INHIBITORS OF RNA HELICASE DHX9 AND USES THEREOF

20250179013 · 2025-06-05

Inventors

Cpc classification

International classification

Abstract

Provided are compounds of the Formula (I): or pharmaceutically acceptable salts thereof, which are useful for the inhibition of DHX9 and in the treatment of a variety of DHX9 mediated conditions or diseases, such as cancer.

##STR00001##

Claims

1. A compound represented by Formula (I): ##STR00215## or a pharmaceutically acceptable salt thereof, wherein: X is H, C.sub.1-4alkyl, C.sub.2-4haloalkyl, or C(O)R.sup.x; R.sup.x is H, OH, OC.sub.1-4alkyl, or C.sub.1-4alkyl; Y is O or NR.sup.y; R.sup.y is H or C.sub.1-4alkyl; R.sup.1 is C.sub.1-4alkyl or C.sub.3-6cycloalkyl; wherein the C.sub.1-4alkyl or C.sub.3-6cycloalkyl are each optionally and independently substituted with 1 to 3 halo; Ring A is a C.sub.3-6cycloalkyl, 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; each R.sup.2 is independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, halo, OR.sup.2a, cyano, NR.sup.2bR.sup.2c, SO.sub.2R.sup.2a, C(O)R.sup.2d, and C(O)NR.sup.2bR.sup.2c, wherein the C.sub.1-4alkyl and C.sub.3-6cycloalkyl are optionally substituted with 1 to 4 R.sup.2e; or 2 R.sup.2 together form oxo; R.sup.2a is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl, or benzyl; R.sup.2d is H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl; OR.sup.2a, phenyl, 4 to 6-membered monocyclic heterocyclyl or 5 to 6-membered monocyclic heteroaryl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 3 halo; R.sup.2b and R.sup.2e are each independently selected from H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclyl and 5 to 6-membered monocyclic heteroaryl; or R.sup.2b and R.sup.2c, together with the nitrogen to which they are attached form a 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl; wherein the 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R.sup.2d; each R.sup.2e is independently selected from halo, cyano, NR.sup.2bR.sup.2c, OR.sup.2a, phenyl, and 4 to 6 membered monocyclic heterocyclyl; Z is a bond, CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1-4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, N(Z.sup.a)C(O)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3; Z.sup.a is H or C.sub.1-4alkyl; provided when X is H and Z is a bond, ring A is phenyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, or 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl; R.sup.3 is C.sub.3-6cycloalkyl, 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.sub.3-6cycloalkyl, 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 are each optionally and independently substituted with 1 to 4 R.sup.4; each R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OR.sup.4a, cyano, NR.sup.4bR.sup.4c, C(O)R.sup.4a, C(O)OR.sup.4a, C(O)NR.sup.4bR.sup.4c, NR.sup.4bC(O)R.sup.4aNR.sup.4bC(O)OR.sup.4a, SR.sup.4a, SO.sub.2R.sup.4a, SO.sub.2NR.sup.4bR.sup.4c, P(O)R.sup.4bR.sup.4c, phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl, and 6 to 10-membered bicyclic heterocyclyl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 4 R.sup.4d, 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.sup.4e; or two R.sup.4 together form oxo; R.sup.4a is H, C.sub.1-4alkyl optionally substituted with 1 to 4 R.sup.4d, C.sub.3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl, or 5 to 6-membered monocyclic heteroaryl; wherein the C.sub.3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 R.sup.4e; R.sup.4b and R.sup.4c are each independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclyl, 5 to 6-membered monocyclic heteroaryl, and C.sub.1-4alkyl optionally substituted with 1 to 4 R.sup.4d; each R.sup.4d is independently selected from halo, OR.sup.4f, C(O)C.sub.1-4alkyl, C(O)NR.sup.4bR.sup.4c, C(O)C.sub.1-4haloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, 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 R.sup.4g; each R.sup.4e is independently selected from halo, C.sub.1-4alkyl optionally substituted with 1 to 3 halo, cyano, OR.sup.4f, NR.sup.4bR.sup.4c, C(O)H, C(O)C.sub.1-4alkyl, C.sub.1-4alkylene-C(O)NR.sup.4bR.sup.4c, and C(O)NR.sup.4bR.sup.4c; or two R.sup.4e together form oxo; R.sup.4f is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl, 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; each R.sup.4g is independently selected from halo, OR.sup.4f, C.sub.1-4alkyl, halo, cyano, NR.sup.4bR.sup.4c, C(O)H, and C(O)OR.sup.4f; provided that the compound is not any one of the compounds shown in Table I.

2. The compound of claim 1, wherein the compound is represented by Formula (I): ##STR00216## or a pharmaceutically acceptable salt thereof, wherein: X is H, C.sub.1-4alkyl, C.sub.2-4haloalkyl, or C(O)R.sup.x; R.sup.x is H, OH, OC.sub.1-4alkyl, or C.sub.1-4alkyl; Y is O or NR.sup.y; R.sup.y is H or C.sub.1-4alkyl; R.sup.1 is C.sub.1-4alkyl or C.sub.3-6cycloalkyl; wherein the C.sub.1-4alkyl or C.sub.3-6cycloalkyl are each optionally and independently substituted with 1 to 3 halo; Ring A is a C.sub.3-6cycloalkyl, 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; each R.sup.2 is independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, halo, OR.sup.2a, cyano, NR.sup.2bR.sup.2c, SO.sub.2R.sup.2a, C(O)R.sup.2d, and C(O)NR.sup.2bR.sup.2c, wherein the C.sub.1-4alkyl and C.sub.3-6cycloalkyl are optionally substituted with 1 to 4 R.sup.2e; or 2 R.sup.2 together form oxo; R.sup.2a is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl, or benzyl; R.sup.2d is H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl; OR.sup.2a, phenyl, 4 to 6-membered monocyclic heterocyclyl or 5 to 6-membered monocyclic heteroaryl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 3 halo; R.sup.2b and R.sup.2c are each independently selected from H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclyl and 5 to 6-membered monocyclic heteroaryl; or R.sup.2b and R.sup.2c, together with the nitrogen to which they are attached form a 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl; wherein the 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R.sup.2d; each R.sup.2e is independently selected from halo, cyano, NR.sup.2bR.sup.2c, OR.sup.2a, phenyl, and 4 to 6 membered monocyclic heterocyclyl; Z is a bond, CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1-4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, N(Z.sup.a)C(O)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3; Z.sup.a is H or C.sub.1-4alkyl; provided when X is H and Z is a bond, ring A is phenyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, or 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl; R.sup.3 is C.sub.3-6cycloalkyl, 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.sub.3-6cycloalkyl, 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 are each optionally and independently substituted with 1 to 4 R.sup.4; each R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OR.sup.4a, cyano, NR.sup.4bR.sup.4c, C(O)R.sup.4a, C(O)OR.sup.4a, C(O)NR.sup.4bR.sup.4c, NR.sup.4bC(O)R.sup.4aNR.sup.4bC(O)OR.sup.4a, SR.sup.4a, SO.sub.2R.sup.4a, SO.sub.2NR.sup.4bR.sup.4c, P(O)R.sup.4bR.sup.4c, phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl, and 6 to 10-membered bicyclic heterocyclyl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 4 R.sup.4d, 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.sup.4e; or two R.sup.4 together form oxo; R.sup.4a is H, C.sub.1-4alkyl optionally substituted with 1 to 4 R.sup.4d, C.sub.3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl, or 5 to 6-membered monocyclic heteroaryl; wherein the C.sub.3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 R.sup.4e; R.sup.4b and R.sup.4c are each independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclyl, 5 to 6-membered monocyclic heteroaryl, and C.sub.1-4alkyl optionally substituted with 1 to 4 R.sup.4d; each R.sup.4d is independently selected from halo, OR.sup.4f, C(O)C.sub.1-4alkyl, C(O)NR.sup.4bR.sup.4c, C(O)C.sub.1-4haloalkyl, 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 R.sup.4g; each R.sup.4e is independently selected from halo, C.sub.1-4alkyl optionally substituted with 1 to 3 halo, cyano, OR.sup.4f, NR.sup.4bR.sup.4c, C(O)H, C(O)C.sub.1-4alkyl, C.sub.1-4alkylene-C(O)NR.sup.4bR.sup.4c, and C(O)NR.sup.4bR.sup.4c; or two R.sup.4e together form oxo; R.sup.4f is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl, 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; each R.sup.4g is independently selected from halo, OR.sup.4f, C.sub.1-4alkyl, halo, cyano, NR.sup.4bR.sup.4c, C(O)H, and C(O)OR.sup.4f; provided that the compound is not any one of the compounds shown in Table I.

3. The compound of claim 1 or 2, wherein R.sup.1 is CH.sub.3 or CH.sub.2CH.sub.3.

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

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is C.sub.1-4alkyl, C.sub.2-4haloalkyl, or C(O)R.sup.x.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein X is CH.sub.3 or C(O)H.

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

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, and 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following formula: ##STR00217## each of which is optionally substituted with 1 to 2 R.sup.2.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following formula: ##STR00218## ##STR00219##

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Z is a bond.

12. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, thiophenyl, pyrazolyl, isothiazolyl, and imidazolyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following formula: ##STR00220## each of which is substituted with 0 to 1 R.sup.2.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein Z is a bond and ring A is represented by the following formula: ##STR00221##

15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein Z is a bond and ring A is represented by the following formula: ##STR00222##

16. The compound of any one of claims 1 to 10, 12, and 13, or a pharmaceutically acceptable salt thereof, wherein Z is CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1-4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, N(Z.sup.a)C(O)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3.

17. The compound of any one of claims 1 to 10, 12, and 13, or a pharmaceutically acceptable salt thereof, wherein Z is C(O)NH* or C(O)NHC.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3.

18. The compound of any one of claims 1 to 10, 12, and 13, or a pharmaceutically acceptable salt thereof, wherein Z is C(O)NH*, wherein * indicates the attachment point to R.sup.3.

19. The compound of any one of claims 16 to 18, or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following formula: ##STR00223##

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is C.sub.1-4alkyl, halo, cyano, C(O)R.sup.2d, or C(O)NR.sup.2bR.sup.2c, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 4 R.sup.2e; R.sup.2b and R.sup.2e are each independently selected from H or C.sub.1-4alkyl optionally substituted with C.sub.1-3alkoxy; R.sup.2d is OH or C.sub.1-3alkoxy; and R.sup.2e is halo, OH or C.sub.1-3alkoxy.

21. The compound of claim 20, wherein R.sup.2 is CH.sub.3, CF.sub.3, CH.sub.2OH, halo, cyano, C(O)OH, or C(O)NHCH.sub.3, or R.sup.2 is represented by the following formula: ##STR00224##

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is selected from cyclopropyl, cyclobutyl, cyclohexyl, piperidinyl, phenyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrazinyl, thiophenyl, tetrahydropyranyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-1H-pyrazoly, benzamidazolyl, indazolyl, indoyl, 2,3-dihydrobenzofuranyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1H-indenyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, and 2-azaspiro[3.3]heptanyl, and 2-oxaspiro[3.3]heptanyl, each of which is optionally substituted with 1 to 3 R.sup.4.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00225## ##STR00226## each of which is optionally substituted with 1 to 3 R.sup.4.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00227## ##STR00228## ##STR00229## ##STR00230##

25. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein Z is a bond, and R.sup.3 is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, thiophenyl, pyrrolyl, pyrazoyl, isothiazoyl, triazoyl, tetrazoyl, and oxadiazoyl, each of which is optionally substituted with 1 to 2 R.sup.4.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00231## each of which is optionally substituted with 1 to 2 R.sup.4.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00232## ##STR00233##

28. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is selected from phenyl, pyridyl, and pyrimidyl, each of which is optionally substituted with 1 to 2 R.sup.4.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00234## each of which is optionally substituted with 1 to 2 R.sup.4.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00235##

31. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein Z is CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1-4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, N(Z.sup.a)C(O)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3, and wherein R.sup.3 is selected from cyclopropyl, cyclohexyl, piperidinyl, phenyl, pyridyl, pyrazoyl, isothiazoyl, 2-oxo-2,3-dihydro-1H-pyrazoly, benzamidazoyl, indazoyl, indoyl, 2,3-dihydrobenzofuranyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1H-indenyl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is optionally substituted with 1 to 3 R.sup.4.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00236## each of which is optionally substituted with 1 to 3 R.sup.4.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00237## ##STR00238##

34. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein Z is C(O)NH*, wherein * indicates the attachment point to R.sup.3, and wherein R.sup.3 is selected from benzamidazolyl and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is optionally substituted with 1 to 2 R.sup.4.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00239## each of which is optionally substituted with 1 to 2 R.sup.4.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00240##

37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein: R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OR.sup.4a, cyano, NR.sup.4bR.sup.4c, C(O)OH, C(O)NR.sup.4bR.sup.4c, NR.sup.4bC(O)R.sup.4a, NR.sup.4bC(O)OR.sup.4a, 4 to 6-membered monocyclic heterocyclyl, phenyl, and 4 to 6-membered monocyclic heteroaryl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 3 substituents selected from OR.sup.4f, cyano, or 4 to 6-membered monocyclic heterocyclyl; and wherein the 4 to 6-membered monocyclic heterocyclyl, phenyl, and to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R.sup.4e; or two R.sup.4 together form oxo; R.sup.4a is H, phenyl, or C.sub.1-4alkyl optionally substituted with 1 to 3 substituents independently selected from halo, phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl, wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 R.sup.4g; R.sup.4b and R.sup.4c are each independently selected from H and C.sub.1-4alkyl; each R.sup.4e is independently selected from C.sub.1-4alkyl, halo, or C(O)C.sub.1-4alkyl; R.sup.4f is H or C.sub.1-4alkyl; and each R.sup.4g is independently halo or OH.

38. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein: R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OR.sup.4a, cyano, NR.sup.4bR.sup.4c, C(O)OH, C(O)NR.sup.4bR.sup.4c, NR.sup.4bC(O)R.sup.4a, NR.sup.4bC(O)OR.sup.4a, 4 to 6-membered monocyclic heterocyclyl, phenyl, and 4 to 6-membered monocyclic heteroaryl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 3 substituents selected from OR.sup.4f, cyano, or 4 to 6-membered monocyclic heterocyclyl; and wherein the 4 to 6-membered monocyclic heterocyclyl, phenyl, and to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R.sup.4e; or two R.sup.4 together form oxo; R.sup.4a is H, phenyl, or C.sub.1-4alkyl optionally substituted with 1 to 3 substituents independently selected from halo, phenyl and 4 to 6-membered monocyclic heterocyclyl; R.sup.4b and R.sup.4c are each independently selected from H and C.sub.1-4alkyl; each R.sup.4e is independently selected from C.sub.1-4alkyl or C(O)C.sub.1-4alkyl; and R.sup.4f is H or C.sub.1-4alkyl.

39. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is represented by the following structural formula: ##STR00241## each of which is optionally substituted with 1 to 2 R.sup.4e.

40. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is represented by the following structural formula: ##STR00242## each of which is optionally substituted with 1 to 2 R.sup.4e.

41. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is represented by the following structural formula: ##STR00243##

42. The compound of claim 39, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is represented by the following structural formula: ##STR00244##

43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R.sup.4e is F, CH.sub.3, or C(O)CH.sub.3.

44. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R.sup.4e is CH.sub.3 or C(O)CH.sub.3.

45. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2CN, CH.sub.2CH.sub.2OH, halo, cyano, OH, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, OCF.sub.3, NH.sub.2, NHC(O)CH.sub.3, C(O)OH, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, C(O)NC(CH.sub.3).sub.3, or R.sup.4 is represented by the following formula: ##STR00245##

46. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2CN, CH.sub.2CH.sub.2OH, halo, cyano, OH, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, OCF.sub.3, NH.sub.2, NHC(O)CH.sub.3, C(O)OH, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, C(O)NC(CH.sub.3).sub.3, or R.sup.4 is represented by the following formula: ##STR00246##

47. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein Z is a bond and R.sup.4 is CH.sub.3, halo, cyano, OH, OCH.sub.3, OCH.sub.2CH.sub.3, NH.sub.2, NHC(O)CH.sub.3, C(O)OH, C(O)NH.sub.2, or R.sup.4 is represented by the following formula: ##STR00247##

48. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is CH.sub.3, NH.sub.2, OH, halo, or NHC(O)CH.sub.3, or R.sup.4 is represented by the following formula: ##STR00248##

49. The compound of claim 47, or a pharmaceutically acceptable salt thereof, wherein Z is CH.sub.2, OCH.sub.2*, S(O).sub.2, S(O).sub.2N(H)*, N(H), N(H)CH.sub.2*, C(O)NH*, or C(O)NHC.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3, and wherein R.sup.4 is CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2CN, CH.sub.2CH.sub.2OH, halo, OCH.sub.3, OCH(CH.sub.3).sub.2, OCF.sub.3, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, C(O)NC(CH.sub.3).sub.3, or R.sup.4 is represented by the following formula: ##STR00249##

50. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is CH.sub.3.

51. The compound of any one of claims 1 to 6, 20 to 30, and 37 to 48, wherein the compound is represented by Formula (IIA), (IIB) or (IIC): ##STR00250## or a pharmaceutically acceptable salt thereof.

52. The compound of any one of claims 1 to 6, 20 to 30, and 37 to 48, wherein the compound is represented by Formula (IIIA) or (IIIB): ##STR00251## or a pharmaceutically acceptable salt thereof.

53. The compound of any one of claims 1 to 6, 20 to 30, and 37 to 48, wherein the compound is represented by Formula (IVA), (IVB), (IVC), or (IVD): ##STR00252## or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1

54. The compound of any one of claims 1 to 6, 16 to 24, 31 to 46, 49, and 50, wherein the compound is represented by Formula (V): ##STR00253## or a pharmaceutically acceptable salt thereof.

55. The compound of claim 1, wherein the compound is represented by Formula (VI): ##STR00254## or a pharmaceutically acceptable salt thereof, wherein; R.sup.1 is C.sub.1-2alkyl; Ring A is selected from phenyl, thiophenyl, pyrazolyl, isothiazolyl, and imidazolyl; m is 0 to 1; each R.sup.2 is independently selected from C.sub.1-4alkyl and C(O)OH; Z is a bond or C(O)NH*, wherein * indicates the attachment point to R.sup.3; R.sup.3 is selected from phenyl, pyridyl, pyrimidyl, benzimidazolyl and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is optionally substituted with 1 to 2 R.sup.4; each R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OH, O-benzyl, cyano, NR.sup.4bR.sup.4c, C(O)NR.sup.4bR.sup.4c, or 4 to 6-membered monocyclic heterocyclyl; R.sup.4b and R.sup.4c are each independently selected from H and C.sub.1-4alkyl.

56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein Z is a bond and wherein ring A is represented by the following formula: ##STR00255## each of which is substituted with 1 R.sup.3 and optionally substituted with 1 R.sup.2.

57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following formula: ##STR00256##

58. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following formula: ##STR00257##

59. The compound of any one of claims 55 to 58, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is CH.sub.3 or C(O)OH.

60. The compound of any one of claims 55 to 59, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is selected from phenyl, pyridyl, and pyrimidyl, each of which is optionally substituted with 1 to 2 R.sup.4.

61. The compound of claim 60, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00258## each of which is optionally substituted with 1 to 2 R.sup.4.

62. The compound of claim 61, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00259##

63. The compound of any one of claims 55 to 62, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is CH.sub.3, NH.sub.2, OH, halo, or NHC(O)CH.sub.3, or R.sup.4 is represented by the following formula: ##STR00260##

64. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein Z is C(O)NH*, wherein * indicates the attachment point to R.sup.3; and wherein ring A is represented by the following formula: ##STR00261## which is substituted with 1 R.sup.3.

65. The compound of claim 64, or a pharmaceutically acceptable salt thereof, wherein ring A is represented by the following formula: ##STR00262##

66. The compound of any one of claims 55, 64, or 65, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is selected from benzamidazolyl and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is optionally substituted with 1 to 2 R.sup.4.

67. The compound of claim 66, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is represented by the following formula: ##STR00263##

68. The compound of any of claims 55 and 64 to 67, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is CH.sub.3.

69. The compound of claim 1, wherein the compound is selected from: N-(3-(methylsulfonamido)phenyl)-1-phenyl-1H-pyrazole-4-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-phenylpicolinamide; 4-(benzyloxy)-N-(3-(methylsulfonamido)phenyl)benzamide; 3-(benzyloxy)-N-(3-(methylsulfonamido)phenyl)benzamide; N-(3-(methylsulfonamido)phenyl)-5-phenylthiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; 4-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-(methylsulfonamido)phenyl)benzamide; N-(3-(methylsulfonamido)phenyl)-4-(1H-tetrazol-5-yl)benzamide; N-(3-(methylsulfonamido)phenyl)-2-(4H-1,2,4-triazol-3-yl)thiazole-4-carboxamide; 1-benzyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide; N-(3-(methylsulfonamido)phenyl)-[1,1-biphenyl]-3-carboxamide; N-(3-(methylsulfonamido)phenyl)-[1,1-biphenyl]-4-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(1H-pyrazol-1-yl)benzamide; N-(3-(methylsulfonamido)phenyl)-3-(1H-pyrazol-1-yl)benzamide; N-(3-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-phenylthiazole-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-1-(pyrimidin-2-yl)-1H-pyrazole-4-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(thiophen-2-yl)picolinamide; 4-(3-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(o-tolyl)thiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(m-tolyl)thiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(p-tolyl)thiophene-2-carboxamide; 5-methyl-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; 4-(3-carbamoylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(3-cyanophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(2-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(4-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(pyridin-4-yl)thiophene-2-carboxamide; 4-(3-methoxyphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(2-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(3-aminophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(2-methoxyphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(2-methylpyridin-3-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(4-methylpyridin-3-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(pyrimidin-5-yl)thiophene-2-carboxamide; 4-(2-ethoxypyrimidin-5-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 5-(4-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide; 4-(6-methylpyridin-3-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(pyridazin-3-yl)thiophene-2-carboxamide; 4-(3-methoxy-2-methylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(5-methoxy-2-methylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(3-hydroxypyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(2-fluoro-6-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-benzyl-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; tert-butyl (3-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)phenyl)carbamate; 4-(3-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(3-hydroxy-2-methylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(5-hydroxy-2-methylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(2,6-difluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(2-(benzyloxy)phenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 5-(4-methoxyphenyl)-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide; 5-(4-hydroxyphenyl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide; 5-methyl-N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide; 4-(3-methylpyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(pyrimidin-2-yl)thiophene-2-carboxamide; 4-(6-aminopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(4-aminopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 2-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)isonicotinic acid; 4-(2-aminophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(3-aminopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)-1H-imidazole-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-(5-(piperazin-1-yl)pyridin-2-yl)thiophene-2-carboxamide; 2-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)isonicotinamide; 4-(2-acetamidophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(3-acetamidopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; 4-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; N-(3-(ethylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; N-(3-(ethylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide; 5-bromo-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; N-(3-(methylsulfonamido)phenyl)-4-phenyl-5-(trifluoromethyl)thiophene-2-carboxamide; 5-cyano-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; 5-((3-(methylsulfonamido)phenyl)carbamoyl)-3-phenylthiophene-2-carboxylic acid; N2-(3-(methylsulfonamido)phenyl)-N4-phenylthiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(2-(pyridin-3-yl)ethyl)thiophene-2,4-dicarboxamide; N4-(3-chloro-4-methylphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-((1-hydroxycyclohexyl)methyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(6-methoxypyridin-3-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(4-(trifluoromethoxy)phenyl)thiophene-2,4-dicarboxamide; N4-(5-fluoro-2-methoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(1-phenylethyl)thiophene-2,4-dicarboxamide; N4-((5-fluoropyridin-3-yl)methyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(2,3-dihydro-1H-inden-2-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(4-chloro-3-methylphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(4-(dimethylcarbamoyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(2-phenoxyphenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(4-morpholinobenzyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(4-phenoxyphenyl)thiophene-2,4-dicarboxamide; N4-(4-isopropoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(cyclopropylmethyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(4-(morpholinomethyl)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(3-(trifluoromethoxy)phenyl)thiophene-2,4-dicarboxamide; N4-(3-isopropoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(4-(2-morpholinoethoxy)phenyl)thiophene-2,4-dicarboxamide; N4-(2,3-dihydrobenzofuran-4-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(4-(morpholinomethyl)benzyl)thiophene-2,4-dicarboxamide; N4-(3-chloro-5-methoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(4-(tert-butylcarbamoyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(4-(pyridin-4-yl)phenyl)thiophene-2,4-dicarboxamide; N4-(imidazo[1,2-a]pyridin-3-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(4-methoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(1-methyl-1H-benzo [d]imidazol-6-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(3-(pyridin-3-yl)phenyl)thiophene-2,4-dicarboxamide; N4-(3-(methoxymethyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(2-isopropoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(2,3-dihydro-1H-inden-1-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(4-chlorophenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(2-(cyanomethyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(4-(methylcarbamoyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(2-(1H-indol-3-yl)ethyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-((1H-benzo[d]imidazol-2-yl)methyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(2,5-dimethoxyphenethyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(2-(2-hydroxyethyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-((1H-indazol-3-yl)methyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-((1H-indol-5-yl)methyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N4-(1H-benzo[d]imidazol-2-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(3-(2-methylthiazol-4-yl)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(5-phenyl-1H-pyrazol-3-yl)thiophene-2,4-dicarboxamide; N4-(4-(2-hydroxyethyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(2-(piperidin-1-yl)ethyl)thiophene-2,4-dicarboxamide; N2-(3-(methylsulfonamido)phenyl)-N4-(3-(piperidin-1-ylmethyl)phenyl)thiophene-2,4-dicarboxamide; N2-methyl-N5-(3-(methylsulfonamido)phenyl)-3-phenylthiophene-2,5-dicarboxamide; 5-(hydroxymethyl)-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; 1-benzyl-5-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide; 4-(benzylamino)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; N-(6-(methylsulfonamido)pyridin-2-yl)-4-phenylthiophene-2-carboxamide; N-(3-(methylsulfonoamidimidamido)phenyl)-4-phenylthiophene-2-carboxamide; N-(3-methyl-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; N-(3-formyl-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; 5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide; 5-(3,5-difluoropyridin-2-yl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide; and N4-(2-cyclopropylethyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; or a pharmaceutically acceptable salt thereof.

70. A pharmaceutical composition comprising a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

71. A method of treating a DHX9 mediated disease or disorder in a subject, comprising administering to the subject a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 69, or the pharmaceutical composition of claim 70.

72. A method of treating a DHX9 mediated disease or disorder in a subject, comprising administering to the subject a compound represented by Formula (I): ##STR00264## or a pharmaceutically acceptable salt thereof, wherein: X is H, C.sub.1-4alkyl, C.sub.2-4haloalkyl, or C(O)R.sup.x; R.sup.x is H, OH, OC.sub.1-4alkyl, or C.sub.1-4alkyl; Y is O or NR.sup.y; R.sup.y is H or C.sub.1-4alkyl; R.sup.1 is C.sub.1-4alkyl or C.sub.3-6cycloalkyl; wherein the C.sub.1-4alkyl or C.sub.3-6cycloalkyl are each optionally and independently substituted with 1 to 3 halo; Ring A is a C.sub.3-6cycloalkyl, 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; each R.sup.2 is independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, halo, OR.sup.2a, cyano, NR.sup.2bR.sup.2c, SO.sub.2R.sup.2a, C(O)R.sup.2d, and C(O)NR.sup.2bR.sup.2c, wherein the C.sub.1-4alkyl and C.sub.3-6cycloalkyl are optionally substituted with 1 to 4 R.sup.2e; or 2 R.sup.2 together form oxo; R.sup.2a is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl, or benzyl; R.sup.2d is H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl; OR.sup.2a, phenyl, 4 to 6-membered monocyclic heterocyclyl or 5 to 6-membered monocyclic heteroaryl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 3 halo; R.sup.2b and R.sup.2c are each independently selected from H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclyl and 5 to 6-membered monocyclic heteroaryl; or R.sup.2b and R.sup.2c, together with the nitrogen to which they are attached form a 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl; wherein the 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R.sup.2d; each R.sup.2e is independently selected from halo, cyano, NR.sup.2bR.sup.2c, OR.sup.2a, phenyl, and 4 to 6 membered monocyclic heterocyclyl; Z is a bond, CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1-4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3; Z.sup.a is H or C.sub.1-4alkyl; provided when X is H and Z is a bond, ring A is phenyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, or 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl; R.sup.3 is C.sub.3-6cycloalkyl, 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.sub.3-6cycloalkyl, 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 are each optionally and independently substituted with 1 to 4 R.sup.4; each R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OR.sup.4a, cyano, NR.sup.4bR.sup.4c, C(O)R.sup.4a, C(O)OR.sup.4a, C(O)NR.sup.4bR.sup.4c, NR.sup.4bC(O)R.sup.4aNR.sup.4bC(O)OR.sup.4a, SR.sup.4a, SO.sub.2R.sup.4a, SO.sub.2NR.sup.4bR.sup.4c, P(O)R.sup.4bR.sup.4c, phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl, and 6 to 10-membered bicyclic heterocyclyl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 4 R.sup.4d, 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.sup.4e; or two R.sup.4 together form oxo; R.sup.4a is H, C.sub.1-4alkyl optionally substituted with 1 to 4 R.sup.4d, C.sub.3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl, or 5 to 6-membered monocyclic heteroaryl; wherein the C.sub.3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 R.sup.4e; R.sup.4b and R.sup.4c are each independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclyl, 5 to 6-membered monocyclic heteroaryl, and C.sub.1-4alkyl optionally substituted with 1 to 4 R.sup.4d; each R.sup.4d is independently selected from halo, OR.sup.4f, C(O)C.sub.1-4alkyl, C(O)NR.sup.4bR.sup.4c, C(O)C.sub.1-4haloalkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, 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 R.sup.4g; each R.sup.4e is independently selected from halo, C.sub.1-4alkyl optionally substituted with 1 to 3 halo, cyano, OR.sup.4f, NR.sup.4bR.sup.4c, C(O)H, C(O)C.sub.1-4alkyl, C.sub.1-4alkylene-C(O)NR.sup.4bR.sup.4c, and C(O)NR.sup.4bR.sup.4c; or two R.sup.4e together form oxo; R.sup.4f is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl, 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; each R.sup.4g is independently selected from halo, OR.sup.4f, C.sub.1-4alkyl, halo, cyano, NR.sup.4bR.sup.4c, C(O)H, and C(O)OR.sup.4f.

73. The method of claim 72, wherein: X is H, C.sub.1-4alkyl, C.sub.2-4haloalkyl, or C(O)R.sup.x; R.sup.x is H, OH, OC.sub.1-4alkyl, or C.sub.1-4alkyl; Y is O or NR.sup.y; R.sup.y is H or C.sub.1-4alkyl; R.sup.1 is C.sub.1-4alkyl or C.sub.3-6cycloalkyl; wherein the C.sub.1-4alkyl or C.sub.3-6cycloalkyl are each optionally and independently substituted with 1 to 3 halo; Ring A is a C.sub.3-6cycloalkyl, 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; each R.sup.2 is independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, halo, OR.sup.2a, cyano, NR.sup.2bR.sup.2c, SO.sub.2R.sup.2a, C(O)R.sup.2d, and C(O)NR.sup.2bR.sup.2c, wherein the C.sub.1-4alkyl and C.sub.3-6cycloalkyl are optionally substituted with 1 to 4 R.sup.2e; or 2 R.sup.2 together form oxo; R.sup.2a is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl, or benzyl; R.sup.2d is H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl; OR.sup.2a, phenyl, 4 to 6-membered monocyclic heterocyclyl or 5 to 6-membered monocyclic heteroaryl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 3 halo; R.sup.2b and R.sup.2c are each independently selected from H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclyl and 5 to 6-membered monocyclic heteroaryl; or R.sup.2b and R.sup.2c, together with the nitrogen to which they are attached form a 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl; wherein the 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R.sup.2d; each R.sup.2e is independently selected from halo, cyano, NR.sup.2bR.sup.2c, OR.sup.2a, phenyl, and 4 to 6 membered monocyclic heterocyclyl; Z is a bond, CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1-4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, N(Z.sup.a)C(O)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3; Z.sup.a is H or C.sub.1-4alkyl; provided when X is H and Z is a bond, ring A is phenyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, or 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl; R.sup.3 is C.sub.3-6cycloalkyl, 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.sub.3-6cycloalkyl, 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 are each optionally and independently substituted with 1 to 4 R.sup.4; each R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OR.sup.4a, cyano, NR.sup.4bR.sup.4c, C(O)R.sup.4a, C(O)OR.sup.4a, C(O)NR.sup.4bR.sup.4c, NR.sup.4bC(O)R.sup.4a NR.sup.4bC(O)OR.sup.4a, SR.sup.4a, SO.sub.2R.sup.4a, SO.sub.2NR.sup.4bR.sup.4c, P(O)R.sup.4bR.sup.4c, phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl, and 6 to 10-membered bicyclic heterocyclyl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 4 R.sup.4d, 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.sup.4e; or two R.sup.4 together form oxo; R.sup.4a is H, C.sub.1-4alkyl optionally substituted with 1 to 4 R.sup.4d, C.sub.3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl, or 5 to 6-membered monocyclic heteroaryl; wherein the C.sub.3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 R.sup.4e; R.sup.4b and R.sup.4c are each independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclyl, 5 to 6-membered monocyclic heteroaryl, and C.sub.1-4alkyl optionally substituted with 1 to 4 R.sup.4d; each R.sup.4d is independently selected from halo, OR.sup.4f, C(O)C.sub.1-4alkyl, C(O)NR.sup.4bR.sup.4c, C(O)C.sub.1-4haloalkyl, 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 R.sup.4g; each R.sup.4e is independently selected from halo, C.sub.1-4alkyl optionally substituted with 1 to 3 halo, cyano, OR.sup.4f, NR.sup.4bR.sup.4c, C(O)H, C(O)C.sub.1-4alkyl, C.sub.1-4alkylene-C(O)NR.sup.4bR.sup.4c, and C(O)NR.sup.4bR.sup.4c; or two R.sup.4e together form oxo; R.sup.4f is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl, 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; each R.sup.4g is independently selected from halo, OR.sup.4f, C.sub.1-4alkyl, halo, cyano, NR.sup.4bR.sup.4c, C(O)H, and C(O)OR.sup.4f.

74. The method of any one of claims 71 to 73, wherein the disease or disorder is cancer, viral infection or autoimmune disease.

75. The method of claim 74, wherein the disease or disorder is cancer.

76. The method of claim 75, wherein the cancer is selected from colorectal, endometrial, ovarian, gastric, hematopoietic, breast, brain, skin, lung, blood, prostate, head and neck, pancreatic, bladder, bone, soft-tissue, kidney and liver cancer.

77. The method of claim 75, wherein the cancer is selected from colorectal, endometrial, ovarian, gastric, hematopoietic, breast, brain, skin, lung, blood, prostate, head and neck, pancreatic, and liver cancer.

78. The method of claim 77, wherein the cancer is selected from colorectal, endometrial, ovarian, hematopoietic, and gastric cancer.

79. The method of any one of claims 75 to 78, wherein the cancer is a microsatellite instability (MSI) cancer.

80. The method of any one of claims 75 to 78, wherein the cancer has mutations or defects in DNA mis-match repair (MMR), and/or mutations or defects in RNA splicing and the kinetochore complex.

81. The method of claim 79, wherein the cancer is a microsatellite instability-high (MSI-H) colorectal cancer.

82. The method of claim 76, wherein the cancer is Ewing's Sarcoma.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0035] The present disclosure provides compounds and pharmaceutical compositions thereof that may be useful in the treatment of diseases or disorders through mediation of DHX9 function/activity. In some embodiments, the compounds of present disclosure are DHX9 inhibitors.

Compounds and Compositions

[0036] In a first embodiment, the present disclosure provides a compound of Formula (I):

##STR00003##

or a pharmaceutically acceptable salt thereof, wherein: [0037] X is H, C.sub.1-4alkyl, C.sub.2-4haloalkyl, or C(O)R.sup.x; [0038] R.sup.x is H, OH, OC.sub.1-4alkyl, or C.sub.1-4alkyl; [0039] Y is O or NR.sup.y; [0040] R.sup.y is H or C.sub.1-4alkyl; [0041] R.sup.1 is C.sub.1-4alkyl or C.sub.3-6cycloalkyl; wherein the C.sub.1-4alkyl or C.sub.3-6cycloalkyl are each optionally and independently substituted with 1 to 3 halo; [0042] Ring A is a C.sub.3-6cycloalkyl, 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; [0043] m is 0 to 3; [0044] each R.sup.2 is independently selected from C.sub.1-4alkyl, C.sub.3-6cycloalkyl, halo, OR.sup.2a, cyano, NR.sup.2bR.sup.2c, SO.sub.2R.sup.2a, C(O)R.sup.2d, and C(O)NR.sup.2bR.sup.2c, wherein the C.sub.1-4alkyl and C.sub.3-6cycloalkyl are optionally substituted with 1 to 4 R.sup.2e; or 2 R.sup.2 together form oxo; [0045] R.sup.2a is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxyC.sub.1-4alkyl, or benzyl; [0046] R.sup.2d is H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl; OR.sup.2a, phenyl, 4 to 6-membered monocyclic heterocyclyl or 5 to 6-membered monocyclic heteroaryl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 3 halo; [0047] R.sup.2b and R.sup.2e are each independently selected from H, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, phenyl, 4 to 6-membered monocyclic heterocyclyl and 5 to 6-membered monocyclic heteroaryl; or [0048] R.sup.2b and R.sup.2c, together with the nitrogen to which they are attached form a 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl; wherein the 4 to 6 membered monocyclic heterocyclyl or 6 to 10 membered bicyclic heterocyclyl are each optionally substituted with 1 to 3 R.sup.2d; [0049] each R.sup.2e is independently selected from halo, cyano, NR.sup.2bR.sup.2c, OR.sup.2a, phenyl, and 4 to 6 membered monocyclic heterocyclyl; [0050] Z is a bond, CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1-4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, N(Z.sup.a)C(O)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3; [0051] Z.sup.a is H or C.sub.1-4alkyl; [0052] provided when X is H and Z is a bond, ring A is phenyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, or 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl; [0053] R.sup.3 is C.sub.3-6cycloalkyl, 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.sub.3-6cycloalkyl, 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 are each optionally and independently substituted with 1 to 4 R.sup.4; [0054] each R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OR.sup.4a, cyano, NR.sup.4bR.sup.4c, C(O)R.sup.4a, C(O)OR.sup.4a, C(O)NR.sup.4bR.sup.4c, NR.sup.4bC(O)R.sup.4aNR.sup.4bC(O)OR.sup.4a, SR.sup.4a, SO.sub.2R.sup.4a, SO.sub.2NR.sup.4bR.sup.4c, P(O)R.sup.4bR.sup.4c, phenyl, 5 to 6-membered monocyclic heteroaryl, 4 to 6-membered monocyclic heterocyclyl, and 6 to 10-membered bicyclic heterocyclyl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 4 R.sup.4d, 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.sup.4e; or two R.sup.4 together form oxo; [0055] R.sup.4a is H, C.sub.1-4alkyl optionally substituted with 1 to 4 R.sup.4d, C.sub.3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl, or 5 to 6-membered monocyclic heteroaryl; wherein the C.sub.3-6cycloalkyl, 4 to 6-membered monocyclic heterocyclyl, phenyl or 5 to 6-membered monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 R.sup.4e; [0056] R.sup.4b and R.sup.4c are each independently selected from H, phenyl, 4 to 6-membered monocyclic heterocyclyl, 5 to 6-membered monocyclic heteroaryl, and C.sub.1-4alkyl optionally substituted with 1 to 4 R.sup.4d; [0057] each R.sup.4d is independently selected from halo, OR.sup.4f, C(O)C.sub.1-4alkyl, C(O)NR.sup.4bR.sup.4c, C(O)C.sub.1-4haloalkyl, 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 R.sup.4g; [0058] each R.sup.4f is independently selected from halo, C.sub.1-4alkyl optionally substituted with 1 to 3 halo, cyano, OR.sup.4f, NR.sup.4bR.sup.4c, C(O)H, C(O)C.sub.1-4alkyl, C.sub.1-4alkylene-C(O)NR.sup.4bR.sup.4c, and C(O)NR.sup.4bR.sup.4c; or two R.sup.4e together form oxo; [0059] R.sup.4f is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl, 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; [0060] each R.sup.4g is independently selected from halo, OR.sup.4f, C.sub.1-4alkyl, halo, cyano, NR.sup.4bR.sup.4c, C(O)H, and C(O)OR.sup.4f.

[0061] In some embodiments, the compound of Formula (I) is not any one of the compounds listed in Table I below.

[0062] In a second embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.1 is CH.sub.3 or CH.sub.2CH.sub.3; and the remaining variables are as described in the first aspect or the first embodiment.

[0063] In a third embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, X is H; and the remaining variables are as described in the first aspect or the first or second embodiment.

[0064] In a fourth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, X is C.sub.1-4alkyl, C.sub.2-4haloalkyl, or C(O)R.sup.x; and the remaining variables are as described in the first aspect or the first or second embodiment.

[0065] In a fifth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, X is CH.sub.3 or C(O)H; and the remaining variables are as described in the first aspect or the first or second embodiment.

[0066] In a sixth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is phenyl, thiophenyl, pyrrolyl, pyrazoyl, furanyl, isothiazoyl, thiazoyl, imidazoyl, cyclobutyl, benzofuranyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, imidazo[1,2-a]pyridin-6-yl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2-oxo-2,3-dihydro-1H-imidazolyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-c]pyrimidinyl, pyrrolo[1,2-a]pyrazinly, 5-oxo-5H-thiazolo[3,2-a]pyridinyl, thieno[3,2-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, benzothiophenyl, thieno[3,2-d]pyrimidinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2-c]pyrimidinyl, 1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazinyl, pyrrolo[2,1-f][1,2,4]triazinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, or 4,7-dihydro-5H-thieno[2,3-c]pyranyl; and the remaining variables are as described in first aspect or the first, second, third, fourth, or fifth embodiment.

[0067] In a seventh embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is phenyl, pyridinyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, or 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

[0068] In an eighth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is

##STR00004##

each of which is optionally substituted with 1 to 2 R.sup.2; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

[0069] In a ninth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is

##STR00005## ##STR00006##

and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

[0070] In a tenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.

[0071] In an eleventh embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is phenyl, thiophenyl, pyrazolyl, isothiazolyl, or imidazolyl; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

[0072] In a twelfth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is

##STR00007##

each of which is substituted with 0 to 1 R.sup.2; and the remaining variables are as described in the first aspect the first, second, third, fourth, or fifth embodiment.

[0073] In a thirteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond and ring A is

##STR00008##

and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

[0074] In a fourteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond and ring A is

##STR00009##

and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

[0075] In a fifteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1 4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, N(Z.sup.a)C(O)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, or twelfth embodiment.

[0076] In a sixteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is C(O)NH* or C(O)NHC.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, or twelfth embodiment.

[0077] In a seventeenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is C(O)NH*, wherein * indicates the attachment point to R.sup.3; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, or twelfth embodiment.

[0078] In an eighteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, ring A is

##STR00010##

and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, twelfth, fifteenth, sixteenth, or seventeenth embodiment.

[0079] In a nineteenth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.2 is C.sub.1-4alkyl, halo, cyano, C(O)R.sup.2d, or C(O)NR.sup.2bR.sup.2c, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 4 R.sup.2e; R.sup.2b and R.sup.2e are each independently selected from H or C.sub.1-4alkyl optionally substituted with C.sub.1-3alkoxy; R.sup.2d is OH or C.sub.1-3alkoxy; and R.sup.2e is halo, OH or C.sub.1-3alkoxy; 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, or eighteenth embodiment.

[0080] In a twentieth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.2 is CH.sub.3, CF.sub.3, CH.sub.2OH, halo, cyano, C(O)OH, C(O)NHCH.sub.3, or

##STR00011##

[0081] In a twenty-first embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.3 is cyclopropyl, cyclobutyl, cyclohexyl, piperidinyl, phenyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyrazinyl, thiophenyl, tetrahydropyranyl, thiazolyl, triazolyl, tetrazolyl, oxadiazolyl, 3-oxo-2,3-dihydro-1H-pyrazoly, benzamidazolyl, indazolyl, indoyl, 2,3-dihydrobenzofuranyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1H-indenyl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, and 2-azaspiro[3.3]heptanyl, or 2-oxaspiro[3.3]heptanyl, each of which is optionally substituted with 1 to 3 R.sup.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, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0082] In a twenty-second embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.3 is

##STR00012## ##STR00013##

each of which is optionally substituted with 1 to 3 R.sup.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, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0083] In a twenty-third embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.3 is

##STR00014## ##STR00015## ##STR00016## ##STR00017##

[0084] In a twenty-fourth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R.sup.3 is phenyl, pyridyl, pyrimidyl, pyrazinyl, thiophenyl, pyrrolyl, pyrazoyl, isothiazoyl, triazoyl, tetrazoyl, or oxadiazoyl, each of which is optionally substituted with 1 to 2 R.sup.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, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0085] In a twenty-fifth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R.sup.3 is

##STR00018##

each of which is optionally substituted with 1 to 2 R.sup.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, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0086] In a twenty-sixth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R.sup.3 is

##STR00019## ##STR00020##

[0087] In a twenty-seventh embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R.sup.3 is phenyl, pyridyl, or pyrimidyl, each of which is optionally substituted with 1 to 2 R.sup.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, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0088] In a twenty-eighth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R.sup.3 is

##STR00021##

[0089] In a twenty-ninth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is a bond, R.sup.3 is

##STR00022##

[0090] In a thirtieth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1-4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, N(Z.sup.a)C(O)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3, R.sup.3 is cyclopropyl, cyclohexyl, piperidinyl, phenyl, pyridyl, pyrazoyl, isothiazoyl, 2-oxo-2,3-dihydro-1H-pyrazoly, benzamidazoyl, indazoyl, indoyl, 2,3-dihydrobenzofuranyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1H-indenyl, or 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is optionally substituted with 1 to 3 R.sup.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, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0091] In a thirty-first embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1-4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, N(Z.sup.a)C(O)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3, R.sup.3 is

##STR00023##

each of which is optionally substituted with 1 to 3 R.sup.4; and the remaining variables are as described in the first aspect of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0092] In a thirty-second embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is CH.sub.2, O, OC.sub.1-4alkylene-*, C.sub.1-4alkylene-O*, C(O), C(O)O*, OC(O)*, S(O).sub.2, S(O).sub.2N(Z.sup.a)*, N(Z.sup.a)S(O).sub.2*, N(Z.sup.a), N(Z.sup.a)C.sub.1-4alkylene-*, C.sub.1-4alkylene-N(Z.sup.a)*, C(O)N(Z.sup.a)*, N(Z.sup.a)C(O)*, or C(O)N(Z.sup.a)C.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3, R.sup.3 is

##STR00024## ##STR00025##

[0093] In a thirty-third embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is C(O)NH*, wherein * indicates the attachment point to R.sup.3, R.sup.3 is benzamidazolyl or 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is optionally substituted with 1 to 2 R.sup.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, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0094] In a thirty-fourth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is C(O)NH*, wherein * indicates the attachment point to R.sup.3, R.sup.3 is

##STR00026##

[0095] In a thirty-fifth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is C(O)NH*, wherein * indicates the attachment point to R.sup.3, R.sup.3 is

##STR00027##

[0096] In a thirty-sixth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OR.sup.4a, cyano, NR.sup.4bR.sup.4c, C(O)OH, C(O)NR.sup.4bR.sup.4c, NR.sup.4bC(O)R.sup.4a, NR.sup.4bC(O)OR.sup.4a, 4 to 6-membered monocyclic heterocyclyl, phenyl, and 4 to 6-membered monocyclic heteroaryl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 3 substituents selected from OR.sup.4f, cyano, or 4 to 6-membered monocyclic heterocyclyl; and wherein the 4 to 6-membered monocyclic heterocyclyl, phenyl, and to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R.sup.4e; or two R.sup.4 together form oxo; R.sup.4a is H, phenyl, or C.sub.1-4alkyl optionally substituted with 1 to 3 substituents independently selected from halo, phenyl and 4 to 6-membered monocyclic heterocyclyl; R.sup.4b and R.sup.4c are each independently selected from H and C.sub.1-4alkyl; each R.sup.4e is independently selected from C.sub.1-4alkyl or C(O)C.sub.1-4alkyl; R.sup.4f is H or C.sub.1-4alkyl; 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, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment. In an alternative thirty-sixth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OR.sup.4a, cyano, NR.sup.4bR.sup.4c, C(O)OH, C(O)NR.sup.4bR.sup.4c, NR.sup.4bC(O)R.sup.4a, NR.sup.4bC(O)OR.sup.4a, 4 to 6-membered monocyclic heterocyclyl, phenyl, and 4 to 6-membered monocyclic heteroaryl, wherein the C.sub.1-4alkyl is optionally substituted with 1 to 3 substituents selected from OR.sup.4f, cyano, or 4 to 6-membered monocyclic heterocyclyl; and wherein the 4 to 6-membered monocyclic heterocyclyl, phenyl, and to 6-membered monocyclic heteroaryl are each optionally substituted with 1 to 3 R.sup.4e; or two R.sup.4 together form oxo; R.sup.4a is H, phenyl, or C.sub.1-4alkyl optionally substituted with 1 to 3 substituents independently selected from halo, phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl, wherein the phenyl, 5 to 6-membered monocyclic heteroaryl, and 4 to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 R.sup.4g; R.sup.4b and R.sup.4c are each independently selected from H and C.sub.1-4alkyl; each R.sup.4e is independently selected from C.sub.1-4alkyl, halo, or C(O)C.sub.1-4alkyl; R.sup.4f is H or C.sub.1-4alkyl; and each R.sup.4g is independently halo or OH.

[0097] In a thirty-seventh embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4 is

##STR00028##

each of which is optionally substituted with 1 to 2 R.sup.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, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, or thirty-sixth embodiment or any alternative embodiments described therein. In an alternative thirty-seventh embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4 is represented by the following structural formula:

##STR00029##

[0098] In a thirty-eighth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4 is

##STR00030##

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, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, or thirty-sixth embodiment or any alternative embodiments described therein. In an alternative thirty-eighth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4 is represented by the following structural formula:

##STR00031##

[0099] In a thirty-ninth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4e is CH.sub.3 or C(O)CH.sub.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, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, or thirty-eighth embodiment or any alternative embodiments described therein. In an alternative thirty-ninth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4e is F, CH.sub.3, or C(O)CH.sub.3; 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, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, or thirty-eighth embodiment or any alternative embodiments described therein.

[0100] In a fortieth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4 is CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2CN, CH.sub.2CH.sub.2OH, halo, cyano, OH, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, OCF.sub.3, NH.sub.2, NHC(O)CH.sub.3, C(O)OH, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, C(O)NC(CH.sub.3).sub.3,

##STR00032##

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, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment. In an alternative fortieth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4 is CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2CN, CH.sub.2CH.sub.2OH, halo, cyano, OH, OCH.sub.3, OCH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, OCF.sub.3, NH.sub.2, NHC(O)CH.sub.3, C(O)OH, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, C(O)NC(CH.sub.3).sub.3, or R.sup.4 is represented by the following formula:

##STR00033##

[0101] In a forty-first embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4 is CH.sub.3, halo, cyano, OH, OCH.sub.3, OCH.sub.2CH.sub.3, NH.sub.2, NHC(O)CH.sub.3, C(O)OH, C(O)NH.sub.2,

##STR00034##

[0102] In a forty-second embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, R.sup.4 is CH.sub.3, NH.sub.2, OH, halo, or NHC(O)CH.sub.3,

##STR00035##

[0103] In a forty-third embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is CH.sub.2, OCH.sub.2*, S(O).sub.2, S(O).sub.2N(H)*, N(H), N(H)CH.sub.2*, C(O)NH*, or C(O)NHC.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3, R.sup.4 is CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2CN, CH.sub.2CH.sub.2OH, halo, OCH.sub.3, OCH(CH.sub.3).sub.2, OCF.sub.3, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, C(O)NC(CH.sub.3).sub.3,

##STR00036##

and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, twelfth, fifteenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, thirtieth, thirty-first, thirty-second, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment or any alternative embodiments.

[0104] In a forty-fourth embodiment, for the compounds of Formula (I) described in the first aspect, or a pharmaceutically acceptable salt thereof, Z is CH.sub.2, OCH.sub.2*, S(O).sub.2, S(O).sub.2N(H)*, N(H), N(H)CH.sub.2*, C(O)NH*, or C(O)NHC.sub.1-3alkylene-*, wherein * indicates the attachment point to R.sup.3, R.sup.4 is CH.sub.3; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, eleventh, twelfth, fifteenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, thirtieth, thirty-first, thirty-second, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment or any alternative embodiments described therein.

[0105] In a forty-fifth embodiment, the compound of the present disclosure is represented by Formula (IIA), (IIB) or (IIC):

##STR00037##

or a pharmaceutically acceptable salt thereof; where the variables X, R.sup.1, R.sup.2 and R.sup.3 depicted in Formula (IIA), (IIB) or (IIC) are as described in the first aspect or the first, second, third, fourth, fifth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, or forty-second embodiment or any alternative embodiments described therein.

[0106] In a forty-sixth embodiment, the compound of the present disclosure is represented by Formula (IIIA) or (IIIB):

##STR00038##

or a pharmaceutically acceptable salt thereof; where the variables X, R.sup.1, and R.sup.3 depicted in Formula (IIIA) or (IIIB) are as described in the first aspect or the first, second, third, fourth, fifth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, or forty-second embodiment or any alternative embodiments described therein.

[0107] In a forty-seventh embodiment, the compound of the present disclosure is represented by Formula (IVA), (IVB), (IVC), or (IVD):

##STR00039##

or a pharmaceutically acceptable salt thereof; where m is 0 or 1, and where the variables X, R.sup.1, R.sup.2 and R.sup.3 depicted in Formula (IVA), (IVB), (IVC), or (IVD) are as described in the first aspect or the first, second, third, fourth, fifth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, or forty-second embodiment or any alternative embodiments described therein.

[0108] In a forty-eighth embodiment, the compound of the present disclosure is represented by Formula (V):

##STR00040##

or a pharmaceutically acceptable salt thereof; where the variables X, R.sup.1, and R.sup.3 depicted in Formula (V) are as described in the first aspect or the first, second, third, fourth, fifth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-third, or forty-fourth embodiment or any alternative embodiments described therein.

[0109] In a forty-ninth embodiment, the compound of the present disclosure is represented by Formula (VI):

##STR00041##

or a pharmaceutically acceptable salt thereof, wherein; [0110] R.sup.1 is C.sub.1-2alkyl; [0111] Ring A is selected from phenyl, thiophenyl, pyrazolyl, isothiazolyl, and imidazolyl; [0112] m is 0 to 1; [0113] each R.sup.2 is independently selected from C.sub.1-4alkyl and C(O)OH; [0114] Z is a bond or C(O)NH*, wherein * indicates the attachment point to R.sup.3; [0115] R.sup.3 is selected from phenyl, pyridyl, pyrimidyl, benzimidazolyl and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is optionally substituted with 1 to 2 R.sup.4; [0116] each R.sup.4 is independently selected from C.sub.1-4alkyl, halo, OH, O-benzyl, cyano, NR.sup.4bR.sup.4c, C(O)NR.sup.4bR.sup.4c, or 4 to 6-membered monocyclic heterocyclyl; [0117] R.sup.4b and R.sup.4c are each independently selected from H and C.sub.1-4alkyl.

[0118] In a fiftieth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, Z is a bond, ring A is

##STR00042##

each of which is substituted with 1 R.sup.3 and optionally substituted with 1 R.sup.2; and the remaining variables are as described in the forty-ninth embodiment.

[0119] In a fifty-first embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, Z is a bond, ring A is

##STR00043##

and the remaining variables are as described in the forty-ninth embodiment.

[0120] In a fifty-second embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, Z is a bond, ring A is

##STR00044##

and the remaining variables are as described in the forty-ninth embodiment.

[0121] In a fifty-third embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R.sup.2 is CH.sub.3 or C(O)OH; and the remaining variables are as described in the forty-ninth, fiftieth, fifty-first, or fifty-second embodiment.

[0122] In a fifty-fourth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R.sup.3 is phenyl, pyridyl, or pyrimidyl, each of which is optionally substituted with 1 to 2 R.sup.4; and the remaining variables are as described in the forty-ninth, fiftieth, fifty-first, fifty-second, or fifty-third embodiment.

[0123] In a fifty-fifth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R.sup.3 is

##STR00045##

each of which is optionally substituted with 1 to 2 R.sup.4; and the remaining variables are as described in the forty-ninth, fiftieth, fifty-first, fifty-second, or fifty-third embodiment.

[0124] In a fifty-sixth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R.sup.3 is

##STR00046##

and the remaining variables are as described in the forty-ninth, fiftieth, fifty-first, fifty-second, or fifty-third embodiment.

[0125] In a fifty-seventh embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R.sup.4 is CH.sub.3, NH.sub.2, OH, halo, or NHC(O)CH.sub.3,

##STR00047##

and the remaining variables are as described in the forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third, fifty-fourth, fifty-fifth, or fifty-sixth embodiment.

[0126] In a fifty-eighth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, Z is C(O)NH*, wherein * indicates the attachment point to R.sup.3, ring A is

##STR00048##

which is substituted with 1 R.sup.3; and the remaining variables are as described in the forty-ninth embodiment.

[0127] In a fifty-ninth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, Z is C(O)NH*, wherein * indicates the attachment point to R.sup.3, ring A is

##STR00049##

and the remaining variables are as described in the forty-ninth embodiment.

[0128] In a sixtieth embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R.sup.3 is benzamidazolyl or 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, each of which is optionally substituted with 1 to 2 R.sup.4; and the remaining variables are as described in the forty-ninth, fifth-eighth, or fifth-ninth embodiment.

[0129] In a sixty-first embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R.sup.3 is

##STR00050##

and the remaining variables are as described in the forty-ninth, fifth-eighth, or fifth-ninth embodiment.

[0130] In a sixty-second embodiment, for the compounds of Formula (VI) described in the forty-ninth embodiment, or a pharmaceutically acceptable salt thereof, R.sup.4 is CH.sub.3; and the remaining variables are as described in the forty-ninth, fifth-eighth, fifth-ninth, sixtieth, or sixty-first embodiment.

[0131] In a sixty-third embodiment, the present disclosure provides a compound described herein (e.g., a compound of any one of Examples 1-162), or a pharmaceutically acceptable salt thereof.

[0132] In a sixty-fourth embodiment, the present disclosure provides a compound selected from the group consisting of: [0133] N-(3-(methylsulfonamido)phenyl)-1-phenyl-1H-pyrazole-4-carboxamide; [0134] N-(3-(methylsulfonamido)phenyl)-4-phenylpicolinamide; [0135] 4-(benzyloxy)-N-(3-(methylsulfonamido)phenyl)benzamide; [0136] 3-(benzyloxy)-N-(3-(methylsulfonamido)phenyl)benzamide; [0137] N-(3-(methylsulfonamido)phenyl)-5-phenylthiophene-2-carboxamide; [0138] N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; [0139] 4-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-(methylsulfonamido)phenyl)benzamide; [0140] N-(3-(methylsulfonamido)phenyl)-4-(1H-tetrazol-5-yl)benzamide; [0141] N-(3-(methylsulfonamido)phenyl)-2-(4H-1,2,4-triazol-3-yl)thiazole-4-carboxamide; [0142] 1-benzyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide; [0143] N-(3-(methylsulfonamido)phenyl)-[1,1-biphenyl]-3-carboxamide; [0144] N-(3-(methylsulfonamido)phenyl)-[1,1-biphenyl]-4-carboxamide; [0145] N-(3-(methylsulfonamido)phenyl)-4-(1H-pyrazol-1-yl)benzamide; [0146] N-(3-(methylsulfonamido)phenyl)-3-(1H-pyrazol-1-yl)benzamide; [0147] N-(3-(methylsulfonamido)phenyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxamide; [0148] N-(3-(methylsulfonamido)phenyl)-4-phenylthiazole-2-carboxamide; [0149] N-(3-(methylsulfonamido)phenyl)-1-(pyrimidin-2-yl)-1H-pyrazole-4-carboxamide; [0150] N-(3-(methylsulfonamido)phenyl)-4-(thiophen-2-yl)picolinamide; [0151] 4-(3-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0152] N-(3-(methylsulfonamido)phenyl)-4-(o-tolyl)thiophene-2-carboxamide; [0153] N-(3-(methylsulfonamido)phenyl)-4-(m-tolyl)thiophene-2-carboxamide; [0154] N-(3-(methylsulfonamido)phenyl)-4-(p-tolyl)thiophene-2-carboxamide; [0155] 5-methyl-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; [0156] 4-(3-carbamoylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0157] 4-(3-cyanophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0158] 4-(2-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0159] 4-(4-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0160] N-(3-(methylsulfonamido)phenyl)-4-(pyridin-3-yl)thiophene-2-carboxamide; [0161] N-(3-(methylsulfonamido)phenyl)-4-(pyridin-4-yl)thiophene-2-carboxamide; [0162] 4-(3-methoxyphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0163] 4-(2-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0164] 4-(3-aminophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0165] 4-(2-methoxyphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0166] 4-(2-methylpyridin-3-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0167] 4-(4-methylpyridin-3-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0168] N-(3-(methylsulfonamido)phenyl)-4-(pyrimidin-5-yl)thiophene-2-carboxamide; [0169] 4-(2-ethoxypyrimidin-5-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0170] 5-(4-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide; [0171] 4-(6-methylpyridin-3-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0172] N-(3-(methylsulfonamido)phenyl)-4-(pyridazin-3-yl)thiophene-2-carboxamide; [0173] 4-(3-methoxy-2-methylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0174] 4-(5-methoxy-2-methylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0175] 4-(3-hydroxypyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0176] 4-(2-fluoro-6-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0177] 4-benzyl-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; tert-butyl (3-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)phenyl)carbamate; [0178] 4-(3-hydroxyphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0179] 4-(3-hydroxy-2-methylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0180] 4-(5-hydroxy-2-methylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0181] 4-(2,6-difluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0182] 4-(2-(benzyloxy)phenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0183] 5-(4-methoxyphenyl)-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide; [0184] 5-(4-hydroxyphenyl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide; [0185] 5-methyl-N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide; [0186] N-(3-(methylsulfonamido)phenyl)-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamide; [0187] N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide; [0188] 4-(3-methylpyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0189] N-(3-(methylsulfonamido)phenyl)-4-(pyrimidin-2-yl)thiophene-2-carboxamide; [0190] 4-(6-aminopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0191] 4-(4-aminopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0192] 2-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)isonicotinic acid; [0193] 4-(2-aminophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0194] 4-(3-aminopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0195] N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)-1H-imidazole-2-carboxamide; [0196] N-(3-(methylsulfonamido)phenyl)-4-(5-(piperazin-1-yl)pyridin-2-yl)thiophene-2-carboxamide; [0197] 2-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)isonicotinamide; [0198] 4-(2-acetamidophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0199] 4-(3-acetamidopyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0200] 4-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0201] N-(3-(ethylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; [0202] N-(3-(ethylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide; [0203] 5-bromo-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; [0204] N-(3-(methylsulfonamido)phenyl)-4-phenyl-5-(trifluoromethyl)thiophene-2-carboxamide; [0205] 5-cyano-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; [0206] 5-((3-(methylsulfonamido)phenyl)carbamoyl)-3-phenylthiophene-2-carboxylic acid; [0207] N2-(3-(methylsulfonamido)phenyl)-N4-phenylthiophene-2,4-dicarboxamide; [0208] N2-(3-(methylsulfonamido)phenyl)-N4-(2-(pyridin-3-yl)ethyl)thiophene-2,4-dicarboxamide; [0209] N4-(3-chloro-4-methylphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0210] N4-((1-hydroxycyclohexyl)methyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0211] N4-(6-methoxypyridin-3-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0212] N4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0213] N2-(3-(methylsulfonamido)phenyl)-N4-(4-(trifluoromethoxy)phenyl)thiophene-2,4-dicarboxamide; [0214] N4-(5-fluoro-2-methoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0215] N2-(3-(methylsulfonamido)phenyl)-N4-(1-phenylethyl)thiophene-2,4-dicarboxamide; [0216] N4-((5-fluoropyridin-3-yl)methyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0217] N4-(2,3-dihydro-1H-inden-2-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0218] N4-(4-chloro-3-methylphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0219] N4-(4-(dimethylcarbamoyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0220] N2-(3-(methylsulfonamido)phenyl)-N4-(2-phenoxyphenyl)thiophene-2,4-dicarboxamide; [0221] N2-(3-(methylsulfonamido)phenyl)-N4-(4-morpholinobenzyl)thiophene-2,4-dicarboxamide; [0222] N2-(3-(methylsulfonamido)phenyl)-N4-(4-phenoxyphenyl)thiophene-2,4-dicarboxamide; [0223] N4-(4-isopropoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0224] N4-(cyclopropylmethyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0225] N2-(3-(methylsulfonamido)phenyl)-N4-(4-(morpholinomethyl)phenyl)thiophene-2,4-dicarboxamide; [0226] N2-(3-(methylsulfonamido)phenyl)-N4-(3-(trifluoromethoxy)phenyl)thiophene-2,4-dicarboxamide; [0227] N4-(3-isopropoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0228] N2-(3-(methylsulfonamido)phenyl)-N4-(4-(2-morpholinoethoxy)phenyl)thiophene-2,4-dicarboxamide; [0229] N4-(2,3-dihydrobenzofuran-4-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0230] N2-(3-(methylsulfonamido)phenyl)-N4-(4-(morpholinomethyl)benzyl)thiophene-2,4-dicarboxamide; [0231] N4-(3-chloro-5-methoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0232] N4-(4-(tert-butylcarbamoyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0233] N2-(3-(methylsulfonamido)phenyl)-N4-(4-(pyridin-4-yl)phenyl)thiophene-2,4-dicarboxamide; [0234] N4-(imidazo[1,2-a]pyridin-3-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0235] N4-(4-methoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0236] N4-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0237] N4-(1-methyl-1H-benzo[d]imidazol-6-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0238] N2-(3-(methylsulfonamido)phenyl)-N4-(3-(pyridin-3-yl)phenyl)thiophene-2,4-dicarboxamide; [0239] N4-(3-(methoxymethyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0240] N4-(2-isopropoxyphenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0241] N4-(2,3-dihydro-1H-inden-1-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0242] N4-(4-chlorophenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0243] N4-(2-(cyanomethyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0244] N4-(4-(methylcarbamoyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0245] N4-(2-(1H-indol-3-yl)ethyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0246] N4-((1H-benzo[d]imidazol-2-yl)methyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0247] N4-(2,5-dimethoxyphenethyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0248] N4-(2-(2-hydroxyethyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0249] N4-((1H-indazol-3-yl)methyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0250] N4-((1H-indol-5-yl)methyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0251] N4-(1H-benzo[d]imidazol-2-yl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0252] N2-(3-(methylsulfonamido)phenyl)-N4-(3-(2-methylthiazol-4-yl)phenyl)thiophene-2,4-dicarboxamide; [0253] N2-(3-(methylsulfonamido)phenyl)-N4-(5-phenyl-1H-pyrazol-3-yl)thiophene-2,4-dicarboxamide; [0254] N4-(4-(2-hydroxyethyl)phenyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0255] N2-(3-(methylsulfonamido)phenyl)-N4-(2-(piperidin-1-yl)ethyl)thiophene-2,4-dicarboxamide; [0256] N2-(3-(methylsulfonamido)phenyl)-N4-(3-(piperidin-1-ylmethyl)phenyl)thiophene-2,4-dicarboxamide; [0257] N2-methyl-N5-(3-(methylsulfonamido)phenyl)-3-phenylthiophene-2,5-dicarboxamide; [0258] 5-(hydroxymethyl)-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; [0259] 1-benzyl-5-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide; [0260] 4-(benzylamino)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide; [0261] N-(6-(methylsulfonamido)pyridin-2-yl)-4-phenylthiophene-2-carboxamide; [0262] N-(3-(methylsulfonoamidimidamido)phenyl)-4-phenylthiophene-2-carboxamide; [0263] N-(3-methyl-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; [0264] N-(3-formyl-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide; [0265] 5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide; [0266] 5-(3,5-difluoropyridin-2-yl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide; and [0267] N4-(2-cyclopropylethyl)-N2-(3-(methylsulfonamido)phenyl)thiophene-2,4-dicarboxamide; [0268] or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, the compounds of Table I are excluded from the compounds of the present disclosure (e.g., compounds of Formula (I)).

TABLE-US-00001 TABLE I Compound Name N-(3-(methylsulfonamido)phenyl)-4-(1H-pyrrol-1-yl)benzamide 5-(2-methoxyphenyl)-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide N-(3-(methylsulfonamido)phenyl)-4-(tetrahydro-2H-pyran-4-yl)benzamide N-(3-(methylsulfonamido)phenyl)-5-(thiophen-2-yl)-1H-pyrazole-3-carboxamide 5-(furan-2-yl)-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide N-(3-(methylsulfonamido)phenyl)-2-(pyrazin-2-yl)thiazole-4-carboxamide 4-methyl-N-(3-(methylsulfonamido)phenyl)-2-(tetrahydro-2H-pyran-3-yl)thiazole-5- carboxamide 3-(4-fluorophenyl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-5- carboxamide N-(3-(methylsulfonamido)phenyl)-[1,1-biphenyl]-2-carboxamide N-(3-(methylsulfonamido)phenyl)-4-(pyrrolidin-1-yl)benzamide 3-fluoro-N-(3-(methylsulfonamido)phenyl)-[1,1-biphenyl]-4-carboxamide 2-methyl-N-(3-(methylsulfonamido)phenyl)-6-phenylnicotinamide N-(3-(methylsulfonamido)phenyl)-2-(1H-pyrazol-1-yl)benzamide N-(3-(methylsulfonamido)phenyl)-3-(1H-tetrazol-1-yl)benzamide 5-(2-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide N-(3-(methylsulfonamido)phenyl)-2-(1H-pyrrol-1-yl)thiazole-4-carboxamide 1-methyl-N-(3-(methylsulfonamido)phenyl)-3-phenyl-1H-pyrazole-5-carboxamide 5-methyl-N-(3-(methylsulfonamido)phenyl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide 2-(3-chlorophenyl)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 1-(4-bromophenyl)-5-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-4- carboxamide 1-(3-chlorophenyl)-5-ethyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 5-ethyl-1-(4-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 1-(3-methoxyphenyl)-2,5-dimethyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3- carboxamide 1-(3-chlorophenyl)-5-isopropyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-4- carboxamide 1-(4-fluorophenyl)-5-isopropyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-4- carboxamide 1-(4-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)-2-(methylthio)-1H-imidazole-5- carboxamide N-(3-(methylsulfonamido)phenyl)-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3- carboxamide 2-(1H-indol-2-yl)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 3-(tert-butyl)-5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-hydroxy-N-(3- (methylsulfonamido)phenyl)benzamide 1-(3-chlorophenyl)-N-(3-(methylsulfonamido)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4- carboxamide 1-(4-chlorophenyl)-N-(3-(methylsulfonamido)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4- carboxamide 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,5-dimethyl-N-(3-(methylsulfonamido)phenyl)- 1H-pyrrole-3-carboxamide 2-cyclobutyl-N-(3-(methylsulfonamido)phenyl)benzamide N-(3-(methylsulfonamido)phenyl)-4-(2H-tetrazol-5-yl)benzamide N-(3-(methylsulfonamido)phenyl)-2-(piperidin-1-yl)benzamide N-(3-(methylsulfonamido)phenyl)-2-(pyrrolidin-1-yl)nicotinamide 4-(5-methyl-1H-tetrazol-1-yl)-N-(3-(methylsulfonamido)phenyl)benzamide 5-methyl-N-(3-(methylsulfonamido)phenyl)-2-(2-oxopyrrolidin-1-yl)benzamide N-(3-(methylsulfonamido)phenyl)-5-phenyl-1H-pyrazole-3-carboxamide 2-cyclopropyl-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 1-cyclohexyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide N-(3-(methylsulfonamido)phenyl)-2-phenylthiazole-4-carboxamide N-(3-(methylsulfonamido)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-3-carboxamide 5-methyl-N-(3-(methylsulfonamido)phenyl)-1-phenyl-1H-pyrazole-4-carboxamide N-(3-(methylsulfonamido)phenyl)-1-(piperidin-3-yl)-1H-pyrazole-3-carboxamide 5-cyclopropyl-1-ethyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 3-(tert-butyl)-2-methoxy-N-(3-(methylsulfonamido)phenyl)-5-(2-oxo-1,2-dihydropyridin- 3-yl)benzamide N-(3-(methylsulfonamido)phenyl)-2-(o-tolyl)thiazole-4-carboxamide 1-cyclopropyl-2,5-dimethyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide 3-cyclohexyl-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-4-carboxamide 5-(4-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide N-(3-(methylsulfonamido)phenyl)-2-(1H-1,2,4-triazol-5-yl)thiazole-4-carboxamide N-(3-(methylsulfonamido)phenyl)-5-(2-methylthiazol-4-yl)furan-3-carboxamide 5-cyclopentyl-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide N-(3-(methylsulfonamido)phenyl)-2-(piperidin-1-yl)thiazole-4-carboxamide 2-cyclopentyl-4-methyl-N-(3-(methylsulfonamido)phenyl)thiazole-5-carboxamide 2-(4-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 1-(2,6-difluorophenyl)-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide 5-methyl-N-(3-(methylsulfonamido)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4- carboxamide 2-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-3- carboxamide 1-(4-methoxyphenyl)-5-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-3- carboxamide 1-cyclohexyl-2,5-dimethyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrrole-3-carboxamide 3-(3-methoxyphenyl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-5- carboxamide 2-(2,4-dichlorophenyl)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 1-(4,6-dimethylpyrimidin-2-yl)-5-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole- 3-carboxamide N-(3-(methylsulfonamido)phenyl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrazole-3-carboxamide 3-(2,5-dimethoxyphenyl)-1-methyl-N-(3-(methylsulfonamido)phenyl)-1H-pyrazole-5- carboxamide 3-(4-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-1H-1,2,3-triazol-1-yl)-4-methyl-N-(3- (methylsulfonamido)phenyl)benzamide 2-(1-methyl-1H-indol-2-yl)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 2-(1-ethyl-1H-indol-2-yl)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 1-(2-chloro-5-(trifluoromethyl)phenyl)-N-(3-(methylsulfonamido)phenyl)-1,4,5,6- tetrahydrocyclopenta[c]pyrazole-3-carboxamide 6-(3-bromophenyl)-2-methyl-N-(3-(methylsulfonamido)phenyl)nicotinamide N-(3-(methylsulfonamido)phenyl)-3-nitro-4-(pyrrolidin-1-yl)benzamide N-(3-(methylsulfonamido)phenyl)-2-(methylthio)-1-phenyl-1H-imidazole-5-carboxamide 2-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-(methylsulfonamido)phenyl)-[1,1- biphenyl]-4-carboxamide 5-((3-(methylsulfonamido)phenyl)carbamoyl)-1-phenyl-1H-pyrazole-3-carboxylic acid 5-(N,N-dimethylsulfamoyl)-N-(3-(methylsulfonamido)phenyl)-2-morpholinobenzamide N-(3-(methylsulfonamido)phenyl)-5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1- yl)nicotinamide 2,5-dimethyl-N-(3-(methylsulfonamido)phenyl)-1-(2-(trifluoromethyl)phenyl)-1H-pyrrole- 3-carboxamide (1R,5S,6r)-3-(6-(isopentyloxy)-5-((3-(methylsulfonamido)phenyl)carbamoyl)pyridin-2-yl)- 3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl (1R,5S,6r)-3-(6-(isopentyloxy)-5-((3-(methylsulfonamido)phenyl)carbamoyl)pyridin- 2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate 5-cyclopropyl-1-ethyl-N-(3-(propylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide 1-(piperidin-4-yl)-N-(3-(propylsulfonamido)phenyl)-1H-pyrrole-2-carboxamide N-(3-(cyclopropanesulfonamido)phenyl)-5-cyclopropyl-1-ethyl-1H-pyrazole-3- carboxamide N-(3-(cyclopropanesulfonamido)phenyl)-4-cyclopropyl-1H-pyrrole-3-carboxamide 1-(piperidin-3-yl)-N-(3-(propylsulfonamido)phenyl)-1H-pyrazole-3-carboxamide 1-phenyl-5-((3-(propylsulfonamido)phenyl)carbamoyl)-1H-pyrazole-3-carboxylic acid 1-(piperidin-4-yl)-N-(3-(propylsulfonamido)phenyl)-1H-pyrrole-2-carboxamide N-(3-(methylsulfonamido)phenyl)-3-(tetrazolidin-1-yl)benzamide 5-methyl-N-(3-(methylsulfonamido)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-3- carboxamide N-(3-(cyclopropanesulfonamido)phenyl)-2-cyclopropylfuran-3-carboxamide 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)-N-(3-(methylsulfonamido)phenyl)picolinamide N-(3-(methylsulfonamido)phenyl)-1-(tetrahydrofuran-2-carbonyl)piperidine-3- carboxamide N-(3-(methylsulfonamido)phenyl)-1-(5-nitrofuran-2-carbonyl)azetidine-3-carboxamide N-(3-(methylsulfonamido)phenyl)-1-(pyrazine-2-carbonyl)azetidine-3-carboxamide 1-(benzo[d][1,3]dioxole-5-carbonyl)-N-(3-(methylsulfonamido)phenyl)azetidine-3- carboxamide 1-(3,4-difluorobenzoyl)-N-(3-(methylsulfonamido)phenyl)azetidine-3-carboxamide N-(3-(methylsulfonamido)phenyl)-2-(thiophene-2-carbonyl)benzamide 1-(furan-2-carbonyl)-N-(3-(methylsulfonamido)phenyl)piperidine-3-carboxamide N-(3-(cyclopropanesulfonamido)phenyl)-4-(3-fluorobenzoyl)piperazine-1-carboxamide N-(3-(methylsulfonamido)phenyl)-1-(tetrahydrothiophene-2-carbonyl)piperidine-3- carboxamide N-(3-(methylsulfonamido)phenyl)-1-(thiophene-2-carbonyl)azetidine-3-carboxamide 1-(1H-indole-3-carbonyl)-N-(3-(methylsulfonamido)phenyl)azetidine-3-carboxamide 1-(5-methylisoxazole-3-carbonyl)-N-(3-(methylsulfonamido)phenyl)azetidine-3- carboxamide N-(3-(methylsulfonamido)phenyl)-1-(pyrrolidine-1-carbonyl)piperidine-3-carboxamide 2-(4-methylbenzoyl)-N-(3-(methylsulfonamido)phenyl)benzamide N-(3-(methylsulfonamido)phenyl)-1-(thiophene-2-carbonyl)piperidine-3-carboxamide N4-(3-(methylsulfonamido)phenyl)-N1-(thiophen-2-yl)piperidine-1,4-dicarboxamide N1-cyclopropyl-N4-(3-(methylsulfonamido)phenyl)piperidine-1,4-dicarboxamide 3-iodo-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)-N2-(3- (methylsulfonamido)phenyl)phthalamide N1-cyclopropyl-N4-(3-(methylsulfonamido)phenyl)terephthalamide 3-iodo-N1-(2-methyl-4-(perfluoropropan-2-yl)phenyl)-N2-(3- ((trifluoromethyl)sulfonamido)phenyl)phthalamide N3-(3-(methylsulfonamido)phenyl)-N1-(thiophen-2-yl)piperidine-1,3-dicarboxamide N1-cyclopropyl-N3-(3-(methylsulfonamido)phenyl)piperidine-1,3-dicarboxamide N-(3-(methylsulfonamido)phenyl)-3-(phenoxymethyl)furan-2-carboxamide 2-((2,4-dimethoxyphenyl)amino)-N-(3-(methylsulfonamido)phenyl)thiazolidine-4- carboxamide 2-((3,4-dimethoxyphenyl)amino)-N-(3-(methylsulfonamido)phenyl)thiazolidine-4- carboxamide 4-((5-chloro-4-(1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxy-N-(3- (methylsulfonamido)phenyl)benzamide 3-((6-methylpyridazin-3-yl)amino)-N-(3-(methylsulfonamido)phenyl)benzamide 3-((1-cyclopentyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido[3,4-b]pyrazin-7-yl)amino)- N-(3-(methylsulfonamido)phenyl)benzamide 3-((2,4-dimethyl-3-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido[3,4- b]pyrazin-7-yl)amino)-N-(3-(methylsulfonamido)phenyl)benzamide N-(3-(methylsulfonamido)phenyl)-2-(pyridin-3-ylamino)thiazole-4-carboxamide N-(3-(methylsulfonamido)phenyl)-2-(pyrimidin-2-ylamino)thiazole-4-carboxamide 2-((4,6-dimethylpyrimidin-2-yl)amino)-N-(3-(methylsulfonamido)phenyl)thiazole-4- carboxamide N-(3-(methylsulfonamido)phenyl)-2-((4-(trifluoromethoxy)phenyl)amino)thiazole-4- carboxamide 2-((2,4-dimethoxyphenyl)amino)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 2-((4-fluorophenyl)amino)-N-(3-(methylsulfonamido)phenyl)benzamide 1-ethyl-N-(3-(methylsulfonamido)phenyl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1H- pyrazolo[3,4-b]pyridine-5-carboxamide 2-((4,6-dimethylpyrimidin-2-yl)amino)-N-(3-(methylsulfonamido)phenyl)thiazolidine-4- carboxamide 2-((4-ethoxyphenyl)amino)-N-(3-(methylsulfonamido)phenyl)thiazolidine-4-carboxamide N-(3-(methylsulfonamido)phenyl)-2-((4-(trifluoromethoxy)phenyl)amino)thiazolidine-4- carboxamide 2-(cyclopropylamino)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 4-methyl-N-(3-(methylsulfonamido)phenyl)-3-((4-(pyridin-3-yl)-5H-pyrrolo[3,2- d]pyrimidin-2-yl)amino)benzamide 3-((1-isopropyl-2,4-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido[3,4-b]pyrazin-7-yl)amino)-N- (3-(methylsulfonamido)phenyl)benzamide N-(3-(methylsulfonamido)phenyl)-2-(pyridin-2-ylamino)thiazole-4-carboxamide 2-((6-methylpyridin-2-yl)amino)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide N-(3-(methylsulfonamido)phenyl)-3-(pyrimidin-2-ylamino)benzamide 2-((3,4-dimethoxyphenyl)amino)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 2-((4-ethoxyphenyl)amino)-N-(3-(methylsulfonamido)phenyl)thiazole-4-carboxamide 2-ethyl-3-(methyl((1-methyl-1H-imidazol-2-yl)methyl)amino)-N-(3- (methylsulfonamido)phenyl)imidazo[1,2-a]pyridine-6-carboxamide 3-((3-bromobenzyl)(ethyl)amino)-2-ethyl-N-(3-(methylsulfonamido)phenyl)imidazo[1,2- a]pyridine-6-carboxamide 2-ethyl-3-(methyl(3-phenylpropyl)amino)-N-(3-(methylsulfonamido)phenyl)imidazo[1,2- a]pyridine-6-carboxamide 4-((4-acetylphenyl)sulfonamido)-N-(3-(methylsulfonamido)phenyl)benzamide N-(3-(methylsulfonamido)phenyl)-2-((tetrahydrofuran-3-yl)oxy)nicotinamide N-(3-(methylsulfonamido)phenyl)-4-(thiazol-2-yloxy)benzamide N-(3-(methylsulfonamido)phenyl)-2-((tetrahydrothiophen-3-yl)oxy)nicotinamide 5-chloro-N-(3-(methylsulfonamido)phenyl)-6-((tetrahydro-2H-pyran-4- yl)oxy)nicotinamide N-(3-(methylsulfonamido)phenyl)-2-((tetrahydrofuran-3-yl)oxy)isonicotinamide N-(3-(methylsulfonamido)phenyl)-3-(pyridin-2-yloxy)benzamide 4-(cyclopentyloxy)-N-(3-(methylsulfonamido)phenyl)benzamide N-(3-(methylsulfonamido)phenyl)-2-((tetrahydrothiophen-3-yl)oxy)isonicotinamide 2-(cyclopentyloxy)-N-(3-(methylsulfonamido)phenyl)isonicotinamide N-(3-(methylsulfonamido)phenyl)-6-((tetrahydrothiophen-3-yl)oxy)nicotinamide N-(3-(methylsulfonamido)phenyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)nicotinamide N-(3-(methylsulfonamido)phenyl)-6-((tetrahydrofuran-3-yl)oxy)nicotinamide 5-chloro-N-(3-(methylsulfonamido)phenyl)-6-((tetrahydrofuran-3-yl)oxy)nicotinamide 2-(2,4-dichlorophenoxy)-N-(3-(methylsulfonamido)phenyl)benzamide 4-(tert-butyl)-2-(2-chloro-4-fluorophenoxy)-N-(3-(methylsulfonamido)phenyl)benzamide 6-(benzyloxy)-N-(3-(methylsulfonamido)phenyl)pyrimidine-4-carboxamide 8-((2,6-difluorobenzyl)oxy)-2,6-dimethyl-N-(3-(methylsulfonamido)phenyl)imidazo[1,2- a]pyridine-3-carboxamide 3-((2-methylbenzyl)oxy)-N-(3-(methylsulfonamido)phenyl)azetidine-1-carboxamide N-(3-(methylsulfonamido)phenyl)-6-(1-phenylethoxy)nicotinamide 3-ethoxy-N-(3-(methylsulfonamido)phenyl)-4-(pyridin-3-ylmethoxy)benzamide 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(methylsulfonamido)phenyl)benzamide N-(3-(methylsulfonamido)phenyl)-4-((2-methylthiazol-4-yl)methoxy)benzamide N-(3-(methylsulfonamido)phenyl)-6-((tetrahydrofuran-2-yl)methoxy)nicotinamide 3-(benzyloxy)-N-(3-(methylsulfonamido)phenyl)isoxazole-5-carboxamide 2-(benzyloxy)-N-(3-(methylsulfonamido)phenyl)-4-(3-(pyrrolidin-1-yl)propoxy)benzamide N-(3-(methylsulfonamido)phenyl)-4-((4-methylthiazol-2-yl)methoxy)benzamide N-(3-(methylsulfonamido)phenyl)-3-(thiophen-2-ylmethoxy)benzamide N-(3-(methylsulfonamido)phenyl)-4-(quinolin-2-ylmethoxy)benzamide 3-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(3-(methylsulfonamido)phenyl)benzamide 5-((3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)-N-(3-(methylsulfonamido)phenyl)thiophene- 3-carboxamide N-(3-(methylsulfonamido)phenyl)-5-(morpholinosulfonyl)thiophene-3-carboxamide N-(3-(methylsulfonamido)phenyl)-1-(phenylsulfonyl)pyrrolidine-2-carboxamide N-(3-(methylsulfonamido)phenyl)-1-(phenylsulfonyl)pyrrolidine-2-carboxamide 2-methyl-N-(3-(methylsulfonamido)phenyl)-5-(piperidin-1-ylsulfonyl)benzamide 1-(cyclopropylsulfonyl)-N-(3-(methylsulfonamido)phenyl)azetidine-3-carboxamide 1-((3,5-dimethylisoxazol-4-yl)sulfonyl)-N-(3-(methylsulfonamido)phenyl)piperidine-4- carboxamide N-(3-(methylsulfonamido)phenyl)-1-(phenylsulfonyl)pyrrolidine-2-carboxamide 4-ethyl-N-(3-(methylsulfonamido)phenyl)-3-(morpholinosulfonyl)benzamide 1-((3,5-dimethylisoxazolidin-4-yl)sulfonyl)-N-(3-(methylsulfonamido)phenyl)piperidine-4- carboxamide N-(3-(methylsulfonamido)phenyl)-4-(N-(pyridin-4-yl)sulfamoyl)benzamide 4-(N-cyclohexyl-N-methylsulfamoyl)-N-(3-(methylsulfonamido)phenyl)benzamide N-(3-(methylsulfonamido)phenyl)-4-(N-(p-tolyl)sulfamoyl)benzamide 3-(N-(4-fluorophenyl)sulfamoyl)-N-(3-(methylsulfonamido)phenyl)benzamide 4-(N-ethyl-N-phenylsulfamoyl)-N-(3-(methylsulfonamido)phenyl)benzamide 5-(N-cyclohexylsulfamoyl)-2-methyl-N-(3-(methylsulfonamido)phenyl)benzamide 5-(N-cyclopropylsulfamoyl)-2-methyl-N-(3-(methylsulfonamido)phenyl)benzamide 3-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(3- (methylsulfonamido)phenyl)benzamide 2-methyl-N-(3-(methylsulfonamido)phenyl)-5-(N-(m-tolyl)sulfamoyl)benzamide 4-(N-(2-methoxyphenyl)sulfamoyl)-N-(3-(methylsulfonamido)phenyl)benzamide N3-(3-(methylsulfonamido)phenyl)-N1-(thiophen-2-ylmethyl)piperidine-1,3- dicarboxamide 4-benzyl-N-(3-(methylsulfonamido)phenyl)-5-oxomorpholine-3-carboxamide 1-((6-methyl-1H-benzo[d]imidazol-2-yl)methyl)-N-(3- (methylsulfonamido)phenyl)piperidine-4-carboxamide 1-((1H-benzo[d]imidazol-2-yl)methyl)-N-(3-(methylsulfonamido)phenyl)piperidine-4- carboxamide 2-benzyl-N-(3-(methylsulfonamido)phenyl)benzamide 2-benzyl-4-methyl-N-(3-(methylsulfonamido)phenyl)thiazolidine-5-carboxamide 1-((4-methoxynaphthalen-1-yl)methyl)-2-methyl-N-(3- (methylsulfonamido)phenyl)azetidine-2-carboxamide 1-(2-(difluoromethoxy)benzyl)-2-methyl-N-(3-(methylsulfonamido)phenyl)azetidine-2- carboxamide 5-((3,5-dimethyl-1H-pyrazol-1-yl)methyl)-N-(3-(methylsulfonamido)phenyl)furan-2- carboxamide N-(3-(methylsulfonamido)phenyl)-2,4-dioxo-3-(thiophen-2-ylmethyl)-1,2,3,4- tetrahydropyrimidine-5-carboxamide 3-(benzo[d][1,3]dioxol-5-ylmethyl)-N-(3-(methylsulfonamido)phenyl)-2,4-dioxo-1,2,3,4- tetrahydropyrimidine-5-carboxamide 3-(2-chlorobenzyl)-N-(3-(methylsulfonamido)phenyl)-2,4-dioxo-1,2,3,4- tetrahydropyrimidine-5-carboxamide N-(3-(methylsulfonamido)phenyl)-1-((3-(pyridin-4-yl)-1,2,4-oxadiazol-5- yl)methyl)piperidine-3-carboxamide N-(3-(methylsulfonamido)phenyl)-1-((3-(pyrimidin-2-yl)-1,2,4-oxadiazol-5- yl)methyl)piperidine-3-carboxamide 3-((1H-imidazol-1-yl)methyl)-N-(3-(methylsulfonamido)phenyl)piperidine-1-carboxamide 4-benzyl-N-(3-(propylsulfonamido)phenyl)piperazine-1-carboxamide 1-benzyl-N-(3-(methylsulfonamido)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide 4-((1H-imidazol-1-yl)methyl)-N-(3-(methylsulfonamido)phenyl)benzamide 2-benzyl-4-methyl-N-(3-(methylsulfonamido)phenyl)thiazole-5-carboxamide 2-(1-(4-isopropylbenzyl)-2-((3-(methylsulfonamido)phenyl)carbamoyl)-1H-indol-3- yl)acetic acid 4-(imidazolidin-1-ylmethyl)-N-(3-(methylsulfonamido)phenyl)benzamide 1-(2,3-dimethoxybenzyl)-2-methyl-N-(3-(methylsulfonamido)phenyl)azetidine-2- carboxamide 2-methyl-N-(3-(methylsulfonamido)phenyl)-1-(4-(methylthio)benzyl)azetidine-2- carboxamide 1-(cyclobutylmethyl)-N-(3-(propylsulfonamido)phenyl)-1H-pyrazole-5-carboxamide 3-(furan-2-ylmethyl)-N-(3-(methylsulfonamido)phenyl)-2,4-dioxo-1,2,3,4- tetrahydropyrimidine-5-carboxamide 1-(4-methylbenzyl)-N-(3-(methylsulfonamido)phenyl)-6-oxo-1,6-dihydropyridazine-3- carboxamide 3-(2-fluorobenzyl)-N-(3-(methylsulfonamido)phenyl)-2,4-dioxo-1,2,3,4- tetrahydropyrimidine-5-carboxamide N-(3-(methylsulfonamido)phenyl)-1-((3-(pyridin-3-yl)-1,2,4-oxadiazol-5- yl)methyl)piperidine-3-carboxamide N-(3-(methylsulfonamido)phenyl)-1-((3-(thiophen-2-yl)-1,2,4-oxadiazol-5- yl)methyl)piperidine-3-carboxamide 2-ethyl-3-(3-methoxy-N-methylbenzamido)-N-(3-(methylsulfonamido)phenyl)imidazo[1,2- a]pyridine-6-carboxamide 4-(cyclopropanecarboxamido)-N-(3-(methylsulfonamido)phenyl)cyclohexane-1- carboxamide 2-benzamido-N-(3-(methylsulfonamido)phenyl)oxazole-4-carboxamide N-(2-chloro-5-((3-(methylsulfonamido)phenyl)carbamoyl)phenyl)thiophene-2- carboxamide N-(2-chloro-5-((3-(methylsulfonamido)phenyl)carbamoyl)phenyl)tetrahydrothiophene-2- carboxamide 2-(cyclopropanecarboxamido)-N-(3-(methylsulfonamido)phenyl)oxazole-4-carboxamide 5-methyl-N-(4-((3-(methylsulfonamido)phenyl)carbamoyl)oxazol-2-yl)isoxazole-3- carboxamide 2-(furan-2-carboxamido)-N-(3-(methylsulfonamido)phenyl)oxazole-4-carboxamide N-(3-(methylsulfonamido)phenyl)-2-(thiophene-2-carboxamido)oxazole-4-carboxamide 3-(2-methylcyclopropane-1-carboxamido)-N-(3-(methylsulfonamido)phenyl)benzamide

[0270] The compounds and intermediates described herein may be isolated and used as the compound per se. Alternatively, when a moiety is present that is capable of forming a salt, the compound or intermediate may be isolated and used as its corresponding salt. As used herein, the terms salt or salts refers to an acid addition or base addition salt of a compound described herein. Salts include in particular pharmaceutical acceptable salts. The term pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds described herein and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

[0271] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids or organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.

[0272] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0273] 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.

[0274] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0275] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the 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.

[0276] 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, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0277] The salts can be synthesized by conventional chemical methods from a compound containing a basic or acidic moiety. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0278] Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed. In one embodiment, the present disclosure provides deuterated compounds described herein or a pharmaceutically acceptable salt thereof.

[0279] Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone, d.sub.6-DMSO.

[0280] It will be recognized by those skilled in the art that the compounds of the present disclosure may contain chiral centers and as such may exist in different stereoisomeric forms.

[0281] As used herein, the term an optical isomer or a stereoisomer refers to any of the various stereo isomeric configurations which may exist for a given compound of the present disclosure. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound.

[0282] 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 term racemic or rac is used to designate a racemic mixture where appropriate. When designating the stereochemistry for the compounds of the present disclosure, a single stereoisomer with known relative and absolute configuration of the two chiral centers is designated using the conventional RS system (e.g., (1S,2S)). Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or () depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Alternatively, the resolved compounds can be defined by the respective retention times for the corresponding enantiomers/diastereomers via chiral HPLC.

[0283] 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 that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0284] Unless specified otherwise, 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 may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., separated on chiral SFC or HPLC chromatography columns, such as CHIRALPAK and CHIRALCEL available from DAICEL Corp. using the appropriate solvent or mixture of solvents to achieve good separation). If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0285] The present disclosure also provides a pharmaceutical composition comprising a compound described herein (e.g., a compound according to any one of the preceding embodiments), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

Methods of Use

[0286] 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 10% decrease in DHX9 activity as measured by a given assay such as the bioassay described in the examples and known in the art).

[0287] In certain embodiments, the present disclosure provides a method of treating a disease or disorder responsive to inhibition of DHX9 activity (referred herein as DHX9 mediated disease or disorder) in a subject in need of the treatment. The method comprises administering to the subject a compound described herein (e.g., a compound described in any one of the first to sixty-fourth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0288] 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 sixty-fourth embodiments) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a DHX9 mediated disorder or disease in a subject in need of the treatment.

[0289] In certain embodiments, the present disclosure provides a compound described herein (e.g., a compound described in any one of the first to sixty-fourth 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 the treatment of a DHX9 mediated disorder or disease in a subject in need of the treatment.

[0290] In certain embodiments, the DHX9 mediated disease or disorder is selected from cancer, viral infections, and autoimmune disease.

[0291] In some embodiments, the present disclosure provides a method of treating cancer. In some embodiments, the cancer is selected from colorectal, endometrial, ovarian, gastric, hematopoietic, breast, brain, skin, lung, blood, prostate, head and neck, pancreatic, bladder, bone, soft-tissue, kidney, and liver cancer. In some embodiments the cancer is selected from colorectal, endometrial, ovarian, hematopoietic, and gastric cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is Ewing's sarcoma.

[0292] In some embodiments, the cancer is a microsatellite instable (MSI) cancer. In some embodiments, the cancer is MSI-high cancer. In other embodiments, the cancer is MSI-low cancer. MSI is determined by PCR analysis of 5 different nucleotide repeats, which is dependent on the cancer type. MSI-low cancers are characterized by instability at only 1 of the 5 sites; while MSI-high cancers are characterized by instability at 2 or more of the 5 sites (G. Yang et al. Correlations between microsatellite instability and the biological behavior of tumors. Journal of Cancer Research and Clinical Oncology, 2019).

[0293] MSI-high cancer is additionally characterized by defective mismatch repair (dMMR) (M. Lorenzi, et al. Epidemiology of Microsatellite Instability High (MSI-H) and Deficient Mismatch Repair (dMMR) in Solid Tumors: A Structured Literature Review. Journal of Oncology, Volume 2020, Article ID 1897929). For example, dMMR in colorectal cancer can be determined by MLH1 promoter hypermethylation, rendering MLH1 inactive, which comprises about 80-90% of MSI-high colorectal cancers. MSI-high colorectal cancer with inactivated MLH1 is also named sporadic MSI-high colorectal cancer. Alternatively, dMMR can be determined by immunohistochemistry 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 2 predominantly mutated MMR proteins. They are mutated in about 10-20% of MSI-high colorectal cancers. MSI-high colorectal cancers with these mutations are also known as Lynch Syndrome cancers.

[0294] In some embodiments, the cancer is a MSI cancer and/or has mutations or defects in DNA mis-match repair (MMR), and/or mutations or defects in RNA splicing and the kinetochore complex.

[0295] The compounds, or pharmaceutically acceptable salts thereof described herein may be used to decrease the expression or activity of DHX9, or to otherwise affect the properties and/or behavior of DHX9 in a cell.

[0296] One embodiment of the present disclosure includes a method of decreasing the expression or activity of DHX9, or to otherwise affect the properties and/or behavior of DHX9 in a subject comprising administering to said subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0297] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a mammal.

[0298] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a primate.

[0299] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a human.

[0300] As used herein, an effective amount and a therapeutically effective amount can used interchangeably. It means an amount effective for treating or lessening the severity of one or more of the diseases, disorders or conditions as recited herein. In some embodiments, the effective dose can be between 10 g and 500 mg.

[0301] The compounds and compositions, according to the methods of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the diseases, disorders or conditions recited above.

[0302] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered parenterally.

[0303] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, rectally, intrathecally, topically or intranasally.

[0304] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said compound is administered systemically.

[0305] The compounds of the present disclosure are typically used as a pharmaceutical composition (e.g., a compound of the present disclosure and at least one pharmaceutically acceptable carrier). As used herein, the term pharmaceutically acceptable carrier includes generally recognized as safe (GRAS) solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. For purposes of this disclosure, solvates and hydrates are considered pharmaceutical compositions comprising a compound of the present disclosure and a solvent (i.e., solvate) or water (i.e., hydrate).

[0306] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present disclosure or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present disclosure is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

[0307] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0308] The pharmaceutical composition comprising a compound of the present disclosure is generally formulated for use as a parenteral or oral administration or alternatively suppositories.

[0309] For example, the pharmaceutical oral compositions of the present disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

[0310] Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with [0311] a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; [0312] b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also [0313] c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired [0314] d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or [0315] e) absorbents, colorants, flavors and sweeteners.

[0316] Tablets may be either film coated or enteric coated according to methods known in the art.

[0317] Suitable compositions for oral administration include a compound of the disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are 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. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0318] The parenteral compositions (e.g, intravenous (IV) formulation) are aqueous isotonic solutions or suspensions. The parenteral compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.

[0319] The compound of the present disclosure or pharmaceutical composition thereof for use in a subject (e.g., human) is typically administered orally or parenterally at a therapeutic dose. When administered intravenously via infusion, the dosage may depend upon the infusion rate at which an IV formulation is administered. In general, the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, pharmacist, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.

[0320] The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present disclosure can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10.sup.3 molar and 10.sup.9 molar concentrations.

Definitions

[0321] As used herein, a patient, subject or individual are used interchangeably and refer to either a human or non-human animal. The term includes mammals such as humans. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0322] As used herein, the term inhibit, inhibition or inhibiting refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0323] As used herein, the term 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 a compound of the present disclosure to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, condition or disorder; ameliorating or improving a clinical symptom, complications or indicator associated with the disease, condition or disorder; or delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or disorder; or eliminating the disease, condition or disorder. In certain embodiments, the effect can be to prevent the onset of the symptoms or complications of the disease, condition or disorder.

[0324] As used herein the term cancer has the meaning normally accepted in the art. The term can broadly refer to abnormal cell growth.

[0325] As used herein, a subject is in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment (in some embodiments, a human).

[0326] As used herein, the phrase optionally substituted is used interchangeably with the phrase substituted or unsubstituted. In general the term optionally substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. 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 either the same or different at every position.

[0327] As used herein, the term alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety. The term C.sub.1-4alkyl refers to an alkyl having 1 to 4 carbon atoms. The terms C.sub.1-3alkyl and C.sub.1-2alkyl are to be construed accordingly. Representative examples of C.sub.1-4alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy have the same definition as above. When indicated as being optionally substituted, the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls).

[0328] As used herein, the term alkylene refers to a fully saturated branched or unbranched divalent hydrocarbon radical. The term C.sub.1-4alkylene refers to an alkylene having 1 to 4 carbon atoms. The terms C.sub.1-3alkylene and C.sub.1-2alkylene are to be construed accordingly. Representative examples of C.sub.1-4alkylene include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec-butylene, iso-butylene, and tert-butylene.

[0329] As used herein, the term alkoxy refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e. a OC.sub.1-4 alkyl group wherein C.sub.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, alkoxy groups have about 1-4 carbons, and in some embodiments about 1-2 carbons. The term C.sub.1-2 alkoxy is to be construed accordingly.

[0330] As used herein, the term C.sub.1-4 alkoxyC.sub.1-4 alkyl refers to a C.sub.1-4 alkyl group as defined herein, wherein at least of the hydrogen atoms is replaced by an C.sub.1-4 alkoxy. The C.sub.1-4alkoxyC.sub.1-4 alkyl group is connected through the rest of the molecule described herein through the alkyl group.

[0331] The number of carbon atoms in a group is specified herein by the prefix C.sub.x-xx, wherein x and xx are integers. For example, C.sub.1-3 alkyl is an alkyl group which has from 1 to 3 carbon atoms.

[0332] Halogen or halo may be fluorine, chlorine, bromine or iodine.

[0333] As used herein, the term halo-substituted-C.sub.1-4alkyl or C.sub.1-4haloalkyl refers to a C.sub.1-4alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halo atom. The C.sub.1-4haloalkyl group can be monohalo-C.sub.1-4alkyl, dihalo-C.sub.1-4alkyl or polyhalo-C.sub.1-4 alkyl including perhalo-C.sub.1-4alkyl. A monohalo-C.sub.1-4alkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihalo-C.sub.1-4alkyl and polyhalo-C.sub.1-4alkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically the polyhalo-C.sub.1-4alkyl group contains up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halo groups. Non-limiting examples of C.sub.1-4haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhalo-C.sub.1-4alkyl group refers to a C.sub.1-4alkyl group having all hydrogen atoms replaced with halo atoms.

[0334] The term aryl refers to an aromatic carbocyclic single ring or two fused ring system containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl.

[0335] The term heteroaryl refers to a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some instances, nitrogen atoms in a heteroaryl may be quaternized. The term heteroaryl may be used interchangeably with the terms heteroaryl ring, heteroaryl group, or heteroaromatic. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, and the like. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, indazoyl, benzofuranyl, benzimidazolyl, and imidazo[1,2-a]pyridine.

[0336] The term carbocyclic ring or carbocyclyl refers to a 4- to 12-membered saturated or partially unsaturated hydrocarbon ring and may exist as a single ring, bicyclic ring (including fused, spiral or bridged carbocyclic rings) or a spiral ring. Bi-cyclic carbocyclyl groups include, e.g., unsaturated carbocyclic radicals fused to another unsaturated carbocyclic radical, cycloalkyl, or aryl, such as, for example, cyclohexyl, cyclohexenyl, 2,3-dihydroindenyl, decahydronaphthalenyl, and 1,2,3,4-tetrahydronaphthalenyl. Unless specified otherwise, the carbocyclic ring generally contains 4- to 10-ring members.

[0337] The term C.sub.3-6 cycloalkyl refers to a carbocyclic ring which is fully saturated (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

[0338] 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. A heterocyclyl group may be mono- or bicyclic (e.g., a bridged, fused, or spiro bicyclic ring). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, piperdinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and pyrrolidinyl. Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as, for example, 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and 4,7-dihydro-5H-thieno[2,3-c]pyranyl. In some embodiments, the heterocyclyl group is a 4 to 6 membered monocyclic heterocyclyl group. In some embodiments, the heterocyclyl group is a 8 to 10 membered bicyclic heterocyclyl group.

[0339] As used herein the term spiral ring means a two-ring system wherein both rings share one common atom. Examples of spiral rings include 5-oxaspiro[2.3]hexane, oxaspiro[2.4]heptanyl, 5-oxaspiro[2.4]heptanyl, 4-oxaspiro[2.4]heptane, 4-oxaspiro[2.5]octanyl, 6-oxaspiro[2.5]octanyl, oxaspiro[2.5]octanyl, oxaspiro[3.4]octanyl, oxaspiro[bicyclo[2.1.1]hexane-2,3-oxetan]-1-yl, oxaspiro[bicyclo[3.2.0]heptane-6,1-cyclobutan]-7-yl, 2,6-diazaspiro[3.3]heptanyl, -oxa-6-azaspiro[3.3]heptane, 2,2,6-diazaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, 7-azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, 8-azaspiro[4.5]decane, 1,6-diazaspiro[3.3]heptane, 5-azaspiro[2.5]octane, 4,7-diazaspiro[2.5]octane, 5-oxa-2-azaspiro[3.4]octane, 6-oxa-1-azaspiro[3.3]heptane, 3-azaspiro[5.5]undecanyl, 3,9-diazaspiro[5.5]undecanyl, and the like.

[0340] The term fused ring refers to two ring systems share two adjacent ring atoms. Fused heterocycles have at least one the ring systems contain a ring atom that is a heteroatom selected from O, N and S (e.g., 3-oxabicyclo[3.1.0]hexane).

[0341] As used herein the term bridged refers to a 5 to 10 membered cyclic moiety connected at two non-adjacent ring atoms (e.g. bicyclo[1.1.1]pentane, bicyclo [2.2.1]heptane and bicyclo [3.2.1]octane).

[0342] The phrase pharmaceutically acceptable indicates that the substance, composition or dosage form must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

[0343] Unless specified otherwise, the term compounds of the present disclosure refers to compounds of Formula (I), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, isotopically labeled compounds (including deuterium substitutions). When a moiety is present that is capable of forming a salt, then salts are included as well, in particular pharmaceutically acceptable salts.

[0344] As used herein, the term a, an, the and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g. such as) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed.

[0345] It is also possible that the intermediates and compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure. The term tautomer or tautomeric form refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0346] In one embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in free form. In another embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in salt form. In another embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in acid addition salt form. In a further embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in pharmaceutically acceptable salt form. In yet a further embodiment, the present disclosure relates to a compound of the Formula (I) as defined herein, in pharmaceutically acceptable acid addition salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in free form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in acid addition salt form. In yet a further embodiment, the present disclosure relates to any one of the compounds of the Examples in pharmaceutically acceptable salt form. In still another embodiment, the present disclosure relates to any one of the compounds of the Examples in pharmaceutically acceptable acid addition salt form.

[0347] Compounds of the present disclosure may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0348] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present disclosure as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.

EXEMPLIFICATION

Abbreviation:

[0349] PE=petroleum ether [0350] EtOAc=EA=ethyl acetate [0351] ESI=electrospray ionisation [0352] MeOH=methanol [0353] EtOH=ethanol [0354] DCM=dichloromethane [0355] DIAD=Diisopropyl azodicarboxylate [0356] DMF=dimethylformamide [0357] DPPA=Diphenylphosphoryl azide [0358] EDCI=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide [0359] HATU=Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium [0360] HCl=hydrochloric acid [0361] H.sub.2O=water [0362] NBS=N-bromosuccinimide [0363] LCMS=liquid chromatography mass spectrometry [0364] HPLC=high pressure liquid chromatography [0365] THF=tetrahydrofuran [0366] MeCN=ACN=acetonitrile [0367] DMSO=dimetylsulfoxide [0368] AcOH=acetic acid [0369] CDI=carbonyldiimidazole [0370] TFA=trifluoroacetic acid [0371] FA=formic acid [0372] DIPEA=diisopropylethyl amine [0373] TLC=Thin Layer Chromatography [0374] N2=Nitrogen [0375] KOH=Potassium Hydroxide [0376] NH.sub.4HCO.sub.3=Ammonium Bicarbonate [0377] t-BuOH=tert-butanol [0378] NH.sub.4Cl=ammonium chloride [0379] t-BuOK=potassium tert-butoxide [0380] NaH=sodium hydride [0381] Xantphos=4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene [0382] Na.sub.2SO.sub.4=sodium sulfate [0383] K.sub.2CO.sub.3=potassium carbonate [0384] NaHCO.sub.3=sodium bicarbonate [0385] Pd(OAc).sub.2=Palladium (II) Acetate [0386] NaOH=Sodium Hydroxide [0387] TCFH=N-tetramethylformamidinium hexafluorophosphate [0388] NMI=1-Methylimidazole [0389] XantPhosPdG.sub.3=[(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2-amino-1,1-biphenyl)]palladium(II) methanesulfonate [0390] Pd/C=Palladium on Carbon [0391] Pd(dppf)Cl.sub.2 DCM=[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [0392] Pd(dppf)Cl.sub.2=[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) [0393] Pd(PPh.sub.3).sub.4=Tetrakis(triphenylphosphine)palladium(0) [0394] Pd(PPh.sub.3)Cl.sub.2=Bis(triphenylphosphine)palladium(II) dichloride [0395] PPh.sub.3=triphenylphosphine [0396] AlMe.sub.3Al(CH.sub.3).sub.3=trimethylaluminum [0397] Et.sub.2O=diethyl ether [0398] C.sub.2Cl.sub.6=hexachloroethane [0399] PEPPSI IHept-Cl=(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-xN)palladium (ACI) [0400] Br.sub.2=bromine [0401] B.sub.2pin.sub.2=bis(pinacoloto)diboron

General Methods

1. .sup.1H NMR Spectra were Recorded on: [0402] NMR10 Bruker AVANCE III HD 300 MHz [0403] NMR16 Bruker AVANCE III HD 300 MHz [0404] NMR19 Bruker AVANCE III HD 400 MHz [0405] NMR24 Bruker AVANCE NEO 400 MHz [0406] NMR30 Bruker AVANCE NEO 400 MHz

2. LCMS Measurement was Run on SHIMADZU LCMS-2020 Using the Follow Conditions:

[0407] Method A: Mobile Phase: A: Water (0.05% TFA) B: Acetonitrile (0.05% TFA); Gradient Phase: 5% B to 100% B within 2.0 min, 100% B with 0.7 min (total runtime: 2.8 min); Flow Rate: 1.5 mL/min; Column: HALO C18, 3.0*30 mm, 2.0 m; Column Temperature: 40 C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI. [0408] Method B: Mobile Phase: A: Water (0.1% FA) B: Acetonitrile (0.1% FA); Gradient Phase: 5% B to 100% B within 2.0 min, 100% B with 0.7 min (total runtime: 2.8 min); Flow Rate: 1.5 mL/min; Column: HALO C18, 3.0*30 mm, 2.0 m; Column Temperature: 40 C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI. [0409] Method C: Mobile Phase: A: Water (5 mM NH.sub.4HCO.sub.3) B: Acetonitrile; Gradient Phase: 10% B to 95% B within 2.0 min, 100% B with 0.6 min (total runtime: 2.8 min); Flow Rate: 1.5 mL/min; Column: Poroshell HPHC18, 3.0*50 mm, 4.0 m; Column Temperature: 40 C. Detectors: AD2 ELSD, PDA (220 nm and 254 nm), ESI.

[0410] The observed molecular ion for all compounds listed below is for [M+H].sup.+, unless otherwise indicated.

Preparation of Intermediates

Intermediate A: N-(3-amino-5-bromophenyl) methanesulfonamide

##STR00051##

[0411] Step 1: A mixture of 1-bromo-3-fluoro-5-nitrobenzene (50.00 g, 227.27 mmol, 1.00 equiv) and methanesulfonamide (21.62 g, 227.27 mmol, 1.00 equiv) and Cs.sub.2CO.sub.3 (222.15 g, 681.83 mmol, 3.00 equiv) in 500 mL of DMSO, the resulted solution was stirred for 1 hour at 60 C. The mixture was cooled then quenched with 1000 mL of water. The aqueous layer was extracted with 3500 mL of ethyl acetate. Dried over anhydrous Na.sub.2SO.sub.4 and concentrated and the residue was purified onto silica gel column eluted with 35% of ethyl acetate in petroleum ether to afford N-(3-bromo-5-nitrophenyl)methanesulfonamide (35.2 g, 52.5%) as a yellow solid. LCMS (ESI) [M+H].sup.+: 295

[0412] Step 2: A mixture of N-(3-bromo-5-nitrophenyl)methanesulfonamide (35.2 g, 119.28 mmol, 1.00 equiv) and Fe (66.61 g, 1192.78 mmol, 10 equiv) and NH.sub.4Cl (63.80 g, 1192.78 mmol, 10.00 equiv) in 200 mL of ethanol and 50 mL of water and this was stirred for 2 hours at 90 C. The resulting mixture was filtered, the filter cake was washed with 650 mL of methanol. The filtrate was concentrated under reduced pressure. The residue was purified onto silica gel column eluted with 50% of ethyl acetate in petroleum ether to afford N-(3-amino-5-bromophenyl)methanesulfonamide (25.1 g, 81.2%) as a yellow solid. LCMS (ESI) [M+H].sup.+: 265. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.63 (s, 1H), 6.58-6.36 (m, 3H), 5.53 (s, 2H), 2.98 (s, 3H).

Intermediate B: 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-3-carboxylate

##STR00052##

[0413] Step 1: To a stirred solution of methyl 1H-pyrrole-3-carboxylate (100 g, 800 mmol, 1 equiv) and NaH (60%) (64 g, 1.6 mol, 2 equiv) in DMF (1 L) was added iodomethane (227.2 g, 1.6 mol, 2 equiv) dropwise at 0 C. The resulting mixture was stirred for additional 3 hours at room temperature. The reaction was quenched by the addition of water (5 L) at 0 C. The resulting mixture was extracted with EtOAc (35 L). The combined organic layers were washed with brine (35 L), dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford methyl 1-methylpyrrole-3-carboxylate (95 g, 85.6%) as a white solid

[0414] LCMS (ESI) [M+H].sup.+: 140

[0415] Step 2: A solution of methyl 1-methylpyrrole-3-carboxylate (95 g, 683.5 mmol, 1 equiv), B.sub.2Pin.sub.2 (138.9 g, 546.7 mmol, 0.8 equiv), Di-mu-methoxobis(1,5-cyclooctadiene)diiridium(I) (6.7 g, 10.3 mmol, 0.015 equiv) and 4,4-Di-tert-butyl-2,2-bipyridine (5.49 g, 20.5 mmol, 0.03 equiv) in 1,4-dioxane (1 L) was stirred for 3 hours at 100 C. under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1). The residue was triturated with PE for 12 hours at room temperature and filtered to afford 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-3-carboxylate (105 g, 57.8% yield) as a white solid.

[0416] LCMS (ESI) [M+H].sup.+: 266

[0417] .sup.1H NMR (300 MHz, Chloroform-d) 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).

Example 1: 1-(cyclohex-2-en-1-yl)-N-(5-(methylsulfonamido)cyclohexa-1,5-dien-1-yl)-1H-pyrazole-4-carboxamide

##STR00053##

[0418] Into an 8-mL sealed tube, was placed N-(3-aminophenyl)methanesulfonamide (100.0 mg, 0.54 mmol, 1.00 equiv) and 1-phenyl-1H-pyrazole-4-carboxylic acid (100 mg, 0.54 mmol, 1.00 equiv), DIEA (109.1 mg, 1.62 mmol, 3.00 equiv) in 4 mL of DMF, to this was added HATU (266.7 mg, 0.7 mmol, 1.30 equiv) and this was stirred for 1 h at room temperature. The mixture was then quenched with 10 mL of water and extracted with 320 mL of ethyl acetate and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified onto silica gel column chromatography, eluted with 50% of ethyl acetate in petroleum ether to afford N-(3-methanesulfonamidophenyl)-1-phenyl-1H-pyrazole-4-carboxamide (28.8 mg, 14.9%) as a white solid. LCMS (ESI) [M+H].sup.+: 357.09. .sup.1H NMR (300 MHz, DMSO-d6) 10.05 (s, 1H), 9.80 (s, 1H), 9.11 (s, 1H), 8.32 (s, 1H), 7.90 (d, J=8.0 Hz, 2H), 7.68 (s, 1H), 7.55 (q, J=6.9, 6.1 Hz, 3H), 7.40 (t, J=7.4 Hz, 1H), 7.31 (t, J=8.1 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 3.02 (s, 3H).

[0419] The compounds listed in the following table were prepared using a procedure similar to that described for Example 1:

TABLE-US-00002 MS Example (ESI) Structure No. [M + H].sup.+ .sup.1H NMR [00054] embedded image 2 368 .sup.1H NMR (400 MHz, DMSO-d6) 10.72 (s, 1H), 9.81 (s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.41 (d, J = 1.9 Hz, 1H), 8.01 (dd, J = 5.1, 1.9 Hz, 1H), 7.91 (dt, J = 5.2, 1.6 Hz, 3H), 7.65 7.52 (m, 4H), 7.32 (t, J = 8.1 Hz, 1H), 6.98 - 6.93 (m, 1H), 3.05 (s, 3H). [00055] 3 397 .sup.1H NMR (400 MHz, DMSO-d6) 10.14 (s, 1H), 9.73 (s, 1H), 7.98 7.92 (m, 2H), 7.73 (t, J = 2.1 Hz, 1H), 7.49 (ddd, J = 13.4, 7.8, 1.6 Hz, 3H), 7.44 7.38 (m, 2H), 7.37 7.31 (m, 1H), 7.27 (t, J = 8.1 Hz, 1H), 7.17 7.10 (m, 2H), 6.92 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 5.21 (s, 2H), 3.00 (s, 3H). [00056] embedded image 4 397 .sup.1H NMR (400 MHz, DMSO-d6) 10.26 (s, 1H), 9.77 (s, 1H), 7.74 (t, J = 2.1 Hz, 1H), 7.59 7.22 (m, 11H), 6.94 (dd, J = 8.0, 2.1 Hz, 1H), 5.19 (s, 2H), 3.01 (s, 3H). [00057] 5 373 .sup.1H NMR (300 MHz, DMSO-d6) 10.32 (s, 1H), 9.81 (s, 1H), 8.05 (d, J = 4.0 Hz, 1H), 7.84 7.72 (m, 2H), 7.68 (t, J = 2.1 Hz, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.56 7.43 (m, 3H), 7.43 7.36 (m, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.00 6.90 (m, 1H), 3.02 (s, 3H). [00058] embedded image 6 373 .sup.1H NMR (400 MHz, DMSO-d6) 10.34 (s, 1H), 9.82 (s, 1H), 8.49 (d, J = 1.5 Hz, 1H), 8.19 (d, J = 1.4 Hz, 1H), 7.79 7.72 (m, 2H), 7.69 (t, J = 2.1 Hz, 1H), 7.55 7.44 (m, 3H), 7.39 7.29 (m, 2H), 6.95 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H), 3.02 (s, 3H). [00059] 7 378 [00060] 8 388 [00061] embedded image 9 374 [00062] 10 398 [00063] 11 373 [00064] 12 393 [00065] 13 353 [00066] 14 374 [00067] 15 [00068] 16 325 [00069] 17 379 [00070] 18 [00071] 19 381 [00072] 20 488 [00073] 21 359 [00074] 22 418 [00075] 23 356 [00076] 24 392 [00077] 25 348 [00078] 26 390 [00079] 27 447 [00080] 28 403 [00081] embedded image 29 363 [00082] 30 446 [00083] 31 [00084] 32 338 [00085] 33 365 [00086] 34 389

Example 35: 1-benzyl-N-(3-methanesulfonamidophenyl)pyrazole-4-carboxamide

##STR00087##

[0420] The solution of 1-benzylpyrazole-4-carboxylic acid (130.3 mg, 0.644 mmol, 1.20 equiv), NMI (88.2 mg, 1.074 mmol, 2.00 equiv) in ACN (3 mL) was added TCFH (226 mg, 0.805 mmol, 1.50 equiv) at room temperature. The reaction mixture was stirred for 10 m, then N-(3-aminophenyl)methanesulfonamide (100 mg, 0.537 mmol, 1 equiv) was added and stirred for another one hour. The reaction mixture was purified by HPLC to afford 1-benzyl-N-(3-methanesulfonamidophenyl)pyrazole-4-carboxamide (85.7 mg, 42.96%) as a white solid. LCMS (ESI) [M+H].sup.+=371. H NMR (300 MHz, DMSO-d6) 9.90 (s, 1H), 9.76 (s, 1H), 8.45 (d, J 0.8 Hz, 1H), 8.06 (d, J 0.8 Hz, 1H), 7.64 (t, J 2.1 Hz, 1H), 7.53-7.44 (m, 1H), 7.42-7.23 (m, 6H), 6.90 (ddd, J=8.1, 2.2, 1.0 Hz, 1H), 5.40 (s, 2H), 3.00 (s, 3H). The compounds listed in the following table were prepared using a procedure similar to that described for Example 36:

TABLE-US-00003 MS Example (ESI) Structure No. [M + H].sup.+ .sup.1H NMR [00088] embedded image 36 357 .sup.1H NMR (400 MHz, DMSO-d6) 13.80 (s, 1H), 10.20 (d, J = 58.7 Hz, 1H), 9.78 (s, 1H), 7.93 7.64 (m, 3H), 7.62 7.11 (m, 6H), 6.93 (d, J = 8.0 Hz, 1H), 3.03 (s, 3H) [00089] 37 367 .sup.1H NMR (300 MHz, DMSO-d6) 10.42 (s, 1H), 9.80 (s, 1H), 8.22 (t, J = 1.8 Hz, 1H), 8.01 7.86 (m, 2H), 7.82 7.72 (m, 3H), 7.63 (t, J = 7.7 Hz, 1H), 7.59 7.49 (m, 3H), 7.47 7.38 (m, 1H), 7.32 (t, J = 8.1 Hz, 1H), 6.96 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 3.02 (s, 3H) [00090] embedded image 38 367 .sup.1H NMR (300 MHz, DMSO-d6) 10.37 (s, 1H), 9.79 (s, 1H), 8.14 7.94 (m, 2H), 7.90 7.65 (m, 5H), 7.65 7.40 (m, 4H), 7.31 (t, J = 8.1 Hz, 1H), 6.95 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 3.03 (s, 3H) [00091] 39 357 .sup.1H NMR (300 MHz, DMSO-d6) 10.36 (s, 1H), 9.79 (s, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.11 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 1.7 Hz, 1H), 7.76 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.66 6.55 (m, 1H), 3.02 (d, J = 1.4 Hz, 3H) [00092] embedded image 40 357 .sup.1H NMR (400 MHz, DMSO-d6) 10.53 (s, 1H), 9.23 9.04 (m, 1H), 8.70 (dd, J = 3.9, 1.9 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 8.11 7.95 (m, 2H), 7.76 (d, J = 2.0 Hz, 4H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 7.02 (s, 1H), 6.59 (t, J = 2.2 Hz, 1H), 6.48 (dt, J = 8.4, 2.2 Hz, 1H), 4.63 (d, J = 5.6 Hz, 2H), 3.83 (d, J = 2.0 Hz, 3H), 3.74 (d, J = 2.0 Hz, 3H) [00093] embedded image 41 358 .sup.1H NMR (300 MHz, DMSO-d6) 10.17 (s, 1H), 9.80 (s, 1H), 9.43 (s, 1H), 8.57 (dd, J = 4.6, 1.6 Hz, 1H), 8.31 (s, 1H), 8.19 7.90 (m, 2H), 7.71 (t, J = 2.1 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.49 7.43 (m, 1H), 7.30 (t, J = 8.1 Hz, 1H), 6.93 (dd, J = 7.9, 2.1 Hz, 1H), 3.02 (s, 3H). [00094] embedded image 42 374 .sup.1H NMR (300 MHz, DMSO-d6) 10.68 (s, 1H), 9.85 (s, 1H), 8.51 (s, 1H), 8.29 8.12 (m, 2H), 7.83 (t, J = 2.1 Hz, 1H), 7.65 7.58 (m, 1H), 7.57 7.47 (m, 2H), 7.47 7.39 (m, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.00 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 3.05 (s, 3H). [00095] 43 359 .sup.1H NMR (400 MHz, DMSO-d6) 10.19 (s, 1H), 9.45 (s, 1H), 8.95 (d, J = 4.8 Hz, 2H), 8.32 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.61 7.50 (m, 2H), 7.29 (t, J = 8.1 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 3.00 (s, 3H). [00096] embedded image 44 374 .sup.1H NMR (400 MHz, DMSO-d6) 10.70 (s, 1H), 9.82 (s, 1H), 8.73 (dd, J = 5.2, 0.7 Hz, 1H), 8.38 8.26 (m, 1H), 7.97 (dd, J = 3.7, 1.2 Hz, 1H), 7.95 (dd, J = 5.1, 2.0 Hz, 1H), 7.90 (t, J = 2.1 Hz, 1H), 7.83 (dd, J = 5.0, 1.1 Hz, 1H), 7.69 7.54 (m, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.28 (dd, J = 5.0, 3.7 Hz, 1H), 6.95 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 3.05 (s, 3H).

Example 45: 4-(3-fluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide

##STR00097##

[0421] A solution of 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (100 mg, 0.266 mmol), Pd(dppf)Cl.sub.2 (19.4 mg, 0.0266 mmol), K.sub.2CO.sub.3 (110 mg, 0.798 mmol) and (3-fluorophenyl)boronic acid (74.4 mg, 0.532 mmol) in dioxane (4 mL) was stirred for 2 h at 80 C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (0-100%) to afford 4-(3-fluorophenyl)-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (62.8 mg, 0.160 mmol) as a white solid. LCMS (ESI) [M+H].sup.+: 391. .sup.1H NMR (300 MHz, DMSO-d6) 10.32 (s, 1H), 9.83 (s, 1H), 8.52 (d, J=1.5 Hz, 1H), 8.30 (d, J=1.4 Hz, 1H), 7.69 (t, J=2.0 Hz, 1H), 7.66-7.46 (m, 4H), 7.33 (t, J=8.1 Hz, 1H), 7.26-7.13 (m, 1H), 6.96 (dd, J=7.7, 2.2 Hz, 1H), 3.03 (s, 3H).

[0422] The compounds listed in the following table were prepared using a procedure similar to that described for example 45:

TABLE-US-00004 Example MS (ESI) Structure No. [M + H].sup.+ .sup.1H NMR [00098] embedded image 46 387 .sup.1H NMR (300 MHz, DMSO-d6) 10.27 (s, 1H), 9.81 (s, 1H), 8.18 (d, J = 1.4 Hz, 1H), 7.86 (d, J = 1.4 Hz, 1H), 7.67 (t, J = 2.1 Hz, 1H), 7.51 (ddd, J = 8.2, 2.1, 1.0 Hz, 1H), 7.44 7.23 (m, 5H), 6.95 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 3.01 (s, 3H), 2.37 (s, 3H). [00099] 47 387 .sup.1H NMR (300 MHz, DMSO-d6) 10.33 (s, 1H), 9.82 (s, 1H), 8.49 (d, J = 1.4 Hz, 1H), 8.17 (d, J = 1.3 Hz, 1H), 7.70 (t, J = 2.1 Hz, 1H), 7.63 7.46 (m, 3H), 7.34 (dt, J = 13.5, 7.8 Hz, 2H), 7.18 (d, J = 7.5 Hz, 1H), 6.96 (ddd, J = 8.0, 2.3, 1.0 Hz, 1H), 3.02 (s, 3H), 2.39 (s, 3H). [00100] embedded image 48 387 .sup.1H NMR (400 MHz, DMSO-d6) 10.32 (s, 1H), 9.82 (s, 1H), 8.47 (d, J = 1.5 Hz, 1H), 8.13 (d, J = 1.3 Hz, 1H), 7.69 (t, J = 2.1 Hz, 1H), 7.64 (d, J = 7.8 Hz, 2H), 7.52 (dd, J = 8.0, 1.9 Hz, 1H), 7.37 7.22 (m, 3H), 6.95 (dd, J = 8.1, 2.0 Hz, 1H), 3.02 (s, 3H), 2.34 (s, 3H). [00101] embedded image 49 387 .sup.1H NMR (300 MHz, DMSO-d6) 10.20 (s, 1H), 9.79 (s, 1H), 8.10 (s, 1H), 7.67 (t, J = 2.0 Hz, 1H), 7.57 7.46 (m, 5H), 7.45 7.35 (m, 1H), 7.30 (t, J = 8.1 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 3.01 (s, 3H), 2.54 (s, 3H). [00102] 50 416 .sup.1H NMR (300 MHz, DMSO-d6) 10.42 (s, 1H), 9.83 (s, 1H), 8.58 (d, J = 1.4 Hz, 1H), 8.33 8.23 (m, 2H), 8.10 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.62 7.44 (m, 3H), 7.33 (t, J = 8.1 Hz, 1H), 7.01 6.93 (m, 1H), 3.03 (s, 3H). [00103] embedded image 51 398 .sup.1H NMR (300 MHz, DMSO-d6) 10.33 (s, 1H), 9.84 (s, 1H), 8.56 (d, J = 1.5 Hz, 1H), 8.39 (d, J = 1.4 Hz, 1H), 8.24 (t, J = 1.7 Hz, 1H), 8.10 (dt, J = 8.0, 1.4 Hz, 1H), 7.83 (dt, J = 7.7, 1.3 Hz, 1H), 7.76 7.65 (m, 2H), 7.52 (ddd, J = 8.2, 2.0, 1.0 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 6.97 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 3.03 (s, 3H). [00104] embedded image 52 391 .sup.1H NMR (300 MHz, DMSO-d6) 10.38 (s, 1H), 9.82 (s, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 7.76 (td, J = 7.7, 1.6 Hz, 1H), 7.69 (t, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.2, 1.7 Hz, 1H), 7.48 7.26 (m, 4H), 7.03 6.90 (m, 1H), 3.02 (s, 3H). [00105] 53 391 .sup.1H NMR (300 MHz, DMSO-d6) 10.33 (s, 1H), 9.82 (s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.17 (d, J = 1.4 Hz, 1H), 7.88 7.74 (m, 2H), 7.69 (t, J = 2.0 Hz, 1H), 7.58 7.47 (m, 1H), 7.33 (ddd, J = 9.0, 6.9, 2.3 Hz, 3H), 6.96 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 3.02 (s, 3H). [00106] embedded image 54 374 .sup.1H NMR (300 MHz, DMSO-d6) 10.35 (s, 1H), 9.83 (s, 1H), 9.01 (dd, J = 2.4, 0.8 Hz, 1H), 8.63 8.48 (m, 2H), 8.35 (d, J = 1.4 Hz, 1H), 8.14 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H), 7.69 (t, J = 2.1 Hz, 1H), 7.59 7.47 (m, 2H), 7.33 (t, J = 8.1 Hz, 1H), 6.96 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 3.02 (s, 3H). [00107] embedded image 55 374 .sup.1H NMR (300 MHz, DMSO-d6) 10.40 (s, 1H), 9.83 (s, 1H), 8.79 8.63 (m, 2H), 8.59 (d, J = 1.4 Hz, 1H), 8.51 (d, J = 1.4 Hz, 1H), 7.87 7.66 (m, 3H), 7.53 (d, J = 8.1 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 7.05 6.91 (m, 1H), 3.03 (s, 3H). [00108] 56 403 .sup.1H NMR (300 MHz, DMSO-d6) 10.32 (s, 1H), 9.82 (s, 1H), 8.49 (d, J = 1.5 Hz, 1H), 8.22 (d, J = 1.4 Hz, 1H), 7.69 (t, J = 2.1 Hz, 1H), 7.56 7.49 (m, 1H), 7.45 7.27 (m, 4H), 6.99 6.90 (m, 2H), 3.84 (s, 3H), 3.02 (s, 3H). [00109] embedded image 57 389 .sup.1H NMR (300 MHz, DMSO-d6) 10.32 (s, 1H), 9.93 (s, 1H), 9.80 (s, 1H), 8.47 (d, J = 1.4 Hz, 1H), 8.12 (d, J = 1.3 Hz, 1H), 7.70 (t, J = 2.1 Hz, 1H), 7.54 (ddd, J = 6.7, 4.9, 1.7 Hz, 2H), 7.31 (t, J = 8.1 Hz, 1H), 7.21 7.13 (m, 1H), 7.02 6.87 (m, 3H), 3.02 (s, 3H). [00110] embedded image 58 388 .sup.1H NMR (300 MHz, DMSO-d6) 10.35 (s, 1H), 9.81 (s, 1H), 8.38 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.69 (t, J = 2.0 Hz, 1H), 7.57 7.50 (m, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 6.99 6.87 (m, 3H), 6.58 (d, J = 8.2 Hz, 1H), 5.37 (s, 2H), 3.02 (s, 3H). [00111] embedded image 59 40 Observed molecular ion is [M H].sup. .sup.1H NMR (300 MHz, DMSO-d6) 10.30 (s, 1H), 9.79 (s, 1H), 8.40 (d, J = 1.4 Hz, 1H), 8.06 (d, J = 1.4 Hz, 1H), 7.68 (t, J = 2.1 Hz, 1H), 7.58 (dd, J = 7.6, 1.7 Hz, 1H), 7.55 7.48 (m, 1H), 7.41 7.26 (m, 2H), 7.15 (dd, J = 8.4, 1.1 Hz, 1H), 7.06 (td, J = 7.5, 1.1 Hz, 1H), 6.95 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 3.88 (s, 3H), 3.01 (s, 3H). [00112] embedded image 60 388 .sup.1H NMR (300 MHz, DMSO-d6) 10.31 (s, 1H), 9.75 (s, 1H), 8.47 (dd, J = 4.8, 1.7 Hz, 1H), 8.21 (d, J = 1.5 Hz, 1H), 7.97 (d, J = 1.4 Hz, 1H), 7.76 (dd, J = 7.7, 1.8 Hz, 1H), 7.67 (t, J = 2.1 Hz, 1H), 7.60 7.45 (m, 1H), 7.43 7.20 (m, 2H), 6.95 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 3.01 (s, 3H), 2.57 (s, 3H) [00113] embedded image 61 388 .sup.1H NMR (300 MHz, DMSO-d6) 10.29 (s, 1H), 9.81 (s, 1H), 8.54 (s, 1H), 8.44 (d, J = 5.0 Hz, 1H), 8.23 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 1.4 Hz, 1H), 7.66 (t, J = 2.1 Hz, 1H), 7.50 (dt, J = 8.3, 1.2 Hz, 1H), 7.40 7.24 (m, 2H), 7.06 6.80 (m, 1H), 3.01 (s, 3H), 2.40 (s, 3H) [00114] embedded image 62 375 .sup.1H NMR (300 MHz, DMSO-d6) 10.39 (s, 1H), 9.83 (s, 1H), 9.22 (s, 2H), 9.17 (s, 1H), 8.54 (dd, J = 28.5, 1.4 Hz, 2H), 7.69 (t, J = 2.1 Hz, 1H), 7.59 7.50 (m, 1H), 7.33 (t, J = 8.1 Hz, 1H), 6.96 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H), 3.02 (s, 3H) [00115] 63 419 .sup.1H NMR (300 MHz, DMSO-d6) 10.35 (s, 1H), 9.83 (s, 1H), 8.98 (s, 2H), 8.47 (d, J = 1.5 Hz, 1H), 8.29 (d, J = 1.4 Hz, 1H), 7.68 (t, J = 2.1 Hz, 1H), 7.58 7.43 (m, 1H), 7.33 (t, J = 8.1 Hz, 1H), 6.96 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H) [00116] embedded image 64 373 .sup.1H NMR (400 MHz, DMSO-d6) 13.55 (s, 1H), 10.08 (s, 1H), 9.76 (s, 2H), 7.77 (s, 1H), 7.69 7.60 (m, 2H), 7.54 (dt, J = 8.1, 1.4 Hz, 1H), 7.28 (t, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.97 6.91 (m, 1H), 6.85 (d, J = 8.3 Hz, 2H), 3.03 (s, 3H) [00117] 65 388 .sup.1H NMR (300 MHz, DMSO-d6) 10.34 (s, 1H), 9.82 (s, 1H), 8.90 8.74 (m, 1H), 8.51 (d, J = 1.5 Hz, 1H), 8.27 (d, J = 1.3 Hz, 1H), 8.03 (dd, J = 8.1, 2.4 Hz, 1H), 7.69 (t, J = 2.1 Hz, 1H), 7.56 7.47 (m, 1H), 7.40 7.18 (m, 2H), 6.96 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 3.02 (s, 3H), 2.50 (s, 3H) [00118] embedded image 66 375 .sup.1H NMR (300 MHz, DMSO-d6) 10.54 (s, 1H), 9.83 (s, 1H), 9.21 (dd, J = 4.9, 1.5 Hz, 1H), 8.95 (d, J = 1.3 Hz, 1H), 8.68 (d, J = 1.3 Hz, 1H), 8.22 (dd, J = 8.7, 1.6 Hz, 1H), 7.82 (dd, J = 8.6, 4.9 Hz, 1H), 7.74 (t, J = 2.1 Hz, 1H), 7.56 (dt, J = 8.4, 1.2 Hz, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.10 6.87 (m, 1H), 3.03 (s, 3H) [00119] embedded image 67 417 .sup.1H NMR (400 MHz, DMSO-d6) 10.27 (s, 1H), 9.80 (s, 1H), 8.12 (d, J = 1.4 Hz, 1H), 7.80 (d, J = 1.4 Hz, 1H), 7.66 (t, J = 2.1 Hz, 1H), 7.51 (ddd, J = 8.3, 2.1, 1.0 Hz, 1H), 7.28 (dt, J = 21.5, 8.0 Hz, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.95 (ddd, J = 7.1, 2.9, 1.2 Hz, 2H), 3.84 (s, 3H), 3.01 (s, 3H), 2.18 (s, 3H). [00120] embedded image 68 417 .sup.1H NMR (400 MHz, DMSO-d6) 10.26 (s, 1H), 9.81 (s, 1H), 8.18 (d, J = 1.4 Hz, 1H), 7.86 (d, J = 1.4 Hz, 1H), 7.66 (t, J = 2.1 Hz, 1H), 7.50 (dt, J = 8.1, 1.3 Hz, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.98 6.91 (m, 2H), 6.88 (dd, J = 8.3, 2.8 Hz, 1H), 3.77 (s, 3H), 3.01 (s, 3H), 2.29 (s, 3H). [00121] embedded image 69 390 .sup.1H NMR (300 MHz, DMSO-d6) 10.52 (s, 1H), 8.82 (d, J = 1.4 Hz, 1H), 8.52 (d, J = 1.3 Hz, 1H), 8.15 (dd, J = 4.5, 1.4 Hz, 1H), 7.74 (t, J = 2.2 Hz, 1H), 7.60 7.51 (m, 1H), 7.37 (dd, J = 8.2, 1.5 Hz, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.22 (dd, J = 8.2, 4.5 Hz, 1H), 6.94 (dd, J = 8.0, 2.2 Hz, 1H), 3.02 (s, 3H). [00122] embedded image 70 407 .sup.1H NMR (400 MHz, DMSO-d6) 10.31 (s, 1H), 10.20 (d, J = 1.6 Hz, 1H), 9.79 (s, 1H), 8.27 (t, J = 1.5 Hz, 1H), 7.93 (t, J = 1.3 Hz, 1H), 7.68 (t, J = 2.1 Hz, 1H), 7.55 7.48 (m, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.20 (td, J = 8.3, 6.7 Hz, 1H), 6.94 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 6.86 6.80 (m, 1H), 6.76 (ddd, J = 9.6, 8.3, 1.1 Hz, 1H), 3.01 (s, 3H). [00123] embedded image 71 387 .sup.1H NMR (400 MHz, DMSO-d6) 10.23 (s, 1H), 9.77 (s, 1H), 7.87 (d, J = 1.4 Hz, 1H), 7.63 (t, J = 2.1 Hz, 1H), 7.54 (s, 1H), 7.47 7.43 (m, 1H), 7.36 7.19 (m, 6H), 6.91 (dd, J = 7.8, 1.6 Hz, 1H), 3.97 (s, 2H), 2.99 (s, 3H).

Example 72: tert-butyl (3-(5-((5-(methylsulfonamido)cyclohex-2-en-1-yl)carbamoyl)thiophen-3-yl)phenyl)carbamate

##STR00124##

[0423] A mixture of 4-(3-aminophenyl)-N-(3-methanesulfonamidophenyl) thiophene-2-carboxamide (30 mg, 0.077 mmol, 1 equiv), (BOC).sub.2O (20.28 mg, 0.092 mmol, 1.2 equiv) and DIEA (30.02 mg, 0.231 mmol, 3 equiv) in DCM (3 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash with the following conditions (Water: ACN=2:3) to afford tert-butyl N-(3-15-[(3-methanesulfonamidophenyl) carbamoyl]thiophen-3-yl}phenyl) carbamate (25.2 mg, 66.75%) as a white solid. LCMS (ESI) [M+H].sup.+: 488. .sup.1H NMR (300 MHz, DMSO-d6) 10.42 (s, 1H), 9.81 (s, 1H), 9.46 (s, 1H), 8.39 (d, J=1.4 Hz, 1H), 8.05 (d, J=1.3 Hz, 1H), 7.92 (s, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.33 (d, J=6.5 Hz, 4H), 6.96 (d, J=7.9 Hz, 1H), 3.02 (s, 3H), 1.50 (s, 9H).

Example 73: 4-(5-hydroxycyclohexa-2,4-dien-1-yl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide

##STR00125##

[0424] To a stirred solution of N-(3-methanesulfonamidophenyl)-4-(3-methoxyphenyl) thiophene-2-carboxamide (125 mg, 0.310 mmol) in DCM was added BBr.sub.3 (388.53 mg, 1.55 mmol, 5 equiv) dropwise. The reaction was stirred for 3 h at room temperature under nitrogen atmosphere. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H.sub.2O (5-95%, acidic system) to afford 4-(3-hydroxyphenyl)-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (35.5 mg, 99.876%) as a white solid. LCMS (ESI) [M+H].sup.+: 389. .sup.1H NMR (300 MHz, DMSO-d6) 10.33 (s, 1H), 9.82 (s, 1H), 9.58 (s, 1H), 8.44 (d, J=1.5 Hz, 1H), 8.11 (d, J=1.3 Hz, 1H), 7.70 (t, J=2.1 Hz, 1H), 7.57-7.48 (m, 1H), 7.30 (dt, J=15.8, 8.0 Hz, 2H), 7.21-7.08 (m, 2H), 7.01-6.91 (m, 1H), 6.77 (ddd, J=7.9, 2.5, 1.0 Hz, 1H), 3.02 (s, 3H).

Example 74: 4-(3-hydroxy-2-methylphenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide

##STR00126##

[0425] Step 1: To a stirred solution of 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (300 mg, 0.799 mmol), (3-methoxy-2-methylphenyl)boronic acid (197 mg, 1.19 mmol) and Pd(dppf)Cl.sub.2 (58.4 m g, 0.07 99 mmol), K.sub.2CO.sub.3 (332 mg, 2.39 mmol) was added dioxane (10 mL). Then the mixture was stirred for 2 h at 80 C. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H.sub.2O (0-100%, acidic system) to afford N-(3-methan esulfonamidophenyl)-4-(3-methoxy-2-methylphenyl)thiophene-2-carboxamide (87.0 mg, 0.208 mmol) as an off-white solid. LCMS (ESI) [M+H].sup.+: 417.09 Step 2: To a stirred solution of N-(3-methanesulfonamidophenyl)-4-(3-methoxy-2-methylphenyl)thiophene-2-carboxamide (87 mg, 0.208 mmol), BCl.sub.3 (72.3 mg, 0.624 mmol) was added DCM (5 mL) dropwise. Then the mixture was stirred for 2 h at room temperature.

[0426] The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H.sub.2O (0-100%, acidic system) to afford 4-(3-hydroxy-2-methylphenyl)-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (25.7 mg, 0.0629 mmol) as a white solid. LCMS (ESI) [M+H].sup.+: 403.07. .sup.1H NMR (300 MHz, DMSO-d6) 10.26 (s, 1H), 9.81 (s, 1H), 9.48 (s, 1H), 8.12 (d, J=1.4 Hz, 1H), 7.77 (d, J=1.3 Hz, 1H), 7.67 (t, J=2.1 Hz, 1H), 7.56-7.46 (m, 1H), 7.31 (t, J=8.1 Hz, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.95 (ddd, J=8.1, 2.2, 1.0 Hz, 1H), 6.82 (ddd, J=11.6, 7.8, 1.3 Hz, 2H), 3.01 (s, 3H), 2.15 (s, 3H).

[0427] The compounds listed in the following table were prepared using a procedure similar to that described for Example 74:

TABLE-US-00005 Example MS (ESI) Structure No. [M + H].sup.+ .sup.1H NMR [00127] embedded image 75 403 .sup.1H NMR (300 MHz, DMSO-d6) 10.26 (s, 1H), 9.79 (s, 1H), 9.32 (s, 1H), 8.16 (d, J = 1.4 Hz, 1H), 7.81 (d, J = 1.3 Hz, 1H), 7.67 (t, J = 2.1 Hz, 1H), 7.54-7.45 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.01- 6.85 (m, 1H), 6.77 (d, J = 2.6 Hz, 1H), 6.70 (dd, J = 8.2, 2.6 Hz, 1H), 3.01 (s, 3H), 2.24 (s, 3H)

Example 76: 4-(2,6-difluorophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide

##STR00128##

[0428] A solution of 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (100 mg, 0.266 mmol), XPhos Pd G3 (22.5 mg, 0.0266 mmol), K.sub.3PO.sub.4 (169 mg, 0.798 mmol) and 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (191 mg, 0.798 mmol) in dioxane (5 mL) was stirred for 2 h at 80 C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (0-100%) to afford 4-(2,6-difluorophenyl)-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (69.5 mg, 0.169 mmol) as a white solid. LCMS (ESI) [M+H].sup.+: 409. .sup.1H NMR (300 MHz, DMSO-d6) 10.39 (s, 1H), 9.81 (s, 1H), 8.31 (q, J=1.5 Hz, 1H), 8.12 (q, J=1.3 Hz, 1H), 7.68 (t, J=2.0 Hz, 1H), 7.58-7.42 (m, 2H), 7.30 (dt, J=10.7, 8.2 Hz, 3H), 6.96 (ddd, J=8.1, 2.2, 1.0 Hz, 1H), 3.02 (s, 3H).

[0429] The compounds listed in the following table were prepared using a procedure similar to that described for Example 76:

TABLE-US-00006 Example MS (ESI) Structure No. [M + H].sup.+ .sup.1H NMR [00129] embedded image 77 479 .sup.1H NMR (300 MHz, DMSO- d6) 10.30 (s, 1H), 9.80 (s, 1H), 8.45 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 1.3 Hz, 1H), 7.69 (t, J = 2.1 Hz, 1H), 7.60 (dd, J = 7.6, 1.7 Hz, 1H), 7.50 (t, J = 7.7 Hz, 3H), 7.41-7.27 (m, 5H), 7.23 (d, J = 8.2 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.24 (s, 2H), 3.02 (s, 3H). [00130] embedded image 78 387 .sup.1H NMR (300 MHz, DMSO- d6) 13.67 (s, 1H), 10.14 (s, 1H), 9.78 (s, 1H), 7.76 (s, 3H), 7.55 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H) 7.28 (t, J = 8.2 Hz, 1H), 7.05 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.1 Hz, 1H), 3.81 (s, 3H), 3.03 (s, 3H) [00131] 79 387 .sup.1H NMR (400 MHz, DMSO- d6) 10.08 (s, 1H), 9.80 (d, J = 32.6 Hz, 2H), 7.78 (t, J = 2.1 Hz, 1H), 7.55 (dt, J = 8.5, 1.2 Hz, 1H), 7.47-7.35 (m, 2H), 7.26 (t, J = 8.1 Hz, 1H), 7.02- 6.84 (m, 3H), 6.80 (s, 1H), 3.93 (s, 3H), 3.03 (s, 3H)

Example 80: 5-methyl-N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide

##STR00132##

[0430] A solution of 4-bromo-N-(3-methanesulfonamidophenyl)-5-methylthiophene-2-carboxamide (300 mg, 0.770 mmol), 2-(tributylstannyl)pyridine (563 mg, 1.53 mmol) and Pd(PPh.sub.3).sub.4 (177 mg, 0.154 mmol) in Toluene (5 mL) was stirred for 2 h at 120 C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (0-100%) to afford N-(3-methanesulfonamidophenyl)-5-methyl-4-(pyridin-2-yl)thiophene-2-carboxamide (28.8 mg, 0.0740 mmol) as a yellow solid. LCMS (ESI) [M+H].sup.+: 388 .sup.1H NMR (300 MHz, DMSO-d6) 10.31 (s, 1H), 9.79 (s, 1H), 8.69 (ddd, J=4.8, 1.9, 0.9 Hz, 1H), 8.40 (s, 1H), 7.93 (td, J=7.7, 1.9 Hz, 1H), 7.75-7.66 (m, 2H), 7.57-7.47 (m, 1H), 7.37 (ddd, J=7.5, 4.8, 1.1 Hz, 1H), 7.30 (t, J=8.1 Hz, 1H), 6.93 (ddd, J=8.0, 2.2, 1.0 Hz, 1H), 3.01 (s, 3H), 2.71 (s, 3H). The compounds listed in the following table were prepared using a procedure similar to that described for Example 80:

TABLE-US-00007 Example MS (ESI) Structure No. [M + H].sup.+ .sup.1H NMR [00133] embedded image 81 358 .sup.1H NMR (400 MHz, DMSO-d6) 14.06 (d, J = 47.7 Hz, 1H), 10.26 (d, J = 62.3 Hz, 1H), 9.79 (s, 1H), 8.65 (s, 1H), 8.04-7.81 (m, 2H), 7.79 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 46.0 Hz, 2H), 6.93 (d, J = 8.1 Hz, 1H), 3.03 (s, 3H)

Example 82: N-(3-(methylsulfonamido)phenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide

##STR00134##

[0431] Step 1: A solution of 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (400 mg, 1.066 mmol, 1 equiv) and bis(pinacolato)diboron (2706.82 mg, 10.660 mmol, 10 equiv) and Pd(dppf)Cl.sub.2 (77.99 mg, 0.107 mmol, 0.1 equiv) and KOAc (313.84 mg, 3.198 mmol, 3 equiv) in Dioxane (5 mL) was stirred for 2 h at 80 C. under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (1:1) to afford N-(3-methanesulfonamidophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxamide (352 mg, 78.19%) as a yellow oil. LCMS (ES, m/z): LCMS (ESI) [M+H].sup.+: 423.

[0432] Step 2: A solution of N-(3-methanesulfonamidophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thio phene-2-carboxamide (352 mg, 0.833 mmol, 1.5 equiv) and 2-bromopyridine (87.79 mg, 0.555 mmol, 1 equiv) and Pd(dppf)Cl.sub.2 (40.66 mg, 0.056 mmol, 0.1 equiv) and K.sub.2CO.sub.3 (230.39 mg, 1.666 mmol, 3 equiv) in Dioxane (3 mL) and H.sub.2O (1 mL) was stirred for 2 h at 80 C. under nitrogen atmosphere. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in N-(3-methanesulfonamidophenyl)-4-(pyridin-2-yl)thiophene-2-carboxamide (68.8 mg, 33.15%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H].sup.+: 374. .sup.1H NMR (300 MHz, DMSO-d6) 10.48 (s, 1H), 9.81 (s, 1H), 8.75 (d, J=1.4 Hz, 1H), 8.65 (m, J=4.8, 1.4 Hz, 1H), 8.49 (d, J=1.3 Hz, 1H), 7.96-7.88 (m, 2H), 7.73 (t, J=2.0 Hz, 1H), 7.58-7.51 (m, 1H), 7.42-7.28 (m, 2H), 6.95 (m, J=8.1, 2.1, 1.0 Hz, 1H), 3.02 (s, 3H).

[0433] The compounds listed in the following table were prepared using a procedure similar to that described for Example 82:

TABLE-US-00008 Example MS (ESI) Structure No. [M + H].sup.+ .sup.1H NMR [00135] embedded image 83 388 .sup.1H NMR (400 MHz, DMSO-d6) 10.43 (s, 1H), 9.80 (s, 1H), 8.51 (q, J = 2.3 Hz, 2H), 8.16 (d, J = 1.4 Hz, 1H), 7.80- 7.60 (m, 2H), 7.57- 7.47 (m, 1H), 7.40- 7.22 (m, 2H), 6.94 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H), 3.01 (s, 2H), 2.49 (s, 3H) [00136] 84 375 .sup.1H NMR (300 MHz, DMSO-d6) 10.55 (s, 1H), 9.80 (s, 1H), 8.90 (d, J = 4.9 Hz, 2H), 8.84 (d, J = 1.3 Hz, 1H), 8.65 (d, J = 1.3 Hz, 1H), 7.75 (t, J = 2.1 Hz, 1H), 7.56 (ddd, J = 8.3, 2.1, 1.0 Hz, 1H), 7.45 (t, J = 4.9 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 6.95 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 3.03 (s, 3H) [00137] embedded image 85 389 .sup.1H NMR (300 MHz, Methanol-d4) 8.41 (d, J = 1.4 Hz, 1H), 8.15 (d, J = 1.4 Hz, 1H), 7.77 (t, J = 2.0 Hz, 1H), 7.60- 7.43 (m, 2H), 7.35 (t, J = 8.1 Hz, 1H), 7.14-6.85 (m, 2H), 6.54 (dd, J = 8.3, 0.8 Hz, 1H), 3.03 (s, 3H) [00138] 86 389 .sup.1H NMR (400 MHz, DMSO-d6) 10.46 (s, 1H), 9.80 (s, 1H), 8.59 (d, J = 1.4 Hz, 1H), 8.19 (d, J = 1.3 Hz, 1H), 8.05 (d, J = 5.6 Hz, 1H), 7.72 (t, J = 2.1 Hz, 1H), 7.60- 7.47 (m, 1H), 7.30 (t, J = 8.1 Hz, 1H), 6.95- 6.86 (m, 2H), 6.45 (dd, J = 5.6, 2.1 Hz, 1H), 6.12 (s, 2H), 3.02 (s, 3H) [00139] embedded image 87 418 .sup.1H NMR (300 MHz, DMSO-d6) 13.83 (s, 1H), 10.49 (s, 1H), 9.82 (s, 1H), 8.87-8.78 (m, 2H), 8.63 (d, J = 1.3 Hz, 1H), 8.30 (t, J = 1.2 Hz, 1H), 7.82-7.70 (m, 2H), 7.60-7.50 (m, 1H), 7.32 (t, J = 8.1 Hz, 1H), 6.96 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 3.03 (s, 3H). [00140] 88 388 .sup.1H NMR (300 MHz, DMSO-d6) 10.30 (s, 1H), 9.81 (s, 1H), 8.24 (d, J = 1.4 Hz, 1H), 7.85 (d, J = 1.3 Hz, 1H), 7.68 (t, J = 2.0 Hz, 1H), 7.52 (ddd, J = 8.2, 2.0, 1.0 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.16 (dd, J = 7.6, 1.6 Hz, 1H), 7.07 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 6.94 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 6.79 (dd, J = 8.1, 1.2 Hz, 1H), 6.64 (td, J = 7.4, 1.2 Hz, 1H), 5.03 (s, 2H), 3.01 (s, 3H). [00141] embedded image 89 389 .sup.1H NMR (300 MHz, DMSO-d6) 10.44 (s, 1H), 9.80 (s, 1H), 8.54 (d, J = 1.4 Hz, 1H), 8.15 (d, J = 1.3 Hz, 1H), 7.93 (dd, J = 4.4, 1.5 Hz, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.59-7.50 (m, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.20 (dd, J = 8.1, 1.6 Hz, 1H), 7.09 (dd, J = 8.1, 4.4 Hz, 1H), 6.94 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 5.33 (s, 2H), 3.02 (s, 3H). [00142] embedded image 90 358 .sup.1H NMR (300 MHz, DMSO-d6) 13.57 (s, 1H), 10.38 (s, 1H), 9.77 (s, 1H),8.57 (d, J = 4.8 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.87 (ddd, J = 7.4, 6.2, 2.0 Hz, 3H), 7.67-7.54 (m, 1H), 7.36-7.18 (m, 2H), 7.09-6.82 (m, 1H), 3.06 (s, 3H).

Example 91: N-(3-(methylsulfonamido)phenyl)-4-(5-(piperazin-1-yl)pyridin-2-yl)thiophene-2-carboxamide

##STR00143##

[0434] Step 1: To a stirred solution of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (300 mg, 1.07 mmol) and CuBr.sub.2 (119 mg, 0.535 mmol) in CH.sub.2Br.sub.2 (5 mL) was added 3-methylbutyl nitrite (137 mg, 1.17 mmol) dropwise at 0 C. Then the mixture was stirred for 5 h at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc/Petroleum ether (0-100%) to afford tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate (188 mg, 0.549 mmol) as a yellow solid. LCMS (ESI) [M+H].sup.+: 342.

[0435] Step 2: A solution of tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate (190 mg, 0.555 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (77.2 mg, 0.110 mmol), Na.sub.2CO.sub.3 (175 mg, 1.66 mmol) and N-(3-methanesulfonamidophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxamide (257 mg, 0.610 mmol) in EtOH (4 mL) and H.sub.2O (1 mL) was stirred for 2 h at 80 C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (0-100%) to afford tert-butyl 4-(6-{5-[(3-methanesulfonamido phenyl)carbamoyl]thiophen-3-yl}pyridin-3-yl)piperazine-1-carboxylate (178 mg, 0.319 mmol) as a yellow solid. LCMS (ESI) [M+H].sup.+: 558 Step 3: To a stirred solution of tert-butyl 4-(6-{5-[(3-methanesulfonamidophenyl) carbamoyl]thiophen-3-yl}pyridin-3-yl)piperazine-1-carboxylate (180 mg, 0.322 mmol) in DCM (10 mL) was added TFA (365 mg, 3.21 mmol) dropwise at 0 C. for 1 h. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 9 with NaOH. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc/Petroleum ether (0-100%) to afford N-(3-methanesulfonamidophenyl)-4-[5-(piperazin-1-yl) pyridin-2-yl]thiophene-2-carboxamide (19.9 mg, 0.0419 mmol) as a yellow solid. LCMS (ESI) [M+H].sup.+: 458. .sup.1H NMR (300 MHz, DMSO-d6) 8.61 (d, J=1.4 Hz, 1H), 8.37-8.28 (m, 2H), 8.23 (d, J=1.4 Hz, 1H), 7.80-7.69 (m, 2H), 7.57-7.40 (m, 2H), 7.31 (t, J=8.1 Hz, 1H), 6.94 (dd, J=8.2, 2.3 Hz, 1H), 3.34 (t, J=5.1 Hz, 4H), 3.07 (dd, J=6.3, 3.7 Hz, 4H), 3.01 (s, 3H).

Example 92: 2-(5-((3-(methylsulfonamido)phenyl)carbamoyl)thiophen-3-yl)-1,4-dihydropyridine-4-carboxamide

##STR00144##

[0436] To a stirred solution of 2-{5-[(3-methanesulfonamidophenyl)carbamoyl]thiophen-3-yl}pyridine-4-carboxylic acid (100 mg, 0.240 mmol, 1 equiv) and NH.sub.4Cl (12.81 mg, 0.240 mmol, 1 equiv) in DMF (3 mL) were added DIEA (92.88 mg, 0.720 mmol, 3 equiv) and HATU (136.63 mg, 0.360 mmol, 1.5 equiv) in portions at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 2-{5-[(3-methanesulfonamido phenyl)carbamoyl]thiophen-3-yl}pyridine-4-carboxamide (11.3 mg, 11.33%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H].sup.+: 417. .sup.1H NMR (300 MHz, DMSO-d6) 10.51 (s, 1H), 9.76 (s, 1H), 8.84-8.73 (m, 2H), 8.53 (d, J=1.3 Hz, 1H), 8.39-8.26 (m, 2H), 7.83 (s, 1H), 7.73 (m, J=3.3, 1.4 Hz, 2H), 7.55 (m, J=8.4, 1.2 Hz, 1H), 7.31 (t, J=8.1 Hz, 1H), 6.95 (m, J=8.1, 2.2, 1.0 Hz, 1H), 3.02 (s, 3H).

Example 93: 4-(2-acetamidophenyl)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide

##STR00145##

[0437] To a mixture of 4-(2-aminophenyl)-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (80 m g, 0.206 mmol) and Et.sub.3N (62.4 mg, 0.618 mmol) in DCM (1 mL) was added CH.sub.3COCl (19.3 mg, 0.247 mmol). The resulting mixture was stirred for two hours at room temperature. Then it was concentrated, The residue was purified by flash chromatography on silica gel eluting with 35% of ethyl acetate in petroleum ether to afford 4-(2-acetamidophenyl)-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (39.5 mg, 44.4%) as a white solid. LCMS [M+H].sup.+: 430. .sup.1H NMR (300 MHz, DMSO-d6) 10.34 (s, 1H), 9.82 (s, 1H), 9.39 (s, 1H), 8.27 (d, J=1.4 Hz, 1H), 7.91 (d, J=1.3 Hz, 1H), 7.68 (t, J=2.1 Hz, 1H), 7.61-7.43 (m, 3H), 7.41-7.22 (m, 3H), 6.95 (ddd, J=8.0, 2.2, 1.0 Hz, 1H), 3.02 (s, 3H), 2.00 (s, 3H).

[0438] The compounds listed in the following table were prepared using a procedure similar to that described for Example 93:

TABLE-US-00009 Example MS (ESI) Structure No. [M + H].sup.+ .sup.1H NMR [00146] embedded image 94 431 .sup.1H NMR (300 MHz, DMSO-d6) 10.49 (s, 1H), 9.80 (d, J = 9.3 Hz, 2H), 8.60 (d, J = 1.4 Hz, 1H), 8.49 (dd, J = 4.6, 1.6 Hz, 1H), 8.23 (d, J = 1.3 Hz, 1H), 7.93 (dd, J = 8.2, 1.6 Hz, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.60- 7.50 (m, 1H), 7.39 (dd, J = 8.1, 4.6 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 6.95 (ddd, J = 8.0, 2.2, 1.0 Hz, 1H), 3.02 (s, 3H), 2.10 (s, 3H). [00147] embedded image 95 500 .sup.1H NMR (300 MHz, DMSO-d6) 10.45 (s, 1H), 9.82 (s, 1H), 8.65 (d, J = 1.4 Hz, 1H), 8.36 (d, J = 2.9 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H), 7.83-7.62 (m, 2H), 7.58-7.40 (m, 2H), 7.31 (t, J = 8.1 Hz, 1H), 7.01- 6.78 (m, 1H), 3.64- 3.49 (m, 4H), 3.30 (d, J = 7.1 Hz, 2H), 3.26- 3.13 (m, 2H), 3.02 (s, 3H), 2.06 (s, 3H)

Example 96: N-(3-(ethylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide

##STR00148##

[0439] Step 1: A solution of phenyl boronic acid (5 g, 41.007 mmol, 1 equiv) and 4-bromothiophene-2-carboxylic acid (8.49 g, 41.007 mmol, 1 equiv) and Pd(PPh.sub.3).sub.2Cl.sub.2 (2.88 g, 4.101 mmol, 0.1 equiv) and Na.sub.2CO.sub.3 (13.04 g, 123.021 mmol, 3 equiv) in EtOH (20 mL) and H.sub.2O (5 mL) was stirred for 2 h at 80 C. under nitrogen atmosphere. The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (1:1) to afford 4-phenylthiophene-2-carboxylic acid (4.5 g, 53.73%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H].sup.+: 205 Step 2: To a stirred solution of 4-phenylthiophene-2-carboxylic acid (100 mg, 0.490 mmol, 1.0 equiv) and benzene-1,3-diamine (52.95 mg, 0.490 mmol, 1 equiv) in ACN (3 mL) were added TCFH (206.07 mg, 0.735 mmol, 1.5 equiv) and NMI (120.60 mg, 1.470 mmol, 3 equiv) in portions at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in N-(3-aminophenyl)-4-phenylthiophene-2-carboxamide (130 mg, 90.20%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H].sup.+: 295.

[0440] Step 3: A solution of N-(3-aminophenyl)-4-phenylthiophene-2-carboxamide (70 mg, 0.238 mmol, 1.0 equiv) and ethanesulfonyl chloride (36.69 mg, 0.286 mmol, 1.2 equiv) in pyridine (3 mL) was stirred for 1 h at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in N-(3-ethanesulfonamidophenyl)-4-phenyl thiophene-2-carboxamide (15.0 mg, 16.32%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H].sup.+: 387. .sup.1H NMR (300 MHz, DMSO-d6) 10.33 (s, 1H), 9.86 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.20 (d, J=1.4 Hz, 1H), 7.78-7.73 (m, 2H), 7.70 (t, J=2.1 Hz, 1H), 7.56-7.43 (m, 3H), 7.41-7.21 (m, 2H), 7.01-6.92 (m, 1H), 3.13 (m, J=7.3 Hz, 2H), 1.22 (t, J=7.3 Hz, 3H).

[0441] The compounds listed in the following table were prepared using a procedure similar to that described for Example 96, using a synthesized or commercial carboxylic acid:

TABLE-US-00010 Example MS (ESI) Structure No. [M + H].sup.+ .sup.1H NMR [00149] embedded image 97 388 .sup.1H NMR (300 MHz, DMSO- d6) 10.48 (s, 1H), 9.86 (s, 1H), 8.75 (d, J = 1.3 Hz, 1H), 8.65 (d, J = 4.7 Hz, 1H), 8.49 (d, J = 1.3 Hz, 1H), 7.96- 7.87 (m, 2H), 7.73 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.38- 7.20 (m, 2H), 6.96 (d, J = 7.9 Hz, 1H), 3.13 (q, J = 7.3 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H)

Example 98: 5-bromo-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide

##STR00150##

[0442] Step 1: To a solution of 4-phenylthiophene-2-carboxylic acid (1.5 g, 7.344 mmol, 1 equiv) and NBS (1.57 g, 8.813 mmol, 1.2 equiv) in CHCl.sub.3 (20 mL) was added AcOH (1.32 g, 22.032 mmol, 3 equiv) at room temperature. The resulting solution was stirred for 4 hours at room temperature. The resulting solution was concentrated under vacuum. The residue was purified by flash chromatography on C18 column gel eluting with ACN/water (0.05% FA) (28%) to afford 5-bromo-4-phenylthiophene-2-carboxylic acid (850 mg, 39.04%) as a yellow solid. LCMS: (ES, m/z): [M+H].sup.+:283

[0443] Step 2: To a solution of 5-bromo-4-phenylthiophene-2-carboxylic acid (850 mg, 3.002 mmol, 1 equiv), NMI (492.9 mg, 6.003 mmol, 2.00 equiv) and TCFH (1.3 g, 4.633 mmol, 1.54 equiv) in ACN (10 mL) at room temperature. The resulting solution was stirred for 10 minus at room temperature. Then N-(3-aminophenyl)methanesulfonamide (838.6 mg, 4.503 mmol, 1.50 equiv) was added and stirred at room temperature for one hours. The residue was purified by flash chromatography on C18 Column gel eluting with ACN/water (0.05% NH.sub.4HCO.sub.3) (56%) to afford 5-bromo-N-(3-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (1.0 g, 67.90%) as a yellow solid and crude product (100 mg) was purify by Pre-HPLC on condition Column: XBridge Prep C18 OBD Column, 19*150 mm, 5 m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 41% B to 77% B in 8 min, 77% B; Wave Length: 220 nm; RT1(min): 6.88 to afford 5-bromo-N-(3-methanesulfonamidophenyl)-4-phenylthio phene-2-carboxamide (29.2 mg, 50%) as a yellow solid. LCMS: (ES, m/z): [M+H].sup.+: 451. .sup.1H NMR (400 MHz, DMSO-d6) 10.34 (s, 1H), 9.81 (s, 1H), 8.15 (s, 1H), 7.68-7.59 (m, 3H), 7.57-7.41 (m, 4H), 7.31 (t, J=8.1 Hz, 1H), 6.95 (ddd, J=8.0, 2.2, 1.0 Hz, 1H), 3.00 (s, 3H).

Example 99: N-(3-(methylsulfonamido)phenyl)-4-phenyl-5-(trifluoromethyl)thiophene-2-carboxamide

##STR00151##

[0444] Step 1: To a solution of 5-bromo-N-(3-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (200 mg, 0.443 mmol, 1 equiv), CuI (8.4 mg, 0.044 mmol, 0.10 equiv), NMP (5 mL) in NMP (5 mL) was added methyl 2,2-difluoro-2-sulfoacetate (127.7 mg, 0.665 mmol, 1.50 equiv) at room temperature under nitrogen. The resulting solution was stirred for two hours at 135 C. The residue was purified by Pre-HPLC on condition: Column: Xselect CSH C18 OBD Column 30*150 mm 5 m, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 66% B in 11 min, 66% B; Wave Length: 254/220 nm; RT1(min): 8.47 to afford N-(3-methanesulfonamidophenyl)-4-phenyl-5-(trifluoromethyl) thiophene-2-carboxamide (7.5 mg, 3.82%) as a white solid. LCMS: (ES, m/z): [M+1]=441. .sup.1H NMR (300 MHz, DMSO-d6) 10.55 (s, 1H), 9.86 (s, 1H), 8.12 (s, 1H), 7.69-7.53 (m, 6H), 7.36-7.30 (m, 1H), 6.97 (t, J=8.1 Hz, 1H), 3.02 (s, 3H).

Example 100: 5-cyano-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide

##STR00152##

[0445] To a solution of 5-bromo-N-(3-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (120 mg, 0.266 mmol, 1 equiv) and CuCN (47.6 mg, 0.531 mmol, 2.00 equiv) in NMP (5 mL) at room temperature under nitrogen. The resulting solution was stirred overnight at 160 C. The residue was purified by Pre-HPLC on condition: Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 m; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 52% B to 60% B in 8 min, 60% B; Wave Length: 220 nm; RT1(min): 7.58 to afford 5-cyano-N-(3-methane sulfonamidophenyl)-4-phenylthiophene-2-carboxamide (24.7 mg, 23.31%) as a yellow solid. LCMS: (ES, m/z): [M+1]=398. .sup.1H NMR (300 MHz, DMSO-d6) 10.65 (s, 1H), 9.88 (s, 1H), 8.45 (s, 1H), 7.89-7.73 (m, 2H), 7.71-7.45 (m, 5H), 7.35 (t, J=8.1 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 3.02 (s, 3H).

Example 101: 5-[(3-methanesulfonamidophenyl) carbamoyl]-3-phenylthiophene-2-carboxylic acid

##STR00153##

[0446] To a solution of 5-bromo-N-(3-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (100 mg, 0.222 mmol, 1 equiv), acetic anhydride (45.3 mg, 0.444 mmol, 2.00 equiv), oxalic acid (39.9 mg, 0.443 mmol, 2.00 equiv), Pd(OAc).sub.2 (5 mg, 0.022 mmol, 0.10 equiv), and Xantphos (25.6 mg, 0.044 mmol, 0.20 equiv) in DMF (5 mL) was added DIEA (85.9 mg, 0.665 mmol, 3.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 2 hours at 100 C. The mixture was purified by Prep-HPLC to afford 5-[(3-methanesulfonamidophenyl) carbamoyl]-3-phenylthiophene-2-carboxylic acid (30.5 mg, 33.05%) as a yellow solid.

[0447] LCMS (ESI) [M+H].sup.+=417

[0448] .sup.1H NMR (300 MHz, DMSO-d6) 10.42 (s, 1H), 9.83 (s, 1H), 8.09 (s, 1H), 7.68 (t, J=2.1 Hz, 1H), 7.53 (ddd, J=7.2, 6.1, 2.0 Hz, 3H), 7.48-7.39 (m, 3H), 7.32 (t, J=8.1 Hz, 1H), 6.97 (ddd, J=8.0, 2.2, 1.0 Hz, 1H), 3.01 (s, 3H).

Example 102: N2-(3-(methylsulfonamido)phenyl)-N4-phenylthiophene-2,4-dicarboxamide

##STR00154##

[0449] Step 1: To a stirred solution of 4-bromothiophene-2-carboxylic acid (500 mg, 2.41 mmol), TCFH (1.024 g, 3.615 mmol) and NMI (0.598 mg, 7.23 mmol) in ACN (4.00 mL) was added N-(3-aminophenyl)methanesulfonamide (448 mg, 24.1 mmol). Then the mixture was stirred for 4 hours at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H.sub.2O (5-95%, acidic system) to afford 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (850 mg, 95%) as a brown solid. Step 2: A solution of 4-bromo-N-(3-methanesulfonamidophenyl)thiophene-2-carboxamide (100 mg, 0.266 mmol, 1 equiv), acetic anhydride (54.41 mg, 0.532 mmol, 2 equiv), Pd(OAc).sub.2 (11.97 mg, 0.053 mmol, 0.2 equiv), Xantphos (30.84 mg, 0.053 mmol, 0.2 equiv), oxalic acid (47.99 mg, 0.532 mmol, 2 equiv) and DIEA (103.32 mg, 0.798 mmol, 3 equiv) in DMSO (3 mL) was stirred for 2 hours at 100 C. under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc=2:3, to afford 5-[(3-methanesulfonamidophenyl)carbamoyl]thiophene-3-carboxylic acid (63 mg, 69.46%) as white solid.

[0450] Step 3: A solution of 5-[(3-methanesulfonamidophenyl)carbamoyl]thiophene-3-carboxylic acid (50 mg, 0.147 mmol, 1 equiv), aniline (15.05 mg, 0.162 mmol, 1.1 equiv), TCFH (82.43 mg, 0.294 mmol, 2 equiv) and NMI (36.18 mg, 0.441 mmol, 3 equiv) in ACN (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase Flash Chromatography with the following conditions (water/ACN=2:3) to afford N2-(3-(methylsulfonamido)phenyl)-N4-phenylthiophene-2,4-dicarboxamide (13.2 mg, 21.63%) as a white solid.

[0451] LCMS (ESI) [M+H].sup.+=416

[0452] .sup.1H NMR (300 MHz, DMSO-d6) 10.50 (s, 1H), 10.24 (s, 1H), 9.80 (s, 1H), 8.63 (d, J=1.3 Hz, 1H), 8.53 (d, J=1.4 Hz, 1H), 7.81-7.73 (m, 2H), 7.71 (t, J=2.1 Hz, 1H), 7.59-7.51 (m, 1H), 7.38 (t, J=7.9 Hz, 2H), 7.31 (t, J=8.1 Hz, 1H), 7.12 (t, J=7.4 Hz, 1H), 7.00-6.91 (m, 1H), 3.02 (s, 3H).

[0453] The compounds listed in the following table were prepared using a procedure similar to that described for Example 102:

TABLE-US-00011 MS Example (ESI) Structure No. [M + H].sup.+ .sup.1H NMR [00155] embedded image 103 444 [00156] 104 463 [00157] 105 451 [00158] 106 446 [00159] 107 526 [00160] 108 499 [00161] 109 463 [00162] 110 443 [00163] 111 444 [00164] 112 455 [00165] 113 463 [00166] 114 486 [00167] 115 507 [00168] 116 514 [00169] 117 507 [00170] 118 473 [00171] 119 473 [00172] 120 499 [00173] embedded image 121 473 [00174] 122 544 [00175] 123 457 [00176] 124 528 [00177] 125 479 [00178] 126 479 [00179] 127 514 [00180] 128 492 [00181] 129 455 [00182] 130 445 [00183] 131 500 [00184] 132 499 [00185] 133 492 [00186] 134 459 [00187] 135 473 [00188] 136 455 [00189] 137 499 [00190] 138 454 [00191] embedded image 139 472 [00192] 140 483 [00193] 141 469 [00194] 142 503 [00195] 143 459 [00196] 144 469 [00197] 145 468 [00198] 146 455 [00199] 147 513 [00200] 148 481 [00201] 149 459 [00202] 150 450 [00203] 151 469 [00204] 152 430 .sup.1H NMR (400 MHz, DMSO-d6) 10.38 (s, 1H), 9.81 (s, 1H), 8.20 (d, J = 22.8 Hz, 2H), 7.67 (t, J = 2.1 Hz, 1H), 7.55-7.42 (m, 6H), 7.41- 7.36 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.95 (ddd, J = 8.1, 2.3, 0.9 Hz, 1H), 3.00 (s, 3H), 2.68 (d, J = 4.6 Hz, 3H). [00205] embedded image 162 407.8

Example 153: 5-(hydroxymethyl)-N-(3-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide

##STR00206##

[0454] Step 1: To a solution of 5-[(3-methanesulfonamidophenyl)carbamoyl]-3-phenylthiophene-2-carboxylic acid (60 mg, 0.144 mmol, 1 equiv), HATU (82.2 mg, 0.216 mmol, 1.50 equiv) and DIEA (55.8 mg, 0.432 mmol, 3.00 equiv) in DMF (2 mL) was added methanol (9.2 mg, 0.287 mmol, 1.99 equiv) at room temperature. The resulting solution was stirred for two hours at room temperature. The residue was purified by C18 Column on condition: ACN/water (0.05% FA)(45%) to afford methyl 5-[(3-methanesulfonamidophenyl) carbamoyl]-3-phenylthiophene-2-carboxylate (40 mg, 58.37%) as a yellow solid.

[0455] Step 2: To a solution of methyl 5-[(3-methanesulfonamidophenyl)carbamoyl]-3-phenylthiophene-2-carboxylate (40 mg, 0.093 mmol, 1 equiv) in EtOH (5 mL, 86.067 mmol, 926.27 equiv) was added NaBH.sub.4 (7.03 mg, 0.186 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred for 2 hours at room temperature. The residue was purified by Pre-HPLC on condition: Column: XBridge Prep C18 OBD Column, 19*150 mm, 5 m; Mobile Phase A: Water (10 mmol/L NH.sub.4HCO.sub.3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 29% B to 45% B in 8 min, 45% B; Wave Length: 220 nm; RT1(min): 7.3 to afford 5-(hydroxymethyl)-N-(3-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (8.8 mg, 23.34%) as a yellow solid. LCMS: (ES, m/z): [M+1]=403. .sup.1H NMR (300 MHz, DMSO-d6) 10.24 (s, 1H), 9.79 (s, 1H), 8.14 (s, 1H), 7.69 (t, J=2.1 Hz, 1H), 7.51 (q, J=4.1, 3.1 Hz, 5H), 7.39 (ddd, J=8.6, 5.3, 2.5 Hz, 1H), 7.30 (t, J=8.1 Hz, 1H), 6.94 (dd, J=8.0, 2.1 Hz, 1H), 5.85 (t, J=5.4 Hz, 1H), 4.73 (d, J=5.3 Hz, 2H), 3.01 (s, 3H).

Example 154: 1-benzyl-N-(3-methane sulfonamidophenyl)-5-methyl-1H-pyrazole-3-carboxamide

##STR00207##

[0456] Step 1: To a stirred solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (500 mg, 3.24 mmol) and Cs.sub.2CO.sub.3 (3.15 g, 9.72 mmol), (bromomethyl)benzene (554 mg, 3.24 mmol) was added in DMSO (10 mL) dropwise. The mixture was stirred for 2 hours at 80 C. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H.sub.2O (0-100%, acidic system) to afford ethyl 1-benzyl-5-methyl-1H-pyrazole-3-carboxylate (420 mg, 1.71 mmol) as a yellow solid. LCMS (ESI) [M+H].sup.+=245.

[0457] Step 2: To a stirred mixture of ethyl 1-benzyl-5-methyl-1H-pyrazole-3-carboxylate (420 mg, 1.71 mmol) and LiOH (123 mg, 5.13 mmol) was added THF (6 mL) and H.sub.2O (2 mL) dropwise. The mixture was stirred for 2 hours at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H.sub.2O (0-100%, acidic system) to afford 1-benzyl-5-methyl-1H-pyrazole-3-carboxylic acid (300 mg, 1.38 mmol) as a yellow solid. LCMS (ESI) [M+H].sup.+: 217.

[0458] Step 3: To a stirred mixture of 1-benzyl-5-methyl-1H-pyrazole-3-carboxylic acid (60 mg, 0.277 mmol), TCFH (116 mg, 0.415 mmol), N-(3-aminophenyl)methanesulfonamide (51.5 mg, 0.277 mmol) and NMI (113 mg, 1.38 mmol) was added ACN (5 mL). Then the mixture was stirred for 2 hours at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H.sub.2O (0-100%, acidic system) to afford 1-benzyl-N-(3-methane sulfonamidophenyl)-5-methyl-1H-pyrazole-3-carboxamide (58.7 mg, 0.152 mmol) as a white solid. LCMS (ESI) [M+H].sup.+: 385. .sup.1H NMR (300 MHz, DMSO-d6) 10.04 (s, 1H), 9.78 (s, 1H), 7.81 (s, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.31 (dq, J=21.2, 7.7 Hz, 4H), 7.17 (d, J=7.4 Hz, 2H), 6.93 (d, J=8.1 Hz, 1H), 6.66 (s, 1H), 5.45 (s, 2H), 3.03 (s, 3H), 2.25 (s, 3H).

Example 155: 4-(benzylamino)-N-(3-(methylsulfonamido)phenyl)thiophene-2-carboxamide

##STR00208##

[0459] Step 1: A solution of methyl 4-aminothiophene-2-carboxylate (100 mg, 0.636 mmol, 1 equiv) and benzyl bromide (119.69 mg, 0.700 mmol, 1.1 equiv) and Cs.sub.2CO.sub.3 (621.83 mg, 1.908 mmol, 3 equiv) in DMSO (3 mL) was stirred for 1 h at 60 C. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in methyl 4-(benzylamino)thiophene-2-carboxylate (130 mg, 82.63%) as a yellow solid.

[0460] LCMS (ESI) [M+H].sup.+: 248.

[0461] Step 2: A solution of methyl 4-(benzylamino) thiophene-2-carboxylate (130 mg, 0.526 mmol, 1 equiv) an d LiOH (37.77 mg, 1.578 mmol, 3 equiv) in EtOH (3 mL) and H.sub.2O (1 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 6 with HCl (aq.). The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 4-(benzylamino) thiophene-2-carboxylic acid (90 mg, 73.39%) as a yellow solid. LCMS (ESI) [M+H].sup.+: 234.

[0462] Step 3: To a stirred solution of 4-(benzylamino) thiophene-2-carboxylic acid (90 mg, 0.386 mmol, 1 equiv) and N-(3-aminophenyl) methanesulfonamide (71.84 mg, 0.386 mmol, 1 equiv) in ACN (3 mL) were added NMI (95.02 mg, 1.158 mmol, 3 equiv) and TCFH (162.37 mg, 0.579 mmol, 1.5 equiv) in portions at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in 4-(benzylamino)-N-(3-methanesulfonamidophenyl) thiophene-2-carboxamide (66.2 mg, 42.74%) as a light yellow solid. LCMS (ES, m/z): LCMS (ESI) [M+H].sup.+: 402. .sup.1H NMR (300 MHz, DMSO-d6) 10.21 (s, 1H), 9.75 (s, 1H), 7.65 (t, J=2.1 Hz, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.51-7.43 (m, 1H), 7.42-7.20 (m, 6H), 6.92 (m J=8.0, 2.2, 1.0 Hz, 1H), 6.35-6.12 (m, 2H), 4.23 (d, J=6.0 Hz, 2H), 3.01 (s, 3H).

Example 156: N-(6-methanesulfonamidopyridin-2-yl)-4-phenylthiophene-2-carboxamide

##STR00209##

[0463] Step 1: To a stirred solution of 4-phenylthiophene-2-carboxylic acid (150 mg, 0.734 mmol), TCFH (309.381 mg, 1.101 mmol) and NMI (180.5 mg, 2.202 mmol) in ACN (10.00 mL) was added 6-bromopyridin-2-amine (126 mg, 0.734 mmol). Then the mixture was stirred for 8 hours at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H.sub.2O (5-95%, acidic system) to afford N-(6-bromopyridin-2-yl)-4-phenylthiophene-2-carboxamide (120 mg, 95%) as a yellow solid. LCMS (ESI) [M+H].sup.+: 359.

[0464] Step 2: To a stirred solution of N-(6-bromopyridin-2-yl)-4-phenylthiophene-2-carboxamide (100 mg, 0.278 mmol), CuI (10 mg, 0.0556 mmol) and K.sub.2CO.sub.3 (115.092 mg, 0.834 mmol) in DMSO (5.0 mL) was added methanesulfonamide (132 mg, 1.39 mmol) at 0 C. Then the mixture was stirred for 1 hour at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc/Petroleum ether (0-100%) to afford N-(6-methanesulfonamidopyridin-2-yl)-4-phenylthiophene-2-carboxamide (26.8 mg, 98.887%) as a yellow solid. LCMS (ESI) [M+H].sup.+: 374. .sup.1H NMR (400 MHz, DMSO-d6) 10.54 (d, J=11.1 Hz, 2H), 8.61 (d, J=1.5 Hz, 1H), 8.24 (d, J=1.5 Hz, 1H), 7.80-7.69 (m, 4H), 7.48 (t, J=7.7 Hz, 2H), 7.40-7.31 (m, 1H), 6.69 (dd, J=7.3, 1.4 Hz, 1H), 3.52 (s, 3H).

Example 157: N-(3-(methylsulfonoamidimidamido)phenyl)-4-phenylthiophene-2-carboxamide

##STR00210##

[0465] Step 1: To a stirred solution of methanesulfonamide (500 mg, 5.25 mmol) and Et.sub.3N (1.58 g, 15.7 mmol) in DCM (10 mL) was added TBS-Cl (869 mg, 5.77 mmol) dropwise at 0 C. Then the mixture was stirred for 1 h at room temperature. The mixture was concentrated and purified by flash chromatography on silica gel eluting with EtOAc/Petroleum ether (0-100%) to afford N-(tert-butyldimethylsilyl)methanesulfonamide (752 mg, 3.59 mmol) as a yellow solid. LCMS (ESI) [M+H].sup.+: 210

[0466] Step 2: PPh.sub.3 (962 mg, 3.67 mmol) and C.sub.2Cl.sub.6 (868 mg, 3.67 mmol) were dissolved in dry CHCl3 (10 mL) under argon atmosphere. The resulting solution was heated at 70 C. for 6 h, and the formation of a white suspension was observed. The reaction mixture was cooled to room temperature and Et.sub.3N (439 mg, 4.34 mmol) was added. After stirring for additional 10 min, the formation of a yellow suspension was observed. The reaction mixture was cooled to 0 C. and a solution of N-(tert-butyldimethylsilyl)methanesulfonamide (700 mg, 3.34 mmol) was added dropwise. The mixture was stirred for 30 min and a solution of 1H-imidazole (249 mg, 3.67 mmol) and Et.sub.3N (371 mg, 3.67 mmol) in THF (3 mL) was added dropwise. After stirring at 0 C. for an additional 30 min, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, the obtained solids were extracted with hexanes (200 ml), and the hexane solution was evaporated under vacuum. The residue was dissolved in CH.sub.2Cl.sub.2 (150 mL) and washed with H.sub.2O (3200 mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc/hexane (3:2) as eluent, Rf=0.50) to afford (tert-butyldimethylsilyl)[(1H-imidazol-1-yl)(methyl) oxo-.sup.6-sulfanylidene]amine (390 mg, 1.50 mmol) as a yellow solid. LCMS (ESI) [M+H].sup.+: 260.

[0467] Step 3: A solution of (tert-butyldimethylsilyl)[(1H-imidazol-1-yl)(methyl)oxo-.sup.6-sulfanylidene]amine (370 mg, 1.42 mmol) in dry Et.sub.2O (10 mL) was cooled to 0 C. in an argon atmosphere, methyl trifluoromethanesulfonate (255 mg, 1.56 mmol) was added dropwise and the reaction mixture was stirred at 0 C. for 1 h. The obtained solids were filtered, washed with dry Et.sub.2O (2200 mL), and dried under vacuum to afford 1-{[(tert-butyldimethylsilyl)imino](methyl)oxo-.sup.6-sulfanyl}-3-methyl-1H-imidazol-3-ium (300 mg, 1.09 mmol) as white solid. LCMS (ESI) [M+H].sup.+: 275

[0468] Step 4: To a stirred solution of benzene-1,3-diamine (150 mg, 1.38 mmol), TCFH (502 mg, 1.79 mmol) and NMI (339 mg, 4.14 mmol) in ACN (3 mL) was added 4-phenylthiophene-2-carboxylic acid (308 mg, 1.51 mmol). Then the mixture was stirred for 1 h at room temperature. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H.sub.2O (5-95%, acidic system) to afford N-(3-aminophenyl)-4-phenylthiophene-2-carboxamide (247 mg, 0.840 mmol) as a yellow solid. LCMS (ESI) [M+H].sup.+: 295

[0469] Step 5: A solution of 1-{[(tert-butyldimethylsilyl)imino](methyl)oxo-.sup.6-sulfanyl}-3-methyl-1H-imidazol-3-ium (300 mg, 1.09 mmol) and N-(3-aminophenyl)-4-phenylthiophene-2-carboxamide (350 mg, 1.19 mmol) in ACN (10 mL) was stirred for 0.5 hours at 80 C. The mixture was concentrated and purified by reverse phase flash chromatography eluting with ACN/H.sub.2O (5-95%, acidic system) to afford N-{3-[N-(tert-butyldimethylsilyl)methanesulfonoimidamido]phenyl}-4-phenylthiophene-2-carboxamide (178 mg, 0.366 mmol) as a white solid. LCMS (ESI) [M+H].sup.+: 486 Step 6: HCl (3.08 mmol) in dioxane (5 mL) was added portion-wise to a stirred solution of N-13-[N-(tert-butyldimethylsilyl)methanesulfonoimidamido]phenyl}-4-phenylthiophene-2-carboxamide (150 mg, 0.308 mmol) in dry dioxane (5 mL) at 0 C. The reaction mixture was stirred at 0 C. for an additional 10 min and then it was allowed to warm to room temperature. The obtained mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (0-100%) to afford N-(3-methanesulfonoimidamidophenyl)-4-phenylthiophene-2-carboxamide (26.8 mg, 0.0713 mmol) as a white solid. LCMS (ESI) [M+H].sup.+: 372. .sup.1H NMR (300 MHz, DMSO-d6) 10.12 (s, 1H), 8.50 (d, J=1.4 Hz, 1H), 8.17 (d, J=1.4 Hz, 1H), 7.80-7.71 (m, 2H), 7.50-7.23 (m, 5H), 7.14 (t, J=8.0 Hz, 1H), 6.77 (d, J=9.9 Hz, 3H), 3.14 (s, 3H).

Example 158: N-(3-methyl-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide

##STR00211##

[0470] Step 1: To a mixture of 4-phenylthiophene-2-carboxylic acid (110 mg, 0.538 mmol) and 3-methyl-5-nitroaniline (98.1 mg, 0.645 mmol) in CAN (2 mL) was added TCFH (225 mg, 0.807 mmol) and NMI (132 mg, 1.61 mmol) at room temperature for two hours. Then it was concentrated, the residue was purified by reverse phase flash chromatography eluting with 50% of acetonitrile in water (0.1% NH.sub.4HCO.sub.3) to afford N-(3-methyl-5-nitrophenyl)-4-phenylthiophene-2-carboxamide (112 mg, 61.2%) as a white solid. LCMS [M+H].sup.+: 339. Step 2: To a mixture of N-(3-methyl-5-nitrophenyl)-4-phenylthiophene-2-carboxamide (110 mg, 0.325 mmol), Pd/C (13.0 mg, 0.325 mmol) was added MeOH (1 mL). The resulting mixture was stirred for 1 hours at room temperature under H.sub.2 atmosphere. The reaction mixture filter and washed with Methanol, then the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 35% of ethyl acetate in petroleum ether to afford N-(3-amino-5-methylphenyl)-4-phenylthiophene-2-carboxamide (82 mg, 81.7%) as a light yellow solid. LCMS [M+H].sup.+: 309.

[0471] Step 3: To a mixture of N-(3-amino-5-methylphenyl)-4-phenylthiophene-2-carboxamide (82 mg, 0.265 mmol) and methanesulfonyl methanesulfonate (55.3 mg, 0.318 mmol) in ACN (1 mL) was added TCFH (111 mg, 0.397 mmol) and NMI (65.1 mg, 0.795 mmol). The resulting mixture was stirred at room temperature for two hours. Then it was concentrated, the residue was purified by reverse phase flash chromatography eluting with 55% of acetonitrile in water (0.1% NH.sub.4HCO.sub.3) to afford N-(3-methanesulfonamido-5-methylphenyl)-4-phenylthiophene-2-carboxamide (34.0 mg, 33.1%) as a white solid. LCMS [M+H].sup.+: 387. .sup.1H NMR (300 MHz, DMSO-d6) 10.26 (s, 1H), 9.76 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.19 (d, J=1.4 Hz, 1H), 7.80-7.71 (m, 2H), 7.55-7.43 (m, 3H), 7.42-7.30 (m, 2H), 6.79 (d, J=2.3 Hz, 1H), 3.01 (s, 3H), 2.30 (s, 3H).

Example 159: N-(3-formyl-5-(methylsulfonamido)phenyl)-4-phenylthiophene-2-carboxamide

##STR00212##

[0472] Step 1: To a mixture of methyl 4-bromothiophene-2-carboxylate (30 g, 135 mmol), phenylboronic acid (32.9 g, 270 mmol), Pd(dppf)Cl.sub.2 (11.0 g, 13.5 mmol) and K.sub.3PO.sub.4 (85.8 g, 405 mmol) was added dioxane (300 mL) and H.sub.2O (30 mL). The resulting mixture was stirred for 2 hours at 80 C. under N2 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 20% of ethyl acetate in petroleum ether to afford methyl 4-phenylthiophene-2-carboxylate (27.1 g, 124 mmol) as a light yellow solid.

[0473] Step 2: To a stirred solution of methyl 4-phenylthiophene-2-carboxylate (26.1 g, 119 mmol) in 260 mL of THF and 260 mL of water was added LiOH (24.9 g, 595 mmol). The resulting mixture was stirred overnight at room temperature. Then it was concentrated, and the pH value of the residue solution was adjusted to 3 with 1M HCl (aq). The product was precipitated from the solution. After filtration, obtained 4-phenylthiophene-2-carboxylic acid (24.4 g, 119 mmol) as a white solid.

[0474] 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 it was concentrated, the residue was purified by reverse phase flash chromatography eluting with 60% of acetonitrile in water (0.1% FA) to afford N-(3-bromo-5-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (11.0519 g, 24.486 mmol) as a light yellow solid. LCMS (ESI) [MH].sup.: 449. .sup.1H NMR (300 MHz, DMSO-d6) 10.46 (s, 1H), 10.09 (s, 1H), 8.49 (d, J=1.5 Hz, 1H), 8.23 (d, J=1.4 Hz, 1H), 7.96-7.60 (m, 4H), 7.57-7.24 (m, 3H), 7.11 (t, J=1.9 Hz, 1H), 3.08 (s, 3H).

[0475] Step 4: A solution of N-(3-bromo-5-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (100 mg, 0.222 mmol, 1 equiv) and HCOOH (20.39 mg, 0.444 mmol, 2 equiv) and Pd(OAc).sub.2 (9.95 mg, 0.044 mmol, 0.2 equiv) and Ac.sub.2O (45.24 mg, 0.444 mmol, 2 equiv) and HCOONa (75.33 mg, 1.110 mmol, 5 equiv) in Et.sub.3N (44.84 mg, 0.444 mmol, 2 equiv) was stirred overnight at 90 C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (310 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH.sub.4HCO.sub.3), 0% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in N-(3-formyl-5-methanesulfonamidophenyl)-4-phenylthiophene-2-carboxamide (11.1 mg, 12.51%) as a white solid. LCMS (ES, m/z): LCMS (ESI) [M+H].sup.+: 401. .sup.1H NMR (300 MHz, DMSO-d6) 10.59 (s, 1H), 9.96 (s, 1H), 8.53 (d, J=1.5 Hz, 1H), 8.23 (d, J=1.4 Hz, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.81-7.71 (m, 2H), 7.55-7.44 (m, 3H), 7.41-7.34 (m, 1H), 3.07 (d, J=1.2 Hz, 3H).

Example 160: 5-[5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-N-(3-methanesulfonamidophenyl)-1-methylpyrrole-3-carboxamide

##STR00213##

[0476] Step 1: To a mixture of 5-bromo-2-iodopyridine (5.1 g, 17.9 mmol), methyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (5.67 g, 21.4 mmol), Pd(dppf)Cl.sub.2 (1.45 g, 1.78 mmol) and K.sub.3PO.sub.4 (11.3 g, 53.6 mmol) was added 1,4-dioxane (60 ml) and H.sub.2O (6 ml). The resulting mixture was stirred for 2 hours at 70 C. under N2 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 15% of ethyl acetate in petroleum ether to afford methyl 5-(5-bromopyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (5.10 g, 96.5%) as a white solid.

[0477] LCMS [M+H].sup.+: 295

[0478] Step 2: To a mixture of methyl 5-(5-bromopyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (3.1 g, 10.5 mmol), 3,3-difluoroazetidine hydrochloride (4.08 g, 31.5 mmol), Cs.sub.2CO.sub.3 (10.28 g, 31.6 mmol) and PEPPSI IHept-Cl (510 mg, 525 mol) was added dioxane (30 mL). The resulting mixture was stirred for 1 hours at 120 C. under N2 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% of ethyl acetate in petroleum ether to afford methyl 5-[5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-1-methyl-1H-pyrrole-3-carboxylate (2.20 g, 68.3%) as a yellow solid. LCMS [M+H].sup.+: 308

[0479] Step 3: A solution of methyl 5-[5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-1-methylpyrrole-3-carboxylate (140 mg, 0.456 mmol, 1 equiv) and N-(3-aminophenyl)methanesulfonamide (102 mg, 0.547 mmol, 1.2 equiv) in toluene (4 mL) was stirred for 10 min at 0 C. under nitrogen atmosphere. To the above mixture was added AlMe.sub.3 (0.14 mL, 1.368 mmol, 3 equiv) dropwise over 1 min at 0 C. The resulting mixture was stirred for additional 1 hour at 80 C. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at 0 C. The resulting mixture was concentrated under reduced pressure. The residue (120 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*150 mm, 5 m; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 21% B to 52% B in 7 min, 52% B; Wave Length: 254/220 nm; RT1(min): 7.20) to afford 5-[5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-N-(3-methanesulfonamidophenyl)-1-methylpyrrole-3-carboxamide (104.9 mg, 49.9% yield) as a white solid. LCMS (ESI) [M+H].sup.+: 462.15

[0480] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 9.64 (s, 1H), 7.98 (d, J=2.9 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.61-7.44 (m, 3H), 7.25 (t, J=8.1 Hz, 1H), 7.14-6.98 (m, 2H), 6.95-6.82 (m, 1H), 4.39 (t, J=12.3 Hz, 4H), 3.92 (s, 3H), 3.00 (s, 3H).

Example 161: 5-(3,5-difluoropyridin-2-yl)-N-(3-fluoro-5-methanesulfonamidophenyl)-1-methyl-1H-pyrrole-3-carboxamide

##STR00214##

[0481] Step 1: A solution of 2-bromo-3,5-difluoropyridine (1.5 g, 7.73 mmol), methyl 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (2.04 g, 7.73 mmol), Pd(dppf)Cl.sub.2 (630 mg, 773 mol) and K.sub.2CO.sub.3 (3.18 g, 23.1 mmol) in dioxane (10 mL) and H.sub.2O (2 mL) was stirred for 1 hour at 80 C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash with the following conditions (20-80% acetonitrile in water) to afford methyl 5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (1.20 g, 4.75 mmol) as white solid.

[0482] LCMS (ESI) [M+H].sup.+: 253.00.

[0483] Step 2: A solution of methyl 5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (150 mg, 594 mol) and lithium hydroxide (113 mg, 4.75 mmol) in H.sub.2O (0.4 mL) and EtOH (2 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The mixture was acidified to pH 7 with HCl (aq.). The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. to afford 5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylic acid (120 mg, 503 mol) as a white solid. LCMS (ESI) [M+H].sup.+: 239.00.

[0484] Step 3: A solution of 5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylic acid (120 mg, 503 mol), N-(3-amino-5-fluorophenyl)methanesulfonamide (102 mg, 503 mol), TCFH (140 mg, 503 mol) and NMI (41 mg, 503 mol) in ACN (2 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-(3,5-difluoropyridin-2-yl)-N(3-fluoro-5-methanesulfonamidophenyl)-1-methyl-1H-pyrrole-3-carboxamide (135.6 mg, 321 mol) as a light yellow solid. LCMS (ESI) [M+H].sup.+: 407.10. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.74 (d, J=8.4 Hz, 2H), 8.59 (d, J=2.4 Hz, 1H), 8.08 (ddd, J=11.2, 8.9, 2.5 Hz, 1H), 7.75 (d, J=1.9 Hz, 1H), 7.69 (t, J=2.1 Hz, 1H), 7.52 (dd, J=7.8, 2.2 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 7.21 (dd, J=3.7, 1.9 Hz, 1H), 6.92-6.85 (m, 1H), 3.88 (s, 3H), 3.00 (s, 3H).

Assays

[0485] Compounds of the disclosure were assessed for their ability to inhibit DHX9 activity. The inhibitory properties of the compounds of the disclosure described herein can be evidenced by testing in any one of the following assays.

1. Biochemical Assay

Materials and Methods

[0486] Recombinant DHX9Human recombinant DHX9 protein was custom ordered from Viva.

[0487] RNA substrateOligos for double-stranded RNA substrate were custom ordered from IDT Technologies. (Oligo1GCCUGGUCCCUGUCCUUGUUAUUUUCCUUGGUUAAUU (SEQ ID NO:1). Oligo2GAAUUAACCAAGGAAAAUAACAAGGACAGGGACCAGG (SEQ ID NO:2)). Each oligo was reconstituted in RNAse/DNAse-free water to achieve a 100 uM solution. The two oligo solutions were mixed in 1:1 ratio and and annealed by heating at 70 C. for 5 minutes and cooling gradually to room temperature on the benchtop.

[0488] Chemicals and Assay ComponentsAurintricarboxylic Acid and dimethylsulfoxide were purchased from Sigma-Aldrich (St. Louis, MO). White 384-well assay plates (Catalog #781075) were obtained from Greiner Bio-One (Frickenhausen, Germany). The ADP-Glo kinase assay kit from Promega Corporation is composed of ADP-Glo reagent, kinase detection reagent (made by mixing kinase detection buffer with a lyophilized kinase detection substrate), Ultra Pure ATP and ADP.

ATPase Assay

[0489] DHX9 ATPase assay was performed in small-volume, nonbinding, 384-well white plates at a final volume of 10 L/well. Test compounds (10 mM solution in DMSO; 100 nL/well) were serially diluted on Bravo (Agilent, Santa Clara, CA) and dispensed into wells of columns 3-22 of the plates using an Echo 555 acoustic dispenser (Labcyte, Sunnyvale, CA). 100 nL of Aurintricarboxylic acid was dispensed into low control wells and 100 nL of DMSO was dispensed into high control wells. Then, a Multidrop Combi Reagent Dispenser (Thermo Fisher Scientific, Waltham, MA) was used to add a solution of DHX9 (1.25 nM, 5 L/well) in assay buffer (40 mM HEPES [pH 7.5], 0.01% Tween 20, 0.01% BSA, 1 mM DTT, 5 mM MgCl.sub.2, 0.004 U/ml RNAseOUT). The reaction was initiated by the addition of 5 L of substrate solution (30 nM double-stranded RNA substrate, 10 M Ultra Pure ATP in assay buffer) into the wells. The plates were incubated at room temperature for 1 h. After the indicated incubation times, 10 L ADP-Glo reagent was added to the reactions and the plate was incubated at room temperature for 40 min. Then, 20 L of kinase detection reagent was added and after an incubation time of 40 min, luminescence was recorded on Envision plate reader (Perkin-Elmer, Billerica, MA).

Data Processing and Analysis

[0490] All data was analyzed by Accent Therapeutics internal data analysis software developed by Scigilian (Montreal, Canada). The percentage inhibition was calculated based on the high control (DMSO) as 0% inhibition, and low control (10 M Aurintricarboxylic acid) control as 100% inhibition and used for the calculation of IC.sub.50 and IP (inflection point) values by fitting the dose-response curves to a four-parameter logistic model. Assay results reported IP values instead of IC.sub.50 values since several compounds did not reach 100% inhibition at higher compound concentrations.

2. DHX9 Cellular Proliferation Assay

[0491] The CellTiter-Glo Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.

[0492] The following cell lines were obtained from ATCC: HCT116 (CCL-247) and Colo205 (CCL-222). HCT116 cells were grown and assayed in McCoy's 5a growth media supplemented with 10% FBS, and Colo205 cells were grown in RPMI 1640 media supplemented with 10% FBS.

[0493] The cells are plated at pre-determined cell densities in 384-well solid white cell culture plates and incubated overnight in 37 C. at 5% CO.sub.2. In a separate plate, reference and test compounds were prepared in DMSO stock solution and serially diluted 3-fold for 10 points. Compound (0.1% final DMSO concentration) was transferred to the cell plate in designated wells, and incubated 37 C. at 5% CO.sub.2 for 120 hours. CellTiter-Glo reagent was prepared fresh according to manufacturer's (Promega) directions and added to each well. The plate is then shaken at 300 rpm for 10 minutes at RT, and then read on an Envision plate reader using a Luminescence protocol.

[0494] Data analysis was performed by normalizing the raw data (raw luminescence units or R.sub.Sample) to an average of the positive control values for wells containing culture media only (100% cell death or R.sub.LC) and the negative control values for 0.1% DMSO (0% cell death or R.sub.HC). An IC.sub.50 was calculated using a 4-parameter logistic nonlinear regression model in Scigilian Analyzer or GraphPad Prism, constraining the top parameter to 100 and the bottom parameter to 0.

[00001] $% Inhibition = 100 % (1 - \frac{R_{Sample} - R_{L C}}{R_{HC} - R_{L C}})$
IC.sub.50 Fit formula=(A+((BA)/(1+((x/C){circumflex over ()}D)))) [0495] whereas A: Bottom; B: Top; C: IC.sub.50; D: Slope
3. DHX9 circBRIP1 Cellular Target Engagement SYBR Green Assay

[0496] Evaluation of the circular and linear format of BRIP1 mRNA in HCT116 cells by Quantitative Polymerase Chain Reaction (qPCR). Upon DHX9 inhibition circBRIP1 levels are increased and linear BRIP1 mildly decreases or remains unchanged.

[0497] HCT116 cells were obtained from ATCC (CCL-247) and were grown and assayed in McCoy's 5a growth media supplemented with 10% FBS.

[0498] The cells are plated at pre-determined cell densities in 384-well cell culture plates and incubated overnight in 37 C. at 5% CO.sub.2. In a separate plate, reference and test compounds were prepared in DMSO stock solution and serially diluted 3-fold for 10 points. Compound (0.1% final DMSO concentration) was transferred to the cell plate in designated wells, and incubated 37 C. at 5% CO.sub.2 for 72 hours.

[0499] RNA is extracted from the cells using the SYBR Green Fast Advanced Cell-to-CT kit according to manufacturer's (Invitrogen) protocol, and cDNA is reverse transcribed using the High Capacity RNA-to-cDNA Kit according to the manufacturer's (Invitrogen) protocol. Using SYBR Green Master Mix and thermal cycler conditions for the QuantStudio Thermocycler, qPCR is carried out using the below custom primer sequences:

TABLE-US-00012 BRIP1-Circular-Forward (TCTGTGTGCCAGACTGTGAG(SEQIDNO:3)) BRIP1-Circular-Reverse (ACACCAAGTTCTGACGAAAAGG(SEQIDNO:4)) BRIP1-Linear-Forward (GTCCATCCTGAGGTAGTCGG(SEQIDNO:5)) BRIP1-Linear-Reverse (TTCCCCAGGCTGACAAGTTC(SEQIDNO:6) GAPDH-Forward (GTCTCCTCTGACTTCAACAGCG(SEQIDNO:7)) GAPDH-Reverse (ACCACCCTGTTGCTGTAGCCAA(SEQIDNO:8))

[0500] Note: Forward and Reverse primers are combined per gene, and each sample has to be run on a separate plate for each gene.

[0501] Data analysis was performed by using the QuantStudio Thermocycler software to determine threshold Ct values. Ct for circBRIP1 or linBRIP1 is calculated by normalizing the target gene Ct to the GAPDH housekeeping gene Ct for each sample. The inhibition activity is calculated by the following formula, whereas: [0502] Cts: Mean of Ct(target gene)Mean of Ct(GAPDH) for each sample [0503] Ctc: Mean of Ct(target gene)Mean of Ct(GAPDH) for DMSO control.

[00002] $% Inhibition = 100 % \frac{2^{Cts}}{2^{Ctc}}$

[0504] An EC.sub.50 was then calculated using a 4-parameter logistic nonlinear regression model in Scigilian Analyzer or GraphPad Prism, floating both the top and bottom parameters.

EC.sub.50 Fit formula=(A+((BA)/(1+((x/C){circumflex over ()}D)))) [0505] whereas A: Bottom; B: Top; C: IC.sub.50; D: Slope
4. DHX9 circBRIP1 Cellular Target Engagement TaqMan Multiplex Assay:

[0506] Evaluation of the circular and linear format of BRIP1 mRNA in HCT116 cells by Quantitative Polymerase Chain Reaction (qPCR). Upon DHX9 inhibition circBRIP1 levels are increased and linear BRIP1 mildly decreases or remains unchanged.

[0507] HCT116 cells were obtained from ATCC (CCL-247) and were grown and assayed in McCoy's 5a growth media supplemented with 10% FBS.

[0508] The cells are plated at pre-determined cell densities in 384-well cell culture plates and incubated overnight in 37 C. at 5% CO.sub.2. In a separate plate, reference and test compounds were prepared in DMSO stock solution and serially diluted 3-fold for 10 points. Compound (0.1% final DMSO concentration) was transferred to the cell plate in designated wells, and incubated 37 C. at 5% CO.sub.2 for 72 hours.

[0509] RNA is extracted from the cells using the TaqMan Gene Expression Cells-to-CT kit according to manufacturer's (Invitrogen) protocol, and cDNA is reverse transcribed using the High Capacity RNA-to-cDNA Kit according to the manufacturer's (Invitrogen) protocol. Using TaqMan Multiplex Mastermix and thermal cycler conditions for the QuantStudio Thermocycler, qPCR is carried out using TaqMan Gene Expression Assay with VIC Dye for Linear BRIP1 (Assay ID: Hs00908156_m1), TaqMan GAPDH primer limited assay with JUN dye/QSY probe, and the below custom TaqMan Gene Expression Assay with FAM Dye for circBRIP1:

TABLE-US-00013 ForwardPrimer: (SEQIDNO:9) GTGAGCCAAGGAATTTTGTGTTT ReversePrimer: (SEQIDNO:10) GGTCTGAACTTTGCCATTAATATCTG Probe: (SEQIDNO:11) CCATCTTACAAGGCCTTT
Note: All target genes can be combined in one well per sample.

[0510] Data analysis was performed by using the QuantStudio Thermocycler software to determine threshold Ct values. Ct for circBRIP1 or linBRIP1 is calculated by normalizing the target gene Ct to the GAPDH housekeeping gene Ct for each sample. The inhibition activity is calculated by the following formula, whereas: [0511] Cts: Mean of Ct(target gene)Mean of Ct(GAPDH) for each sample [0512] Ctc: Mean of Ct(target gene)Mean of Ct(GAPDH) for DMSO control.

[00003] $% Inhibition = 100 % \frac{2^{Cts}}{2^{Ctc}}$

[0513] An EC.sub.50 was then calculated using a 4-parameter logistic nonlinear regression model in Scigilian Analyzer or GraphPad Prism, floating both the top and bottom parameters.

IC50 Fit formula=(A+((BA)/(1+((x/C){circumflex over ()}D)))) [0514] whereas A: Bottom; B: Top; C: IC50; D: Slope

5. DHX9 Cellular Proliferation Assay

[0515] The CellTiter-Glo Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.

[0516] The following cell lines were obtained from ATCC: LS411N (CRL-2159) and NCI-H747 (CCL-252). LS411N and NCI-H747 cells were grown in RPMI-1640 media supplemented with 10% FBS. The cells are plated at pre-determined cell densities in 384-well solid white cell culture plates and incubated overnight in 37 C. at 5% CO.sub.2. In a separate plate, reference and test compounds were prepared in DMSO stock solution and serially diluted 3-fold for 10 points. Compound (0.1% final DMSO concentration) was transferred to the cell plate in designated wells, and incubated 37 C. at 5% CO.sub.2 for 120 hours. CellTiter-Glo reagent was prepared fresh according to manufacturer's (Promega) directions and added to each well. The plate is then shaken at 300 rpm for 10 minutes at RT, and then read on an Envision plate reader using a Luminescence protocol. Data analysis was performed by normalizing the raw data (raw luminescence units or RSample) to an average of the positive control values for wells containing culture media only (100% cell death or RLC) and the negative control values for 0.1% DMSO (0% cell death or RHC). An IC.sub.50 was calculated using a 4-parameter logistic nonlinear regression model in Scigilian Analyzer or GraphPad Prism, constraining the top parameter to 100 and the bottom parameter to 0.

[00004] $% Inhibition = 100 % (1 - \frac{R_{Sample} - R_{L C}}{R_{HC} - R_{L C}})$
IC50 Fit formula=(A+((BA)/(1+((x/C){circumflex over ()}D)))) [0517] whereas A: Bottom; B: Top; C: IC.sub.50; D: Slope

Data for Examples

TABLE-US-00014 DHX9 DHX9 DHX9 LS411N H747 Bio- Bio- Cellular (CRC- (CRC- chemical chemical Target MSI-H) MSS) Inflection Max Engagement Antiprolif- Antiprolif- Example Point Inhibition EC.sub.50 erative erative Number (M) (%) (M) IC.sub.50 IC.sub.50 1 0.339 71.6 >30 2 7.27 50.4 3 1.23 44.3 4 3.05 55.1 5 2.97 37.7 6 0.0824 79.7 16.1 7 0.804 73.3 8 1.76 47.7 9 3.94 48.3 10 1.54 79.8 11 5.65 47.5 12 0.355 83.3 >30 13 2.39 52.5 14 5.09 70.4 15 0.579 70.4 >30 16 3.62 65.3 17 2.54 50.7 18 92.4 58.6 19 6.33 49.6 20 0.664 72 >30 21 3.85 72.4 22 1.22 71.7 23 0.943 51.4 24 1.04 62.5 25 2.32 67.1 26 56.9 60.6 27 1.61 63.8 28 4.08 76.4 29 1.43 81.3 30 34.1 69.1 31 0.864 80.3 >30 32 5.77 67.9 33 1.02 65.4 >30 34 4.85 70.4 35 1.49 69.3 36 1.86 56.3 37 1.72 67 38 0.345 38.6 39 0.994 55.3 40 0.371 72.8 >30 41 0.285 61.2 27.4 42 0.544 71.4 43 0.373 68.7 44 6.51 47.2 >30 45 0.0989 68.7 12.8 46 0.123 73.9 47 0.264 67.7 48 0.105 67.5 49 0.0406 78.4 9.04 50 0.0458 66.5 >30 51 0.335 77.3 13.4 52 0.111 68.5 20.7 53 0.188 70.4 22.7 54 0.0907 72.8 6.32 55 0.0461 69.4 6.32 56 0.148 68.2 21.4 57 0.0419 70.7 25.3 58 0.0558 69.2 3.12 59 0.0543 70.8 8.13 60 0.0766 69.2 10.9 61 0.0746 68.7 15.1 62 0.271 60.8 >30 63 0.121 66.9 18.8 64 0.589 78.1 65 0.0418 66.9 8.56 66 0.0875 71.3 >30 67 0.98 70.1 68 0.108 70.3 13.2 69 0.0163 75.6 4.79 70 0.0322 71.2 4.37 71 1.86 66.5 72 0.494 64.4 >30 73 0.109 63.7 6.15 74 0.0806 71.4 30 75 0.0821 70.1 8.28 76 0.0424 75.4 6.67 77 0.0894 72.3 2.04 78 0.698 61.5 79 0.467 71.2 >30 80 0.0041 80.5 1.29 81 1.07 68.3 >30 82 0.0203 79 2.11 83 0.0173 73.1 0.917 84 0.0125 71.4 4.84 85 0.0195 70.7 1.39 86 0.0453 71.1 19.5 87 0.0226 77.2 30 88 0.0654 68.2 10.5 89 0.0097 76.4 1.03 90 19 61.2 >30 91 0.0072 74.6 7.63 92 0.0554 75.5 >30 93 0.0399 74 11.5 94 0.125 71.2 >30 95 0.0076 73.1 >30 96 0.0899 59.6 22.2 97 0.0247 70 4.32 98 0.543 77.7 99 0.716 35.8 >30 100 0.333 65.8 28.5 101 0.054 79.1 102 0.159 72.5 18.9 103 0.126 71.7 104 0.504 67.3 105 0.21 70.3 106 0.0679 72.3 107 0.168 74.6 108 0.708 64.4 109 0.221 59 110 0.0819 68.9 111 0.0696 68.5 112 0.101 68.9 113 0.515 59.7 114 0.0714 73.5 115 0.436 75 116 0.0708 74.5 117 0.686 52.7 118 0.0994 66.2 119 0.131 67.4 120 0.0505 70.4 121 1.07 68.9 122 0.196 69.7 123 0.0592 68.3 124 0.182 66.5 125 0.0649 71.7 126 0.502 67 127 0.115 68.3 128 0.146 64.6 129 0.0889 67.2 130 0.324 69.2 131 0.0522 65.8 132 0.0738 70 133 0.171 70.3 134 0.058 66.9 135 0.211 65.6 136 0.127 72.9 137 0.547 67.5 138 0.116 76.6 139 0.0405 68.9 140 0.189 70.1 141 0.0926 66.3 142 0.167 72.6 143 0.0915 73.3 144 0.146 65.9 145 0.105 67.7 146 0.0387 71.2 147 0.229 64.7 148 5.36 58.2 149 0.0507 69.8 150 0.102 68.6 151 0.0459 70.1 152 0.123 69.7 16.6 153 0.0432 77.9 5.91 154 3.89 68.4 155 1.01 72.3 156 1.92 63.7 157 0.205 68.6 >30 158 0.223 56.3 10.9 159 0.69 50.7 >10 160 0.0284 89.6 1.41* 9.4500 >10 161 0.108 68.8 3.4* 162 0.0811 68.5 *Compounds of examples 160 and 161 were tested using TagMan Multiplex Assay; the rest of the compounds were tested using SYBR Green Assay.

INHIBITORS OF RNA HELICASE DHX9 AND USES THEREOF

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