FAHR BRUCE (US)
RAI ROOPA (US)
GREEN MICHAEL J (US)
| WO2020252146A1 | 2020-12-17 | |||
| WO2020160151A1 | 2020-08-06 | |||
| WO2022082009A1 | 2022-04-21 |
| US20100324011A1 | 2010-12-23 |
| CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof: wherein, ring Q is C6 aryl or 5 to 10-membered heteroaryl; A1 is CR1 or N and A2 is CR2 or N, provided that at least one of A1 or A2 is N; A3 is N or CR7; W is -CR6R6- , -O-, -S-, -NR5-, -S(O)-, -S(O)2-, or -C(O)-; R1 and R2 are each independently H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, – C(O)NR8R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3 is independently selected from H, halogen, -CN, –NR8R9, –OR10, CN, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, – NR12C(O)NR8R9, -OC(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; R5 is H or C1-C6 alkyl; and each R6 is independently H, halogen, -CN, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1-C6 alkyl; or two R6 can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; R7 is H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, -NR8C(O)R9, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8 and R9 are independently selected at each occurrence from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C10 cycloalkyl; each R10 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl; each R11 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl; each R12 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; n and m are each independently 0, 1, 2, or 3; q is 0, 1, or 2; and p is 1, 2, or 3. 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is a bicyclic or monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from O, S, and N. 3. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is a phenyl, pyrimidinyl, or pyridinyl. 4. The compound of any one of claims 1-3, wherein the compound has the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof: wherein, X2 is N, NR3A, or CR3A; X3 is N or CR3B; X4 is N, NR3C, or CR3C; and R3A, R3B, and R3C are each independently H, halogen, -CN, –NR8R9, –OR10, CN, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)OR10, – NR12C(O)NR8R9, –NR12SO2R10, –NR12SO2NR8R9, -OC(O)NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; R3A and R3B together with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl; or R3B and R3C together with the atoms to which they are attached form a substituted or unsubstituted 5 to 6-membered aryl or heteroaryl; and wherein CR3A, CR3B, and CR3C are not all H at the same time. 5. The compound of claim 4, wherein the compound has the structure of Formula (VIa), (VIb), or (VIc), or a pharmaceutically acceptable salt or solvate thereof: . 6. The compound of claim 4 or 5, or a pharmaceutically acceptable salt or solvate thereof, wherein X4 is CR3C and X5 is CH. 7. The compound of claim 4 or 5, or a pharmaceutically acceptable salt or solvate thereof, wherein X4 is CR3C and X5 is N. 8. The compound of claim 4 or 5, or a pharmaceutically acceptable salt or solvate thereof, wherein X4 is N and X5 is CH. 9. The compound of any one of claims 4-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R3B and R3C together with the atoms to which they are attached form a substituted or unsubstituted 5-membered heteroaryl. 10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R3B and R3C together with the atoms to which they are attached form a 5-membered heteroaryl comprising 1, 2, or 3 N atoms. 11. The compound of claim 4, wherein the compound has the structure of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIII) wherein, X2 is N or CH; and R3C is H or halogen and R3B is selected from H, halogen, -CN, –NR8R9, –OR10, –C(O)R10, – C(O)OR10, –C(O)NR8R9, -NR12C(O)NR8R9, -NR12C(O)OR10, -OC(O)NR8R9, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl; or R3B is selected from H, halogen, -CN, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, - NR12C(O)NR8R9, -NR12C(O)OR10, -OC(O)NR8R9, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3- C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. 12. The compound of claim 11, wherein the compound has the structure of Formula (VIIa), (VIIb), or (VIIc), or a pharmaceutically acceptable salt or solvate thereof: 13. The compound of claim 11 or 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R3C is H or halogen; and R3B is selected from H, halogen, -CN, –NR8R9, –OR10, – C(O)R10, –C(O)OR10, –C(O)NR8R9, -NR12C(O)NR8R9, -NR12C(O)OR10, -OC(O)NR8R9, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. 14. The compound of claim 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R3C is H; and R3B is –C(O)R10, –C(O)NR8R9, -NR12C(O)OR10, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. 15. The compound of claim 11 or 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R3B is a selected from H, halogen, -CN, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, – C(O)NR8R9, -NR12C(O)NR8R9, -NR12C(O)OR10, -OC(O)NR8R9, substituted or unsubstituted C1- C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl; and R3C is H or halogen. 16. The compound of claim 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R3B is –C(O)R10, –C(O)NR8R9, -NR12C(O)OR10, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl; and R3C is H. 17. The compound of any one of claims 4-16, or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is N. 18. The compound of any one of claims 4-16, or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is CH. 19. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is a 5-membered heteroaryl selected from triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl. 20. The compound of any one of claims 1, 2, or 19, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is Y1 is O, S, or NR3D; Y2 is N or CR3A; Y3 and Y4 are each independently N or CR3B; R3A and R3B are each independently selected from H, halogen, -CN, –NR8R9, –OR10, – C(O)R10, –C(O)OR10, –C(O)NR8R9, -NR8C(O)NR8R9, -NR8C(O)OR10, - OC(O)NR8R9, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. 21. The compound of claim 20, wherein the compound has the structure of Formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf), or a pharmaceutically acceptable salt or solvate thereof: 22. The compound of claim 20 or 21, or a pharmaceutically acceptable salt or solvate thereof, wherein: Y1 is O or S; Y2 is CR3A; and Y3 and Y4 are each independently N or CR3B. 23. The compound of claim 20 or 21, or a pharmaceutically acceptable salt or solvate thereof, wherein: Y1 is O or S; Y2 is N; and Y3 and Y4 are each independently N or CR3B. 24. The compound of claim 1 or 2, wherein ring Q is a bicyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected form N, S, and O. 25. The compound of any one of clams 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein W is -O-, -S-, or -S(O)2-. 26. The compound of any one of clams 1-24, of a pharmaceutically acceptable salt or solvate thereof, wherein W is -NR13-. 27. The compound of any one of claims 1-24, of a pharmaceutically acceptable salt or solvate thereof, wherein W is -CR6R6-. 28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently halogen, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, –C(O)NR8R9, or substituted or unsubstituted C1-C6 alkyl. 29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently F, -NH2, -OH, -OCH3, or -CH3. 30. The compound of any one of claims 1-27, wherein R6 is not halogen. 31. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, two R6 can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl ring. 32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2; and m is 0 or 1. 33. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein: 34. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein: 35. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: Formula (I) wherein, ring Q is C6 aryl or 5- to 10-membered heteroaryl; L is -CR13AR13B-, -C(O)-, -S-, -S(O)-, -S(O)2-, or -S(O2)NH-; A1 is N or CR1 and A2 is N or CR2, provided that at least one of A1 or A2 is N; A3 is N or CR7; R1 and R2 are each independently H, halogen, -CN, –OR10, –C(O)R10, –C(O)OR10, –NR8R9, – C(O)NR8R9, -NR8C(O)R9 substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R3 is independently selected from H, halogen, -CN, –NR8R9, –OR10, CN, –C(O)R10, – C(O)OR10, –C(O)NR8R9, –SOR11, –SO2R11, –SO2NR8R9, –NR12C(O)R10, –NR12C(O)NR8R9, – NR12SO2R10, –NR12SO2NR8R9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; R4 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 heteroalkyl; , wherein W is -CR6R6- , -O-, -S-, -NR5-, -S(O)2-, or -C(O)-; R5 is H or substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; each R6 is independently H, halogen, CN, –NR8R9, –OR10, –C(O)R10, –C(O)OR10, – C(O)NR8R9, –SOR11, –SO2R11, substituted or unsubstituted C1-C6 alkyl, -NR8C(O)R9, - SR8, or C3-C8 cycloalkyl; or two R6 can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3-C8 heterocycloalkyl ring; n and m are each independently 0, 1, 2, or 3; and q is 0, 1, 2, 3, 4, 5, or 6; R7 is H, halogen, –OR10, –C(O)R10, –C(O)OR10, -CN, –C(O)NR8R9, -NR8C(O)R9, or substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; each R8 and R9 are independently selected at each occurrence from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl and C3-C10 heterocycloalkyl each R10 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl; each R11 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl; each R12 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; R13A and R13B are each independently H, CF3, halogen, or C1-C6 alkyl; and p is 1, 2, 3, or 4. 36. The of claim 35, wherein the compound has the structure of Formula (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof: 37. The compound of claim 35 or 36, or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -S-, -S(O)-, or -S(O)2-; and R4 is substituted or unsubstituted C1-C8 alkyl. 38. The compound of claim 35 or 36, or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -C(O)-; and . 39. The compound of any one of claims 35-38, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1 or 2. 40. The compound of any one of claims 35-39, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is phenyl or a 6-membered heteroaryl. 41. The compound of any one of claims 35-39, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is phenyl, pyrimidinyl, or pyridinyl. 42. The compound of any one of claims 35-39, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is wherein; X1, X2, X3, X4, and X5 are each independently N or CR3; and wherein at least two of X1-X5 is CR3. 43. The compound of claim 42, or a pharmaceutically acceptable salt or solvate thereof, wherein: X1 and X5 are each independently N or CH; X2 is N or CR3A; X3 is N or CR3B; X4 is N, NR3C, or CR3C; and R3A, R3B, and R3C are each independently selected from H, halogen, -CN, –NR8R9, –OR10, – C(O)R10, –C(O)OR10, –C(O)NR8R9, -NR8C(O)NR8R9, -NR8C(O)OR10, -OC(O)NR8R9, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5- membered heteroaryl. 44. The compound of any one of claims 35-39, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is a 5-membered heteroaryl. 45. The compound of any one of claims 35-39, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is a 5-membered heteroaryl selected from triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl. 46. The compound of any one of claims 35-39, or a pharmaceutically acceptable salt or solvate thereof, wherein ring Q is , wherein Y1 is O, S, or NR3D; Y2 is N or CR3A; Y3 and Y4 are each independently N or CR3B; R3A and R3B are each independently selected from H, halogen, -CN, –NR8R9, –OR10, – C(O)R10, –C(O)OR10, –C(O)NR8R9, -NR8C(O)NR8R9, -NR8C(O)OR10, - OC(O)NR8R9, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. 47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from H, halogen, -CN, –NR8R9, –OR10, –C(O)R10, – C(O)OR10, –C(O)NR8R9, -NR8C(O)NR8R9, -NR8C(O)OR10, -OC(O)NR8R9, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. 48. The compound of claim 47, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from H, halogen, –C(O)R10, –C(O)NR8R9, -NR8C(O)NR8R9, - NR8C(O)OR10, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. 49. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from the group consisting of 50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is H or substituted or unsubstituted C1-C6 alkyl; and R2 is H or substituted or unsubstituted C1-C6 alkyl. 51. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is H and R2 is H. 52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt or solvate thereof, wherein A3 is N. 53. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt or solvate thereof, wherein A3 is CR7. 54. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is H. 55. The compound of any one of claims 1-54, wherein the compound is selected from Table 1a or Table 1b, or a pharmaceutically acceptable salt or solvate thereof. 56. A pharmaceutical composition comprising a compound of any one of claims 1-55, or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable excipient. 57. A method of promoting and/or stimulation skin pigmentation, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 58. A method of inhibiting hair loss, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 59. A method of preventing and/or treating skin inflammation and/or damage, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 60. A method of preventing and/or treating vascular insufficiency, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 61. A method of preventing, treating, minimizing and/or reversing congestive heart failure, cardiomyopathy, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 62. A method of reducing cardiac ejection fraction, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 63. A method of preventing and/or treating a gastrointestinal disease, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 64. A method of preventing and/or treating renal dysfunction, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 65. A method of stimulation bone resorption and bone formation, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 66. A method of stimulating tissue regeneration by stimulating, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 67. A method of modulating cervical ripening, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 68. A method of promoting neuroprotection and/or stimulating neuronal regeneration, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 69. A method of treating and/or preventing a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 70. A method of treating and/or preventing fibrotic or adhesion disease, disorder or condition, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 71. A method of reducing and/or preventing scar formation, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 72. A method of treating and/or preventing muscle disorder, muscle injury and/or muscle atrophy, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 73. A method of treating and/or preventing fibrosis, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 74. A method of treating and/or preventing idiopathic pulmonary fibrosis, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 75. A method of treating and/or preventing kidney fibrosis, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 76. A method of stimulating muscle regeneration, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 77. A method of promoting organ fitness, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 78. A method of promoting wound healing, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 79. A method of treating acute kidney injury, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 80. A method of treating sarcopenia, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. 81. A method of treating a neuromuscular disease, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof. |
[ 0125] In some embodiments, each R 3 is independently –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , or – NR 12 C(O)OR 10 . In some embodiments, each R 3 is independently –C(O)R 10 , –C(O)NR 8 R 9 , or – NR 12 C(O)OR 10 . In some embodiments, each R 3 is independently –C(O)R 10 . In some embodiments, each R 3 is independently –C(O)OR 10 . In some embodiments, each R 3 is independently–C(O)NR 8 R 9 . In some embodiments, each R 3 is independently –NR 12 C(O)OR 10 . [0126] In some embodiments, each R 3 is independently selected from , , [0127] In some embodiments, the definitions of R 3 are each independently the same as the definitions of R 3A , R 3B , and R 3C . In some embodiments, the definitions of R 3 are the same as the definitions of R 3A . In some embodiments, the definitions of R 3 are the same as the definitions of R 3B . In some embodiments, the definitions of R 3 are the same as the definitions of R 3C . [0128] In some embodiments, ring Q is a bicyclic heteroaryl. In some embodiments, ring Q is a bicyclic heteroaryl comprising 1-3 heteroatoms selected from N, O, and S atoms. In some embodiments, ring Q is a bicyclic heteroaryl comprising 1, 2, or 3 N atoms. In some embodiments, ring Q is [1,2,4]triazolo[1,5- a]pyridine. [0129] In some embodiments, ring Q is wherein, ring A is a 5-membered heteroaryl optionally comprising 1 or 2 N atoms; X 6 is C or N; and R 15 is H, halogen, –NR 8 R 9 , –substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalkyl. [0130] In some embodiments, ring A is imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In some embodiments, ring Q is pyrazolyl. In some embodiments, ring Q is imidazolyl. In some embodiments, ring Q is triazolyl. [0131] In some embodiments, X 6 is C. In some embodiments, X 6 is N. [0132] In some embodiments, R 15 is H, halogen, –NR 8 R 9 , –C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, R 15 is H. In some embodiments, R 15 is –NR 8 R 9 . In some embodiments, R 15 is -NH 2 , - NHCH3, or -N(CH3)2. In some embodiments, R 15 is –C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments, R 15 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, or CHF2. [0133] In some embodiments, R 15 is substituted or unsubstituted C 3 -C 8 cycloalkyl. In some embodiments, R 15 is substituted or unsubstituted C 3 -C 8 heterocycloalkyl. In some embodiments, R 15 is [0134] In some embodiments, L is -S-, -S(O)-, or -S(O)2-. In some embodiments, L is -S-. In some embodiments, L is -S(O)-. In some embodiments, L is -S(O)2-. In some embodiments, L is -C(O)-. In some embodiments, L is -O-. In some embodiments, L is -CR 6 R 6 - . In some embodiments, L is -C(O)R 10 -. [0135] In some embodiments, L is -S-, -S(O)-, or -S(O)2-; and R 4 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 heteroalkyl. [0136] In some embodiments, L is -S-, -S(O)-, or -S(O) 2 -; and R 4 is substituted or unsubstituted C 1 -C 6 alkyl. [0137] In some embodiments, R 4 is substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 1 -C 8 heteroalkyl. In some embodiments, R 4 is substituted or unsubstituted C 1 -C 8 alkyl. In some embodiments, R 4 is substituted or unsubstituted C 2 -C 8 alkenyl. In some embodiments, R 4 is substituted or unsubstituted C 1 -C 8 heteroalkyl. [0138] In some embodiments, L is C(O); and R 4 is . [0139] In another aspect, provided herein is a compound having the structure of Formula (V), or a pharmaceutically acceptable salt or solvate thereof: wherein, ring Q is C 6 aryl or 5 or 10-membered heteroaryl; A 1 is CR 1 or N and A 2 is CR 2 or N, provided that at least one of A 1 or A 2 is N; A 3 is N or CR 7 ; W is -CR 6 R 6 - , -O-, -S-, -NR 5 -, -S(O) 2 -, or -C(O)-; R 1 and R 2 are each independently H, halogen, -CN, –OR 10 , –C(O)R 10 , –C(O)OR 10 , –NR 8 R 9 , –C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; each R 3 is independently selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)OR 10 , – C(O)NR 8 R 9 , –SOR 11 , –SO 2 R 11 , –SO 2 NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , –NR 12 C(O)NR 8 R 9 , - OC(O)NR 8 R 9 , –NR 12 SO 2 R 10 , –NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, substituted or unsubstituted C 6 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; R 5 is H or C 1 -C 6 alkyl; and each R 6 is independently CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –SOR 11 , –SO2R 11 , substituted or unsubstituted C 1 -C 6 alkyl; or two R 6 can join together with the atom(s) to which they are attached to form a C3-C6 cycloalkyl or C3- C8 heterocycloalkyl ring; R 7 is H, halogen, –OR 10 , –C(O)R 10 , –C(O)OR 10 , -CN, –C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; each R 8 and R 9 are independently selected at each occurrence from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, and C 3 -C 10 cycloalkyl; each R 10 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; each R 11 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; each R 12 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, and C 3 -C 8 cycloalkyl; n and m are each independently 0, 1, 2, or 3; q is 0, 1, or 2; and p is 1, 2, or 3. [0140] In some embodiments, the compound has the structure of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof: Formula (VI), wherein, X 2 is N, NR 3A , or CR 3A ; X 3 is N or CR 3B ; X 4 is N, NR 3C , or CR 3C ; and R 3A , R 3B , and R 3C are each independently H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)OR 10 , – C(O)NR 8 R 9 , –SOR 11 , –SO2R 11 , –SO2NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , –NR 12 C(O)NR 8 R 9 , – NR 12 SO2R 10 , –NR 12 SO2NR 8 R 9 , -OC(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; R 3A and R 3B together with the atoms to which they are attached form a substituted or unsubstituted 5 to 6- membered aryl or heteroaryl; or R 3B and R 3C together with the atoms to which they are attached form a substituted or unsubstituted 5 to 6- membered aryl or heteroaryl; and wherein CR 3A , CR 3B , and CR 3C are not all H at the same time. [0141] In some embodiments, the compound has the structure of Formula (VIa), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIa). [0142] In some embodiments, the compound has the structure of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIb). [0143] In some embodiments, the compound has the structure of Formula (VIc), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIc). [0144] In some embodiments, X 4 is N and X 5 is CH. In some embodiments, X 4 is CR 3C and X 5 is N. In some embodiments, X 4 is CR 3C and X 5 is CH. [0145] In some embodiments, X 2 is N and X 4 is CR 3C . In some embodiments, R 3B is H, and R 3C is – C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3C is H, and R 3B is –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. [0146] In some embodiments, X 2 is C 3A and X 4 is N. In some embodiments, R 3A is H, and R 3B is – C(O)R 10 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3B is H, and R 3A is –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. [0147] In some embodiments, X 2 is CR 3A and X 4 is CR 3C . In some embodiments, R 3A and R 3B are each H; and R 3C is –C(O)R 10 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3A and R 3C are each H; and R 3B is –C(O)R 10 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3B and R 3C are each H; and R 3A is –C(O)R 10 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. [0148] In some embodiments, the compound has the structure of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof: Formula (VII), wherein, X 2 is N or CH; and R 3C is H or halogen and R 3B is selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , –C(O)OR 10 , – C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl; or R 3B is selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , - NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl. [0149] In some embodiments, the compound has the structure of Formula (VIIa), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIIa). [0150] In some embodiments, the compound has the structure of Formula (VIIb), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIIb). [0151] In some embodiments, the compound has the structure of Formula (VIIc), or a pharmaceutically acceptable salt or solvate thereof: Formula (VIIc). [0152] In some embodiments, the compound has the structure of Formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf), or a pharmaceutically acceptable salt or solvate thereof:
[0153] In another aspect, provided herein is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof: wherein, ring Q is C 6 aryl or 5 or 10-membered heteroaryl; W is -CR 6 R 6 - , -O-, -S-, -NR 5 -, -S(O) 2 -, or -C(O)-; R 1 is H, halogen, -CN, –OR 10 , –C(O)R 10 , –C(O)OR 10 , –NR 8 R 9 , –C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; each R 3 is independently selected from H, halogen, -CN, –NR 8 R 9 , –OR 10 , CN, –C(O)R 10 , –C(O)OR 10 , – C(O)NR 8 R 9 , –SOR 11 , –SO 2 R 11 , –SO 2 NR 8 R 9 , –NR 12 C(O)R 10 , –NR 12 C(O)OR 10 , –NR 12 C(O)NR 8 R 9 , - OC(O)NR 8 R 9 , –NR 12 SO 2 R 10 , –NR 12 SO 2 NR 8 R 9 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, substituted or unsubstituted C 6 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; R 5 is H or C 1 -C 6 alkyl; and each R 6 is independently H, halogen, CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , –SOR 11 , –SO 2 R 11 , substituted or unsubstituted C 1 -C 6 alkyl; or two R 6 can join together with the atom(s) to which they are attached to form a C 3 -C 6 cycloalkyl or C 3 - C8 heterocycloalkyl ring; R 7 is H, halogen, –OR 10 , –C(O)R 10 , –C(O)OR 10 , -CN, –C(O)NR 8 R 9 , -NR 8 C(O)R 9 , substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl; each R 8 and R 9 are independently selected at each occurrence from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, and cyc Clo 3 -aClk 1 y 0 l; each R 10 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; each R 11 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl; each R 12 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, and C 3 -C 8 cycloalkyl; n and m are each independently 0, 1, 2, or 3; q is 0, 1, or 2; and p is 1, 2, or 3. [0154] In some embodiments, the compound has the structure of Formula (X), or a pharmaceutically acceptable salt or solvate thereof: Formula (X) X 2 is N or CR 3A ; and R 3A , R 3B , and R 3C are each independently selected from H, halogen, -CN, –NR 8 R 9 , –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, or substituted or unsubstituted 5- membered heteroaryl; provided that R 3A , R 3B , and R3 are not all H at the same time. [0155] In some embodiments, the compound has the structure of Formula (XIa) or (XIb), or a pharmaceutically acceptable salt or solvate thereof: Formula (XIb). [0156] In some embodiments, the compound has the structure of Formula (XII), or a pharmaceutically acceptable salt or solvate thereof: Formula (XII) wherein, ring A is a 5-membered heteroaryl optionally comprising 1 or 2 N atoms; and R 15 is H, halogen, –NR 8 R 9 , –substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted C 3 -C 8 heterocycloalkyl. [0157] In some embodiments, W is -CR 6 R 6 -, -O-, -S-, -NR 5 -, -S(O)-, or -S(O)2-. In some embodiments, W is -O-, -S- or -S(O)2-. In some embodiments, W is -O-. In some embodiments, W is -S-. In some embodiments, W is -NR 5 -. In some embodiments, W is -S(O)2-. In some embodiments, W is -S(O)-. [0158] In some embodiments, W is -CR 6 R 6 -. In some embodiments, W is -CH2-. In some embodiments, W is -CF2-. In some embodiments, W is -CHF-. [0159] In some embodiments, each R 6 is independently H, halogen, CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , – C(O)OR 10 , –C(O)NR 8 R 9 , -NR 8 C(O)R 11 -–SOR 11 , –SO 2 R 11 , -SR 11 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl. In some embodiments, each R 6 is independently H, halogen, CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , –C(O)OR 10 , –C(O)NR 8 R 9 , -NR 8 C(O)R 11 -– SOR 11 , –SO 2 R 11 , -SR 11 , substituted or unsubstituted C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl. [0160] In some embodiments, each R 6 is independently H, halogen, CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , – C(O)OR 10 , –C(O)NR 8 R 9 , or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 6 is halogen. [0161] In some embodiments, each R 6 is independently F, -NH 2 , -CF 3 , -CHF 2 , -CF 2 CH 3 , -OH, -OCH 3 , or -CH 3 . In some embodiments, each R 6 is independently F, -NH 2 , -OH, -OCH 3 , or -CH 3 . In some embodiments, each R 6 is independently F. In some embodiments, each R 6 is independently -CH 3 . [0162] In some embodiments, two R 6 can join together with the atom(s) to which they are attached to form a C 3 -C 6 cycloalkyl ring. In some embodiments, two R 6 on the same carbon atom can join together to form a cycloalkyl ring. In some embodiments, two R 6 on different carbon atoms can join together to form a cycloalkyl ring. In some embodiments, the ring is a spirocycle. In some embodiments, two R 6 join together to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, two R 6 join together to form a cyclopropyl. [0163] In some embodiments, R 7 is H, halogen, –OR 10 , –C(O)R 10 , –C(O)OR 10 , or substituted or unsubstituted C 1 -C 6 alkyl. In some embodiments, R 7 is H. [0164] In some embodiments, [0165] In some embodiments, WSGR Docket No.55773-715.601 [0166] In some embodiments, or [0167] In some embodiments, , . so e e bod e ts, . some embodiments, . [0168] In some embodiments, . [0169] In some embodiments, . [0170] In some embodiments, . [0171] In some embodiments, each R 8 and R 9 are independently selected at each occurrence from H, C 1 - C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, and C 3 -C c 1 y 0 cloalkyl. In some embodiments, each R 8 and R 9 are independently selected at each occurrence from H or C 1 -C 6 alkyl. In some embodiments, each R 8 and R 9 are independently selected at each occurrence from H. In some embodiments, each R 8 and R 9 are independently selected at each occurrence from C 1 -C 6 alkyl. [0172] In some embodiments, each R 10 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 - C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 10 is independently selected from H or C 1 -C 6 alkyl. In some embodiments, each R 10 is independently selected from C 1 -C 6 haloalkyl. In some embodiments, each R 10 is independently selected from C 3 -C 8 cycloalkyl. In some embodiments, each R 10 is independently selected from C 6 -C 10 aryl and 5- to 10-membered heteroaryl. In some embodiments, each R 10 is independently 5-membered heteroaryl. [0173] In some embodiments, each R 11 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R 11 is independently selected from C 1 -C 6 alkyl. In some embodiments, each R 11 is selected from C 1 -C 6 haloalkyl. In some embodiments, each R 11 is selected from C 3 -C 8 cycloalkyl. In some embodiments, each R 11 is selected from C 6 -C 10 aryl, and 5- to 10-membered heteroaryl. [0174] In some embodiments, each R 12 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C1- C6 haloalkyl, and C 3 -C 8 cycloalkyl. In some embodiments, each R 12 is independently selected from H or C 1 -C 6 alkyl. In some embodiments, each R 12 is independently selected from C 1 -C 6 haloalkyl. In some embodiments, each R 12 is independently selected from C 3 -C 8 cycloalkyl. [0175] In some embodiments, each R 14 is independently selected from -CN, –NR 8 R 9 , –OR 10 , –C(O)R 10 , – C(O)OR 10 , –C(O)NR 8 R 9 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, or C 3 -C 10 heterocycloalkyl. In some embodiments, each R 14 is independently selected from –NR 8 R 9 or –OR 10 . In some embodiments, each R 14 is independently selected from –C(O)R 10 , – C(O)OR 10 , or –C(O)NR 8 R 9 . In some embodiments, each R 14 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, or C 1 -C 6 haloalkyl. In some embodiments, each R 14 is independently selected fromC 3 -C 10 cycloalkyl or C 3 -C 1 h 0 eterocycloalkyl. [0176] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. I some embodiments, p is 3. In some embodiments, p is 5. In some embodiments, p is 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1. [0177] In some embodiments, q is q is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, q is 1 or 2. In some embodiments, q is 6. In some embodiments, q is 5. In some embodiments, q is 4. In some embodiments, q is 3. In some embodiments, q is 2. In some embodiments, q is 1. In some embodiments, q is 0. [0178] In some embodiments, n and m are independently 0, 1, or 2. In some embodiments, n and m are independently 0. In some embodiments, n and m are independently 1. In some embodiments, n and m are independently 2. In some embodiments, n is 0, 1, or 2; and m is 1 or 2. In some embodiments, n is 0; and m is 1 or 2. In some embodiments, n is 1; and m is 1 or 2. In some embodiments, n is 2; and m is 1 or 2. [0179] In some embodiments, the PDGH inhibitor is a compound presented in Table 1a, or pharmaceutically acceptable salt or solvate thereof. Table 1a. Representative sulfoxide PGDH inhibitors. [0180] In some embodiments, the PGDH inhibitor is a compound provided in Table 1b, or a pharmaceutically acceptable salt or solvate thereof. Table 1b. Representative sulfoxide PGDH inhibitors
[0181] In some embodiments, the PGDH inhibitor is a compound provided in Table 1c, or a pharmaceutically acceptable salt or solvate thereof. Table 1c. Representative PGDH inhibitors. Methods of Use [0182] In one aspect, provided herein are methods for treating various disorders in a subject in need thereof, comprising administering to said subject a compound described herein. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein may be used for the prevention or treatment of a disease or a disorder that is associated with hydroxyprostaglandin dehydrogenase (such as 15-PGDH) and/or decreased levels of prostaglandins. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein may be used for the prevention or treatment of a disease or a disorder in which it is desirable to increase prostaglandin levels in the subject having said disease or disorder. [0183] In some embodiments, the methods for treating the disorders comprises administering to said subject a 15-PGDH inhibitor. In some embodiments, a compound described herein is the 15-PGDH inhibitor (e.g. a compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the methods comprise administering a therapeutically effective amount of a compound described herein. In some embodiments, the methods comprise administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof (e.g. a compound of Formula (V) or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the compound described herein is a 15-PGDH inhibitor (e.g. a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the administration takes place in vitro. In other embodiments, the administration takes place in vivo. [0184] As used herein, a therapeutically effective amount of a 15-PGDH inhibitor refers to an amount sufficient to effect the intended application, including but not limited to, disease treatment, as defined herein. Also contemplated in the subject methods is the use of a sub-therapeutic amount of a 15-PGDH inhibitor for treating an intended disease condition. [0185] The amount of the 15-PGDH inhibitor administered may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. [0186] Measuring inhibition of biological effects of 15-PGDH can comprise performing an assay on a biological sample, such as a sample from a subject. Any of a variety of samples may be selected, depending on the assay. Examples of samples include, but are not limited to, blood samples (e.g. blood plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples. [0187] A subject being treated with a 15-PGDH inhibitor may be monitored to determine the effectiveness of treatment, and the treatment regimen may be adjusted based on the subject’s physiological response to treatment. For example, if inhibition of a biological effect of 15-PGDH is above or below a threshold, the dosing amount or frequency may be decreased or increased, respectively. The methods can further comprise continuing the therapy if the therapy is determined to be efficacious. The methods can comprise maintaining, tapering, reducing, or stopping the administered amount of a compound in the therapy if the therapy is determined to be efficacious. The methods can comprise increasing the administered amount of a compound in the therapy if it is determined not to be efficacious. Alternatively, the methods can comprise stopping therapy if it is determined not to be efficacious. In some embodiments, treatment with a 15-PGDH inhibitor is discontinued if inhibition of the biological effect is above or below a threshold, such as in a lack of response or an adverse reaction. The biological effect may be a change in any of a variety of physiological indicators. [0188] In general, a 15-PGDH inhibitor is a compound that inhibits one or more biological effects of 15- PGDH. Such biological effects may be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more. [0189] In some other embodiments, the subject methods are useful for treating a disease condition associated with 15-PGDH. Any disease condition that results directly or indirectly from an abnormal activity or expression level of 15-PGDH can be an intended disease condition. [0190] In one aspect, provided herein is a method of promoting and/or stimulation skin pigmentation, comprising administering one or more of the compositions described herein to a subject in need thereof. Inhibitors of 15-PGDH are known to promote skin pigmentation (Markowitz et. al., WO 2015/065716). The hydroxyprostaglandin dehydrogenase inhibitors described herein can be used for promoting and/or inducing and/or stimulating pigmentation of the skin and/or skin appendages, and/or as an agent for preventing and/or limiting depigmentation and/or whitening of the skin and/or skin appendages, in particular as an agent for preventing and/or limiting canities. In some embodiments, the 15-PGDH inhibitors provided herein can be applied to skin of a subject, e.g., in a topical application, to promote and/or stimulate pigmentation of the skin and/or hair growth, inhibit hair loss, and/or treat skin damage or inflammation, such as skin damage caused by physical or chemical irritants and/or UV-exposure. [0191] In another aspect, provided herein is a method of inhibiting hair loss, comprising administering one or more of the compositions described herein to a subject in need thereof. It is known that prostaglandins play an important role in hair growth. Prostaglandins such as prostaglandin A1, F2a and E2 are stored in hair follicles or adjacent skin environments and have been shown to be essential in maintaining and increasing hair density (Colombe L et. al, 2007, Exp. Dermatol, 16(9), 762-9). It has been reported that 15-PGDH, which is involved in the degradation of prostaglandins is present in the hair follicle dermal papillae, inactivates prostaglandins, especially, PGF2a and PGE2, to cause scalp damage and alopecia (Michelet J F et. al., 2008, Exp. Dermatol, 17(10), 821-8). Thus, the hydroxyprostaglandin dehydrogenase inhibitors described herein that have a suppressive or inhibitory activity against 15-PGDH can improve scalp damage, prevent alopecia and promote hair growth and be used in a pharmaceutical composition for the prevention of alopecia and the promotion of hair growth. [0192] In another aspect, provided herein is a method of preventing and/or treating skin inflammation and/or damage, comprising administering one or more of the compositions described herein to a subject in need thereof. [0193] In another aspect, provided herein is a method of preventing and/or treating vascular insufficiency, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins including prostaglandin homologues produced in the body have been known to maintain the proper action of the blood vessel wall, especially to contribute to vasodilation for blood flow, preventing platelet aggregation and modulating the proliferation of smooth muscle that surrounds blood vessel walls (Yan. Cheng et. al., 2006, J. Clin., Invest). In addition, the inhibition of prostaglandins production or the loss of their activity causes the degeneration of the endothelium in the blood vessel walls, platelet aggregation and the dysfunction of cellular mechanism in the smooth muscle. Among others, the production of prostaglandins in blood vessels was shown to be decreased in hypertension patients, including pulmonary artery hypertension. the 15-PGDH inhibitors described herein can be used in a pharmaceutical composition for the prevention or the treatment of cardiovascular disease and/or diseases of vascular insufficiency, such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary artery hypertension. [0194] In another aspect, provided herein is a method of preventing, treating, minimizing and/or reversing congestive heart failure, cardiomyopathy, comprising administering one or more of the compositions described herein to a subject in need thereof. In another aspect, provided herein is a method of reducing cardiac ejection fraction, comprising administering one or more of the compositions described herein to a subject in need thereof. It has been shown that administration of a 15-PGDH inhibitor can be used to treat, prevent, minimize, and/or reverse congestive heart failure, cardiomyopathy, and/or reduction of cardiac ejection fraction (Markowitz et. al., WO2018/187810). As such, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be administered to a subject in need to treat, prevent, minimize and/or reverse congestive heart failure, cardiomyopathy, and/or reduction of cardiac ejection fraction. [0195] In another aspect, provided herein is a method of preventing and/or treating a gastrointestinal disease, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins are essential for maintaining the mechanism for protecting and defending gastric mucus membrane (Wallace J L., 2008, Physiol Rev., 88(4), 1547-65, S. J. Konturek et al., 2005, Journal of Physiology and Pharmacology, 56(5)).The inhibitors of hydroxyprostaglandin dehydrogenase described herein show a suppressive or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect gastric mucus membranes. As such, the hydroxyprostaglandin dehydrogenase inhibitors can be effective for the prevention or the treatment of gastrointestinal diseases, inter alia, gastritis and gastric ulcer. In addition, the hydroxyprostaglandin dehydrogenase inhibitors provided herein may be used to prevent and/or treat other forms of intestinal injury including toxicity from radiation and/or chemotherapy, and chemotherapy-induced mucositis. [0196] Additionally, it has been shown that administration of 15-PGDH inhibitors, alone or in combination with corticosteroids and/or TNF inhibitors can treat intestinal, gastrointestinal, or bowel disorders such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn’s disease (Markowitz et. al., WO 2018/102552). As such, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat and/or prevent treat intestinal, gastrointestinal, or bowel disorders such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn’s disease. [0197] In another aspect, provided herein is a method of preventing and/or treating renal dysfunction, comprising administering one or more of the compositions described herein to a subject in need thereof. In the kidney, prostaglandins modulate renal blood flow and may serve to regulate urine formation by both renovascular and tubular effects. In clinical studies, inhibitors of prostaglandin have been used to improve creatinine clearance in patients with chronic renal disease, to prevent graft rejection and cyclosporine toxicity in renal transplant patients, to reduce the urinary albumin excretion rate and N- acetyl-beta-D-glucosaminidase levels in patients with diabetic nephropathy (Porter, Am., 1989, J. Cardiol., 64: 22E-26E). Furthermore, it has been reported that prostaglandins serve as vasodilators in the kidney, and, thus, the inhibition of prostaglandin production in the kidney results in renal dysfunction (Hao. C M, 2008, Annu Rev Physiol, 70, 357.about.77). The hydroxyprostaglandin dehydrogenase inhibitors described herein have a suppressive or inhibitory activity against 15-PGDH that degrades prostaglandins and can be used for the prevention and/or treatment of renal diseases that are associated with renal dysfunction. [0198] In another aspect, provided herein is a method of stimulation bone resorption and bone formation, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins have been shown to stimulate bone resorption and bone formation to increase the volume and the strength of the bone (H. Kawaguchi et. al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculoskeletal Res., 1, 1992, 8692). Furthermore, inhibition of 15-PGDH increases callus size and mineralization after bone fracture (Collier et. al., ORS 2017 Annual Meeting Paper No.0190). Considering that 15-PGDH inhibits the activities of prostaglandins as mentioned in the above, the inhibition of 15-PGDH activity may lead to the promotion of bone resorption and bone formation that are inhibited by 15-PGDH. Thus, the inhibitors of hydroxyprostaglandin dehydrogenase described herein can be effective for the promotion of bone resorption and bone formation by inhibiting 15-PGDH activity. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can also be used to increase bone density, treat osteoporosis, promote healing of fractures, promote healing after bone surgery or joint replacement, and/or to promote healing of bone to bone implants, bone to artificial implants, dental implants, and bone grafts. [0199] In another aspect, provided herein is a method of stimulating tissue regeneration by stimulating, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin PGE2 supports expansion of several types of tissue stem cells. Inhibition of 15- hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs. Studies show that inhibition of 15-PGDH increases prostaglandin PGE2 levels in bone marrow and other tissues; accelerates hematopoietic recovery following a bone marrow transplant; promotes tissue regeneration of colon and liver injury (Zhang, Y. et. al. Science 2015, 348 (6240)). The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for tissue regeneration by supporting the expansion of tissue stem cells. [0200] In another aspect, provided herein is a method of modulating cervical ripening, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin E2 (PGE2) is a known cervical ripening agent that mediates EP2-receptor- signaling pathways in human cervical stromal cells; targets its own synthesis by increasing COX-2 and PTGES expression; and decreases its metabolism by loss of its degradative enzyme 15-PGDH (Word et. Al., WO2019010482) Downregulation of 15-PGDH was also found to be crucial for PGE2-induced cervical ripening and preterm birth. Modulation of 15-PDGH activity can be used to modulate cervical ripening; and induce or prevent preterm labor. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to induce cervical ripening and labor, alone or in combination with another labor inducing agent. [0201] In another aspect, provided herein is a method of promoting neuroprotection and/or stimulating neuronal regeneration, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins, via their specific G protein coupled receptors, have a variety of physiological functions in the central nervous system. The major prostaglandin, prostaglandin E2 (PGE2) can activate receptor types EP1, 2, 3, and 4. Activation of EP2 and EP4 receptors can regulate adenylate cyclase and the generation of 3, 5′-cyclic adenosine monophosphate (cAMP), whereas the activation of EP1 and EP3 receptors can regulate Ca2+ signaling. Studies show that the EP1 and EP2 receptors are expressed in neurons and microglia as well as neurons of the cerebral cortex, striatum, and hippocampus. In addition, activation of the EP2 receptor by PGE2 is involved in long-term synaptic plasticity and cognitive function (Chemtob et al. Semin Perinatol.1994 Feb; 18(1):23-9; Yang et al., J Neurochem.2009 Jan; 108(1):295-304). Studies also show that following activation, different PGE2 receptors can contribute or protect against N-methyl-D-aspartate (NMDA) neurotoxicity and ischemic stroke (Ahmad et al., Exp Transl Stroke Med.2010 Jul 8; 2(1):12). Other studies show that activation of the EP2 receptors protected neurons from amyloid β-peptide neurotoxicity in vitro (Echeverria et al., Eur J Neurosci.2005 Nov; 22(9):2199-206). Several studies suggest that the mechanism by which PGE2 affords neuroprotection is through EP2 or EP4 receptors, as they both increases cAMP, followed by a protein kinase A (PKA)- dependent pathway (Echeverria et al. Eur J Neurosci.2005 Nov; 22(9):2199-206; McCullough et al., J Neurosci.2004 Jan 7; 24(1):257-68). Stimulation of these receptors with PGE2 by administration of a compound that inhibits, reduces, and/or antagonizes 15-PGDH activity, such as the hydroxyprostaglandin dehydrogenase inhibitors that can inhibit 15-PGDH described herein, can promote neuroprotection in a subject from axonal degeneration, neuronal cell death, and/or glia cell damage after injury, augment neuronal signaling underlying learning and memory, stimulate neuronal regeneration after injury, and/or treat diseases, disorders, and/or conditions of the nervous system. [0202] In another aspect, provided herein is a method of treating and/or preventing a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder, comprising administering one or more of the compositions described herein to a subject in need thereof. In some embodiments, the disease, disorder, and/or condition of the nervous system, which can be treated with hydroxyprostaglandin dehydrogenase inhibitors provided herein, can include at least one of a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder. For example, the neurological disorder can include at least one of traumatic or toxic injuries to peripheral or cranial nerves, spinal cord or brain, such as traumatic brain injury, stroke, cerebral aneurism, and spinal cord injury. The neurological disorder can also include at least one of Alzheimer's disease, dementias related to Alzheimer's disease, Parkinson's, Lewy diffuse body diseases, senile dementia, Huntington's disease, Gilles de Ia Tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Jakob- Creutzfieldt disease. [0203] In some embodiments, the neural injury can be caused by or associated with at least one of epilepsy, cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic disorders, urinary bladder disorders, abnormal metabolic states, disorders of the muscular system, infectious and parasitic diseases, neoplasms, endocrine diseases, nutritional and metabolic diseases, immunological diseases, diseases of the blood and blood-forming organs, mental disorders, diseases of the nervous system, diseases of the sense organs, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the genitourinary system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, congenital anomalies, or conditions originating in the perinatal period. [0204] In certain embodiments, the hydroxyprostaglandin dehydrogenase inhibitors can be administered to a subject or neurons of the subject to promote the survival, growth, development and/or function of the neurons, particularly, the central nervous system (CNS), brain, cerebral, and hippocampal neurons. In certain embodiments, the hydroxyprostaglandin dehydrogenase inhibitors can be used stimulate hippocampal neurogenesis, for the treatment of neuropsychiatric and neurodegenerative diseases, including (but not limited to) schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine. [0205] In another aspect, provided herein is a method of treating and/or preventing fibrotic or adhesion disease, disorder or condition, comprising administering one or more of the compositions described herein to a subject in need thereof. It has been shown that inhibitors of short-chain dehydrogenase activity, such as 15-PGDH inhibitors, can be administered to a subject in need thereof to decrease fibrotic symptoms, such as collagen deposition, collagen accumulation, collagen fiber formation, inflammatory cytokine expression, and inflammatory cell infiltration, and treat and/or prevent various fibrotic diseases, disorders, and conditions characterized, in whole or in part, by the excess production of fibrous material, including excess production of fibrotic material within the extracellular matrix, or the replacement of normal tissue elements by abnormal, non-functional, and/or excessive accumulation of matrix-associated components (Markowitz et. al., WO2016/144958). [0206] Fibrotic diseases, disorders and conditions characterized, in whole or in part, by excess production of fibrotic material can include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma(including morphea, generalized morphea, or linear scleroderma), sclerodermatous graft- vs-host-disease„ kidney fibrosis (including glomerular sclerosis, renal tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g. pulmonary fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, and chemotherapy/radiation induced pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophilic fasciitis, general fibrosis syndrome characterized by replacement of normal muscle tissue by fibrous tissue in varying degrees, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure; myelofibrosis (bone marrow fibrosis), drug induced ergotism, myelodysplastic syndrome, myeloproliferative syndrome, collagenous colitis, acute fibrosis, organ specific fibrosis, and the like. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent a fibrotic disease, disorder or condition. [0207] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent kidney fibrosis, including kidney fibrosis resulting from dialysis following kidney failure, catheter placement, a nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end stage renal disease or renal failure, or combinations thereof. [0208] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent liver fibrosis, including liver fibrosis resulting from a chronic liver disease, viral induced hepatic cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH associated cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, auto-immune hepatitis, cystic fibrosis, alpha- 1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxins, or combinations thereof. [0209] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent heart fibrosis such as cardiac fibrosis, endomyocardial fibrosis, idiopathic pulmonary fibrosis, and kidney fibrosis. [0210] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent systemic sclerosis. [0211] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent fibrotic diseases, disorders or conditions caused by post-surgical adhesion formation. [0212] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce in intensity, severity, or frequency, and/or delay onset of one or more symptoms or features of a fibrotic disease, disorder or condition, or other related diseases, disorders or conditions. [0213] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to decrease or reduce collagen secretion, or collagen deposition, or collagen fiber accumulation, in a tissue or organ, such as the lung, the liver, the intestines, the colon, the skin or the heart, or a combination thereof. [0214] Studies have shown that 15-PGDH inhibition ameliorates inflammatory pathology and fibrosis in pulmonary fibrosis (Smith et. al., bioRxiv 2019.12.16.878215; Barnthaler et. al., J. Allergy Clin. Immunol.2019, 145 (3), 818-833). In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be used to treat or prevent lung fibrosis, including pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitides, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof. [0215] In another aspect, provided herein is a method of reducing and/or preventing scar formation, comprising administering one or more of the compositions described herein to a subject in need thereof. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can used for reducing or preventing scar formation in a subject. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent scar formation on skin or scleroderma. [0216] In another aspect, provided herein is a method of treating and/or preventing muscle disorder, muscle injury and/or muscle atrophy, comprising administering one or more of the compositions described herein to a subject in need thereof. Studies have shown that inhibition of PGE2 degrading enzymes such as 15-PGDH, enable muscle regeneration and muscle repair after injury (Ho et al., PNAS 2017; Dong et al., Stem cell research and therapy 2020). The inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat muscle disorder, muscle injury and/or muscle atrophy in a subject. In some cases, said subject suffering from a muscle disorder, muscle injury and/or muscle atrophy may have Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FHMD), amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), an inherited myopathy, myotonic muscular dystrophy (MDD), oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, myotonia congenita, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, stress induced urinary incontinence, urethral sphincter deficiency, sarcopenia, or a combination thereof. [0217] In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat sarcopenia. In another embodiment, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat diaphragmatic atrophy or limb muscle atrophy due to the use of a mechanical ventilator. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat genetic disorders or neuromuscular disorders such as Spinal Muscular Atrophy (SMA). In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat ptosis, rotator cuff muscle atrophy, immobilization related muscle atrophy, surgical procedure related muscle atrophy, sarcopenia, or a combination thereof. Pharmaceutical Compositions [0218] The inhibitors of hydroxyprostaglandin dehydrogenase can be formulated into pharmaceutical compositions to treat diseases and disorders described herein. In some embodiments, a pharmaceutical composition may comprise a therapeutically effective amount of one or more inhibitors of hydroxyprostaglandin dehydrogenase provided herein. [0219] The pharmaceutical composition described herein may be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, micronized compositions, granules, elixirs, tinctures, suspensions, ointments, vapors, liposomal particles, nanoparticles, syrups and emulsions. In some embodiments, the pharmaceutical composition may also be administered in intravenous (bolus or infusion), subcutaneous injection, suppository, intraperitoneal, topical (e.g., dermal epidermal, transdermal), ophthalmicaly such as ocular eyedrop, intranasally, subcutaneous, inhalation, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts. [0220] In some embodiments, a compound provided herein can be administered as part of a therapeutic regimen that comprises administering one or more second agents (e.g.1, 2, 3, 4, 5, or more second agents), either simultaneously or sequentially with the compound provided herein. When administered sequentially, the compound provided herein may be administered before or after the one or more second agents. When administered simultaneously, the compound provided herein and the one or more second agents may be administered by the same route (e.g. injections to the same location; tablets taken orally at the same time), by a different route (e.g. a tablet taken orally while receiving an intravenous infusion), or as part of the same combination (e.g. a solution comprising a compound provided herein and one or more second agents). [0221] A combination treatment according to the disclosure may be effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the agent selected, the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. EXAMPLES [0222] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. Synthesis and Characterization of Compounds [0223] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein. [0224] Exemplary synthesis schemes for the inhibitors with phenyl core as described herein include: [0225] In some cases, synthesis schemes may be entire synthesis schemes for producing the inhibitors provided herein. In other cases, synthesis schemes may be partial schemes for producing inhibitors provided herein. [0226] Described herein are exemplary synthesis schemes that can be used to synthesize the inhibitors described herein. The following abbreviations are used: [0227] Example 1. Synthesis of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5-b] pyridin-3-yl)benzoic acid (C-1) and 4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-methyl-3H- imidazo[4,5-b]pyridin-3-yl)benzoic acid (C-3) [0228] Scheme 1 [0229] Step-1: Synthesis of 6-chloro-5-nitronicotinic acid, general procedure for ester hydrolysis with LiOH: To a stirred solution of methyl 6-chloro-5-nitronicotinate, (SM-1) (5g, 23.09 mmol, 1.0 eq) in THF: water (1:1, 20 mL) at 0 °C, LiOH.H2O (2.8g, 69.27 mmol, 3 eq) was added at 0 °C. The resultant reaction mixture was stirred at RT for 4 h. The reaction was monitored by crude LCMS/TLC; after completion of the reaction, volatiles were evaporated, neutralized with satd. aqueous citric acid up to PH =7. Filtered solids were washed with Et2O (50 mL) and dried in vacuo to obtain 6-chloro-5-nitronicotinic acid, Int-1 (3g) as yellow solid. The crude was used in the next step without further purification. TLC: 80% EtOAc/ Heptane (Rf: 0.15). MS: m/z = 203.5 [M+H] + . [0230] Step-2: Synthesis of (6-chloro-5-nitropyridin-3-yl)(4,4-difluoropiperidin-1-yl) methanone (Int-2) (General procedure for acid-amine coupling using HATU): To the stirred solution of 6-chloro- 5-nitronicotinic acid, Int-1 (3g, 14.81 mmol, 1.0 eq.) in DMF (20 mL) at 0 o C, HATU (6.75g, 17.77 mmol, 1.2 eq), 4,4-difluoropiperidine hydrochloride (2.80g, 17.17mmol, 1.2 eq) were added. To this stirred solution N, N’-diisopropylethylamine (7.76 mL, 44.43 mmol, 3 eq) was added at 0 °C and then continued for stirring at RT for 16 h. The progress of the reaction was monitored with TLC and LCMS. After consumption of starting material, the mixture was diluted with ice cold water (10 mL) and extracted with EtOAc (3x30 mL). The combined extracts were washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by combi-flash column chromatography using 70% EtOAc:heptane to afford (6-chloro-5-nitropyridin-3-yl)(4,4- difluoropiperidin-1-yl)methanone, Int-2 (2g, 46.70%) as off white solid. TLC: 40% EtOAc/ Heptane (Rf: 0.40) MS: m/z=306.6 [M+H] + . [0231] Step-3: Synthesis of methyl 4-((5-(4,4-difluoropiperidine-1-carbonyl)-3-nitropyridin-2-y l) amino) benzoate (Int-3) (General procedure for Buchwald coupling): To a stirring solution of (6- chloro-5-nitropyridin-3-yl)(4,4-difluoropiperidin-1-yl)metha none (Int-2) (1 g, 3.27 mmol, 1.0 eq) in dioxane (30 mL) in a sealed tube under inert atmosphere, Cs2CO3 (3.18 g, 9.83 mmol, 3 eq), methyl 4- aminobenzoate (SM-2) (593 mg, 3.93 mmol, 1.2 eq) were added at RT. Argon gas was purged for 15 min then Xantphos (378mg, 0.654 mmol, 0.2 eq) and Pd2(dba)3 (300mg, 0.327 mmol, 0.1 eq), were added under argon atmosphere, then resultant reaction mixture was heated in the microwave at 150 o C for 20 min. The reaction was monitored by crude LCMS/TLC; after consumption of starting material, the mixture was quenched with saturated NH4Cl (10 mL), filtered through a celite bed and washed with EtOAc (2x50 mL). The combined EtOAc extracts were washed with brine (100 mL); dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified by combi-flash column purification using 60% EtOAc: heptane to afford methyl 4-((5-(4,4-difluoropiperidine-1- carbonyl)-3-nitropyridin-2-yl) amino) benzoate, Int-3 (555mg) as a brownish semi-solid. The crude was used in the next step without further purification. TLC: 80% EA: Hex (Rf: 0.5). MS: m/z = 421.2 [M+H] + . [0232] Step-4: Synthesis of methyl 4-((3-amino-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-y l) amino)benzoate (Int-4), general procedure for reduction of aryl nitro compounds: To a stirred solution of compound methyl 4-((3-amino-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2- yl)amino)benzoate Int-3 (500mg, 1.19 mmol, 1.0 eq.) in ethanol (5 mL) was added Fe (5.0 eq ) followed by ammonium chloride (10 eq.) in water (5 mL) and the reaction mixture was heated at 80 °C for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered and filtrate was concentrated under reduced pressure. The crude residue was suspended in water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford methyl 4-((3-amino-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-y l) amino)benzoate (Int-4) (118 mg, 25.43%) as pale brown solid which was used for next step without purification. TLC: 60% EtOAc:heptane (R f : 0.3); MS: m/z = 391.2 [M+H] + . [0233] Step-5: Synthesis of methyl 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5- b]pyridin-3-yl) benzoate (Int-5): To a solution of methyl 4-((3-amino-5-(4,4-difluoropiperidine-1- carbonyl)pyridin-2-yl) amino) benzoate (Int-4) (110mg, 0.282 mmol, 1eq) dissolved in 1, 4-dioxane (5mL) was added NaNO 2 (38.91 mg, 0.564 mmol, 2 eq) at 0 o C followed by catalytic amount of HCl (conc). The mixture was stirred at 30 °C for 12h. The reaction was monitored by TLC; after consumption of starting material, it was quenched with ice-water (10mL), extracted with EtOAc (3 ×10 mL), combined extracts were washed with brine (10 mL), dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude product was purified by combi-flash column chromatography using 80% EtOAc:heptane to afford methyl 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5- b]pyridin-3-yl)benzoate, Int-5 (69mg, 61.06%) as an off white solid. TLC: 80% EtOAc:heptane (Rf: 0.2); MS: m/z = 402.1 [M+H] + . [0234] Step-6: Synthesis of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5-b] pyridine -3-yl) benzoic acid (C-1): methyl 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)benzoate, (Int-5) (55mg, 0.137mmol, 1eq) was converted to 4-(6-(4,4- difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridine -3-yl) benzoic acid (C-1) using general procedure for ester hydrolysis with LiOH to afford 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H- [1,2,3]triazolo[4,5-b] pyridine -3-yl) benzoic acid (C-1) (24 mg, 45.28%) as an off white solid. TLC: 80% EtOAc:heptane (Rf: 0.2); LCMS: 95.63%, MS: m/z = 388.1 [M+H] + . [0235] Step-7: Synthesis of methyl 4-((3-acetamido-5-(4,4-difluoropiperidine-1-carbonyl) pyridin-2- yl) amino)benzoate (Int-6): To a stirred solution of methyl 4-((3-amino-5-(4,4-difluoropiperidine-1- carbonyl)pyridin-2-yl)amino)benzoate, (Int-4) (165mg, 0.422 mmol, 1eq) in anhydrous DCM (5 mL) cooled to 0 o C was added trimethylamine (0.115 mL, 0.84 mmol, 2 eq) followed by acetyl chloride (0.036 mL, 0.50 mmol, 1.2 eq ). The mixture was stirred at 30 °C for 6h. The reaction was monitored by crude LCMS/ TLC; after completion the reaction was quenched with ice-water (10mL) and extracted with DCM (3 ×10 mL). The combined extracts were washed with brine (10 mL), dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude product was purified by combi-flash column chromatography using 80% EtOAc: heptane to afford methyl 4-((3-acetamido-5-(4,4-difluoropiperidine- 1-carbonyl) pyridin-2-yl) amino) benzoate (Int-6) (116 mg, 66%) as an brown sticky oil. TLC: 100% EtOAc (R f : 0.4) [0236] Step-8: Synthesis of methyl 4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-methyl-3H-imidazo [4,5-b]pyridin-3-yl)benzoate (Int-7), general procedure for cyclization to make imidazole: To a stirred solution methyl 4-((3-acetamido-5-(4,4-difluoropiperidine-1-carbonyl) pyridin-2-yl) amino)benzoate, (Int-6) (116mg, 0.26 mmol, 1eq) in toluene (5 mL) was added PTSA (20 mg, 0.133 mmol, 0.5 eq) followed by 4A⁰ molecular sieves. The mixture was stirred at reflux for 12 h. The reaction was monitored by TLC and after completion, the solvent was removed in vacuo. The crude product was triturated with n-pentane to afford methyl 4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-methyl-3H-imidazo [4,5-b] pyridin-3-yl)benzoate, (44 mg,) as an brown sticky oil. TLC: 20% Acetone:Toluene (R f : 0.4); MS: m/z = 415.1 [M+H] + . [0237] Step-9: Synthesis of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-methyl-3H-imidazo [4,5-b] pyridin-3-yl)benzoic acid (C-3): Int-7 (40 mg, 0.096 mmol, 1 eq)) was hydrolyzed using the general procedure for ester hydrolysis with LiOH to afford 4-(6-(4,4-difluoropiperidine-1-carbonyl)-2-methyl-3H- imidazo[4,5-b] pyridin-3-yl)benzoic acid (C-3) (31.3 mg, 81%) MS: m/z = 401.1 [M+H] + . [0238] Example 2. Synthesis of (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo [d] imidazol-5- yl)(4,4-difluoropiperidin-1-yl)methanone (C-15), (1-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1H- benzo[d]imidazol-5- difluoropiperidin-1-yl)methanone (C-16), and 4-(5-(4,4- difluoropiperidine-1-carbonyl)-1H-benzo[d]imidazol-1-yl) benzoic acid (C-17) [0239] Scheme 2 [0240] Step-1: Int-1: Previously described in the synthesis of C-9. [0241] Step-2: Synthesis of Int-2a, Int-2b and Int-2c: (4,4-difluoropiperidin-1-yl)(4-fluoro-3- nitrophenyl) methanone, Int-1 using the general procedure for SNAr reaction described earlier using appropriate amines to afford Int-2a, Int2b and Int2c. [0242] Int-2a (for C-15): (74.50% yield, m/z =388.1 [M+H] + ). [0243] Int-2b (for C-16): (57% yield, m/z = 387.1 [M+H] + ). [0244] Int-2c (for C-17): (56% yield, m/z = 420.1 [M+H] + ). [0245] Step-3: Synthesis of Int-3a, Int-3b and Int-3c: Int-2a, Int-2b, and Int-2c was subjected to the general procedure for aryl nitro reduction with Fe. The crude was purified by combiflash column chromatography using 60% EtOAc/ heptane to obtain Int-3a, Int-3b and Int-3c. [0246] Int-3a (for C-15): (38% yield, m/z = 358.1 [M+H] + ). [0247] Int-3b (for C-16): (56% yield, m/z = 357.1 [M+H] + ). [0248] Int-3c (for C-17): (98.10% yield, m/z = 390.2 [M+H] + ). [0249] Step-4: Synthesis of Int-4a, Int-4b and Int-4c: Int-3a, Int-3b and Int-3c, was converted to Int- 4a, Int-4b and Int-4c using the general procedure for imidazole cyclisation with PTSA and trimethyl orthoformate to afford Int-4a, Int-4b and Int-4c [0250] Int-4a (for C-15): (60.80% yield, m/z = 368.1 [M+H] + ). [0251] Int-4b (for C-16): (56% yield, m/z =367.13 [M+H] + ). [0252] Int-4c (for C-17): (54.7% yield, m/z = 400.2 [M+H] + ). [0253] Step-5: Synthesis of Int-5a and Int-5b: Int-4a and Int-4b was converted to Int-5a and Int-5b using the general procedure for the oxidation of nitriles to afford crude Int-5a and Int-5b. The crude obtained was triturated with n-pentane filtered and dried in vacuo. [0254] Int-5a (for C-15): (100% crude yield, m/z = 386.2 [M+H] + ) [0255] Int-5b (for C-16): (100% crude yield, m/z = 385.14 [M+H] + ) [0256] Step-5A: Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d]imidazol -1-yl) benzoic acid, C-17: methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] imidazol-1- yl)benzoate, Int-4c (280 mg, 0.701 mmol, 1 eq) using the general procedure for ester hydrolysis with LiOH to afford 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d]imidazol -1-yl) benzoic acid, C-17 (52mg, 19.28%) MS: m/z =386.2 [M+H] + . [0257] Step-6: Synthesis of (E)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] imidazol-1- yl)-N-((dimethylamino)methylene)picolinamide, Int-6a and (E)-4-(5-(4,4-difluoropiperidine-1- carbonyl)-1H-benzo[d]imidazol-1-yl)-N-((dimethylamino) methylene) benzamide, Int-6b: Int-5a and Int-5b was converted to (E)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] imidazol-1-yl)-N- ((dimethylamino)methylene)picolinamide, Int-6a and (E)-4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d]imidazol-1-yl)-N-((dimethylamino) methylene) benzamide, Int-6b using general procedure for enamine formation to afford crude Int-6a and Int-6b. The crude obtained was triturated with n-pentane filtered and dried in vacuo to afford. [0258] Int-6a (for C-15): (100% crude yield, m/z = 441.2 [M+H] + ). [0259] Int-6b (for C-16): (100% crude yield, m/z = 440.1 [M+H] + ). [0260] Step-7: Synthesis of (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d]imidaz ol-5-yl) (4,4-difluoropiperidin-1-yl)methanone, MH-DH-650 and (1-(4-(1H-1,2,4-triazol-5-yl) phenyl)-1H- benzo [d] imidazol-5-yl) (4,4-difluoropiperidin-1-yl)methanone, C-16: Int-6a and Int-6b was converted to (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d]imidaz ol-5-yl) (4,4-difluoropiperidin- 1-yl)methanone, C-15 and (1-(4-(1H-1,2,4-triazol-5-yl) phenyl)-1H-benzo [d] imidazol-5-yl) (4,4- difluoropiperidin-1-yl) methanone, C-16 using general procedure for triazole formation using hydrazine acetate to afford (1-(6 -(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d]imidazol-5- yl)(4,4- difluoropiperidin-1-yl) methanone, C-15 as an off-white solid and (1-(4-(1H-1,2,4-triazol-5-yl)phenyl)- 1H-benzo[d]imidazol-5-yl) (4,4-difluoropiperidin-1-yl)methanone, C-16 as an off white solid after Prep- HPLC purification. [0261] C-15: (7.3% yield, m/z = 410.2 [M+H] + . [0262] C-16: (37.30% yield, m/z = 409.1 [M+H] + ). [0263] Example 3. Synthesis of (3-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3H-[1,2,3]triazol o[4,5-b] pyridin-6-yl) (4,4-difluoropiperidin-1-yl)methanone (C-5) and (4,4-difluoropiperidin-1-yl)(3-(6-(1- methyl-1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3H-[1,2,3] triazolo [4,5-b]pyridin-6-yl)methanone (C-8) [0264] Scheme 3 [0265] Step-1: Synthesis of methyl 6-((6-cyanopyridin-3-yl)amino)-5-nitronicotinate (Int-1), general procedure for S N Ar reaction using NaH: To a stirred solution of 5-aminopicolinonitrile (880 mg, 7.39 mmol, 0.8 eq.) in DMF (40mL) at 0 o C, NaH (738 mg, 18.47 mmol, 2.0 eq.) was added portion wise at 0 °C and the reaction was stirred for 10 mins followed by addition of methyl 6-chloro-5-nitronicotinate (SM-1) (2g, 9.23 mmol, 1.0 eq.) at RT. The resultant sealed reaction mixture was heated to 100 o C for 16 h. The progress of the reaction was monitored with TLC and LCMS. The reaction was quenched (ice- water, 20mL) and extracted with ethyl acetate (2X 50 mL). The combined extracts were dried over sodium sulphate, filtered and concentrated to afford methyl 6-((6-cyanopyridin-3-yl)amino)-5- nitronicotinate, Int-1 (2.2g) as a brown oil. The crude was used in the next step without further purification TLC: 30% EtOAc/heptane (R f : 0.45). MS: m/z = 300.5 [M+H] + . [0266] Step-2: Synthesis of methyl 5-amino-6-((6-cyanopyridin-3-yl)amino)nicotinate (Int-2) methyl 6-((6-cyanopyridin-3-yl)amino)-5-nitronicotinate (Int-1) (2.2g, 7.35 mmol, 1.0 eq) was converted to methyl 5-amino-6-((6-cyanopyridin-3-yl)amino)nicotinate (Int-2) using the general procedure for reduction of nitro compounds using Fe/NH 4 Cl. The crude was purified by combi-flash column chromatography using 55% EtOAc: heptane to afford methyl 5-amino-6-((6-cyanopyridin-3-yl) amino) nicotinate, Int-2 (1.2g, 60%) as a yellow solid. TLC: 50% EtOAc (R f : 0.35); MS: m/z = 270.1 [M+H] + . [0267] Step-3: Synthesis of methyl 3-(6-cyanopyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6- carboxylate (Int-3) (General procedure for triazolo formation with NaNO 2 ): To a solution of methyl 5-amino-6-((6-cyanopyridin-3-yl) amino) nicotinate (Int-2) (1.2 g, 4.46 mmol, 1 eq) dissolved in water (36 mL) was added NaNO 2 (992 mg, 13.38 mmol, 3 eq) at 0 o C followed by catalytic amount of conc. HCl (3.6 mL). The mixture was stirred at RT for 2 h. The progress of the reaction was monitored with TLC. The precipitated solid obtained in the reaction mixture was filtered, washed with water and dried. Trituration with Et2O afforded methyl 3-(6-cyanopyridin-3-yl)-3H-[1, 2, 3] triazolo [4,5-b]pyridine-6- carboxylate, Int-3 (1.1g) as a yellow solid. The crude was used in the next step without further purification. TLC: 70% EtOAc: heptane (R f : 0.5); MS: m/z = 280.2 [M+H] + . [0268] Step-4: Synthesis of 3-(6-cyanopyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6- carboxylic acid (Int-4): methyl 3-(6-cyanopyridin-3-yl)-3H-[1, 2, 3] triazolo [4,5-b]pyridine-6-carboxylate, (Int-3) (1.1g, 3.93 mmol, 1.0 eq) was converted to 3-(6-cyanopyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6- carboxylic acid using general procedure for ester hydrolysis with LiOH. The crude obtained was triturated with Et 2 O to afford 3-(6-cyanopyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6- carboxylic acid, Int-4 (1.04g, 95.69%) as an off-white solid. The crude was used in the next step without further purification TLC: 80% EtOAc (Rf: 0.2); MS: m/z =264.9 [M-H]-. [0269] Step-5: Synthesis of 5-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5-b] pyridin-3-yl) picolinonitrile (Int-5): 3-(6-cyanopyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6- carboxylic acid (Int-4) (1g, 3.76 mmol, 1.0 eq.) was converted to 5-(6-(4,4-difluoropiperidine-1- carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-3-yl) picolinonitrile (Int-5) using general procedure for acid- amine coupling with HATU/4,4-difluoropiperidine hydrochloride (886mg, 5.63 mmol, 1.5 eq.). The crude obtained was triturated with Et2O to afford 5-(6-(4,4-difluoropiperidine-1-carbonyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl) picolinonitrile, Int-5 (500 mg, 36.23%) as an off-white solid. The crude was used in the next step without further purification. TLC: 5% MeOH/CH2Cl2 (Rf: 0.4); MS: m/z = 370.25 [M+1] + . [0270] Step-6: Synthesis of 5-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5-b] pyridin-3-yl) picolinimidohydrazide (Int-6) (General procedure for imidohydrazide formation using hydrazine ): To a stirred solution of 5-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5- b]pyridin-3-yl) picolinonitrile (300 mg, 0.812 mmol, 1.0 eq) in ethanol (3 mL) was added hydrazine monohydrate (6 mL). The mixture was stirred at 60 °C for 1h. The progress of the reaction was monitored with TLC. The solid obtained was filtered and dried. Trituration with Et2O afforded 5-(6-(4,4- difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-3-yl) picolinimidohydrazide , Int-6 (170mg) as yellow solid. The crude obtained was used in the next step without further purification. TLC: 5% MeOH/CH2Cl2 (Rf: 0.25) MS: m/z = 402.53 [M+H] + . [0271] Step-7: Synthesis of (3-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3H-[1,2,3]triazol o[4,5-b] pyridin-6-yl) (4,4-difluoropiperidin-1-yl)methanone (C-5) (General procedure for triazole formation using triethylorthoformate): To a stirred solution of 5-(6-(4,4-difluoropiperidine-1-carbonyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl) picolinimidohydrazide (Int-6) (170 mg, 0.423 mmol, 1.0 eq) in 1,4- dioxane (5 mL), was added triethylorthoformate (0.251 mL, 2.11 mmol, 5.0 eq) and p-toluenesulfonic acid monohydrate (14.5 mg, 0.086 mmol, 0.2 eq). The mixture was stirred at 100 °C for 16h. The progress of the reaction was monitored with TLC/LCMS, After consumption of starting material, the mixture was quenched with saturated NaHCO 3 (10 mL). The solution was extracted with EtOAc (2 X 20 mL) and the organic extracts washed with water (5 mL) and brine (5mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated. The crude was purified by combi-flash column chromatography using 5% MeOH: DCM to afford (3-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3H-[1,2,3] triazolo [4,5-b] pyridin-6- yl)(4,4-difluoropiperidin-1-yl)methanone (C-5) (130mg, 74.71%) as off white solid. TLC: 5% MeOH/CH 2 Cl 2 (R f : 0.2); LCMS: 98.33%, MS: m/z = 412.1 [M+H] + . [0272] Step-7: Synthesis of (4,4-difluoropiperidin-1-yl)(3-(6-(1-methyl-1H-1,2,4-triazol -5-yl) pyridin-3-yl) -3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl) methanone (C-8) (General procedure for methylation of amine using NaH): To a stirred solution of (3-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3H- [1,2,3] triazolo [4,5-b] pyridin-6-yl)(4,4-difluoropiperidin-1-yl)methanone (C-8) (100 mg, 0.243 mmol, 1 eq) in DMF (5 mL), NaH (60% in mineral oil) (19 mg, 0.486 mmol, 2 eq) was added at 0 o C, slowly brought to RT and stirred for 1h. MeI (0.05 mL, 0.729 mmol, 3 eq) was added and then the resulting mixture was stirred for 1h. The reaction was monitored by crude LCMS/TLC; after complete consumption of the starting material, the reaction mixture was quenched with sat. NH4Cl (10 ml) and extracted with EtOAc (2 x 20 mL). Combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified by combi-flash column chromatography using 5% MeOH: DCM to afford (4,4-difluoropiperidin-1-yl) (3-(6-(1-methyl- 1H-1,2,4-triazol-5-yl) pyridin-3-yl) -3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl) methanone (10 mg, 9.70% ) ( (C-8) as an off-white solid. TLC: 10% MeOH: DCM (Rf: 0.35). LCMS: 96.35%, m/z = 426.2[M+H] + . [0273] Example 4. Synthesis of (3-(4-(1H-1,2,4-triazol-5-yl)phenyl)-3H-[1,2,3]triazolo[4,5- b]pyridin-6-yl) (4,4-difluoropiperidin-1-yl)methanone (C-7) [0274] Scheme 4 [0275] Step-1: methyl 6-((4-cyanophenyl)amino)-5-nitronicotinate (Int-1): methyl 6-chloro-5- nitronicotinate (SM-1) (2.6g, 12 mmol, 1.0 eq), was converted to methyl 6-((4-cyanophenyl)amino)-5- nitronicotinate (Int-1) using general procedure for S N Ar reaction using NaH (as described above) to afford methyl 6-((4-cyanophenyl)amino)-5-nitronicotinate, Int-1 ( 1.5g, 42%) as a brown oil. The crude was used in the next step without further purification TLC: 30% EtOAc/heptane (R f : 0.45). MS: m/z = 299.2[M+H] +. [0276] Step-2: Synthesis of methyl 5-amino-6-((4-cyanophenyl)amino)nicotinate (Int-2): methyl 6- ((4-cyanophenyl) amino)-5-nitronicotinate (Int-1) (1.5g, 5.03 mmol, 1.0 eq) was converted to methyl 5- amino-6-((4-cyanophenyl)amino)nicotinate (Int-2) using the general procedure for reduction of nitro compounds using Fe/NH 4 Cl. The crude was purified by combi-flash column chromatography using 40% EtOAc:heptane to afford methyl 5-amino-6-((4-cyanophenyl)amino)nicotinate, Int-2 (1.21g, 89.55%) as a yellow solid. TLC: 50% EtOAc (Rf: 0.35); LCMS: 87.63% MS: m/z = 269.19 [M+H] + . [0277] Step-3: Synthesis of methyl 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6- carboxylate (Int-3): methyl 5-amino-6-((4-cyanophenyl)amino)nicotinate (Int-2) (1.1g, 4.10 mmol, 1eq) was converted to methyl 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carbox ylate using the general procedure for triazole formation using NaNO 2 /conc. HCl to afford methyl 3-(4-cyanophenyl)-3H- [1,2,3]triazolo[4,5-b] pyridine-6-carboxylate, Int-3 (1g). The crude was used in the next step without further purification. TLC: 60% EtOAc: heptane (R f : 0.5); MS: m/z = 280.17 [M+H] + . [0278] Step-4: Synthesis of 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carbox ylic acid (Int-4) : methyl 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carbox ylate, (Int-3) (1g, 3.58 mmol, 1.0 eq) was converted to 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b] pyridine-6-carboxylic acid (Int-4) using the general procedure for ester hydrolysis with LiOH. The crude obtained was triturated with Et2O to afford 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carbox ylic acid, Int-4 (900mg, 94.83%) as an off-white solid. The crude was used in the next step without further purification TLC: 80% EtOAc:heptane (Rf: 0.2); MS: m/z =266.1 [M+H] + . [0279] Step-5: Synthesis of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5-b] pyridin-3-yl) benzonitrile (Int-5): 3-(4-cyanophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-6-carbox ylic acid (Int-4) (900mg, 3.39 mmol, 1.0 eq.) was converted to 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)benzonitrile (Int-5) using general procedure for acid-amine coupling with HATU/4,4-difluoropiperidine hydrochloride (886mg, 5.63 mmol, 1.5 eq.). The crude obtained was triturated with n-pentane to afford 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5- b]pyridin-3-yl)benzonitrile, Int-5 (1g, 80.64%) as off white solid. The crude was used in the next step without further purification. TLC: 5% MeOH/CH2Cl2 (Rf: 0.5); LCMS: 86.30%, MS: m/z = 369.2 [M+H] + . [0280] Step-6: Synthesis of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5-b] pyridin-3-yl) benzamide (Int-6), general procedure for amide formation using H2O2: . To a stirred solution of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[ 4,5-b]pyridin-3-yl)benzonitrile (Int-5) (500mg, 1.4 mmol, 1eq) in DMSO (10 ml) cooled in an ice bath was added H2O2 (30%, 0.33 ml, 2.8 mmol, 2.0 eq) and potassium carbonate (202 mg, 1.40 mmol, 1.0 eq). The mixture was then allowed to warm up to room temperature and stirred at 60 °C for 2h. The progress of the reaction was monitored with TLC. The solid obtained was filtered and dried. Trituration with Et2O afforded 4-(6-(4,4- difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-3-yl) benzamide, Int-6 (400mg) as a yellow solid. The crude obtained was used in the next step without further purification. TLC: 80% EtOAc: heptane (R f : 0.35) MS: m/z = 387.02 [M+H] + . [0281] Step-7: Synthesis of (E)-4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H-[1,2,3]triaz olo[4,5-b] pyridin-3-yl)-N-((dimethylamino)methylene)benzamide (Int-7) (General procedure for enamine formation with DMF-DMA): A solution of 4-(6-(4,4-difluoropiperidine-1-carbonyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)benzamide (Int-6) (400mg, 1.04 mmol, 1.0 eq) and N,N- dimethylformamide dimethyl acetal (DMF-DMA) (10mL) were stirred at 100 o C under nitrogen atmosphere for 1h. The progress of the reaction was monitored with TLC. The mixture was evaporated under reduced pressure, crude obtained was triturated with Et 2 O to afford (E)-4-(6-(4,4- difluoropiperidine-1-carbonyl)-3H-[1,2,3]triazolo[4,5-b]pyri din-3-yl)-N- ((dimethylamino)methylene)benzamide, Int-7 (350mg, 76.75%) as pale yellow solid. The crude obtained was used in the next step without further purification. TLC: 5% MeOH/CH 2 Cl 2 (Rf: 0.35) LCMS: 95.34%, MS: m/z = 442.3 [M+H]+. [0282] Step-8:(3-(4-(1H-1,2,4-triazol-5-yl)phenyl)-3H-[1,2,3]triazo lo[4,5-b]pyridin-6-yl)(4,4- difluoropiperidin-1-yl) methanone (MH-DH-613) (General procedure for triazole formation using hydrazine acetate): To a stirred solution of (E)-4-(6-(4,4-difluoropiperidine-1-carbonyl) -3H-[1, 2, 3] triazolo [4, 5-b] pyridin-3-yl)-N-((dimethylamino)methylene) benzamide, (Int-7) (100mg, 0.226 mmol, 1.0 eq) dissolved in acetic acid (0.5 mL) was added hydrazine acetate (104mg, 1.13 mmol, 5.0 eq) at room temperature. The resultant mixture was stirred at 95°C for 2h. The progress of the reaction was monitored with TLC. After consumption of starting material, the mixture was quenched with saturated NaHCO3 (10 mL). The solution was extracted with EtOAc (2 X 20 mL) and washed with water (5 mL) and brine (5mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude was purified by combi-flash column chromatography using 5% MeOH: DCM to afford (3-(4-(1H-1,2,4-triazol-5-yl) phenyl) -3H-[1,2,3] triazolo[4,5-b] pyridin-6-yl) (4,4-difluoropiperidin-1-yl) methanone (C-7) (65mg, 67.39%) as off white solid. TLC: 5% MeOH/CH2Cl2 (Rf: 0.35) LCMS: 97.21%, MS: m/z = 411.1 [M+H] + . [0283] Example 5. Synthesis of (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d][1,2,3 ]triazol- 5-yl) (4,4-difluoropiperidin-1-yl)methanone (C-9) [0284] Scheme 5 [0285] Step-1: Synthesis of (4,4-difluoropiperidin-1-yl)(4-fluoro-3-nitrophenyl)methanon e (Int-1): 4-fluoro-3-nitrobenzoic acid, SM-1 (2 g, 10.80 mmol, 1.0 eq.) was converted to (4,4-difluoropiperidin-1- yl)(4-fluoro-3-nitrophenyl)methanone (Int-1) using general procedure for acid-amine coupling with HATU/4,4-difluoropiperidine hydrochloride (2.04 g, 12.97 mmol, 1.2 eq). The crude solid obtained was filtered, washed with diethyl ether (2 X 5 mL) and dried under reduced pressure to afford (4,4- difluoropiperidin-1-yl)(4-fluoro-3-nitrophenyl)methanone, Int-1 (1.2 g, 38.50%) as off white solid. TLC: 50% EtOAc/ Heptane (Rf: 0.40) MS: m/z=289.2 [M+H] + . [0286] Step-2: Synthesis of 5-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) picolinonitrile (Int-2): (4,4-difluoropiperidin-1-yl)(4-fluoro-3-nitrophenyl)methanon e, (Int-1) (1.2g, 4.16 mmol, 1.0 eq) was converted to 5-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino)picolinonitrile (Int-2) using general procedure for S N Ar reaction using NaH. The crude was purified by combi-flash column chromatography using 50% EtOAc:heptane to afford methyl 5-((4-(4,4- difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) picolinonitrile, Int-2 (900mg, 55.80%) as a pale brown oil. TLC: 40% EA: Hex (Rf: 0.3). MS: m/z = 388.2 [M+H] + . [0287] Step-3: Synthesis of 5-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl) phenyl) amino) picolinonitrile (Int-3): methyl 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzoate (Int-2) (800mg, 3.34 mmol, 1.0 eq) was converted to 5-((2-amino-4-(4,4-difluoropiperidine-1- carbonyl)phenyl)amino)picolinonitrile (Int-3) using the general procedure for reduction of nitro compounds with Fe/NH4Cl. The crude product was purified by combi-flash column chromatography using 50% EtOAc:heptane to afford 5-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl) phenyl)amino)picolinonitrile, Int-3 (620 mg, 84%) as a yellow solid. TLC: 60% EtOAc: heptane (Rf: 0.3); MS: m/z = 358.3 [M+H] + . [0288] Step-4: Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3]triazol-1- yl) picolinonitrile (Int-4): 5-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl) phenyl) amino) picolinonitrile (Int-3) (500 mg, 1.40 mmol, 1eq) was converted to 5-(5-(4,4-difluoropiperidine-1- carbonyl)-1H-benzo[d][1,2,3]triazol-1-yl)picolinonitrile using general procedure for triazolo formation to afford 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3]t riazol-1-yl) picolinonitrile, Int-4 (300 mg, 58.30%) as a yellow solid. TLC: 70% EtOAc: heptane (Rf: 0.4); MS: m/z = 369.2 [M+H] + . [0289] Step-5: Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3]triazol-1- yl) picolinimidohydrazide (Int-5): 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3] triazol- 1-yl)picolinonitrile (300 mg, 0.814 mmol, 1.0 eq) was converted to 5-(5-(4,4-difluoropiperidine-1- carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl)picolinimidohydrazide, (Int-5), using the general procedure for imidohydrazide formation using hydrazine to afford 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d][1,2,3]triazol-1-yl)picolinimidohydrazide, Int-5 (180 mg, 66.40%) as pale yellow solid. TLC: 100% EtOAc (Rf: 0.25) MS: m/z = 401.56 [M+H] + . [0290] Step-7: Synthesis of (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d] [1,2,3]triazol-5-yl) (4,4-difluoropiperidin-1-yl)methanone (C-9): 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d][1,2,3]triazol-1-yl)picolinimidohydrazide (Int-5) (180 mg, 0.450 mmol, 1.0 eq) was converted to (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d][1,2,3 ]triazol-5-yl) (4,4-difluoropiperidin-1-yl) methanone (C-9) using the general procedure for triazole formation with triethylorthoformate to afford (1- (6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-benzo[d][1,2,3]tr iazol-5-yl) (4,4-difluoropiperidin-1- yl)methanone (C-9) (60mg, 32.6%) as off white solid. TLC: 10% MeOH/CH 2 Cl 2 (R f : 0.2); LCMS: 98.33%, MS: m/z = 411.5 [M+H] + . [0291] Example 6. Synthesis of (1-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1H-benzo[d][1,2,3]triaz ol-5-yl) (4,4-difluoropiperidin-1-yl)methanone (C-10) [0292] Scheme 6 [0293] Step-1: Synthesis of (4,4-difluoropiperidin-1-yl)(4-fluoro-3-nitrophenyl)methanon e (Int-1): Previously described in the synthesis of C-9. [0294] Step-2: Synthesis of 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzonitrile (Int-2): (4,4-difluoropiperidin-1-yl)(4-fluoro-3-nitrophenyl)methanon e, (Int-1) (1g, 3.47 mmol, 1.0 eq) was converted 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzonitrile (Int-2) using general procedure for SNAr reaction with NaH. The crude was purified by combi-flash column chromatography using 50% EtOAc: heptane to afford 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2- nitrophenyl)amino)benzonitrile, Int-2 (850 mg, 63.40%) as pale brown oil. TLC: 40% EA: Hex (Rf: 0.3). MS: m/z = 387.4 [M+H] + . [0295] Step-3: Synthesis of 4-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl)phenyl) amino) benzonitrile (Int-3):4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophe nyl) amino) benzonitrile (Int-2) (850mg, 3.34 mmol, 1.0 eq) was converted to 4-((2-amino-4-(4,4-difluoropiperidine-1- carbonyl)phenyl)amino)benzonitrile (Int-3) using the general procedure for reduction of nitro compounds with Fe/NH 4 Cl. The crude product was purified by combi-flash column chromatography using 50% EtOAc:heptane to afford 4-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl)phenyl)amin o)benzonitrile, Int-3 (750 mg, 95.70%) as yellow solid. TLC: 60% EtOAc: heptane (Rf: 0.3); MS: m/z = 357.2 [M+H] + . [0296] Step-4: Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl) picolinonitrile (Int-4): 4-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl)phenyl) amino) benzonitrile (Int-3) (370 mg, 1.04 mmol, 1eq) was converted to 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d][1,2,3]triazol-1-yl)benzonitrile (Int-4) using general procedure for triazolo formation with NaNO 2 to afford 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3]t riazol-1-yl)benzonitrile, Int-4 (310 mg, 81.50%) as a yellow solid. TLC: 70% EtOAc: heptane (Rf: 0.4); MS: m/z = 368.2 [M+H] + . [0297] Step-5: Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl) benzamide (Int-5): .4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3] triazol-1-yl)benzonitrile (Int-4) (250mg, 0.680 mmol, 1.0 eq) was converted to 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d][1,2,3]triazol-1-yl)benzamide using general procedure for amide formation with H 2 O 2 to afford 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3]t riazol-1-yl)benzamide (180 mg, 69%) Int-5, as pale yellow solid TLC: 80% EtOAc: heptane (R f : 0.35) MS: m/z = 386.2 [M+H] + . [0298] Step-6: Synthesis of (E)-4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3]triazol- 1-yl)-N-((dimethylamino) methylene)benzamide (Int-6): 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H- benzo[d] [1,2,3]triazol-1-yl)benzamide (Int-5) (180 mg, 1.04 mmol, 1.0 eq) was converted to (E)-4-(5- (4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl)-N-((dimethylamino)methylene) benzamide (Int-6) using the general procedure for enamine formation with DMF-DMA. The crude obtained was triturated with Et2O to afford (E)-4-(5-(4, 4-difluoropiperidine-1-carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl)-N-((dimethylamino)methylene) benzamide (150mg) as a pale brown solid. TLC: 80% EtOAc (Rf: 0.5) MS: m/z = 441.2 [M+H] + . [0299] Step-7: Synthesis of (1-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1H-benzo[d][1,2,3]triaz ol-5-yl)(4,4- difluoropiperidin-1-yl)methanone (C-10): (E)-4-(5-(4,4-difluoropiperidine-1-carbonyl) -1H- benzo[d][1,2,3]triazol-1-yl)-N-((dimethylamino)methylene) benzamide, (Int-6) (150 mg) was converted to (1-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1H-benzo[d][1,2,3]triaz ol-5-yl)(4,4-difluoropiperidin -1-yl) methanone using general procedure for triazole formation using hydrazine acetate. The crude was purified by combi-flash column chromatography using 5% MeOH: DCM to afford (1-(4-(1H-1, 2, 4- triazol-5-yl) phenyl)-1H-benzo[d] [1, 2, 3] triazol-5-yl) (4, 4-difluoropiperidin -1-yl) methanone (C-10) (75 mg, 54%) as off white solid. TLC: 5% MeOH/CH2Cl2 (Rf: 0.25) LCMS: 92.19%, MS: m/z = 410.1 [M+H] + . [0300] Example 7. Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3]t riazol- 1-yl) benzoic acid (C-11) [0301] Scheme 7 [0302] Step-1: Int-1: Previously described in the synthesis of C-9. [0303] Step-2: Synthesis of methyl 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzoate (Int-2): 4,4-difluoropiperidin-1-yl)(4-fluoro-3-nitrophenyl)methanone , (Int-1) (2g, 6.94 mmol, 1.0 eq) was converted to methyl 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzoate (Int-2) using general procedure for S N Ar reaction with NaH. The crude was purified by combi-flash column chromatography using 50% EtOAc:heptane to afford methyl 4-((4-(4,4-difluoropiperidine-1- carbonyl)-2-nitrophenyl) amino) benzoate , Int-2 (1.4g, 48.10%) as pale brown oil. TLC: 40% EA: Hex (R f : 0.3). MS: m/z =420.40 [M+H] + . [0304] Step-3: Synthesis of methyl 4-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl) phenyl) amino) benzoate (Int-3):- methyl 4-((4-(4,4-difluoropiperidine-1-carbonyl)-2-nitrophenyl) amino) benzoate (Int-2) (1.4, 3.34 mmol, 1.0 eq) was converted to methyl 4-((3-amino-5-(4,4-difluoropiperidine- 1-carbonyl)pyridin-2-yl) amino)benzoate (Int-3) using the general procedure for reduction of nitro compounds using Fe/NH4Cl. The crude product was purified by combi-flash column chromatography using 50% EtOAc: heptane to afford methyl 4-((3-amino-5-(4,4-difluoropiperidine-1-carbonyl)pyridin-2- yl) amino)benzoate, Int-3 (705 mg, 54.26%) as a yellow solid. TLC: 60% EtOAc: heptane (Rf: 0.3); MS: m/z = 390.2 [M+H] + . [0305] Step-4: Synthesis of methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3] triazol-1-yl)benzoate (Int-4): methyl 4-((2-amino-4-(4,4-difluoropiperidine-1-carbonyl) phenyl) amino) benzoate (Int-3) (250mg, 0.642 mmol, 1eq) was converted to methyl 4-(5-(4,4-difluoropiperidine-1- carbonyl)-1H-benzo[d] [1,2,3]triazol-1-yl) benzoate using general procedure for triazolo formation to afford methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3]triazol-1-yl)benzoate, Int-4 (200mg, 77.8%) as a yellow solid. TLC: 70% EtOAc:heptane (Rf: 0.4); MS: m/z = 401.2 [M+H] + . [0306] Step-5: Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3] triazol-1- yl) benzoic acid (C-11): methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo [d] [1,2,3] triazol-1- yl)benzoate, (Int-4) (200 mg, 0.499 mmol, 1eq) was converted to 4-(5-(4,4-difluoropiperidine-1- carbonyl)-1H-benzo[d][1,2,3]triazol-1-yl) benzoic acid (C-11) using general procedure for hydrolysis with LiOH to afford 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3]t riazol-1-yl)benzoic acid (C-11) (35 mg, 24.47%) as an off white solid. TLC: 80% EtOAc: heptane (Rf: 0.2); LCMS: 95.63%, MS: m/z = 387.1 [M+H] + . [0307] Example 8. Synthesis of Compounds C-2 and C-14 [0308] Scheme 8 [0309] Step-1: Synthesis of Int-5a and Int-5b was accomplished using the general procedure for Ullmann coupling as described above; Int-5a (m/z= 401.1, [M+H] + ), Int-5b (60.19%, m/z= 442.2, [M+H] + ). [0310] Step-2A: Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrazolo[3,4-b] pyridin- 1-yl) benzoic acid, C-2: Int-5a was hydrolyzed using the general procedure for ester hydrolysis with LiOH to C-2 (31%, m/z= 385.25, [M-H] + ) as an off white solid. [0311] Step-2B: Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-indazol-1-yl) benzoic acid, C-14 and 4-(5-(4,4-difluoropiperidine-1-carbonyl)-2H-indazol-2-yl) benzoic acid: To a stirred solution of tert-butyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-indazol-1-yl)ben zoate (Int-5b) (180 mg, 0.407 mmol, 1 eq) in DCM (6 mL), TFA (2 mL) was added at 0 o C. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by crude LCMS/TLC; upon completion, the reaction mixture was concentrated in vacuo to afford crude. Crude was purified by prep- HPLC to afford 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-indazol-1-yl) benzoic acid, C-14 (25.5%, m/z= 386.2, [M+H] + ) as off white solid and 4-(5-(4,4-difluoropiperidine-1-carbonyl)-2H-indazol-2-yl) benzoic acid (11.5%, m/z= 386.2, [M+H] + ) as off white solid. [0312] Example 9. Synthesis of (S)-(3-(4-(4H-1,2,4-triazol-3-yl)phenyl)-3H-[1,2,3]triazolo[ 4,5- b]pyridin-6-yl)(3-methylpiperidin-1-yl)methanone (C-18) / (S)-(3-(6-(4H-1,2,4-triazol-3-yl)pyridin- 3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)(3-methylpiperid in-1-yl)methanone (C-19) [0313] Scheme 9 [0314] Step-1: Synthesis of methyl 6-((6-cyanopyridin-3-yl)amino)-5-nitronicotinate/ methyl 6-((4- cyanophenyl)amino)-5-nitronicotinate (Int-1): To a stirred solution of methyl 6-chloro-5-nitronicotinate SM-1 (1.0 eq) in DMF (5 v) at 0 o C, was added NaH (60% in paraffin oil, 2.0 eq). After 1h, at 0 o C, respective amine (SM-2) in DMF (3 v) was added and heated to 60 o C for 16h. The progress of the reaction was monitored by TLC and LCMS. Reaction was quenched with saturated ammonium chloride and extracted with EtOAc. Combined extracts were washed with water and brine solution. Dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 6-((6-cyanopyridin-3- yl)amino)-5-nitronicotinate/ methyl 6-((4-cyanophenyl)amino)-5-nitronicotinate Int-1a, X=N (79% yield, MS: m/z= 300.05 [M+1] + ); Int-1b, X=C (76% yield, MS: m/z= 299.2 [M+1] + ). [0315] Step-2: Synthesis of methyl 5-amino-6-((6-cyanopyridin-3-yl)amino)nicotinate / methyl 5- amino-6-((4-cyanophenyl)amino)nicotinate (Int-2a/Int-2b): methyl 6-((6-cyanopyridin-3-yl)amino)-5- nitronicotinate/ methyl 6-((4-cyanophenyl)amino)-5-nitronicotinate Int-1a/1b (1.0 eq) was reduced into methyl 5-amino-6-((6-cyanopyridin-3-yl)amino)nicotinate / methyl 5-amino-6-((4- cyanophenyl)amino)nicotinate, Int-2a/Int-2b using general reduction condition with Fe/NH 4 Cl to afford Int-2a/Int-2b, X=N (60% yield, MS: m/z=270.1 [M+1] + )/ X=C (56% yield, MS: m/z= 269.3 [M+1] + ). [0316] Step-3: Synthesis of Int-3a/Int-3b: Using the general procedure for triazole formation with sodium nitrate, Int-2a/Int-2b was converted to Int-3a/Int-3b; X=N (88% yield, MS: m/z=280.1 [M+1] + ); X=C (96% yield, MS: m/z= 279.1 [M+1] + ). [0317] Step-4: Synthesis of Int-4a/Int-4b: Int-4a/Int-4b was synthesized from Int-3a/Int-3b (1.0 eq) using the general hydrolysis condition with LiOH to afford Int-4a/Int-4b; X=N (95% yield, MS: m/z=264.1 [M-1]); X=C (94% yield, MS: m/z= 266.2 [M+1] + ). [0318] Step-5: Synthesis of Int-5a/Int-5b: Int-5a/Int-5b were synthesized from Int-4a/Int-4b (1.0 eq) and S-3-methyl piperidine (1.1 eq) using the general procedure for acid-amine coupling using HATU (1.2 eq), DIPEA (2.0 eq) in DMF (10 v) to obtain Int-5a/Int-5b; X=N (43% yield, MS: m/z=348.1 [M+1] + ); X=C (58% yield, MS: m/z= 347.1 [M+1] + ). [0319] Step-6: Synthesis of Int-6a/Int-6b: Int-6a/Int-6b was synthesized from Int-5a/Int-5b using general procedure for oxidation of nitrile using K2CO3 (2.0 eq) and H2O2 (5.0 eq) in DMSO (10 v) to obtain Int-6a/Int-6b as an off-white solids. X=N (58% yield, MS: m/z=366.1 [M+1] + ); X=C (66% yield, MS: m/z= 365.3 [M+1] + ). [0320] Step-7: Synthesis of Int-7a/Int-7b: Int-6a/Int-6b (1.0 eq) was taken in DMF-DMA (10 v) and heated to 90 o C for 1h. The progress of the reaction was monitored with TLC. The solvent was evaporated under reduced pressure and triturated with ether to afford, Int-7a/Int-7b as off-white solids. X=N (58% yield). X=C (62% yield). [0321] Step-8: Synthesis of (S)-(3-(4-(4H-1,2,4-triazol-3-yl)phenyl)-3H-[1,2,3]triazolo[ 4,5-b]pyridin- 6-yl)(3-methylpiperidin-1-yl)methanone (C-18) / (S)-(3-(6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3H- [1,2,3]triazolo[4,5-b]pyridin-6-yl)(3-methylpiperidin-1-yl)m ethanone (C-19) (General procedure for triazole synthesis using hydrazine acetate) : To a stirred solution of Int-7a/Int-7b (1.0 eq) in acetic acid (10 v), was added hydrazine acetate (5.0 eq) and heated to 80 o C, for 1h. The progress of the reaction was monitored with TLC LCMS. The acetic acid was evaporated, diluted with EtOAc and washed with NaHCO3 solution, water and brine solution. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford C-18/ C-19 as an off-white solids, X=N, C-18 (81% yield, MS : m/z=390.0 [M+1] + ). X=C, C-19 (76% yield, MS : m/z= 389.2 [M+1] + ). [0322] Example 10. Synthesis of Compounds C-4, C-6, C-12, and C-13 [0323] Scheme 10
[0324] Step-1: Int1a/Int-b were prepared using the general procedure for amide coupling with HATU. The crude was purified by combi-flash column purification using 70% EtOAc/ heptane to afford, Int-1a (m/z=267.1, [M+H] + ) and Int-1b (m/z= 266.2, [M+H] + ). [0325] Step-2: General procedure for Ullmann coupling (Int2a-d): To a stirred solution of Int-2 (1 eq) in Dioxane (100 mL), heteroaryl bromide (1.2 eq), K 3 PO 4 ( 2.0 eq), CuI (0.2 eq), trans- dimethylcyclohexane-1,2-diamine (0.2 eq) were added at room temperature. Reaction mixture was purged with argon gas for 15 min and then continued the reaction at 100 °C for 16 h. The reaction was monitored by TLC and after completion of the reaction, quenched with sat.NH 4 Cl solution (10 mL), and stirred at room temperature for 1h. The solvent was evaporated under reduced pressure and diluted with ethyl acetate (10 mL), washed with sat. NaHCO3 solution (50 mL), and brine solution (50 mL) and the organic phase dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude. The crude products were further purified by flash chromatography to afford Int-2a (46.4%, m/z= 369.2 [M+H] + ), Int-2b (51.7%, m/z= 368.2, [M+H] + ), Int-2c (43.50%, m/z= 368.05, [M+H] + ), Int-2d (58%, m/z= 367.26, [M+H] + ). [0326] Step-3: General procedure for oxidation of nitriles (Int-3a-d): To a stirred solution (Int-2a-d) (1eq) in DMSO (10 V) was added H2O2 (30%, 2.0 eq) and potassium carbonate (1.0 eq), the resultant mixture was stirred at 60 °C for 2h. The progress of the reaction was monitored by TLC. After completion of the reaction, solid obtained was filtered, washed with Et2O and dried in vacuo to afford Int-3a (m/z= 387.2 [M+H] + ), Int-3b (48%, m/z= 386.1, [M+H] + ), (79%, m/z= 386.1, [M+H] + ), Int-3d (86%, m/z= 385.30, [M+H] + ). [0327] Step-4: General procedure for synthesis of Int-4a-4dusing DMF-DMA: A solution of amide (Int-3a-3d) (1.0 eq) and N,N-dimethylformamide dimethyl acetal (DMF-DMA) (10 V) were stirred at 100 o C under nitrogen atmosphere for 1h. The progress of the reaction was monitored by TLC. The mixture was evaporated under reduced pressure, solid obtained was triturated with n-pentane, filtered and dried in vacuo to afford Int-4a, Int-4b, Int-4c, and Int-4d. [0328] Step-5A: General procedure for 1H-1, 2, 4-triazole formation using hydrazine acetate, C-4, C-6, C-12, C-13: To a stirred solution of appropriate Int-4 (1.0 eq) dissolved in acetic acid (0.5 V) was added hydrazine acetate (5.0 eq) at room temperature. The resultant mixture was stirred at 95°C for 2h. The progress of the reaction was monitored with TLC. After completion of the reaction, the mixture was quenched with saturated NaHCO 3 (10 mL). The solution was extracted with EtOAc (2 X 20 mL) and washed with water (5 mL) and brine (5mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated. C-4, crude was purified by Prep-HPLC to afford C-4 (34%, m/z= 411.1, [M+H] + ) as off- white solid. C-6, the crude was purified by combi-flash column chromatography using 5% MeOH: DCM to afford C-6(54%, m/z= 410.15, [M+H] + ) as off white solid. C-12, the crude was purified by combi-flash column chromatography using 5% MeOH: DCM to afford C-12(63%, m/z= 410.1, [M+H] + ) as off white solid. C-13, the crude was purified by combi-flash column chromatography using 5% MeOH: DCM to afford C-13 (51%, m/z= 409.05, [M+H] + ) as off white solid. [0329] Example 11. Synthesis of Compounds C-20, C-21, and C-22 [0330] Scheme 11 [0331] Step-1: Int1a/Int-1b/Int-1c: These were prepared using the general procedure for amide coupling with HATU. The crude was purified by combi-flash column purification using 70% EtOAc/ heptane to afford, Int-1a (66% yield, m/z=245.3, [M+H] + ) Int-1b (m/z=231.1, [M+H] + ) and Int-1c (64.1%, m/z= 257.2, [M+H] + ). [0332] Step-2: Int-2a/ Int-2b/ Int-2c: These were prepared from Int-1 using the general procedure for Ullman coupling. The crude products were further purified by flash chromatography to afford Int-2a (57.6%, m/z= 347.2 [M+H] + ), Int-2b (51.7%, m/z= 332.1, [M+H] + ), and Int-2c (35.7%, m/z= 359.05, [M+H] + ). [0333] Step-3: Int-3a/ Int-3b/ Int-3c: Int-2 was converted to Int-3 using the general procedure for oxidation of nitrile with H2O2. After completion of the reaction, solid obtained was filtered, washed with Et2O and dried in vacuo to afford Int-3a (63%, m/z= 365.3 [M+H] + ), Int-3b (48%, m/z= 349.1, [M+H] + ), and Int-3c (81%, m/z= 377.0, [M+H] + ). [0334] Step-4: General procedure for synthesis of Int-4a/ Int-4b/ Int-4c) using DMF-DMA: A solution of amide Int-3 (1.0 eq) and N,N-dimethylformamide dimethyl acetal (DMF-DMA) (10 V) were stirred at 100 o C under nitrogen atmosphere for 1h. The progress of the reaction was monitored by TLC. The mixture was evaporated under reduced pressure, solid obtained was triturated with n-pentane, filtered and dried in vacuo to afford Int-4a (78.9%, m/z= 420.1 [M+H] + ), Int-4b ( m/z=405.1, [M+H] + ), and Int- 4c (81.9%, m/z= 432.1, [M+H] + ). [0335] Step-5: General procedure for 1H-1, 2, 4-triazole formation using hydrazine acetate, C-20, C-21, and C-22: To a stirred solution of appropriate Int-4 (1.0 eq) dissolved in acetic acid (0.5 V) was added hydrazine acetate (5.0 eq) at room temperature. The resultant mixture was stirred at 95°C for 2h. The progress of the reaction was monitored with TLC. After completion of the reaction, the mixture was quenched with saturated NaHCO3 (10 mL). The solution was extracted with EtOAc (2 X 20 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over Na2SO4, C-20 (59%, m/z= 389.2 [M+H] + ) as off white solid. C-21 (64%, m/z= 375.3.2 [M+H] + ), as off white solid the crude was purified by combi-flash column chromatography using 5% MeOH: DCM to afford C-22 (64%, m/z= 401.1 [M+H] + ) as off white solid. [0336] Example 12. Synthesis of (1-(3-(4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrazolo[3,4-b]pyrid in-5- yl)(4,4-difluoropiperidin-1-yl)methanone (C-41) [0337] Scheme 12 [0338] Step 1: To a mixture of (4,4-difluoropiperidin-1-yl)(1H-pyrazolo[3,4-b]pyridin-5-yl) methanone (150 mg, 563 µmol, 1.00 eq.), 3-(3-iodophenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triaz ole (240 mg, 676 µmol, 1.20 eq.), CuI (21.5 mg, 113 µmol, 0.2 eq.), K3PO4 (239 mg, 1.13 mmol, 2.00 eq.), dimethylcyclohexane-1,2-diamine (16.0 mg, 113 µmol, 0.20 eq.) in DMA (1.5 mL), and the mixture was degassed and purged with N23 times, then the mixture was stirred at 90 °C for 5 hours under N2 atmosphere (15 psi). The reaction mixture was diluted with H 2 O (20 mL) and EtOAc (10 mL), then filtered to give a filtrate and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate = 2/1 to 1/3) to give (4,4-difluoropiperidin-1-yl)(1-(3-(4-(tetrahydro-2H-pyran-2- yl)-4H-1,2,4-triazol-3- yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone (270 mg, 498 µmol, 88% yield, 91% purity) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.94 (s, 1H), 8.87 - 8.77 (m, 2H), 8.62 - 8.51 (m, 2H), 8.44 - 8.34 (m, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 5.64 (dd, J = 2.4, 9.6 Hz, 1H), 3.97 (br s, 1H), 3.88 - 3.45 (m, 5H), 2.30 - 1.99 (m, 7H), 1.71 (dt, J = 4.0, 8.0 Hz, 1H), 1.63 - 1.51 (m, 2H). [0339] Step 2: To a mixture of (4,4-difluoropiperidin-1-yl)(1-(3-(4-(tetrahydro-2H-pyran-2- yl)-4H-1,2,4- triazol-3-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)methanon e (200 mg, 405 µmol, 1.00 eq.) in MeOH (2 mL) was added p-TsOH (83.7 mg, 486 µmol, 1.20 eq.) and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with H 2 O (20 mL) and quenched with NaHCO 3 at 0°C to adjust pH to neutral, and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 × 25mm × 10um; mobile phase: [water (FA) - ACN]; B%: 27% - 57%, 11min) to give (1-(3-(4H-1,2,4-triazol-3-yl)phenyl)-1H- pyrazolo[3,4-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)meth anone (64.2 mg, 156 µmol, 38 % yield, 99% purity) as a white solid. LCMS (ESI, M+1): m/z = 410.1. 1 H NMR (400 MHz, DMSO-d6) δ = 14.23 (br s, 1H), 8.97 (t, J = 2.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.59 (s, 1H), 8.54 (d, J = 2.0 Hz, 2H), 8.40 - 8.33 (m, 1H), 8.18 - 7.85 (m, 1H), 7.70 (t, J = 8.0 Hz, 1H), 3.66 (br s, 4H), 2.21 - 1.99 (m, 4H). [0340] Example 13. Synthesis of [(2R)-2-methylmorpholin-4-yl]-[1-[3-(4H-1,2,4-triazol-3- yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]methanone (C-39) [0341] Scheme 13 [0342] Step 1: To a mixture of 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (4.00 g, 24.5 mmol, 1.00 eq.), (2R)-2-methylmorpholine (4.05 g, 29.4 mmol, 1.20 eq. HCl), EDCI (9.40 g, 49.0 mmol, 2.00 eq.), HOBt (6.63 g, 49.0 mmol, 2.00 eq.) in DMF (40.0 mL) was added DIEA (9.51 g, 73.6 mmol, 12.8 mL, 3.00 eq.) and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (300 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (basic condition). The desired fraction was collected and lyophilized to give [(2R)-2-methylmorpholin-4-yl]-(1H-pyrazolo[3,4-b]pyridin-5-y l)methanone (3.20 g, 12.7 mmol, 52% yield, 98% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 13.87 (br s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H), 4.57 - 4.04 (m, 1H), 3.94 - 3.73 (m, 1H), 3.69 - 3.40 (m, 3H), 3.21 - 2.70 (m, 2H), 1.26 - 0.95 (m, 3H). [0343] Step 2: To a mixture of [(2R)-2-methylmorpholin-4-yl]-(1H-pyrazolo[3,4-b]pyridin-5- yl)methanone (200 mg, 812 µmol, 1.00 eq.), 3-(3-iodophenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (346 mg, 975 µmol, 1.20 eq.), CuI (30.9 mg, 162 µmol, 0.20 eq.), K 3 PO 4 (345 mg, 1.62 mmol, 2.00 eq.) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (23.1 mg, 162 µmol, 0.20 eq.) in DMA (4.00 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 90 °C for 3 hours under N 2 atmosphere (15 psi). The reaction mixture was filtered and diluted with H 2 O (20.0 mL), then extracted with EtOAc (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 1), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 3 / 1 to 0 / 1) to give [(2R)-2- methylmorpholin-4-yl]-[1-[3-(4-tetrahydropyran-2-yl-1,2,4-tr iazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5- yl]methanone (254 mg, 520 µmol, 64% yield, 97% purity) as a white solid. LCMS (ESI, M-84): m/z = 390.0. [0344] Step 3: To a mixture of [(2R)-2-methylmorpholin-4-yl]-[1-[3-(4-tetrahydropyran-2-yl- 1,2,4- triazol-3-yl)phenyl]pyrazolo[3,4-b]pyridin-5-yl]methanone (100 mg, 211 µmol, 1.00 eq.) in MeOH (2.00 mL) was added TsOH (43.6 mg, 253 µmol, 1.20 eq.). Then the mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with saturated NaHCO3 (10.0 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic layers were washed with brine (10.0 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150 × 50mm × 3 um; mobile phase: [water (FA)-ACN]; B%: 22%-52%, 7 minutes) to give [(2R)-2-methylmorpholin-4-yl]-[1-[3-(4H-1,2,4-triazol-3-yl)p henyl]pyrazolo[3,4- b]pyridin-5-yl]methanone (75.7 mg, 192 µmol, 91% yield, 99% purity) as a white solid. LCMS (ESI, M + 1): m/z = 390.0. 1 H NMR (400 MHz, DMSO-d6) δ = 14.35 - 14.26 (m, 1H), 8.98 (s, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.68 - 8.46 (m, 3H), 8.38 (br d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 4.38 - 4.35 (m, 1H), 3.88 - 3.77 (m, 1H), 3.66 - 3.45 (m, 3H), 3.33 - 3.13 (m, 1H), 2.99 - 2.89 (m, 1H), 1.15 - 1.04 (m, 3H). [0345] Example 14. Synthesis of (1-(3-chloro-5-(4H-1,2,4-triazol-3-yl) phenyl)-1H-pyrazolo[3,4- b]pyridin-5-yl)(thiomorpholino)methanone (C-66) [0346] Scheme 14 [0347] Step 1: A mixture of (1H-pyrazolo[3,4-b]pyridin-5-yl)(thiomorpholino)methanone (150 mg, 604 µmol, 1.00 eq.), 3-(3-chloro-5-iodophenyl)-4-(tetrahydro-2H-pyran-2-yl)- 4H-1,2,4-triazole (282 mg, 725 µmol, 1.20 eq.), (1R,2R)-N1,N2-dimethylcyclohexane-1,2- diamine (85.9 mg, 604 µmol, 1.00 eq.), K3PO4 (256 mg, 1.21 mmol, 2.00 eq.) and CuI (57.5 mg, 302 µmol, 0.50 eq.) in DMAC (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 3 hours under N2 atmosphere (15 psi). The mixture was diluted with H2O (30 mL) and extracted with EA (20 mL × 3), the organic layers were washed with saturated salt solution (30 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a reside. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 3/1 to 1/1) to give (1-(3-chloro-5-(4-(tetrahydro-2H- pyran-2-yl)-4H-1,2,4-triazol-3- yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(thiomorpholino)me thanone (250 mg, 441 µmol, 73% yield, 90% purity) as a yellow liquid. LCMS (ESI, M+1): m/z = 510.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.98 - 8.92 (m, 1H), 8.90 (s, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.62 (s, 1H), 8.57 (t, J = 2.0 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.03 - 7.91 (m, 1H), 5.66 (dd, J = 2.4, 9.6 Hz, 1H), 3.97 - 3.58 (m, 5H), 3.31 (s, 2H), 2.77 - 2.66 (m, 4H), 2.24 - 2.13 (m, 1H), 2.10 - 2.03 (m, 1H), 1.77 - 1.56 (m, 3H). [0348] Step 2: To a solution of (1-(3-chloro-5-(4-(tetrahydro-2H-pyran-2-yl)- 4H-1,2,4-triazol-3- yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(thiomorpholino)me thanone (200 mg, 392 µmol, 1.00 eq.) in MeOH (2 mL) was added TsOH (81.0 mg, 471 µmol, 1.20 eq.). The mixture was stirred at 50 °C for 2 hours. The reaction mixture was extracted with EtOAc (30 mL), then added saturated sodium bicarbonate to added pH = 8 and diluted with H2O (40 mL). The combined organic layers were washed with brine (40 mL × 2), dried over Na2SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 × 25 mm × 10 um; mobile phase: [water (FA)-ACN]; B%: 40%-70%, 10min) to give (1-(3-chloro-5-(4H-1,2,4-triazol-3-yl) phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)(thiomorpholino)metha none (95.0 mg, 220 µmol, 56% yield, 98.5% purity) as a white solid. LCMS (ESI, M+1): m/z = 426.0. 1 H NMR (400 MHz, DMSO-d6) δ = 14.42 (br dd, J = 3.2, 5.6 Hz, 1H), 9.04 - 8.96 (m, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.75 - 8.59 (m, 2H), 8.57 - 8.47 (m, 2H), 8.08 - 7.92 (m, 1H), 4.03 - 3.59 (m, 4H), 2.69 (br d, J = 12.0 Hz, 4H). [0349] The additional compounds of this application have been synthesized by the methods described in Examples 1-14. [0350] Analytical data for compounds described herein can be seen in Table 2a. Table 2a. Analytica data for representative compounds described herein. [0351] Example 15. Synthesis of 4-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridi n-3- yl)benzoic acid (D-1) / 5-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridi n-3-yl)picolinic acid (D-2) [0352] Scheme 15
[0353] Step-1: Synthesis of methyl 3-bromoimidazo[1,2-a]pyridine-7-carboxylate (Int-2): [0354] To a stirred solution of methyl imidazo[1,2-a]pyridine-7-carboxylate (SM-1) (1.0 g, 5.6 mmol, 1.0 eq) in methanol (10 mL) at 0 o C, sodium acetate (0.56 g, 6.8 mmol, 1.2 eq) and Bromine ( 0.32 mL, 6.2 mmol, 1.1 eq) were added. The reaction was stirred at RT for 1h. The progress of the reaction was monitored by TLC. The reaction was diluted with ice water, solid was filtered to obtain methyl 3- bromoimidazo[1,2-a]pyridine-7-carboxylate (Int-1) (1.3 g, 89.6% MS: m/z=257.0 [M+2] + as an off-white solid. [0355] Step-2: Synthesis of 3-bromoimidazo[1,2-a]pyridine-7-carboxylic acid (Int-2): 3- bromoimidazo[1,2-a]pyridine-7-carboxylic acid (Int-2) was synthesized from methyl 3- bromoimidazo[1,2-a]pyridine-7-carboxylate (Int-1) (1.3 g, 5.0 mmol, 1.0 eq) using the general hydrolysis condition with lithium hydroxide (0.63 g, 15.0 mmol, 3.0 eq) to obtain 3-bromoimidazo[1,2-a]pyridine-7- carboxylic acid (Int-2) (1.1 g, 90%, MS: m/z=243.0 [M+2] + ) as an off-white solid. [0356] Step-3: Synthesis of (3-bromoimidazo[1,2-a]pyridin-7-yl)(4,4-difluoropiperidin-1- yl)methanone (Int-3): (3-bromoimidazo[1,2-a]pyridin-7-yl)(4,4-difluoropiperidin-1- yl)methanone (Int- 3) was synthesized from 3-bromoimidazo[1,2-a]pyridine-7-carboxylic acid (Int-2) (1.1 g, 4.5 mmol, 1.0 eq) using the general procedure for amide coupling with HATU to afford (3-bromoimidazo[1,2-a]pyridin- 7-yl)(4,4-difluoropiperidin-1-yl)methanone (Int-3) (1.42 g, 91.61%, MS :345.2 [M+1] + ) as an off-white solid. [0357] Step-4: Synthesis of Int-4: In a sealed tube, to the stirred solution of (3-bromoimidazo[1,2- a]pyridin-7-yl)(4,4-difluoropiperidin-1-yl)methanone (Int-3) (1.0 eq) in 1,4- dioxane : water (8:2, 10 v), degassed with argon. The respective boronic acid (1.3 eq) and sodium carbonate (3.0 eq) was added. After 15 min, Pd(dppf)Cl2 DCM adduct (0.1 eq) was added and stirred at 90 o C, for 8h. The progress of the reaction was monitored by the TLC. The reaction mass was filtered through the celite bed and the organic layer was washed with water and brine solution, dried over sodium sulfate, filtered and concentrated. The crude was purified using combi flash, 60% EtOAc/ Hex as an eluent.to afford obtain Int-4a (X=C and R=OEt, 75% yield, MS : m/z= 414.61 [M+1] + ) and Int-4b X=N and R=OMe, 34% yield, MS : m/z=401.2 [M+1]) as an off-white solid. [0358] Step-5: Synthesis of 4-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridi n-3- yl)benzoic acid (D-1) / 5-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridi n-3-yl)picolinic acid (D-2): 4-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridi n-3-yl)benzoic acid D-1/ 5-(7- (4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridin-3-y l)picolinic acid MF-DH-657 was synthesized from Int-4a/ Int-4b using general procedure for hydrolysis using LiOH to afford D-1 (19.2% yield, MS : m/z= 386.1 [M+1] + ) and D-2 (62% yield, MS : m/z= 387.2[M+1] + ). [0359] Example 16. Synthesis of (3-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)imidazo[1,2-a]pyri din-7- yl)(4,4-difluoropiperidin-1-yl)methanone (D-3) [0360] Scheme 16 [0361] Synthesis of Int-3 is described above in the synthesis of D-1. [0362] Step-1: Synthesis of 5-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridi n-3- yl)picolinonitrile (Int-4): In a sealed tube, to the stirred solution of (3-bromoimidazo[1,2-a]pyridin-7- yl)(4,4-difluoropiperidin-1-yl)methanone (Int-3) (0.6 g, 1.74 mmol, 1.0 eq) in 1,4- Dioxane:water (8:2, 10 v), degassed with argon. (6-cyanopyridin-3-yl)boronic acid (0.33g, 2.2 mmol, 1.3 eq), sodium carbonate (0.55 g, 1.74 mmol, 3.0 eq) was added. After 15 min, Pd(dppf)Cl2 DCM adduct (0.14 g, 0.174 mmol, 0.1 eq) was added and stirred at 90 o C, for 8h. The progress of the reaction was monitored by the TLC. The reaction mass was filtered through the celite bed and the organic layer was washed with water and brine solution, dried over sodium sulfate, filtered and concentrated. Crude was purified using combi flash, 60% EtOAc/ Hex as an eluent to afford 5-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridi n-3- yl)picolinonitrile, Int-4 (0.39g, 60.9% yield, MS: m/z= 368.15 [M+1] + ) as an off-white solid. [0363] Step-2: Synthesis of 5-(7-(4,4-difluoropiperidine-1-carbonyl)imidazo[1,2-a]pyridi n-3- yl)picolinimidohydrazide (Int-5): To a stirred solution of 5-(7-(4,4-difluoropiperidine-1- carbonyl)imidazo[1,2-a]pyridin-3-yl)picolinonitrile Int-4 (0.15 g, 0.42 mmol, 1.0 eq) in ethanol (10 v) Hydrazine hydrate (2 mL) was added and stirred at 80 o C for 1h. The progress of the reaction was monitored by TLC and LCMS. The solvent was concentrated under reduced pressure, triturated with pentane to afford Int-5 (0.13 g, 79.7% m/z= 400.1 [M+1] + ) which was used in the next step without further purification. [0364] Step-3: Synthesis of (3-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)imidazo[1,2-a]pyri din-7-yl)(4,4- difluoropiperidin-1-yl)methanone (D-3): To Int-5 (0.13 g, 0.32 mmol, 1.0 eq) in Dioxane (10 v) was added p-TSA (0.012g, 0.06 mmol, 0.2 eq) and trimethyl orthoformate ( 0.17g, 0.16 mmol, 5.0 eq) and heated to 90 o C for 3h. The progress of the reaction was monitored with TLC and LCMS. The reaction mixture was diluted with EtOAC (4x 10 mL), washed with 10 % Na2CO3. Organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified using prep HPLC to afford (3-(6-(1H- 1,2,4-triazol-5-yl)pyridin-3-yl)imidazo[1,2-a]pyridin-7-yl)( 4,4-difluoropiperidin-1-yl)methanone, D-3 (40 mg, 30%, MS: m/z=410.2 [M+1] + ). [0365] Analytical data for compounds described herein can be seen in Table 2b. Table 2b. Analytica data for representative compounds described herein. BIOLOGICAL EXAMPLES [0366] Example B-1. hPGDH Inhibitor Screening Biochemical Assay [0367] A hydroxyprostaglandin dehydrogenase inhibition screening biochemical assay can be performed to assess the synthesized inhibitors provided herein. Provided herein is an exemplary biochemical assay for hPGDH inhibitor screening. [0368] The in vitro biochemical assay can be performed in white, 384 plates in total 20 µl reaction volume consisting of 10 nM of 15-PGDH/HPGD (R&D System# 5660-DH), 15 μM Prostaglandin E2 (Sigma, Cat # P5640-10MG) and 0.25 mM β-Nicotinamide adenine dinucleotide sodium salt (Sigma, Cat# N0632-5G) made in reaction buffer (50 mM Tris-HCl, pH 7.5, 0.01% Tween 20) at 10-point dose response curve for test/tool compounds. Briefly, 5 µl (4x) of compounds solution and 5 µl (final concentration, 10 nM) of enzyme solution is added to white 384 well plates and incubated for 10 mins at 37 °C.5 µl (4X) of Prostaglandin E2 and 5 µl (4X) of β-Nicotinamide adenine dinucleotide sodium salt is added to the wells and incubated for 10 mins at room temperature. Fluorescence is recorded at ex/em = 340 nm/485 nm. The percentage (%) inhibition of enzyme activity was determined relative to positive control (1% DMSO) and IC50 was calculated using GraphPad prism software (four parameter-variable slope equation). Exemplary data are shown in Table 3. Table 3. hPGDH inhibition potency. A < 0.1 µM; 0.1 µM ≤ B < 1 µM; 1 µM ≤ C [0369] Example B-2. Additional Biochemical Assays [0370] Cell Based Assay: 15-PGDH is highly expressed in resting human lung adenocarcinoma cells (A549) (Tong et al., 2006), and this cell line was used to assess 15-PGDH inhibition by MF-300Na in vitro. [0371] In this assay, A549 cells are treated with interleukin (IL) 1β, which induces the expression of cycloxygenase-2 and the synthesis of PGE2 (Tong et al., 2006). In the studies evaluating test articles, thirty thousand A549 cells were seeded in 100 µL F12K completed media and incubated for 24 hours at 37°C with 5% CO 2 before being serum-starved for 24 hours. On the day of the experiment, buffer was changed to complete medium, and cells were incubated for 30 minutes with compounds prior to the addition of IL-1β (final concentration of 0.1-0.25 ng/mL) overnight at 37°C with 5% CO 2 . Each concentration was run in triplicate. In this assay, tool compounds increased PGE 2 in the supernatant, and a half maximal effective concentration (EC 50 ) was calculated for each compound. The PGE2 in the supernatant was detected and quantified using a Cisbio HTRF technology (Homogeneous Time-Resolved Fluorescence) kit (62P2APEG-62P2APEH) according to the manufacturer’s recommendations, quantifying the fold induction of PGE2 of cells treated with IL-1b plus test article, versus treatment with IL-1b only. Data can be seen in Table 4. Table 4. PGE2 – HTRF over IL1-β [0372] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.