BOILY MARC-OLIVIER (CA)
DING JINYUE (CA)
GOMEZ ROBERT (CA)
SHENG TAO (CA)
WO2016109559A2 | 2016-07-07 |
WHAT IS CLAIMED IS: 1. A compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: Y is O or S; X1 is hydrogen, fluoro or chloro; X2 is hydrogen, fluoro or chloro; R3a is hydrogen, fluoro, chloro, cyano, C1-3haloalkyl, C1-3alkoxy or C1-3haloalkoxy; R3b is hydrogen, fluoro, chloro, cyano or C1-3haloalkyl; R3c is hydrogen, fluoro or chloro; R3d is hydrogen, fluoro or chloro; R10 is C1-3alkyl, C3-4cycloalkyl or C3-4cycloalkylC1-3alkyl; provided (i) when R3b is fluoro, R3a is methoxy and R3c and R3d are each hydrogen, or (ii) when R3b is hydrogen, R3a is isopropyloxy and R3c and R3d are each hydrogen, or (iii) when R3a, R3b, R3c and R3d are all hydrogen, then at least one of X1 and X2 is fluoro or chloro; and provided, when R3a is CF3, R3b is fluoro, and R3c and R3d are each hydrogen, then R10 is not cyclopropylmethyl. 2. The compound of claim 1, wherein R3a is hydrogen, fluoro, chloro, cyano, C1- 3haloalkyl, C1-3alkoxy or C1-3haloalkoxy; R3b is fluoro or chloro, R3c is hydrogen, fluoro or chloro and R3d is hydrogen. 3. The compound of claim 1 or 2, wherein R3a is hydrogen, fluoro, chloro, cyano, C1- 3haloalkyl, C1-3alkoxy or C1-3haloalkoxy; R3b is fluoro or chloro; R3c and R3d are each hydrogen. 4. The compound of any one of claims 1 to 3, wherein R3b is fluoro or chloro and R3a, R3c and R3d are each hydrogen. 5. The compound of claim 1, wherein one of R3a, R3b, R3c and R3d is fluoro, chloro or cyano and the remainder of R3a, R3b, R3c and R3d are each hydrogen. 6. The compound of claim 1, wherein one of R3a and R3b is fluoro, chloro, cyano or C1- 3alkoxy; the other of R3a and R3b is fluoro or hydrogen; and R3c and R3d are each hydrogen. 7. The compound of claim 1, wherein (i) R3a is fluoro or cyano; and R3b, R3c and R3d are each hydrogen or (ii) R3a is hydrogen, chloro or C1-3alkoxy; R3b is fluoro or cyano; and R3c and R3d are each hydrogen. 8. The compound of claim 1 or 2, having the Formula (Ia): or a pharmaceutically acceptable salt or solvate thereof wherein: Y is O or S; X1 is hydrogen, fluoro or chloro; X2 is hydrogen, fluoro or chloro; R3a is hydrogen, fluoro, chloro, cyano, C1-3haloalkyl, C1-3alkoxy or C1-3haloalkoxy; R3c is hydrogen or fluoro; and R10 is C1-3alkyl, C3-4cycloalkyl or C3-4cycloalkylC1-3alkyl; provided when R3a is methoxy and R3c is hydrogen, then at least one of X1 and X2 is fluoro or chloro; and provided, when R3a is CF3, and R3c is hydrogen, then R10 is not cyclopropylmethyl. 9. The compound of any one of claims 1 to 3, having the Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof, wherein Y, R3a, R10, X1 and X2 are as described above. 10. The compound of any one of claims 1 to 5, having the Formula (Ic): or a pharmaceutically acceptable salt or solvate thereof, wherein Y, R10, X1 and X2 are as described above. 11. The compound of any one of claims 1 to 9, wherein R3a is hydrogen, fluoro, chloro, cyano, C1-3alkoxy or C1-3haloalkoxy. 12. The compound of any one of claims 1 to 11, wherein Y is S. 13. The compound of any one of claims 1 to 12, wherein R10 is C3-4cycloalkylC1- 3alkyl. 14. The compound of any one of claims 1 to 13, wherein R10 is cyclopropylmethyl. 15. The compound of any one of claims 1 to 14, wherein X1 is fluoro or chloro. 16. The compound of claim 1, selected from: or a pharmaceutically acceptable salt or solvate thereof. 17. A compound of Formula (II): or a pharmaceutically acceptable salt or solvate thereof, wherein: X1 is hydrogen, fluoro or chloro; X2 is hydrogen, fluoro or chloro; R3a is fluoro, chloro, cyano, C1-3haloalkyl, C1-3alkoxy or C1-3haloalkoxy; R3c is hydrogen, fluoro or chloro; and R10 is C1-3alkyl, C3-4cycloalkyl or C3-4cycloalkylC1-3alkyl. 18. The compound of claim 17, wherein R3a is fluoro or chloro and R3c is fluoro or chloro. 19. The compound of claim 17 or 18, having the Formula (IIa): or a pharmaceutically acceptable salt or solvate thereof; wherein R3a, R10, X1 and X2 are as described above. 20. The compound of any one of claims 17 to 19, wherein R3a is fluoro or chloro. 21. The compound of any one of claims 17 to 20, wherein X1 is fluoro or chloro. 22. The compound of any one of claims 17 to 21, wherein X1 is fluoro or chloro and X2 is hydrogen. 23. The compound of any one of claims 1 to 22, wherein the compound is present in the form of a pharmaceutically acceptable salt. 24. The compound of any one of claims 1 to 22, wherein the compound is present in the form of a solvate. 25. The compound of claim 24, wherein the solvate is a hydrate. 26. A pharmaceutical composition comprising a compound of any one of claims 1 to 25 and a pharmaceutically acceptable carrier. 27. A method of treating a disease or disorder associated with elevated oxalate levels, comprising administering to a subject having such disease or disorder, a therapeutically effective amount of a compound of any one of claims 1 to 25, or a pharmaceutical composition of claim 26. 28. The method of claim 27, wherein the elevated oxalate levels is elevated urinary oxalate levels. 29. The method of claim 27, wherein the elevated oxalate levels is elevated plasma oxalate levels. 30. The method of any one of claims 27 to 29, wherein the disease or disorder is hyperoxaluria, chronic kidney disease (CKD), end stage renal disease (ESRD) or kidney stone disease. 31. The method of claim 30, wherein the hyperoxaluria is primary hyperoxaluria or secondary hyperoxaluria. 32. The method of claim 31, wherein the primary hyperoxaluria is primary hyperoxaluria type 1 (PH-1), primary hyperoxaluria type 2 (PH-2) or primary hyperoxaluria type 3 (PH-3). 33. The method of any one or claims 27 to 32, wherein the subject with the disease or disorder has an AGXT, GRHPR or HOGA1 mutation, or a combination of mutations thereof. 34. A method of lowering oxalate levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 25, or a pharmaceutical composition of claim 26. 35. A method of treating kidney stone formation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound any one of claims 1 to 25, or a pharmaceutical composition of claim 26. 36. The method of any one of claims 27 to 35, further comprising administering to the subject a therapeutically effective amount of a second therapeutic agent. 37. The method of claim 36, wherein the second therapeutic agent is a glyoxylate or oxalate lowering therapeutic. 38. The method of claim 37, wherein the glyoxylate or oxalate lowering therapeutic is an RNAi therapeutic. 39. The method of claim 37, wherein the glyoxylate or oxalate lowering therapeutic is lumasiran, nedosiran, reloxaliase, stiripentol, oxalobacter formigenes or vitamin B6. 40. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 26, for use in treating a disease or disorder associated with elevated oxalate levels. 41. The compound of any one claims 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, for use in claim 40, wherein the disease or disorder is hyperoxaluria, chronic kidney disease (CKD), end stage renal disease (ESRD) or kidney stone disease. 42. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, for use in claim 41, wherein the hyperoxaluria is primary hyperoxaluria or secondary hyperoxaluria. 43. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, for use in claim 40, wherein the disease or disorder is associated with an AGXT, GRHPR or HOGA1 mutation, or a combination of mutations thereof. |
or a pharmaceutically acceptable salt or solvate thereof, wherein: Y is O or S; X 1 is hydrogen, fluoro or chloro; X 2 is hydrogen, fluoro or chloro; R 3a is hydrogen, fluoro, chloro, cyano, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; R 3b is hydrogen, fluoro, chloro, cyano or C 1-3 haloalkyl; R 3c is hydrogen, fluoro or chloro; R 3d is hydrogen, fluoro or chloro; R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl; provided (i) when R 3b is fluoro, R 3a is methoxy and R 3c and R 3d are each hydrogen, or (ii) when R 3b is hydrogen, R 3a is isopropyloxy and R 3c and R 3d are each hydrogen, or (iii) when R 3a , R 3b , R 3c and R 3d are all hydrogen, then at least one of X 1 and X 2 is fluoro or chloro; and provided, when R 3a is CF3, R 3b is fluoro, and R 3c and R 3d are each hydrogen, then R 10 is not cyclopropylmethyl. [00043] In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the substituents R 3a , R 3b , R 3c , R 3d , R 10 , X 1 and X 2 are selected such that (i) when R 3b is fluoro, R 3a is methoxy and R 3c and R 3d are each hydrogen, or (ii) when R 3b is hydrogen, R 3a is isopropyloxy and R 3c and R 3d are each hydrogen, or (iii) when R 3a , R 3b , R 3c and R 3d are all hydrogen, then at least one of X 1 and X 2 is fluoro or chloro; and provided, when R 3a is CF3, R 3b is fluoro, and R 3c and R 3d are each hydrogen, then R 10 is C 1-3 alkyl or C 3-4 cycloalkyl. [00044] In certain embodiments, provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: Y is O or S; X 1 is fluoro or chloro; X 2 is hydrogen, fluoro or chloro; R 3a is hydrogen, fluoro, chloro, cyano, C 1-3 alkoxy or C 1-3 haloalkoxy; R 3b is hydrogen, fluoro, chloro, cyano or C 1-3 haloalkyl; R 3c is hydrogen, fluoro or chloro; R 3d is hydrogen, fluoro or chloro; and R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl. [00045] In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is hydrogen, fluoro, chloro, cyano, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; R 3b is fluoro or chloro; R 3c is hydrogen, fluoro or chloro; R 3d is hydrogen; and the other variables are as described for Formula (I) elsewhere herein. [00046] In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is hydrogen, fluoro, chloro, cyano, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; R 3b is fluoro or chloro; R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. [00047] In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b is fluoro or chloro; R 3a , R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. [00048] In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein one of R 3a , R 3b , R 3c and R 3d is fluoro, chloro or cyano and the remainder of R 3a , R 3b , R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein one of R 3a , R 3b , R 3c and R 3d is fluoro or chloro and the remainder of R 3a , R 3b , R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein one of R 3a and R 3b is fluoro, chloro, cyano or C1- 3alkoxy; the other of R 3a and R 3b is fluoro or hydrogen; R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein one of R 3a and R 3b is fluoro, chloro, cyano or isopropyloxy; the other of R 3a and R 3b is fluoro or hydrogen; R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein one of R 3a and R 3b is fluoro, chloro or cyano; the other of R 3a and R 3b is fluoro or hydrogen; R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein (i) R 3a is fluoro or cyano; and R 3b , R 3c and R 3d are each hydrogen or (ii) R 3a is hydrogen, chloro or C 1-3 alkoxy; R 3b is fluoro or cyano; and R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein (i) R 3a is fluoro or cyano; and R 3b , R 3c and R 3d are each hydrogen or (ii) R 3a is hydrogen, chloro, methoxy or isopropyloxy; R 3b is fluoro or cyano; and R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein (i) R 3a is fluoro or cyano; and R 3b , R 3c and R 3d are each hydrogen or (ii) R 3a is hydrogen, chloro, methoxy or isopropyloxy; R 3b is fluoro or cyano; and R 3c and R 3d are each hydrogen; X 1 is fluoro or chloro; and the other variables are as described for Formula (I) elsewhere herein. In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein (i) R 3a is fluoro or cyano; and R 3b , R 3c and R 3d are each hydrogen or (ii) R 3a is hydrogen or chloro; R 3b is fluoro or cyano; and R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein one of R 3a and R 3b is fluoro or cyano and the other of R 3a and R 3b is hydrogen, methoxy or isopropyloxy; R 3c and R 3d are each hydrogen; X 1 is fluoro or chloro; and the other variables are as described for Formula (I) elsewhere herein. [00049] In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro, chloro, cyano, C 1- 3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; R 3b , R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. [00050] In certain embodiments, provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b is fluoro, chloro, cyano or C 1- 3 haloalkyl; R 3a , R 3c and R 3d are each hydrogen; and the other variables are as described for Formula (I) elsewhere herein. [00051] In certain embodiments, provided herein are compounds of Formula (I) having the Formula (Ia): or a pharmaceutically acceptable salt or solvate thereof. [00052] In certain embodiments, provided herein are compounds of Formula (I) having the Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein: Y is O or S; X 1 is hydrogen, fluoro or chloro; X 2 is hydrogen, fluoro or chloro; R 3a is hydrogen, fluoro, chloro, cyano, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; R 3c is hydrogen or fluoro; and R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl; provided when R 3a is methoxy and R 3c is hydrogen, then at least one of X 1 and X 2 is fluoro or chloro; and provided, when R 3a is CF 3 , and R 3c is hydrogen, then R 10 is not cyclopropylmethyl. [00053] In certain embodiments, provided herein are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the substituents R 3a , R 3c , R 10 , X 1 and X 2 are selected such that when R 3a is methoxy and R 3c is hydrogen, then at least one of X 1 and X 2 is fluoro or chloro; and provided, when R 3a is CF3, and R 3c is hydrogen, then R 10 is C 1-3 alkyl or C 3- 4 cycloalkyl. [00054] In certain embodiments, provided herein are compounds having the Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is hydrogen, fluoro, chloro, cyano or C 1-3 alkoxy; X 1 is fluoro or chloro; and the other variables are as described for Formula (I) elsewhere herein. In certain embodiments, provided herein are compounds having the Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is hydrogen, fluoro, chloro, cyano or isopropyloxy; X 1 is fluoro or chloro; and the other variables are as described for Formula (I) elsewhere herein. [00055] In certain embodiments, provided herein are compounds of Formula (I) or (Ia) having the Formula (Ib): or a pharmaceutically acceptable salt or solvate thereof. [00056] In certain embodiments, provided herein are compounds of Formula (Ib) wherein R 3a is hydrogen, fluoro or chloro; R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3- 4cycloalkylC 1- 3 alkyl; X 1 is fluoro or chloro; and X 2 is hydrogen. In yet certain embodiments, provided herein are compounds of Formula (Ib) wherein R 3a is hydrogen or fluoro; R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl; X 1 is fluoro or chloro; and X 2 is hydrogen. In yet certain embodiments, provided herein are compounds of Formula (Ib) wherein R 3a is hydrogen or fluoro; R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl; X 1 is fluoro; and X 2 is hydrogen. In certain embodiments, provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is hydrogen, fluoro, chloro, cyano or difluoromethoxy, and the remaining variables are as described for Formula (I) or (Ia) elsewhere herein. In certain embodiments, provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is hydrogen, fluoro, chloro, cyano or difluoromethoxy, R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl; X 1 is fluoro or chloro; and X 2 is hydrogen. In certain embodiments, provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is hydrogen, fluoro, chloro, cyano or isopropyloxy, and the remaining variables are as described for Formula (I) or (Ia) elsewhere herein. [00057] In yet certain embodiments, provided herein are compounds of Formula (I), (Ia) or (Ib) wherein R 3a is hydrogen, fluoro, chloro, cyano, C 1-3 alkoxy or C 1-3 haloalkoxy, and the other variables are as described for Formula (I), (Ia) or (Ib) elsewhere herein. In yet certain embodiments, provided herein are compounds of Formula (I), (Ia) or (Ib) wherein R 3a is hydrogen, fluoro, chloro, cyano or C 1-3 haloalkoxy, and the other variables are as described for Formula (I), (Ia) or (Ib) elsewhere herein. [00058] In certain embodiments, provided herein are compounds of Formula (I), (Ia) or (Ib) having the Formula having the Formula (Ic): or a pharmaceutically acceptable salt or solvate thereof. [00059] In certain embodiments, provided herein are compounds of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl; X 1 is fluoro or chloro; and X 2 is hydrogen. In certain embodiments, provided herein are compounds of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is S; R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl; X 1 is fluoro or chloro; and X 2 is hydrogen. In yet certain embodiments, provided herein are compounds of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is O or S; R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl; X 1 is fluoro; and X 2 is hydrogen. In yet certain embodiments, provided herein are compounds of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is S; R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl; X 1 is fluoro; and X 2 is hydrogen. [00060] In certain embodiments, provided herein are compounds of Formula (II): or a pharmaceutically acceptable salt or solvate thereof, wherein: X 1 is hydrogen, fluoro or chloro; X 2 is hydrogen,fluoro or chloro; R 3a is fluoro, chloro, cyano, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 haloalkoxy; R 3c is hydrogen, fluoro or chloro; and R 10 is C 1-3 alkyl, C 3-4 cycloalkyl or C 3-4 cycloalkylC 1-3 alkyl. [00061] In certain embodiments, provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro or chloro and R 3c is fluoro or chloro. In certain embodiments, provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro or chloro; R 3c is fluoro or chloro; X 1 is fluoro or chloro; and X 2 is hydrogen. In certain embodiments, provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a and R 3c are both fluoro. In certain embodiments, provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a and R 3c are both fluoro; X 1 is fluoro or chloro; and X 2 is hydrogen. In certain embodiments, provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a , R 3c and X 1 are fluoro; and X 2 is hydrogen. In certain embodiments, provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3c is hydrogen. In certain embodiments, provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro, chloro, cyano, CF3, methoxy, ethoxy or trifluoromethoxy and R 3c is hydrogen, fluoro or chloro. In certain embodiments, provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro, chloro, cyano, CF3, methoxy, ethoxy or trifluoromethoxy and R 3c is fluoro or chloro. In certain embodiments, provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro, chloro, cyano, CF3, methoxy, ethoxy or trifluoromethoxy; R 3c is fluoro or chloro; X 1 is fluoro or chloro; and X 2 is hydrogen. [00062] In certain embodiments, provided herein are compounds of Formula (II) having the Formula (IIa) or a pharmaceutically acceptable salt or solvate thereof. [00063] In certain embodiments, provided herein are compounds of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro, chloro, cyano, C 1-3 haloalkyl or C 1-3 haloalkoxy. In certain embodiments, provided herein are compounds of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro, chloro, cyano, CF3, or trifluoromethoxy. In certain embodiments, provided herein are compounds of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro, chloro, cyano, CF3, ethoxy or trifluoromethoxy. [00064] In certain embodiments, provided herein are compounds of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro or chloro. In certain embodiments, provided herein are compounds of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is fluoro or chloro. In certain embodiments, provided herein are compounds of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro or chloro and X 1 is fluoro or chloro. In certain embodiments, provided herein are compounds of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is fluoro or chloro and X 2 is hydrogen. In certain embodiments, provided herein are compounds of Formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluoro or chloro, X 1 is fluoro or chloro and X 2 is hydrogen. [00065] In yet certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib) or (Ic) wherein Y is S and the other variables are as described elsewhere herein for Formula (I), (Ia), (Ib) or (Ic) elsewhere herein. [00066] In yet certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa) wherein R 10 is C 3-4 cycloalkylC 1-3 alkyl and the other variables are as described for Formula (I), (Ia), (Ib), (Ic), (II) or (IIa) elsewhere herein. [00067] In yet certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa) wherein R 10 is cyclopropylmethyl and the other variables are as described for Formula (I), (Ia), (Ib), (Ic), (II) or (IIa) elsewhere herein. [00068] In yet certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa) wherein X 1 is fluoro or chloro and the other variables are as described for Formula (I), (Ia), (Ib), (Ic), (II) or (IIa) elsewhere herein. [00069] In certain embodiments, provided herein is a compound of Formula (I) wherein the compound is selected from: 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4 -fluorophenyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(3-(3-cyano-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-flu oro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-5-methy l-1H-pyrazol-1- yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4 -fluorophenyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-3-(4-fluorophenyl)-4-(4-sulfamoylbe nzyl)-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid; 2-(5-(2-cyclopropylethyl)-3-(4-fluorophenyl)-4-(4-sulfamoylb enzyl)-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-isopropoxyphenyl)-4-( 3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(3-(3-chloro-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fl uoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4 -fluorophenyl)-1H- pyrazol-1-yl)oxazole-4-carboxylic acid; 2-(4-(3-chloro-4-sulfamoylbenzyl)-5-(cyclopropylmethyl)-3-(4 -fluorophenyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(3-(3-cyanophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sul famoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-3-(3,4-difluorophenyl)-4-(3-fluoro- 4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-3-(3-(difluoromethoxy)-4-fluorophen yl)-4-(3-fluoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3 -fluorophenyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-3-(3,5-difluorophenyl)-4-(3-fluoro- 4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(3-(4-chlorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-su lfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(3-(3-chlorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-su lfamoylbenzyl)-1H- pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3 - (trifluoromethyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxyl ic acid; 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3 - (trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxy lic acid; 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-ph enyl-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-3-(4-(difluoromethyl)phenyl)-4-(3-f luoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3 -(2,2,2- trifluoroethoxy)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxyli c acid; 2-(3-(4-cyano-3-methoxyphenyl)-5-(cyclopropylmethyl)-4-(3-fl uoro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3 -fluoro-5- methoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3 -fluoro-5- methoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-3-(3,5-dichlorophenyl)-4-(3-fluoro- 4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylic acid; 2-(5-(cyclopropylmethyl)-4-(3,5-difluoro-4-sulfamoylbenzyl)- 3-(4-fluorophenyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylic acid; and 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3 ,4,5- trifluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid, or a pharmaceutically acceptable salt or solvate thereof. [00070] In certain embodiments, provided herein are isotopically enriched analogs of the compounds disclosed herein, for example, deuterated analogs, to improve pharmacokinetics (PK), pharmacodynamics (PD) and toxicity profiles of the compounds. [00071] In certain embodiments, provided herein are pharmaceutical compositions comprising a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. [00072] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [00073] The compounds of the present disclosure include the compounds themselves, as well as their salts, solvate and solvate of the salt, if applicable. Salts for the purposes of the present disclosure are preferably pharmaceutically acceptable salts of the compounds according to the present disclosure. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the disclosure are also included. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. [00074] As used herein, “pharmaceutically acceptable salts” refer to acid or base addition salts, including but not limited to, base addition salts formed by the compound of Formula (I) having an acidic moiety with pharmaceutically acceptable cations, for example, sodium, potassium, magnesium, calcium, aluminum, lithium, and ammonium. [00075] Lists of suitable salts may be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; S. M. Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 1977, 66, 1-19; and “Pharmaceutical Salts: Properties, Selection, and Use. A Handbook”; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8]; each of which is incorporated herein by reference in its entirety. [00076] Solvates in the context of the present disclosure are designated as those forms of the compounds according to the present disclosure which form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. The formation of solvates is described in greater detail in “Solvents and Solvent Effects in Organic Chemistry”; Reichardt, C. and Welton T.; John Wiley & Sons, 2011 [ISBN: 978-3-527-32473-6], the contents of which is incorporated herein by reference in its entirety. [00077] In some embodiments, the compound of Formula (I) is present in pharmaceutically acceptable salt form. In some embodiments, the compound of Formula (I) is present in free acid form. In some embodiments, the compound of Formula (I) is present in free acid form. In some embodiments, the compound of Formula (I) is present in the form of a solvate. In some embodiments, the solvate is a hydrate. In some embodiments, the compound of Formula (I) is present as a solvate of a pharmaceutically acceptable salt form. [00078] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not. An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I. Particular isotopic variants of a compound according to the present disclosure, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Compounds labelled with 3 H, 14 C and/or 18 F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. In certain embodiments, “deuterated” as applied to a chemical group and unless otherwise indicated, refers to a chemical group that is isotopically enriched with deuterium in an amount substantially greater than its natural abundance. Isotopic variants of the compounds according to the present disclosure can be prepared by various, including, for example, the methods described below and in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein. [00079] In certain embodiments, the compounds provided herein have physicochemical properties which promote a liver targeted tissue distribution profile, and which maximizes their exposure in the liver while minimizing exposure in other tissues (e.g. plasma, muscle, spleen, testes). In certain embodiments, the compounds provided herein have demonstrated a liver-targeted tissue distribution profile in rodents, as evident by a greater drug exposure in liver versus other tissues (e.g. plasma, muscle), for example, 4 h after PO dosing or 24 h after PO dosing. In certain embodiments, the compounds provided herein have physicochemical properties that promote uptake by OATP subfamily of receptors that are expressed in the liver. The OATP subfamily members OATP1B1, OATP1B3 and OATP2B1 are transporters principally expressed on human hepatocytes, where they mediate the uptake of substrates from blood to liver. Hence, OATP substrates are expected to have higher exposure in the liver compared to systemic and peripheral tissues. In certain embodiments, the compounds provided herein are substrates for OATP. In certain embodiments, the compounds provided herein are substrates for OATP1B1, OATP1B3, OATP2B1 or a combination thereof. In yet certain embodiments, the compounds provided herein have physicochemical properties that minimize passive diffusion of the compounds into off-target tissues lacking membrane transporters, thereby promoting liver selectivity. In certain embodiments, the compounds provided herein have an octanol-water partition coefficients (XlogP) that fall in a range that minimizes their passive diffusion potential, promotes liver targeting and reduces exposure to tissues outside the liver. In certain embodiments, the compounds provided herein have a calculated octanol-water partition coefficient (XlogP) of about 4 to about 6.5. In certain embodiments, the compounds provided herein have an XlogP of about 4 to about 6. In yet certain embodiments, the compounds provided herein have an XlogP of about 4 to about 5.5. In yet certain embodiments, the compounds provided herein have an XlogP of about 4 to about 5. In yet certain embodiments, the compounds provided herein have an XlogP of about 4.5 to about 5. C. FORMULATIONS [00080] The term “pharmaceutical composition” as used herein is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure, or a pharmaceutically acceptable salt, or solvate or solvate of the salt thereof, and a pharmaceutically acceptable carrier. [00081] The term “pharmaceutically acceptable carrier” refers to a carrier or an adjuvant that may be administered to a patient, together with a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, salt of the solvate or prodrug thereof, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. [00082] The amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined, and variations will necessarily occur depending on the target, the host, and the route of administration, etc. Generally, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 milligram (mg) to about 100 mg or from about 1 mg to about 1000 mg, according to the particular application. For convenience, the total daily dosage may be divided and administered in portions during the day. [00083] Solid dosage forms of the instant pharmaceutical compositions for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00084] Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. [00085] The solid dosage forms of the instant pharmaceutical compositions of tablets, dragées, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other pharmaceutical coatings. They may optionally contain opacifying agents and can also be of a formulation that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding pharmaceutical compositions which can be used include polymeric substances and waxes. [00086] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. [00087] Liquid dosage forms of the instant pharmaceutical compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. [00088] Suspensions of the instant compounds, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof. [00089] Pharmaceutical compositions of the present disclosure for injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. [00090] Besides inert diluents, these pharmaceutical compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, dispersing agents, sweetening, flavoring, and perfuming agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. The compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. Such formulations may provide more effective distribution of the compounds. [00091] The pharmaceutical compositions that are injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00092] Dosage forms for topical administration of a compound or pharmaceutical composition of the present disclosure include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants which may be required. [00093] The compounds and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously or intramuscularly), topically, rectally, nasally sublingually or buccally, with a dosage ranging from about 0.01 milligrams per kilogram (mg/kg) to about 1000 mg/kg, (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg) every 4 to 120 hours, or according to the requirements of the particular drug, dosage form, and/or route of administration. Other routes of administration include enteric, intraarterial, intraperitoneal and intrathecal administration. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep.50, 219-244 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). In certain embodiments, the compositions are administered by oral administration or by injection. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve a desired or stated effect. Typically, the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. [00094] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, and the judgment of the treating physician. [00095] Dosage forms include from about 0.001 mg to about 2,000 mg (including, from about 0.001 mg to about 1,000 mg, from about 0.001 mg to about 500 mg, from about 0.01 mg to about 250 mg) of a compound of Formula (I), or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein. The dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent. [00096] Appropriate dosage levels may be determined by any suitable method. Preferably, the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less often if a drug delivery system is used. Nevertheless, actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve a desired therapeutic response for a particular patient, composition and mode of administration, without being intolerably toxic to the patient. In certain cases, dosages may deviate from the stated amounts, in particular as a function of age, gender, body weight, diet and general health status of the patient, route of administration, individual response to the active ingredient, nature of the preparation, and time or interval over which administration takes place. Thus, it may be satisfactory in some cases to manage with less than the aforementioned minimum amount, whereas in other cases the stated upper limit may be exceeded. It may in the event of administration of larger amounts be advisable to divide these into multiple individual doses spread over the day. D. EVALUATION OF THE ACTIVITY OF THE COMPOUNDS [00097] Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess biological activity as LDH inhibitors. [00098] Biochemical assays include recombinant human LDH enzymatic assays in which purified recombinant human lactate dehydrogenase A (LDHA) is incubated with test compound, substrate pyruvate and coenzyme NADH+, and its enzymatic activity measured by the formation of NAD upon conversion of pyruvate to lactate. [00099] LDH inhibitors can also be evaluated in an ex vivo assay consisting of primary mouse hepatocytes. Following isolation, viable wild-type murine hepatocytes are incubated with test compound in presence of pyruvate. Compound potency to modulate LDH enzymatic activity is then evaluated by measuring the conversion of pyruvate to lactate by the cells. [000100] Genetically engineered alanine-glyoxylate aminotransferase-deficient mice such as knockout AGT -/- may also serve as a primary hyperoxaluria model. In addition, silencing of AGT hepatic expression can be rendered via sustained liver-targeted RNA interference in both wild-type rats and mice. In some specific cases, model may also require saturation of the glycolate metabolic pathway through chronic exposure to ethylene glycol or sodium glycolate. In all instance, the efficacy of test compounds is assessed by their potency to reduce the urinary oxalate or glycolate burden [primary endpoint], which is expressed either as oxalate /creatinine ratio, or as the total amount of oxalate excreted over a 24-hour period. Additional endpoints can be considered, including histological evaluation of structural integrity of kidneys and presence of calcium oxalate crystal deposition, as well as renal function assessment (e.g. estimated glomerular filtration rate or eGFR). E. METHODS OF USE [000101] LDH inhibitors may prove to be effective for diseases resulting from an increase in oxalate or where oxalate reduction may be beneficial. An example is primary hyperoxaluria, which is a disease resulting from an overproduction of oxalate, for example, due to overproduction or accumulation of its precursor, glyoxylate. Provided herein therefore are methods of treating or preventing diseases or disorders associated with elevated oxalate levels. Diseases or disorders associated with elevated oxalate levels include hyperoxaluria, chronic kidney disease (CKD), end stage renal disease (ESRD) or kidney stone disease. In certain embodiments, the hyperoxaluria is associated with various digestive or bowel diseases such as Crohn’s diseases, Hirschspring’s disease, cystic fibrosis and chronic biliary or pancreatic pathology. In certain embodiments, the hyperoxaluria is associated with bariatric surgery and ileal resection. In certain embodiments, the chronic kidney disease is associated with diabetes, hypertension, previous episode(s) of acute kidney injury, cardiovascular disease or dyslipidemia. In certain embodiments, the kidney stone disease is idiopathic kidney stone disease, or kidney stone disease associated with hyperparathyroidism or other disorders of calcium metabolism. In certain embodiments, the elevated oxalate levels is associated with diabetes mellitus, obesity or metabolic syndrome (MS). The compounds and compositions provided herein may be used to treat or prevent hyperoxaluria, including primary hyperoxaluria and the subtypes PH1, PH2 and PH3 as well as secondary hyperoxaluria, including enteric hyperoxaluria and idiopathic hyperoxaluria. The compounds and compositions provided herein may be used to treat calcium oxalate stone formation, for example, in the kidney, urinary tract or bladder, treat calcium oxalate deposition in other tissues and organs outside the kidney (systemic oxalosis) or prevent or delay kidney damage or the onset of chronic kidney disease (CKD) or end stage renal disease (ESRD). [000102] In certain embodiments, elevated oxalate levels means having a urinary oxalate excretion rate of greater than about 0.5 mmol/1.73 m 2 per day, greater than about 0.7 mmol/1.73 m 2 per day, greater than about 0.8 mmol/1.73 m 2 per day, greater than about 1.0 mmol/1.73 m 2 per day, greater than about 1.2 mmol/1.73 m 2 per day or greater than about 2 mmol/1.73 m 2 per day. In certain embodiments, elevated oxalate levels means having a urinary oxalate excretion rate that is greater than normal urinary oxalate excretion. In certain embodiments, normal oxalate urinary excretion is less than about 0.45 mmol/1.73 m 2 per day, less than about 0.46 mmol/1.73 m 2 per day or less than about 0.5 mmol/1.73 m 2 per day. In certain embodiments, elevated oxalate levels means having a urinary oxalate excretion rate that is greater than about 40 mg/day. In certain embodiments, elevated oxalate levels means having a urinary oxalate excretion rate that is greater than about 45 mg/day. In certain embodiments, the urinary oxalate excretion rate is about two-fold higher than normal. In certain embodiments, the urinary oxalate excretion rate is about four-fold higher than normal. In certain embodiments, elevated oxalate levels means having a plasma oxalate levels greater than normal plasma oxalate levels of about 1µmol/L to about 3 µmol/L. In certain embodiments, elevated oxalate levels means having a plasma oxalate level equal to or greater than about 10 µmol/L. In certain embodiments, elevated oxalate levels means having a plasma oxalate level equal to or greater than about 20 µmol/L. [000103] Method of treating primary hyperoxaluria may include the step of selecting patients with the genetic mutation underlying PH1, PH2 or PH3, for example, using a diagnostic test to detect the presence of mutation in the AGXT, GRHPR, HOGA1 genes, or to detect the level of expression or activity of the AGXT, GRHPR, HOGA1 genes, before administering any of the compound or composition provided herein. Hyperoxaluria patients may also be diagnosed by kidney stone biopsy, measurement of urinary levels of oxalate, calcium, citrate, sodium, magnesium, urate, urinary pH and volume, or a combination of any such measurements, prior to administering a compound or composition provided herein. [000104] Efficacy of the agent can be measured in a patient by reduction in the plasma or urinary oxalate, for example, in the course of days, weeks, months or years. Both plasma and urinary oxalate can be measured in patients in several ways, including concentration or mg of oxalate, moles of oxalate or concentration of oxalate in the biological media (urine or plasma). In addition, oxalate can be normalized to other proteins, such as creatinine, or evaluated over a 24 h period and or normalized based on age, body mass or body surface area. [000105] In certain embodiments, provided herein are methods of treating a disease or disorder associated with elevated oxalate levels, comprising administering to a subject having such disease or disorder, a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the elevated oxalate levels is elevated urinary oxalate levels. In certain embodiments, the elevated oxalate levels is elevated plasma oxalate levels. In certain embodiments, the disease or disorder is hyperoxaluria, chronic kidney disease (CKD), end stage renal disease (ESRD) or kidney stone disease. In certain embodiments, the disease or disorder associated with elevated oxalate levels is hyperoxaluria. In certain embodiments, the hyperoxaluria is primary hyperoxaluria or secondary hyperoxaluria. In certain embodiments, the disease or disorder associated with elevated oxalate levels is primary hyperoxaluria, idiopathic hyperoxaluria or idiopathic oxalate kidney stone disease. In yet certain embodiments, the primary hyperoxaluria is primary hyperoxaluria type 1 (PH-1), primary hyperoxaluria type 2 (PH-2) or primary hyperoxaluria type 3 (PH-3). In yet certain embodiments, the disease or disorder associated with elevated oxalate levels is associated with AGXT, GRHPR or HOGA1 mutation, or a combination of mutations thereof. [000106] In certain embodiments, provided herein are methods of treating hyperoxaluria, comprising administering to a subject having such disease or disorder, a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, provided herein are methods of treating hyperoxaluria, chronic kidney disease (CKD), end stage renal disease (ESRD) or kidney stone disease, comprising administering to a subject having such disease or disorder, a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. [000107] In certain embodiments, provided herein are methods of treating primary hyperoxaluria type 1 (PH-1), primary hyperoxaluria type 2 (PH-2) or primary hyperoxaluria type 3 (PH-3), comprising administering to a subject having such disease or disorder, a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, provided herein are methods of treating disease or disorder associated with an AGXT, GRHPR or HOGA1 mutation, or a combination of mutations thereof, comprising administering to a subject having such disease or disorder, a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. [000108] In certain embodiments, provided herein are methods of lowering oxalate levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, provided herein are methods of treating kidney stone formation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. [000109] In certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating a disease or disorder associated with elevated oxalate levels. [000110] In certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating hyperoxaluria. In certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating hyperoxaluria, chronic kidney disease (CKD), end stage renal disease (ESRD) or kidney stone disease. [000111] In certain embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, may be used in a variety of combination therapies to treat the conditions, diseases and disorders described above. Thus, also contemplated herein is the use of the compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, in combination with an additional pharmaceutical agent for the treatment of the conditions, diseases and disorders described herein. Additional agents which may be utilized for co-administration with the compound or composition provided herein, include, for example, an additional agent that lowers glyoxylate or oxalate levels, such as an RNAi therapeutic targeting GO expression (e.g. lumasiran (ALN-GO1), Alnylam’s GalNAc-siRNA conjugates targeting GO), RNAi therapeutic targeting LDHA (e.g. nedosiran, Dicerna’s GalNAc- siRNA conjugates targeting LDHA), other inhibitors in the oxalate synthesis pathways (e.g. stiripentol a weak LDH-inhibitor), or agents capable of reducing exogenous oxalate, such as oxalate decarboxylase (e.g. reloxaliase, formerly ALLN-177) or the oxalate degrading bacteria, oxalobacter formigenes (e.g. Oxabact ® ). The compound or composition provided herein may also be administered in conjunction with dietary modifications such as increased water consumption or avoidance of oxalate-rich food. The compound of composition provided herein may also be co- administered with vitamin B6 (pyridoxine). [000112] In certain embodiments, provided herein are methods of treating the diseases or disorders described herein, further comprising administering to the subject in need thereof a therapeutically effective amount of a second therapeutic agent. In certain embodiments, the second therapeutic agent is a glyoxylate or oxalate lowering therapeutic. In certain embodiments, the glyoxylate or oxalate lowering therapeutic is an RNAi therapeutic. In yet certain embodiments, the glyoxylate or oxalate lowering therapeutic is lumasiran, nedosiran, reloxaliase, stiripentol, oxalobacter formigenes or vitamin B6. F. PREPARATION OF THE COMPOUNDS [000113] The starting materials used for the synthesis were synthesized according to known literature procedures or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, VWR Scientific, and the like. Nuclear Magnetic Resonance (NMR) analysis was conducted using a Bruker Acuity 300 MHz or 400 MHz spectrometer with an appropriate deuterated solvent. NMR chemical shift (δ) is expressed in units of parts per million (ppm). LCMS analysis was conducted using a Waters Acquity UPLC with a QDA MS detector using a Waters C18 BEH 1.7 µm, 2.1 × 50 mm column, eluting with 95:5 to 0:100 H 2 O:MeCN + 0.1% formic acid at a flow rate of 0.6 mL/min over 3.5 minutes. or using a Shimadzu LCMS-2020 using a Ascentis Express C182.7 µm, 3.0 × 50 mm column, eluting with 95:5 to 0:100 H 2 O:MeCN + 0.05% trifluoroacetic acid at a flow rate of 1.5 mL/min over 3.0 minutes. The MS detector was set up to scan under both positive and negative mode ions ranging from 100-1200 Daltons. General methods for the preparation of compounds can be modified using appropriate reagents and conditions for the introduction of the various moieties found in the structures as provided herein. [000114] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. Various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. [000115] Standard abbreviations and acronyms as defined in Journal of Organic Chemistry’s Author’s Guideline at https://pubs.acs.org/userimages/ContentEditor/1218717864819/ joceah_abbreviations.pdf are used herein. Other abbreviations and acronyms used herein are as follows: Table 1: Abbreviations GENERAL SYNTHETIC SCHEME [000116] In some embodiments, compounds described herein can be prepared as outlined in the following general synthetic schemes. Method A: S N Ar Reaction [000117] Pyrazole intermediate A-1 is reacted with a halogenated or methylsulfonyl- heteroaryl carboxylate A-2, via an SNAr reaction, yielding the desired N-arylation product. This is then followed by ester hydrolysis, to yield the corresponding carboxylic acid targets A-3. Method B: Borylation of Br-Pyrazole and Suzuki Coupling [000118] The bromo-pyrazole intermediate B-1 can undergo a Miyaura borylation reaction in the presence of a Pd catalyst and B2pin2 or HBpin as pinacol boronic ester source, resulting in the desired borylated pyrazole product B-2. In some cases, the borylated pyrazole can undergo a sequential Suzuki coupling reaction with the 4-bromomethyl- benzenesulfonamide B-3 in one-pot. Otherwise, the borylated pyrazoles B-2 were isolated before Suzuki coupling with 4- bromomethyl- benzenesulfonamide B-3. The coupling product can be hydrolyzed under ester saponification conditions, yielding the final carboxylic acid product B-4. Method C: Suzuki Coupling of Pyrazole Triflate [000119] Triflyl pyrazole intermediate C-1 is reacted with various aryl boronic acids or boronate esters (C-2) via a Pd-catalyzed coupling reaction, providing direct access to 2-aryl pyrazoles. This step is followed by ester hydrolysis, to yield the corresponding carboxylic acid targets C-3. G. EXAMPLES PREPARATION OF INTERMEDIATES Intermediate A: Preparation of Ethyl 2-(3-(3-bromo-4-fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazo l-1- yl)thiazole-4-carboxylate [000120] Step 1: Preparation of ethyl 2-hydrazinylthiazole-4-carboxylate hydrobromide [000121] To a stirred solution of N-(carbamothioylamino)acetamide (1.0 equiv) in EtOH (0.3 M) at 23 °C was added ethyl 3-bromo-2-oxopropanoate (1.0 equiv). The mixture was stirred at this temperature for 30 mins then heated to reflux for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with MeOH/Et2O (1/6, v/v) to afford the title product as a yellow solid (49% yield). [000122] Step 2: Preparation of 1-(1H-benzo[d][1,2,3]triazol-1-yl)-2- cyclopropylethan-1-one [000123] To a stirred solution of benzotriazole (4.0 equiv) in CH 2 Cl 2 (0.3 M) at 23 °C was added thionyl chloride dropwise (1.0 equiv). The resulting mixture was stirred at this temperature for 30 mins. To this mixture was added cyclopropylacetic acid dropwise (1.0 equiv). The mixture was stirred for another 6 h. The resulting suspension was filtered. The filtrate was washed with aqueous sat. NaHCO 3 and brine. The organic layer was dried over Na 2 SO 4 , filtered and concentrated under vacuum to afford the title product as a red oil (63% yield, 72% purity by LCMS), which was used directly in the next step without further purification. [000124] Step 3: Preparation of 1-(3-bromo-4-fluorophenyl)-4-cyclopropylbutane- 1,3-dione [000125] To a stirred mixture of 1-(1,2,3-benzotriazol-1-yl)-2-cyclopropylethanone (1.0 equiv) in CH 2 Cl 2 (0.3 M) at 23 °C was added magnesium bromide ethyl etherate (2.5 equiv) and 1-(3-bromo-4-fluorophenyl) ethanone (1.0 equiv). The resulting mixture was stirred at this temperature for 10 mins. To this mixture was added N,N-diisopropylethylamine dropwise (3.0 equiv). The resulting mixture was stirred for another 2 h. The mixture was acidified with 1M aqueous HCl solution until the pH was ~1 and the mixture was extracted with CH 2 Cl 2 (3 × 3 volumes). The organic layers were combined, washed with saturated aqueous NaHCO 3 solution and brine, dried over Na 2 SO 4 , and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0% to 5% EtOAc in petroleum ether as a gradient, to afford the title product as a yellow solid (51% yield). [000126] Step 4: Preparation of 4-(2-(3-bromo-4-fluorobenzoyl)-4-cyclopropyl-3- oxobutyl)-2-fluorobenzenesulfonamide [000127] A mixture of 1-(3-bromo-4-fluorophenyl)-4-cyclopropylbutane-1,3-dione (1.0 equiv), 4-(bromomethyl)-2-fluorobenzenesulfonamide (1.1 equiv), Cs 2 CO 3 (1.5 equiv) and potassium iodide (1.0 equiv) in DMSO (1.1 M) was stirred at 23 °C for 2 h then diluted with EtOAc. The organic layer was washed with 1M aqueous HCl solution, brine, dried over Na 2 SO 4 , filtered and concentrated under vacuum. The residue was purified by column chromatography through silica gel, eluting with 0% to 30% EtOAc in petroleum ether, to afford the title product as a yellow solid (64% yield). [000128] Step 5: Preparation of ethyl 2-(3-(3-bromo-4-fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazo l-1-yl)thiazole-4-carboxylate [000129] To a stirred solution of 4-[2-(3-bromo-4-fluorobenzoyl)-4-cyclopropyl-3- oxobutyl]-2-fluorobenzenesulfonamide (1.0 equiv) in EtOH (0.2 M) at 23 °C was added pyrrolidine (0.3 equiv) and p-toluenesulfonic acid (0.5 equiv). The resulting mixture was stirred at this temperature for 30 mins. To this mixture was added ethyl 2-hydrazinyl-1,3- thiazole-4-carboxylate dihydrobromide (1.2 equiv). The reaction was stirred at 80 °C under nitrogen for 2 h. Upon completion of reaction, the mixture was concentrated under vacuum. The residue was purified by reverse phase column chromatography on C18, eluting with 95:5 to 15:85 H 2 O:MeCN + 0.1% formic acid as a gradient to afford the title product as a light yellow solid (15% yield). Intermediate B: Preparation of Ethyl 2-(3-(3-bromophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazo l-1- yl)thiazole-4-carboxylate [000130] Intermediate B was prepared in the same manner as Intermediate A above, starting with 3-bromoacetophenone as a starting material. Intermediate C: Preparation of 4-(Bromomethyl)-2-fluoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide Step 1: Preparation of 4-(bromomethyl)-2-fluorobenzenesulfonyl chloride [000131] To a degassed solution of 2-fluoro-4-methyl-benzenesulfonyl chloride (1.0 equiv) in MeCN (0.4 M) was added N-bromosuccinimide (1.1 equiv), 2,2'-azo-bis(2- methylpropionitrile) (0.1 equiv) and the mixture was heated to 80 °C in an oil bath for 8 hours. This mixture was concentrated under reduced vacuum. The resulting oil was purified by column chromatography through silica gel, eluting with 0 to 10% EtOAc in hexanes as a gradient. Select fractions were monitored by TLC (EtOAc:hexanes 1:9, UV). The desired fractions from the major peak which elutes centered at 7% EtOAc in hexanes were combined and concentrated to provide the title compound as a white crystalline solid (53% yield). [000132] Step 2: Preparation of 4-(bromomethyl)-2-fluoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide [000133] To a solution of 4-(bromomethyl-2-fluorobenzenesulfonyl chloride (1.0 equiv) in CH 2 Cl 2 (0.3 M) under nitrogen and cooled in a dry ice/acetone bath was added N-(4- methoxybenzyl)-1-(4-methoxyphenyl)methanamine (1.0 equiv). Once cooled, diisopropylethylamine (1.1 equiv) was added portion-wise over 10 minutes and the mixture was allowed to stir in the dry ice/acetone bath for 30 minutes. After this time, the cooling bath was exchanged with a salt/wet ice bath (-10 °C) and stirring was continued for 2 hours. This mixture was quenched with ice (1 volume), water (1 volume) and then extracted with CH 2 Cl 2 (2 × 1 volume). The combined organic extracts were washed with water (0.25 volumes), dried over MgSO 4 , filtered and concentrated under vacuum to afford an oil. The resulting oil was dissolved in CH 2 Cl 2 (0.1 volumes), applied to a silica gel pre-cartridge and purified by column chromatography through silica gel, eluting with 0-20% EtOAc in CH 2 Cl 2 as a gradient to provide the title compound as a white solid (73% yield). Intermediate D: Preparation of Ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyraz ol-1- yl)thiazole-4-carboxylate [000134] Step 1: Preparation of ethyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3- fluorobenzyl)-4-cyclopropyl-3-oxobutanoate [000135] To a suspension of ethyl 4-cyclopropyl-3-oxobutanoate (1.2 equiv), 4- (bromomethyl)-2-fluoro-N,N-bis[(4-methoxyphenyl)methyl]benze nesulfonamide (Intermediate C, 1.0 equiv) and lithium bromide (0.4 equiv) in THF (0.2 M) was added N,N- diisopropylethylamine (2.0 equiv). The mixture was stirred at reflux for 6 hours. This mixture was cooled to 23 °C and partitioned between sat. aq. NH 4 Cl solution (0.6 volumes), water (0.6 volumes) and EtOAc (2 × 1 volume). The combined extracts were washed with brine (0.3 volumes) before concentrated under vacuum. This oil was purified by column chromatography through silica gel eluting with 0-40% EtOAc in hexanes as a gradient. The desired fractions were combined and concentrated under vacuum to provide the title compound as a colourless oil (77% yield). [000136] Step 2: Preparation of 4-((5-(cyclopropylmethyl)-3-hydroxy-1H-pyrazol- 4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfona mide [000137] To a solution of ethyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3- fluorobenzyl)-4-cyclopropyl-3-oxobutanoate (1.0 equiv) in ethanol (0.22 M) was added hydrazine-hydrate (2.0 equiv). The mixture was heated to 70 °C for 2.5 hours. This solution was cooled to 23 °C, yielding a white solid. This solid was filtered, washed with hexanes (0.2 volumes) and dried under vacuum for 18 hours to provide the title compound as a white solid (86% yield). [000138] Step 3: Preparation of 4-((1-acetyl-5-(cyclopropylmethyl)-3-hydroxy-1H- pyrazol-4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzen esulfonamide [000139] To a solution of 4-((5-(cyclopropylmethyl)-3-hydroxy-1H-pyrazol-4- yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonami de (1.0 equiv) in pyridine (0.23 M) was added acetic anhydride (0.98 equiv) and the mixture was heated to 90 °C for 48 hours. This mixture was concentrated under reduced vacuum. The resulting oil was partitioned between sat. aq. NH 4 Cl solution (1.5 volumes) and EtOAc (2 × 1.5 volumes). The combined extracts were washed with brine (0.5 volumes), dried over MgSO 4 , filtered and concentrated under vacuum to afford a red oil. This oil was purified by column chromatography through silica gel using a 0-30% EtOAc + 1% MeOH in CH 2 Cl 2 gradient followed by 100% EtOAc. The fractions from the major peak which eluted at 9% EtOAc in CH 2 Cl 2 were combined and concentrated under vacuum to provide the title compound as a white solid (63% yield). The fractions from the peak eluting at 20% EtOAc in CH 2 Cl 2 were combined to provide isomeric acetate (17% yield) and the fractions from the peak eluting at 100% EtOAc were combined to provide recovered starting compound (13% recovered starting material). [000140] Step 4: Preparation of 4-((1-acetyl-5-(cyclopropylmethyl)-3-((2- (trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)methyl)-2-fl uoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide [000141] To a solution of 4-((1-acetyl-5-(cyclopropylmethyl)-3-hydroxy-1H- pyrazol-4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzen esulfonamide (1.0 equiv) in DMF (0.15 M) was cooled in an ice bath. Solid cesium carbonate (2.0 equiv) was added followed by addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.5 equiv). This mixture was stirred in the ice bath for 30 minutes then stirred at 23 °C for 1 hour. The resulting mixture was quenched with crushed ice (0.5 volumes), diluted with sat. aq. NH 4 Cl solution (0.5 volumes) and water (0.5 volumes) and extracted with ether (2 × 1.5 volumes). The combined organic extracts were washed with brine and concentrated under vacuum. The resulting oil was purified by column chromatography through silica gel, eluting with 0-50% EtOAc in hexanes as a gradient which was increased to 100% EtOAc at the end of the purification. The fractions from the major peak which eluted at 40% EtOAc in hexanes were combined and concentrated under vacuum to provide the title compound as a golden-colored oil (93% yield). [000142] Step 5: Preparation of 4-((5-(cyclopropylmethyl)-3-((2- (trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)methyl)-2-fl uoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide [000143] To a solution of 4-((1-acetyl-5-(cyclopropylmethyl)-3-((2- (trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)methyl)-2-fl uoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide (1.0 equiv) in THF/MeOH (1:1 v/v) (0.27 M) was added drop-wise, via an addition funnel, 1 M aq. lithium hydroxide solution (1.25 equiv). The mixture was stirred at 23 °C for 30 minutes. The mixture was cooled in an ice bath and 1 M aq. HCl solution (1.1 equiv) was added drop-wise via an addition funnel. This mixture was further treated with sat. aq. NH 4 Cl solution (1 volume) and extracted with EtOAc (2 × 2 volumes). The combined extracts were washed with brine (1 volume), dried over MgSO 4 , filtered and concentrated. This material was dried under vacuum to provide the title compound as a golden-colored gummy oil (95% yield). [000144] Step 6: Preparation of ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethy l)-3-((2- (trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-1-yl)thiazole-4-c arboxylate [000145] To a solution of 4-((5-(cyclopropylmethyl)-3-((2- (trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)methyl)-2-fl uoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide (1.0 equiv) in DMF (0.18 M) under nitrogen and cooled in an ice bath was added portion-wise sodium tert-pentoxide (1.2 equiv). The mixture was stirred at this temperature for 5 minutes. After this time, ethyl 2-fluorothiazole-4-carboxylate (1.1 equiv) was added. The resulting mixture was stirred in the ice bath for 15 minutes then stirred at 23 °C for 20 minutes. LCMS analysis indicated starting material remaining. The reaction mixture was re-cooled in the ice bath. Sodium tert-pentoxide (0.15 equiv) was added and the mixture was stirred in the ice bath for 15 minutes then warmed with stirring at 23 °C for 20 minutes. This mixture was partitioned between diethyl ether (2 × 2 volumes) and water (1 volume), followed by sat. aq. NH 4 Cl solution (1 volume). The combined organic extracts were concentrated under vacuum. The crude oil was purified through a silica gel column, eluting with 5-40% EtOAc in hexanes as a gradient followed by increasing to 100% EtOAc at the end of the purification. The fractions from an early peak eluting at 10% EtOAc in hexanes and a large broad peak centered at 30% EtOAc in hexanes were combined and concentrated under vacuum to provide the title compound as a gummy solid (80% yield). [000146] Step 7: Preparation of ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-hydroxy-1H-pyrazol-1-yl)thiazole-4-carbox ylate [000147] To a solution of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3- fluorobenzyl)-5-(cyclopropylmethyl)-3-((2-(trimethylsilyl)et hoxy)methoxy)-1H-pyrazol-1- yl)thiazole-4-carboxylate (1.0 equiv) in CH 2 Cl 2 (0.42 M) at 23 °C was added triethylsilane (5.0 equiv) and trifluoroacetic acid (78 equiv) and the mixture stirred at 23 °C for 5 hours. The resulting mixture was concentrated under vacuum to afford a white solid. The crude solid was suspended in CH 2 Cl 2 (3.5 volumes) and stirred for 16 hours at 23 °C. This mixture was filtered, washed with CH 2 Cl 2 (2 volumes) and dried under vacuum to provide the title compound as a white solid (62% yield). The filtrate was concentrated under vacuum. The resulting crude filtrate was purified by column chromatography through silica cartridge, eluting with a 0-15% MeOH in CH 2 Cl 2 gradient to provide additional title compound as a white solid (33% yield). The combined overall yield was 95%. [000148] Step 8: Preparation of Ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyraz ol-1-yl)thiazole-4-carboxylate [000149] To a suspension of ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-hydroxy-1H-pyrazol-1-yl)thiazole-4-carbox ylate (1.0 equiv) in CH 2 Cl 2 (0.1 M) was added N,N-diisopropylethylamine (1.5 equiv). The mixture was stirred at 23 °C for 15 minutes until all the solid was dissolved. This solution was cooled over a dry ice/acetone bath for 10 minutes after which trifluoromethanesulfonic anhydride (1.3 equiv) was added slowly over 5 minutes. This mixture was stirred in the dry ice/acetone bath for 15 minutes before warmed in a wet ice bath and stirred for an additional 30 minutes at this temperature. The resulting solution was poured over crushed ice (1 volume), diluted with sat. aq. NH 4 Cl solution (4 volumes) and extracted with CH 2 Cl 2 (2 × 2 volumes). The combined organic layers were washed with water (0.5 volumes) and concentrated under vacuum. The resulting oil was purified by column chromatography through silica gel, eluting with a 5-100% EtOAc + 10% MeOH in CH 2 Cl 2 gradient. The fractions from the major peak which eluted at 55% EtOAc in CH 2 Cl 2 were combined and concentrated under vacuum to provide the title compound as a white solid (74% yield). Intermediate E: Preparation of Ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethy l)-3-(4- fluoro-3-hydroxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxyla te [000150] Step 1: Preparation of ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-3-(3-bromo-4-fluoro phenyl)-5-(cyclopropylmethyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylate [000151] To a round-bottom flask equipped with a magnetic stir bar and under nitrogen was added ethyl 2-(3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-flu oro-4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (Intermediate A, 1.0 equiv), 4- methoxybenzyl chloride (2.5 equiv) and DMF (0.16 M). The mixture was cooled in an ice bath and sodium hydride (60% dispersion in mineral oil, 2.5 equiv) was added portion-wise to the cooled mixture. The reaction mixture was stirred cold for 10 minutes then stirred at 23 °C for 2 hours. This mixture was partitioned between EtOAc (2 × 5 volumes) and water (4 volumes) and the combined organic layers were concentrated under vacuum. The crude oil was loaded directly to a silica gel pre-cartridge and purified by column chromatography through a silica gel column, eluting with a 0-100% EtOAc in hexanes gradient. The fractions from the major peak which eluted at 60% EtOAc in hexanes were concentrated under vacuum to provide the title compound as an oil (76% yield). [000152] Step 2: Preparation of ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethy l)-3-(4-fluoro-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-1-yl) thiazole-4-carboxylate [000153] To a degassed mixture of ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-3-(3-bromo-4-fluoro phenyl)-5-(cyclopropylmethyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv), bis(pinacolato)diboron (2.0 equiv), Pd(dppf)Cl2·CH 2 Cl 2 (0.1 equiv) in dioxane (0.2 M) was added potassium acetate (4.0 equiv). The mixture was heated to 100 °C for 4 hours. The mixture was diluted with EtOAc (4 volumes), filtered and concentrated under vacuum. This residue was purified by column chromatography through silica gel, eluting with a 0-50% EtOAc in hexanes gradient. The fractions from the major peak which eluted at 45% EtOAc in hexanes were combined and concentrated under vacuum to give the title compound as a solid (76% yield). [000154] Step 3: Preparation of ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethy l)-3-(4-fluoro-3- hydroxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate [000155] To a suspension of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3- fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-(4,4,5,5-t etramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv) in methanol (0.07 M) and DMF (0.07 M) was added urea-hydrogen peroxide adduct (2.0 equiv). The mixture was stirred at 23 °C for 21 hours. This mixture was concentrated under vacuum to remove MeOH. This solution was partitioned between sat. aq. NH 4 Cl solution (2 volumes), water (2 volumes) and EtOAc (2 × 10 volumes). The combined organic layers were concentrated under vacuum to yield a crude oil. This crude was purified by column chromatography through a silica gel column, eluting with a 0-70% EtOAc in hexanes gradient. The fractions from the major peak which eluted at 55% EOAc in hexanes were combined and concentrated under vacuum to provide the title compound as a clear viscous oil (95% yield). [000156] Intermediate F: Preparation of 4-Cyclopropyl-1-(4- fluorophenyl)butane-1,3-dione [000157] Step 1: Preparation of 1-(1H-benzo[d][1,2,3]triazol-1-yl)-2- cyclopropylethan-1-one [000158] Into a round-bottom flask equipped with a magnetic stir bar and under N2 was added benzotriazole (4.0 equiv) and CH 2 Cl 2 (0.3 M). The resulting clear solution was cooled to 0 °C in an ice bath and thionyl chloride (1.0 equiv) was added drop-wise over 10 minutes to the cooled solution. The resulting light-yellow solution was warmed and stirred at 23 °C for 1 h and then cooled to 0 °C in an ice bath. Cyclopropylacetic acid (1.0 equiv) was added in a single portion and the resulting white suspension was stirred at 23 °C for 16 h overnight. The resulting white suspension was filtered through Whatman #1 filter paper on a Hirsch funnel under vacuum, washing with CH 2 Cl 2 (3 × 5 volumes). The clear filtrate was concentrated under reduced pressure and loaded onto a silica gel pre-cartridge and dried under vacuum. The mixture was purified by column chromatography through silica gel, eluting with 95:5 to 50:50 hexanes:EtOAc as a gradient over 25 minutes, collecting all peaks. The desired product containing fractions were concentrated and dried under vacuum to afford a clear oil which crystallized slowly upon standing (81% yield). [000159] Step 2: Preparation of 4-cyclopropyl-1-(4-fluorophenyl)butane-1,3-dione [000160] Into a round-bottom flask equipped with a magnetic stir bar was added 1- (benzotriazol-1-yl)-2-cyclopropyl-ethanone (1.2 equiv), 4'-fluoroacetophenone (1.0 equiv) and CH 2 Cl 2 (0.3 M). The mixture was cooled to 0 °C in an ice bath. With stirring, magnesium bromide ethyl etherate (2.5 equiv) was added in a single portion. N,N- Diisopropylethylamine (3.0 equiv) was added drop-wise via an additional funnel. Upon addition, the reaction mixture turned yellow, as the solid started to dissolve. Upon completion of addition, the ice bath was removed. The reaction was warmed to room temperature and stirred for another 30 min. LC-MS analysis indicated completion of reaction. The reaction was cooled back to 0 °C in an ice bath, and slowly quenched with the addition of 1 M aqueous HCl solution to pH~2. The resulting aqueous mixture was partitioned into a separatory funnel. The aqueous layer was back extracted with CH 2 Cl 2 (3 × 3 volumes). The combined organic layers were washed with brine, dried with MgSO 4 , filtered and concentrated under reduced pressure. The resulting crude reaction mixture was loaded onto a silica gel pre-cartridge and purified by column chromatography, eluting with 0:100 to 80:20 hexanes:EtOAc as a gradient over 30 min. The desired product eluted from 90:10 to 80:20 hexanes:EtOAc. The desired product containing fractions were concentrated and dried under vacuum to afford a yellow oil (64% yield). Intermediate G: Preparation of 4-((5-(Cyclopropylmethyl)-3-(4- fluorophenyl)-1H-pyrazol-4-yl)methyl)-2-fluorobenzenesulfona mide [000161] Step 1: Preparation of 4-(4-cyclopropyl-2-(4-fluorobenzoyl)-3-oxobutyl)- 2-fluorobenzenesulfonamide [000162] Into a round-bottom flask equipped with a magnetic stir bar was added 4- cyclopropyl-1-(4-fluorophenyl)butane-1,3-dione (Intermediate F, 1.0 equiv) and DMSO (0.4 M). The solution was treated with cesium carbonate (1.5 equiv) and potassium iodide (1.0 equiv). The resulting suspension was stirred at 23 °C for 30 minutes. After this time, 4-(bromomethyl)-2- fluorobenzenesulfonamide (1.1 equiv) was added. The mixture was stirred at 23 °C for 2 h and upon completion of reaction by LCMS, the reaction mixture was treated with EtOAc, followed by addition of 1 M aqueous HCl solution until the aqueous layer pH was ~2. The mixture was stirred for 10 minutes and partitioned into a separatory funnel. The organic layer was removed, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was loaded onto a silica gel pre-cartridge and dried. Purification by column chromatography through silica gel, eluting with 95:5 to 10:90 hexanes:EtOAc as a gradient over 30 min, collecting all peaks. The desired product containing fractions were concentrated and dried under vacuum, yielding the title product (77% yield). [000163] Step 2: Preparation of 4-((5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H- pyrazol-4-yl)methyl)-2-fluorobenzenesulfonamide [000164] Into a round bottom flask equipped with a magnetic stir bar was added 4- [4-cyclopropyl-2-(4-fluorobenzoyl)-3-oxo-butyl]-2-fluoro-ben zenesulfonamide (1.0 equiv) and EtOH (0.3 M). Liquid hydrazine monohydrate (6.0 equiv) was added to the flask and the solution was heated to 70 °C in an oil bath for 2 h. LC-MS analysis indicated consumption of starting material and formation of product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting yellow oil was loaded into a silica gel pre- cartridge and dried. The mixture was purified by column chromatography through silica gel, eluting with 80:20 to 0:100 hexanes:EtOAc as a gradient over 25 min. The desired product containing fractions (75% to 100% EtOAc) were concentrated and dried under vacuum, yielding the title product as a white solid (76% yield). Intermediate H: Preparation of Ethyl 2-(methylsulfonyl)thiazole-4- carboxylate [000165] Step 1: Preparation of ethyl 2-(methylsulfanyl)-1,3-thiazole-4-carboxylate [000166] Into a round bottom flask equipped with a magnetic stir bar was added ethyl 2-chloro-1,3-thiazole-4-carboxylate (1.0 equiv), DMF (0.9 M), K 2 CO 3 (2 equiv) and sodium methanethiolate (1.2 equiv). The resulting mixture was stirred at 23 °C for 1 h. LC-MS analysis indicated consumption of starting material and formation of product. The resulting mixture was poured into a separatory funnel containing water (10 volumes) and the aqueous layer was extracted with ethyl acetate (3 × 2 volumes). The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford the title product as a dark yellow solid (68% yield). [000167] Step 2: Preparation of ethyl 2-(methylsulfonyl)thiazole-4-carboxylate [000168] Into a round bottom flask equipped with a magnetic stir bar was added ethyl 2-(methylsulfanyl)-1,3-thiazole-4-carboxylate (1.0 equiv) and CH 2 Cl 2 (0.9 M). The mixture was cooled to 0 °C in an ice water bath. Solid m-CPBA (2.5 equiv) was slowly added over 15 minutes. The resulting solution was stirred at 23 °C for 1 h. LC-MS analysis indicated consumption of starting material and formation of product. The resulting mixture was diluted with CH 2 Cl 2 (3 volumes) and washed with brine (3 × 1 volume). The organic layer was dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (5:1) to afford the title product as a white solid (66% yield). PREPARATION OF EXAMPLES Example 1: Preparation of 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid [000169] Step 1: Preparation of ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole -4-carboxylate [000170] Into a round-bottom flask equipped with a magnetic stir bar and under N2 was added 4-((5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl )methyl)-2- fluorobenzenesulfonamide (Intermediate G, 1.0 equiv) and DMF (0.25 M). The mixture was treated with solid sodium tert-pentoxide (2.0 equiv) and cooled to 0 °C in an ice bath. Solid ethyl 2-fluorothiazole-4-carboxylate (1.5 equiv) was added and the mixture was allowed to warm to 23 °C with stirring over 2 h. LCMS analysis after this time reveals product formation as the major isomer, with the regioisomeric ratio being 3:7. The reaction was quenched with saturated aqueous NH 4 Cl solution (2 volumes) and poured into a separatory funnel containing water and extracted with CH 2 Cl 2 (3 × 4 volumes). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The mixture was purified by column chromatography through silica gel, eluting with 95:5 to 10:90 hexanes:EtOAc as a gradient over 25 min. The desired product containing fractions were concentrated and dried under vacuum, yielding the title product as a white solid (55% yield). [000171] Step 2: Preparation of 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid [000172] Into a round bottom flask equipped with a magnetic stir bar was added ethyl 2-[5-(cyclopropylmethyl)-3-(4-fluorophenyl)-4-[(3-fluoro-4-s ulfamoyl-phenyl)methyl]pyrazol-1- yl]thiazole-4-carboxylate (1.0 equiv) and THF/MeOH (1:1 v/v, 0.2 M). The mixture was stirred at 23 °C until most of solid was dissolved. Aqueous 1.0 M LiOH solution (2.5 equiv) was added. The reaction was stirred at 23 °C for 2 h and the mixture was quenched with drop-wise addition of concentrated formic acid. Purification by reverse-phase column chromatography using a C18 column, eluting with 90:10 to 0:100 H 2 O:MeCN + 0.1% formic acid as a gradient. Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (79% yield). 1 H NMR (400 MHz, d6-DMSO) δH 13.16 (s, 1H), 8.28 (s, 1H), 7.67-7.58 (m, 5H), 7.23 (dd, J = 10.0, 8.0 Hz, 2H), 7.11 (d, J = 11.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.13 (s, 2H), 3.13 (d, J = 7.0 Hz, 2H), 1.17-1.05 (m, 1H), 0.36-0.27 (m, 2H), 0.23-0.15 (m, 2H). LC- MS (ESI) m/z 531 (M+H) + . MW: 530.56.
Example 2: Preparation of 2-(3-(3-Cyano-4-fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazo l-1- yl)thiazole-4-carboxylic acid [000173] Step 1: Preparation of ethyl 2-(3-(3-cyano-4-fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazo l-1-yl)thiazole-4-carboxylate [000174] To a mixture of ethyl 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4- sulfamoyl-phenyl)methyl]-3-(trifluoromethylsulfonyloxy)pyraz ol-1-yl]thiazole-4-carboxylate (Intermediate D, 1.0 equiv), tBuXPhos-Pd-G3 (0.1 equiv) and (3-cyano-4-fluorophenyl)boronic acid (2.0 equiv) in 1,4-dioxane (0.11 M) was added water (0.001 M) and potassium phosphate (3.0 equiv). This mixture was degassed under N2 and heated to 90 °C for 1 hour. To this mixture was added sat. aq. NH 4 Cl solution (1 volume) and water (2.5 volumes) and the mixture extracted with EtOAc (2 × 5 volumes). The combined organic extracts were washed with water (1.5 volumes) and concentrated under vacuum. The resulting yellow oil was loaded into a silica gel pre-cartridge and dried. The mixture was purified by column chromatography through silica gel, eluting with 80:20 to 0:100 hexanes:EtOAc as a gradient over 25 min. The desired product containing fractions (75% to 100% EtOAc) were concentrated and dried under vacuum, yielding the title product as a white solid (75% yield). [000175] Step 2: Preparation of 2-(3-(3-cyano-4-fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazo l-1-yl)thiazole-4-carboxylic acid [000176] Into a round bottom flask was added ethyl 2-(3-(3-cyano-4-fluorophenyl)- 5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyra zol-1-yl)thiazole-4-carboxylate (1.0 equiv), THF (0.06 M), MeOH (0.06 M) and 1M aqueous LiOH (1.0 equiv). The reaction was stirred at 23 °C for 2 hours at which time LCMS reveals complete conversion to product. Purification by reverse-phase column chromatography using a C18 column, eluting with 90:10 to 0:100 H 2 O:MeCN + 0.1% formic acid as a gradient. Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (58% yield). 1 H NMR (400 MHz, d6-DMSO) δH 8.27 (s, 1H), 8.09 (dd, J = 6.0, 2.5 Hz, 1H), 7.92 (ddd, J = 8.0, 5.0, 2.5 Hz, 1H), 7.58 (m, 4H), 7.11 (d, J = 11.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 4.18 (s, 2H), 3.16 (d, J = 7.0 Hz, 2H), 1.15-1.06 (m, 1H), 0.35-0.29 (m, 2H), 0.23-0.17 (m, 2H). LC-MS (ESI) m/z 556 (M+H) + . MW: 555.08 Example 3: Preparation of 2-(4-(3-Fluoro-4-sulfamoylbenzyl)-3-(4- fluorophenyl)-5-methyl-1H-pyrazol-1-yl)thiazole-4-carboxylic acid [000177] Step 1: Preparation of 4-bromo-3-(4-fluorophenyl)-5-methyl-1H-pyrazole [000178] Into a round bottom flask was added 3-(4-fluorophenyl)-5-methyl-1H- pyrazole (1.0 equiv) and MeCN (0.3 M). The mixture was cooled to 0 °C in an ice bath and N- bromosuccinimide (1.5 equiv) was added. The reaction was stirred at 23 °C for 18 h overnight. LCMS analysis indicated all starting material has been converted to the bromination product. The reaction mixture was partitioned between EtOAc (2 volumes) and sat. aq. NaHCO 3 solution (2 volumes). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 volumes). The organic layers were combined, dried, filtered and concentrated, yielding a yellow oil crude, which was loaded onto a silica gel pre-cartridge and dried. The mixture was purified by column chromatography through silica gel, eluting with 80:20 to 0:100 hexanes:EtOAc as a gradient over 17 min. The desired product containing fractions were concentrated and dried under vacuum, yielding the title product as a yellow solid (96% yield). [000179] Step 2: Preparation of ethyl 2-(4-bromo-3-(4-fluorophenyl)-5-methyl-1H- pyrazol-1-yl)thiazole-4-carboxylate [000180] Into a round bottom flask was added 4-bromo-3-(4-fluorophenyl)-5-methyl- 1H-pyrazole (1.0 equiv), ethyl-2-bromothiazole-4-carboxylate (1.5 equiv), potassium carbonate (3.0 equiv) and DMF (0.3 M). The mixture was stirred at 100 °C for 18 h overnight. LCMS analysis indicated completion of reaction. The mixture was filtered to remove most of potassium carbonate solid. The filtrate was loaded directly on a silica gel pre-cartridge and dried. The mixture was purified by column chromatography through silica gel, eluting with 80:20 to 0:100 hexanes:EtOAc as a gradient over 20 min. The desired product containing fractions were concentrated and dried under vacuum, yielding the title product as a yellow solid (43% yield). [000181] Step 3: Preparation of ethyl 2-(4-(3-fluoro-4-sulfamoylbenzyl)-3-(4- fluorophenyl)-5-methyl-1H-pyrazol-1-yl)thiazole-4-carboxylat e [000182] Into a reaction vial, equipped with a magnetic stir bar was added B 2 pin 2 (1.5 equiv), ethyl 2-(4-bromo-3-(4-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)thiaz ole-4-carboxylate (1.0 equiv), Pd(PPh 3 ) 2 Cl 2 (0.1 equiv), potassium acetate (2.0 equiv) and 1,4-dioxane (0.3 M). The mixture was purged with nitrogen for 10 min, then heated to 100 °C for 18 hours. Upon completion of the borylation by LCMS, the mixture was treated with Pd(dppf)Cl2·CH 2 Cl 2 (0.1 equiv), ethyl 2-[4-bromo-3-(4-fluorophenyl)-5-methyl-pyrazol-1-yl]thiazole -4-carboxylate (1.0 equiv) and sodium carbonate (2.0 M, 2.0 equiv). The reaction was purged with nitrogen for 10 min then stirred at 80 °C for 1 hour. LCMS analysis indicated completion of the reaction. The mixture was filtered and loaded directly on a silica gel pre-cartridge and dried. The mixture was purified by column chromatography through silica gel, eluting with 80:20 to 0:100 hexanes:EtOAc as a gradient over 20 min. The desired product containing fractions were concentrated and dried under vacuum, yielding the title product as a yellow solid (23% yield). [000183] Step 4: Preparation of 2-(4-(3-fluoro-4-sulfamoylbenzyl)-3-(4- fluorophenyl)-5-methyl-1H-pyrazol-1-yl)thiazole-4-carboxylic acid [000184] Into a round bottom flask equipped with a magnetic stir bar was added ethyl 2-(4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-5-methy l-1H-pyrazol-1-yl)thiazole-4- carboxylate (1.0 equiv) and THF/MeOH (1:1 v/v, 0.3 M). The mixture was stirred at 23 °C for 10 minutes until most of solid was dissolved. Aqueous 1 M LiOH solution (3.0 equiv) was added, yielding a clear solution. The reaction was stirred at 23 °C for 1 h. LC-MS analysis at this time reveals complete conversion of starting material. The reaction mixture was acidified with 1 M aqueous HCl solution to pH~2. Purification by reverse phase preparative HPLC column (C18, 5 μm column), eluting with 90:10 to 0:100 water:MeCN + 0.1% formic acid as a gradient over 25 minutes, collecting all peaks. The desired product containing fractions were concentrated and lyophilized overnight to yield the title product as a white powder (83% yield). LC-MS (ESI) m/z 491 (M+H) + . MW: 490.50 Example 4: Preparation of 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid
[000185] Step 1: Preparation of 1-(1H-benzo[d][1,2,3]triazol-1-yl)propan-1-one [000186] Into a round bottom flask equipped with a magnetic stir bar was added benzotriazole (1.0 equiv), triethylamine (2 equiv) and CH 2 Cl 2 (0.54 M). The resulting solution was cooled in an ice bath to 0 °C. Propanoyl chloride (1 equiv) was added carefully over 30 minutes while cooling. The mixture was stirred at 0 °C for 1 h, water was added (5 volumes) and the organic layer was removed and concentrated under reduced pressure. The resulting yellow oil was loaded into a silica gel pre-cartridge and dried. The mixture was purified by column chromatography through silica gel, eluting with 80:20 to 0:100 hexanes:EtOAc as a gradient over 25 min. The desired product containing fractions were concentrated and dried under vacuum, yielding the title product as a white solid (79% yield). [000187] Step 2: Preparation of 1-(3-bromo-4-fluorophenyl)pentane-1,3-dione [000188] Into a round-bottom flask equipped with a magnetic stir bar was added 1- (1H-benzo[d][1,2,3]triazol-1-yl)propan-1-one (1.5 equiv), 1-(3-bromo-4-fluorophenyl)ethan-1- one (1.0 equiv) and CH 2 Cl 2 (0.5 M). The mixture was cooled to 0 °C in an ice bath. With stirring, magnesium bromide diethyl etherate (2.5 equiv) was added in one portion. N,N- Diisopropylethylamine (3.0 equiv) was added drop-wise via an additional funnel. Upon addition, the reaction mixture turned yellow, as the solid started to dissolve. Upon completion of addition, the ice bath was removed and the reaction was warmed to 23 °C and stirred at this temperature for 30 min. LC-MS analysis indicated completion of reaction. The reaction was cooled to 0 °C in an ice bath, and slowly quenched with the addition of 1 M aqueous HCl solution (5-10 volumes) to pH~2. The resulting aqueous mixture was partitioned in a separatory funnel. The aqueous layer was back extracted with CH 2 Cl 2 (3 × 4 volumes). The combined organic layers were washed with brine, dried with MgSO 4 , filtered and concentrated under reduced pressure. The resulting crude reaction mixture was loaded onto a silica gel pre-cartridge and purified by column chromatography, eluting with 0:100 to 80:20 hexanes:EtOAc as a gradient over 30 min. The desired product eluted from 90:10 to 80:20 hexanes:EtOAc. The desired product containing fractions were concentrated and dried under vacuum to afford a yellow oil (71% yield). [000189] Step 3: Preparation of 4-(2-(3-bromo-4-fluorobenzoyl)-3-oxopentyl)-N,N- bis(4-methoxybenzyl)benzenesulfonamide [000190] Into a round-bottom flask equipped with a magnetic stir bar was added 1- (3-bromo-4-fluorophenyl)pentane-1,3-dione (5.0 equiv) and DMSO (0.14 M). The solution was treated with cesium carbonate (1.2 equiv) and the resulting suspension was stirred at 23 °C for 30 minutes. At this time, 4-(bromomethyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (prepared in the same manner as Intermediate C, 1.0 equiv) was added. The mixture was stirred at 23 °C for 3 h and upon completion of the reaction, the mixture was treated with EtOAc (5 volumes), followed by addition of 1M aqueous HCl solution (5 volumes) , ensuring the aqueous layer is acidic (pH~2). The mixture was stirred for 10 minutes and partitioned into a separatory funnel. The organic layer was removed, dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was loaded onto a silica gel pre-cartridge and dried. Purification by column chromatography through silica gel, eluting with 95:5 to 10:90 hexanes:EtOAc as a gradient over 30 min, collecting all peaks. The desired product containing fractions were concentrated and dried under vacuum, yielding the title product (38% yield). [000191] Step 4: Preparation of 4-((3-(3-bromo-4-fluorophenyl)-5-ethyl-1H- pyrazol-4-yl)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonam ide [000192] Into a round bottom flask equipped with a magnetic stir bar was added 4- (2-(3-bromo-4-fluorobenzoyl)-3-oxopentyl)-N,N-bis(4-methoxyb enzyl)benzenesulfonamide (1.0 equiv) and EtOH (0.3 M). Concentrated hydrazine monohydrate (6.0 equiv) was added to the flask and the solution was heated to 70 °C in an oil bath for 2 h. LC-MS analysis indicated consumption of starting material and formation of product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting yellow oil was loaded into a silica gel pre-cartridge and dried. The mixture was purified by column chromatography through silica gel, eluting with 80:20 to 0:100 hexanes:EtOAc as a gradient over 25 min. The desired product containing fractions, which eluted between 75% to 100% EtOAc in hexanes, were concentrated and dried under vacuum, yielding the title product as a white solid (76% yield). [000193] Step 5: Preparation of ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)benzyl)-3-(3-bromo-4-fluorophenyl)-5 -ethyl-1H-pyrazol-1- yl)thiazole-4-carboxylate [000194] Into a round bottom flask equipped with a magnetic stir bar was added 4- ((3-(3-bromo-4-fluorophenyl)-5-ethyl-1H-pyrazol-4-yl)methyl) -N,N-bis(4- methoxybenzyl)benzenesulfonamide (1.0 equiv) and DMF (0.07 M). Sodium hydride (60% dispersion in mineral oil, 1.5 equiv) was added, and after stirring for 10 minutes, the reaction mixture was cooled to 0 °C in an ice bath. Ethyl 2-fluorothiazole-4-carboxylate (1.2 equiv) was added and reaction mixture was stirred at 23 °C for 1 hour. The reaction mixture was diluted with water (4 volumes) and extracted with EtOAc (5 volumes). The organic layer was concentrated under reduced pressure and the resulting yellow oil was loaded into a pre-cartridge and dried. The mixture was purified by column chromatography through silica gel, eluting with 80:20 to 0:100 hexanes:EtOAc as a gradient over 25 min. The desired product containing fractions, which eluted from 75% to 100% EtOAc in hexanes, were concentrated and dried under vacuum, yielding the title product as a white solid (62% yield). [000195] Step 6: Preparation of ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)benzyl)-5-ethyl-3-(4-fluorophenyl)-1 H-pyrazol-1-yl)thiazole-4- carboxylate [000196] Into a round bottom flask equipped with a magnetic stir bar was added ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)benzyl)-3-(3-brom o-4-fluorophenyl)-5-ethyl-1H- pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv), MeOH (0.02 M) and CH 2 Cl 2 (0.02 M). The reaction mixture was degassed and Pd/C (10 wt. % loading) was added. The reaction was charged with hydrogen via a balloon and stirred at 23 °C for 6 hours. The crude mixture was purged with air, diluted with CH 2 Cl 2 and concentrated to a slurry. Purification by reverse-phase column chromatography using a C18 column, eluting with 90:10 to 0:100 H 2 O:MeCN + 0.1% formic acid as a gradient. Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (66% yield). [000197] Step 7: Preparation of 2-(5-ethyl-3-(4-fluorophenyl)-4-(4- sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid [000198] Into a round bottom flask was added ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)benzyl)-5-ethyl-3-(4-fluorophenyl)-1 H-pyrazol-1-yl)thiazole-4- carboxylate (1.0 equiv) and TFA (100 equiv). The reaction was stirred at 23 °C for 1 hour then concentrated under reduced pressure. To the resulting solid crude was added 1 M aqueous LiOH solution (10 equiv), MeOH (0.04 M) and THF (0.04 M). The resulting mixture was heated at 50 °C for 3 hours. Purification by reverse-phase column chromatography using a C18 column, eluting with 90:10 to 0:100 H 2 O:MeCN + 0.1% formic acid as a gradient. Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (15% yield). LC- MS (ESI) m/z 487 (M+H) + . MW: 486.08 [000199] The following compounds were prepared in a similar manner as Example 4, by replacing propionic acid with the corresponding alkyl carboxylic acids in the first step.
Example 7: Preparation of 2-(5-(Cyclopropylmethyl)-3-(4-fluoro-3- isopropoxyphenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol- 1-yl)thiazole- 4-carboxylic acid [000200] Step 1: Preparation of ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethy l)-3-(4-fluoro-3- isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate [000201] Into a round-bottom flask equipped with a magnetic stir bar was added ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)- 5-(cyclopropylmethyl)-3-(4- fluoro-3-hydroxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxyla te (Intermediate E, 1.0 equiv), triphenylphosphine (2.3 equiv), isopropanol (3.0 equiv) and CH 2 Cl 2 (0.06 M). The mixture was cooled in an ice bath and diisopropyl azodicarboxylate (2.0 equiv) was added. The reaction was stirred in the ice bath for 5 minutes then warmed to 23 °C for 30 minutes. This mixture was purified directly by column chromatography through silica gel, eluting with a 0-70% EtOAc in hexanes gradient. The fractions from the major peak which eluted at 25-30% EtOAc in hexanes were combined and concentrated under vacuum to provide the title compound as a colorless oil (75% yield). [000202] Step 2: Preparation of 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3- fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-isopropoxy phenyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid [000203] To a solution of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3- fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-isopropoxy phenyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylate (1.0 equiv) in THF/MeOH (1:1 v/v, 0.02 M) was added 1 M aqueous LiOH solution (8.0 equiv) and the mixture was heated to 40 °C for 16 hours. This mixture was concentrated under vacuum to remove the MeOH and THF. The residue was then acidified with formic acid (8.0 equiv). This mixture was partitioned between CH 2 Cl 2 (2 × 10 volumes) and water (5 volumes). The combined organic layers were concentrated under vacuum to provide the title compound (99% yield). [000204] Step 3: Preparation of 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3- isopropoxyphenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol- 1-yl)thiazole-4-carboxylic acid [000205] To a solution of 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3- fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-isopropoxy phenyl)-1H-pyrazol-1-yl)thiazole- 4-carboxylic acid (1.0 equiv) in CH 2 Cl 2 (0.03 M) was added triethylsilane (6.0 equiv) and trifluoroacetic acid (50 equiv). The resulting solution was stirred at 23°C for 24 hours. This mixture was concentrated under vacuum and the resulting residue was purified by reverse phase column chromatography using a C18 column, eluting with a 10-100% CH3CN in water gradient containing 0.1% HCO 2 H. The fractions from the major peak eluting at 75% CH3CN were combined and lyophilized to provide the title product as a white solid (67% yield). LC-MS (ESI) m/z 567.1 (M+H) + . MW: 566.1 Example 8: Preparation of 2-(3-(3-Chloro-4-fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazo l-1- yl)thiazole-4-carboxylic acid [000206] Step 1: Preparation of ethyl 2-[3-(3-bromo-4-fluorophenyl)-5- (cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]py razol-1-yl]-1,3-thiazole-4- carboxylate [000207] Into a round-bottom flask equipped with a magnetic stir bar was added ethyl 2-[3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-[(3-fl uoro-4- sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxyl ate (Intermediate A, 1.0 equiv), DMF (0.25 M), FeCl3 (0.3 equiv) and CuCl (5.0 equiv). The resulting mixture was heated to 110 °C in an oil bath for 16 h. LC-MS analysis indicated consumption of starting material and formation of product. The reaction mixture was cooled to 23 °C and the resulting mixture was poured into a separatory funnel containing water (5 volumes) and the aqueous layer was extracted with ethyl acetate (3 × 5 volumes). The combined organic layers were washed with brine and then dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow solid (82% yield). [000208] Step 2: Preparation of 2-(3-(3-chloro-4-fluorophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazo l-1-yl)thiazole-4-carboxylic acid [000209] Into a round bottom flask equipped with a magnetic stir bar was added ethyl 2-[3-(3-chloro-4-fluorophenyl)-5-(cyclopropylmethyl)-4-[(3-f luoro-4- sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxyl ate (1.0 equiv), MeOH (0.1 M) and H 2 O (0.1 M). Solid NaOH (5.0 equiv) was added to the flask and the resulting solution was stirred at 23 °C for 30 min. LC-MS analysis indicated consumption of starting material and formation of product. The resulting mixture was concentrated under reduced pressure, and the residue was acidified to pH~5 with 3 M aqueous HCl solution. The aqueous layer was extracted with ethyl acetate (3 × 2 volumes). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was purified by preparative-HPLC through a XBridge Phenyl OBD column, eluting with 55% to 65% MeOH in water + 10 mM NH 4 HCO 3 as a gradient. The product containing fractions were combined, concentrated and dried under vacuum to afford the title product as a white solid (58% yield). 1 H NMR (300 MHz, d6- DMSO) δH 7.91 (s, 1H), 7.76-7.58 (m, 2H), 7.63-7.50 (m, 1H), 7.43-7.40 (m, 1H), 7.34 (s, 1H), 7.15-7.09 (m, 1H), 7.05-6.94 (m, 1H), 4.17 (s, 2H), 3.17 (d, J = 6.9 Hz, 2H), 1.0-1.1 (m, 1H), 0.38- 0.15 (m, 4H). LC-MS (ESI) m/z 566 (M+H) + . MW: 565.01 Example 9: Preparation of 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)oxazole- 4-carboxylic acid
[000210] Step 1: Preparation of ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)oxazole- 4-carboxylate [000211] Into a round-bottom flask equipped with a magnetic stir bar and under N2 was added 4-((5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl )methyl)-2- fluorobenzenesulfonamide (Intermediate G, 1.0 equiv), ethyl 2-chlorooxazole-4-carboxylate (1.5 equiv) and DMF (0.1 M). The solution was cooled to 0 °C in an ice bath and sodium tert-pentoxide (2.0 equiv) was added. The mixture was allowed to warm to 23 °C over 30 minutes and stirred at this temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH 4 Cl solution (3 volumes) and the residue was poured into a Cl-phase separatory cartridge and extracted with CH 2 Cl 2 (3 × 2 volumes). The combined organic layers were concentrated and loaded onto a C18 precartridge and dried. Purification by reverse-phase column chromatography through a C18 column, eluting with 95:5 to 20:80 H 2 O:MeCN + 0.1% HCO 2 H as a gradient over 25 min, collecting all peaks. The desired product containing fractions were concentrated and dried under vacuum, yielding the title product (34% yield). [000212] Step 2: Preparation of 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-(4-fluorophenyl)-1-pyrazol-1-yl)oxazole-4 -carboxylic acid [000213] Into a round-bottom flask equipped with a magnetic stir bar and under N2 was added ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4 -fluorophenyl)- 1H-pyrazol-1-yl)oxazole-4-carboxylate (1.0 equiv) and THF/MeOH (1:1 v/v, 0.2 M). The solution was treated with 1.0 M aqueous LiOH solution (2.5 equiv) and the mixture was stirred at 23 °C for 18 h overnight. The mixture was quenched dropwise with concentrated formic acid until the pH was 4 and the mixture concentrated under reduced pressure. The residue was loaded onto a C18 precartridge and dried. Purification by reverse-phase column chromatography through a C18 column, eluting with 90:10 to 10:90 H 2 O:MeCN + 0.1% HCO 2 H as a gradient over 25 min, collecting all peaks. The desired product containing fractions were concentrated and dried under vacuum, yielding the title product as a white solid (49% yield). 1 H NMR (400 MHz, d6-DMSO) δH 8.80 (s, 1H), 7.67 – 7.54 (m, 5H), 7.22 (t, J = 8.5 Hz, 2H), 7.09 (d, J = 11.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 4.14 (s, 2H), 2.96 (d, J = 7.0 Hz, 2H), 1.00-0.98 (m, 1H), 0.34-0.29 (m, 2H), 0.11- 0.08 (m, 2H). LC-MS (ESI) m/z 515 (M+H) + . MW: 514.1 Example 10: Preparation of 2-(4-(3-Chloro-4-sulfamoylbenzyl)-5- (cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiaz ole-4- carboxylic acid
[000214] Step 1: Preparation of 2-chloro-4-(4-cyclopropyl-2-(4-fluorobenzoyl)-3- oxobutyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide [000215] Into a round-bottom flask equipped with a magnetic stir bar was placed 4- cyclopropyl-1-(4-fluorophenyl)butane-1,3-dione (Intermediate F, 1.0 equiv), 4-(bromomethyl)- 2-chloro-N,N-bis[(4-methoxyphenyl)methyl]benzenesulfonamide (prepared in the same manner as Intermediate C, 0.5 equiv), K 3 PO 4 (0.5 equiv) and DMSO (0.9 M). The resulting mixture was stirred at room temperature for 12 h. When the reaction was complete, as evident by LCMS analysis, the reaction mixture quenched by the addition of water (4 volumes) and poured into a separatory funnel and extracted with EtOAc (3 × 3 volumes). The organic layers were washed with brine (2 volumes), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (3:2). The title compound was obtained as yellow oil (23% yield). [000216] Step 2: Preparation of 2-chloro-4-[[3-(cyclopropylmethyl)-5-(4- fluorophenyl)-2H-pyrazol-4-yl]methyl]-N,N-bis[(4-methoxyphen yl)methyl]benzenesulfonamide [000217] Into a round-bottom flask equipped with a magnetic stir bar, was placed 2- chloro-4-[4-cyclopropyl-2-(4-fluorobenzoyl)-3-oxobutyl]-N,N- bis[(4- methoxyphenyl)methyl]benzenesulfonamide (1.0 equiv), hydrazine monohydrate (8.0 equiv) and EtOH (0.11 M).The resulting solution was heated in an oil bath to 70 °C for 1 h. LC-MS analysis indicated consumption of starting material and formation of product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (2:3). The product containing fractions were combined, concentrated and dried under vacuum to afford the title compound as a yellow solid (50% yield). [000218] Step 3: Preparation of ethyl 2-[4-[(4-[bis[(4- methoxyphenyl)methyl]sulfamoyl]-3-chlorophenyl)methyl]-5-(cy clopropylmethyl)-3-(4- fluorophenyl)pyrazol-1-yl]-1,3-thiazole-4-carboxylate [000219] Into a round bottom flask equipped with a magnetic stir bar, 2-chloro-4-[[3- (cyclopropylmethyl)-5-(4-fluorophenyl)-2H-pyrazol-4-yl]methy l]-N,N-bis[(4- methoxyphenyl)methyl]benzenesulfonamide (1.0 equiv), ethyl 2-methanesulfonyl-1,3-thiazole-4- carboxylate (Intermediate H, 5.0 equiv), DMSO (0.03 M) and K 2 CO 3 (3.0 equiv). The resulting solution was heated to 120 °C for 12 h in an oil bath. When the reaction was completed, as evident by LCMS analysis, the reaction mixture was cooled to 23 °C and quenched by the addition of water (2 volumes). The resulting mixture was extracted with ethyl acetate (3 × 2 volumes) and the organic fractions were combined and concentrated under reduced pressure. The resulting residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (1:1). The product containing fractions were combined, concentrated and dried under vacuum to afford the desired compound as a white solid (88% yield). [000220] Step 4: Preparation of ethyl 2-(4-(3-chloro-4-sulfamoylbenzyl)-5- (cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiaz ole-4-carboxylate [000221] Into a round bottom flask equipped with a magnetic stir was added ethyl 2- [4-[(4-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-3-chloropheny l)methyl]-5- (cyclopropylmethyl)-3-(4-fluorophenyl)pyrazol-1-yl]-1,3-thia zole-4-carboxylate (1.0 equiv), TFA (0.12 M) and triethylsilane (0.03 M). The resulting mixture was stirred at 23 °C for 4 h. The reaction was monitored for consumption of starting material, and when complete, concentrated under reduced pressure. The crude residue was applied onto a silica gel column and the column was eluted with petroleum ether/ethyl acetate (2:1). The product containing fractions were combined, concentrated and dried under vacuum to afford the title compound as a white solid (84% yield). [000222] Step 5: Preparation of 2-[4-[(3-chloro-4-sulfamoylphenyl)methyl]-5- (cyclopropylmethyl)-3-(4-fluorophenyl)pyrazol-1-yl]-1,3-thia zole-4-carboxylic acid [000223] Into a round-bottom flask equipped with a magnetic stir, was added ethyl 2- (4-(3-chloro-4-sulfamoylbenzyl)-5-(cyclopropylmethyl)-3-(4-f luorophenyl)-1H-pyrazol-1- yl)thiazole-4-carboxylate (1.0 equiv), MeOH (0.02 M), H 2 O (0.09 M) and solid NaOH (5.0 equiv). The resulting mixture was heated to 80 °C for 4 h. When the was reaction complete, as evident by LCMS analysis, the reaction mixture was cooled to room temperature and quenched by the addition of water (2 volumes). The mixture was extracted with ethyl acetate (3 × 2 volumes) and the combined organic layers were concentrated under reduced pressure. The crude product was purified by preparative HPLC through a C18 column, eluting with 90:10 to 50:50 water:MeCN as a gradient over 10 min. The product containing fractions were combined, concentrated and dried under vacuum to afford the desired compound as a white solid (18% yield). 1 H NMR (300 MHz, CD 3 OD) δ H 8.08 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.58-7.53 (m, 2H), 7.30 (s, 1H), 7.19-7.00 (m, 3H), 4.13 (s, 2H), 3.24 (d, J = 7.0 Hz, 2H), 1.00-0.98 (m, 1H), 0.37-0.35 (m, 2H), 0.25-0.15 (m, 2H). LC-MS (ESI) m/z 547 (M+H) + . MW: 546.06 Example 11: Preparation of 2-(3-(3-Cyanophenyl)-5-(cyclopropylmethyl)-4- (3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carb oxylic acid [000224] Step 1: Preparation of ethyl 2-(3-(3-cyanophenyl)-5-(cyclopropylmethyl)- 4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-ca rboxylate [000225] Into a reaction vial was added ethyl 2-(3-(3-bromophenyl)-5- (cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazo l-1-yl)thiazole-4-carboxylate (Intermediate B, 1.0 equiv), zinc cyanide (2.0 equiv), Pd(PPh3)4 (0.2 equiv) and DMF (0.2 M). The mixture was heated to 100 °C for 2 hours. LCMS analysis after this time indicated completion of reaction. The mixture was loaded onto a silica gel pre-cartridge and dried under vacuum. The mixture was purified by column chromatography through silica gel, eluting with 95:5 to 0:100 hexanes:EtOAc as a gradient over 25 minutes, collecting all peaks. The desired product containing fractions were concentrated and dried under vacuum to afford a clear oil (45% yield). [000226] Step 2: Preparation of 2-(3-(3-cyanophenyl)-5-(cyclopropylmethyl)-4-(3- fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxy lic acid [000227] Into a round bottom flask equipped with a magnetic stir bar was added ethyl 2-(3-(3-cyanophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sul famoylbenzyl)-1H-pyrazol-1- yl)thiazole-4-carboxylate (1.0 equiv), THF/MeOH (1:1 v/v, 0.2 M) and 1 M aqueous LiOH solution (3 equiv). The mixture was stirred at 23 °C for 2 hours after which LCMS indicated completion of hydrolysis. The reaction was quenched with formic acid to pH~2. The mixture was concentrated and purified by reverse phase preparative HPLC on a C18 column, eluting with 90:10 to 0:100 water:MeCN + 0.1% formic acid as a gradient over 25 minutes, collecting all peaks. The desired product containing fractions were concentrated and lyophilized overnight to yield the title product as a white powder (89% yield). LC-MS (ESI) m/z 538 (M+H) + . MW: 537.58
Example 12: Preparation of 2-(5-(Cyclopropylmethyl)-3-(3,4-difluorophenyl)- 4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-ca rboxylic acid [000228] To a mixture of ethyl 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoyl- phenyl)methyl]-3-(trifluoromethylsulfonyloxy)pyrazol-1-yl]th iazole-4-carboxylate (Intermediate D) (1.0 equiv), tBuXPhos-Pd-G3 (0.1 equiv) and 3,4-difluorophenylboronic acid (2.0 equiv) in 1,4-dioxane (0.05 M) was added anhydrous potassium phosphate (3.0 equiv). This mixture was degassed with nitrogen for 10 minutes before being heated to 90 °C for 2 hours. To this mixture was added sat. aq. NH 4 Cl solution (1 volume) and water (2.5 volumes) and extracted with EtOAc (2 × 5 volumes). The combined extracts were washed with water (1.5 volumes) and concentrated under vacuum. This residue was dissolved in THF/MeOH (1:1 v/v) (1 volume). A solution of 1 M aqueous LiOH (6.0 equiv) was added and the mixture was stirred at 23 °C for 16 hours. Upon completion of hydrolysis indicated by LCMS analysis the mixture was acidified with formic acid (15 equiv). The reaction mixture was loaded directly to a C18 pre-cartridge and dried. This material was purified by reverse phase column chromatography using a C18 column eluting with a 10-100% CH3CN/water gradient containing 0.1% HCO 2 H. The pure fractions from the major peak which eluted at 83% CH 3 CN were combined and lyophilized to provide the title product as a white solid (86% yield). 1 H NMR (400 MHz, d6-DMSO) δH 13.16 (br s, 1H), 8.28 (s, 1H), 7.65-7.55 (m, 2H), 7.58 (br s, 2H), 7.50-7.35 (m, 2H), 7.12 (d, J = 11.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.16 (s, 2H), 3.15 (d, J = 6.5 Hz, 2H), 1.15-1.07 (m, 1H), 0.36-0.28 (m, 2H), 0.23- 0.17 (m, 2H). LC-MS (ESI) m/z 549 (M+H) + . MW: 548.1 [000229] The following examples were prepared as in Example 12 by replacing 3,4- difluorophenylboronic acid with the requisite boronic acids or boronate esters. Additionally, the tBuXPhos-Pd-G3 may be replaced with other metal catalyst systems including XPhos-Pd-G3 and Pd(dppf)Cl2·CH 2 Cl 2 . Example 27: 2-(5-(Cyclopropylmethyl)-4-(3,5-difluoro-4-sulfamoylbenzyl)- 3- (4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid [000230] Step 1: Preparation of 4-(bromomethyl)-2,6-difluorobenzenesulfonyl chloride [000231] Into a round bottom flask equipped with a magnetic stir bar was placed 2,6- difluoro-4-methylbenzenesulfonyl chloride (1.0 equiv), NBS (1.1 equiv), AIBN (0.1 equiv) and MeCN (0.2 M). The resulting suspension was stirred at -10 °C for 4 h. LCMS analysis indicated conversion of starting material, and the resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative-HPLC through a C18 column, eluting with 90:10 to 50:50 water:MeCN. The product containing fractions were combined, concentrated and dried under vacuum to afford the desired compound as a brown yellow oil (55% yield). [000232] Step 2: Preparation of 4-(bromomethyl)-2,6-difluoro-N,N-bis(4- methoxybenzyl)benzenesulfonamide [000233] Into a round bottom flask equipped with a magnetic stir bar was placed bis[(4-methoxyphenyl)methyl]amine (1.0 equiv), 4-(bromomethyl)-2,6-difluorobenzenesulfonyl chloride (0.6 equiv), Na2CO3 (3.0 equiv) and CH 2 Cl 2 (0.16 M). The resulting suspension was stirred at -10 °C for 4 h. The reaction quenched with water (2 volumes), poured into a separatory funnel and extracted with CH 2 Cl 2 (3 × 2 volumes). The organic layers were combined and concentrated under reduced pressure. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). This product containing fractions were combined, concentrated and dried under vacuum to afford the title product as a white solid (27% yield). [000234] Step 3: Preparation of ethyl 2-(4-(4-(N,N-bis(4- methoxybenzyl)sulfamoyl)-3,5-difluorobenzyl)-5-(cyclopropylm ethyl)-3-(4-fluorophenyl)-1H- pyrazol-1-yl)thiazole-4-carboxylate [000235] Into a round bottom flask equipped with a magnetic stir bar, purged and maintained with an inert atmosphere of nitrogen was added 4-(bromomethyl)-2,6-difluoro-N,N- bis[(4-methoxyphenyl)methyl]benzenesulfonamide (1.0 equiv), ethyl 2-[5-(cyclopropylmethyl)- 3-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)pyrazol-1-yl]-1,3-thiazole-4- carboxylate (prepared in the same manner as described in the borylation step 3 for the synthesis of Example 3, 1.0 equiv), Pd(dppf)Cl2 (0.1 equiv), Na 2 CO 3 (3.0 equiv), dioxane (0.15 M) and H 2 O (0.03 M). The resulting mixture was heated to 40 °C for 4 h. The reaction was monitored for consumption of starting material, and when complete, the reaction mixture was cooled and quenched with water (2 volumes). The resulting mixture was extracted with ethyl acetate (4 × 2 volumes). The organic layers were combined and concentrated under reduced pressure. The resulting residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). The product containing fractions were combined, concentrated and dried under vacuum to afford the title product as a yellow green solid (32% yield). [000236] Step 4: Preparation of ethyl 2-(5-(cyclopropylmethyl)-4-(3,5-difluoro-4- sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole -4-carboxylate [000237] Into a round bottom flask equipped with a magnetic stir bar was placed ethyl 2-[4-[(4-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-3,5-difluor ophenyl)methyl]-5- (cyclopropylmethyl)-3-(4-fluorophenyl)pyrazol-1-yl]-1,3-thia zole-4-carboxylate (1.0 equiv), TFA (0.01 M) and triethylsilane (0.05 M). The resulting mixture was heated to 40 °C for 2 h. The reaction was monitored for consumption of starting material, and when complete, the cooled reaction mixture was quenched with water (2 volumes). The resulting mixture was extracted with ethyl acetate (3 × 2 volumes). The organic layers were combined and concentrated under reduced pressure. The crude product was used in the next step directly without further purification. [000238] Step 5: Preparation of 2-(5-(cyclopropylmethyl)-4-(3,5-difluoro-4- sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid [000239] Into a round bottom flask equipped with a magnetic stir bar was placed ethyl 2-[5-(cyclopropylmethyl)-4-[(3,5-difluoro-4-sulfamoylphenyl) methyl]-3-(4- fluorophenyl)pyrazol-1-yl]-1,3-thiazole-4-carboxylate (1.0 equiv), solid LiOH (8.0 equiv), MeOH (0.04 M) and H 2 O (0.04 M). The resulting solution was stirred at room temperature for 4 h. The resulting mixture concentrated under reduced pressure. The crude product was purified by preparative HPLC through an XBridge C18 column, eluting with 27:82 to 57:43 MeCN:water (+10 mM NH4HCO3) as a gradient over 7 minutes. The product containing fractions were combined, concentrated and dried under vacuum to afford the title product as a white solid (9% yield). LC- MS (ESI) m/z 549 (M+H) + . MW: 548.56 Example 28: Preparation of 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4- sulfamoylbenzyl)-3-(3,4,5-trifluorophenyl)-1H-pyrazol-1-yl)t hiazole-4- carboxylic acid
[000240] To a mixture of ethyl 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoyl- phenyl)methyl]-3-(trifluoromethylsulfonyloxy)pyrazol-1-yl]th iazole-4-carboxylate (Intermediate D, 1.0 equiv), tBuXPhos-Pd-G3 (0.1 equiv) and 3,4,5-trifluorophenylboronic acid (2.0 equiv) in 1,4-dioxane (0.06 M) was added anhydrous potassium phosphate (3.0 equiv). This mixture was degassed with nitrogen for 10 minutes before heated to 90 °C for 2 hours. To this mixture was added sat. aq. NH 4 Cl solution (1 volume) and water (2.5 volumes) and extracted with EtOAc (2 × 5 volumes). The combined extracts were washed with water (1.5 volumes) and concentrated under vacuum. This residue was dissolved in THF/MeOH (1:1 v/v) (1 volume).1 M aq. LiOH solution (6.0 equiv) was added and the mixture was stirred at 23 °C for 16 hours. This mixture was acidified with formic acid (15 equiv) upon completion of hydrolysis indicated by LCMS analysis. The reaction mixture was loaded directly to a C18 pre-cartridge and dried. This material was purified by reverse phase column chromatography using a C18 column eluting with a 10-100% CH3CN/water gradient containing 0.1% HCO 2 H. The pure fractions from the major peak which eluted at 83% CH3CN were combined and lyophilized to provide the title product as a white solid (55% yield). 1H NMR (400 MHz, d6-DMSO) δH 13.22 (br s, 1H), 8.29 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (br s, 2H), 7.46 (dd, J = 6.5, 8.5 Hz, 2H), 7.12 (d, J = 11.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.18 (s, 2H), 3.16 (d, J = 7.0 Hz, 2H), 1.15-1.07 (m, 1H), 0.36-0.28 (m, 2H), 0.23-0.17 (m, 2H). LC-MS (ESI) m/z 567 (M+H)+. MW: 566.07 Example 29: Human LDHA Enzyme Assay [000241] Compounds were dissolved in DMSO and preincubated with human recombinant C-terminal His-tagged LDHA (0.070 μg/mL) for 10 min at room temperature in assay buffer consisting 50 mM Tris, pH 7.5 and 100 mM NaCl in black walled, clear bottom, non-binding 96-well plates. Equal volumes of substrate solution containing 100 μM of pyruvate and 100 μM of NADH in assay buffer was added to each well (final concentration 0.035 μg/mL enzyme, 50 μM pyruvate, 50 μM NADH, and 1% DMSO). For human serum albumin (HSA) shift assay, the compounds were preincubated with the enzyme in assay buffer containing 20% HSA before substrate addition (final concentration 10% HSA). The reaction was monitored at 340 nm on a plate reader (Molecular Devices) in kinetic mode for 15 min. The rate of the reaction was determined by plotting absorbance vs time. [000242] Table 2 shows LDHA enzyme inhibition for the compounds described below, categorized according to potency: IC 50 < 1 nM = +++; IC 50 between 1 to 10 nM = ++; IC 50 between 10 nM and 100 nM = +. Table 2. Example 30: Primary Mouse Hepatocyte Assay [000243] Compounds were evaluated in an ex vivo assay consisting of fresh primary mouse hepatocytes. Hepatocytes were isolated from wild type mice (C57BL/6NCrl from Charles River Labs) using a two-step collagenase perfusion technique which involves a sequential perfusion of anesthetized mice with Hanks’ balanced salt solution and collagenase. Following isolation, viable wild type hepatocytes (0.1 M cells/well) were incubated with test compound in presence of pyruvate and compound potency was evaluated by measuring the lactate produced by the cells using liquid chromatography coupled to mass spectrometry. Chromatographic separation was achieved on an XDB-C184.6 × 50 mm column (Agilent, Cat# 927975-902) at a flow rate of 1 mL/min. Mobile phase A consisted of 0.1 % formic acid in water and mobile phase B consisted of acetonitrile. A gradient program was initiated starting at 5% B which was held for 1 minutes, then ramped from 5% to 95% B over 1 minute. After holding at 95% B for 1 minute, the program changed back to 5% B. The column was equilibrated with 5% B for 1.5 minutes before the next injection. The mass spectrometer was operated in negative mode with electrospray ionization. The following transition along with their collision energy (CE) were used: 89→43 (CE: -16 V) for lactate and 92 → 45 (CE: -16 V) for 13 C 3 -Lactate (internal standard). [000244] Table 3 shows inhibition of lactate production in the primary mouse hepatocyte assay for the compounds described below. IC 50 < 100 nM = +++; IC 50 between 100 and 250 nM = ++; IC 50 between 250 nM and 1000 nM = +. Table 3. *Run at 0.4 M cells/well concentration of hepatocytes Example 31: PH1 AGXT Knockdown Mouse Model [000245] To assess the in vivo efficacy of LDH inhibitors, a mouse model with hepatic knockdown of the AGXT gene was developed. The model was generated through systemic administration of 0.4 mg/kg siRNA to c57bl/6 male mice (8 – 12 weeks of age, Charles River Labs). The AGXT siRNA was encapsulated in a lipid nanoparticle (XL-10 (KL-52) LNP as described in WO2016/205410) and its sequence was: 5'-AcAAcuGGAGGGAcAucGudTsdT-3' (modified sense strand sequence, N: RNA residues; dN: DNA residues; n: 2'-O-methyl residues; s: phosphorothioate residues) and 5'-ACGAUGUCCCUCcAGUUGUdTsdT-3' (modified antisense strand sequence, see annotation above for residue modifications). Administration of the AGXT siRNA was done intravenously on day 0 and day 7 to maintain >90% knockdown of hepatic AGXT expression throughout the experimental study. The AGXT-KD model presented robust elevation of the urinary oxalate excretion within 7 days post-administration to a similar extent as AGXT-null mice (Salido, Proc Natl Acad Sci, 2006, 103(48), 18249–18254). Prior to initiation of treatment with LDH inhibitor, oxalate and creatinine levels in urine were assessed and animals were assigned to treatment groups. [000246] Certain select compounds disclosed herein were administered at 5 mg/kg QD (PO) per os over 5 consecutive days, starting 8 days after initial AGXT-siRNA administration. Once oral treatment was completed, mice were placed in metabolic cages and urine was collected over 24 hours. Sacrifice was performed after completion of the urine collection, and plasma / selected organs were collected and analyzed for drug concentrations. [000247] Urinary oxalate and creatinine were quantified using commercially available kits according to manufacturer’s protocol (Trinity Biotech USA Inc., catalog #591; R&D Systems, Inc., catalog #KGE005). Oxalate results were normalized to creatinine to account for urine diluteness. Tested compounds of Formula (I) were found to reduce urinary oxalate (normalized for creatinine) on day 5, ranging from a reduction of 17% to 55% as shown in Table 4 and in FIG.1. Table 4. Example 32: Liver-Targeted Tissue Distribution Profile Studies [000248] Plasma and liver (target organ) concentrations of test compounds were determined in rats following a single per os (PO) administration of the test compounds. Male Sprague Dawley rats (6 – 8 weeks of age, Charles River Labs) were fasted overnight and a single dose of test compounds (10 mg/kg; as a suspension in 0.5% methyl cellulose) was administered by PO gavage. Rats were then sacrificed at 4 and 24 h after administration of the test compounds, and plasma and liver tissue samples were collected. Liver tissue samples were homogenized in 5 volumes of water:acetonitrile (50/50; v/v) mixture using a bead mill homogenizer. Plasma and liver homogenate samples were processed by protein precipitation using acetonitrile and the concentrations of the test compounds were determined by liquid chromatography – tandem mass spectrometry (SciEx triple quad 5500+ with Exion UPLC). [000249] Liver and plasma exposures at the 4 h and 24 h timepoints for the various compounds are described in Table 5 below. Measured compound concentrations are as follows: ++++ > 10 μM; 10 μM ≥ +++ > 5 μM; 5 μM ≥ ++ > 1 μM; 1 μM ≥ + > 0.25 μM; and 0.25 μM ≥ -. Table 5. *Data obtained in c57/bl6 mice after a 20 mg/kg PO dose [000250] The XlogP values were also calculated for the compounds in Table 4 using Vortex v2018.09.76561.64-s, by Dotmatics Ltd. The XlogP distribution of the compounds in Table 5 are shown in FIG.2. Example 32: Rat Tolerability Assessment [000251] To assess the potential tolerability profile of the compounds provided herein, an in-house 7-day dose-limiting toxicity (DLT) studies in rats was performed. The primary variables assessed were body weight change, CBC parameters (including red-blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and reticulocytes), and serum biochemistry (alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total bilirubin and creatine kinase). [000252] Male Sprague Dawley Rats (Charles River Laboratories) of 8 weeks of age were weighed daily and test compound was dosed per os QD over 7 consecutive days. Animals were sacrificed 24h post 7 th dose. [000253] At study termination, spleen weight was recorded, and portions of liver, muscle, testes, spleen and kidney were collected to evaluate drug levels in those organs. Blood was collected and divided as follows: 1) serum sample for biochemistry, 2) CBC + manual reticulocyte count (K 3 EDTA), 3) CBC + automated reticulocyte count (K 3 EDTA), and 4) plasma sample for systemic drug level assessment. [000254] A compound of Formula (I) was tested at doses of 75, 125 and 300 mg/kg PO QD, and compared to a reference LDH inhibitor disclosed as Compound ID 408 in WO2016/109559 dosed at 65 and 100 mg/kg PO QD. As shown in Table 6, the measures for body weight, spleen weight, CBC parameters and serum biochemistry after seven days were found to be in the normal range at all three doses, compared to the reference LDH inhibitor, indicating that a seven-day QD dose at 300 mg/kg of this compound of Formula (I) is well tolerated in rats and provided a wider therapeutic window versus the LDH reference inhibitor (>40x). Table 6. [000255] Analysis of drug concentrations of the compound of Formula (I) in liver, muscle, testes, spleen, kidney and plasma collected at study termination (24 h post last PO dose) showed higher liver-to-non-liver tissue ratios than was found for the reference LDH inhibitor, which suggest that this compound has greatly improved liver exposure compared to the reference compound. The reference LHD inhibitor exhibited a liver-to-muscle ratio of about 2:1 and in certain embodiments, the compound of Formula (I) exhibits a liver-to-muscle ratio of greater than about 20:1, greater than about 25:1, greater than about 50:1, greater than about 80:1, or greater than about 100:1. The reference LDH inhibitor exhibited a liver-to-testes ratio of 6:1 while in certain embodiments, the compound of Formula (I) exhibits a liver-to-testes ratio of greater than about 20:1, greater than about 25:1, greater than about 50:1, greater than about 80:1, or greater than about 100:1. [000256] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials and procedures. All such equivalents are considered to be within the scope of the claimed subject matter and are encompassed by the appended claims. Since modifications will be apparent to those of skill in the art, it is intended that the claimed subject matter be limited only by the scope of the appended claims.
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