Inhibitors of RNA helicase DHX9 and uses thereof

Abstract

The present disclosure provides a compound of Formula (I): # imgabs0 #, or a pharmaceutically acceptable salt thereof, which can be used to inhibit DHX9 and treat a variety of DHX9-mediated conditions or diseases, such as cancer.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 309,917, filed on February 14, 2022. The entire contents of the foregoing application are expressly incorporated herein by reference. Technical Field

[0003] The present disclosure relates to inhibitors of RNA helicase DHX9 and pharmaceutically acceptable salts thereof, compositions of these compounds, methods for preparing the same and uses thereof in treating diseases. Background Art

[0004] 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 the cytoplasm and can use all four NTPs to power the directional movement cycle from 3' to 5'. Functionally, DHX9 can bind to and unfold or unravel dsDNA / RNA, ssDNA / RNA, DNA: RNA hybrids (such as R-loops), circular RNAs, and DNA / RNA G quadruplexes. Therefore, DHX9 has a regulatory role in various RNA and DNA-related cellular processes, such as transcription, translation, RNA splicing, editing, RNA transport and processing, microRNA generation, and the maintenance of genomic stability (Pan et al., 2021, Current Protein & Peptide Science (22), 29-40).

[0005] Due to its regulatory role in processes such as transcription and maintenance of genomic stability, DHX9 has been shown to be a key regulator in multiple cancer types (Gulliver et al., 2020, Future Science OA (2), FSO650). DHX9 has been shown to be involved in the regulation of genes associated with sustained proliferation signaling, escape from growth inhibitors, avoidance of apoptosis, angiogenesis, and metastasis, all hallmarks of cancer. Specifically, microsatellite instability cancers, such as microsatellite instability (MSI) colorectal cancer, and tumors with defective mismatch repair (MMR) express a strong dependence on DHX9.

[0006] 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.

[0007] Therefore, there is a need for DHX9 inhibitors as potential therapeutic agents for treating diseases or disorders responsive to DHX9 inhibition. Summary of the invention

[0008] The present disclosure provides compounds that are DHX9 inhibitors. In a first aspect, the present disclosure relates to compounds having Formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein:

[0011] X is a halogen group;

[0012] Y is O or NR y ;

[0013] R y H or C 1-4 alkyl;

[0014] R 1 C 1-4 Alkyl or C 3-6 Cycloalkyl; wherein the C 1-4 Alkyl or C 3-6 The cycloalkyl groups are each optionally and independently substituted with 1 to 3 halo groups or -OH,

[0015] Ring A is C 3-6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl; phenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl;

[0016] m is 0 to 3;

[0017] n is 0 or 2;

[0018] Each R 2 Independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen, OR 2a , cyano, -NR 2b R 2c 、-SO 2 R 2a 、-C(O)R 2d and -C(O)NR 2b R 2c , wherein the C 1-4 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with 1 to 4 R 2e Replacement; or 2 R 2 Together they form oxygen;

[0019] R 2a H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy C 1-4 alkyl;

[0020] R 2d H, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 2a , phenyl, 4 to 6-membered monocyclic heterocyclic group, 6 to 8-membered bicyclic heterocyclic group or 5 to 6-membered monocyclic heteroaryl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 halo groups and the 5 to 6 membered monocyclic heteroaryl group is optionally substituted with 1 to 3 C 1-4 Alkyl, C 1-4 Haloalkyl or phenyl substitution;

[0021] R 2b and R 2c Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclic group and 5- to 6-membered monocyclic heteroaryl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 groups independently selected from halo and C 1-3 The alkoxy substituent is substituted; or R 2b and R 2c Together with the nitrogen to which it is attached, it forms a 4- to 6-membered monocyclic heterocyclic group or a 6- to 10-membered bicyclic heterocyclic group; wherein each of the 4- to 6-membered monocyclic heterocyclic group or the 6- to 10-membered bicyclic heterocyclic group is optionally substituted by 1 to 3 R 2d replace;

[0022] Each R 2e are independently selected from halo, cyano, NR 2b R 2c , OR 2a , phenyl and 4- to 6-membered monocyclic heterocyclic groups;

[0023] Z is a bond, -CH 2 -、-O-、-OC 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 )-*, -N(Za)C(O)-* or -C(O)N(Z a)-C 1-3 Alkylene-*, where * indicates the 3 The connection point;

[0024] Z a H or C 1-4 alkyl;

[0025] R 3 C 3-6 cycloalkyl, 7- to 10-membered bicyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl, wherein the C 3-6 cycloalkyl, 7 to 10 membered bicyclic carbocyclyl, 4 to 6 membered monocyclic heterocyclyl, 6 to 10 membered bicyclic heterocyclyl, phenyl, 5 to 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl, each optionally and independently substituted with 1 to 4 R 4 replace;

[0026] Each R 4 Independently selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, Halogen, 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 NR 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, wherein the C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 The alkynyl group is optionally substituted with 1 to 4 R 4d substituted, and wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl and 6 to 10-membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R 4eand further optionally substituted with 1 or 2 oxo groups; or two R 4 Together they form oxygen;

[0027] R 4a is H, optionally 1 to 4 R 4d Substituted C 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; wherein the C 3-6 Cycloalkyl, 4 to 6 membered monocyclic heterocyclyl, phenyl or 5 to 6 membered monocyclic heteroaryl each optionally and independently substituted with 1 to 3 R 4e replace;

[0028] R 4b and R 4c Each is independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclic group, 5 to 6-membered monocyclic heteroaryl and optionally 1 to 4 R 4d Substituted C 1-4 Alkyl; or R 4b and R 4c Together with the nitrogen atom to which it is attached, it forms a 4- to 6-membered monocyclic heterocyclic group;

[0029] Each R 4d are independently selected from 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, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 R 4g replace;

[0030] Each R 4e independently selected from halogen, 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 , where C 1-4 The alkyl group is optionally substituted with 1 to 3 groups independently selected from halo, -SO 2 C 1-3 Alkyl and -C(O)NR4b R 4c Substituents substituted; and -C(O)NR 4b R 4c ; or two R 4e Together they form oxygen;

[0031] R 4f H, C 1-4 Alkyl, C 1-4 haloalkyl, phenyl or 5- to 6-membered monocyclic heteroaryl, wherein the phenyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with one to three halo groups;

[0032] Each R 4g are independently selected from halo, OR 4f , C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, cyano, -NR 4b R 4c , -C(O)H and -C(O)OR 4f ;and

[0033] Each R 4h Independently for C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkoxy or -N(R 4b ) 2 .

[0034] 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.

[0035] In another aspect, the present disclosure provides a method of treating a disease or condition 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 used to treat cancer.

[0036] Another aspect of the present disclosure relates to the use of at least one compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease or condition responsive to inhibition of DHX9. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof for use in treating a disease or condition responsive to inhibition of DHX9. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1a and Figure 1b Shown are tumor volumes over time for in vivo efficacy studies of the compound of Example 31 in LS411N xenografts.

[0038] Figure 1cShown are the percent changes in tumor volume over time for the in vivo efficacy study of the compound of Example 31 in LS411N xenografts.

[0039] Figure 2 Shown are the percent body weight changes over time for the in vivo efficacy study of the compound of Example 31 in LS411N xenografts.

[0040] Figure 3a Tumor volumes over time during and after the dosing period are shown for the in vivo efficacy study of the compound of Example 31 in LS411N xenografts.

[0041] Figure 3b Shown are the percent change in tumor volume over time during and after the 28-day dosing period for the in vivo efficacy study of the compound of Example 31 in LS411N xenografts.

[0042] Figure 4 The anti-proliferative activity of 290 DHX9 inhibitor compounds described herein is shown in CRC-MSI (LS411N) cells versus CRC-MSS (NCI-H747) cells.

[0043] Figure 5a A 10-day proliferation screen of the compound of Example 18 in a panel of various cancer cell lines is shown.

[0044] Figure 5b The compound of Example 18 was shown to inhibit the proliferation of EC in MSI cell lines relative to MSS cell lines, as represented by colorectal cancer, endometrial cancer, and hematopoietic cancer. 50 . DETAILED DESCRIPTION

[0045] The present disclosure provides compounds and pharmaceutical compositions thereof that can be used to treat diseases or disorders by mediating DHX9 function / activity.In some embodiments, the compounds of the present disclosure are DHX9 inhibitors.

[0046] Compounds and compositions

[0047] In a first embodiment, the present disclosure provides a compound of formula (I):

[0048]

[0049] or a pharmaceutically acceptable salt thereof, wherein the variables in formula (I) are as defined below:

[0050] X is a halogen group;

[0051] Y is O or NR y ;

[0052] Ry H or C 1-4 alkyl;

[0053] R 1 C 1-4 Alkyl or C 3-6 Cycloalkyl; wherein the C 1-4 Alkyl or C 3-6 Each cycloalkyl is optionally and independently substituted with 1 to 3 halo groups;

[0054] Ring A is C 3-6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl; phenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl;

[0055] m is 0 to 3;

[0056] n is 0 or 1;

[0057] Each R 2 Independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen, OR 2a , cyano, -NR 2b R 2c 、-SO 2 R 2a 、-C(O)R 2d and -C(O)NR 2b R 2c , wherein the C 1-4 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with 1 to 4 R 2e Replacement; or 2 R 2 Together they form oxygen;

[0058] R 2a H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy C 1-4 alkyl;

[0059] R 2d H, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 2a , phenyl, 4 to 6-membered monocyclic heterocyclic group or 5 to 6-membered monocyclic heteroaryl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 halo groups;

[0060] R 2b and R 2c Each independently selected from H, C 1-4 Alkyl, C 3-6cycloalkyl, 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 it is attached, it forms a 4- to 6-membered monocyclic heterocyclic group or a 6- to 10-membered bicyclic heterocyclic group; wherein each of the 4- to 6-membered monocyclic heterocyclic group or the 6- to 10-membered bicyclic heterocyclic group is optionally substituted by 1 to 3 R 2d replace;

[0061] Each R 2e are independently selected from halo, cyano, NR 2b R 2c , OR 2a , phenyl and 4- to 6-membered monocyclic heterocyclic groups;

[0062] Z is a bond, -CH 2 -、-O-、-OC 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 * indicates the 3 The connection point;

[0063] Z a H or C 1-4 alkyl;

[0064] R 3 C 3-6 cycloalkyl, 7- to 10-membered bicyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl, wherein the C 3-6 cycloalkyl, 7 to 10 membered bicyclic carbocyclyl, 4 to 6 membered monocyclic heterocyclyl, 6 to 10 membered bicyclic heterocyclyl, phenyl, 5 to 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl, each optionally and independently substituted with 1 to 4 R 4 replace;

[0065] Each R 4 Independently selected from C1-4 Alkyl, halogen, 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 NR 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, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 4 R 4d substituted, and wherein the phenyl, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered monocyclic heterocyclyl and 6- to 10-membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R 4e Replace; or two R 4 Together they form oxygen;

[0066] R 4a is H, optionally 1 to 4 R 4d Substituted C 1-4 Alkyl, C 3-6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, phenyl or 5- to 6-membered monocyclic heteroaryl; wherein the C 3-6 Cycloalkyl, 4 to 6 membered monocyclic heterocyclyl, phenyl or 5 to 6 membered monocyclic heteroaryl each optionally and independently substituted with 1 to 3 R 4e replace;

[0067] R 4b and R 4c Each is independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclic group, 5 to 6-membered monocyclic heteroaryl and optionally 1 to 4 R 4d Substituted C 1-4 alkyl;

[0068] Each R 4d are independently selected from halo, OR 4f 、-C(O)C 1-4 Alkyl, -C(O)NR 4b R 4c 、-C(O)C 1-4haloalkyl, phenyl and 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 R 4g replace;

[0069] Each R 4e independently selected from 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 they form oxygen;

[0070] R 4f H, C 1-4 Alkyl, C 1-4 haloalkyl, phenyl or 5- to 6-membered monocyclic heteroaryl, wherein the phenyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with one to three halo groups;

[0071] Each R 4g are independently selected from halo, OR 4f , C 1-4 Alkyl, halide, cyano, -NR 4b R 4c , -C(O)H and -C(O)OR 4f In some embodiments, Y is O.

[0072] In a second embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, X is Cl, Br or F; and the remaining variables are as described in the first aspect or the first embodiment.

[0073] In a third embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, X is Cl or Br; and the remaining variables are as described in the first aspect or the first embodiment.

[0074] In a fourth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, X is Cl; and the remaining variables are as described in the first aspect or the first embodiment.

[0075] In a fifth embodiment, for the compound of formula (I) described in the first aspect or the first embodiment, or a pharmaceutically acceptable salt thereof, ring A is selected from phenyl, thienyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, thiazolyl, imidazolyl, 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]pyrazine, 5,6-dihydro-4H-cyclopenta[b]thienyl, 5-oxo-5H-thiazolo[3,2-a]pyridinyl, thieno[3,2-b] pyridyl, thieno[3,2-c]pyridyl, thieno[2,3-c]pyridyl, benzothienyl, 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-dihydro pyrrolo[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]thienyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl; and the remaining variables are as described in the first aspect or the first, second, third or fourth embodiment.In an alternative fifth embodiment, Ring A is phenyl, thienyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, thiazolyl, imidazolyl, 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, benzothienyl, 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]thienyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl; and the remaining variables are as described in the first aspect or the first, second, third or fourth embodiment.

[0076] In a sixth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, ring A is represented by the following formula:

[0077] Each of them is treated with 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

[0078] Each of them is treated with 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.

[0079] In a seventh embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, ring A is represented by the following formula:

[0080]

[0081] 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

[0082]

[0083] And the remaining variables are as described in the first aspect or the first, second, third or fourth embodiment.

[0084] In an eighth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, ring A is phenyl, thienyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl and imidazolyl; and the remaining variables are as described in the first aspect or the first, second, third or fourth embodiment.

[0085] In the ninth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, ring A Each of them is 0 to 1 R 2 and 1 R 3 and the remaining variables are as described in the first, second, third or fourth embodiment.

[0086] In the tenth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, Ring A is And the remaining variables are as described in the first aspect or the first, second, third or fourth embodiment.

[0087] In an eleventh embodiment, for the compound of formula (I) described in the first aspect or the first embodiment, R 2 Selected from -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 NH 2 、-N(CH 3 ) 2 、-SO 2 CH 3 , cyano, halogen, -C(O)OH, -C(O)N(CH 3 ) 2 and -C(O)NHCH 3 Or the following structure: 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 described therein. In an alternative eleventh embodiment, R 2 -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 NH 2 、-N(CH 3 ) 2 , cyano, halogen, -C(O)OH, -C(O)N(CH 3 ) 2 、-C(O)NHCH 3 , 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 embodiments described therein.

[0088] In a twelfth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, 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 embodiments described therein.

[0089] In a thirteenth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or in the first embodiment, n is 1 and Z is a bond; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, eleventh or twelfth embodiment.

[0090] In a fourteenth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, n is 1 and Z is -CH 2 -、-CH(CH 3 )-、-O-、-N(H)-、-N(C 1-4 alkyl)- or -C(O)NH-*, where * indicates the 3 and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, eleventh or twelfth embodiment.

[0091] In the fifteenth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 3 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, thienyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-1H-pyrazolyl, benzimidazolyl, indole oxazolyl, indolyl, 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]heptyl, 2-azaspiro[3.3]heptyl and 2-oxaspiro[3.3]heptyl, each of which is optionally substituted with 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 described therein. In an alternative fifteenth embodiment, R 3 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, thienyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-1H-pyrazolyl , benzimidazolyl, indazolyl, indolyl, 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]heptyl, 2-azaspiro[3.3]heptyl and 2-oxaspiro[3.3]heptyl, each of which is optionally substituted with 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 embodiments described therein. In some embodiments, R 3 Optionally, 1 to 2 R 4 In some embodiments, R 3 After 1 R 4 In some embodiments, R 3 Not replaced.

[0092] In a sixteenth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, Z is -CH 2 -, R 3 is thienyl, pyrrolyl and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is optionally substituted with 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 embodiments described therein.

[0093] In the seventeenth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 3 Represented by the following structural formula:

[0094]

[0095] Each of which is optionally substituted with 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 described therein. In an alternative seventh embodiment, R 3 for

[0096] Each of which is optionally substituted with 1 to 3 R 4 and the remaining variables are as described in the first embodiment or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiment or any alternative embodiments described therein. In some embodiments, R 3 Optionally, 1 to 2 R 4 In some embodiments, R 3 After 1 R 4 In some embodiments, R 3 Not replaced.

[0097] In the eighteenth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 3 Represented by the following structural formula:

[0098]

[0099]

[0100] 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 described therein. In an alternative eighteenth embodiment, R 3 for

[0101]

[0102] 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 embodiments described therein.

[0103] In the nineteenth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 3 is phenyl or a 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted by 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 embodiments described therein.

[0104] In the twentieth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 3 is phenyl, pyrazolyl, pyridinyl and pyrimidinyl, each of which is optionally substituted with 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 embodiments described therein.

[0105] In the first embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 3 for Each of which is optionally substituted with 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 embodiments described therein.

[0106] In the twenty-second embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 3 Represented by the following structural formula: 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 described therein. In an alternative twenty-second embodiment, R 3 for 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 embodiments described therein.

[0107] In the twenty-third embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first embodiment or the first embodiment, R 4 Selected from C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OR 4a 、-CN、-NH 2 、-NR 4b R 4c , halogen, -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 NR 4b R 4c 、-P(O)R 4b R 4c 、-C(O)OC 1-4 alkyl, benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl, 6- to 10-membered bicyclic heterocyclic group and 4- to 6-membered monocyclic heterocyclic group, wherein R 4 C 1-3 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl is optionally substituted with 1 to 3 substituents independently selected from halo, phenyl, optionally substituted with 1 or 2 R 4g substituted 5- to 6-membered monocyclic heteroaryl, and optionally 1 or 2 R 4g Substituted 4- to 6-membered monocyclic heterocyclic group, -C(O)NR 4b R 4c 、-C(O)R 4a OR 4f ; and by R 4 The benzyl group, phenyl group, 5- to 6-membered monocyclic heteroaryl group, 6- to 10-membered bicyclic heterocyclic group and 4- to 6-membered monocyclic heterocyclic group represented by each optionally have 1 to 3 R 4e substituted and further optionally substituted with one or two oxo groups, or two R 4 Together they form an oxo group; R 4ais H, optionally 1 to 4 R 4d Substituted C 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 or 5 to 6-membered monocyclic heteroaryl is optionally substituted by 1 to 3 R 4e Replace; each R 4b are independently H or C 1-4 Alkyl; R 4c is H, optionally 1 to 4 R 4d Substituted C 1-4 alkyl, 4- to 6-membered monocyclic heterocyclic group or 5- to 6-membered monocyclic heteroaryl; each R 4d are independently selected from halo, -OR 4f , C 3-6 Cycloalkyl, -C(O)OH, -NR 4b R 4c , phenyl and 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from the following: 1-3 Alkyl, C 1-3 haloalkyl, halogen, CN and OH; each R 4e independently selected from 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 Alkyl SO 2 C 1-3 Alkyl, -C(O)N(C 1-3 alkyl) 2 and cyano; or two R 4e Together they form an oxo group; R 4f H, C 1-4 alkyl, phenyl or 5- to 6-membered monocyclic heteroaryl, wherein the phenyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 halogen groups; each R 4g Independently for C 1-3 alkyl or halo; and each R 4h Independently for C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkoxy or -N(R 4b ) 2and 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 described therein. In an alternative twenty-third embodiment, R 4 C 1-3 Alkyl, -OR 4a 、-CN、-NH 2 , halogen, -C(O)R 4a 、-NHC(O)R 4a 、-NHC(O)OR 4a 、-SR 4a 、-SO 2 R 4a 、-SO 2 NR 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 heterocyclic group, wherein R 4 C 1-3 The alkyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, OR 4f 、-C(O)NR 4b R 4c , phenyl and 5- to 6-membered monocyclic heteroaryl; R 4 The benzyl group, phenyl group, 5- to 6-membered monocyclic heteroaryl group and 4- to 6-membered monocyclic heterocyclic group represented by each optionally have 1 to 3 R 4e Replace, or two R 4 Together they form an oxo group; R 4a is H, optionally 1 to 4 R 4d Substituted C 1-4 Alkyl, -NR 4b R 4c , phenyl or 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are optionally substituted by 1 to 3 R 4e Replacement; R 4b H or C 1-4 Alkyl; R 4c is H, optionally 1 to 4 R 4d Substituted C 1-4 alkyl, 4- to 6-membered monocyclic heterocyclic group or 5- to 6-membered monocyclic heteroaryl; each R 4d Independently selected from C 1-3alkyl, halo, phenyl and 5- to 6-membered monocyclic heteroaryl, wherein the phenyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from halo, CN and OH; each R 4e independently selected from halogen, 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 they form an oxo group; R 4f H, C 1-4 alkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl, wherein phenyl and 5- to 6-membered monocyclic heteroaryl 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 or twenty-second embodiment, or any alternative embodiment described therein.

[0108] In the twenty-fourth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 4 Represented by the following structural formula:

[0109]

[0110] Each of which is optionally substituted with 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 described therein. In an alternative twenty-fourth embodiment, R 4 for

[0111] Each of which is optionally substituted with 1 to 3 R 4e and the remaining variables are as described in the first aspect or in 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 embodiments described therein.

[0112] In the twenty-fifth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 4 Represented by the following structural formula:

[0113]

[0114] 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 described therein. In an alternative twenty-fifth embodiment, R 4 for

[0115]

[0116]

[0117] 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 embodiments described therein.

[0118] In the twenty-sixth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, 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; 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 described therein. In an alternative twenty-sixth embodiment, R 4e -CH 3 、-C(O)CH 3 、-C(O)CH(CH 3 ) 2 、-C(O)N(CH 3 ) 2 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 described therein.

[0119] In the twenty-seventh embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 4 For-OR 4a ; R 4a is optionally 1 to 3 R 4d Substituted C 1-3 alkyl or optionally 1 to 3 R 4e substituted 4- to 6-membered monocyclic heterocyclic group; each R 4d are independently halogen, C 1-2 alkyl, phenyl or 5- to 6-membered monocyclic heteroaryl, if two or three R 4d Existence, R 4d One of them is phenyl or a 5- to 6-membered monocyclic heteroaryl group, and the other R 4d are each independently halogen or C 1-2 Alkyl; wherein R 4d The phenyl group and the 5- to 6-membered monocyclic heteroaryl group represented by each optionally substituted by 1 to 3 independently selected C 1-3 Alkyl, C 1-3 haloalkyl and halo substituents; each R 4e Independently for C 1-4 Alkyl, C 1-4 Haloalkyl, -SO 2 C 1-3Alkyl or -C(O)C 3-6 cycloalkyl; 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 described therein. In an alternative twenty-seventh embodiment, R 4 For-OR 4a ; R 4a For 1 to 3 R 4d Substituted C 1-3 Alkyl; R 4d One of them is phenyl or a 5- to 6-membered monocyclic heteroaryl group, and the other R 4d are each independently halogen or C 1-2 Alkyl; wherein R 4d The phenyl and 5- to 6-membered monocyclic heteroaryl represented are each optionally substituted with 1 to 3 halo groups; and the remaining variables are as described in the first aspect or in 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 described therein.

[0120] In the twenty-eighth embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the first aspect or the first embodiment, R 4 -CH 3 , CH 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 、-C≡CC(CH 3 ) 2 OH, -OH, -OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 OCH 3 、-OCH(CH 3 )2 、-OCF 3 、-OCHF 2 、-OCH 2 CF 3 , -O-cyclopropyl, -O-cyclobutyl, -OC(CH 3 ) 3 、-OC(CH 3 ) 2 CH 2 OH, -OCH(CH 3 )C(O)OH、-OC(CH 3 ) 2 C(O)OH, -OCH(CH 3 )CH 2 OH, -OCH 2 CH 2 N(CH 3 ) 2 、-CN、-NH 2 、-NHCH 3 , halogen, -C(O)H, -C(O)CH(CH 3 ) 2 、-C(O)OCH 3 , -C(O)O-tert-butyl, -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 Represented by the following structural formula:

[0121]

[0122]

[0123] 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 described therein. In an alternative twenty-eighth embodiment, R 4 -CH 3 , CH 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 、-NHR 4c , halogen, -C(O)H, -C(O)CH(CH 3 ) 2 、-C(O)OCH 3 、-C(O)O-tert-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 2N(CH 3 ) 2 、-P(O)(CH 3 ) 2 , phenyl,

[0124]

[0125] 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 embodiments described therein.

[0126] In a twenty-ninth embodiment, the compound of the present disclosure is represented by formula (IIA), (IIB) or (IIC):

[0127]

[0128]

[0129] or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; and the variables X, R depicted in Formula (IIA), (IIB) or (IIC) 1 , R 2 and R 3 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 embodiments described therein.

[0130] In a thirtieth embodiment, the compound of the present disclosure is represented by formula (IIIA) or (IIIB):

[0131]

[0132] or a pharmaceutically acceptable salt thereof, wherein the variables X, R 1 , R 2 and R 3 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 embodiments described therein.

[0133] In a thirty-first embodiment, the compound of the present disclosure is represented by Formula (IVA), (IVB), (IVC) or (IVD):

[0134]

[0135] or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; and the variables X, R depicted in Formula (IVA), (IVB), (IVC) or (IVD) are 1 , R 2 and R 3 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 embodiments described therein.

[0136] In the thirty-second embodiment, for the compound of Formula (I), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IVA), (IVB), (IVC) or (IVD) or a pharmaceutically acceptable salt thereof, R 1 -CH 3 or -CH 2 CH 3 , 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, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth or thirty-first embodiment or any alternative embodiments described therein.

[0137] In the thirty-third embodiment, for the compound of Formula (I), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IVA), (IVB), (IVC) or (IVD) or a pharmaceutically acceptable salt thereof, R 1 -CH 3 , 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, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth or thirty-first embodiment or any alternative embodiments described therein.

[0138] In a thirty-fourth embodiment, the compound of the present disclosure is represented by formula (V):

[0139]

[0140] or a pharmaceutically acceptable salt thereof, wherein:

[0141] X is Cl or Br;

[0142] R 1 -CH 3 or -CH 2 CH 3 ;

[0143] Ring A is selected from phenyl, thienyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl and imidazolyl;

[0144] m is 0 or 1;

[0145] Each R 2 Independently selected from C 1-3 Alkyl and -C(O)R 2d , wherein the C 1-3 The alkyl group is optionally 2g replace;

[0146] R 2d is a 4- to 6-membered monocyclic heterocyclic group;

[0147] R 2g is cyano or OH;

[0148] R 3 is phenyl or 5 to 6-membered monocyclic heteroaryl, wherein the phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 or 2 R 4 replace;

[0149] Each R 4 independently selected from halogen, C 1-4 Alkyl, -O-benzyl, -OC 1-3 Alkyl, cyano, -NH 2 and a 4- to 6-membered monocyclic heterocyclic group, wherein the benzyl group is optionally substituted by 1 to 3 halogen or C 1-3 Haloalkyl substitution.

[0150] In an alternative thirty-fourth embodiment, for the compound of formula (V) or a pharmaceutically acceptable salt thereof, the variables are defined as:

[0151] X is Cl or Br;

[0152] R 1 -CH 3 or -CH 2 CH 3 ;

[0153] Ring A is selected from phenyl, thienyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl and imidazolyl;

[0154] m is 0 or 1;

[0155] Each R 2 Independently selected from C 1-3 Alkyl and -C(O)R 2d , wherein the C 1-3 The alkyl group is optionally 2g replace;

[0156] R 2d is a 4- to 6-membered monocyclic heterocyclic group;

[0157] R 2g is cyano or OH;

[0158] R 3 is phenyl or 5 to 6-membered monocyclic heteroaryl, wherein the phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 or 2 R 4 replace;

[0159] Each R 4 Independently selected from C 1-4 Alkyl, -O-benzyl, cyano, -NH 2 and a 4- to 6-membered monocyclic heterocyclyl group, wherein the benzyl group is optionally substituted with a halogen group.

[0160] In the thirty-fifth embodiment, for the compound of formula (V) or a pharmaceutically acceptable salt thereof, Ring A is

[0161] And the remaining variables are as described in the thirty-fourth embodiment or any alternative embodiment described therein.

[0162] In a thirty-sixth embodiment, the compound of the present disclosure is represented by formula (IIB), (IIIA), (IVA) or (IVB):

[0163]

[0164]

[0165] or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; and the variables X, R depicted in Formula (IIIA), (IVA) or (IVB) 1 , R 2 and R 3 As described in the thirty-fourth embodiment or any alternative embodiment described therein.

[0166] In the thirty-seventh embodiment, for the compound of Formula (V), (IIB), (IIIA), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 3 is phenyl, pyrazolyl, pyridinyl and pyrimidinyl, each of which is optionally substituted with 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 described therein.

[0167] In the thirty-eighth embodiment, for the compound of Formula (V), (IIB), (IIIA), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 3 Represented by the following structural formula: Each of which is optionally substituted with 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 described therein. In an alternative thirty-eighth embodiment, R 3 for and; and the remaining variables are as described in the thirty-fourth, thirty-fifth or thirty-sixth embodiment or any alternative embodiment described therein.

[0168] In the thirty-ninth embodiment, for the compound of Formula (V), (IIB), (IIIA), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 4 -F, -OCH(CH 3 ) 2 、-OC(CH 3 ) 3 、-CH 3 , cyano, -NH 2 or R 4 Represented by the following structural formula: 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 described therein. In an alternative thirty-ninth embodiment, R 4 -CH 3 , cyano, -NH 2 , 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 described therein.

[0169] In the fortieth embodiment, for the compound of Formula (V), (IIB), (IIIA), (IVA) or (IVB) or a pharmaceutically acceptable salt thereof, R 2-CH 3 、-CH 2 CN、-CH 2 OH, 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 described therein.

[0170] In a forty-first embodiment, the present disclosure provides a compound represented by formula (IIB) or (IVB):

[0171]

[0172] or a pharmaceutically acceptable salt thereof, wherein:

[0173] m is 1;

[0174] R 1 -CH 3 ;

[0175] X is Cl;

[0176] R 2 -CH 3 ;

[0177] R 3 is pyrimidinyl or pyridinyl, each of which is optionally substituted with 1 or 2 R 4 replace;

[0178] R 4 Halogen, -OC 1-3 alkyl or a 4 to 6-membered monocyclic heterocyclic group, wherein the 4 to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 halogen or C 1-3 Haloalkyl substitution.

[0179] In the forty-second embodiment, for the compound of formula (IIB) or (IVB) or a pharmaceutically acceptable salt thereof, R 3 Represented by the following structural formula: And the remaining variables are as described in the forty-first embodiment.

[0180] In the forty-third embodiment, for the compound of formula (IIB) or (IVB) or a pharmaceutically acceptable salt thereof, each R 4 are independently -F, -OCH(CH 3 ) 2 or -OC(CH 3 ) 3 , or R 4 Represented by the following structural formula: And the remaining variables are as described in the forty-first or forty-second embodiment.

[0181] In a forty-fourth embodiment, the present disclosure provides a compound described herein (eg, the compound of any one of Examples 1-736) or a pharmaceutically acceptable salt thereof.

[0182] In a forty-fifth embodiment, the present disclosure provides a compound selected from the group consisting of:

[0183] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-phenyl-1H-imidazole-4-carboxamide;

[0184] 5-Bromo-N-(3-fluoro-5-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide;

[0185] N-(3-Fluoro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0186] 5-Bromo-N-(3-fluoro-5-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide;

[0187] N-(3-Fluoro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0188] N-(3-chloro-5-(methylsulfonamido)phenyl)-2-phenyl-1H-imidazole-4-carboxamide;

[0189] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-phenylfuran-2-carboxamide;

[0190] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-phenyl-1H-pyrrole-2-carboxamide;

[0191] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-phenyl-1H-imidazole-2-carboxamide;

[0192] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-methyl-3-(1H-pyrazol-1-yl)benzamide;

[0193] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-phenylthiophene-2-carboxamide;

[0194] N-(3-bromo-5-(methylsulfonamido)phenyl)-2-phenylcyclobutane-1-carboxamide;

[0195] N-(3-chloro-5-(methylsulfonamido)phenyl)-3'-cyano-[1,1'-biphenyl]-3-carboxamide;

[0196] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(pyridin-4-yl)benzamide;

[0197] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide;

[0198] N-(3-iodo-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide;

[0199] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0200] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(pyrazin-2-yl)thiophene-2-carboxamide;

[0201] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(2-hydroxy-6-methylphenyl)thiophene-2-carboxamide;

[0202] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(2-hydroxyphenyl)-5-methylthiophene-2-carboxamide;

[0203] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(2-hydroxyphenyl)thiophene-2-carboxamide;

[0204] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(pyrimidin-2-yl)thiophene-2-carboxamide;

[0205] N-(3-bromo-5-(methylsulfonamido)phenyl)-5-methyl-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0206] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0207] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(pyrimidin-2-yl)thiophene-2-carboxamide;

[0208] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(pyrimidin-2-yl)thiophene-2-carboxamide;

[0209] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methyl-4-(pyrimidin-2-yl)thiophene-2-carboxamide;

[0210] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methyl-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0211] 4-(3-(Benzyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0212] 4-(2-(Benzyloxy)phenyl)-N-(3-bromo-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0213] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0214] 4-(3-(Benzyloxy)pyridin-2-yl)-N-(3-bromo-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0215] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0216] 4-(3-(Benzyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0217] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0218] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0219] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0220] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(4-cyanopyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0221] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-fluoropyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0222] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide;

[0223] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-cyanopyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0224] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0225] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0226] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(2-cyano-6-methylphenyl)-1H-pyrazole-4-carboxamide;

[0227] N-(3-bromo-5-(methylsulfonamido)phenyl)-5-methyl-1-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0228] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-cyanopyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0229] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0230] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-cyclohexyl-1H-pyrazole-4-carboxamide;

[0231] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(3-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0232] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(pyrimidin-2-yl)-1H-pyrazole-4-carboxamide;

[0233] 1-(2-(Benzyloxy)phenyl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0234] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(3-cyanophenyl)-1H-pyrazole-4-carboxamide;

[0235] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-cyano-2-methylphenyl)-1H-pyrazole-4-carboxamide;

[0236] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0237] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-morpholinylpyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0238] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(6-(difluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0239] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(6-(difluoromethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0240] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(2-formylphenyl)-1H-pyrazole-4-carboxamide;

[0241] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0242] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(1H-pyrazol-1-yl)thiophene-2-carboxamide;

[0243] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyridin-3-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0244] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(1-phenylethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0245] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyridin-2-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0246] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyridin-4-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0247] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3-fluorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0248] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(oxazol-5-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0249] 1-(2-(Benzyloxy)-5-cyanophenyl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0250] 1-(3-(Benzyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0251] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((4-fluorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0252] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3-chlorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0253] 4-Bromo-N-(3-fluoro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0254] 4-Bromo-N-(3-(ethylsulfonamido)-5-fluorophenyl)thiophene-2-carboxamide;

[0255] N-(3-Fluoro-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide;

[0256] N-(3-(ethylsulfonamido)-5-fluorophenyl)-4-phenylthiophene-2-carboxamide;

[0257] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide;

[0258] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0259] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0260] N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide;

[0261] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-ethyl-5-phenyl-1H-pyrrole-3-carboxamide;

[0262] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide;

[0263] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0264] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0265] 5-Bromo-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide;

[0266] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0267] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxamide;

[0268] 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0269] 1-(5-(4-acetylpiperazin-1-yl)-3-methylpyridin-2-yl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0270] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(5-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0271] 4-(6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)pyridin-3-yl)-N,N-dimethylpiperazine-1-carboxamide;

[0272] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0273] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(4-morpholinylpyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0274] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(2-methylmorpholinyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0275] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-morpholinylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0276] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0277] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(cyanomethyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0278] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxamide;

[0279] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(difluoro(phenyl)methoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0280] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyano-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0281] 1-Benzyl-N-(3-bromo-5-(methylsulfonamido)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide;

[0282] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(3-cyano-1H-pyrazol-1-yl)benzamide;

[0283] N-(3-bromo-5-(methylsulfonamido)phenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide;

[0284] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(2-chloropyridin-4-yl)benzamide;

[0285] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazole-4-carboxamide;

[0286] 4-((1H-pyrrol-2-yl)methyl)-N-(3-bromo-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0287] N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide;

[0288] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2-hydroxyphenyl)thiophene-2-carboxamide;

[0289] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2-methoxyphenyl)thiophene-2-carboxamide;

[0290] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluorophenyl)thiophene-2-carboxamide;

[0291] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-phenyl-1H-pyrrole-3-carboxamide;

[0292] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide;

[0293] 4-(2-(Benzyloxy)phenyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0294] N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0295] N-(3-(ethylsulfonamido)-5-fluorophenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0296] N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-(2-hydroxyphenyl)thiophene-2-carboxamide;

[0297] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2,6-difluorophenyl)thiophene-2-carboxamide;

[0298] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide;

[0299] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(1H-pyrazol-1-yl)benzamide;

[0300] N-(3-bromo-5-(methylsulfonamido)phenyl)-3-(1H-pyrazol-1-yl)benzamide;

[0301] 1-ethyl-N-(3-fluoro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrazole-3-carboxamide;

[0302] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)-4-phenylthiophene-2-carboxamide;

[0303] N-(3-bromo-5-(methylsulfonylimino)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0304] N-(3-bromo-5-(methylsulfonylimino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0305] N-(3-bromo-5-(methylsulfonylimino)phenyl)-5-methyl-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0306] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-phenylthiophene-3-carboxamide;

[0307] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-phenylfuran-3-carboxamide;

[0308] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxypropyl)-1H-pyrazole-4-carboxamide;

[0309] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-hydroxyethyl)-1H-pyrazole-4-carboxamide;

[0310] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-oxaspiro[3.3]hept-6-yl)-1H-pyrazole-4-carboxamide;

[0311] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-phenyl-1H-pyrrole-3-carboxamide;

[0312] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0313] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide;

[0314] N-(3-chloro-5-(methylsulfonamido)phenyl)-2-ethylimidazole[1,2-a]pyridine-6-carboxamide;

[0315] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(dimethylamino)-2-ethylimidazole[1,2-a]pyridine-6-carboxamide;

[0316] N-(3-chloro-5-(methylsulfonamido)phenyl)imidazole[1,2-a]pyridine-6-carboxamide;

[0317] N-(3-chloro-5-(methylsulfonamido)phenyl)benzofuran-7-carboxamide;

[0318] tert-Butyl 4-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;

[0319] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(pyridin-2-yl)isothiazole-5-carboxamide;

[0320] 5-(2-(Benzyloxy)phenyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrazole-3-carboxamide;

[0321] 3-(2-(Benzyloxy)phenyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrazole-5-carboxamide;

[0322] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(pyridin-2-yl)-1H-pyrazole-3-carboxamide;

[0323] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamide;

[0324] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(1-phenylethyl)-1H-pyrazole-4-carboxamide;

[0325] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-difluoroethyl)-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0326] tert-Butyl 6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate;

[0327] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide;

[0328] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazole-4-carboxamide;

[0329] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(4-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0330] 1-(4-(4-acetylpiperazin-1-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0331] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(4-isobutyrylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0332] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide;

[0333] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(4-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide;

[0334] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxycyclohexyl)-1H-pyrazole-4-carboxamide;

[0335] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-2-phenyl-1H-imidazole-4-carboxamide;

[0336] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxamide;

[0337] N-(3-bromo-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0338] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(2-oxopiperidin-1-yl)-1H-pyrrole-3-carboxamide;

[0339] 1-(2-(Benzyloxy)cyclobutyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0340] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(3-(hydroxymethyl)-1H-pyrazol-1-yl)benzamide;

[0341] N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(2-(hydroxymethyl)phenyl)-1H-pyrazole-4-carboxamide;

[0342] 1-(3-aminopyridin-2-yl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0343] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0344] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(phenylamino)-1H-pyrazole-5-carboxamide;

[0345] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(piperazine-1-carbonyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0346] N2-(3-chloro-5-(methylsulfonamido)phenyl)-N4-phenylthiophene-2,4-dicarboxamide;

[0347] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(phenoxymethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0348] 1-(3-(Benzylamino)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0349] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0350] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0351] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0352] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-ethoxypyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0353] N-(3-chloro-5-(ethylsulfonamido)phenyl)-1-methyl-5-(pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0354] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0355] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0356] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2-oxopyrrolidin-1-yl)thiophene-2-carboxamide;

[0357] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyclopropyl-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0358] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(pyrimidin-2-yloxy)pyridin-2-yl)thiophene-2-carboxamide;

[0359] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3-hydroxybenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0360] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3-oxomorpholinyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0361] 5-(Aminomethyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0362] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide;

[0363] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-2-yl)-1H-pyrazole-4-carboxamide;

[0364] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(4-methyl-3-oxopiperazin-1-yl)pyrazin-2-yl)-1H-pyrazole-4-carboxamide;

[0365] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-(pyridin-3-ylmethoxy)pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide;

[0366] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0367] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0368] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyrimidin-5-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0369] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((2-fluorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0370] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0371] 1-(5-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0372] 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;

[0373] 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;

[0374] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-morpholinyl-3-(pyridin-3-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0375] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0376] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyrimidin-2-yloxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0377] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-methoxypyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0378] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(methylsulfonyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0379] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(methylsulfonyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0380] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(N,N-dimethylsulfamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0381] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(dimethylphosphoryl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0382] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-((3-fluorobenzyl)oxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0383] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3-cyanobenzyl)oxy)-5-fluoropyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0384] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3-fluorobenzyl)oxy)-6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0385] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(thiazol-2-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0386] 1-(3-((1H-pyrazol-4-yl)methoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0387] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoropyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0388] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-ethoxypyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0389] N-(3-chloro-5-(methylsulfonamido)phenyl)indolizine-2-carboxamide;

[0390] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-((3-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide;

[0391] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-fluoro-6-((3-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide;

[0392] 3-(3-(Benzyloxy)pyridin-2-yl)-N5-(3-chloro-5-(methylsulfonamido)phenyl)-N2-methylthiophene-2,5-dicarboxamide;

[0393] 3-(3-(Benzyloxy)pyridin-2-yl)-N5-(3-chloro-5-(methylsulfonamido)phenyl)-N2,N2-dimethylthiophene-2,5-dicarboxamide;

[0394] 4-(3-(Benzyloxy)pyridin-2-yl)-N-(3-fluoro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0395] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(oxazol-5-ylmethoxy)pyridin-2-yl)thiophene-2-carboxamide;

[0396] 4-(3-(Benzyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)thiophene-2-carboxamide;

[0397] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(pyridin-3-ylmethoxy)pyridin-2-yl)thiophene-2-carboxamide;

[0398] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(methylthio)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0399] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(methylthio)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0400] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(cyclopropanecarboxamido)pyridin-2-yl)thiophene-2-carboxamide;

[0401] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(2-(dimethylamino)-2-oxoethyl)pyridin-2-yl)thiophene-2-carboxamide;

[0402] 2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)-N,N-dimethylnicotinamide;

[0403] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide;

[0404] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0405] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)thiophene-2-carboxamide;

[0406] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0407] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-hydroxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0408] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((3,5-difluorophenoxy)methyl)pyridin-2-yl)thiophene-2-carboxamide;

[0409] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5'-fluoro-[3,3'-bipyridinyl]-2-yl)-5-methylthiophene-2-carboxamide;

[0410] N-(3-chloro-5-(methylsulfonamido)phenyl)thieno[2,3-c]pyridine-2-carboxamide;

[0411] 1-(3-((3-bromobenzyl)oxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0412] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-ethyl-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0413] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-isopropyl-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0414] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(methoxymethyl)-4-(pyridin-2-yl)thiophene-2-carboxamide;

[0415] 4-(1-Benzyl-1H-1,2,3-triazol-4-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0416] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(1-phenyl-1H-1,2,3-triazol-4-yl)thiophene-2-carboxamide;

[0417] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(pyrimidin-2-ylamino)pyridin-2-yl)thiophene-2-carboxamide;

[0418] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(methyl(pyrimidin-2-yl)amino)pyridin-2-yl)thiophene-2-carboxamide;

[0419] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(pyridin-3-yloxy)pyridin-2-yl)thiophene-2-carboxamide;

[0420] 4-(2-(Benzyloxy)-6-fluorophenyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0421] 4-Bromo-N-(3-chloro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0422] (5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)proline methyl ester;

[0423] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(piperidin-4-yl)thiophene-2-carboxamide;

[0424] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(piperazin-1-yl)thiophene-2-carboxamide;

[0425] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-morpholinothiophene-2-carboxamide;

[0426] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiophene-2-carboxamide;

[0427] N-(3-chloro-5-(cyclopropanesulfonamido)phenyl)-5-methyl-1-(5-morpholinylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0428] N-(3-chloro-5-((difluoromethyl)sulfonamido)phenyl)-5-methyl-1-(5-morpholinylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0429] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methyl-1-(5-morpholinylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0430] 1-(8-Oxabicyclo[3.2.1]oct-3-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0431] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-(3-fluorophenethyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0432] 1-(3-((1H-imidazol-2-yl)methoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0433] 1-(3-((1H-pyrazol-5-yl)methoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0434] 1-(3-((1H-imidazol-4-yl)methoxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0435] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-((3-fluorobenzyl)oxy)-6-methylphenyl)-1H-pyrazole-4-carboxamide;

[0436] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorophenoxy)methyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0437] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(5-fluoropyridin-3-yl)phenyl)-1H-pyrazole-4-carboxamide;

[0438] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((3,5-difluorobenzyl)oxy)-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0439] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-phenoxycyclopentyl)-1H-pyrazole-4-carboxamide;

[0440] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-phenylcyclopentyl)-1H-pyrazole-4-carboxamide;

[0441] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-methyl-3-(oxazol-5-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0442] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(((5-fluoropyridin-3-yl)oxy)methyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0443] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(pyrimidin-2-yloxy)phenyl)-1H-pyrazole-4-carboxamide;

[0444] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(pyridin-3-yloxy)phenyl)-1H-pyrazole-4-carboxamide;

[0445] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(3-fluorophenoxy)phenyl)-1H-pyrazole-4-carboxamide;

[0446] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(1-methyl-2-oxopiperidin-4-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0447] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrrole-3-carboxamide;

[0448] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-(oxazol-5-ylmethoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0449] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methyl(tetrahydrofuran-3-yl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0450] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(pyrrolidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0451] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-morpholinylpyridin-2-yl)-5-(trifluoromethyl)-1H-pyrrole-3-carboxamide;

[0452] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(2,2-dimethylmorpholinyl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0453] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-morpholinylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0454] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-ethyl-5-(5-morpholinylpyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0455] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-morpholinylpyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide;

[0456] 1-(5-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0457] 5-(5-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide;

[0458] 5-(5-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide;

[0459] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(3-(thiazol-2-ylmethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0460] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(3-(thiazol-2-ylmethoxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0461] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0462] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-cyclopentyl-5-methyl-1H-pyrrole-3-carboxamide;

[0463] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(4-isobutyrylpiperazin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0464] 4-(6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methyl-1H-pyrrol-1-yl)pyridin-3-yl)-N,N-dimethylpiperazine-1-carboxamide;

[0465] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(1,1-dioxothiomorpholinyl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0466] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-difluoroethyl)-5-(5-fluoropyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0467] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(1-hydroxyethyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0468] N-(3-chloro-5-(methylsulfonamido)phenyl)thieno[3,2-c]pyridine-2-carboxamide;

[0469] N-(3-chloro-5-(methylsulfonamido)phenyl)thieno[3,2-b]pyridine-2-carboxamide;

[0470] N-(3-chloro-5-(methylsulfonamido)phenyl)-7-methylthieno[3,2-c]pyridine-2-carboxamide;

[0471] N-(3-chloro-5-(methylsulfonamido)phenyl)-5,6-dimethoxybenzo[b]thiophene-2-carboxamide;

[0472] N-(3-chloro-5-(methylsulfonamido)phenyl)pyrrolo[1,2-b]pyridazine-6-carboxamide;

[0473] 6-Chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)benzo[b]thiophene-2-carboxamide;

[0474] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-fluorobenzo[b]thiophene-2-carboxamide;

[0475] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-fluorobenzo[b]thiophene-2-carboxamide;

[0476] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-fluorobenzo[b]thiophene-2-carboxamide;

[0477] N-(3-chloro-5-(methylsulfonamido)phenyl)-7-fluorobenzo[b]thiophene-2-carboxamide;

[0478] 5-Chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)benzo[b]thiophene-2-carboxamide;

[0479] 6-Chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)indolizine-2-carboxamide;

[0480] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methylindolizine-2-carboxamide;

[0481] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazine-7-carboxamide;

[0482] N-(3-chloro-5-(methylsulfonamido)phenyl)-8-(trifluoromethyl)indolizine-2-carboxamide;

[0483] N-(3-chloro-5-(methylsulfonamido)phenyl)-7-methoxybenzo[b]thiophene-2-carboxamide;

[0484] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylindolizine-2-carboxamide;

[0485] N-(3-chloro-5-(methylsulfonamido)phenyl)-8-fluindolizine-2-carboxamide;

[0486] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-hydroxycyclobutyl)-1H-pyrazole-4-carboxamide;

[0487] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(1-methyl-2-oxopiperidin-4-yl)-1H-pyrazole-4-carboxamide;

[0488] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-phenethyl-1H-pyrazole-4-carboxamide;

[0489] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-cyclopentyl-1H-pyrazole-4-carboxamide;

[0490] 1-(6-Acetamidospiro[3.3]hept-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0491] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-methyl-2-azaspiro[3.3]hept-6-yl)-1H-pyrazole-4-carboxamide;

[0492] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]hept-6-yl)-1H-pyrazole-4-carboxamide;

[0493] 1-(2-Acetyl-2-azaspiro[3.3]hept-6-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0494] N-(3-bromo-5-(methylsulfonamido)phenyl-2,4,6-d3)-4-phenylthiophene-2-carboxamide;

[0495] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-dimethylpiperidin-4-yl)-1H-pyrazole-4-carboxamide;

[0496] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazole-4-carboxamide;

[0497] 1-(1-acetylpiperidin-4-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0498] tert-Butyl (6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)spiro[3.3]hept-2-yl)carbamate;

[0499] 1-(6-aminospiro[3.3]hept-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide; and

[0500] 1-(3-fluoro-5-morpholinylpyridin-2-yl)-5-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide;

[0501] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-fluoro-5-morpholinylpyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0502] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyridin-2-yl)-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide;

[0503] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-methyl-3-oxopiperazin-1-yl)thiophene-2-carboxamide;

[0504] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-morpholinopyrimidin-2-yl)-1H-pyrazole-4-carboxamide;

[0505] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5'-fluoro-[3,3'-bipyridinyl]-2-yl)-1H-pyrazole-4-carboxamide;

[0506] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-methyl-2-oxoimidazolidin-1-yl)thiophene-2-carboxamide;

[0507] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-methoxybenzo[b]thiophene-2-carboxamide;

[0508] N-(3-chloro-5-(methylsulfonamido)phenyl)-1,3-dimethylpyrrolo[1,2-a]pyrazine-7-carboxamide;

[0509] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(4-phenylpiperazine-1-carbonyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0510] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(trifluoromethyl)benzo[b]thiophene-2-carboxamide;

[0511] N-(3-chloro-5-(methylsulfonamido)phenyl)-4,5-difluorobenzo[b]thiophene-2-carboxamide;

[0512] N-(3-chloro-5-(methylsulfonamido)phenyl)-4,7-difluorobenzo[b]thiophene-2-carboxamide;

[0513] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(trifluoromethyl)benzo[b]thiophene-2-carboxamide;

[0514] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyrimidin-5-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0515] N-(3-chloro-5-(methylsulfonamido)phenyl)-6-methoxybenzo[b]thiophene-2-carboxamide;

[0516] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(piperidine-1-carbonyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0517] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(morpholine-4-carbonyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0518] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)thiophene-2-carboxamide;

[0519] 4-(3-(2-(azetidin-1-yl)-2-oxoethyl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0520] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2-oxooxazolidin-3-yl)thiophene-2-carboxamide;

[0521] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-morpholinylpyrazin-2-yl)-1H-pyrazole-4-carboxamide;

[0522] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(pyrimidin-2-ylmethyl)pyridin-2-yl)thiophene-2-carboxamide;

[0523] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-5-(4-(2,2,2-trifluoroethyl)piperazine-1-carbonyl)-1H-pyrrole-3-carboxamide;

[0524] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(2-oxopyrrolidin-1-yl)thiophene-2-carboxamide;

[0525] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxy-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0526] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-2-yl)thiophene-2-carboxamide;

[0527] N-(3-fluoro-5-(methylsulfonamido)phenyl)-5-methyl-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0528] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(4-methylpiperazine-1-carbonyl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0529] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyridin-3-yloxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0530] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(3-(pyridin-3-yloxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0531] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(2-(dimethylamino)-2-oxoethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0532] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(2-hydroxypropan-2-yl)-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0533] N-(3-chloro-5-(methylsulfonamido)phenyl)-6,8-dimethylindolizine-2-carboxamide;

[0534] N-(3-fluoro-5-(methylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0535] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-5-(2,6-diazaspiro[3.3]heptane-2-carbonyl)-1H-pyrrole-3-carboxamide;

[0536] N-(3-chloro-5-(methylsulfonamido)phenyl)-8-methylindolizine-2-carboxamide;

[0537] N-(3-chloro-5-(methylsulfonamido)phenyl)pyrrolo[1,2-a]pyrazine-7-carboxamide;

[0538] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0539] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-methoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0540] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0541] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-cyanopyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0542] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylbenzo[b]thiophene-2-carboxamide;

[0543] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-ethoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0544] 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;

[0545] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0546] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-ethoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0547] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0548] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(methoxymethyl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0549] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoropyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0550] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-ethoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0551] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0552] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide;

[0553] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-ethoxypyridin-2-yl)thiophene-2-carboxamide;

[0554] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-chloropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0555] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-methoxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0556] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yloxy)-5,6-dihydro-4H-cyclopenta[b]thiophene-2-carboxamide;

[0557] 4-Chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)benzo[b]thiophene-2-carboxamide;

[0558] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(3-fluorophenoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0559] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-methoxy-1H-pyrazol-1-yl)thiophene-2-carboxamide;

[0560] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0561] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(1-phenethyl-1H-imidazol-2-yl)thiophene-2-carboxamide;

[0562] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-methoxy-1H-pyrazol-1-yl)-5-methylthiophene-2-carboxamide;

[0563] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(methoxymethyl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0564] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-cyanopyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0565] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-chloropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0566] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-chloropyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0567] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3-fluoroazetidin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0568] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-fluoropyridin-2-yl)-5-(methoxymethyl)-1H-pyrrole-3-carboxamide;

[0569] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-ethoxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0570] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-ethoxy-1H-pyrazol-1-yl)-5-methylthiophene-2-carboxamide;

[0571] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-fluoro-1H-pyrazol-1-yl)-5-methylthiophene-2-carboxamide;

[0572] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4-fluoro-1H-pyrazol-1-yl)thiophene-2-carboxamide;

[0573] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-methoxypyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0574] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(methoxymethyl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0575] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-methoxypyrimidin-2-yl)thiophene-2-carboxamide;

[0576] 5-(5-(azetidin-1-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide;

[0577] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-methoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0578] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0579] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0580] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methyl(tetrahydrofuran-3-yl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0581] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methyl(tetrahydrofuran-3-yl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0582] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0583] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(2-methoxyethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0584] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-ethoxypyrimidin-2-yl)thiophene-2-carboxamide;

[0585] 1-(5-(azetidin-1-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0586] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-(cyclopropylmethoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0587] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyclopropyl-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide;

[0588] 1-(5-(azetidin-1-yl)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0589] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3-fluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0590] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide;

[0591] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-chloropyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0592] 5-Chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoropyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0593] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0594] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5,5'-difluoro-[3,3'-bipyridinyl]-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0595] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-1'-methyl-2'-oxo-1',2'-dihydro-[3,4'-bipyridinyl]-2-yl)-5-methylthiophene-2-carboxamide;

[0596] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-1'-methyl-6'-oxo-1',6'-dihydro-[3,3'-bipyridinyl]-2-yl)-5-methylthiophene-2-carboxamide;

[0597] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5,5'-difluoro-[3,3'-bipyridinyl]-2-yl)-5-methylthiophene-2-carboxamide;

[0598] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0599] N-(3-chloro-5-(methylsulfonyl)phenyl)-5-methyl-1-(5-(methylsulfonyl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0600] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0601] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(cyclopropylmethoxy)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0602] tert-Butyl 3-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-(5-fluoropyrimidin-2-yl)-1H-pyrrol-1-yl)azetidine-1-carboxylate;

[0603] 1-(5-(3-azabicyclo[3.1.0]hex-3-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0604] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoropyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0605] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-cyclopropyl-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide;

[0606] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methylthio)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0607] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(methylsulfinyl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0608] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(pyrrolidin-1-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0609] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyclopropyl-1-(5-fluoropyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0610] 5-(5-(azetidin-1-yl)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide;

[0611] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(4,4-dimethyl-2,5-dioxo-3-(pyridin-2-yl)imidazolidin-1-yl)-5-methylthiophene-2-carboxamide;

[0612] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-2'-methyl-[3,3'-bipyridinyl]-2-yl)-5-methylthiophene-2-carboxamide;

[0613] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(oxazol-5-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0614] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(oxetan-3-yloxy)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0615] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0616] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-ethoxypyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrrole-3-carboxamide;

[0617] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(difluoromethoxy)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0618] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-methoxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0619] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3,5-difluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0620] 5-Chloro-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide;

[0621] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0622] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-ethyl-4-(5-fluoropyrimidin-2-yl)thiophene-2-carboxamide;

[0623] 1-(5-(5-azaspiro[2.4]hept-5-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0624] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3-fluoroazetidin-1-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0625] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(N-methylmethylsulfonamido)pyrimidin-2-yl)thiophene-2-carboxamide;

[0626] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-cyclopropyl-5-(5-fluoropyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0627] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(2-oxopyrrolidin-1-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0628] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyrimidin-2-yl)-1-isopropyl-1H-pyrrole-3-carboxamide;

[0629] N-(3-chloro-5-(methylsulfonyl)phenyl)-5-methyl-4-(5-(methylsulfonyl)pyrimidin-2-yl)thiophene-2-carboxamide;

[0630] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5,5'-difluoro-[3,3'-bipyridinyl]-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0631] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3,4-dimethyl-2,5-dioxo-4-(pyridin-2-yl)imidazolidin-1-yl)-5-methylthiophene-2-carboxamide;

[0632] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0633] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-methylpyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0634] 4-(6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)piperazine-1-carboxylic acid methyl ester;

[0635] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0636] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-((1-methylazetidin-3-yl)oxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0637] 4-(6-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methylthiophenyl-3-yl)-5-methylpyridin-3-yl)piperazine-1-carboxylic acid methyl ester;

[0638] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3,5-difluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0639] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(5-fluoropyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0640] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3-fluoroazetidin-1-yl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0641] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0642] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3,5-difluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0643] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0644] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0645] N-(3-chloro-5-(ethylsulfonamido)phenyl)-1-(3-chloro-5-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0646] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0647] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0648] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0649] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(pyrrolidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0650] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0651] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-chloro-5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0652] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-methylpyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0653] N-(3-chloro-5-(ethylsulfonamido)phenyl)-1-(3,5-difluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0654] 1-(azetidin-3-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0655] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-cyano-5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0656] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-methoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0657] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0658] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3-chloro-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0659] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(methylamino)pyrimidin-2-yl)thiophene-2-carboxamide;

[0660] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(2-oxooxazolidin-3-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0661] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(2,4,6-trifluorophenyl)-1H-pyrrole-3-carboxamide;

[0662] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(3-fluoro-5-methylpyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0663] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(2,4,6-trifluorophenyl)thiophene-2-carboxamide;

[0664] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(2-oxooxazolidin-3-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0665] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0666] 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;

[0667] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide;

[0668] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0669] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-carboxamide;

[0670] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0671] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-chloro-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0672] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(4-pivaloylpiperazin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0673] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-methoxypyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0674] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4-(cyclopentanecarbonyl)piperazin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0675] 1-(5-(7-azabicyclo[2.2.1]hept-7-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0676] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3-methoxyazetidin-1-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0677] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0678] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(2-cyano-4-fluoro-6-methylphenyl)-1-methyl-1H-pyrrole-3-carboxamide;

[0679] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-methylpyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0680] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3-fluoro-5-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0681] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methyl-4-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide;

[0682] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0683] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4-(cyclobutanecarbonyl)piperazin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0684] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(4,4-difluoropiperidin-1-yl)-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0685] 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;

[0686] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0687] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0688] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-methoxy-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0689] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3,5-difluoropyridin-4-yl)-5-methylthiophene-2-carboxamide;

[0690] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-methylpyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0691] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-cyano-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0692] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0693] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0694] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0695] 1-(3-chloro-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0696] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-isopropoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0697] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4,4-difluoropiperidin-1-yl)-3-methylpyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0698] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-(difluoromethoxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0699] N-(3-chloro-5-(ethylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0700] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(4-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0701] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-chloro-5-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0702] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-methoxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0703] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(2,2,2-trifluoroethoxy)pyrimidin-2-yl)thiophene-2-carboxamide;

[0704] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0705] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-isopropoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0706] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyclobutoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0707] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-ethoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0708] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0709] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-methoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0710] 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;

[0711] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(difluoromethoxy)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0712] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0713] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0714] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-(3-fluoroazetidin-1-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0715] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-ethoxy-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0716] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-carboxamide;

[0717] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3-fluorooxetane-3-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0718] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoropyridin-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide;

[0719] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-methoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0720] 4-(5-(1-acetylpiperidin-4-yl)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0721] N-(3-chloro-5-(cyclopropanesulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0722] N-(3-chloro-5-(propylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0723] 4-(6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)-5-fluoropyridin-3-yl)piperazine-1-carboxylic acid methyl ester;

[0724] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4-methoxypiperidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0725] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-cyano-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0726] 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;

[0727] 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;

[0728] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-cyclobutoxy-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0729] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)thiophene-2-carboxamide;

[0730] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-(difluoromethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0731] 4-(5-(tert-Butyloxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0732] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0733] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-ethoxy-5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0734] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3-fluoro-3-methylazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0735] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-cyclobutoxy-5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0736] N-(3-chloro-5-(methylsulfonyl)phenyl)-1-methyl-5-(5-(3-(methylsulfonyl)azetidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0737] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3-methoxyazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0738] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(3-fluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0739] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0740] 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;

[0741] 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;

[0742] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0743] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(4,4-dimethyl-1,4-azasilan-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0744] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0745] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(4,4-difluoropiperidin-1-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0746] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0747] N-(3-chloro-5-(methylsulfonyl)phenyl)-1-methyl-5-(5-(3-((methylsulfonyl)methyl)azetidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0748] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0749] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(4,4-dimethyl-1,4-azasilan-1-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0750] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0751] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0752] 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;

[0753] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoroazetidin-1-yl)-3-isopropoxypyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0754] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0755] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0756] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoropyrrolidin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0757] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0758] N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0759] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0760] N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0761] 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;

[0762] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoropyrrolidin-1-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0763] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((1-(cyclopropanecarbonyl)azetidin-3-yl)oxy)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0764] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0765] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoroazetidin-1-yl)-3-isopropoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0766] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0767] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoropiperidin-1-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0768] 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;

[0769] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoropiperidin-1-yl)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0770] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)pyridin-2-yl)thiophene-2-carboxamide;

[0771] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(1-(2,2-difluoroethyl)piperidin-4-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0772] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoropyrrolidin-1-yl)-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0773] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-cyano-5-(trifluoromethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0774] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0775] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0776] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0777] 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;

[0778] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-((1-methylazetidin-3-yl)oxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0779] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyanopyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0780] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-isopropoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0781] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-ethoxy-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0782] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0783] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-isopropoxypyrimidin-2-yl)thiophene-2-carboxamide;

[0784] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-isopropoxypyridin-2-yl)thiophene-2-carboxamide;

[0785] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(trifluoromethyl)pyrimidin-2-yl)thiophene-2-carboxamide;

[0786] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyano-3-methylpyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0787] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyanopyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0788] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide;

[0789] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-cyano-3-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0790] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl)thiophene-2-carboxamide;

[0791] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-isopropoxypyridin-2-yl)thiophene-2-carboxamide;

[0792] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoropyrrolidin-1-yl)-3-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0793] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)thiophene-2-carboxamide;

[0794] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(3,3-difluoropyrrolidin-1-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0795] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-fluoropyridin-2-yl)thiophene-2-carboxamide;

[0796] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-2-yl)thiophene-2-carboxamide;

[0797] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoropyrrolidin-1-yl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0798] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0799] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0800] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyrimidin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0801] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0802] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)-3-fluoropyridin-2-yl)-5-methyl-1H-pyrrole-3-carboxamide;

[0803] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0804] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-((1-hydroxy-2-methylpropan-2-yl)oxy)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0805] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-ethyl-4-(3-fluoropyridin-2-yl)thiophene-2-carboxamide;

[0806] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)thiophene-2-carboxamide;

[0807] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0808] 4-(5-(tert-Butyloxy)-3-fluoropyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0809] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(dimethylphosphoryl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0810] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3,5-difluoropyridin-2-yl)-5-ethylthiophene-2-carboxamide;

[0811] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0812] N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-4-(5-(3,3-difluoroazetidin-1-yl)-3-methoxypyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0813] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0814] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-4-(5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)thiophene-2-carboxamide;

[0815] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-5-(5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0816] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-ethyl-4-(5-fluoropyridin-2-yl)thiophene-2-carboxamide;

[0817] 4-(5-(tert-Butyloxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0818] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(dimethylphosphoryl)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0819] 4-(5-(tert-Butyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0820] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0821] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0822] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-(1,1-difluoro-5-azaspiro[2.4]hept-5-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0823] 1-(5-(tert-Butyloxy)-3-fluoropyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0824] 1-(5-(tert-Butyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0825] 5-(5-(tert-Butyloxy)pyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide;

[0826] N-(3-chloro-5-(propylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0827] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3,5-difluoropyridin-2-yl)-1H-pyrrole-3-carboxamide;

[0828] 4-(5-(tert-Butyloxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)thiophene-2-carboxamide;

[0829] N-(3-chloro-5-((1-methylethyl)sulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0830] 5-(5-(tert-Butyloxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide;

[0831] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0832] N-(3-chloro-5-(N-methylmethylsulfonamido)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0833] 1-(5-(tert-butoxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrrole-3-carboxamide;

[0834] 5-(5-(tert-Butyloxy)-3-fluoropyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide;

[0835] 5-(3,5-difluoropyridin-2-yl)-N-(3-fluoro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide;

[0836] N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0837] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-fluoro-4-(5-isopropoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0838] N-(3-chloro-5-(methylsulfonamido)phenyl)-3-methyl-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;

[0839] 4-(3-fluoro-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-N-(3-fluoro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0840] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoropyridin-2-yl)-5-methylthiazole-2-carboxamide;

[0841] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(3-fluoro-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0842] N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-4-(3-fluoro-5-(3-(trifluoromethyl)azetidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0843] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-((1-methylazetidin-3-yl)oxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0844] 4-(5-(azetidin-3-yloxy)-3-fluoropyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0845] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1,1-dioxothiomorpholinyl)-5-fluoropyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0846] 4-(3-(4-acetylpiperazin-1-yl)-5-fluoropyridin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0847] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(3-methoxypyrrolidin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0848] N-(3-chloro-5-((methyl)sulfonamido-1,1,1-d3)phenyl)-4-(5-isopropoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0849] N-(3-chloro-5-(methylsulfonyl)phenyl)-4-(5-fluoro-3-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0850] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0851] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-(5-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0852] 2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methylthiophenyl-3-yl)-3,5-difluoropyridine 1-oxide;

[0853] 4-(5-(azetidin-3-yloxy)pyrimidin-2-yl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0854] 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;

[0855] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-fluoro-5-(3-hydroxy-1-methylazetidin-3-yl)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0856] N-(2-fluoro-3-(methylsulfonamido)phenyl)-4-(3-(pyridin-3-ylmethoxy)pyridin-2-yl)thiophene-2-carboxamide;

[0857] 1-(2-(Benzyloxy)cyclopentyl)-N-(3-chloro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0858] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(((5-fluoropyridin-3-yl)oxy)methyl)phenyl)-1H-pyrazole-4-carboxamide;

[0859] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-fluoro-6-((5-fluoropyridin-3-yl)methoxy)phenyl)-1H-pyrazole-4-carboxamide;

[0860] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-(dimethylcarbamoyl)-6-((3-fluorobenzyl)oxy)phenyl)-1H-pyrazole-4-carboxamide;

[0861] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,4-difluoro-6-(oxazol-5-ylmethoxy)phenyl)-1H-pyrazole-4-carboxamide;

[0862] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(5-fluoro-3-(oxazol-5-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0863] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)thiophene-2-carboxamide;

[0864] 1-(2-(Benzyloxy)phenyl)-N-(3-fluoro-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide;

[0865] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-fluoro-6-(oxazol-5-ylmethoxy)phenyl)-1H-pyrazole-4-carboxamide;

[0866] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2-((3-fluorobenzyl)oxy)-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)phenyl)-1H-pyrazole-4-carboxamide;

[0867] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0868] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-(hydroxymethyl)-1H-pyrrole-3-carboxamide;

[0869] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-(thiazol-2-ylmethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0870] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-fluoro-3-((2-methylthiazol-4-yl)methoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0871] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((3,5-dimethylisoxazol-4-yl)methoxy)-5-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0872] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-fluoro-3-(pyrimidin-5-ylmethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0873] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(2-((5-fluoropyridin-3-yl)methoxy)-4-methylpyridin-3-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0874] 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;

[0875] (E)-N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(2-(2-(5-fluoropyridin-3-yl)vinyl)phenyl)-1-methyl-1H-pyrrole-3-carboxamide;

[0876] 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;

[0877] 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;

[0878] (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;

[0879] 4-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methyl-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide;

[0880] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-(1-(3-fluoro-5-(trifluoromethyl)phenyl)ethoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0881] 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;

[0882] 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;

[0883] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-((5-ethylpyridin-3-yl)methoxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0884] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(5-fluoropyridin-3-yl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0885] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(5-fluoropyridin-3-yl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0886] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(5-fluoropyridin-3-yl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0887] N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-4-(3-((5-fluoropyridin-3-yl)methoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0888] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-fluoro-3-(oxazol-5-ylmethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0889] 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;

[0890] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((3,5-difluorobenzyl)oxy)-2-methylpyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0891] 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;

[0892] 5-(3-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methoxy)pyridin-2-yl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide;

[0893] 5-(3-((3-hydroxybenzyl)oxy)pyridin-2-yl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide;

[0894] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(3,5-difluorophenyl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0895] (S)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(3,5-difluorophenyl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0896] (R)-N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(3-(1-(3,5-difluorophenyl)ethoxy)pyridin-2-yl)-5-methylthiophene-2-carboxamide;

[0897] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-((3,5-difluorobenzyl)oxy)pyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0898] 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;

[0899] (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;

[0900] (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;

[0901] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-difluoroethyl)-5-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0902] 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;

[0903] (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;

[0904] (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;

[0905] 2-((2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methylthiophenyl-3-yl)pyrimidin-5-yl)oxy)propanoic acid;

[0906] N-(3-chloro-5-((2-hydroxyethyl)sulfonamido)phenyl)-4-(5-isopropoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0907] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-hydroxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0908] 4-(5-(tert-Butyloxy)pyrimidin-2-yl)-N-(3-chloro-5-(ethylsulfonamido)phenyl)-5-methylthiophene-2-carboxamide;

[0909] 2-((2-(5-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-2-methylthiophenyl-3-yl)pyrimidin-5-yl)oxy)-2-methylpropanoic acid;

[0910] N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(5-((1-hydroxypropan-2-yl)oxy)pyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0911] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-(2-(dimethylamino)ethoxy)-3-fluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0912] 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;

[0913] N-(3-chloro-5-(ethylsulfonamido)phenyl)-4-(5-isopropoxypyrimidin-2-yl)-5-methylthiophene-2-carboxamide;

[0914] 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;

[0915] 2-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1-methyl-1H-pyrrol-2-yl)-3,5-difluoropyridine 1-oxide;

[0916] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-5-((1-isopropylazetidin-3-yl)oxy)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0917] 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;

[0918] N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-difluoroethyl)-5-(5-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-2-yl)-1H-pyrrole-3-carboxamide;

[0919] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoro-6-methoxypyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxamide;

[0920] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(3-fluoropyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide;

[0921] N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(5-methoxypyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide;

[0922] 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;

[0923] or a pharmaceutically acceptable salt thereof.

[0924] The compounds and intermediates described herein can be separated and used as the compounds themselves. Alternatively, when there is a part capable of forming a salt, the compound or intermediate can be separated and used in the form of its corresponding salt. As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of the compounds described herein. "Salt" especially includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compounds described herein and is generally not biologically or otherwise undesirable. In most cases, the compounds of the present disclosure can form acid salts and / or base salts by means of the presence of amino and / or carboxyl groups or their analogous groups.

[0925] Pharmaceutically acceptable acid addition salts can be formed with inorganic or organic acids, such as acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate and trifluoroacetate.

[0926] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0927] 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.

[0928] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0929] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from rows I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0930] 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. Certain organic amines include isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0931] Salts can be synthesized from compounds containing alkaline or acidic parts by conventional chemical methods. Generally, the salt can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (e.g., hydroxide, carbonate, bicarbonate or the like of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. The reaction is usually carried out in water or an organic solvent, or in a mixture of the two. Generally, when feasible, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Other suitable salts can be listed in, for example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0932] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents in place of the unlabeled reagents previously employed. In one embodiment, the present disclosure provides a deuterated compound described herein or a pharmaceutically acceptable salt thereof.

[0933] Pharmaceutically acceptable solvates according to the present disclosure include those in which the solvent of crystallization may be isotopically substituted, for example D 2 O、d 6 -acetone, d 6 -DMSO.

[0934] Those skilled in the art will recognize that the compounds of the present disclosure may contain chiral centers and thus may exist in different stereoisomeric forms. As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations in which a given compound of the present disclosure may exist. It should be understood that substituents may be attached at the chiral center of a carbon atom. Therefore, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0935] "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 the disclosed compounds, a single stereoisomer with a known relative and absolute configuration of two chiral centers is specified using the conventional RS system (e.g., (1S, 2S)). "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-lngold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Analytical compounds with unknown absolute configurations can be specified as (+) or (-), depending on the direction (right-handed or left-handed) of their rotation of plane polarized light at the wavelength of the sodium D line. Alternatively, resolved compounds can be defined by the individual retention times of corresponding enantiomers / diastereomers by chiral HPLC.

[0936] Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which, in terms of absolute stereochemistry, may be defined as (R)- or (S)-.

[0937] 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 synthons or chiral reagents, or separated using conventional techniques (e.g., on chiral SFC or HPLC columns, such as CHIRALPAK RTM and CHIRALCEL RTM , which can be purchased from DAICEL Corp., using a suitable solvent or solvent mixture to achieve good separation) analysis. If the compound contains a double bond, the substituent can be in E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent can have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0938] The present disclosure also provides a pharmaceutical composition comprising a compound described herein (eg, a compound according to any of the preceding embodiments) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0939] How to use

[0940] 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 a detectable decrease in DHX9 activity in vivo or in vitro (e.g., at least a 10% decrease in DHX9 activity as measured by a given assay such as a biological assay described in the Examples and known in the art).

[0941] In certain embodiments, the present disclosure provides a method of treating a disease or condition responsive to inhibition of DHX9 activity (referred to herein as a "DHX9-mediated disease or condition") in a subject in need of treatment. 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.

[0942] 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 treating a DHX9-mediated disorder or disease in a subject in need of treatment.

[0943] In certain embodiments, the present disclosure provides 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 use in treating a DHX9-mediated disorder or disease in a subject in need of treatment.

[0944] In certain embodiments, the DHX9-mediated disease or disorder is selected from cancer, viral infection, and autoimmune disease.

[0945] In some embodiments, the present disclosure provides a method for 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.

[0946] In some embodiments, cancer is microsatellite instability (MSI) cancer. In some embodiments, cancer is high MSI cancer. In other embodiments, cancer is low MSI cancer. MSI is determined by PCR analysis of 5 different nucleotide repeats, and the analysis depends on the type of cancer. Low MSI cancer is characterized by only 1 site instability in 5 sites; while high MSI cancer is characterized by 2 or more sites instability in 5 sites (G. Yang et al., Correlations between microsatellite instability and the biological behavior of tumors. Journal of Cancer Research and Clinical Oncology, 2019).

[0947] MSI-high cancers are also 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, Vol. 2020, Document ID 1897929). For example, dMMR in colorectal cancer can be determined by hypermethylation of the MLH1 promoter, which makes MLH1 inactive, accounting for about 80-90% of MSI-high colorectal cancers. MSI-high colorectal cancers with MLH1 inactivity are also called sporadic MSI-high colorectal cancers. Alternatively, dMMR can be determined by immunohistochemical mutation status of MLH1, MSH2, MSH6, MSH3, PMS1 and / or PMS2 mismatch repair (MMR) proteins. In MSI-high colorectal cancer, MLH1 and MSH2 are the two major mutated MMR proteins. They are mutated in approximately 10-20% of MSI-high colorectal cancers. MSI-high colorectal cancers with these mutations are also called Lynch Syndrome cancers.

[0948] In some embodiments, the cancer is an MSI cancer and / or has a mutation or defect in DNA mismatch repair (MMR), and / or a mutation or defect in RNA splicing and centromere complexes.

[0949] The compounds described herein, or pharmaceutically acceptable salts thereof, can be used to reduce the expression or activity of DHX9, or otherwise affect the properties and / or behavior of DHX9 in a cell.

[0950] One embodiment of the present disclosure includes a method of reducing the expression or activity of DHX9 in a subject or otherwise affecting the properties and / or behavior of DHX9, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof.

[0951] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a mammal.

[0952] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the subject is a primate.

[0953] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein the subject is a human.

[0954] As used herein, "effective amount" and "therapeutically effective amount" can be used interchangeably. It means an amount that can effectively treat or reduce the severity of one or more diseases, disorders or conditions as described herein. In some embodiments, the effective dose can be between 10 μg and 500 mg.

[0955]

[00136] According to the methods of the present disclosure, the compounds and compositions 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-mentioned diseases, disorders, or conditions.

[0956] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered parenterally.

[0957] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectal, intrathecally, topically, or intranasally.

[0958] In certain embodiments, the present disclosure relates to the aforementioned method, wherein the compound is administered systemically.

[0959] The compounds of the present disclosure are generally used as pharmaceutical compositions (e.g., compounds 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), isotonic agents, salts, preservatives, pharmaceutical stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), etc. and combinations thereof (see, e.g., Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pages 1289-1329). Unless any conventional carrier is incompatible with the active ingredient, it is considered to be used in treatment or pharmaceutical compositions. For the purposes of the present disclosure, solvates and hydrates are considered to be pharmaceutical compositions comprising compounds of the present disclosure and solvents (i.e., solvates) or water (i.e., hydrates).

[0960] The formulation can be prepared using conventional dissolution and mixing procedures. For example, a bulk drug substance (i.e., a compound of the present disclosure or a stable 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 generally formulated into pharmaceutical dosage forms to provide a drug that can be easily dosed and to provide patients with a delicate and easily handled product.

[0961] Depending on the method used to administer the drug, the pharmaceutical composition (or formulation) for administration can be packaged in a variety of ways. In general, the article for distribution includes a container in which the pharmaceutical formulation is stored 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, etc. The container may also include an anti-opening assembly to prevent easy access to the packaged contents. In addition, the container is attached with a label describing the contents of the container. The label may also include appropriate warnings.

[0962] Pharmaceutical compositions containing compounds of the present disclosure are typically formulated for parenteral or oral administration or alternatively as suppositories.

[0963] For example, the oral pharmaceutical composition of the present disclosure can be made in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical operations such as sterilization, and / or can contain conventional inert diluents, lubricants or buffers, and adjuvants (such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.).

[0964] The pharmaceutical composition is usually a tablet or gelatin capsule containing the active ingredient and:

[0965] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0966] b) lubricants, such as silicon dioxide, talc, stearic acid, magnesium or calcium stearic acid and / or polyethylene glycol; for tablets, also

[0967] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary

[0968] d) disintegrants, for example starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or

[0969] e) Adsorbents, colorants, flavorings and sweeteners.

[0970] Tablets may be film coated or enteric coated according to methods known in the art.

[0971] Suitable compositions for oral administration include 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 are prepared according to any method known in the art for making pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of each of the following: sweeteners, flavoring agents, coloring agents, and preservatives to provide pharmaceutically refined and oral preparations. Tablets may contain a mixture of active ingredients and pharmaceutically acceptable non-toxic excipients suitable for making tablets. For example, these excipients are inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are either uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin or olive oil.

[0972] Parenteral compositions (e.g., intravenous (IV) formulations) are isotonic aqueous solutions or suspensions. Parenteral compositions may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, dissolution promoters, salts for regulating osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically valuable substances. Compositions are typically prepared separately according to conventional mixing, granulation or coating methods and contain about 0.1-75% of active ingredient, or contain about 1-50% of active ingredient.

[0973] The compounds of the present disclosure or their pharmaceutical compositions for subjects (e.g., humans) are generally administered orally or parenterally at therapeutic doses. When administered intravenously by infusion, the dosage may depend on the infusion rate of the IV formulation. In general, the therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the subject species, body weight, age, and subject condition, disorder, or disease or its severity to be treated. A physician, pharmacist, clinician, or veterinarian who is generally familiar with the field can easily determine the effective amount of each active ingredient required for preventing, treating, or inhibiting the progression of a disorder or disease.

[0974] The dosage characteristics cited above can be advantageously demonstrated in vitro and in vivo tests using mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues, and specimens thereof. The compounds disclosed herein can be administered in vitro in the form of a solution (e.g., an aqueous solution), and in vivo enterally, parenterally, advantageously intravenously (e.g., in the form of a suspension or in an aqueous solution). In vitro doses can be administered at about 10 -3 Molar concentration and 10 -9 The molar concentration range is between .

[0975] definition

[0976] As used herein, the terms "patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. The terms include mammals, such as humans. Typically, the animal is a mammal. The subject also refers to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0977] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0978] As used herein, "treat," "treating," or "treatment" of any disease, condition, or disorder refers to the management and care of a patient for the purpose of combating the disease, condition, or disorder, and includes the administration of the compounds disclosed herein to obtain the desired pharmacological and / or physiological effects. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or completely reducing the extent of the disease, condition, or disorder; alleviating or improving 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.

[0979] As used herein, the term "cancer" has the generally recognized meaning in the art. The term can generally refer to abnormal cell growth.

[0980] As used herein, a subject (in some embodiments, a human) is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life due to such treatment.

[0981] As used herein, the phrase "optionally substituted" can be used interchangeably with the phrase "substituted or unsubstituted". In general, the term "optionally substituted" refers to the replacement of hydrogen radicals in a given structure with the group of a specified substituent. The specific substituents are described in the definitions and in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be the same or different at each position.

[0982] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. The term "C 1-3 Alkyl" and "C 1-2 Alkyl". "C 1-4 Representative examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Similarly, the alkyl portion of an alkoxy group (i.e., the alkyl moiety) has the same definition as above. When indicated as "optionally substituted", the alkane group or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally one to three substituents, such as in the case of halogen substituents of perchloro or perfluoroalkyl groups).

[0983] As used herein, the term "alkylene" refers to a fully saturated branched or unbranched divalent hydrocarbon group. The term "C1-4 alkylene" refers to an alkylene group having 1 to 4 carbon atoms. The terms "C1-3 alkylene" and "C1-2 alkylene" are interpreted accordingly. Representative examples of "C1-4 alkylene" include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, and tert-butylene.

[0984] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., --O--C 1-4 Alkyl, where C 1-4 Alkyl is as defined herein). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. In some embodiments, the alkoxy has about 1 to 4 carbons, and in some embodiments about 1 to 2 carbons. Accordingly, the term "C 1-2 "Alkoxy".

[0985] As used herein, the term “C 1-4 Alkoxy C 1-4 "Alkyl" means a C 1-4 Alkyl, wherein at least one hydrogen atom is C 1-4 Alkoxy substitution. 1-4 Alkoxy C 1-4 The alkyl group is attached to the rest of the molecule described herein through the alkyl group.

[0986] In this document, the prefix “C x-xx ” specifies the number of carbon atoms in a group, where x and xx are integers. For example, “C 1-3 The "alkyl group" is an alkyl group having 1 to 3 carbon atoms.

[0987] "Halogen" or "halo" may be fluorine, chlorine, bromine or iodine.

[0988] As used herein, the term "halo-C 1-4 Alkyl" or "C 1-4 "Haloalkyl" refers to a C 1-4 Alkyl group in which at least one hydrogen atom is replaced by a halogen atom. 1-4 The haloalkyl group may be a monohalogen-C 1-4 Alkyl, dihalogen-C 1-4 Alkyl or polyhalogenated C 1-4 Alkyl, including perhalogenated-C 1-4 Alkyl. Monohalogen-C 1-4 The alkyl group may have one iodine, bromine, chlorine or fluorine within the alkyl group. 1-4 Alkyl and polyhalogenated C 1-4The alkyl group may have two or more identical halogen atoms or a combination of different halogen groups within the alkyl group. 1-4 The alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halogen 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 Alkyl refers to a C-alkyl group in which all hydrogen atoms are replaced by halogen atoms. 1-4 alkyl.

[0989] The term "aryl" refers to an aromatic carbocyclic monocyclic ring or two fused ring systems containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene and naphthyl.

[0990] The term "heteroaryl" refers to a 5- to 12-membered aromatic group containing 1 to 4 heteroatoms selected from N, O and S. In some cases, the nitrogen atom in the heteroaryl group may be quaternized. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaryl group". The heteroaryl group may be monocyclic or bicyclic. Monocyclic heteroaryl includes, for example, pyrrolyl, furanyl, thiophenyl or thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathiinyl, triazinyl, tetrazinyl, etc. Bicyclic heteroaryl includes a group 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.

[0991] The term "carbocycle" or "carbocyclyl" refers to a 4 to 12-membered saturated or partially unsaturated hydrocarbon ring, and may exist in the form of a monocycle, a bicyclic (including fused, spiro or bridged carbocycle) or a spirocycle. Bicyclic carbocyclic groups include, for example, unsaturated carbocyclic groups fused to another unsaturated carbocyclic group, a cycloalkyl or an aryl, such as cyclohexyl, cyclohexenyl, 2,3-dihydroindenyl, decahydronaphthyl and 1,2,3,4-tetrahydronaphthyl. Unless otherwise specified, carbocycles typically contain 4 to 10 ring members.

[0992] The term "C 3-6 "Cycloalkyl" refers to a fully saturated carbocyclic ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0993] 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. The heterocyclyl group can be a monocyclic or bicyclic ring (e.g., a bridged, fused or spiro bicyclic ring). Examples of monocyclic saturated or partially unsaturated heterocyclyl groups include, but are not limited to, piperazinyl, piperazinyl, tetrahydropyranyl, morpholinyl and pyrrolidinyl. Bicyclic heterocyclyl includes, for example, an unsaturated heterocyclyl fused to another unsaturated heterocyclyl, 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]thienyl and 4,7-dihydro-5H-thieno[2,3-c]pyranyl. In some embodiments, the heterocyclyl is a 4- to 6-membered monocyclic heterocyclyl. In some embodiments, the heterocyclyl is an 8- to 10-membered bicyclic heterocyclyl.

[0994] As used herein, the term "spiro" ring means a bicyclic ring system in which both rings share one common atom. Examples of spiro rings include 5-oxaspiro[2.3]hexane, oxaspiro[2.4]heptyl, 5-oxaspiro[2.4]heptyl, 4-oxaspiro[2.4]heptane, 4-oxaspiro[2.5]octyl, 6-oxaspiro[2.5]octyl, oxaspiro[2.5]octyl, oxaspiro[3.4]octyl, oxaspiro[bicyclo[2.1.1]hexane-2,3'-oxetane]-1-yl, oxaspiro[bicyclo[3.2.0]heptane-6,1'-cyclobutane]-7-yl, 2,6-diazaspiro[3.3]heptyl, 2,2 ,6-diazaspiro[3.3]heptane, 3-azaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane, 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]undecane, 3,9-diazaspiro[5.5]undecane, etc.

[0995] The term "fused" ring refers to a bicyclic ring system that shares two adjacent ring atoms. A fused heterocyclic ring has at least one ring system containing a ring atom that is a heteroatom selected from O, N and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0996] As used herein, the term "bridged" refers to a 5- to 10-membered cyclic moiety that is linked at two non-adjacent ring atoms (eg, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptane, and bicyclo[3.2.1]octane).

[0997] 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.

[0998] Unless otherwise specified, the term "compound of the present disclosure" refers to a compound of formula (I), as well as all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, isotope-labeled compounds (including deuterium substitution). When a part capable of forming a salt exists, then salts, especially pharmaceutically acceptable salts, are also included.

[0999] As used herein, unless otherwise indicated herein or clearly contradictory to the context, the terms "a", "an", "said" and similar terms used in the context of the present disclosure (especially in the case of the technical solution) should be interpreted as covering both the singular and the plural. The use of any and all examples or exemplary language (such as "for example") provided by the present disclosure is intended only to better illustrate the present disclosure and does not limit the scope of the present disclosure otherwise claimed.

[1000] The intermediates and compounds of the present disclosure may also 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 with different energies that can be interconverted through a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions through proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens as follows. Valence tautomers include interconversions through the reorganization of some bonding electrons.

[1001] In one embodiment, the present disclosure relates to a compound of formula (I) as defined herein in free form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in salt form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in acid addition salt form. In another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in pharmaceutically acceptable salt form. In yet another embodiment, the present disclosure relates to a compound of formula (I) as defined herein in pharmaceutically acceptable acid addition salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the examples in free form. In yet another embodiment, the present disclosure relates to any one of the compounds of the examples in salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the examples in acid addition salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the examples in pharmaceutically acceptable salt form. In yet another embodiment, the present disclosure relates to any one of the compounds of the examples in pharmaceutically acceptable acid addition salt form.

[1002] The compounds of the present disclosure can be synthesized by synthetic routes, including methods similar to those well known in chemical technology, specifically synthesized according to the descriptions contained herein. The starting material is generally purchased from commercial sources such as Sigma-Aldrich, or is easily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Vol. 1-19, Wiley, New York (1967-1999 edition), or Beilsteins Handbuch der organischen Chemie, 4th edition. Springer-Verlag, Berlin, including supplements (also available through the Beilstein online database)).

[1003] For the purpose of illustration, the reaction schemes described below provide potential pathways for synthesizing compounds disclosed herein and key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. Although specific starting materials and reagents are described in the flow and discussed below, other starting materials and reagents are easily substituted to provide a variety of derivatives and / or reaction conditions.

[1004] Examples

[1005] abbreviation:

[1006] PE = Petroleum Ether

[1007] EtOAc=EA=ethyl acetate

[1008] ESI = Electrospray Ionization

[1009] MeOH = methanol

[1010] EtOH = ethanol

[1011] DCM = dichloromethane

[1012] DIAD = diisopropyl azodicarboxylate

[1013] DMF = dimethylformamide

[1014] DPPA = diphenylphosphoryl azide

[1015] EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[1016] HATU = azabenzotriazole tetramethyl urea hexafluorophosphate

[1017] HCl = hydrochloric acid

[1018] H 2 O=Water

[1019] NBS = N-bromosuccinimide

[1020] LCMS = Liquid Chromatography Mass Spectrometry

[1021] HPLC = High Pressure Liquid Chromatography

[1022] THF = Tetrahydrofuran

[1023] MeCN=ACN=acetonitrile

[1024] DMSO = dimethyl sulfoxide

[1025] PhMe = Toluene

[1026] AcOH = acetic acid

[1027] CDI = Carbonyldiimidazole

[1028] TFA = trifluoroacetic acid

[1029] DIPEA=DIEA=diisopropylethylamine

[1030] TLC = Thin Layer Chromatography

[1031] N 2 = Nitrogen

[1032] KOH = Potassium Hydroxide

[1033] NH 4 HCO3 =Ammonium bicarbonate

[1034] t-BuOH = tert-butyl alcohol

[1035] NH 4 Cl = ammonium chloride

[1036] t-BuOK = Potassium tert-butoxide

[1037] NaH = Sodium hydride

[1038] Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[1039] Na 2 SO 4 =Sodium sulfate

[1040] K 2 CO 3 = Potassium carbonate

[1041] K 3 PO 4 = Potassium phosphate

[1042] Cs 2 CO 3 =Cesium carbonate

[1043] NaHCO 3 =Sodium bicarbonate

[1044] Pd(OAc) 2 =Palladium(II) acetate

[1045] Pd 2 (dba) 3 =Tris(dibenzylideneacetone)dipalladium(0)

[1046] NaOH = Sodium Hydroxide

[1047] TCFH=N'-Tetramethylformamidine hexafluorophosphate

[1048] NMI=1-methylimidazole

[1049] Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[1050] XantPhosPd 3 =[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II)

[1051] RuPhos=2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[1052] RuPhos Pd G 3 =(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II)

[1053] Pd / C = Palladium / Carbon

[1054] Pd(dppf)Cl 2 DCM = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane

[1055] Pd(dppf)Cl 2 =[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[1056] Pd(PPh 3 ) 4 =Tetrakis(triphenylphosphine)palladium(0)

[1057] Pd(PPh 3 )Cl 2 =Bis(triphenylphosphine)palladium(II) dichloride

[1058] STAB=NaBH(AcO) 3 =Sodium triacetoxyborohydride

[1059] AlMe 3 =Al(CH 3 ) 3 =Trimethylaluminum

[1060] DIAD = diisopropyl azodicarboxylate

[1061] 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

[1062] Er(OTf) 3 = Erbium(III) trifluoromethanesulfonate

[1063] Br 2 =Br

[1064] KOAc = Potassium acetate

[1065] TEBAc = benzyltriethylammonium chloride

[1066] B 2 pin 2 =Bis(pinacol)diboron

[1067] BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[1068] BPO = Benzoyl Peroxide

[1069] Py = Pyridine

[1070] LiAlH 4 =Lithium Aluminum Hydride

[1071] General approach

[1072] 1. 1 H NMR spectra were recorded at:

[1073] NMR10 Bruker AVANCEⅢHD 300MHz

[1074] NMR16 Bruker AVANCEⅢHD 300MHz

[1075] NMR19 Bruker AVANCEⅢHD 400MHz

[1076] NMR24 Bruker AVANCE NEO 400MHz

[1077] NMR30 Bruker AVANCE NEO 400MHz

[1078] 2. LCMS measurements were run on a SHIMADZU LCMS-2020 using the following conditions:

[1079] Method A: Mobile phase: A: water (0.05% TFA) B: acetonitrile (0.05% TFA); Gradient phase: 5% B to 100% B in 2.0 minutes, 100% B in 0.7 minutes (total run time: 2.8 minutes); Flow rate: 1.5 mL / min; Column: HALO C18, 3.0*30 mm, 2.0 μm; Column temperature: 40° C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[1080] Method B: Mobile phase: A: water (0.1% FA) B: acetonitrile (0.1% FA); Gradient phase: 5% B to 100% B in 2.0 minutes, 100% B in 0.7 minutes (total running time: 2.8 min); Flow rate: 1.5 mL / min; Column: HALO C18, 3.0*30 mm, 2.0 μm; Column temperature: 40° C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[1081] Method C: Mobile phase: A: Water (5 mM NH 4HCO 3 ) B: acetonitrile; gradient phase: 10% B to 95% B in 2.0 minutes, 100% B in 0.6 minutes (total run time: 2.8 minutes); flow rate: 1.5 mL / min; column: Poroshell HPH-C18, 3.0*50 mm, 4.0 μm; column temperature: 40° C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[1082] Preparation of intermediates

[1083] The compounds claimed herein were prepared following the procedures outlined in the following schemes. The compound names were generated using software built into ChemDraw. Insofar as there are discrepancies between the compound names and their depicted structures, the depicted chemical structures should be considered the appropriate compounds.

[1084] Intermediate A: N-(3-amino-5-chlorophenyl)methanesulfonamide

[1085]

[1086] Step 1: To 1-chloro-3-fluoro-5-nitrobenzene (45 g, 256.35 mmol, 1.00 equiv) and methanesulfonamide (24.38 g, 256.35 mmol, 1.00 equiv), Cs 2 CO 3 (250.57 g, 769.05 mmol, 3.00 equiv) was added to a stirred mixture of 500 mL of DMSO and the resulting solution was stirred at 60 °C for 2 hours. The mixture was cooled and then quenched with 1000 mL of water and extracted with 3 x 1000 mL of ethyl acetate and washed with anhydrous Na 2 SO 4 Dried and concentrated, and the residue was purified on a silica gel column eluting with 50% ethyl acetate / petroleum ether to give N-(3-chloro-5-nitrophenyl)methanesulfonamide (41 g, 63.81%) as a light yellow solid. LCMS (ESI) [M+H] + :249.9

[1087] Step 2: To N-(3-chloro-5-nitrophenyl)methanesulfonamide (41.00 g, 163.57 mmol, 1.00 equiv) and Fe (91.35 g, 1635.75 mmol, 10.00 equiv), NH 4A stirred solution of Cl (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 hours. The resulting mixture was filtered and the filter cake was washed with 6 x 50 mL of methanol. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column eluting with 50% ethyl acetate / petroleum ether to give N-(3-amino-5-chlorophenyl)methanesulfonamide (25.3 g, 70.1%) as a light yellow solid.

[1088] LCMS(ESI)[M+H] + :220.01. 1 H NMR (300 MHz, DMSO-d 6 )δ9.64(s,1H),6.41-6.31(m,3H),5.54(s,2H),2.98(s,3H)

[1089] Intermediate E: N-(3-amino-5-chlorophenyl)propane-1-sulfonamide

[1090]

[1091] 3-Bromo-5-chloroaniline (1 g, 4.843 mmol, 1 equivalent), propane-1-sulfonamide (1.19 g, 9.686 mmol, 2 equivalents), (1S,2S)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (2.07 g, 14.529 mmol, 3 eq.), CuI (2.77 g, 14.529 mmol, 3 eq.) and K 2 CO 3 A solution of (2.01 g, 14.529 mmol, 3 eq.) in ACN (10 mL) was stirred at 110 °C under nitrogen atmosphere for 2 hours. 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.

[1092] LCMS(ESI)[M+H] + :249

[1093] Intermediate H: N-(3-amino-5-chlorophenyl)cyclopropanesulfonamide

[1094]

[1095] Step 1: A solution of 3-chloro-5-nitroaniline (300 mg, 1.738 mmol, 1 eq.) and cyclopropanesulfonyl chloride (244 mg, 1.738 mmol, 1 eq.) 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.

[1096] LCMS(ESI)[M+H] + :277

[1097] Step 2: N-(3-chloro-5-nitrophenyl)cyclopropanesulfonamide (235 mg, 0.849 mmol, 1 eq), Fe (474 ​​mg, 8.490 mmol, 10 eq) and NH 4 Cl (136 mg, 2.547 mmol, 3 eq.) in ethanol (5 ml) and H 2 The solution in 4-nitro-2-yl pyridine-2-yl pyridine-1 ...

[1098] LCMS(ESI)[M+H] + :247

[1099] The following intermediates were prepared using similar experimental procedures as Intermediate A, E or H:

[1100]

[1101]

[1102] Intermediate J: 2-bromo-5-(tert-butoxy)pyrimidine

[1103]

[1104] 2-Bromopyrimidin-5-ol (2.5 g, 14.3 mmol, 1 eq.) and Er(OTf) 3 (0.44 g, 0.7 mmol, 0.05 eq.) in Boc 2The mixture in 4% 4-(tert-butyloxy)pyrimidine (400 mg, 6% yield) 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-butyloxy)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

[1105] Intermediate K: 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

[1106]

[1107] Step 1: 5-Methylthiophene-2-carboxylic acid (100 g, 703.383 mmol, 1 eq.) and Br 2 A mixture of (123.65 g, 773.721 mmol, 1.1 eq.) in AcOH (1 L) was stirred at 60 °C for 2 hours. 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

[1108] Step 2: 4-bromo-5-methylthiophene-2-carboxylic acid (100 g, 452.345 mmol, 1 eq.) and H 2 SO 4 A mixture of 1,2-dihydro-1,4-dihydro-2-nitropropene (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 washed with anhydrous Na 2 SO 4 After drying, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (10:1) as eluent to give methyl 4-bromo-5-methylthiophene-2-carboxylate (80 g, 74% yield) as a light yellow solid. GCMS: 234. 1 HNMR (300 MHz, DMSO-d 6 )δ7.70(s,1H),3.82(s,3H),2.43(s,3H).

[1109] Step 3: 4-bromo-5-methylthiophene-2-carboxylic acid methyl ester (80 g, 340.281 mmol, 1 equivalent), bis(pinacolato)diboron (172.82 g, 680.562 mmol, 2 equivalents), Pd(dppf)Cl2 A mixture of (12.45g, 17.014mmol, 0.05 equivalent) and KOAc (100.19g, 1020.843mmol, 3 equivalents) in 1,4-dioxane (800mL) was stirred overnight at 80 ° C 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, eluted with PE / EA (15: 1) to give 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid methyl esters (90g, crude product). The crude product was recrystallized from hexane to give 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid methyl esters (35g, 36% yield) as a white solid. LCMS(ESI)[M+H] + :283.

[1110] 1 H NMR (400 MHz, DMSO-d 6 )δ7.70(s,1H),3.79(s,3H),2.65(s,3H),1.28(s,12H)

[1111] Intermediate L: 5-methyl-1H-pyrrole-3-carboxylic acid methyl ester

[1112]

[1113] Step 1: Tosylmethyl isocyanide (200 g, 1.03 mol, 1 equivalent) was dissolved in dichloromethane 1.5 L and cooled to 0 ° C. Benzyl triethylammonium chloride (46.62 g, 2.05 mol, 2 equivalents), iodomethane 126.3 mL (2.05 mol, 2 equivalents) and 1.5 L of 30% aqueous sodium hydroxide solution were added. The mixture was stirred at 0 ° C for 3 hours. Water (4 L) was added to the reaction mixture and 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, eluted with PE / EA (4: 1) to give 1- ((1-isocyanoethyl) sulfonyl) -4- toluene (167 g, 78.0% yield) as a brown oil. Step 2: A solution of methyl acrylate (138.2 mL, 1.55 mol, 0.97 eq) and 1-(1-isocyanoethylsulfonyl)-4-toluene (335 g, 1.60 mol, 1 eq) in diethyl ether (3 L) and DMSO (1.5 L) was added dropwise to a stirred suspension of sodium hydride (60% purity) (99.7 g, 2.49 mol, 1.55 eq) in diethyl ether (4 L) under nitrogen. The resulting suspension was stirred at room temperature for 4 hours. 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 organic layers were combined and washed with water (5 L), and the mixture was purified by HPLC. 2 SO 4 Drying, filtration and evaporation gave a beige solid. The crude product was purified by flash silica gel chromatography (elution gradient 0 to 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.

[1114] 1 H NMR (400 MHz, DMSO-d 6 )δ11.18(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).

[1115] Intermediate M: 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-3-carboxylate

[1116]

[1117] Step 1: To a stirred solution of 1H-pyrrole-3-carboxylic acid methyl ester (100 g, 800 mmol, 1 eq.) and NaH (60%) (64 g, 1.6 mol, 2 eq.) in DMF (1 L) was added CH 3 I (227.2 g, 1.6 mol, 2 eq.). The resulting mixture was stirred at room temperature for another 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 purified by anhydrous Na 2 SO 4 After drying, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (5:1) as eluent to give methyl 1-methylpyrrole-3-carboxylate (95 g, 85.6%) as a white solid. LCMS (ESI) [M+H] + :140

[1118] Step 2: 1-methylpyrrole-3-carboxylic acid methyl ester (95 g, 683.5 mmol, 1 equivalent), B 2 Pin 2 (138.9g, 546.7mmol, 0.8 equivalents), bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (6.7g, 10.3mmol, 0.015 equivalents) and 4,4'-di-tert-butyl-2,2'-bipyridine (5.49g, 20.5mmol, 0.03 equivalents) in 1,4-dioxane (1L) were stirred at 100 ° C under a nitrogen atmosphere for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 1) to give a crude product. The crude product was wet-ground with PE at room temperature for 12 hours and filtered to give 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-3-carboxylate (105g, 57.8% yield) as a white solid. LCMS(ESI)[M+H] + :266. 1 H 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).

[1119] The following intermediates were prepared using a similar experimental procedure as Intermediate M:

[1120]

[1121] General Process

[1122] The compounds described below can be prepared, for example, by the following general schemes and other methods known to those skilled in the art:

[1123] General process A:

[1124]

[1125] Commercially available or prepared by various means (e.g., Suzuki coupling, Buchwald coupling, alkylation, SNAr, cyclocondensation, or multi-step synthesis) carboxylic acid esters are hydrolyzed with various reagents (e.g., lithium hydroxide) to give carboxylic acids. The carboxylic acids are then coupled with appropriate reagents (e.g., one of the above-mentioned anilines or other amines) using various reagents to give the desired product.

[1126] General process B:

[1127]

[1128] Carboxylic acid esters, either commercially available or prepared by various means (e.g., Suzuki coupling, Buchwald coupling, alkylation, SNAr, cyclocondensation, or multi-step synthesis), are reacted with an appropriate reagent (e.g., one of the above-mentioned anilines or other amines) in the presence of trimethylaluminum or other appropriate reagents to give the desired product.

[1129] In general, any method can be used to obtain the examples shown below and can be considered interchangeable. For the examples shown below, those skilled in the art can determine alternative conditions for individual steps, such as alkylation, hydrolysis, displacement, cross-coupling or other chemical transformations.

[1130] Examples

[1131] Example 1: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-phenyl-1H-imidazole-4-carboxamide

[1132]

[1133] 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 two hours. It was then concentrated and the residue was purified by reverse phase flash chromatography with 60% acetonitrile / water (0.1% NH 4 HCO 3) to give N-(3-chloro-5-methanesulfonylaminophenyl)-1-phenyl-1H-imidazole-4-carboxamide (47.2 mg, 32.4%) as a white solid. LCMS [M+H] + :391. 1 H NMR (400 MHz, DMSO-d 6 )δ10.27(s,1H),10.05(s,1H),8.53-8.44(m,2H),7.83-7.74(m,4H),7.57(d d, J=8.6, 7.2Hz, 2H), 7.48-7.39 (m, 1H), 6.92 (t, J=2.0Hz, 1H), 3.10 (s, 3H).

[1134] Examples 2-14 and 321-332

[1135] The compounds listed in the following table were prepared using procedures similar to those described in Example 1:

[1136]

[1137]

[1138]

[1139]

[1140] Example 15: N-(3-bromo-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide

[1141]

[1142] Step 1: 4-bromothiophene-2-carboxylic acid methyl ester (30 g, 135 mmol), phenylboronic acid (32.9 g, 270 mmol), Pd(dppf)Cl 2 (11.0 g, 13.5 mmol) and K 3 PO 4 To a mixture of 1,4-dioxane (300 mL) and H 2 O (30 mL). 2 The resulting mixture was stirred under 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 20% ethyl acetate / petroleum ether to give methyl 4-phenylthiophene-2-carboxylate (27.1 g, 124 mmol) as a light yellow solid.

[1143] Step 2: LiOH (24.9 g, 595 mmol) was added to a stirred solution of 4-phenylthiophene-2-carboxylic acid methyl ester (26.1 g, 119 mmol) in 260 mL THF and 260 mL water. The resulting mixture was stirred overnight at room temperature. It was then concentrated, and the pH value of the residue solution was adjusted to 3 with 1 M HCl (aqueous solution). The product was precipitated from the solution. After filtration, 4-phenylthiophene-2-carboxylic acid (24.4 g, 119 mmol) was obtained as a white solid.

[1144] 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 / water (0.1% FA) to give N-(3-bromo-5-methylsulfonamidophenyl)-4-phenylthiophene-2-carboxamide (11.0519 g, 24.486 mmol) as a light yellow solid. LCMS (ESI) [MH] - :449. 1 H NMR (300 MHz, DMSO-d 6 )δ10.46(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).

[1145] Example 16

[1146] The compounds listed in the following table were prepared using procedures similar to those described in Example 15:

[1147]

[1148] Example 17: N-(3-bromo-5-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide

[1149]

[1150] Step 1: Ethyl 4-bromothiophene-2-carboxylate (250 g, 1063.37 mmol, 1.00 equiv) was reacted with bis(pinacolato)diboron (810.10 g, 3190.13 mmol, 3.00 equiv) and Pd(dppf)Cl2 (38.90g, 53.17mmol, 0.05 equiv) and AcOK (313.09g, 3190.13mmol, 3.00 equiv) in 1500mL 1,4-dioxane, the resulting solution was stirred at 80°C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with 50% ethyl acetate / petroleum ether to give ethyl 4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (231.02g, 81.0%) as a yellow solid.

[1151] Step 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid methyl ester (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 2 (31.52 g, 43.076 mmol, 0.05 eq) and K 2 CO 3 A mixture of (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 under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column eluted with 50% ethyl acetate / 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

[1152] 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 hour. The mixture was adjusted to pH 6 with HCl (aq). The precipitated solid was collected by filtration and washed with 3 x 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

[1153] 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 eluting with 10% methanol / dichloromethane to give 75 g (95% purity) of the desired product. The desired product was purified by trituration with 300 mL of 30% methanol / dichloromethane. This resulted in N-(3-bromo-5-methylsulfonamidophenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide (54.8097 g, 18.7%) as a white solid. LCMS (ESI) [M+H] + :452. 1 H NMR (300 MHz, DMSO-d 6 )δ10.61(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).

[1154] Example 31: N-(3-chloro-5-methylsulfonamidophenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide

[1155]

[1156] Step 1: methyl 4-bromothiophene-2-carboxylate (150 g, 678.52 mmol, 1.00 equiv), Pd(dppf)Cl 2(24.82g, 33.93mmol, 0.05 equiv), AcOK (199.77g, 2035.55mmol, 3.00 equiv) and bis(pinacolato)diboron (206.76g, 814.22mmol, 1.2 equiv) in 1000mL dioxane. This was stirred at 80°C under nitrogen atmosphere for 2 hours. The resulting mixture was cooled and concentrated. The residue was purified on a silica gel column eluted with 10% ethyl acetate / petroleum ether to give methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (170g, 92.5%) as a yellow solid.

[1157] Step 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid methyl ester (170 g, 634.02 mmol, 1.00 equiv), Pd(dppf)Cl 2 (23.20 g, 31.70 mmol, 0.05 eq), K 2 CO 3 A solution of 1,4-dioxane (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 on a silica gel column chromatography eluted with 50% ethyl acetate / petroleum ether to give 4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid methyl ester (115 g, 77%) as a yellow solid. LCMS (ESI) [M+H] +: 234

[1158] 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. 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 in vacuo to give 4-(3-methylpyridin-2-yl)thiophene-2-carboxylic acid (60 g, 54.9%) as a yellow solid.

[1159] LCMS (ESI) [M+H] +: 220

[1160] 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 was added N-(3-amino-5-chlorophenyl)methanesulfonamide (50 g, 226.58 mmol, 0.83 equiv). The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated and purified by reverse phase flash chromatography eluting with 56% acetonitrile / water (0.05% FA) to give N-(3-chloro-5-methylsulfonamidophenyl)-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) δ8.49-8.41(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,1H),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).

[1161] Examples 18-35 and 333-386

[1162] The compounds listed in the following table were prepared using procedures similar to those described in Example 17:

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174] Example 36: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1175] Step 1: To 2-fluoropyridine (150g, 1.54mol), KOH (260g, 4.62mol), 1H-pyrazole-4-carboxylic acid ethyl ester (258.7g, 1.85mol) in 3500mL DMSO. The mixture was then stirred at 100°C for 2 hours. The mixture was cooled and then quenched with 3000mL water. The water layer was extracted with 3×1000mL ethyl acetate. The mixture was concentrated and purified on silica gel with 35% ethyl acetate / petroleum ether to obtain 1- (pyridin-2-yl) -1H-pyrazole-4-carboxylic acid ethyl ester (168g, 49.5%) as a yellow solid.

[1176] LCMS(ESI)[M+H] + :218

[1177] Step 2: To a stirred solution of 1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (168g, 0.77mol), LiOH (53g, 2.32mol) in 1000mL water and 3000mL tetrahydrofuran, the mixture was then stirred at room temperature for 2 hours. The mixture was adjusted to pH 6 with concentrated HCl. The aqueous layer was extracted with 3×500mL ethyl acetate. It was concentrated and purified by reverse phase flash chromatography, eluting with 50% acetonitrile / water (0.05% FA) to give 1-(pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (116g, 80.5%) as an off-white solid. LCMS (ESI) [M+H] + :190

[1178] 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), N-(3-amino-5-bromophenyl) methanesulfonamide (134 g, 0.51 mol) in 300 mL of acetonitrile. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated and purified by reverse phase flash chromatography, eluting with 50% acetonitrile / 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 (300 MHz, acetone-d 6 )δ9.67(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,2 H), 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).

[1179] Examples 37-49 and 387

[1180] The compounds listed in the following table were prepared using procedures similar to those described in Example 36:

[1181]

[1182]

[1183]

[1184] Example 50: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(pyrimidin-2-yl)-1H-pyrazole-4-carboxamide

[1185]

[1186] Step 1: 1H-pyrazole-4-carboxylic acid ethyl ester (500 mg, 3.568 mmol, 1 eq.) and pyrimidine, 2-bromo- (567.23 mg, 3.568 mmol, 1 eq.) and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (101.50 mg, 0.714 mmol, 0.2 eq.) and CuI (67.95 mg, 0.357 mmol, 0.1 eq.) and K 2 CO 3 A solution of (1479.27 mg, 10.704 mmol, 3 eq.) in toluene (5 mL) was stirred at 110 °C under nitrogen atmosphere for 2 hours. 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

[1187] Step 2: Ethyl 1-(pyrimidin-2-yl)pyrazole-4-carboxylate (440 mg, 2.016 mmol, 1 eq.) and LiOH (144.87 mg, 6.048 mmol, 3 eq.) were dissolved in EtOH (4 mL) and H 2 The solution in 4% 4-nitropropane-2-yl)pyrazole-4-carboxylic acid (380 mg, 99.10%) was stirred at 60 °C for 1 hour. 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 / water, 20 min 0% to 100% gradient; detector, UV 254 nm. This produced 11-(pyrimidin-2-yl)pyrazole-4-carboxylic acid (380 mg, 99.10%) as a white solid. LCMS (ESI) [M+H] + :191

[1188] Step 3: To a stirred solution of 1-(pyrimidin-2-yl)pyrazole-4-carboxylic acid (80 mg, 0.421 mmol, 1 eq) and N-(3-amino-5-bromophenyl)methanesulfonamide (111.54 mg, 0.421 mmol, 1 eq) in DMSO (4 mL) was added NMI (103.62 mg, 1.263 mmol, 3 eq) and NMI (103.62 mg, 1.263 mmol, 3 mmol) in portions at room temperature. The residue was purified by reverse phase flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN / water, 20 min 0% to 100% gradient; detector, UV 254 nm. This produced 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 (300 MHz, DMSO-d 6 )δ10.34(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).

[1189] Examples 51-60 and 388-393

[1190] The compounds listed in the following table were prepared using procedures similar to those described in Example 50:

[1191]

[1192]

[1193]

[1194] Example 61: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(pyridin-3-ylmethoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1195]

[1196] Step 1: 3-(Bromomethyl)pyridine (520 mg, 3.02 mmol), 2-bromopyridin-3-ol (629 mg, 3.62 mmol), K 2 CO 3 To a mixture of 1.25 g, 9.06 mmol) was added DMF (5 mL). The mixture was stirred at 60 °C under N 2 The resulting mixture was stirred under 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 silica gel flash chromatography eluting with 15% ethyl acetate / petroleum ether to give 2-bromo-3-[(pyridin-3-yl)methoxy]pyridine (550 mg, 68.6%) as a white solid. LCMS [M+H] + :265

[1197] Step 2: 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), 1H-pyrazole-4-carboxylic acid ethyl ester (434 mg, 3.10 mmol), CuI (78.8 mg, 0.414 mmol) and K were added. 2 CO 3 To a mixture of 1,2-dihydro-1,4-dihydro-2-nitropropene (855 mg, 6.20 mmol) was added ACN (6 mL). The mixture was heated at 90 °C under N 2 The resulting mixture was stirred for 2 hours under atmosphere. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 95% ethyl acetate / petroleum ether to give 1-{3-[(pyridin-3-yl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylic acid ethyl ester (450 mg, 66.9%) as a yellow solid. LCMS [M+H] + :325

[1198] 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 was added LiOH (289 mg, 6.89 mmol). The resulting mixture was stirred at room temperature for two hours. It was then concentrated and the pH of the residue solution was adjusted to 3 with 1M HCl (aq.). The product was precipitated from the solution. After filtration, the filter cake was washed with water and dried in vacuo. This produced 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

[1199] 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 two hours. It was then concentrated and the residue was purified by reverse phase flash chromatography using 65% acetonitrile / water (0.1% NH 4 HCO 3 ) was used for purification by elution 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. 1 H NMR (300 MHz, DMSO-d 6 )δ10.21(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).

[1200] Examples 62-70

[1201] The compounds listed in the following table were prepared using procedures similar to those described in Example 61:

[1202]

[1203]

[1204]

[1205] Example 71: 4-Bromo-N-(3-fluoro-5-(methylsulfonamido)phenyl)thiophene-2-carboxamide

[1206]

[1207] 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) was added 4-bromothiophene-2-carboxylic acid (1.34 g, 6.50 mmol). The mixture was then stirred at room temperature for 1 hour. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (5-95%, acidic system) to obtain methyl 3-(4-bromothiophenol-2-amide)-5-fluorobenzoate (1.28 g, 3.59 mmol) as a yellow solid. LCMS (ESI) [M+H] + :358

[1208] Step 2: To methyl 3-(4-bromothiophene-2-amido)-5-fluorobenzoate (1.25 g, 3.48 mmol) in EtOH (10 mL) and H 2 To the stirred solution in 0 (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 in vacuo to give 3-(4-bromothiophene-2-amide)-5-fluorobenzoic acid (1.02 g, 2.98 mmol) as a white solid. LCMS (ESI) [M+H] + :344

[1209] Step 3: To a stirred solution of 3-(4-bromothiophene-2-amide)-5-fluorobenzoic acid (1 g, 2.906 mmol, 1 eq) and DPPA (1.04 g, 3.778 mmol, 1.3 eq) in t-BuOH (20 mL) was added Et3N (0.88 g, 8.718 mmol, 3 eq) at 80 ° C under nitrogen atmosphere for 6 hours. 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 give tert-butyl N-[3-(4-bromothiophene-2-amide)-5-fluorophenyl]carbamate (750 mg, 61.53%) as a light yellow solid. LCMS (ESI) [M+H] + :415

[1210] 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 hour. 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

[1211] 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 hour. 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 (300 MHz, DMSO-d 6 )δ10.52(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).

[1212] Examples 72-78

[1213] The compounds listed in the following table were prepared using procedures similar to those described in Example 71:

[1214]

[1215]

[1216] Example 79: N-(3-Chloro-5-(methylsulfonamido)phenyl)-1-ethyl-5-phenyl-1H-pyrrole-3-carboxamide

[1217]

[1218] Step 1: NaH (791 mg, 19.8 mmol, 60% purity) was added to a solution of 1H-pyrrole-3-carboxylic acid methyl ester (2.0 g, 15.9 mmol) in DMF (20 mL) at 0 ° C. The mixture was stirred at 0-5 ° C for 15 minutes, 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 hours. The mixture was poured into water (20 mL) and extracted with EA (30 mL * 3). The combined organic layer was washed with brine (15 mL * 2) and washed with Na 2 SO 4 The mixture was dried and filtered, and the filtrate was concentrated in vacuo to give a crude material. The crude product was pre-purified by silica gel column chromatography, eluting 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).

[1219] Step 2: NBS (1.43 g, 8.06 mmol) was added to a solution of 1-ethyl-1H-pyrrole-3-carboxylic acid methyl ester (1.2 g, 7.83 mmol) in THF (20 mL) at 0°C. The mixture was stirred at 25°C for 1 hour. 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) and purified by Na 2 SO 4Dry and concentrate in vacuo to give a residue. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1). 5-bromo-1-ethyl-1H-pyrrole-3-carboxylic acid methyl ester (1.8 g, 7.75 mmol, 99.4% yield) is obtained as a colorless oil. LCMS: MS (ESI) retention time: 0.783 min, (M+1)+=233.9. 1 H 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).

[1220] Step 3: To a solution of 5-bromo-1-ethyl-1H-pyrrole-3-carboxylic acid methyl ester (1.8 g, 7.75 mmol) and phenylboronic acid (1.2 g, 9.84 mmol) in MeOH (4 mL) and toluene (30 mL), tetrakis(triphenylphosphine)palladium (716 mg, 620 μmol) and 2.0 M sodium carbonate aqueous solution (7.75 μl, 15.5 mmol) were added. The mixture was stirred at 80 ° C for 3 hours under a nitrogen atmosphere. The mixture was cooled to 25 ° C, poured into water (20 mL) and extracted with EA (30 mL * 3). The combined organic layer was washed with brine (15 mL * 2) and washed with Na 2 SO 4 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 / hexanes. 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).

[1221] Step 4: To 1-ethyl-5-phenyl-1H-pyrrole-3-carboxylic acid methyl ester (1 g, 3.53 mmol) in THF (10 mL), MeOH (10 mL) and H 2 O (10 mL) was added to the solution 2O (545 mg, 13.0 mmol). The mixture was stirred at 25 ° C for 2 hours. The mixture was cooled to 25 ° C and poured into water (20 mL). The pH of the mixture was adjusted to 3-4 by 1N HCl. The mixture was extracted with EA (30 mL * 3). The combined organic layers were washed with brine (15 mL * 2) and washed with Na 2 SO 4 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)

[1222] Step 5: EDCI (667 mg, 3.48 mmol) was added 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). 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*4) and brine (25 mL*2), and the mixture was purified by anhydrous Na 2 SO 4 Dried, filtered, and the filtrate was evaporated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100C18 Ultra 150*50mm*3μm, mobile phase: [water (0.225% FA)-ACN]; B%: 36%-66%, 10min) and lyophilized. N-(3-chloro-5-(methylsulfonamido)phenyl)-1-ethyl-5-phenyl-1H-pyrrole-3-carboxamide (286.74mg, 98.48% purity, 0.675mmol, 58.2% yield) was obtained as an off-white solid. LCMS: MS (ESI) retention time: 0.920min, (M+1)+=417.9. 1 HNMR (400 MHz, DMSO-d 6)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)

[1223] Examples 80-82

[1224] The compounds listed in the following table were prepared using procedures similar to those described in Example 79:

[1225]

[1226] Example 83: 5-Bromo-N-(3-chloro-5-(methylsulfonamido)phenyl)-1-methyl-1H-pyrrole-3-carboxamide

[1227]

[1228] Step 1: 5-bromo-1H-pyrrole-3-carboxylic acid methyl ester (500 mg, 2.45 mmol), CH3I (521 mg, 3.67 mmol) and Cs 2 CO 3 DMSO (10 mL) was added to a stirred solution of 4-nitro-1-nitro-2-nitropropene (2.38 g, 7.35 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated and purified by flash chromatography using petroleum ether / EtOAc (0-100%, acidic system) to give 5-bromo-1-methyl-1H-pyrrole-3-carboxylic acid methyl ester (500 mg, 2.29 mmol) as a yellow solid. LCMS (ESI) [M+H] + :217.97

[1229] Step 2: To 5-bromo-1-methyl-1H-pyrrole-3-carboxylic acid methyl ester (500 mg, 2.29 mmol) in EtOH (6 mL) and H 2 To the stirred solution in 2% CO (2 mL) was added LiOH (164 mg, 6.86 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (0-100%, acidic system) to elute to give 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

[1230] Step 3: ACN (10 mL) was added 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), NMI (407 mg, 4.97 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (0-100%, acidic system) to elute to give 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 (300 MHz, DMSO-d 6 )δ10.04(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).

[1231] Example 84: N-(3-Bromo-5-(methylsulfonamido)phenyl)-1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide

[1232]

[1233] Step 1: To a stirred solution of 5-bromo-1H-pyrrole-3-carboxylic acid methyl ester (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 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (5-95%, acidic system) to give methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (380 mg, 1.74 mmol) as a white solid.

[1234] 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) at 100 °C were added CuI (66.2 mg, 348 μmol), Pd(PPh 3 ) 4(402 mg, 348 μmol), PPh 3 To the mixture of 4- (684mg, 2.61mmol) and LiCl (95.8mg, 2.26mmol) for 12 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (75ml), then transferred to a separatory funnel, and washed with 10% aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (3×60ml). The combined organic phase was washed with water (3 times 75ml), brine, and dried over magnesium sulfate. The mixture was concentrated and purified by flash chromatography on silica gel, eluted with EA / PE (0-100%) to give 1- methyl -5- (3- methylpyridine -2- bases) -1H- pyrrole -3- carboxylic acid methyl esters (346mg, 1.50mmol) as a white solid.

[1235] Step 3: To 1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylic acid methyl ester (200 mg, 868 μmol) in EtOH (3 mL) and H 2 In the stirring solution of 4-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-1-nitropropene (2-nitropropene)-2-nitropropene (3mL), LiOH (207mg, 8.68mmol) was added. 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 obtained solid was dried in vacuo to obtain 1-methyl-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxylic acid (150mg, 693μmol) as a white solid.

[1236] 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) was added N-(3-amino-5-bromophenyl)methanesulfonamide (134 mg, 508 mol). The mixture was then stirred at room temperature for 1 hour. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (5-95%, acidic system) to elute to give N-(3-bromo-5-methylsulfonylaminophenyl)-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 (300 MHz, DMSO-d 6)δ9.99(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).

[1237] Example 85: N-(3-Bromo-5-(methylsulfonamido)phenyl)-1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxamide

[1238]

[1239] 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) was added NMP (2 mL). 2 The resulting mixture was stirred for 2 hours under atmosphere. The reaction mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 30% ethyl acetate / petroleum ether to give 1-(cyclohex-2-ene-1-yl)-5-methyl-1H-pyrrole-3-carboxylic acid methyl ester (175 mg, 52.8%) as a light yellow solid.

[1240] LCMS [M+H] + :220

[1241] 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) was added EtOAc (2 mL). 2 The resulting mixture was stirred for 2 hours under atmosphere. 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 / petroleum ether to give 1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxylic acid methyl ester (145 mg, 82.1%) as a yellow solid. LCMS [M+H] + :222

[1242] Step 3: To a stirred solution of 1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxylic acid methyl ester (145 mg, 0.656 mmol) in 2 mL THF and 2 mL water was added LiOH (137.7 mg, 3.27 mmol). The resulting mixture was stirred at 50 ° C overnight. It was then concentrated, and the pH value of the residue solution was adjusted to 3 with 1M HCl (aqueous solution). The product was precipitated from the solution. After filtration, the filter cake was washed with water (2 mL) and dried in vacuo. This produced 1-cyclohexyl-5-methyl-1H-pyrrole-3-carboxylic acid (60 mg, 43.9%) as a white solid. LCMS [M + H] + :207

[1243] 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 two hours, then concentrated and the residue was purified by reverse phase flash chromatography eluting with 93% acetonitrile / 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 (300 MHz, DMSO-d 6 )δ9.96(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).

[1244] Example 86: 1-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide

[1245]

[1246] Step 1: To a solution of 5-bromo-2-fluoropyridine (200 mg, 1.136 mmol, 1 eq.) and ethyl 1H-pyrazole-4-carboxylate (238.9 mg, 1.705 mmol, 1.50 eq.) in DMSO (5 mL) was added Cs 2 CO 3 (1110.8mg, 3.409mmol, 3.00 equivalents). The resulting solution was stirred at 60 ° C for two hours. The reactant was quenched with water. The reaction mixture was diluted with water (50mL). The resulting solution was extracted with EtOAc (50*3mL) and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluted with EtOAc / petroleum ether (42%) to give 1-(5-bromopyridin-2-yl)pyrazole-4-carboxylic acid ethyl ester (300mg, 84.69%) as a yellow solid. LCMS (ESI): [M+H] + :296

[1247] Step 2: To a solution of ethyl 1-(5-bromopyridin-2-yl)pyrazole-4-carboxylate (200 mg, 0.675 mmol, 1 eq), 1-(piperazin-1-yl)ethanone (129.8 mg, 1.013 mmol, 1.50 eq), Pd(AcO)2 (15.2 mg, 0.068 mmol, 0.10 eq) and BINAP (84.1 mg, 0.135 mmol, 0.20 eq) in toluene (5 mL) was added Cs 2 CO 3 (660.2 mg, 2.026 mmol, 3.00 equiv). The resulting solution was stirred at 100 °C for two hours. 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

[1248] Step 3: To ethyl 1-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]pyrazole-4-carboxylate (135 mg, 0.393 mmol, 1 eq.) in THF (2 mL) and H 2To the solution in 4% paraformaldehyde (2 mL) was added LiOH (47.1 mg, 1.967 mmol, 5.00 equiv). The resulting solution was stirred at room temperature for one hour. The residue was purified by flash chromatography on a C18 column gel eluting with ACN / water (0.1% FA) (35%) to give 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

[1249] 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 eq), NMI (49.5 mg, 0.603 mmol, 2.00 eq) and TCFH (126.8 mg, 0.452 mmol, 1.50 eq) in ACN (2 mL) was added at room temperature. The resulting solution was stirred at room temperature for 10 minutes. N-(3-amino-5-bromophenyl)methanesulfonamide (119.8 mg, 0.452 mmol, 1.50 eq) was then added and stirred at room temperature for one hour. 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: 7 minutes 33% B to 47% B, 47% B; 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 HNMR (300 MHz, DMSO-d 6 )δ10.24(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).

[1250] Examples 87-94 and 394-423

[1251] The compounds listed in the following table were prepared using procedures similar to those described in Example 86:

[1252]

[1253]

[1254]

[1255]

[1256]

[1257]

[1258]

[1259]

[1260]

[1261]

[1262] Example 95: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-methyl-2-(3-methylpyridin-2-yl)1H-imidazole-4-carboxamide

[1263]

[1264] Step 1: 5-bromo-1H-pyrrole-3-carboxylic acid methyl ester (600 mg, 2.94 mmol), K 2 CO 3 (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 hours. The mixture was concentrated and flash chromatographed with ACN / H 2 The product was purified by eluting with 4% CO (5-95%, acidic system) to give methyl 5-bromo-1-(cyanomethyl)-1H-pyrrole-3-carboxylate (693 mg, 2.85 mmol) as a white solid.

[1265] Step 2: Methyl 5-bromo-1-(cyanomethyl)-1H-pyrrole-3-carboxylate (700 mg, 2.87 mmol), Pd(dppf)Cl 2 (420 mg, 0.574 mmol), KOAc (844 mg, 8.61 mmol) and B 2 Pin 2(3.63 g, 14.3 mmol) was stirred in a solution of dioxane (10 mL) for 2 hours. 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 1-(cyanomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylic acid methyl ester (326 mg, 1.12 mmol) as a yellow solid.

[1266] Step 3: 1-(Cyanomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylic acid methyl ester (330 mg, 1.13 mmol), Pd(PPh 3 ) 2 Cl 2 (158 mg, 0.226 mmol), Na 2 CO 3 (358 mg, 3.38 mmol) and 2-bromopyridine (213 mg, 1.35 mmol) in EtOH (4 mL) and H 2 The solution in 4% 4-(2-nitropropene)-1H-pyrrole-3-carboxylic acid (100 mg, 0.615 mmol) was stirred at 80 °C under nitrogen atmosphere for 2 hours. 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

[1267] Step 4: To 1-(cyanomethyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carboxylic acid methyl ester (150 mg, 0.621 mmol) was added H 2 In the stirring solution in 0 (5mL) and EtOH (5mL), LiOH (148mg, 6.21mmol) was added. 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 obtained solid was dried in vacuo to obtain 1-(cyanomethyl)-5-(pyridin-2-yl)-1H-pyrrole-3-carboxylic acid (108mg, 0.479mmol) as a yellow solid.

[1268] LCMS(ESI)[M+H] + :228

[1269] Step 5: To a stirred solution of 1-(cyanomethyl)-5-(pyridinyl-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) was added N-(3-amino-5-bromophenyl)methanesulfonamide (153 mg, 0.580 mmol). The mixture was then stirred at room temperature for 1 hour. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (5-95%, acidic system) to elute and purify to give 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 (300 MHz, DMSO-d 6 )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).

[1270] Example 96: N-(3-Bromo-5-(methylsulfonamido)phenyl)-1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxamide

[1271]

[1272] Step 1: 2-bromo-3-methylpyridine (51 mg, 2.96 mmol), CuI (1.12 g, 5.92 mmol), Pd(AcO) 2 (132 mg, 0.592 mmol), PPh 3 To a mixture of 1-methyl-1H-imidazole-4-carboxylic acid methyl ester (309 mg, 1.18 mmol), DBU (901 mg, 5.92 mmol), and 1-methyl-1H-imidazole-4-carboxylic acid methyl ester (497 mg, 3.55 mmol) was added dioxane (5 mL). 2The resulting mixture was stirred under 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 / 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

[1273] Step 2: To a stirred solution of 1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid methyl ester (150 mg, 0.648 mmol) in 2 mL THF and 2 mL water was added LiOH (135 mg, 3.23 mmol). The resulting mixture was stirred at room temperature for two hours. It was then concentrated and the pH value of the residue solution was adjusted to 3 with 1M HCl (aqueous solution). The product was precipitated from the solution. After filtration, the filter cake was washed with water and dried in vacuo. This produced 1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid (110 mg, 78.0%) as a white solid. LCMS [M+H] + :218

[1274] 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 two hours. It was then concentrated and the residue was purified by reverse phase flash chromatography using 60% acetonitrile / water (0.1% NH 4 HCO 3 ) was used for purification by elution to obtain N-(3-bromo-5-methanesulfonamidophenyl)-1-methyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxamide (25.9 mg, 11.0%) as a light pink solid. LCMS [M+H] + :464 1 H NMR (300 MHz, DMSO-d 6 )δ10.00(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).

[1275] Example 97: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-(difluoro(phenyl)methoxy)pyridin-2-yl)-1H-pyrazole-4-carboxamide

[1276]

[1277] 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 to a fluorescent lamp at room temperature at night for 50 hours. 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.

[1278] Step 2: (Chlorodifluoromethyl)benzene (350 mg, 2.15 mmol), Cs 2 CO 3 (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 at 120 °C for 3 hours. The mixture was concentrated and flash chromatographed with ACN / H 2 Purification was performed by eluting with 4-(4-(4-nitro-2-yl)-1H-pyridine (4-nitro-2-yl)-1H-pyridine (5-nitro-2-yl)-1H-pyridine (6-nitro-2-yl)-1H-pyridine (7 ... + :300

[1279] Step 3: 2-bromo-3-[difluoro(phenyl)methoxy]pyridine (50 mg, 0.166 mmol), CuI (6.32 mg, 0.0332 mmol), K 2 CO 3 A solution of (68.8 mg, 0.498 mmol), 1H-pyrazole-4-carboxylic acid ethyl ester (25.5 mg, 0.182 mmol) and (1S, 2S)-N1, N2-dimethylcyclohexane-1,2-diamine (9.44 mg, 0.0664 mmol) in ACN (5 mL) was stirred at 90 ° C under a nitrogen atmosphere for 2 hours. 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 1-{3-[difluoro(phenyl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylic acid ethyl ester (40.0 mg, 0.111 mmol) as a yellow solid. LCMS (ESI) [M+H] + :360

[1280] Step 4: To ethyl 1-{3-[difluoro(phenyl)methoxy]pyridin-2-yl}-1H-pyrazole-4-carboxylate (40 mg, 0.111 mmol) in EtOH (3 mL) and H 2 D (3mL) in a stirred solution of 4% paraformaldehyde (20% ethyl acetate) was added to the mixture. LiOH (26.5 mg, 1.11 mmol) was added to the stirred solution in 4% paraformaldehyde (20% ethyl acetate) (3mL). 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 in vacuo 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

[1281] 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 hour. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (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 (300 MHz, DMSO-d 6 )δ10.27(s,1H),10.11(s,1H),9.07(s,1H),8.58(dd,J=4.6,1.5Hz,1H),8.34(s,1H),8.2 4-8.15(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).

[1282] Example 98: N-(3-chloro-5-(methylsulfonamido)phenyl)-5-cyano-1-(pyridin-2-yl)-1H-pyrrole-3-carboxamide

[1283]

[1284] Step 1: To a solution of 1H-pyrrole-3-carboxylic acid methyl ester (1 g, 7.992 mmol, 1 eq), 2-bromopyridine (1.89 g, 11.988 mmol, 1.5 eq), CuI (304.4 mg, 1.598 mmol, 0.20 eq) and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (454.7 mg, 3.197 mmol, 0.40 eq) in ACN (10 mL) was added K under nitrogen at room temperature. 2 CO 3 (3.34 g, 23.992 mmol, 3.00 equiv). The resulting solution was stirred at 90 °C for two hours. 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

[1285] Step 2: To a solution of methyl 1-(pyridin-2-yl)pyrrole-3-carboxylate (850 mg, 4.203 mmol, 1 eq.) in THF (10 mL) was added NBS (897.79 mg, 5.044 mmol, 1.2 eq.) at room temperature. The resulting solution was stirred at room temperature for two hours. The residue was purified by flash chromatography on silica gel, eluting with column gel and eluting 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

[1286] Step 3: Under nitrogen, KI (242.1 mg, 1.458 mmol, 1.00 equiv) was added to a solution of 5-bromo-1-(pyridin-2-yl)pyrrole-3-carboxylic acid methyl ester (410 mg, 1.459 mmol, 1 equiv) and CuCN (261.3 mg, 2.917 mmol, 2.00 equiv) in NMP (5 mL) at room temperature. The resulting solution was stirred at 120 ° C for two hours. 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 layer was 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 give 5-cyano-1-(pyridin-2-yl)pyrrole-3-carboxylic acid methyl ester (180 mg, 46.71%) as a yellow solid. LCMS:(ESI):[M+H] + :228

[1287] Step 4: To methyl 5-cyano-1-(pyridin-2-yl)pyrrole-3-carboxylate (180 mg, 0.753 mmol, 1 eq., 95%) in THF (4 mL) and H 2 To the solution in 4% 4-nitropropane-2-yl)pyrrole-3-carboxylic acid (150 mg, 86.01%) was added LiOH (90.1 mg, 3.762 mmol, 5.00 equiv) in 2% 4-nitropropane-2-yl)pyrrole (2 mL). The resulting solution was stirred at room temperature for one hour. The residue was purified by flash chromatography on a C18 column gel eluting with ACN / water (0.1% FA) (45%) to afford 5-cyano-1-(pyridin-2-yl)pyrrole-3-carboxylic acid (150 mg, 86.01%) as a yellow solid. LCMS: (ESI): [M+H] + :214

[1288] Step 5: A solution of 5-cyano-1-(pyridin-2-yl)pyrrole-3-carboxylic acid (150 mg, 0.704 mmol, 1 eq), NMI (115.5 mg, 1.407 mmol, 2.00 eq) and TCFH (296.1 mg, 1.055 mmol, 1.50 eq) in ACN (5 mL) at room temperature. The resulting solution was stirred at room temperature for 10 minutes. N-(3-amino-5-chlorophenyl)methanesulfonamide (186.3 mg, 0.844 mmol, 1.20 eq) was then added and stirred at room temperature for one hour. 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: 7 minutes 40% B to 60% B, 60% B; wavelength: 254 / 220 nm; RT1 (min): 5.72 to give N-(3-chloro-5-methylsulfonylaminophenyl)-5-(phenylamino)-2H-pyrazole-3-carboxamide (29.6 mg, 48.73%) as a white solid. LCMS: (ESI): [M+H] + :416. 1 H NMR (300 MHz, DMSO-d 6 )δ10.21(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).

[1289] Example 99: 1-Benzyl-N-(3-bromo-5-(methylsulfonamido)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide

[1290]

[1291] Step 1: To a stirred solution of 4-fluoro-3-nitrobenzoic acid (1 g, 5.40 mmol) and 1-phenylmethylamine (578 mg, 5.40 mmol) in DMF (15 mL) was added Cs 2 CO 3 (5.26 g, 16.2 mmol). The mixture was then stirred at 80°C for 2 hours. The mixture was concentrated and flash chromatographed with ACN / H 2 The product was purified by eluting with 4-(benzylamino)-3-nitrobenzoic acid (700 mg, 2.57 mmol) as a yellow solid.

[1292] LCMS(ESI)[M+H] + :273.08

[1293] Step 2: 4-(Benzylamino)-3-nitrobenzoic acid (700 mg, 2.57 mmol) and NH 4 Cl (1.08 g, 20.5 mmol) in EtOH (10 mL) and H 2 To a stirred solution in 2% 4% dHO (3 mL) was added Fe (1.43 g, 25.6 mmol). The mixture was then stirred at 90 °C for 2 hours. 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

[1294] Step 3: In N 2 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 a solution of (trimethylsilyl)diazomethane (4.08 mmol) in hexanes dropwise under a 4% CO atmosphere. The mixture was then stirred at room temperature for 2 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 Purification was performed by eluting with 4-(4-nitropropene)-2-nitropropene (0-100%, acidic system) to give methyl 3-amino-4-(benzylamino)benzoate (265 mg, 1.03 mmol) as a yellow solid. LCMS (ESI) [M+H]+ :357.12

[1295] 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 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (0-100%, acidic system) elution to obtain 1-benzyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carboxylic acid methyl ester (100 mg, 0.354 mmol) as an off-white solid. LCMS (ESI) [M+H] + :283.02

[1296] Step 5: To 1-benzyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carboxylic acid methyl ester (100 mg, 0.354 mmol) in THF (3 mL) and H 2 To the stirred solution in 2% CO (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 using ACN / H 2 O (0-100%, acidic system) to elute and purify to obtain 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

[1297] 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 using ACN / H 2 O (0-100%, acidic system) to elute to obtain 1-benzyl-N-(3-bromo-5-methanesulfonamidophenyl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carboxamide (21.1 mg, 0.0395 mmol) as a white solid. LCMS (ESI) [M+H] + :515.3. 1H NMR (300 MHz, DMSO-d 6 )δ10.61(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=1.9H z, 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).

[1298] Example 100: N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(3-cyano-1H-pyrazol-1-yl)benzamide

[1299]

[1300] Step 1: To a stirred solution of 1H-pyrazole-3-carbonitrile (260 mg, 2.79 mmol), CuI (106 mg, 0.558 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (157 mg, 1.11 mmol) and 3-bromobenzoic acid (560 mg, 2.79 mmol) in DMSO (10 mL) was added Cs 2 CO 3 (2.72 g, 8.37 mmol). 2 The mixture was stirred under atmosphere for 2 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 Purification was performed by eluting with 4% paraformaldehyde (0-100%, acidic system) to obtain 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

[1301] 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 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2O (0-100%, acidic system) to give N-(3-chloro-5-methylsulfonamidophenyl)-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 (300 MHz, DMSO-d 6 )δ10.66(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. 01(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).

[1302] Example 101: N-(3-bromo-5-(methylsulfonamido)phenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxamide

[1303]

[1304] 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 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (0-100%, acidic system) to elute to obtain ethyl 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

[1305] Step 2: To ethyl 2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (235 mg, 1.01 mmol) in EtOH (3 mL) and H 2 To the stirred solution in 2% CO (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 using ACN / H 2 O (0-100%, acidic system) to elute and purify to obtain 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

[1306] 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 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (0-100%, acidic system) to elute and obtain N-(3-bromo-5-methanesulfonylaminophenyl)-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 (300 MHz, DMSO-d 6 )δ10.38(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).

[1307] Example 102: N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(2-chloropyridin-4-yl)benzamide

[1308]

[1309] Step 1: (2-chloropyridin-4-yl)boronic acid (500 mg, 3.17 mmol), Pd(dppf)Cl 2 To a stirred solution of 2-bromobenzoic acid (347 mg, 0.475 mmol) and 3-bromobenzoic acid (637 mg, 3.17 mmol) in dioxane (15 mL) was added K 2 CO 3 (1.32 g, 9.51 mmol). The mixture was then stirred at 80°C for 2 hours. The mixture was concentrated and subjected to reverse phase flash chromatography with ACN / H 2 Purification was performed by eluting with 4-(2-chloropyridin-4-yl)benzoic acid (210 mg, 0.898 mmol) as a yellow solid. LCMS (ESI) [M+H] + :234.02

[1310] 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 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (0-100%, acidic system) to obtain N-(3-chloro-5-methylsulfonylaminophenyl)-3-(2-chloropyridin-4-yl)benzamide (24.8 mg, 0.0566 mmol) as a white solid. LCMS (ESI) [M+H] + :436.02. 1 HNMR (300 MHz, DMSO-d 6 )δ10.59(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=7.8 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.96-7.78 (m, 1H), 7.77-7.66 (m, 3H), 6.99 (t, J = 1.9 Hz, 1H), 3.09 (s, 3H).

[1311] Example 103: N-(3-bromo-5-(methylsulfonamido)phenyl)-1-(2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazole-4-carboxamide

[1312]

[1313] Step 1: 1H-pyrazole-4-carboxylic acid ethyl ester (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 K 2 CO 3 A stirred solution of 1,4-dihydro-1,4-dihydro-2-nitropropene (914 mg, 6.63 mmol) in ACN (10.00 mL) was then stirred at 90 °C under N 2 The mixture was stirred for 4 hours at 4 °C. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2Purification was performed by eluting with 4-nitropropene (5-95%, acidic system) to obtain ethyl 1-(2-formylphenyl)-1H-pyrazole-4-carboxylate (332 mg, 1.36 mmol, 95%) as a yellow solid. LCMS (ESI) [M+H] + :245

[1314] Step 2: To ethyl 1-(2-formylphenyl)-1H-pyrazole-4-carboxylate (350 mg, 1.43 mmol), trimethyl(trifluoromethyl)silane (813 mg, 5.72 mmol) and K 2 CO 3 (592 mg, 4.29 mmol) in DMF (10.00 mL). The mixture was then stirred at room temperature for 4 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (5-95%, acidic system) to elute to obtain 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

[1315] 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 H 2 O (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 in vacuo 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

[1316] 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 using ACN / H 2O (5-95%, acidic system) to elute and purify 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 (400 MHz, DMSO-d 6 )δ10.17(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).

[1317] Example 104: 4-((1H-pyrrol-2-yl)methyl)-N-(3-bromo-5-(methylsulfonamido)phenyl)-thiophene-2-carboxamide

[1318]

[1319] Step 1: Methyl 4-methylthiophene-2-carboxylate (500 mg, 3.201 mmol, 1 eq.) and NBS (854.6 mg, 4.802 mmol, 1.50 eq.) were dissolved in CCl at room temperature under nitrogen. 4 To a solution of 4-(bromomethyl)thiophene-2-carboxylic acid (10 mL) was added BPO (1640.6 mg, 6.402 mmol, 2.00 equiv). 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 give methyl 4-(bromomethyl)thiophene-2-carboxylate (200 mg, 26.5%) as a yellow oil. LCMS: (ESI): [M+H] + :235

[1320] Step 2: Methyl 4-(bromomethyl)thiophene-2-carboxylate (200 mg, 0.851 mmol, 1 eq), Pd(PPh 3 ) 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 H 2 Cs was added to the solution in O (0.5 mL) 2 CO 3(831.5 mg, 2.552 mmol, 3.00 equiv). The resulting solution was stirred at 90 ° C for 2 hours. 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 layer was 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)thiophene-3-yl]methyl}pyrrole-1-carboxylate (80 mg, 27.50%) as a yellow oil. LCMS: (ESI): [M+H] + :322

[1321] Step 3: To tert-butyl 2-{[5-(methoxycarbonyl)thiophen-3-yl]methyl}pyrrole-1-carboxylate (80 mg, 0.249 mmol, 1 eq.) in THF (2 mL) and H 2 To the solution in 4% paraformaldehyde (ImL) was added LiOH (29.8 mg, 1.244 mmol, 5.00 equiv). The resulting solution was stirred at room temperature for one hour. The residue was purified by flash chromatography on a C18 column gel eluting with ACN / water (0.1% FA) (33%) to give 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

[1322] Step 4: A solution of 4-{[1-(tert-butoxycarbonyl)pyrrol-2-yl]methyl}thiophene-2-carboxylic acid (50 mg, 0.163 mmol, 1 eq.), NMI (26.7 mg, 0.325 mmol, 2.00 eq.) and TCFH (68.5 mg, 0.244 mmol, 1.50 eq.) in ACN (2 mL) was added at room temperature. The resulting solution was stirred at room temperature for 10 minutes. N-(3-amino-5-bromophenyl)methanesulfonamide (64.7 mg, 0.244 mmol, 1.50 eq.) was then added and stirred at room temperature for one hour. The residue was passed through a C18 column gel and washed with ACN / water (0.05 NHCl). 4 HCO 3 ) (65%) was used for purification by elution to obtain tert-butyl 2-({5-[(3-bromo-5-methylsulfonamidophenyl)carbamoyl]thiophen-3-yl}methyl)pyrrole-1-carboxylate (55 mg, 59.93%) as a white solid. LCMS: (ESI): [M+H] + :554

[1323] Step 5: To a solution of tert-butyl 2-({5-[(3-bromo-5-methylsulfonamidophenyl)carbamoyl]thiophen-3-yl}methyl)pyrrole-1-carboxylate (55 mg, 0.099 mmol, 1 eq.) in DCM (2 mL) was added TFA (1 mL) at 0°C. The mixture was stirred at room temperature for one hour. The residue was purified by preparative HPLC under the following conditions: Column: YMC-Actus TriartC18 ExRS, 30*150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 60% B, 60% B in 7 minutes; wavelength: 254 / 220 nm; RT1 (min): 9.28 / 11.57, to obtain N-(3-bromo-5-methylsulfonylaminophenyl)-4-(1H-pyrrol-2-ylmethyl)thiophene-2-carboxamide (16.0 mg, 34.89%) as a white solid. LCMS: (ESI): [M+H] + :454

[1324] 1 H NMR (300 MHz, DMSO-d 6 )δ10.65(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).

[1325] Example 105: N-(3-Fluoro-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide

[1326]

[1327] Step 1: 4-Bromo-N-(3-fluoro-5-methanesulfonamidophenyl)thiophene-2-carboxamide (100 mg, 0.254 mmol, 1 eq.) and pyridin-3-ylboronic acid (46.89 mg, 0.381 mmol, 1.5 eq.) and Pd(PPh 3 )2Cl 2 (17.85 mg, 0.025 mmol, 0.1 eq) and Na 2 CO 3 (80.86 mg, 0.762 mmol, 3 eq.) in EtOH (3 mL) and H2 The solution in 4% 4-(pyridin-3-yl)thiophene-2-carboxamide (27.8 mg, 27.93%) was stirred for 2 hours. The residue was purified by reverse phase flash chromatography under the following conditions: column, silica gel; mobile phase, MeCN / water, 0% to 100% gradient in 20 minutes; detector, UV 254 nm. This produced N-(3-fluoro-5-methylsulfonamidophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (27.8 mg, 27.93%) as a light green solid. LCMS: (ESI): LCMS (ESI) [M+H] + :392. 1 H NMR (300 MHz, DMSO-d 6 )δ10.61(s,1H),10.14(s,1H),9.11(s,1H),8.66(d,J=21.6Hz,2H),8.4 8(s,2H),7.75(s,2H),7.49(s,2H),6.76(d,J=10.4Hz,1H),3.09(s,3H).

[1328] Examples 108-111

[1329] The compounds listed in the following table were prepared using procedures similar to those described in Example 105:

[1330]

[1331]

[1332] Example 112: N-(3-Fluoro-5-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide

[1333]

[1334] 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) was added 4-bromothiophene-2-carboxylic acid (111 mg, 0.537 mmol). The mixture was then stirred at room temperature for 1 hour. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (5-95%, acidic system) to give 4-bromo-N-(3-fluoro-5-methanesulfonamidophenyl)thiophene-2-carboxamide (128 mg, 0.327 mmol) as a yellow solid. LCMS (ESI) [M+H] + :393

[1335] Step 2: 4-Bromo-N-(3-fluoro-5-methanesulfonamidophenyl)thiophene-2-carboxamide (130 mg, 0.330 mmol), Pd(dppf)Cl 2 A solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (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-dioxaborolan (335 mg, 1.32 mmol) in DMSO (10 mL) was stirred for 2 hours. The mixture was concentrated and purified by reverse phase flash chromatography with ACN / H 2 O (5-95%, acidic system) to elute and purify to obtain 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

[1336] Step 3: 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 2 (11.5 mg, 0.0158 mmol), K 2 CO 3 A solution of 2-bromopyridine (65.5 mg, 0.474 mmol) and 2-bromopyridine (49.9 mg, 0.316 mmol) in dioxane (5 mL) was stirred for 2 hours. 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 (300 MHz, DMSO-d 6)δ10.64(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).

[1337] Examples 113 and 114

[1338] The compounds listed in the following table were prepared using procedures similar to those described in Example 112:

[1339]

[1340]

[1341] Example 115: N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(2,6-difluorophenyl)thiophene-2-carboxamide

[1342]

[1343] 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 hours. 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

[1344] 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 NH 4 Cl (4.7 g, 88 mmol). 2The resulting mixture was stirred under atmosphere for 2 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give a 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

[1345] 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 hours. 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-methanesulfonamidophenyl)thiophene-2-carboxamide (800 mg, 95%) as a yellow solid. LCMS (ESI) [M+H] + :409

[1346] Step 4: 4-bromo-N-(3-chloro-5-methylsulfonamidophenyl)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 3 (21 mg, 0.0244 mmol) and K 3 PO 4 (155 mg, 0.732 mmol) in 1,4-dioxane (5.00 mL). The mixture was then stirred at 80 °C for 8 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (5-95%, acidic system) to elute and obtain 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 (300 MHz, DMSO-d 6 )δ10.52(s,1H),10.10(s,1H),8.31(s,1H),8.15(s,1H),7.66(d,J=13.3Hz, 2H), 7.50 (q, J = 7.4Hz, 1H), 7.28 (t, J = 8.2Hz, 2H), 6.98 (s, 1H), 3.08 (s, 3H).

[1347] Example 116: N-(3-chloro-5-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide

[1348]

[1349] 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 two hours. It was then concentrated and the residue was purified by reverse phase flash chromatography using 50% acetonitrile / water (0.1% NH 4 HCO 3 ) to give N-(3-chloro-5-nitrophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (212 mg,) as a white solid.

[1350] Step 2: To N-(3-chloro-5-nitrophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (212 mg, 589 μmol), Fe powder (164 mg, 2.94 mmol), 1H-pyrazole-carboxylic acid ethyl ester (434 mg, 3.10 mmol), NH 4 To a mixture of Cl (157 mg, 2.94 mmol) was added EtOH (2 mL) and H 2 O (0.2 mL). 2 The resulting mixture was stirred for 2 hours under atmosphere. 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 / petroleum ether to give N-(3-amino-5-chlorophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (156 mg) as a yellow solid.

[1351] Step 3: N-(3-amino-5-chlorophenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide (156 mg, 473 mmol) and Et 3 A solution of N (142 mg, 1.41 mmol) in DCM (1 mL) was stirred at room temperature. 2O (123 mg, 709 μmol) was added to the solution, and the resulting mixture was stirred at room temperature for 3 hours / the solvent was concentrated in vacuo. The residue was purified on a silica gel column eluted with 60% ethyl acetate / 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 HNMR (300 MHz, DMSO-d 6 )δ10.49(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=7.9,2.0 Hz, 1H), 7.64 (dt, J = 14.6, 1.9 Hz, 2H), 7.52 (dd, J = 7.9, 4.8 Hz, 1H), 6.97 (t, J = 1.9 Hz, 1H), 3.07 (s, 3H).

[1352] Examples 117 and 118

[1353] The compounds listed in the following table were prepared using procedures similar to those described in Example 116:

[1354]

[1355] Example 119: 1-Ethyl-N-(3-fluoro-5-(methylsulfonamido)phenyl)-5-methyl-1H-pyrazole-3-carboxamide

[1356]

[1357] 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) was added 1-ethyl-5-methyl-1H-pyrazole-3-carboxylic acid (1 g, 6.50 mmol). The mixture was then stirred at room temperature for 1 hour. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (5-95%, acidic system) to give methyl 3-(1-ethyl-5-methyl-1H-pyrazole-3-amide)-5-fluorobenzoate (1.09 g, 3.59 mmol) as a white solid. LCMS (ESI) [M+H] + :306

[1358] Step 2: To methyl 3-(1-ethyl-5-methyl-1H-pyrazole-3-amido)-5-fluorobenzoate (1 g, 3.27 mmol) in EtOH (10 mL) and H 2 0 (10mL) in a stirred solution, LiOH (782mg, 32.6mmol) was added. 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 in vacuo to give 3-(1-ethyl-5-methyl-1H-pyrazole-3-amide)-5-fluorobenzoic acid (848mg, 2.91mmol) as a yellow solid. LCMS (ESI) [M+H] + :292

[1359] Step 3: To a stirred mixture of 3-(1-ethyl-5-methylpyrazole-3-amido)-5-fluorobenzoic acid (500 mg, 1.717 mmol, 1 eq) and DPPA (610 mg, 2.22 mmol) in toluene (10 mL) was stirred at 80 °C under nitrogen atmosphere for 2 h. The mixture was cooled to room temperature and H 2 O (1 mL), and the mixture was stirred for another hour. 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

[1360] Step 4: N-(3-amino-5-fluorophenyl)-1-ethyl-5-methyl-1H-pyrazole-3-carboxamide (100 mg, 0.381 mmol) and Et 3 MsCl (47.7 mg, 0.419 mmol) was added dropwise to a stirred solution of N (115 mg, 1.14 mmol) in DCM (10 mL). The mixture was then stirred at room temperature for 1 hour. 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 (400 MHz, DMSO-d 6)δ10.16(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,1 H), 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).

[1361] Example 120: N-(3-chloro-5-(methylsulfonamido)phenyl)-5-(hydroxymethyl)-4-phenylthiophene-2-carboxamide

[1362]

[1363] 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) was added 5-bromo-4-phenylthiophene-2-carboxylic acid (200 mg, 0.706 mmol). The mixture was then stirred at room temperature for 4 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (5-95%, acidic system) to elute to give 5-bromo-N-(3-chloro-5-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (350 mg, 95%) as a white solid. LCMS (ESI) [M+H] + :485

[1364] Step 2: 5-bromo-N-(3-chloro-5-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (350 mg, 0.720 mmol), Ac2O (140 mg, 1.37 mmol), Pd(OAc) were added. 2 (16 mg, 0.071 mmol), Xantphos (80 mg, 0.138 mmol) and (COOH) 2 A stirred solution of 1,2-dihydro-1,4-dihydro-2-nitropropene (129 mg, 1.44 mmol) and DIEA (266 mg, 2.06 mmol) in DMSO (10.00 mL) was then stirred at 90 °C under N 2 The mixture was stirred under atmosphere for 4 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2O (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

[1365] Step 3: To a stirred solution of 5-[(3-chloro-5-methylsulfonamidophenyl)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) was added methanol (5 ml). The mixture was then stirred at room temperature for 4 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 O (5-95%, acidic system) to give methyl 5-[(3-chloro-5-methylsulfonylphenyl)carbamoyl]-3-phenylthiophene-2-carboxylate (180 mg, 95%) as a white solid. LCMS (ESI) [M+H] + :465

[1366] Step 4: To 5-[(3-chloro-5-methylsulfonamidophenyl)carbamoyl]-3-phenylthiophene-2-carboxylic acid methyl ester (180 mg, 0.387 mmol) and NaBH 4 (44mg, 1.16mmol) in EtOH (10.00mL) stirring solution. The mixture was then stirred at room temperature for 1 hour. 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 in vacuo to give N-(3-chloro-5-methanesulfonamidophenyl)-5-(hydroxymethyl)-4-phenylthiophene-2-carboxamide (37.2mg, 98.340%) as a white solid. LCMS (ESI) [M+H] + :437. 1 H NMR (300 MHz, DMSO-d 6 )δ10.38(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).

[1367] Example 121: N-(3-Bromo-5-(methylsulfonylimino)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide

[1368]

[1369] Step 1: A solution of N-(3-amino-5-bromophenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide (180 mg, 0.481 mmol, 1 eq) and 3-{[(tert-butyldimethylsilyl)imino](methyl)oxo-λ6-sulfonyl}-1-methylimidazol-1-ium (158.41 mg, 0.577 mmol, 1.2 eq) in MeCN (3 mL) was stirred at room temperature for 1 hour. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10 min 0% to 100% gradient; detector, UV 254 nm. This resulted in N-{3-bromo-5-[N-(tert-butyldimethylsilyl)methanesulfonylimino]phenyl}-4-(pyridin-2-yl)thiophene-2-carboxamide (170 mg, 62.49%) as a white solid. LCMS: (ESI): LCMS (ESI) [M+H] + :565

[1370] Step 2: N-{3-bromo-5-[N-(tert-butyldimethylsilyl)methanesulfonylimino]phenyl}-4-(pyridin-2-yl)thiophene-2-carboxamide (170 mg, 0.301 mmol, 1 eq) was dissolved in a solution of HCl in 1,4-dioxane (3 mL, 1 N) and stirred at room temperature for 1 hour. The residue was purified by reverse phase flash chromatography under the following conditions: column, C 18 Silica gel; mobile phase, MeCN / water (0.1% FA), 20 min 0% to 100% gradient; detector, UV 254 nm. This produced N-(3-bromo-5-methanesulfonyliminophenyl)-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 (300 MHz, DMSO-d 6 )δ10.38(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).

[1371] Examples 122 and 123

[1372] The compounds listed in the following table were prepared using procedures similar to those described in Example 120:

[1373]

[1374] Example 125: N-(3-Chloro-5-(methylsulfonamido)phenyl)-5-phenylthiophene-3-carboxamide

[1375]

[1376] 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) was added N-(3-amino-5-chlorophenyl)methanesulfonamide (106 mg, 0.482 mmol). The mixture was then stirred at room temperature for 4 hours. The mixture was concentrated and purified by reverse phase flash chromatography using ACN / H 2 The product was purified by eluting with 4% CO (5-95%, acidic system) to give 5-bromo-N-(3-fluoro-5-methanesulfonamidophenyl)thiophene-3-carboxamide (150 mg, 95%) as a yellow solid.

[1377] LCMS(ESI)[M+H] + :409.

[1378] Step 2: 5-bromo-N-(3-fluoro-5-methylsulfonamidophenyl)thiophene-3-carboxamide (90 mg, 0.219 mmol), phenylboronic acid (26.7 mg, 0.219 mmol), Pd(PPh 3 ) 4 (24 mg, 0.0219 mmol) and K 3 PO 4 To a stirred solution of 1,4-dioxane (10.00 mL) was added H 2 O (3.00 mL). The mixture was then stirred at 90 °C under nitrogen for 4 hours. The mixture was concentrated and subjected to reverse phase flash chromatography with ACN / H 2 O (5-95%, acidic system) to elute to obtain N-(3-chloro-5-methylsulfonylaminophenyl)-5-phenylthiophene-3-carboxamide (45 mg, 99.350%) as a white solid. LCMS (ESI) [M+H] + :407. 1H NMR (300 MHz, DMSO-d 6 )δ10.31(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).

[1379] Example 125

[1380] The compounds listed in the following table were prepared using procedures similar to those described in Example 123:

[1381]

[1382] Example 126: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(3-hydroxypropyl)-1H-pyrazole-4-carboxamide

[1383]

[1384] Step 1: 1H-pyrazole-4-carboxylic acid ethyl ester (200 mg, 1.42 mmol) and Cs 2 CO 3 To a solution of (693 mg, 2.13 mmol) in MeCN (5 mL) was added (3-bromopropoxy)(tert-butyl)dimethylsilane (377 mg, 1.49 mmol), and the mixture was stirred at 25 °C for 5 hours. 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 purified by Na 2 SO 4 The mixture was filtered and the filtrate was concentrated in vacuo to give the crude material. 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 HNMR (400 MHz, chloroform-d) δ = 7.85 (d, J = 8.8 Hz, 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 = 7.2 Hz, 3H), 0.86 (s, 9H), 0.08--0.11 (m, 6H).

[1385] 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 LiOH. 2 O (185 mg, 4.41 mmol) in water (5 mL). The mixture was stirred at 25 ° C for 14 hours. 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 washed with Na 2 SO 4 The mixture was dried. 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. 1 H NMR (400 MHz, DMSO-d 6 )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)

[1386] Step 3: EDCI (168 mg, 881 μmol) was added 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). The mixture was stirred at 25 ° C for 3 hours. The mixture was poured into water (20 mL) and extracted with EA (25 mL * 3). The combined organic layer was washed with 0.5N HCl (15 mL * 2), brine (15 mL * 2) and washed with Na 2 SO 4 The mixture was dried and filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC and freeze-dried. 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 (400 MHz, DMSO-d 6)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)

[1387] Examples 127-128

[1388] The compounds listed in the following table were prepared using procedures similar to those described in Example 125:

[1389]

[1390] Example 129: N-(3-Chloro-5-(methylsulfonamido)phenyl)-5-methyl-1-phenyl-1H-pyrrole-3-carboxamide

[1391]

[1392] 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) at 25 °C were 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). The mixture was stirred at 90°C for 16 hours. The mixture was poured into H 2 O (50 mL). The mixture was extracted with EA (30 mL*2). The combined organic layers were washed with brine (30 mL) and purified by Na 2 SO 4 Dry, filter and concentrate 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 (400 MHz, chloroform-d) δ = 7.58-7.38 (m, 4H), 7.35-7.29 (m, 2H), 6.48 (dd, J = 0.8, 1.8 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H)

[1393] Step 2: Ethyl 5-methyl-1-phenyl-1H-pyrrole-3-carboxylate (420 mg, 1.83 mmol) was dissolved in MeOH (3 mL), THF (2 mL) and H 2 Lithium hydroxide (1+) hydrate (230 mg, 5.49 mmol) was added to the solution in 2% O (1 mL). The mixture was stirred at 60 °C for 16 hours. The mixture was poured into 1N HCl (20 mL). The mixture was extracted with EA (30 mL*2). The combined organic layers were washed with brine (30 mL) and washed with Na 2 SO 4 Dry, filter and concentrate 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

[1394] 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) and purified by Na 2 SO 4 The mixture was dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC and freeze-dried. 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 (400 MHz, DMSO-d 6 )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).

[1395] Example 130

[1396] The compounds listed in the following table were prepared using procedures similar to those described in Example 129:

[1397]

[1398] Example 131: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide

[1399]

[1400] 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 H 2 O (50mL). The mixture was extracted with EA (30mL*2). The combined organic layer was washed with brine (30mL), dried over Na2SO4, 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 (54.68mg, 137μmol) as an off-white solid. LCMS: MS (ESI) retention time: 0.738min, (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).

[1401] Examples 132-136

[1402] The compounds listed in the following table were prepared using procedures similar to those described in the Examples:

[1403]

[1404] Example 137: N-(3-Chloro-5-(methylsulfonamido)phenyl)-3-(pyridin-2-yl)isothiazole-5-carboxamide

[1405]

[1406] Step 1: To a solution of picolinamide (1.5 g, 12.2 mmol) in toluene (15 mL) was added chloroformic acid hypochlorous anhydride (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)

[1407] 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) was added ethyl prop-2-ynoate (1.21 g, 12.4 mmol). The mixture was stirred at 160 ° C for 16 hours. The mixture was concentrated in vacuo 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.

[1408] LCMS: MS (ESI) retention time: 0.761 min, (M)+=235.0. 1 H 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)

[1409] 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 H2O (1 mL) was added LiOH.H2O (285 mg, 6.8 mmol). The mixture was stirred at 25°C for 2 hours. The mixture was poured into 1N HCl solution (10 mL). The mixture was extracted with EA (30 mL*2). The combined organic layers were washed with brine (30 mL) and purified by Na 2 SO 4Dry, filter and concentrate under reduced pressure to give the crude product. 3-(Pyridin-2-yl)isothiazole-5-carboxylic acid (200 mg, 969 μmol, crude product) was obtained as a yellow solid.

[1410] 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 h. The mixture was poured into H 2 O (50 mL) and extracted with EA (30 mL * 2). The combined organic layers were washed with brine (30 mL) and purified by Na 2 SO 4 The mixture was dried, 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. 1 H 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)

[1411] Example 138: N-(3-chloro-5-(methylsulfonamido)phenyl)-3-(pyridin-2-yl)isothiazole-5-carboxamide

[1412]

[1413] 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). Subsequently, a solution of 1-(2-(benzyloxy)phenyl)ethan-1-one (3.75 g, 16.5 mmol) in EtOH (20 mL) was added dropwise to the reactant at 0°C, and after addition, the reactant was stirred at 25°C for 16 hours. 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), and purified by Na2 SO 4 Dry and concentrate. 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

[1414] Step 2: NaH (183 mg, 60% purity, 4.59 mmol) was added to the solvent of EtOH (30 mL) at 0 ° C, and the mixture was stirred at 25 ° C for 5 minutes. Subsequently, 4-(2-(benzyloxy)phenyl)-2,4-dioxobutanoic acid ethyl ester (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 minutes and at 60 ° C for 2 hours. The mixture was cooled to 25 ° C and poured into water (35 mL). The pH value of the mixture was adjusted to 4-5 by 1N (HCl) and the mixture was extracted with EA (40 mL * 3). The combined organic layer was washed with brine (25 mL * 2) and washed with Na 2 SO 4 The mixture was dried 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). 3-(2-(benzyloxy)phenyl)-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (0.9 g, 2.67 mmol, 58.4% yield) was obtained as a light yellow oil. 5-(2-(benzyloxy)phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester was also obtained. 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).

[1415] Step 3: To a solution of ethyl 3-(2-(benzyloxy)phenyl)-1-methyl-1H-pyrazole-5-carboxylate (500 mg, 1.48 mmol) in a mixed solvent (MeOH:THF:H2O=1:1:1, 15 mL) was added LiOH (185 mg, 4.43 mmol). The mixture was stirred at 25°C for 2 hours. The pH value 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) and purified by anhydrous Na 2 SO 4 Dry, filter, and evaporate the filtrate 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).

[1416] 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 μmmol) 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 phases were washed with 1N HCl (20 mL*3) and brine (25 mL*2), and the residue was purified by anhydrous Na 2 SO 4 The mixture was dried, filtered, and the filtrate was evaporated in vacuo to give a residue. The residue was purified by preparative HPLC and freeze-dried. 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).

[1417] Examples 139-141

[1418] The compounds listed in the following table were prepared using procedures similar to those described in Example 138:

[1419]

[1420] Example 142: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(1-phenylethyl)-1H-pyrazole-4-carboxamide

[1421]

[1422] Step 1: To a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (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 hours. (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 hours. The mixture was poured into water (80 mL) and extracted with EA (40 mL*3). The combined organic phases were washed with brine (25 mL*3) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to obtain 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. 1 H 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)

[1423] Step 2: Ethyl 1-(1-phenylethyl)-1H-pyrazole-4-carboxylate (1.0 g, 4.09 mmol) was dissolved in a mixed solvent (15 mL, THF / MeOH / H 2 Lithium hydroxide (1+) hydrate (551 mg, 12.2 mmol) was added to a solution in 4% paraformaldehyde (2% paraformaldehyde) (4% paraformaldehyde) ...4% paraformaldehyde) (4% paraformaldehyde) (4% paraformaldehyde) (4% paraformaldehyde) (4% paraformaldehyde) (4% paraformaldehyde) (4% paraformaldehyde 2 SO 4 The mixture was filtered and the filtrate was concentrated in vacuo to give the crude material. The crude material 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

[1424] Step 3: EDCI (264 mg, 1.38 mmol) was added 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). The mixture was stirred at 25 ° C for 5 hours. The mixture was poured into water (40 mL) and extracted with EtOAc (30 mL * 3). The combined organic layer was washed with brine (15 mL * 3) and washed with Na 2 SO 4 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 material was purified by reverse phase chromatography (H 2 0-0.225% FA-MeCN conditions) 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 (400 MHz, DMSO-d 6)δ=10.04(s,1H),8.51(s,1H),8.07(s,1H),7.65(d,J=1.6Hz,1H),7.55(d,J=1.6Hz,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)

[1425] Example 143: N-(3-chloro-5-(methylsulfonamido)phenyl)-1-(2,2-difluoroethyl)-5-(3-methylpyridin-2-yl)-1H-pyrrole-3-carboxamide

[1426]

[1427] 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. 2,2-difluoroethyl trifluoromethanesulfonate (575 mg, 2.69 mmol) was added to the mixture at 0°C. The mixture was stirred at 25°C for 1 h. The mixture was poured into H 2 O (50 mL). The mixture was extracted with EA (30 mL*2). The combined organic layers were washed with brine (30 mL) and purified by Na 2 SO 4 The mixture was dried, 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 (400 MHz, DMSO-d 6 )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)

[1428] Step 2: Pd / C (200 mg, 187 μmol) was added 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) at 25 °C. The mixture was stirred under hydrogen (15 psi) for 14 hours at 25 °C. The mixture was filtered and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated in vacuo 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

[1429] 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 H 2 O (50 mL). The mixture was extracted with EA (30 mL*2). The combined organic layers were washed with brine (30 mL) and purified by Na 2 SO 4 The mixture was dried, 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 (400 MHz, DMSO-d 6 )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=8.4Hz,1H),7.7 7-7.70(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)

[1430] Example 144: tert-Butyl 6-(4-((3-chloro-5-(methylsulfonamido)phenyl)carbamoyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[1431]

[1432] Step 1: PPh3 (243 mg, 927 μmol) and DIAD (187 mg, 927 μmol) were slowly added to a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (100 mg, 0.713 mmol) and 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (174 mg, 820 μmol) in THF (2 mL) at 0 ° C. Th...

Claims

1. A compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is a halogen group; Y is O or NR y ; R y H or C 1-4 alkyl; R 1 C 1-4 Alkyl or C 3-6 Cycloalkyl; wherein the 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- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl; phenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; m is 0 to 3; n is 0 or 2; Each R 2 Independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen, OR 2a , cyano, -NR 2b R 2c 、-SO2R 2a 、-C(O)R 2d and -C(O)NR 2b R 2c , wherein the C 1-4 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with 1 to 4 R 2e Replacement; or 2 R 2 Together they form oxygen; R 2a H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy C 1-4 alkyl; R 2d H, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 2a , phenyl, 4 to 6-membered monocyclic heterocyclic group, 6 to 8-membered bicyclic heterocyclic group or 5 to 6-membered monocyclic heteroaryl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 halo groups and the 5 to 6 membered monocyclic heteroaryl group is optionally substituted with 1 to 3 C 1-4 Alkyl, C 1-4 Haloalkyl or phenyl substitution; R 2b and R 2c Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclic group and 5- to 6-membered monocyclic heteroaryl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 groups independently selected from halo and C 1-3 The alkoxy substituent is substituted; or R 2b and R 2c Together with the nitrogen to which it is attached, it forms a 4- to 6-membered monocyclic heterocyclic group or a 6- to 10-membered bicyclic heterocyclic group; wherein each of the 4- to 6-membered monocyclic heterocyclic group or the 6- to 10-membered bicyclic heterocyclic group is optionally substituted by 1 to 3 R 2d replace; Each R 2e are independently selected from halo, cyano, NR 2b R 2c , OR 2a , phenyl and 4- to 6-membered monocyclic heterocyclic groups; Z is a bond, -CH2-, -O-, -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 * indicates the 3 The connection point; Z a H or C 1-4 alkyl; R 3 C 3-6 cycloalkyl, 7- to 10-membered bicyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl, wherein the C 3-6 cycloalkyl, 7 to 10 membered bicyclic carbocyclyl, 4 to 6 membered monocyclic heterocyclyl, 6 to 10 membered bicyclic heterocyclyl, phenyl, 5 to 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl, each optionally and independently substituted with 1 to 4 R 4 replace; Each R 4 Independently selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, Halogen, 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 S02R 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, wherein the C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 The alkynyl group is optionally substituted with 1 to 4 R 4d substituted, and wherein the phenyl, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered monocyclic heterocyclyl and 6- to 10-membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R 4e and further optionally substituted with 1 or 2 oxo groups; or two R 4 Together they form oxygen; R 4a is H, optionally 1 to 4 R 4d Substituted C 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; wherein the C 3-6 Cycloalkyl, 4 to 6 membered monocyclic heterocyclyl, phenyl or 5 to 6 membered monocyclic heteroaryl each optionally and independently substituted with 1 to 3 R 4e replace; R 4b and R 4c Each is independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclic group, 5 to 6-membered monocyclic heteroaryl and optionally 1 to 4 R 4d Substituted C 1-4 Alkyl; or R 4b and R 4c Together with the nitrogen atom to which it is attached, it forms a 4- to 6-membered monocyclic heterocyclic group; Each R 4d are independently selected from 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, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 R 4g replace; Each R 4e independently selected from halogen, 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 , where C 1-4 The alkyl group is optionally substituted with 1 to 3 groups independently selected from halo, -SO2C 1-3 Alkyl and -C(O)NR 4b R 4c or two R 4e Together they form oxygen; R 4f H, C 1-4 Alkyl, C 1-4 haloalkyl, phenyl or 5- to 6-membered monocyclic heteroaryl, wherein the phenyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with one to three halo groups; Each R 4g are independently selected from halo, OR 4f , C 1-4 Alkyl, C 1-4 Haloalkyl, halogen, cyano, -NR 4b R 4c , -C(O)H and -C(O)OR 4f ;and Each R 4h Independently for C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkoxy or -N(R 4b )2.

2. The compound according to claim 1, wherein the compound is represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: X is a halogen group; Y is O or NR y ; R y H or C 1-4 alkyl; R 1 C 1-4 Alkyl or C 3-6 Cycloalkyl; wherein the C 1-4 Alkyl or C 3-6 Each cycloalkyl is optionally and independently substituted with 1 to 3 halo groups; Ring A is C 3-6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl; phenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl; m is 0 to 3; n is 0 or 1; Each R 2 Independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, halogen, OR 2a , cyano, -NR 2b R 2c 、-SO2R 2a 、-C(O)R 2d and -C(O)NR 2b R 2c , wherein the C 1-4 Alkyl and C 3-6 The cycloalkyl group is optionally substituted with 1 to 4 R 2e Replacement; or 2 R 2 Together they form oxygen; R 2a H, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy C 1-4 alkyl; R 2d H, C 1-4 Alkyl, C 3-6 Cycloalkyl, OR 2a , phenyl, 4 to 6-membered monocyclic heterocyclic group or 5 to 6-membered monocyclic heteroaryl, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 3 halo groups; R 2b and R 2c Each independently selected from 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 it is attached, it forms a 4- to 6-membered monocyclic heterocyclic group or a 6- to 10-membered bicyclic heterocyclic group; wherein each of the 4- to 6-membered monocyclic heterocyclic group or the 6- to 10-membered bicyclic heterocyclic group is optionally substituted by 1 to 3 R 2d replace; Each R 2e are independently selected from halo, cyano, NR 2b R 2c , OR 2a , phenyl and 4- to 6-membered monocyclic heterocyclic groups; Z is a bond, -CH2-, -O-, -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 * indicates the 3 The connection point; Z a H or C 1-4 alkyl; R 3 C 3-6 cycloalkyl, 7- to 10-membered bicyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 6- to 10-membered bicyclic heterocyclyl, phenyl, 5- to 6-membered monocyclic heteroaryl, or 8- to 10-membered bicyclic heteroaryl, wherein the C 3-6 cycloalkyl, 7 to 10 membered bicyclic carbocyclyl, 4 to 6 membered monocyclic heterocyclyl, 6 to 10 membered bicyclic heterocyclyl, phenyl, 5 to 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl, each optionally and independently substituted with 1 to 4 R 4 replace; Each R 4 Independently selected from C 1-4 Alkyl, halogen, 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, wherein the C 1-4 The alkyl group is optionally substituted with 1 to 4 R 4d substituted, and wherein the phenyl, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered monocyclic heterocyclyl and 6- to 10-membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R 4e Replace; or two R 4 Together they form oxygen; R 4a is H, optionally 1 to 4 R 4d Substituted C 1-4 Alkyl, C 3-6 cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, phenyl or 5- to 6-membered monocyclic heteroaryl; wherein the C 3-6 Cycloalkyl, 4 to 6 membered monocyclic heterocyclyl, phenyl or 5 to 6 membered monocyclic heteroaryl each optionally and independently substituted with 1 to 3 R 4e replace; R 4b and R 4c Each is independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclic group, 5 to 6-membered monocyclic heteroaryl and optionally 1 to 4 R 4d Substituted C 1-4 alkyl; Each R 4d are independently selected from 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 the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted by 1 to 3 R 4g replace; Each R 4e independently selected from 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 they form oxygen; R 4f H, C 1-4 Alkyl, C 1-4 haloalkyl, phenyl or 5- to 6-membered monocyclic heteroaryl, wherein the phenyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with one to three halo groups; Each R 4g are independently selected from halo, OR 4f , C 1-4 Alkyl, halide, cyano, -NR 4b R 4c , -C(O)H and -C(O)OR 4f .

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is Cl, Br or F.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein X is Cl or Br.

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein X is Cl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, thienyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, thiazolyl, imidazolyl, 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]thienyl, 5-oxo-5H-thiazolo[3,2-a]pyridinyl , thieno[3,2-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, benzothienyl, 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]thienyl and 4,7-dihydro-5H-thieno[2,3-c]pyranyl.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from phenyl, thienyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl, thiazolyl, imidazolyl, 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]pyrazolyl, ]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, benzothienyl, 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]thienyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein Ring A is represented by the following formula: Each of them is treated with 0 to 2 R 2 and 0 to 1 ZR 3 replace.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein Ring A is represented by the following formula: Each of them is treated with 0 to 2 R 2 and 0 to 1 ZR 3 replace.

10. The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein Ring A is represented by the following formula:

11. The compound or pharmaceutically acceptable salt thereof according to claim 9, wherein Ring A is represented by the following formula:

12. The compound or pharmaceutically acceptable salt thereof according to claim 6 or 7, wherein ring A is selected from phenyl, thienyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl and imidazolyl.

13. The compound or pharmaceutically acceptable salt thereof according to claim 8 or 9, wherein Ring A is represented by the following formula: Each of them is 0 to 1 R 2 and 1 R 3 replace.

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

15. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from -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 the following structural formula:

16. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from -CH3, -CF3, -CH2CH3, -CH(CH3)2, -CH(OH)CH3, -CH2OCH3, -CH2OH, -CH2CF3, -CH2CH2OH, -CH2CH2CH2OH, -CH2CN, -CH2CHF2, -CH2NH2, -N(CH3)2, cyano, halo, -C(O)OH, -C(O)N(CH3)2 and -C(O)NHCH3 or the following structural formula:

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

18. A compound according to any one of claims 1 to 9, 12, 13, 15, 16 and 17, or a pharmaceutically acceptable salt thereof, wherein n is 1 and Z is a bond.

19. A compound according to any one of claims 1 to 9, 12, 13, 15, 16 and 17, or a pharmaceutically acceptable salt thereof, wherein n is 1 and Z is -CH2-, -CH(CH3)-, -O-, -N(H)-, -N(C 1-4 alkyl)- or -C(O)NH-*, where * indicates the 3 connection point.

20. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, thienyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-1H-pyrazolyl, benzimidazolyl, indole oxazolyl, indolyl, 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]heptyl, 2-azaspiro[3.3]heptyl and 2-oxaspiro[3.3]heptyl, each of which is optionally substituted with 1 to 3 R 4 replace.

21. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazinyl, thienyl, tetrahydropyranyl, tetrahydrofuranyl, oxabicyclo[3.2.1]octyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-1H-pyrazolyl , benzimidazolyl, indazolyl, indolyl, 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]heptyl, 2-azaspiro[3.3]heptyl and 2-oxaspiro[3.3]heptyl, each of which is optionally substituted with 1 to 3 R 4 replace.

22. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein Z is -CH2- and R 3 is selected from thienyl, pyrrolyl and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is optionally substituted with 1 to 2 R 4 replace.

23. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 3 Represented by the following structural formula: Each of which is optionally substituted with 1 to 3 R 4 replace.

24. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 3 Represented by the following structural formula: Each of which is optionally substituted with 1 to 3 R 4 replace.

25. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein R 3 Represented by the following structural formula:

26. The compound according to claim 24 or a pharmaceutically acceptable salt thereof, wherein R 3 Represented by the following structural formula:

27. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl or a 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted by 1 to 2 R 4 replace.

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from phenyl, pyrazolyl, pyridinyl and pyrimidinyl, each of which is optionally substituted with 1 to 2 R 4 replace.

29. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein R 3 Represented by the following structural formula: Each of which is optionally substituted with 1 to 2 R 4 replace.

30. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein R 3 Represented by the following structural formula:

31. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, wherein R 3 Represented by the following structural formula:

32. A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein: R 4 Selected from C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OR 4a 、-CN、-NH2、-NR 4b R 4c , halogen, -C(O)R 4a 、-NHC(O)R 4a 、-NHC(O)OR 4a 、-NR 4b S02R 4a 、-SR 4a 、-S(O)R 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, 6- to 10-membered bicyclic heterocyclic group and 4- to 6-membered monocyclic heterocyclic group, wherein R 4 The C 1-3 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl is optionally substituted with 1 to 3 substituents independently selected from halo, phenyl, optionally substituted with 1 or 2 R 4g substituted 5- to 6-membered monocyclic heteroaryl, and optionally 1 or 2 R 4g Substituted 4- to 6-membered monocyclic heterocyclic group, -C(O)NR 4b R 4c 、-C(O)R 4a OR 4f ; and by R 4 The benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl, 6- to 10-membered bicyclic heterocyclic group and 4- to 6-membered monocyclic heterocyclic group represented by each optionally have 1 to 3 R 4e substituted and further optionally substituted with one or two oxo groups, or two R 4 Together they form oxygen; R 4a is H, optionally 1 to 4 R 4d Substituted C 1-4 Alkyl, -NR 4b R 4c , C 3-6 Cycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclic group or 5 to 6-membered monocyclic heteroaryl; wherein the phenyl, 4 to 6-membered monocyclic heterocyclic group and 5 to 6-membered monocyclic heteroaryl are optionally substituted by 1 to 3 R 4e replace; Each R 4b independently H or C 1-4 alkyl; R 4c is H, optionally 1 to 4 R 4d Substituted C 1-4 alkyl, 4- to 6-membered monocyclic heterocyclic group, or 5- to 6-membered monocyclic heteroaryl; Each R 4d are independently selected from halo, -OR 4f , C 3-6 Cycloalkyl, -C(O)OH, -NR 4b R 4c , phenyl and 5 to 6-membered monocyclic heteroaryl, wherein the phenyl and 5 to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from the following: 1-3 Alkyl, C 1-3 Haloalkyl, halo, CN and OH; Each R 4e independently selected from 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 they form oxygen; R 4f H, C 1-4 alkyl, phenyl or 5- to 6-membered monocyclic heteroaryl, wherein phenyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 halo groups; Each R 4g Independently for C 1-3 Alkyl or halo; and Each R 4h Independently for C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkoxy or -N(R 4b )2.

33. A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein: R 4 Selected from C 1-3 Alkyl, -OR 4a 、-CN、-NH2、-NHR 4c , halogen, -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 heterocyclic group, wherein R 4 The C 1-3 The alkyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, phenyl, 5- to 6-membered monocyclic heteroaryl, -C(O)NR 4b R 4c OR 4f ; by R 4 The benzyl, phenyl, 5- to 6-membered monocyclic heteroaryl and 4- to 6-membered monocyclic heterocyclic group represented by each optionally have 1 to 3 R 4e Replace, or two R 4 Together they form oxygen; R 4a is H, optionally 1 to 4 R 4d Substituted C 1-4 Alkyl, -NR 4b R 4c phenyl or 5 to 6 membered monocyclic heteroaryl, wherein the phenyl and 5 to 6 membered monocyclic heteroaryl are optionally substituted by 1 to 3 R 4e replace; R 4b H or C 1-4 alkyl; R 4c is H, optionally 1 to 4 R 4d Substituted C 1-4 alkyl, 4- to 6-membered monocyclic heterocyclic group, or 5- to 6-membered monocyclic heteroaryl; Each R 4d Independently selected from C 1-3 alkyl, halo, phenyl and 5- to 6-membered monocyclic heteroaryl, wherein the phenyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 substituents independently selected from halo, CN and OH; Each R 4e independently selected from halogen, 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 they form oxygen; R 4f H, C 1-4 Alkyl, phenyl or 5- to 6-membered monocyclic heteroaryl, wherein phenyl and 5- to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 halo groups.

34. A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein R 4 Represented by the following structural formula: Each of which is optionally substituted with 1 to 3 R 4e substituted and further optionally substituted with 1 or 2 oxo.

35. A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein R 4 Represented by the following structural formula: Each of which is optionally substituted with 1 to 3 R 4e replace.

36. The compound according to claim 34 or a pharmaceutically acceptable salt thereof, wherein R 4 Represented by the following structural formula:

37. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein R 4 Represented by the following structural formula:

38. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein each R 4e are 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.

39. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R 4e It is -CH3, -C(O)CH3, -C(O)CH(CH3)2, -C(O)N(CH3)2 or cyano.

40. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein: R 4 is - OR 4a ; R 4a is optionally 1 to 3 R 4d Substituted C 1-3 alkyl or optionally 1 to 3 R 4e substituted 4- to 6-membered monocyclic heterocyclyl; Each R 4d are independently halogen, C 1-2 alkyl, phenyl or 5- to 6-membered monocyclic heteroaryl, provided that two or three R 4d When the R 4d One of them is phenyl or a 5- to 6-membered monocyclic heteroaryl group, and the other R 4d are each independently halogen or C 1-2 Alkyl; wherein R 4d The phenyl group and the 5- to 6-membered monocyclic heteroaryl group represented by each optionally substituted by 1 to 3 independently selected C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and halo substituents; Each R 4e Independently for C 1-4 Alkyl, C 1-4 Haloalkyl, -SO2C 1-3 Alkyl or -C(O)C 3-6 Cycloalkyl.

41. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein: R 4 is -OR 4a ; R 4a For 1 to 3 R 4d Substituted C 1-3 alkyl; Each R 4d are independently halogen, C 1-2 alkyl, phenyl or 5- to 6-membered monocyclic heteroaryl, provided that two or three R 4d When the R 4d One of them is phenyl or a 5- to 6-membered monocyclic heteroaryl group, and the other R 4d are each independently halogen or C 1-2 Alkyl; wherein R 4d The phenyl group and the 5- to 6-membered monocyclic heteroaryl group represented are each optionally substituted by 1 to 3 halogen groups.

42. A compound according to any one of claims 1 to 33, wherein R 4 -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)CH2O R is preferably an alkyl, or a alkyl radical; wherein the alkyl radical is an ... 4 Represented by the following structural formula:

43. A compound according to any one of claims 1 to 33, wherein R 4 is -CH3, CH2OH, -CHF2, -CF3, -CH(CF3)OH, -CH2OCH3, -CH2CN, -CH2CF3, -CH2CH2OH, -CH2C(O)N(C H3)2, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -CN, -NH2, halo, -C(O)H, -C(O)CH(CH3)2, -C(O)O CH3, -C(O)O-tert-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, or R 4 Represented by the following structural formula:

44. A compound according to any one of claims 1 to 5, 15, 16, 20, 21 and 23 to 43, wherein the compound is represented by formula (IIA), (IIB) or (IIC): or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

45. A compound according to any one of claims 1 to 5, 15, 16, 20, 21 and 23 to 43, wherein the compound is represented by formula (IIIA) or (IIIB): or a pharmaceutically acceptable salt thereof.

46. ​​A compound according to any one of claims 1 to 5, 15, 16, 20, 21 and 23 to 43, wherein the compound is represented by formula (IVA), (IVB), (IVC) or (IVD): or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

47. A compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -CH3 or -CH2CH3.

48. A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -CH3.

49. The compound according to claim 1, wherein the compound is represented by formula (V): or a pharmaceutically acceptable salt thereof, wherein: X is Cl or Br; R 1 is -CH3 or -CH2CH3; Ring A is selected from phenyl, thienyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl and imidazolyl; m is 0 or 1; Each R 2 Independently selected from C 1-3 Alkyl and -C(O)R 2d , wherein the C 1-3 The alkyl group is optionally 2g replace; R 2d is a 4- to 6-membered monocyclic heterocyclic group; R 2g is cyano or OH; R 3 is phenyl or 5 to 6-membered monocyclic heteroaryl, wherein the phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 or 2 R 4 replace; Each R 4 independently selected from halogen, C 1-4 Alkyl, -O-benzyl, -OC 1-3 alkyl, cyano, -NH2 and 4 to 6 membered monocyclic heterocyclic groups, wherein the benzyl group is optionally substituted by 1 to 3 halogen or C 1-3 Haloalkyl substitution.

50. The compound according to claim 2, wherein the compound is represented by formula (V): or a pharmaceutically acceptable salt thereof, wherein: X is Cl or Br; R 1 is -CH3 or -CH2CH3; Ring A is selected from phenyl, thienyl, pyrrolyl, pyrazolyl, furanyl, isothiazolyl and imidazolyl; m is 0 or 1; Each R 2 Independently selected from C 1-3 Alkyl and -C(O)R 2d , wherein the C 1-3 The alkyl group is optionally 2g Replacement; R 2d is a 4- to 6-membered monocyclic heterocyclic group; R 2g is cyano or OH; R 3 is phenyl or 5 to 6-membered monocyclic heteroaryl, wherein the phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 or 2 R 4 replace; Each R 4 Independently selected from C 1-4 alkyl, -O-benzyl, cyano, -NH2, and 4 to 6 membered monocyclic heterocyclyl, wherein the benzyl group is optionally substituted with a halo group.

51. The compound according to claim 49 or 50, or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by the following formula:

52. The compound of claim 49 or 50, wherein the compound is represented by formula (IIB), (IIIA), (IVA); or (IVB): or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

53. A compound according to any one of claims 49 to 52, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from phenyl, pyrazolyl, pyridinyl and pyrimidinyl, each of which is optionally substituted with 1 to 2 R 4 replace.

54. A compound according to any one of claims 49 to 52, or a pharmaceutically acceptable salt thereof, wherein R 3 Represented by the following structural formula: Each of which is optionally substituted with 1 to 2 R 4 replace.

55. A compound according to any one of claims 49 to 52, or a pharmaceutically acceptable salt thereof, wherein R 3 Represented by the following structural formula:

56. A compound according to any one of claims 49 to 55, wherein R 4 is -F, -OCH(CH3)2, -OC(CH3)3, -CH3, cyano, -NH2, or R 4 Represented by the following structural formula:

57. A compound according to any one of claims 49 to 55, wherein R 4 is -CH3, cyano, -NH2, or R 4 Represented by the following structural formula:

58. A compound according to any one of claims 49 to 57, or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH3, -CH2CN, -CH2OH, or R 2 It is expressed by the following formula:

59. The compound of claim 49, wherein the compound is represented by formula (IIB) or (IVB): 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 optionally substituted with 1 or 2 R 4 replace; R 4 Halogen, -OC 1-3 alkyl or a 4 to 6-membered monocyclic heterocyclic group, wherein the 4 to 6-membered monocyclic heterocyclic group is optionally substituted by 1 or 2 halogen or C 1-3 Haloalkyl substitution.

60. The compound according to claim 59 or a pharmaceutically acceptable salt thereof, wherein R 3 Represented by the following structural formula:

61. The compound according to claim 59 or 60, or a pharmaceutically acceptable salt thereof, wherein each R 4 are independently -F, -OCH(CH3)2 or -OC(CH3)3, or R 4 Represented by the following structural formula:

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

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

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

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

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

67. The method of claim 66, wherein the cancer is selected from the group consisting of 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. The method of claim 67, wherein the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer, and gastric cancer.

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

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

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

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

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