

[0210] Step 2: A solution of methyl 5-bromo-1-(cyanomethyl)-1H-pyrrole-3-carboxylate (700 mg, 2.87 mmol), Pd(dppf)Cl2 (420 mg, 0.574 mmol), KOAc (844 mg, 8.61 mmol), and B2Pin2 (3.63 g, 14.3 mmol) in dioxane (10 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (0–100%) to afford 1-(cyanomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (326 mg, 1.12 mmol) as a yellow solid.

[0211] Step 3: A solution of methyl 1-(cyanomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (330 mg, 1.13 mmol), Pd(PPh)Cl (158 mg, 0.226 mmol), NaCO (358 mg, 3.38 mmol), and 2-bromopyridine (213 mg, 1.35 mmol) in EtOH (4 mL) and HO (1 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (0–100%) to give methyl 1-(cyanomethyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carboxylate (148 mg, 0.615 mmol) as a white solid. LCMS(ESI)[M+H] + :242

[0212] Step 4: To a stirred solution of methyl 1-(cyanomethyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carboxylate (150 mg, 0.621 mmol) in HO (5 mL) and EtOH (5 mL) was added LiOH (148 mg, 6.21 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was acidified to pH 5 with citric acid. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried under vacuum to give 1-(cyanomethyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (108 mg, 0.479 mmol) as a yellow solid. LCMS(ESI)[M+H] + :228

[0213] Step 5: To a stirred solution of 1-(cyanomethyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (110 mg, 0.484 mmol), TCFH (176 mg, 0.629 mmol), and NMI (119 mg, 1.45 mmol) in ACN (5 mL), N-(3-amino-5-bromophenyl)methanesulfonamide (153 mg, 0.580 mmol) was added. The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5–95%, acidic system) to afford N-(3-bromo-5-methanesulfonamidophenyl)-1-(cyanomethyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carboxamide (47.6 mg, 0.1004 mmol) as a white solid. LCMS(ESI)[M+H] + :474. 1 H NMR(300MHz,DMSO-d6)δ10.09(s,1H),10.01(s,1H),8.62(d,J=4.8Hz,1H),7.96-7.75(m,4H),7.67(t,J=1.9Hz ,1H),7.42(d,J=1.9Hz,1H),7.32(ddd,J=6.4,5.0,1.3Hz,1H),7.05(t,J=1.9Hz,1H),5.78(s,2H),3.06(s,3H).

[0214] Example 96: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxamide [ka] Step 1: To a mixture of 2-bromo-3-methylpyridine (51 mg, 2.96 mmol), CuI (1.12 g, 5.92 mmol), Pd(AcO) (132 mg, 0.592 mmol), PPh (309 mg, 1.18 mmol), DBU (901 mg, 5.92 mmol), and methyl 1-methyl-1H-imidazole-4-carboxylate (497 mg, 3.55 mmol), dioxane (5 mL) was added. The resulting mixture was stirred at 140 °C under a N atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 35% ethyl acetate in petroleum ether to give methyl 1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxylate (320 mg, 46.7%) as a white solid. LCMS [M+H] + :232

[0215] Step 2: To a stirred solution of methyl 1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxylate (150 mg, 0.648 mmol) in 2 mL of THF and 2 mL of water, LiOH (135 mg, 3.23 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. It was then concentrated, and the pH value of the residual solution was adjusted to 3 with 1 M HCl (aq). The product precipitated from the solution. After filtration, the filter cake was washed with water and dried under vacuum. This afforded 1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid (110 mg, 78.0%) as a white solid. LCMS [M+H] + :218

[0216] Step 3: To a mixture of 1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid (110 mg, 0.506 mmol) and N-(3-amino-5-bromophenyl)methanesulfonamide (160 mg, 0.607 mmol) in ACN (1 mL) was added TCFH (212 mg, 0.759 mmol) and NMI (123 mg, 1.51 mmol) at room temperature for 2 h. After concentration, the residue was purified by reverse-phase flash chromatography eluting with 60% acetonitrile in water (0.1% NH4HCO3) to give N-(3-bromo-5-methanesulfonamidophenyl)-1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxamide (25.9 mg, 11.0%) as a pale pink solid. LCMS[M+H] + :464 1 H NMR(300MHz,DMSO-d6)δ 10.00(s,2H),8.54(d,J=4.6Hz,1H),8.03(s,1H),7.91-7.76(m,3H),7.43( dd,J=7.8,4.8Hz,1H),7.04(s,1H),3.76(s,3H),3.08(s,3H),2.48(s,3H).

[0217] Example 97: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(difluoro(phenyl)methoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide [ka] Step 1: To a stirred solution of (difluoromethyl)benzene (1.2 g, 9.36 mmol) and NCS (1.36 g, 10.2 mmol) in CCl4 (20 mL). The magnetically stirred mixture was exposed to sunlight during the day and at night at room temperature for 50 h. The resulting mixture was concentrated under reduced pressure at 0 °C to give (chlorodifluoromethyl)benzene (350 mg, 2.15 mmol, low boiling point) as a yellow oil.

[0218] Step 2: To a stirred solution of (chlorodifluoromethyl)benzene (350 mg, 2.15 mmol), CsCO (1.40 g, 4.30 mmol), and 2-bromopyridin-3-ol (410 mg, 2.36 mmol) in DMSO (5 mL). The mixture was then stirred for 3 h at 120 °C. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford 2-bromo-3-[difluoro(phenyl)methoxy]pyridine (50.0 mg, 0.166 mmol) as a yellow solid. LCMS (ESI) [M+H] + :300

[0219] Step 3: A solution of 2-bromo-3-[difluoro(phenyl)methoxy]pyridine (50 mg, 0.166 mmol), CuI (6.32 mg, 0.0332 mmol), KCO (68.8 mg, 0.498 mmol), ethyl 1H-pyrazole-4-carboxylate (25.5 mg, 0.182 mmol), and (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (9.44 mg, 0.0664 mmol) in ACN (5 mL) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (0-100%) to give ethyl 1-{3-[difluoro(phenyl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylate (40.0 mg, 0.111 mmol) as a yellow solid. LCMS (ESI) [M+H] + :360

[0220] Step 4: To a stirred solution of ethyl 1-{3-[difluoro(phenyl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylate (40 mg, 0.111 mmol) in EtOH (3 mL) and HO (3 mL) was added LiOH (26.5 mg, 1.11 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was acidified to pH 5 with citric acid. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried under vacuum to give 1-{3-[difluoro(phenyl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylic acid (28.0 mg, 0.0845 mmol) as a yellow solid. LCMS (ESI) [M+H] + :332

[0221] Step 5: To a stirred solution of 1-{3-[difluoro(phenyl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylic acid (28 mg, 0.0845 mmol), TCFH (23.7 mg, 0.0845 mmol), and NMI (6.93 mg, 0.0845 mmol) in ACN (5 mL) was added N-(3-amino-5-chlorophenyl)methanesulfonamide (20.5 mg, 0.0929 mmol). The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to give N-(3-chloro-5-methanesulfonamidophenyl)-1-{3-[difluoro(phenyl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxamide (6.40 mg, 0.0119 mmol) as an orange solid. LCMS (ESI) [M+H] + :534. 1 H NMR(300MHz,DMSO-d6)δ 10.27(s,1H),10.11(s,1H),9.07(s,1H),8.58(dd,J=4.6,1.5Hz,1H),8.34(s,1H),8.24 -8.15(m,1H),7.79-7.66(m,4H),7.66-7.50(m,4H),6.94(t,J=1.9Hz,1H),3.07(s,3H).

[0222] Example 98: N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyano-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide [ka] Step 1: Under nitrogen, a solution of methyl 1H-pyrrole-3-carboxylate (1 g, 7.992 mmol, 1 equiv.), 2-bromopyridine (1.89 g, 11.988 mmol, 1.5 equiv.), CuI (304.4 mg, 1.598 mmol, 0.20 equiv.), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (454.7 mg, 3.197 mmol, 0.40 equiv.) in ACN (10 mL) was added to K2CO3 (3.34 g, 23.992 mmol, 3.00 equiv.) at room temperature. The resulting solution was stirred at 90 °C for 2 h. The resulting solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (26%) to give methyl 1-(pyridin-2-yl)pyrrole-3-carboxylate (1.2 g, 68.69%) as a yellow solid. LCMS: (ESI): [M+H] + :203

[0223] Step 2: To a solution of methyl 1-(pyridin-2-yl)pyrrole-3-carboxylate (850 mg, 4.203 mmol, 1 equiv.) in THF (10 mL) was added NBS (897.79 mg, 5.044 mmol, 1.2 equiv.) at room temperature. The resulting solution was stirred at room temperature for 2 hours. The residue was purified by flash chromatography on silica gel eluted with EtOAc / petroleum ether (28%) to give methyl 5-bromo-1-(pyridin-2-yl)pyrrole-3-carboxylate (410 mg, 33.31%) as a yellow solid. LCMS: (ESI): [M+H] + :281

[0224] Step 3: Under nitrogen, a solution of methyl 5-bromo-1-(pyridin-2-yl)pyrrole-3-carboxylate (410 mg, 1.459 mmol, 1 equiv.) and CuCN (261.3 mg, 2.917 mmol, 2.00 equiv.) in NMP (5 mL) was added to KI (242.1 mg, 1.458 mmol, 1.00 equiv.) at room temperature. The resulting solution was stirred at 120 °C for 2 h. The reaction mixture was diluted with water (50 mL). The resulting solution was extracted with EtOAc (50 × 3 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (35%) to afford methyl 5-cyano-1-(pyridin-2-yl)pyrrole-3-carboxylate (180 mg, 46.71%) as a yellow solid. LCMS: (ESI): [M+H] + :228

[0225] Step 4: To a solution of methyl 5-cyano-1-(pyridin-2-yl)pyrrole-3-carboxylate (180 mg, 0.753 mmol, 1 equiv, 95%) in THF (4 mL) and HO (2 mL) was added LiOH (90.1 mg, 3.762 mmol, 5.00 equiv) at room temperature. The resulting solution was stirred at room temperature for 1 h. The residue was purified by flash chromatography on a C18 column gel eluted with ACN / water (0.1% FA) (45%) to give 5-cyano-1-(pyridin-2-yl)pyrrole-3-carboxylic acid (150 mg, 86.01%) as a yellow solid. LCMS: (ESI): [M+H] + :214

[0226] Step 5: To a solution of 5-cyano-1-(pyridin-2-yl)pyrrole-3-carboxylic acid (150 mg, 0.704 mmol, 1 equiv.), NMI (115.5 mg, 1.407 mmol, 2.00 equiv.), and TCFH (296.1 mg, 1.055 mmol, 1.50 equiv.) in ACN (5 mL) was added at room temperature. The resulting solution was stirred at room temperature for 10 min. N-(3-amino-5-chlorophenyl)methanesulfonamide (186.3 mg, 0.844 mmol, 1.20 equiv.) was then added and stirred at room temperature for 1 h. The residue was purified by preparative HPLC under the following conditions: Column: Sunfire prep C18 column, 30 × 150 mm, 5 μm, Mobile phase A: water (0.1% FA), Mobile phase B: ACN, Flow rate: 60 mL / min, Gradient: 40% B to 60% B, 60% B in 7 min, Wavelength: 254 / 220 nm, RT1 (min): 5.72 to give N-(3-chloro-5-methanesulfonamidophenyl)-5-(phenylamino)-2H-pyrazole-3-carboxamide (29.6 mg, 48.73%) as a white solid. LCMS: (ESI): [M+H] + :416. 1 H NMR(300MHz,DMSO-d6)δ 10.21(s,1H),10.10(s,1H),8.63(d,J=4.8Hz,1H),8.56(d,J=1.8Hz,1H),8.19-8.08(m,1H),7.89(d,J=8.2Hz,1H),7.81(d, J=1.8Hz,1H),7.71(t,J=1.9Hz,1H),7.62(d,J=2.0Hz,1H),7.57(dd,J=7.4,4.7Hz,1H),6.95(t,J=2.0Hz,1H),3.08(s,3H).

[0227] Example 99: 1-benzyl-N-(3-bromo-5-(methylsulfonamido)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka] Step 1: To a stirred solution of 4-fluoro-3-nitrobenzoic acid (1 g, 5.40 mmol) and 1-phenylmethanamine (578 mg, 5.40 mmol) in DMF (15 mL) was added CsCO (5.26 g, 16.2 mmol). The mixture was then stirred at 80 °C for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0 to 100%, acidic system) to afford 4-(benzylamino)-3-nitrobenzoic acid (700 mg, 2.57 mmol) as a yellow solid. LCMS(ESI)[M+H] + :273.08

[0228] Step 2: To a stirred solution of 4-(benzylamino)-3-nitrobenzoic acid (700 mg, 2.57 mmol) and NHCl (1.08 g, 20.5 mmol) in EtOH (10 mL) and HO (3 mL) was added Fe (1.43 g, 25.6 mmol). The mixture was then stirred at 90 °C for 2 h. The mixture was concentrated and purified by flash chromatography eluting with EtOAc / petroleum ether (0-100%, acidic system) to give 3-amino-4-(benzylamino)benzoic acid (330 mg, 1.36 mmol) as a yellow solid. LCMS (ESI) [M+H] + :243.11

[0229] Step 3: To a stirred solution of 3-amino-4-(benzylamino)benzoic acid (330 mg, 1.36 mmol) in THF (6 mL) and MeOH (2 mL) was added dropwise a solution of (trimethylsilyl)diazomethane (4.08 mmol) in hexane under a N atmosphere. The mixture was then stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0-100%, acidic system) to afford methyl 3-amino-4-(benzylamino)benzoate (265 mg, 1.03 mmol) as a yellow solid. LCMS (ESI) [M+H] + :357.12

[0230] Step 4: To a stirred solution of methyl 3-amino-4-(benzylamino)benzoate (265 mg, 1.03 mmol) in DMF (5 mL) was added CDI (225 mg, 3.09 mmol). The mixture was then stirred at 60 °C for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0-100%, acidic system) to afford methyl 1-benzyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carboxylate (100 mg, 0.354 mmol) as an off-white solid. LCMS (ESI) [M+H] + :283.02

[0231] Step 5: To a stirred solution of methyl 1-benzyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carboxylate (100 mg, 0.354 mmol) in THF (3 mL) and HO (1 mL) was added LiOH (25.3 mg, 1.06 mmol). The mixture was then stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0-100%, acidic system) to afford 1-benzyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carboxylic acid (76.0 mg, 0.283 mmol) as an off-white solid. LCMS (ESI) [M+H] + :269.04

[0232] Step 6: To a stirred solution of 1-benzyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carboxylic acid (76 mg, 0.283 mmol), NMI (115 mg, 1.41 mmol), and TCFH (118 mg, 0.424 mmol) in ACN (5 mL) was added N-(3-amino-5-bromophenyl)methanesulfonamide (75.0 mg, 0.283 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0-100%, acidic system) to give 1-benzyl-N-(3-bromo-5-methanesulfonamidophenyl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carboxamide (21.1 mg, 0.039.5 mmol) as a white solid. LCMS (ESI) [M+H] + :515.3. 1 H NMR(300MHz,DMSO-d6)δ 10.61(s,1H),8.52(d,J=2.6Hz,1H),8.34(s,1H),8.03(d,J=8.1Hz,1H),7.84(d,J=7.7Hz,1H),7.71(d,J=1.9Hz ,2H),7.65(t,J=7.8Hz,1H),6.98(t,J=2.0Hz,1H),6.55(d,J=2.5Hz,1H),5.26(s,1H),4.55(s,2H),3.08(s,3H).

[0233] Example 100: N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(3-cyano-1H-pyrazol-1-yl)benzamide [ka] Step 1: To a stirred solution of 1H-pyrazole-3-carbonitrile (260 mg, 2.79 mmol), CuI (106 mg, 0.558 mmol), (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (157 mg, 1.11 mmol), and 3-bromobenzoic acid (560 mg, 2.79 mmol) in DMSO (10 mL) was added CsCO (2.72 g, 8.37 mmol). The mixture was then stirred at 100 °C under a N atmosphere for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0–100%, acidic system) to afford 3-(3-cyano-1H-pyrazol-1-yl)benzoic acid (85.0 mg, 0.398 mmol) as a yellow solid. LCMS(ESI)[M+H] + :214.05

[0234] Step 2: To a stirred solution of 3-(3-cyano-1H-pyrazol-1-yl)benzoic acid (85 mg, 0.398 mmol), TCFH (167 mg, 0.597 mmol), and NMI (163 mg, 1.99 mmol) in ACN (5 mL) was added N-(3-amino-5-chlorophenyl)methanesulfonamide (87.8 mg, 0.398 mmol). The mixture was then stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0-100%, acidic system) to afford N-(3-chloro-5-methanesulfonamidophenyl)-3-(3-cyano-1H-pyrazol-1-yl)benzamide (24.3 mg, 0.0570 mmol) as a white solid. LCMS (ESI) [M+H] + :416.05. 1 H NMR(300MHz,DMSO-d6)δ 10.66(s,1H),10.12(s,1H),8.92(d,J=2.7Hz,1H),8.43(d,J=2.2Hz,1H),8.19-8.09(m,1H),8.0 1(d,J=7.8Hz,1H),7.81-7.68(m,3H),7.35(d,J=2.6Hz,1H),6.99(t,J=2.0Hz,1H),3.09(s,3H).

[0235] Example 101: N-(3-bromo-5-(methylsulfonamido)phenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide [ka] Step 1: A mixture of phenylurea (500 mg, 3.67 mmol) and ethyl 3-bromo-2-oxopropanoate (715 mg, 3.67 mmol) in EtOH (10 mL) was stirred at 80 °C for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0-100%, acidic system) to give 2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (235 mg, 1.01 mmol) as a yellow solid. LCMS (ESI) [M+H] + :233.08

[0236] Step 2: To a stirred solution of ethyl 2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (235 mg, 1.01 mmol) in EtOH (3 mL) and HO (1 mL) was added LiOH (72.5 mg, 3.03 mmol). The mixture was then stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0-100%, acidic system) to afford 2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic acid (180 mg, 0.881 mmol) as a yellow solid. LCMS (ESI) [M+H] + :205.05

[0237] Step 3: To a stirred solution of 2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic acid (180 mg, 0.881 mmol), TCFH (369 mg, 1.32 mmol), and NMI (360 mg, 4.40 mmol) in ACN (10 mL) was added N-(3-amino-5-bromophenyl)methanesulfonamide (233 mg, 0.881 mmol). The mixture was then stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0 to 100%, acidic system) to afford N-(3-bromo-5-methanesulfonamidophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide (21.1 mg, 0.0466 mmol) as a white solid. LCMS(ESI)[M+H] + :451. 1 H NMR(300MHz,DMSO-d6)δ 10.38(s,1H),10.05(d,J=7.7Hz,2H),8.33(s,1H),7.83(s,1H),7.81-7.71(m ,3H),7.35(t,J=7.8Hz,2H),7.12(s,1H),7.00(t,J=7.3Hz,1H),3.09(s,3H).

[0238] Example 102: N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(2-chloropyridin-4-yl)benzamide [ka] Step 1: To a stirred solution of (2-chloropyridin-4-yl)boronic acid (500 mg, 3.17 mmol), Pd(dppf)Cl (347 mg, 0.475 mmol), and 3-bromobenzoic acid (637 mg, 3.17 mmol) in dioxane (15 mL) was added KCO (1.32 g, 9.51 mmol). The mixture was then stirred at 80 °C for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0-100%, acidic system) to afford 3-(2-chloropyridin-4-yl)benzoic acid (210 mg, 0.898 mmol) as a yellow solid. LCMS (ESI) [M+H]+ :234.02

[0239] Step 2: To a stirred solution of 3-(2-chloropyridin-4-yl)benzoic acid (200 mg, 0.855 mmol), TCFH (358 mg, 1.28 mmol), and NMI (350 mg, 4.27 mmol) in ACN (5 mL) was added N-(3-amino-5-chlorophenyl)methanesulfonamide (188 mg, 0.855 mmol). The mixture was then stirred at room temperature for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (0-100%, acidic system) to afford N-(3-chloro-5-methanesulfonamidophenyl)-3-(2-chloropyridin-4-yl)benzamide (24.8 mg, 0.0566 mmol) as a white solid. LCMS (ESI) [M+H] + :436.02. 1 H NMR(300MHz,DMSO-d6)δ 10.59(s,1H),10.11(s,1H),8.54(d,J=5.3Hz,1H),8.37(s,1H),8.10(d,J=7.7Hz,1H),8.06(d,J=7.8H z,1H),8.00(d,J=1.6Hz,1H),7.96-7.78(m,1H),7.77-7.66(m,3H),6.99(t,J=1.9Hz,1H),3.09(s,3H).

[0240] Example 103: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazole-4-carboxamide [ka] Step 1: To a stirred solution of ethyl 1H-pyrazole-4-carboxylate (310 mg, 2.21 mmol), 2-bromobenzaldehyde (490 mg, 2.65 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (125 mg, 0.884 mmol), CuI (83.9 mg, 0.442 mmol), and K2CO3 (914 mg, 6.63 mmol) in ACN (10.00 mL) was added. The mixture was then stirred at 90 °C under N2 for 4 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford ethyl 1-(2-formylphenyl)-1H-pyrazole-4-carboxylate (332 mg, 1.36 mmol, 95%) as a yellow solid. LCMS (ESI) [M+H] + :245

[0241] Step 2: To a stirred solution of ethyl 1-(2-formylphenyl)-1H-pyrazole-4-carboxylate (350 mg, 1.43 mmol), trimethyl(trifluoromethyl)silane (813 mg, 5.72 mmol), and K2CO3 (592 mg, 4.29 mmol) in DMF (10.00 mL). The mixture was then stirred at room temperature for 4 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford ethyl 1-[2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-1H-pyrazole-4-carboxylate (209 mg, 95%) as a yellow solid. LCMS (ESI) [M+H] + :315

[0242] Step 3: To a stirred solution of ethyl 1-[2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-1H-pyrazole-4-carboxylate (220 mg, 0.700 mmol) and LiOH (10 mg, 2.5 mmol) in THF (10.00 mL) was added HO (2.00 mL). The mixture was then stirred at room temperature for 2 hours. The mixture was acidified to pH 5 with citric acid. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried under vacuum to give 1-[2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-1H-pyrazole-4-carboxylic acid (104 mg, 95%) as a white solid. LCMS (ESI) [M+H] + :310

[0243] Step 4: To a stirred solution of 1-[2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-1H-pyrazole-4-carboxylic acid (110 mg, 0.384 mmol), TCFH (107 mg, 0.384 mmol), and NMI (31.3 mg, 0.384 mmol) in ACN (10.00 mL) was added N-(3-amino-5-bromophenyl)methanesulfonamide (101 mg, 0.384 mmol). The mixture was then stirred at room temperature for 4 hours. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to give N-(3-bromo-5-methanesulfonamidophenyl)-1-[2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-1H-pyrazole-4-carboxamide (34.4 mg, 96.918%) as a white solid. LCMS (ESI) [M+H] + :534. 1 H NMR(400MHz,DMSO-d6)δ 10.17(s,1H),10.09-10.04(m,1H),8.70(s,1H),8.34(d,J=0.6Hz,1H),7.88-7.81(m,2H),7 .69-7.58(m,3H),7.58-7.51(m,1H),7.11-7.05(m,2H),5.61(p,J=6.9Hz,1H),3.07(s,3H).

[0244] Example 104: 4-((1H-pyrrol-2-yl)methyl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-thiophene-2-carboxamide [ka] Step 1: To a solution of methyl 4-methylthiophene-2-carboxylate (500 mg, 3.201 mmol, 1 equiv.) and NBS (854.6 mg, 4.802 mmol, 1.50 equiv.) in CCl4 (10 mL) was added BPO (1640.6 mg, 6.402 mmol, 2.00 equiv.) at room temperature under nitrogen. The resulting solution was stirred at 80 °C overnight. The resulting solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (26%) to afford methyl 4-(bromomethyl)thiophene-2-carboxylate (200 mg, 26.5%) as a yellow oil. LCMS: (ESI): [M+H] + :235

[0245] Step 2: To a solution of methyl 4-(bromomethyl)thiophene-2-carboxylate (200 mg, 0.851 mmol, 1 equiv.), Pd(PPh3)4 (98.3 mg, 0.085 mmol, 0.10 equiv.), and 1-(tert-butoxycarbonyl)pyrrol-2-ylboronic acid (269.3 mg, 1.276 mmol, 1.50 equiv.) in dioxane (5 mL) and HO (0.5 mL) was added Cs2CO3 (831.5 mg, 2.552 mmol, 3.00 equiv.) at room temperature under nitrogen. The resulting solution was stirred at 90 °C for 2 h. The reaction mixture was diluted with water (50 mL). The resulting solution was extracted with EtOAc (50 × 3 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (42%) to give tert-butyl 2-{[5-(methoxycarbonyl)thiophen-3-yl]methyl}pyrrole-1-carboxylate (80 mg, 27.50%) as a yellow oil. LCMS: (ESI): [M+H] + :322

[0246] Step 3: To a solution of tert-butyl 2-{[5-(methoxycarbonyl)thiophen-3-yl]methyl}pyrrole-1-carboxylate (80 mg, 0.249 mmol, 1 equiv.) in THF (2 mL) and HO (1 mL) was added LiOH (29.8 mg, 1.244 mmol, 5.00 equiv.) at room temperature. The resulting solution was stirred at room temperature for 1 h. The residue was purified by flash chromatography on a C18 column gel eluted with ACN / water (0.1% FA) (33%) to afford 4-{[1-(tert-butoxycarbonyl)pyrrol-2-yl]methyl}thiophene-2-carboxylic acid (60 mg, 75.29%) as a white solid. LCMS: (ESI): [M+H] + :308

[0247] Step 4: A solution of 4-{[1-(tert-butoxycarbonyl)pyrrol-2-yl]methyl}thiophene-2-carboxylic acid (50 mg, 0.163 mmol, 1 equiv.), NMI (26.7 mg, 0.325 mmol, 2.00 equiv.), and TCFH (68.5 mg, 0.244 mmol, 1.50 equiv.) in ACN (2 mL) at room temperature. The resulting solution was stirred at room temperature for 10 min. N-(3-amino-5-bromophenyl)methanesulfonamide (64.7 mg, 0.244 mmol, 1.50 equiv.) was then added and stirred at room temperature for 1 h. The residue was purified by C18 column gel eluting with ACN / water (0.05N HCO) (65%) to give tert-butyl 2-({5-[(3-bromo-5-methanesulfonamidophenyl)carbamoyl]thiophen-3-yl}methyl)pyrrole-1-carboxylate (55 mg, 59.93%) as a white solid. LCMS: (ESI): [M+H] + :554

[0248] Step 5: To a solution of tert-butyl 2-({5-[(3-bromo-5-methanesulfonamidophenyl)carbamoyl]thiophen-3-yl}methyl)pyrrole-1-carboxylate (55 mg, 0.099 mmol, 1 equiv) in DCM (2 mL) was added TFA (1 mL) at 0° C. The mixture was stirred at room temperature for 1 h. The residue was purified by preparative HPLC under the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm, Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN, Flow rate: 60 mL / min, Gradient: 40% B to 60% B, 60% B in 7 min, Wavelength: 254 / 220 nm, RT1 (min): 9.28 / 11.57 to give N-(3-bromo-5-methanesulfonamidophenyl)-4-(1H-pyrrol-2-ylmethyl)thiophene-2-carboxamide (16.0 mg, 34.89%) as a white solid. LCMS: (ESI): [M+H] + :454 1 H NMR(300MHz,DMSO-d6)δ 10.65(s,1H),10.36(s,1H),10.08(s,1H),7.89(s,1H),7.77(s,1H),7.65(s,1H),7.50(s, 1H)7.06(s,1H),6.63(s,1H),5.93(d,1H),5.78(s,1H),3.90(s,J=5.2Hz,2H),2.95(s,3H).

[0249] Example 105: N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide [ka] Step 1: A solution of 4-bromo-N-(3-fluoro-5-methanesulfonamidophenyl)thiophene-2-carboxamide (100 mg, 0.254 mmol, 1 equiv.) and pyridin-3-ylboronic acid (46.89 mg, 0.381 mmol, 1.5 equiv.) with Pd(PPh)Cl (17.85 mg, 0.025 mmol, 0.1 equiv.) and NaCO (80.86 mg, 0.762 mmol, 3 equiv.) in EtOH (3 mL) and HO (1 mL) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography under the following conditions: column, silica gel, mobile phase, MeCN in water, gradient from 0% to 100% in 20 min, detector, UV at 254 nm. This gave N-(3-fluoro-5-methanesulfonamidophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (27.8 mg, 27.93%) as a pale green solid. LCMS: (ESI): LCMS (ESI) [M+H] + :392. 1 H NMR(300MHz,DMSO-d6)δ 10.61(s,1H),10.14(s,1H),9.11(s,1H),8.66(d,J=21.6Hz,2H),8.48(s,2H),7.75(s,2H),7.49(s,2H),6.76(d,J=10.4Hz,1H),3.09(s,3H).

[0250] Examples 108 to 111 The compounds listed in the table below were prepared using procedures similar to those described in Example 105. [Table 12-1] [Table 12-2]

[0251] Example 112: N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide [ka] Step 1: To a stirred solution of N-(3-amino-5-fluorophenyl)methanesulfonamide (100 mg, 0.489 mmol), TCFH (178 mg, 0.635 mmol), and NMI (119 mg, 1.46 mmol) in ACN (5 mL), 4-bromothiophene-2-carboxylic acid (111 mg, 0.537 mmol) was added. The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford 4-bromo-N-(3-fluoro-5-methanesulfonamidophenyl)thiophene-2-carboxamide (128 mg, 0.327 mmol) as a yellow solid. LCMS (ESI) [M+H] + :393

[0252] Step 2: A solution of 4-bromo-N-(3-fluoro-5-methanesulfonamidophenyl)thiophene-2-carboxamide (130 mg, 0.330 mmol), Pd(dppf)Cl (24.1 mg, 0.0330 mmol), KOAc (97.1 mg, 0.990 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (335 mg, 1.32 mmol) in DMSO (10 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to give N-(3-fluoro-5-methanesulfonamidophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxamide (69.3 mg, 0.157 mmol) as a yellow solid. LCMS (ESI) [M+H] + :441

[0253] Step 3: A solution of N-(3-fluoro-5-methanesulfonamidophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxamide (70 mg, 0.158 mmol), Pd(dppf)Cl (11.5 mg, 0.0158 mmol), KCO (65.5 mg, 0.474 mmol), and 2-bromopyridine (49.9 mg, 0.316 mmol) in dioxane (5 mL) was stirred at 80° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (0-100%) to give N-(3-fluoro-5-methanesulfonamidophenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide (26.7 mg, 0.0682 mmol) as a white solid. LCMS (ESI) [M+H] + :392. 1 H NMR(300MHz,DMSO-d6)δ 10.64(s,1H),10.13(s,1H),8.75(d,J=1.4Hz,1H),8.65(dt,J=4.8,1.5Hz,1H),8.52(d,J=1.3Hz,1H) ,7.98-7.85(m,2H),7.56-7.43(m,2H),7.41-7.31(m,1H),6.75(dt,J=10.5,2.2Hz,1H),3.09(s,3H).

[0254] Examples 113 and 114 The compounds listed in the table below were prepared using procedures similar to those described in Example 112. [Table 13]

[0255] Example 115: N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2,6-difluorophenyl)thiophene-2-carboxamide [ka] Step 1: To a stirred solution of 4-bromothiophene-2-carboxylic acid (2.02 g, 9.75 mmol), TCFH (4.11 g, 14.6 mmol), and NMI (2.3 g, 29.25 mmol) in ACN (50.00 mL) was added 3-chloro-5-nitroaniline (1.68 g, 9.75 mmol). The mixture was then stirred at room temperature for 4 h. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-100%) to give 4-bromo-N-(3-chloro-5-nitrophenyl)thiophene-2-carboxamide (3.2 g, 95%) as a yellow solid. LCMS (ESI) [M+H] + :361

[0256] Step 2: To a solution of 4-bromo-N-(3-chloro-5-nitrophenyl)thiophene-2-carboxamide (3.2 g, 8.84 mmol) in methanol and water (50 mL) was added Fe (2.4 g, 44 mmol) and NHCl (4.7 g, 88 mmol). The resulting mixture was stirred at 80 °C under a N atmosphere for 2 h. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-100%) to give N-(3-amino-5-chlorophenyl)-4-bromothiophene-2-carboxamide (2.93 g, 95%) as a yellow solid. LCMS (ESI) [M+H] + :331

[0257] Step 3: To a stirred solution of N-(3-amino-5-chlorophenyl)-4-bromothiophene-2-carboxamide (1.02 g, 3.07 mmol) in pyridine (15.00 mL) was added methanesulfonyl chloride (703 mg, 6.14 mmol) dropwise at 0 °C. The mixture was then stirred at room temperature for 4 h. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-100%) to afford 4-bromo-N-(3-chloro-5-methanesulfonamidophenyl)thiophene-2-carboxamide (800 mg, 95%) as a yellow solid. LCMS (ESI) [M+H] + :409

[0258] Step 4: To a stirred solution of 4-bromo-N-(3-chloro-5-methanesulfonamidophenyl)thiophene-2-carboxamide (100 mg, 0.244 mmol), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (117 mg, 0.488 mmol), XPhosPdG (21 mg, 0.0244 mmol), and KPO (155 mg, 0.732 mmol) in 1,4-dioxane (5.00 mL), the mixture was then stirred at 80 °C for 8 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to give N-(3-chloro-5-methanesulfonamidophenyl)-4-(2,6-difluorophenyl)thiophene-2-carboxamide (31.3 mg, 98.180%) as an off-white solid. LCMS (ESI) [M+H] + :443. 1 H NMR(300MHz,DMSO-d6)δ 10.52(s,1H),10.10(s,1H),8.31(s,1H),8.15(s,1H),7.66(d,J=13.3Hz,2 H),7.50(q,J=7.4Hz,1H),7.28(t,J=8.2Hz,2H),6.98(s,1H),3.08(s,3H).

[0259] Example 116: N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide [ka] Step 1: To a mixture of 4-(pyridin-3-yl)thiophene-2-carboxylic acid (280 mg, 1.36 mmol) and 3-chloro-5-nitroaniline (281 mg, 1.63 mmol) in ACN (3 mL) was added TCFH (571 mg, 2.04 mmol) and NMI (334 mg, 4.08 mmol) at room temperature for 2 h. After concentration, the residue was purified by reverse-phase flash chromatography eluting with 50% acetonitrile in water (0.1% NH4HCO3) to give N-(3-chloro-5-nitrophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (212 mg) as a white solid.

[0260] Step 2: To a mixture of N-(3-chloro-5-nitrophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (212 mg, 589 μmol), Fe powder (164 mg, 2.94 mmol), ethyl 1H-pyrazole-4-carboxylate (434 mg, 3.10 mmol), and NHCl (157 mg, 2.94 mmol), EtOH (2 mL) and HO (0.2 mL) were added. The resulting mixture was stirred at 80 °C under a N atmosphere for 2 h. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in petroleum ether to give N-(3-amino-5-chlorophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (156 mg) as a yellow solid.

[0261] Step 3: A solution of N-(3-amino-5-chlorophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (156 mg, 473 μmol) and EtN (142 mg, 1.41 mmol) in DCM (1 mL) was stirred at room temperature. MsO (123 mg, 709 μmol) was then added to the solution at 0° C., and the resulting mixture was stirred at room temperature for 3 h. The solvent was concentrated in vacuo. The residue was purified on a silica gel column eluted with 60% ethyl acetate in petroleum ether to give N-(3-chloro-5-methanesulfonamidophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (9.6 mg) as a white solid. LCMS [M+H] + :408. 1 H NMR(300MHz,DMSO-d6)δ 10.49(s,1H),9.00(d,J=2.2Hz,1H),8.60-8.50(m,2H),8.38(d,J=1.4Hz,1H),8.14(dt,J=7.9,2.0H z,1H),7.64(dt,J=14.6,1.9Hz,2H),7.52(dd,J=7.9,4.8Hz,1H),6.97(t,J=1.9Hz,1H),3.07(s,3H).

[0262] Examples 117 and 118 The compounds listed in the table below were prepared using procedures similar to those described for Example 116. [Table 14]

[0263] Example 119: 1-Ethyl-N-(3-fluoro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrazole-3-carboxamide [ka] Step 1: To a stirred solution of methyl 3-amino-5-fluorobenzoate (1 g, 5.91 mmol), HATU (2.91 g, 7.68 mmol), and DIEA (2.28 g, 17.7 mmol) in DMF (15 mL), 1-ethyl-5-methyl-1H-pyrazole-3-carbonate (1 g, 6.50 mmol) was added. The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford methyl 3-(1-ethyl-5-methyl-1H-pyrazole-3-amido)-5-fluorobenzoate (1.09 g, 3.59 mmol) as a white solid. LCMS (ESI) [M+H] + :306

[0264] Step 2: To a stirred solution of 3-(1-ethyl-5-methyl-1H-pyrazole-3-amido)-5-fluorobenzoate (1 g, 3.27 mmol) in EtOH (10 mL) and HO (10 mL) was added LiOH (782 mg, 32.6 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was acidified to pH 5 with citric acid. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried under vacuum to give 3-(1-ethyl-5-methyl-1H-pyrazole-3-amido)-5-fluorobenzoic acid (848 mg, 2.91 mmol) as a yellow solid. LCMS (ESI) [M+H] + :292

[0265] Step 3: A stirred mixture of 3-(1-ethyl-5-methylpyrazole-3-amido)-5-fluorobenzoic acid (500 mg, 1.717 mmol, 1 equiv.) and DPPA (610 mg, 2.22 mmol) in toluene (10 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature, HO (1 mL) was added, and the mixture was stirred for an additional 1 h. The resulting mixture was concentrated in vacuo. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-100%) to give N-(3-amino-5-fluorophenyl)-1-ethyl-5-methyl-1H-pyrazole-3-carboxamide (119 mg, 0.456 mmol) as a yellow solid. LCMS (ESI) [M+H] + :263

[0266] Step 4: To a stirred solution of N-(3-amino-5-fluorophenyl)-1-ethyl-5-methyl-1H-pyrazole-3-carboxamide (100 mg, 0.381 mmol) and EtN (115 mg, 1.14 mmol) in DCM (10 mL) was added MsCl (47.7 mg, 0.419 mmol) dropwise at 0 °C. The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-100%) to give 1-ethyl-N-(3-fluoro-5-methanesulfonamidophenyl)-5-methyl-1H-pyrazole-3-carboxamide (54.7 mg, 0.1607 mmol) as an off-white solid. LCMS (ESI) [M+H] + :341. 1 H NMR(400MHz,DMSO-d6)δ 10.16(d,J=2.1Hz,1H),10.04(d,J=2.2Hz,1H),7.59(d,J=2.1Hz,1H),7.48(dt,J=11.5,2.2Hz,1H),6.68(dt,J=10.4,2.3Hz,1H ),6.57(d,J=2.1Hz,1H),4.18(qd,J=7.2,2.1Hz,2H),3.09(d,J=2.1Hz,3H),2.33(d,J=2.1Hz,3H),1.37(td,J=7.3,2.1Hz,3H).

[0267] Example 120: N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)-4-phenylthiophene-2-carboxamide [ka] Step 1: To a stirred solution of N-(3-amino-5-chlorophenyl)methanesulfonamide (155 mg, 0.706 mmol), TCFH (297 mg, 1.059 mmol), and NMI (172 mg, 2.118 mmol) in ACN (15.00 mL), 5-bromo-4-phenylthiophene-2-carboxylic acid (200 mg, 0.706 mmol) was added. The mixture was then stirred at room temperature for 4 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford 5-bromo-N-(3-chloro-5-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (350 mg, 95%) as a white solid. LCMS (ESI) [M+H] + :485

[0268] Step 2: To a stirred solution of 5-bromo-N-(3-chloro-5-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (350 mg, 0.720 mmol), AcO (140 mg, 1.37 mmol), Pd(OAc) (16 mg, 0.071 mmol), Xantphos (80 mg, 0.138 mmol), and (COOH) (129 mg, 1.44 mmol) in DMSO (10.00 mL), and DIEA (266 mg, 2.06 mmol) was added. The mixture was then stirred at 90 °C under a N atmosphere for 4 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to give 5-[(3-chloro-5-methanesulfonamidophenyl)carbamoyl]-3-phenylthiophene-2-carboxylic acid (210 mg, 95%) as a yellow solid. LCMS (ESI) [M+H] + :451

[0269] Step 3: To a stirred solution of 5-[(3-chloro-5-methanesulfonamidophenyl)carbamoyl]-3-phenylthiophene-2-carboxylic acid (210 mg, 0.465 mmol), TCFH (196 mg, 0.6975 mmol), and NMI (115 mg, 1.395 mmol) in ACN (5.00 mL), methanol (5 mL) was added. The mixture was then stirred at room temperature for 4 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to afford methyl 5-[(3-chloro-5-methanesulfonamidophenyl)carbamoyl]-3-phenylthiophene-2-carboxylate (180 mg, 95%) as a white solid. LCMS (ESI) [M+H] + :465

[0270] Step 4: To a stirred solution of methyl 5-[(3-chloro-5-methanesulfonamidophenyl)carbamoyl]-3-phenylthiophene-2-carboxylate (180 mg, 0.387 mmol) and NaBH4 (44 mg, 1.16 mmol) in EtOH (10.00 mL) at 0 °C, the mixture was then stirred at room temperature for 1 h. The mixture was acidified to pH 5 with citric acid. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried under vacuum to give N-(3-chloro-5-methanesulfonamidophenyl)-5-(hydroxymethyl)-4-phenylthiophene-2-carboxamide (37.2 mg, 98.340%) as a white solid. LCMS (ESI) [M+H] + :437. 1 H NMR(300MHz,DMSO-d6)δ 10.38(s,1H),10.08(s,1H),8.14(s,1H),7.66(dt,J=15.7,1.9Hz,2H),7.54-7.44(m,4H),7.41(dt, J=5.7,3.4Hz,1H),6.96(t,J=2.0Hz,1H),5.88(t,J=5.4Hz,1H),4.74(d,J=5.4Hz,2H),3.08(s,3H).

[0271] Example 121: N-(3-bromo-5-(methylsulfonamidoimidamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide [ka] Step 1: A solution of N-(3-amino-5-bromophenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide (180 mg, 0.481 mmol, 1 equiv.) and 3-{[(tert-butyldimethylsilyl)imino](methyl)oxo-lambda 6-sulfanyl}-1-methylimidazol-1-ium (158.41 mg, 0.577 mmol, 1.2 equiv.) in MeCN (3 mL) was stirred at room temperature for 1 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 0% to 100% in 10 min, detector, UV 254 nm. This gave N-{3-bromo-5-[N-(tert-butyldimethylsilyl)methanesulfonoimidamido]phenyl}-4-(pyridin-2-yl)thiophene-2-carboxamide (170 mg, 62.49%) as a white solid. LCMS: (ESI): LCMS (ESI) [M+H] + :565

[0272] Step 2: N-{3-bromo-5-[N-(tert-butyldimethylsilyl)methanesulfonimido]phenyl}-4-(pyridin-2-yl)thiophene-2-carboxamide (170 mg, 0.301 mmol, 1 equiv.) was dissolved in HCl solution in 1,4-dioxane (3 mL, 1N) and stirred at room temperature for 1 h. The residue was purified under the following conditions: column, C 18 Purification was performed by reverse-phase flash chromatography on silica gel, mobile phase: MeCN in water (0.1% FA), gradient 0% to 100% in 20 min, UV 254 nm detector. This afforded N-(3-bromo-5-methanesulfonimidamidophenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide (14.3 mg, 10.54%) as a white solid. LCMS: (ESI): LCMS (ESI) [M+H] +:451. 1 H NMR(300MHz,DMSO-d6)δ 10.38(s,1H),8.74(d,J=1.3Hz,1H),8.64(dt,J=4.8,1.4Hz,1H),8.49(d,J=1.3Hz,1H),7. 95-7.88(m,2H),7.58(t,J=1.8Hz,1H),7.44-7.33(m,2H),6.98-6.78(m,3H),3.17(s,3H).

[0273] Examples 122 and 123 The compounds listed in the table below were prepared using procedures similar to those described in Example 120. [Table 15]

[0274] Example 125: N-(3-chloro-5-(methylsulfonamido)phenyl)-5-phenylthiophene-3-carboxamide [ka] Step 1: To a stirred solution of 5-bromothiophene-3-carboxylic acid (100 mg, 0.482 mmol), TCFH (204 mg, 0.723 mmol), and NMI (119 mg, 1.446 mmol) in ACN (5.00 mL), N-(3-amino-5-chlorophenyl)methanesulfonamide (106 mg, 0.482 mmol) was added. The mixture was then stirred at room temperature for 4 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5–95%, acidic system) to afford 5-bromo-N-(3-chloro-5-methanesulfonamidophenyl)thiophene-3-carboxamide (150 mg, 95%) as a yellow solid. LCMS(ESI)[M+H] + :409.

[0275] Step 2: To a stirred solution of 5-bromo-N-(3-chloro-5-methanesulfonamidophenyl)thiophene-3-carboxamide (90 mg, 0.219 mmol), phenylboronic acid (26.7 mg, 0.219 mmol), Pd(PPh) (24 mg, 0.0219 mmol), and KPO (139 mg, 0.657 mmol) in dioxane (10.00 mL) was added HO (3.00 mL). The mixture was then stirred at 90 °C under nitrogen for 4 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5–95%, acidic system) to afford N-(3-chloro-5-methanesulfonamidophenyl)-5-phenylthiophene-3-carboxamide (45 mg, 99.350%) as a white solid. LCMS(ESI)[M+H] + :407. 1 H NMR(300MHz,DMSO-d6)δ 10.31(s,1H),10.09(s,1H),8.35(d,J=1.4Hz,1H),8.00(d,J=1.4Hz,1H),7.71(ddt,J=10.6 ,8.6,1.7Hz,4H),7.54-7.43(m,2H),7.43-7.32(m,1H),6.97(t,J=1.9Hz,1H),3.08(s,3H).

[0276] Example 125 The compounds listed in the table below were prepared using procedures similar to those described in Example 123. [Table 16]

[0277] Example 126: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxypropyl)-1H-pyrazole-4-carboxamide [ka] Step 1: To a solution of ethyl 1H-pyrazole-4-carboxylate (200 mg, 1.42 mmol) and CsCO (693 mg, 2.13 mmol) in MeCN (5 mL) was added (3-bromopropoxy)(tert-butyl)dimethylsilane (377 mg, 1.49 mmol) at 0 °C, and the mixture was stirred at 25 °C for 5 h. The mixture was poured into water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (15 mL × 2) and dried over NaSO. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. Ethyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-pyrazole-4-carboxylate (440 mg, 1.40 mmol, 99.3% yield) was obtained as a colorless oil. LCMS:MS(ESI) retention time: 0.972 min, (M)+=313.2. 1 H NMR (400MHz, chloroform-d) δ=7.85(d,J=8.8Hz,2H),4.33-4.14(m,4H),3.52(t,J=5.6 Hz, 2H), 2.06-1.95 (m, 2H), 1.30 (t, J=7.2Hz, 3H), 0.86 (s, 9H), 0.08--0.11 (m, 6H).

[0278] Step 2: To a solution of ethyl 1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-pyrazole-4-carboxylate (440 mg, 1.47 mg) in THF (5 mL) and MeOH (5 mL) was added a solution of LiOH.HO (185 mg, 4.41 mmol) in water (5 mL). The mixture was stirred at 25 °C for 14 h. The mixture was poured into water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (15 mL × 2) and dried over NaSO. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC and lyophilized. 1-(3-hydroxypropyl)-1H-pyrazole-4-carboxylic acid (160 mg, 0.592 mmol, 40.3% yield) was obtained as a white solid. LCMS:MS(ESI) retention time: 0.115 min, (M+1)+=171.0. 1H NMR(400MHz,DMSO-d6)δ=8.22(s,1H),7.78(s,1H),4.60(br s,1H),4.18(t,J=6.8Hz,2H),3.40-3.35(m,2H),1.91(quin,J=6.8Hz,2H)

[0279] Step 3: To a solution of 1-(3-hydroxypropyl)-1H-pyrazole-4-carboxylic acid (75 mg, 0.441 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (106 mg, 484 μmol) in pyridine (2 mL) was added EDCI (168 mg, 881 μmol). The mixture was stirred at 25 °C for 3 h. The mixture was poured into water (20 mL) and extracted with EA (25 mL × 3). The combined organic layers were washed with 0.5 N HCl (15 mL × 2), brine (15 mL × 2), and dried over Na SO . The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC and lyophilized. N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxypropyl)-1H-pyrazole-4-carboxamide (102.45 mg, 0.269 mmol, 97.96% purity, 60.9% yield) was obtained as a white solid. LCMS: MS (ESI) retention time: 0.718 min, (M+1)+ = 373.0. 1 H NMR(400MHz,DMSO-d6)δ=10.00(s,1H),8.36(s,1H),8.03(s,1H),7.66(t,J=1.6Hz,1H),7.56(t,J=1.6Hz,1H),6.90(t,J=2.0Hz,1H),4.63(br s,1H),4.21(t,J=6.8Hz,2H),3.41-3.37(m,2H),3.05(s,3H),1.93(quin,J=6.4Hz,2H)

[0280] Examples 127 and 128 The compounds listed in the table below were prepared using procedures similar to those described in Example 125. [Table 17]

[0281] Example 129: N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-phenyl-1H-pyrrole-3-carboxamide [ka] Step 1: To a solution of ethyl 5-methyl-1H-pyrrole-3-carboxylate (100 mg, 652 μmol) and iodobenzene (199 mg, 978 μmol) in DMSO (2 mL) was added 1-hydroxypyrrolidine-2,5-dione (7.5 mg, 65.2 μmol), dipotassium carbonate (179 mg, 1.3 mmol) and λ 1 Copper(1+) iodide (12.4 mg, 65.2 μmol) was added at 25°C. The mixture was stirred at 90°C for 16 hours. The mixture was poured into HO (50 mL). The mixture was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE:EA = 10:1 to 1:1) to give ethyl 5-methyl-1-phenyl-1H-pyrrole-3-carboxylate (430 mg, 1.87 mmol) as a colorless oil. 1 H NMR(400MHz,chloroform-d)δ=7.58-7.38(m,4H),7.35-7.29(m,2H),6.48(dd,J=0.8,1.8Hz,1H),4.31(q,J=7.2Hz,2H),1.36(t,J=7.2Hz,3H)

[0282] Step 2: To a solution of ethyl 5-methyl-1-phenyl-1H-pyrrole-3-carboxylate (420 mg, 1.83 mmol) in MeOH (3 mL), THF (2 mL), and HO (1 mL) was added lithium hydroxide(1+) (230 mg, 5.49 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 h. The mixture was poured into 1 N HCl (20 mL). The mixture was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 5-methyl-1-phenyl-1H-pyrrole-3-carboxylic acid (360 mg, 1.83 mmol, crude) as a brown solid. LCMS: MS (ESI) retention time: 0.747 min, (M)+ = 202.0

[0283] Step 3: To a solution of 5-methyl-1-phenyl-1H-pyrrole-3-carboxylic acid (330 mg, 1.63 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (538 mg, 2.44 mmol) in pyridine (3 mL) was added EDCI (624 mg, 3.26 mmol) at 25° C. The mixture was stirred at 25° C. for 2 hours. The mixture was poured into 1N HCl (20 mL). The mixture was extracted with EA (50 mL×2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC and lyophilized. 5-(2-(benzyloxy)phenyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrazole-3-carboxamide (282.58 mg, 0.553 mmol, 98.80% purity, 84.2% yield) was obtained as an off-white solid. LCMS: MS(ESI) retention time: 0.916 min, (M+1)+ = 511.2. 1 H NMR(400MHz,DMSO-d6)δ=10.33(s,1H)9.89-10.21(m,1H)7.68-7.78(m,2H)7.46-7.54(m,1H)7.25-7. 41(m,7H)7.10(t,J=7.6Hz,1H)6.91(t,J=1.6Hz,1H)6.79(s,1H)5.18(s,2H)3.74(s,3H)3.08(s,3H).

[0284] Example 130 The compounds listed in the table below were prepared using procedures similar to those described in Example 129. [Table 18]

[0285] Example 131: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide [ka] To a solution of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylic acid (50 mg, 254 μmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (61.5 mg, 279 μmol) in pyridine (1 mL) was added EDCI (97.3 mg, 508 μmol) at 25° C. The mixture was stirred at 25° C. for 12 hours. The mixture was poured into HO (50 mL). The mixture was extracted with EA (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA) to give N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide (54.68 mg, 137 μmol) as an off-white solid. LCMS: MS (ESI) retention time: 0.738 min, (M+1)+ = 399.1. 1 H NMR(400MHz,DMSO-d6)δ=10.02(s,2H),8.44(s,1H),8.07(s,1H),7.76-7.45(m,2H),6.92(t,J=1.8Hz,1H),4.60-4.39(m,1H),3.98(br dd,J=2.4,11.8Hz,2H),3.50-3.44(m,2H),3.06(s,3H),2.06-1.89(m,4H).

[0286] Examples 132 to 136 The compounds listed in the table below were prepared using procedures similar to those described in the examples. [Table 19]

[0287] Example 137: N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(pyridin-2-yl)isothiazole-5-carboxamide [ka] Step 1: To a solution of picolinamide (1.5 g, 12.2 mmol) in toluene (15 mL) was added carbonated hypochlorite (2.38 g, 18.2 mmol) at 25 °C. The mixture was stirred at 60 °C for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE:EA = 10:1 to 1:1) to give the desired compound. 5-(pyridin-2-yl)-1,3,4-oxathiazol-2-one (550 mg, 3.05 mmol) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=8.85-8.72(m,1H),8.16-7.98(m,2H),7.67(ddd,J=1.8,4.9,6.9Hz,1H)

[0288] Step 2: To a solution of 5-(pyridin-2-yl)-1,3,4-oxathiazol-2-one (450 mg, 2.49 mmol) in xylene (5 mL), ethyl prop-2-ynoate (1.21 g, 12.4 mmol) was added. The mixture was stirred at 160 °C for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE:EA = 10:1 to 1:1) to give the desired compound. Ethyl 3-(pyridin-2-yl)isothiazole-5-carboxylate (330 mg, 1.4 mmol) was obtained as a brown solid. LCMS:MS(ESI) retention time: 0.761 min, (M)+=235.0. 1H NMR (400 MHz, chloroform-d) δ = 8.78-8.65 (m, 1H), 8.56 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.84 (dt, J = 1.8, 7.8 Hz, 1H), 7.35 (ddd, J = 1.0, 4.9, 7.5 Hz, 1H), 4.48-4.40 (m, 2H), 1.44 (t, J = 7.2 Hz, 3H).

[0289] Step 3: To a solution of ethyl 3-(pyridin-2-yl)isothiazole-5-carboxylate (320 mg, 1.36 mmol) in a mixture of MeOH (5 mL), THF (3 mL), and HO (1 mL) was added LiOH.HO (285 mg, 6.8 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was poured into 1 N HCl solution (10 mL). The mixture was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. 3-(pyridin-2-yl)isothiazole-5-carboxylic acid (200 mg, 969 μmol, crude) was obtained as a yellow solid.

[0290] Step 4: To a solution of 3-(pyridin-2-yl)isothiazole-5-carboxylic acid (50 mg, 242 μmol) and compound 7 (69.2 mg, 314 μmol) in pyridine (1 mL) was added EDCI (92.7 mg, 484 μmol) at 25° C. The mixture was stirred at 25° C. for 2 hours. The mixture was poured into HO (50 mL) and extracted with EA (30 mL × 2). The combined organic layer was washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA) to give N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(pyridin-2-yl)isothiazole-5-carboxamide (57.79 mg, 141 μmol) as a yellow solid. LCMS:MS(ESI) retention time: 0.793 min, (M+1)+=409.0. 1H NMR(400MHz,DMSO-d6)δ=10.94(s,1H),10.15(s,1H),8.94(s,1H),8.74(d,J=4.6Hz,1H),8.23(d,J=7.8Hz,1H ),8.01(dt,J=1.8,7.6Hz,1H),7.78-7.67(m,2H),7.54(dd,J=5.4,7.0Hz,1H),7.13-6.91(m,1H),3.09(s,3H)

[0291] Example 138: N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(pyridin-2-yl)isothiazole-5-carboxamide [ka] Step 1: Sodium hydride (723 mg, 18.1 mmol) was added to EtOH (150 mL) at 0 °C, followed by diethyl oxalate (2.41 g, 16.5 mmol). A solution of 1-(2-(benzyloxy)phenyl)ethan-1-one (3.75 g, 16.5 mmol) in EtOH (20 mL) was then added dropwise to the reaction at 0 °C, and after the addition, the reaction was stirred at 25 °C for 16 h. The reaction mixture was concentrated to remove the solvent, and the residue was diluted with water (100 mL), extracted with EA (50 mL × 3), washed with brine (50 mL), dried over Na SO , and concentrated. Ethyl 4-(2-(benzyloxy)phenyl)-2,4-dioxobutanoate (4 g, 11.8 mmol) was obtained as a colorless oil. LCMS:MS(ESI) retention time: 0.982, (M+1)+=326.9

[0292] Step 2: To a solution of EtOH (30 mL) was added NaH (183 mg, 60% purity, 4.59 mmol) at 0 °C, and the mixture was stirred at 25 °C for 5 min. Then, ethyl 4-(2-(benzyloxy)phenyl)-2,4-dioxobutanoate (1.5 g, 4.59 mmol) was added to the above mixture, followed by methylhydrazine sulfate (661 mg, 4.59 mmol). The mixture was stirred at 25 °C for 25 min and at 60 °C for 2 h. The mixture was cooled to 25 °C and poured into water (35 mL). The pH of the mixture was adjusted to 4-5 with 1 N (HCl), and the mixture was extracted with EA (40 mL × 3). The combined organic layers were washed with brine (25 mL × 2) and dried over Na SO . The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give ethyl 3-(2-(benzyloxy)phenyl)-1-methyl-1H-pyrazole-5-carboxylate (0.9 g, 2.67 mmol, 58.4% yield) as a pale yellow oil. Also obtained was ethyl 5-(2-(benzyloxy)phenyl)-1-methyl-1H-pyrazole-3-carboxylate. LCMS: MS (ESI) retention time: 0.947 min, (M+1)+ = 337.2. 1 H NMR (400 MHz, chloroform-d) δ = 7.32-7.39 (m, 1H), 7.15-7.29 (m, 6H), 6.95-7.04 (m, 2H), 6.74 (s, 1H), 5.01 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.71 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).

[0293] Step 3: To a solution of ethyl 3-(2-(benzyloxy)phenyl)-1-methyl-1H-pyrazole-5-carboxylate (500 mg, 1.48 mmol) in a solvent solution (MeOH:THF:HO = 1:1:1, 15 mL) was added LiOH (185 mg, 4.43 mmol). The mixture was stirred at 25 °C for 2 h. The pH of the mixture was adjusted to 3-4. The mixture was partitioned between water (20 mL) and EtOAc (30 mL). The aqueous layer was separated and extracted with EtOAc (30 mL × 2). The combined organic phases were washed with brine (25 mL × 2), dried over anhydrous NaSO, filtered, and the filtrate was evaporated in vacuo to give 5-(2-(benzyloxy)phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (450 mg, 1.45 mmol, 98.6% yield) as a yellow solid. 1 H NMR (400 MHz, methanol-d₄) δ = 7.45-7.56 (m, 1H), 7.22-7.39 (m, 7H), 7.07-7.15 (m, 1H), 6.76 (s, 1H), 5.16 (s, 2H), 3.72 (s, 3H).

[0294] Step 4: To a solution of 5-(2-(benzyloxy)phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (220 mg) in Py (6 mL) was added N-(3-amino-5-chlorophenyl)methanesulfonamide (188 mg, 856 μmol) and EDCI (272 mg, 1.42 mmol). The mixture was stirred at 25° C. for 15 hours. The mixture was partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was separated and extracted with EtOAc (30 mL×2). The combined organic phase was washed with 1N HCl (20 mL×3) and brine (25 mL×2), dried over anhydrous NaSO, filtered, and the filtrate was evaporated in vacuo to give a residue. The residue was purified by preparative HPLC and lyophilized. 5-(2-(benzyloxy)phenyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrazole-3-carboxamide (282.58 mg, 0.553 mmol, 98.80% purity, 84.2% yield) was obtained as an off-white solid. LCMS: MS(ESI) retention time: 0.916 min, (M+1)+ = 511.2. 1H NMR(400MHz,DMSO-d6)δ=10.33(s,1H)9.89-10.21(m,1H)7.68-7.78(m,2H)7.46-7.54(m,1H)7.25-7. 41(m,7H)7.10(t,J=7.6Hz,1H)6.91(t,J=1.6Hz,1H)6.79(s,1H)5.18(s,2H)3.74(s,3H)3.08(s,3H).

[0295] Examples 139 to 141 The compounds listed in the table below were prepared using procedures similar to those described in Example 138. [Table 20]

[0296] Example 142: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(1-phenylethyl)-1H-pyrazole-4-carboxamide [ka] Step 1: To a solution of ethyl 1H-pyrazole-4-carboxylate (1.0 g, 7.13 mmol) in DMF (15 mL) was added NaH (355 mg, 8.91 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. (1-Bromoethyl)benzene (1.64 g, 8.91 mmol) was added to the above mixture at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was poured into water (80 mL) and extracted with EA (40 mL × 3). The combined organic phase was washed with brine (25 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1). Compound 3 (1.67 g, 6.83 mmol, 95.9% yield) was obtained as a colorless oil. LCMS:MS(ESI) retention time: 0.819 min, (M)+=245.0. 1H NMR (400 MHz, chloroform-d) δ = 7.85 (d, J = 16.4 Hz, 2H), 7.33-7.21 (m, 3H), 7.17-7.12 (m, 2H), 5.45 (q, J = 7.2 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.84 (d, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H).

[0297] Step 2: To a solution of ethyl 1-(1-phenylethyl)-1H-pyrazole-4-carboxylate (1.0 g, 4.09 mmol) in a mixed solvent (15 mL, THF / MeOH / HO = 1:1:1), lithium hydroxide(1+) (551 mg, 12.2 mmol) was added. The mixture was stirred at 60 °C for 15 h. The mixture was cooled to 25 °C and poured into water (20 mL). The pH of the mixture was adjusted to 3-4 with 1 N HCl and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (15 mL × 2) and dried over Na SO . The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. The crude product was used in the next step without further purification. 1-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid (880 mg, 4.06 mmol, 99.5% yield) was obtained as a white solid. LCMS:MS(ESI) retention time: 0.715 min, (M+1)+=217.1

[0298] Step 3: To a solution of 1-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.694 mol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (183 mg, 832 ummol) in pyridine (5 mL) was added EDCI (264 mg, 1.38 mmol). The mixture was stirred at 25 °C for 5 h. The mixture was poured into water (40 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (15 mL × 3) and dried over Na2SO4. The filtrate was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 1 / 1). The crude product was repurified by reverse-phase chromatography (HO-0.225% FA-MeCN) and lyophilized. N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(1-phenylethyl)-1H-pyrazole-4-carboxamide (188.2 mg, 0.454 mmol, 99.77% purity, 64.4% yield) was obtained as a white solid. LCMS: MS (ESI) retention time: 0.812 min, (M+1)+ = 419.2. 1 H NMR(400MHz,DMSO-d6)δ=10.04(s,1H),8.51(s,1H),8.07(s,1H),7.65(d,J=1.6Hz,1H),7.55(d,J=1.6 Hz,1H),7.40-7.24(m,5H),6.91(d,J=1.6Hz,1H),5.69(q,J=7.2Hz,1H),3.05(s,3H),1.94-1.73(m,3H)

[0299] Example 143: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-difluoroethyl)-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide [ka] Step 1: To a solution of ethyl 2-chloro-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylate (650 mg, 2.45 mmol) in DMF (6 mL) was added sodium hydride (146 mg, 3.67 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. To the mixture was added 2,2-difluoroethyl trifluoromethanesulfonate (575 mg, 2.69 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into HO (50 mL). The mixture was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE:EA = 10:1 to 0:1) to give the desired compound. 2-Chloro-1-(2,2-difluoroethyl)-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylic acid (300 mg, 1 mmol) was obtained as a yellow solid. LCMS: MS (ESI) retention time: 0.634 min, (M)+ = 301.0. 1 H NMR(400MHz,DMSO-d6)δ=12.77-12.24(m,1H),8.49(d,J=3.6Hz,1H),7.79(d,J=7.4Hz,1H),7.32 (dd,J=4.8,7.7Hz,1H),6.82(s,1H),6.52-6.01(m,1H),4.73(dt,J=3.2,15.2Hz,2H),2.37(s,3H)

[0300] Step 2: To a solution of 2-chloro-1-(2,2-difluoroethyl)-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylic acid (300 mg, 997 μmol) in MeOH (5 mL) was added Pd / C (200 mg, 187 μmol) at 25° C. The mixture was stirred under hydrogen (15 Psi) at 25° C. for 14 hours. The mixture was filtered, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give the crude product. 1-(2,2-difluoroethyl)-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylic acid (280 mg) was obtained as a colorless oil. LCMS: MS (ESI) retention time: 0.354 min, (M)+ = 267.0

[0301] Step 3: To a solution of 1-(2,2-difluoroethyl)-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylic acid (100 mg, 375 μmol) and 1-(2,2-difluoroethyl)-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylic acid (99.3 mg, 450 μmol) in pyridine (1 mL) was added EDCI (143 mg, 750 μmol) at 25° C. The mixture was stirred at 25° C. for 14 hours. The mixture was poured into HO (50 mL). The mixture was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC and lyophilized. N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide (95.7 mg, 0.226 mmol, 99.4% purity, 61.7% yield) was obtained as a white solid. LCMS: MS (ESI) retention time: 0.683 min, (M-1) = 419.0. 1 H NMR(400MHz,DMSO-d6)δ=9.95(s,1H),8.69-8.49(m,1H),8.18-8.14(m,1H),8.11-8.00(m,1H),7.84(d,J=8.4H) z,1H),7.77-7.70(m,1H),7.65(s,1H),7.51-7.41(m,1H),6.91(t,J=1.6Hz,1H),6.83(d,J=1.6Hz,1H),5.32(br t,J=5.6Hz,1H),4.60(br d,J=4.8Hz,2H),3.06(s,3H)

[0302] Example 144: tert-butyl 6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate [ka] Step 1: To a solution of ethyl 1H-pyrazole-4-carboxylate (100 mg, 0.713 mmol) and tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (174 mg, 820 μmol) in THF (2 mL) was slowly added PPh3 (243 mg, 927 μmol) and DIAD (187 mg, 927 μmol) at 0 °C. The mixture was stirred at 25 °C for 15 h. The mixture was poured into water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine (15 mL × 2) and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (10:1 to 2:1) as the eluent. tert-Butyl 6-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (170 mg, 0.507 mmol, 71.1% yield) was obtained as a colorless oil. LCMS: MS (ESI) retention time: 0.899 min, (M+1)+ = 336.3. 1 H NMR (400 MHz, chloroform-d) δ = 7.98 (s, 1H), 7.85 (s, 1H), 7.81 (s, 1H), 4.65-4.50 (m, 1H), 4.30-4.18 (m, 3H), 3.96 (s, 2H), 3.89 (s, 2H), 2.67 (d, J = 8.0 Hz, 4H), 1.37 (s, 9H), 1.32-1.23 (m, 4H).

[0303] Step 2: To a solution of tert-butyl 6-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (170 mg, 0.506 mmol) in THF (2 mL) and MeOH (2 mL) was added a solution of lithium hydroxide hydrate (63.7 mg, 1.52 mmol) in water (2 mL). The mixture was stirred at 25 °C for 15 h. The mixture was poured into water (20 mL). The pH value of the mixture was adjusted to 3-4 with 0.5 N aqueous HCl. It was extracted with EA (30 mL × 3). The combined organic layers were washed with brine (15 mL × 2) and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product. 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-1H-pyrazole-4-carboxylic acid (140 mg, 0.455 mmol, 90.3% yield) was obtained as a white solid. LCMS: MS (ESI) retention time: 0.818 min, (M+1)+ = 308.2

[0304] Step 3: To a solution of 1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-1H-pyrazole-4-carboxylic acid (140 mg, 0.455 mmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (110 mg, 501 μmol) in pyridine (4 mL) was added EDCI (200 mg, 1.04 mmol). The mixture was stirred at 25 °C for 3 h. The mixture was poured into water (20 mL) and extracted with EA (25 mL × 3). The combined organic layers were washed with 0.5 N HCl (15 mL × 2), brine (15 mL × 2) and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC and lyophilized. tert-Butyl 6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (150 mg, 0.294 mmol, 99.59% purity, 64.2% yield) was obtained as a white solid. LCMS: MS (ESI) retention time: 0.840 min, (M+1)+ = 510.2. 1H NMR(400MHz,DMSO-d6)δ=10.01(s,1H),8.42(s,1H),8.06(s,1H),7.64(t,J=1.6Hz,1H),7.54(t,J=1.6Hz,1H ),6.90(t,J=2.0Hz,1H),4.97-4.70(m,1H),4.05-3.72(m,4H),3.04(s,3H),2.73-2.59(m,4H),1.37(s,9H).

[0305] Example 145: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide [ka] To a solution of tert-butyl 4-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (200 mg, 401 μmol) in DCM (4 mL) was added trifluoroacetic acid (744 mg, 6.52 mmol) at 25° C. The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (NH4HCO3) to give the desired compound. N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide (41.59 mg, 104 μmol) was obtained as a white solid. LCMS: MS (ESI) retention time: 0.722 min, (M+1)+ = 425.2. 1 H NMR(400MHz,DMSO-d6)δ=9.97(s,1H),8.41(s,1H),8.04(s,1H),7.62(t,J=1.8Hz,1H),7.52(t,J=1.8Hz,1H),6.89(t,J=1.8Hz,1H),4.29(br s,1H),3.02(s,5H),2.82-2.58(m,2H),2.00(br d,J=10.6Hz,2H),1.88-1.73(m,2H)

[0306] Examples 146-147 The compounds listed in the table below were prepared using procedures similar to those described in Example 145. [Table 21]

[0307] Example 148: 1-(4-(4-acetylpiperazin-1-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide [ka] To a stirred solution of N-(3-chloro-5-methanesulfonamidophenyl)-1-[4-(piperazin-1-yl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (90 mg, 0.189 mmol) and AcO (21.1 mg, 0.206 mmol) in DCM (5 mL) was added EtN (57.3 mg, 0.567 mmol) dropwise at 0 °C. The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0 to 100%) to give 1-[4-(4-acetylpiperazin-1-yl)pyridin-2-yl]-N-(3-chloro-5-methanesulfonamidophenyl)-1H-pyrazole-4-carboxamide (14.6 mg, 0.0282 mmol) as a white solid. LCMS(ESI)[M+H] + :518. 1 H NMR(400MHz,DMSO-d6)δ 10.25(s,1H),9.36(s,1H),8.25(s,1H),8.14(d,J=6.0Hz,1H),7.69(t,J=1.9Hz,1H),7.60(t,J=1.9Hz,1H),7.34(d, J=2.4Hz,1H),6.95-6.87(m,2H),3.60(s,4H),3.52(d,J=5.7Hz,2H),3.46(t,J=5.5Hz,2H),3.04(s,3H),2.05(s,3H).

[0308] Example 149: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(4-isobutyrylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide [ka] Step 1: A solution of ethyl 1-(5-bromopyridin-2-yl)-1H-pyrazole-4-carboxylate (350 mg, 1.18 mmol), Pd(AcO) (52.9 mg, 0.236 mmol), BINAP (293 mg, 0.472 mmol), CsCO (1.15 g, 3.54 mmol), and tert-butyl piperazine-1-carboxylate (240 mg, 1.29 mmol) in toluene (5 mL) was stirred at 110° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (0-100%) to give tert-butyl 4-{6-[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]pyridin-3-yl}piperazine-1-carboxylate (270 mg, 0.672 mmol) as a yellow solid. LCMS (ESI) [M+H] + :402

[0309] Step 2: To a stirred solution of tert-butyl 4-{6-[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]pyridin-3-yl}piperazine-1-carboxylate (270 mg, 0.672 mmol) in EtOH (3 mL) and HO (3 mL) was added LiOH (160 mg, 6.71 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was acidified to pH 5 with citric acid. The precipitated solid was collected by filtration and washed with water. The resulting solid was dried under vacuum to give 1-(5-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (180 mg, 0.482 mmol) as a yellow solid. LCMS (ESI) [M+H] + :374

[0310] Step 3: To a stirred solution of 1-(5-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (180 mg, 0.482 mmol), TCFH (270 mg, 0.964 mmol), and NMI (118 mg, 1.44 mmol) in ACN (5 mL) was added N-(3-amino-5-chlorophenyl)methanesulfonamide (116 mg, 0.530 mmol). The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to give tert-butyl 4-(6-{4-[(3-chloro-5-methanesulfonamidophenyl)carbamoyl]-1H-pyrazol-1-yl}pyridin-3-yl)piperazine-1-carboxylate (220 mg, 0.381 mmol) as a yellow solid. LCMS (ESI) [M+H] + :576

[0311] Step 4: To a stirred solution of tert-butyl 4-(6-{4-[(3-chloro-5-methanesulfonamidophenyl)carbamoyl]-1H-pyrazol-1-yl}pyridin-3-yl)piperazine-1-carboxylate (220 mg, 0.381 mmol) in HCl / dioxane (5 mL) was added HCl at 0 °C for 1 h. The resulting mixture was concentrated in vacuo. The mixture was basified to pH 9 with NaOH. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-100%) to afford N-(3-chloro-5-methanesulfonamidophenyl)-1-[5-(piperazin-1-yl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (140 mg, 0.294 mmol) as a yellow solid. LCMS (ESI) [M+H] + :476

[0312] Step 5: To a stirred solution of N-(3-chloro-5-methanesulfonamidophenyl)-1-[5-(piperazin-1-yl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (140 mg, 0.294 mmol), TCFH (164 mg, 0.588 mmol), and NMI (72.4 mg, 0.882 mmol) in ACN (5 mL) was added 2-methylpropanoic acid (28.4 mg, 0.323 mmol). The mixture was then stirred at room temperature for 1 h. The mixture was concentrated and purified by reverse-phase flash chromatography eluting with ACN / HO (5-95%, acidic system) to give N-(3-chloro-5-methanesulfonamidophenyl)-1-{5-[4-(2-methylpropanoyl)piperazin-1-yl]pyridin-2-yl}-1H-pyrazole-4-carboxamide (13.5 mg, 0.0247 mmol) as a white solid. LCMS (ESI) [M+H] + :546. 1 H NMR(300MHz,DMSO-d6)δ 10.26(s,1H),10.08(s,1H),9.28(s,1H),8.24(d,J=3.1Hz,2H),7.84(d,J=8.9Hz,1H),7.72(t,J=1.9Hz,1H),7.69-7. 60(m,2H),6.94(t,J=1.9Hz,1H),3.67(s,4H),3.26(s,4H),3.07(s,3H),2.94(p,J=6.7Hz,1H),1.03(d,J=6.7Hz,6H).

[0313] Example 150: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(trans-2-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide [ka] Step 1: To a solution of ethyl 1H-pyrazole-4-carboxylate (2 g, 14.2 mmol) and 7-oxabicyclo[4.1.0]heptane (2.09 g, 21.3 mmol) in DMF (20 mL) was added cesium carbonate (13.8 g, 42.6 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 h. The mixture was poured into HO (50 mL). The mixture was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (PE:EA = 10:1 to 1:1) to give ethyl 1-(trans-2-hydroxycyclohexyl)-1H-pyrazole-4-carboxylate (1.8 g, 7.55 mmol) as a colorless oil. LCMS:MS(ESI) retention time: 0.706 min, (M)+=239.0. 1 H NMR(400MHz,DMSO-d6)δ=8.24(s,1H),7.83(s,1H),4.81(d,J=5.8Hz,1H),4.21(q,J=7.0Hz,2H),3. 93(ddd,J=4.4,9.8,11.8Hz,1H),3.68(td,J=4.6,9.8Hz,1H),2.05-1.61(m,6H),1.30-1.24(m,5H)

[0314] Step 2: To a solution of ethyl 1-(trans-2-hydroxycyclohexyl)-1H-pyrazole-4-carboxylate (200 mg, 839 μmol) in MeOH (3 mL), THF (2 mL), and HO (1 mL) was added lithium hydroxide hydrate (105 mg, 2.51 mmol) at 25° C. The mixture was stirred at 25° C. for 16 h. The mixture was poured into 1 N HCl (20 mL). The mixture was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 1-(trans-2-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid (150 mg, 713 μmol) as a white solid. LCMS: MS (ESI) retention time: 0.512 min, (M)+ = 211.0

[0315] Step 3: To a solution of 1-trans-2-hydroxycyclohexyl)-1H-pyrazole-4-carboxylic acid (80 mg, 380 μmol) and N-(3-amino-5-chlorophenyl)methanesulfonamide (100 mg, 455 μmol) in pyridine (2 mL) was added EDCI (145 mg, 760 μmol) at 25° C. The mixture was stirred at 25° C. for 14 h. The mixture was poured into HO (50 mL). The mixture was extracted with EA (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the desired compound. N-(3-chloro-5-(methylsulfonamido)phenyl)-1-trans-2-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide (113.15 mg, 274 μmol) was obtained as a yellow solid. LCMS: MS (ESI) retention time: 0.749 min, (M+1)+ = 413.1. 1 H NMR(400MHz,DMSO-d6)δ=10.03(d,J=17.0Hz,2H),8.34(s,1H),8.04(s,1H),7.80-7.47(m,2H),6. 92(t,J=1.8Hz,1H),4.03-3.87(m,1H),3.75-3.59(m,1H),3.07(s,3H),2.01-1.64(m,5H),1.32(br s,3H)

[0316] Example 151: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-((1s,4s)-4-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide [ka] Step 1: To a solution of (1r,4r)-cyclohexane-1,4-diol (1 g, 8.6 mmol) and 1H-imidazole (614 mg, 9.03 mmol) in DMF (10 mL) and DCM...

Claims

1. A compound represented by formula (I), 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein: X is halo; Y is O or NR ｙ and R ｙ is H or C １－４ is alkyl, R １ But, C １－４ Alkyl or C ３－６ cycloalkyl, １－４ Alkyl or C ３－６ each cycloalkyl is optionally and independently substituted with 1 to 3 halo or —OH; Ring A is C ３－６ cycloalkyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl; m is 0 to 3; n is 0 or 2; Each R ２ But independently, C １－４ Alkyl, C ３－６ Cycloalkyl, halo, OR ２ａ , cyano, -NR ２ｂ R ２ｃ , -SO ２ R ２ａ , -C(O)R ２ｄ and -C(O)NR ２ｂ R ２ｃ and C is selected from １－４ Alkyl and C ３－６ Cycloalkyl is 1 to 4 R ２ｅ or two R ２ together form oxo, R ２ａ But, H, C １－４ Alkyl, C １－４ Haloalkyl or C １－４ Alkoxy C １－４ is alkyl, R ２ｄ But, H, C １－４ Alkyl, C ３－６ Cycloalkyl, OR ２ａ , phenyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 8-membered bicyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, １－４ wherein said alkyl is optionally substituted with 1 to 3 halo, and said 5-6 membered monocyclic heteroaryl is substituted with 1 to 3 C １－４ Alkyl, C １－４ optionally substituted with haloalkyl, or phenyl; R ２ｂ and R ２ｃ Each independently represents H, C １－４ Alkyl, C ３－６ cycloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl; １－４ Alkyl is selected from halo and C １－３ Optionally substituted with 1 to 3 substituents independently selected from alkoxy, or R ２ｂ and R ２ｃ together with the nitrogen to which they are attached form a 4- to 6-membered monocyclic heterocyclyl or a 6- to 10-membered bicyclic heterocyclyl, each of which contains 1 to 3 R ２ｄ and is optionally replaced by Each R ２ｅ However, independently, halo, cyano, NR ２ｂ R ２ｃ , OR ２ａ , phenyl, and 4- to 6-membered monocyclic heterocyclyl; Z is a bond, -CH ２ -, -O-, -O-C １－４ Alkylene-*, -C １－４ Alkylene-O-*, -C(O)-, -C(O)O-*, -OC(O)-*, -S(O) ２ -, -S(O) ２ N (Z ａ ) -*, -N(Z ａ ) S (O) ２ -*, -N(Z ａ ) -, -N(Z ａ ) -C １－４ Alkylene-*, -C １－４ Alkylene-N(Z ａ )-*,-C(O)N(Z ａ )-*, or -C(O)N(Z ａ ) -C １－３ alkylene-*, where * is R ３ indicates the point of attachment to Z ａ is H or C １－４ is alkyl, R ３ But, C ３－６ cycloalkyl, 7-10 membered bicyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl, ３－６ cycloalkyl, 7-10 membered bicyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl are each optionally and independently represented by 1 to 4 R ４ is replaced by Each R ４ But independently, C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, halo, OR ４ａ , cyano, -NR ４ｂ R ４ｃ , -C(O)R ４ａ , -C(O)OR ４ａ , -C(O)NR ４ｂ R ４ｃ , -NR ４ｂ C(O)R ４ａ , -NR ４ｂ C(O)OR ４ａ , -NR ４ｂ SO ２ R ４ａ , -SR ４ａ , -S(O)R ４ａ , -SO ２ R ４ａ , -SO ２ N.R. ４ｂ R ４ｃ , -P(O)R ４ｂ R ４ｃ , phenyl, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered monocyclic heterocyclyl, and 6- to 10-membered bicyclic heterocyclyl; １－４ Alkyl, C ２－４ Alkenyl, or C ２－４ Alkynyl is 1 to 4 R ４ｄ and said phenyl, 5-6 membered monocyclic heteroaryl, 4-6 membered monocyclic heterocyclyl, and 6-10 membered bicyclic heterocyclyl are each optionally substituted with 1-3 R ４ｅ and optionally further substituted with one or two oxo, or two R ４ together form oxo, R ４ａ H, 1 to 4 R ４ｄ C optionally substituted with １－４ Alkyl, -NR ４ｂ R ４ｃ , C ３－６ cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, ３－６ Cycloalkyl, 4-6 membered monocyclic heterocyclyl, phenyl, or 5-6 membered monocyclic heteroaryl are each optionally and independently represented by 1-3 R ４ｅ is replaced by R ４ｂ and R ４ｃ are each independently selected from H, phenyl, 4- to 6-membered monocyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 1 to 4 R ４ｄ C optionally substituted with １－４ alkyl, or R ４ｂ and R ４ｃ together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic heterocyclyl; Each R ４ｄ But independently, halo, OR ４ｆ , -C(O)C １－４ Alkyl, —C(O)NR ４ｂ R ４ｃ , -C(O)C １－４ Haloalkyl, —C(O)OR ４ｆ , -NR ４ｂ R ４ｃ , phenyl, and 5-6 membered monocyclic heteroaryl, each of said phenyl and 5-6 membered monocyclic heteroaryl being selected from 1-3 R ４ｇ and is optionally replaced by Each R ４ｅ But independently, Halo, C １－４ Alkyl, cyano, OR ４ｆ , -NR ４ｂ R ４ｃ , -C(O)H, -C(O)R ４ｈ , -SO ２ C １－３ Alkyl, and -C(O)NR ４ｂ R ４ｃ is selected from C １－４ Alkyl is halo, -SO ２ C １－３ Alkyl and -C(O)NR ４ｂ R ４ｃ or optionally substituted with 1 to 3 substituents independently selected from two R ４ｅ together form oxo, R ４ｆ But, H, C １－４ Alkyl, C １－４ haloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, wherein said phenyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 halo; Each R ４ｇ But independently, halo, OR ４ｆ , C １－４ Alkyl, C １－４ Haloalkyl, halo, cyano, -NR ４ｂ R ４ｃ , —C(O)H, and —C(O)OR ４ｆ is selected from Each R ４ｈ But independently, C １－４ Alkyl, C ３－６ Cycloalkyl, C １－３ Alkoxy or -N(R ４ｂ ) ２ or a pharma- ceutically acceptable salt thereof.

2. The compound represented by formula (I), 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, wherein: X is halo; Y is O or NR ｙ and R ｙ is H or C １－４ is alkyl, R １ But, C １－４ Alkyl or C ３－６ cycloalkyl, １－４ Alkyl or C ３－６ each cycloalkyl is optionally and independently substituted with 1 to 3 halo; Ring A is C ３－６ cycloalkyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl; m is 0 to 3; n is 0 or 1; Each R ２ But independently, C １－４ Alkyl, C ３－６ Cycloalkyl, halo, OR ２ａ , cyano, -NR ２ｂ R ２ｃ , -SO ２ R ２ａ , -C(O)R ２ｄ and -C(O)NR ２ｂ R ２ｃ and C is selected from １－４ Alkyl and C ３－６ Cycloalkyl is 1 to 4 R ２ｅ or two R ２ together form oxo, R ２ａ But, H, C １－４ Alkyl, C １－４ Haloalkyl or C １－４ Alkoxy C １－４ is alkyl, R ２ｄ But, H, C １－４ Alkyl, C ３－６ Cycloalkyl, OR ２ａ , phenyl, 4- to 6-membered monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, １－４ the alkyl is optionally substituted with 1 to 3 halo; R ２ｂ and R ２ｃ Each independently represents H, C １－４ Alkyl, C ３－６ cycloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl, or R ２ｂ and R ２ｃ together with the nitrogen to which they are attached form a 4- to 6-membered monocyclic heterocyclyl or a 6- to 10-membered bicyclic heterocyclyl, each of which contains 1 to 3 R ２ｄ and is optionally replaced by Each R ２ｅ However, independently, halo, cyano, NR ２ｂ R ２ｃ , OR ２ａ , phenyl, and 4- to 6-membered monocyclic heterocyclyl; Z is a bond, -CH ２ -, -O-, -O-C １－４ Alkylene-*, -C １－４ Alkylene-O-*, -C(O)-, -C(O)O-*, -OC(O)-*, -S(O) ２ -, -S(O) ２ N (Z ａ ) -*, -N(Z ａ ) S (O) ２ -*, -N(Z ａ ) -, -N(Z ａ ) -C １－４ Alkylene-*, -C １－４ Alkylene-N(Z ａ )-*,-C(O)N(Z ａ )-*, or -C(O)N(Z ａ ) -C １－３ alkylene-*, where * is R ３ indicates the point of attachment to Z ａ is H or C １－４ is alkyl, R ３ But, C ３－６ cycloalkyl, 7-10 membered bicyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl, ３－６ cycloalkyl, 7-10 membered bicyclic carbocyclyl, 4-6 membered monocyclic heterocyclyl, 6-10 membered bicyclic heterocyclyl, phenyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered bicyclic heteroaryl are each optionally and independently represented by 1 to 4 R ４ is replaced by Each R ４ But independently, C １－４ Alkyl, halo, OR ４ａ , cyano, -NR ４ｂ R ４ｃ , -C(O)R ４ａ , -C(O)OR ４ａ , -C(O)NR ４ｂ R ４ｃ , -NR ４ｂ C(O)R ４ａ , -NR ４ｂ C(O)OR ４ａ , -SR ４ａ , -SO ２ R ４ａ , -SO ２ N.R. ４ｂ R ４ｃ , -P(O)R ４ｂ R ４ｃ , phenyl, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered monocyclic heterocyclyl, and 6- to 10-membered bicyclic heterocyclyl; １－４ Alkyl is 1 to 4 R ４ｄ and said phenyl, 5-6 membered monocyclic heteroaryl, 4-6 membered monocyclic heterocyclyl, and 6-10 membered bicyclic heterocyclyl are each optionally substituted with 1-3 R ４ｅ or two R ４ together form oxo, R ４ａ is H, 1 to 4 R ４ｄ C optionally substituted with １－４ Alkyl, C ３－６ cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, ３－６ Cycloalkyl, 4-6 membered monocyclic heterocyclyl, phenyl, or 5-6 membered monocyclic heteroaryl are each optionally and independently represented by 1-3 R ４ｅ is replaced by R ４ｂ and R ４ｃ are each independently selected from H, phenyl, 4- to 6-membered monocyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, and 1 to 4 R ４ｄ C optionally substituted with １－４ alkyl, Each R ４ｄ But independently, halo, OR ４ｆ , -C(O)C １－４ Alkyl, —C(O)NR ４ｂ R ４ｃ , -C(O)C １－４ haloalkyl, phenyl, and 5- to 6-membered monocyclic heteroaryl, each of which is selected from 1 to 3 R ４ｇ and is optionally replaced by Each R ４ｅ is independently halo, C optionally substituted with 1 to 3 halo １－４ Alkyl, cyano, OR ４ｆ , -NR ４ｂ R ４ｃ , -C(O)H, -C(O)C １－４ Alkyl, -C １－４ Alkylene-C(O)NR ４ｂ R ４ｃ and -C(O)NR ４ｂ R ４ｃ or two R ４ｅ together form oxo, R ４ｆ But, H, C １－４ Alkyl, C １－４ haloalkyl, phenyl, or 5-6 membered monocyclic heteroaryl, wherein said phenyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 halo; Each R ４ｇ But independently, halo, OR ４ｆ , C １－４ Alkyl, halo, cyano, -NR ４ｂ R ４ｃ , —C(O)H, and —C(O)OR ４ｆ 2. The compound of claim 1, selected from:

3. 3. The compound of claim 1 or 2, wherein X is Cl, Br, or F, or a pharma- ceutically acceptable salt thereof.

4. 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof, wherein X is Cl or Br.

5. 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof, wherein X is Cl.

6. Ring A is phenyl, thiophenyl, pyrrolyl, pyrazoyl, furanyl, isothiazolyl, thiazoyl, imidazoyl, cyclobutyl, benzofuranyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, imidazo[1,2-a]pyridin-6-yl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2-oxo-2,3-dihydro-1H-imidazolyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, 5-oxo-5H-thiazolo[3,2-a]pyridinyl, thieno[3,2-b]pyridinyl, thieno[3,2-c]pyri phenyl, thieno[2,3-c]pyridinyl, benzothiophenyl, thieno[3,2-d]pyrimidinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-b]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, 1-oxo-1,2-dihydropyrrolo[1,2-a]pyra 6. The compound according to claim 1, wherein the aryl group is selected from the group consisting of 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl, or a pharma- ceutically acceptable salt thereof.

7. Ring A is phenyl, thiophenyl, pyrrolyl, pyrazoyl, furanyl, isothiazolyl, thiazoyl, imidazoyl, cyclobutyl, benzofuranyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, imidazo[1,2-a]pyridin-6-yl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2-oxo-2,3-dihydro-1H-imidazolyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, 5-oxo-5H-thiazolo[3,2-a]pyridinyl, thieno[3,2-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, 6. The compound according to any one of claims 1 to 5, selected from pyridinyl, benzothiophenyl, thieno[3,2-d]pyrimidinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-b]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, 1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazinyl, pyrrolo[2,1-f][1,2,4]triazinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl, or a pharma- ceutically acceptable salt thereof.

8. Ring A is of the following formula: 【Chemistry 3】 each of which is represented by 0 to 2 R ２ and 0 to 1 Z-R ３ 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, substituted with:

9. Ring A is of the following formula: 【Chemistry 4】 each of which is represented by 0 to 2 R ２ and 0 to 1 Z-R ３ 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, substituted with:

10. Ring A is of the following formula: 【Chemistry 5-1】 【Chemistry 5-2】 9. The compound of claim 8, represented by: or a pharma- ceutically acceptable salt thereof.

11. Ring A is of the following formula: 【Chemistry 6-1】 【Chemistry 6-2】 10. The compound of claim 9, represented by: or a pharma- ceutically acceptable salt thereof.

12. 8. The compound according to claim 6 or 7, or a pharma- ceutically acceptable salt thereof, wherein Ring A is selected from phenyl, thiophenyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, and imidazolyl.

13. Ring A is of the following formula: 【Chemistry 7】 each of which is represented by 0 to 1 R ２ and one R ３ 10. The compound of claim 8 or 9, or a pharma- ceutically acceptable salt thereof, substituted with:

14. Ring A is of the following formula: 【Chemistry 8】 14. The compound of claim 13, represented by: or a pharma- ceutically acceptable salt thereof.

15. R ２ But, -OCH ３ , cyclopropyl, -CH ３ , -CF ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH(OH)CH ３ , -C(CH ３ ) ２ OH, -CH ２ OCH ３ , -CH ２ OH, -CH ２ CF ３ , -CH ２ CH ２ OH, -CH ２ CH ２ CH ２ OH, -CH ２ CN, -CH ２ CHF ２ , -CH ２ N.H. ２ , -N(CH ３ ) ２ , -SO ２ CH ３ , cyano, halo, -C(O)OH, -C(O)N(CH ３ ) ２ and -C(O)NHCH ３ or the following structural formula: 【Chemistry 9】 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, selected from:

16. R ２ But -CH ３ , -CF ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH(OH)CH ３ , -CH ２ OCH ３ , -CH ２ OH, -CH ２ CF ３ , -CH ２ CH ２ OH, -CH ２ CH ２ CH ２ OH, -CH ２ CN, -CH ２ CHF ２ , -CH ２ N.H. ２ , -N(CH ３ ) ２ , cyano, halo, -C(O)OH, -C(O)N(CH ３ ) ２ and -C(O)NHCH ３ or the following structural formula: 【Chemistry 10】 15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, selected from:

17. 17. The compound according to any one of claims 1 to 9, 12, 13, 15, and 16, or a pharma- ceutically acceptable salt thereof, wherein n is 1.

18. 18. The compound of any one of claims 1 to 9, 12, 13, 15, 16, and 17, or a pharma- ceutically acceptable salt thereof, wherein n is 1 and Z is a bond.

19. n is 1 and Z is -CH ２ -, -CH(CH ３ )-, -O-, -N(H)-, -N(C １－４ alkyl)-, or -C(O)NH-*, where * is R ３ 18. A compound according to any one of claims 1 to 9, 12, 13, 15, 16 and 17, or a pharma- ceutically acceptable salt thereof, showing a point of attachment to:

20. R ３ cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrazinyl, thiophenyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octanyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-1 H-pyrazoly, benzamidazolyl, indazolyl, indoyl, imidazolidinyl, azetidinyl, 2,3-dihydrobenzofuranyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1H-indenyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, spiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, and 2-oxaspiro[3.3]heptanyl, each of which is selected from 1 to 3 R ４ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

21. R ３ cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrazinyl, thiophenyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octanyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-diphenyl ... thiophenyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octanyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-diphenyl, phenyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, thiophenyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octanyl, thiazoly and selected from hydro-1H-pyrazolyl, benzamidazolyl, indazolyl, indoyl, 2,3-dihydrobenzofuranyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1H-indenyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, spiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, and 2-oxaspiro[3.3]heptanyl, each of which is selected from 1 to 3 R ４ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

22. Z is -CH ２ - and R ３ is selected from thiophenyl, pyrrolyl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is selected from 1 to 2 R ４ 20. The compound of claim 19, optionally substituted with:

23. R ３ has the following structural formula: 【Chemistry 11】 each of which is represented by 1 to 3 R ４ 23. The compound of any one of claims 1 to 22, optionally substituted with:

24. R ３ has the following structural formula: 【Chemistry 12】 each of which is represented by 1 to 3 R ４ 23. The compound of any one of claims 1 to 22, optionally substituted with:

25. R ３ has the following structural formula: 【Chemistry 13-1】 【Chemistry 13-2】 24. The compound of claim 23, represented by: or a pharma- ceutically acceptable salt thereof.

26. R ３ has the following structural formula: 【Chemistry 14-1】 【Chemistry 14-2】 25. The compound of claim 24, represented by: or a pharma- ceutically acceptable salt thereof.

27. R ３ is phenyl or 5-6 membered monocyclic heteroaryl, each of which is represented by 1-2 R ４ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

28. R ３ is selected from phenyl, pyrazolyl, pyridyl, and pyrimidyl, each of which is selected from 1 to 2 R ４ 28. The compound of claim 27, optionally substituted with:

29. R ３ has the following structural formula: 【Chemistry 15】 each of which is represented by 1 to 2 R ４ 30. The compound of claim 28, optionally substituted with:

30. R ３ has the following structural formula: 【Chemistry 16】 30. The compound of claim 28, represented by: or a pharma- ceutically acceptable salt thereof.

31. R ３ has the following structural formula: 【Chemistry 17】 30. The compound of claim 28, represented by: or a pharma- ceutically acceptable salt thereof.

32. R ４ But, C １－３ Alkyl, C ２－４ Alkenyl, C ２－４ Alkynyl, -OR ４ａ , -CN, -NH ２ , -NR ４ｂ R ４ｃ , halo, -C(O)R ４ａ , -NHC(O)R ４ａ , -NHC(O)OR ４ａ , -NR ４ｂ SO ２ R ４ａ , -SR ４ａ , -S(O)R ４ａ , -SO ２ R ４ａ , -SO ２ N.R. ４ｂ R ４ｃ , -P(O)R ４ｂ R ４ｃ , -C(O)O-C １－４ is selected from alkyl, benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl, 6- to 10-membered bicyclic heterocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ４ The C represented by １－３ Alkyl, C ２－４ Alkenyl, or C ２－４ Alkynyl is selected from the group consisting of halo, phenyl, and one or two R ４ｇ and one or two R ４ｇ 4-6 membered monocyclic heterocyclyl optionally substituted with -C(O)NR ４ｂ R ４ｃ , -C(O)R ４ａ , and OR ４ｆ and optionally substituted with 1 to 3 substituents independently selected from ４ The benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl, 6- to 10-membered bicyclic heterocyclyl, and 4- to 6-membered monocyclic heterocyclyl represented by the formula (I) each contain 1 to 3 R ４ｅ and optionally substituted with one or two oxo, or two R ４ together form oxo, R ４ａ is H, 1 to 4 R ４ｄ C optionally substituted with １－４ Alkyl, -NR ４ｂ R ４ｃ , C ３－６ cycloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl, wherein the phenyl, 4- to 6-membered monocyclic heterocyclyl, and 5- to 6-membered monocyclic heteroaryl are each independently selected from 1 to 3 R ４ｅ and is optionally replaced by Each R ４ｂ are independently H or C １－４ is alkyl, R ４ｃ is H, 1 to 4 R ４ｄ C optionally substituted with １－４ alkyl, 4- to 6-membered monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl; Each R ４ｄ are independently halo, -OR ４ｆ , C ３－６ Cycloalkyl, —C(O)OH, —NR ４ｂ R ４ｃ , phenyl, and 5-6 membered monocyclic heteroaryl, wherein said phenyl and 5-6 membered monocyclic heteroaryl are each selected from C １－３ Alkyl, C １－３ optionally substituted with 1 to 3 substituents independently selected from haloalkyl, halo, CN, and OH; Each R ４ｅ are independently halo, —OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, -C(O)R ４ｈ , -SO ２ C １－３ Alkyl, -C １－３ AlkylSO ２ C １－３ Alkyl, -C(O)N(C １－３ Alkyl) ２ or two R ４ｅ together form oxo, R ４ｆ But, H, C １－４ alkyl, phenyl, or 5-6 membered monocyclic heteroaryl, wherein phenyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 halo; Each R ４ｇ But independently, C １－３ alkyl or halo; Each R ４ｈ But independently, C １－４ Alkyl, C ３－６ Cycloalkyl, C １－３ Alkoxy, or -N(R ４ｂ ) ２ 32. The compound according to any one of claims 1 to 31, wherein:

33. R ４ But, C １－３ Alkyl, -OR ４ａ , -CN, -NH ２ , -NHR ４ｃ , halo, -C(O)R ４ａ , -NHC(O)R ４ａ , -NHC(O)OR ４ａ , -SR ４ａ , -SO ２ R ４ａ , -SO ２ N.R. ４ｂ R ４ｃ , -P(O)R ４ｂ R ４ｃ , -C(O)O-C １－４ alkyl, benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl, and 4- to 6-membered monocyclic heterocyclyl; R ４ The C represented by １－３ Alkyl is halo, phenyl, 5-6 membered monocyclic heteroaryl, -C(O)NR ４ｂ R ４ｃ , and OR ４ｆ and optionally substituted with 1 to 3 substituents independently selected from ４ The benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl, and 4- to 6-membered monocyclic heterocyclyl represented by the formula (I) each comprises 1 to 3 R ４ｅ or two R ４ together form oxo, R ４ａ is H, 1 to 4 R ４ｄ C optionally substituted with １－４ Alkyl, -NR ４ｂ R ４ｃ phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein the phenyl and the 5- to 6-membered monocyclic heteroaryl are each independently selected from 1 to 3 R ４ｅ and is optionally replaced by R ４ｂ is H or C １－４ is alkyl, R ４ｃ H, 1 to 4 R ４ｄ C optionally substituted with １－４ alkyl, 4- to 6-membered monocyclic heterocyclyl, or 5- to 6-membered monocyclic heteroaryl; Each R ４ｄ But independently, C １－３ selected from alkyl, halo, phenyl, and 5-6 membered monocyclic heteroaryl, each of said phenyl and 5-6 membered monocyclic heteroaryl being optionally substituted with 1-3 substituents independently selected from halo, CN, and OH; Each R ４ｅ But independently, Halo, C １－４ Alkyl, -C(O)C １－３ Alkyl, -C(O)N(C １－３ Alkyl) ２ or two R ４ｅ together form oxo, R ４ｆ But, H, C １－４ 32. The compound of any one of claims 1 to 31, wherein: alkyl, phenyl, or 5-6 membered monocyclic heteroaryl, wherein phenyl and 5-6 membered monocyclic heteroaryl are each optionally substituted with 1-3 halo; or a pharma- ceutically acceptable salt thereof.

34. R ４ has the following structural formula: 【Chemistry 18】 each of which is represented by 1 to 3 R ４ｅ 32. The compound of any one of claims 1 to 31, optionally substituted with and further optionally substituted with one or two oxo, or a pharma- ceutically acceptable salt thereof.

35. R ４ has the following structural formula: 【Chemistry 19】 each of which is represented by 1 to 3 R ４ｅ 32. The compound of any one of claims 1 to 31, optionally substituted with:

36. R ４ has the following structural formula: 【Chemistry 20】 35. The compound of claim 34, represented by: or a pharma- ceutically acceptable salt thereof.

37. R ４ has the following structural formula: 【Chemistry 21】 36. The compound of claim 35, represented by: or a pharma- ceutically acceptable salt thereof.

38. Each R ４ｅ are independently -F, -CH ３ , -CF ３ , -CH ２ CHF ２ , -CH ２ CF ３ , -CH ２ SO ２ CH ３ , -OH, -OCH ３ , -SO ２ CH ３ , -C(O)CH ３ , —C(O)cyclopropyl, —C(O)cyclobutyl, —C(O)cyclopentyl, —C(O)CH(CH ３ ) ２ , -C(O)C(CH ３ ) ３ -C(O)N(CH ３ ) ２ , -C(O)OCH ３ or cyano, or a pharma- ceutically acceptable salt thereof.

39. R ４ｅ But -CH ３ , -C(O)CH ３ , -C(O)CH(CH ３ ) ２ -C(O)N(CH ３ ) ２ or cyano, or a pharma- ceutically acceptable salt thereof.

40. R ４ But, -OR ４ａ and R ４ａ But 1 to 3 R ４ｄ C optionally substituted with １－３ Alkyl, or 1 to 3 R ４ｅ is a 4-6 membered monocyclic heterocyclyl optionally substituted with Each R ４ｄ But independently, Halo, C １－２ alkyl, phenyl, or 5-6 membered monocyclic heteroaryl, provided that 2 or 3 R ４ｄ When R is present, ４ｄ is phenyl or 5-6 membered monocyclic heteroaryl, and the other R ４ｄ each independently represents halo or C １－２ alkyl, R ４ｄ The phenyl and 5-6 membered monocyclic heteroaryl represented by １－３ Alkyl, C １－３ optionally substituted with 1 to 3 substituents independently selected from haloalkyl, and halo; Each R ４ｅ But independently, C １－４ Alkyl, C １－４ Haloalkyl, -SO ２ C １－３ Alkyl, or -C(O)C ３－６ 34. The compound of any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

41. R ４ But, -OR ４ａ and R ４ａ But 1 to 3 R ４ｄ C substituted with １－３ is alkyl, Each R ４ｄ But independently, Halo, C １－２ alkyl, phenyl, or 5-6 membered monocyclic heteroaryl, provided that 2 or 3 R ４ｄ When R is present, ４ｄ is phenyl or 5-6 membered monocyclic heteroaryl, and the other R ４ｄ each independently represents halo or C １－２ alkyl, R ４ｄ or a pharma- ceutically acceptable salt thereof.

34. The compound of any one of claims 1 to 33, wherein said phenyl and 5-6 membered monocyclic heteroaryl represented by the following formula:

42. R ４ が、-CH ３ ,H ２ OH、-HF ２ 、-CF ３ 、-EH(CF ３ )OH、-H ２ OCH ３ 、-CH ２ CN、-H ２ CF ３ 、-CH ２ CH ２ OH、-H ２ C(O)N(CH ３ ) ２ 、-C≡CC(CH ３ ) ２ O, -O, -O ３ 、-OCH ２ CH ３ 、-OCH ２ CH ２ OCH ３ ,-OCH(CH ３ ) ２ 、-OCF ３ 、-OCHF ２ 、-OCH ２ CF ３ 、-O-シクロロッピル、-O-シクロブテル、-OC(CH ３ ) ３ ,-OC(EH ３ ) ２ CH ２ OH、-OCH(CH ３ )C(O)OH、-OC(CH ３ ) ２ C(O)OH、-OH(OH ３ )CH ２ OH、-OCH ２ CH ２ N(CH) ３ ) ２ ,-CN,-NH ２ 、-NHCH ３ 、ハロ、-C(O)H、-C(O)CH(CH ３ ) ２ 、-C(O)OCH ３ 、-C(O)O---ブテル、-N(CH ３ )So ２ CH ３ 、-NHC(O)CH ３ , -NHC(O)cyclopropyl, -NHC(O)OC(CH ３ ) ３ , -C(O)CH ３ , -C(O)OH, -C(O)NH ２ , -C(O)NHCH ３ , -C(O)N(CH ３ ) ２ , -C(O)NC(CH ３ ) ３ , -SCH ３ , -S(O)CH ３ , -SO ２ CH ３ , -SO ２ N (CH ３ ) ２ , -P(O)(CH ３ ) ２ , phenyl, or R ４ has the following structural formula: 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】 The compound according to any one of claims 1 to 33, represented by:

43. R ４ But -CH ３ , C.H. ２ OH, -CHF ２ , -CF ３ , -CH(CF ３ )OH, -CH ２ OCH ３ , -CH ２ CN, -CH ２ CF ３ , -CH ２ CH ２ OH, -CH ２ C(O)N(CH ３ ) ２ , -OH, -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OCF ３ , -CN, -NH ２ , halo, -C(O)H, -C(O)CH(CH ３ ) ２ , -C(O)OCH ３ , —C(O)O-t-butyl, —NHC(O)CH ３ , -NHC(O)cyclopropyl, -NHC(O)OC(CH ３ ) ３ , -C(O)CH ３ , -C(O)OH, -C(O)NH ２ , -C(O)NHCH ３ , -C(O)N(CH ３ ) ２ , -C(O)NC(CH ３ ) ３ , -SCH ３ , -SO ２ CH ３ , -SO ２ N (CH ３ ) ２ , -P(O)(CH ３ ) ２ , phenyl, or R ４ has the following structural formula: 【Chemistry 23】 The compound according to any one of claims 1 to 33, represented by:

44. The compound has the formula (IIA), (IIB), or (IIC): 【Chemistry 24】 or a pharma- ceutically acceptable salt thereof, wherein m is 0 or 1.

45. The compound has the formula (IIIA) or (IIIB): 【Chemistry 25】 44. The compound according to any one of claims 1 to 5, 15, 16, 20, 21, and 23 to 43, represented by:

46. The compound has the formula (IVA), (IVB), (IVC), or (IVD), 【Chemistry 26】 or a pharma- ceutically acceptable salt thereof, wherein m is 0 or 1.

47. R １ But -CH ３ or -CH ２ CH ３ 47. The compound according to any one of claims 1 to 46, wherein:

48. R １ But -CH ３ 48. The compound according to any one of claims 1 to 47, wherein:

49. The compound has the formula (V): 【Chemistry 27】 or a pharma- ceutically acceptable salt thereof, wherein: X is Cl or Br; R １ But -CH ３ or -CH ２ CH ３ and Ring A is selected from phenyl, thiophenyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, and imidazolyl; m is 0 or 1; Each R ２ But independently, C １－３ Alkyl and -C(O)R ２ｄ and C is selected from １－３ Alkyl is R ２ｇ and is optionally replaced by R ２ｄ is 4-6 membered monocyclic heterocyclyl; R ２ｇ is cyano or OH; R ３ is phenyl or 5-6 membered monocyclic heteroaryl, each of which optionally and independently comprises one or two R ４ is replaced by Each R ４ But independently, Halo, C １－４ Alkyl, —O-benzyl, —O—C １－３ Alkyl, cyano, -NH ２ and 4-6 membered monocyclic heterocyclyl, wherein the benzyl is selected from 1-3 halo or C １－３ The compound of claim 1 optionally substituted with haloalkyl.

50. The compound has the formula (V): 【Chemistry 28】 or a pharma- ceutically acceptable salt thereof, wherein: X is Cl or Br; R １ But -CH ３ or -CH ２ CH ３ and Ring A is selected from phenyl, thiophenyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, and imidazolyl; m is 0 or 1; Each R ２ But independently, C １－３ Alkyl and -C(O)R ２ｄ and C is selected from １－３ Alkyl is R ２ｇ and is optionally replaced by R ２ｄ is 4-6 membered monocyclic heterocyclyl; R ２ｇ is cyano or OH; R ３ is phenyl or 5-6 membered monocyclic heteroaryl, each of which optionally and independently comprises one or two R ４ is replaced by Each R ４ But independently, C １－４ Alkyl, -O-benzyl, cyano, -NH ２ and 4-6 membered monocyclic heterocyclyl, wherein said benzyl is optionally substituted with halo.

51. Ring A is of the following formula: 【Chemical 29】 51. The compound of claim 49 or 50, represented by: or a pharma- ceutically acceptable salt thereof.

52. The compound has the formula (IIB), (IIIA), (IVA), or (IVB): 【Chemistry 30】 or a pharma- ceutically acceptable salt thereof, wherein m is 0 or 1.

53. R ３ is selected from phenyl, pyrazolyl, pyridyl, and pyrimidyl, each of which is selected from 1 to 2 R ４ 53. The compound of any one of claims 49 to 52, optionally substituted with:

54. R ３ has the following structural formula: 【Chemistry 31】 each of which is represented by 1 to 2 R ４ 53. The compound of any one of claims 49 to 52, optionally substituted with:

55. R ３ has the following structural formula: 【Chemistry 32】 53. The compound according to any one of claims 49 to 52, represented by: or a pharma- ceutically acceptable salt thereof.

56. R ４ is -F, -OCH(CH ３ ) ２ , -OC(CH ３ ) ３ , -CH ３ , cyano, -NH ２ or R ４ has the following structural formula: 【Chemical 33】 The compound according to any one of claims 49 to 55, represented by:

57. R ４ But -CH ３ , cyano, -NH ２ or R ４ has the following structural formula: 【Chemical 34】 The compound according to any one of claims 49 to 55, represented by:

58. R ２ But -CH ３ , -CH ２ CN, -CH ２ OH or R ２ is expressed by the following formula: 【Chemistry 35】 58. The compound according to any one of claims 49 to 57, represented by: or a pharma- ceutically acceptable salt thereof.

59. The compound has formula (IIB) or (IVB): 【Chemical 36】 or a pharma- ceutically acceptable salt thereof, wherein: m is 1, R １ But -CH ３ and X is Cl; R ２ But -CH ３ and R ３ is pyrimidinyl or pyridinyl, each of which is selected from the group consisting of one or two R ４ and is optionally replaced by R ４ But, Halo, -OC １－３ alkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the 4- to 6-membered monocyclic heterocyclyl is selected from the group consisting of 1 or 2 halo or C １－３ 50. The compound of claim 49, optionally substituted with haloalkyl.

60. R ３ has the following structural formula: 【Chemical 37】 60. The compound of claim 59, represented by: or a pharma- ceutically acceptable salt thereof.

61. Each R ４ are independently -F, -OCH(CH ３ ) ２ , or -OC(CH ３ ) ３ or R ４ has the following structural formula: 【Chemical 38】 61. The compound of claim 59 or 60, represented by: or a pharma- ceutically acceptable salt thereof.

62. The compound of claim 1, wherein the compound is selected from any one of Examples 1-736, or a pharma- ceutically acceptable salt thereof.

63. 63. A pharmaceutical composition comprising a compound according to any one of claims 1 to 62, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

64. 64. A method of treating a DHX9-mediated disease or disorder in a subject, comprising administering to the subject a compound according to any one of claims 1 to 62, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 63.

65. 65. The method of claim 64, wherein the disease or disorder is cancer, a viral infection, or an autoimmune disease.

66. 66. The method of claim 65, wherein the disease or disorder is cancer.

67. 67. The method of claim 66, wherein the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft tissue cancer, kidney cancer, and liver cancer.

68. 68. The method of claim 67, wherein the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer, and gastric cancer.

69. 69. The method of any one of claims 66 to 68, wherein the cancer is a microsatellite instability (MSI) cancer.

70. 69. The method of any one of claims 66 to 68, wherein the cancer has a mutation or deficiency in DNA mismatch repair (MMR) and / or a mutation or deficiency in RNA splicing and the kinetochore complex.

71. 70. The method of claim 69, wherein the cancer is microsatellite instability-high (MSI-H) colorectal cancer.

72. 67. The method of claim 66, wherein the cancer is Ewing's sarcoma.

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