| JPWO2003031414 | New heterocyclic compounds and anti-inflammatory drugs |
| JP2017048212 | BACE INHIBITORS |
| JPH0710850 | [Title of Invention] Arylpiperidin derivative |
DURON SERGIO G (US)
PEREZ CHRISTIAN (US)
| WO2007067614A1 | 2007-06-14 | |||
| WO2007115058A2 | 2007-10-11 | |||
| WO2022261145A1 | 2022-12-15 |
| CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (I), wherein: Ring A is a heterocycloalkyl or heteroaryl; each R1 is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a; or two R1 on the same atom are taken together to form an oxo; or two R1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; each R1a is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R1a on the same atom are taken together to form an oxo; n is 0-11; or - R2 is hydrogen, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R; or two R3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; m is 1-4; each R4 is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 0-2; W is CRW or N; RW is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OC1-C3alkyl, -OC1-C3haloalkyl, -S(=O)C1-C3alkyl, -S(=O)2C1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, - C(=O)N(C1-C3alkyl)2, C1-C3alkyl, C1-C3deuteroalkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C1- C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the compound is of Formula (Ia): Formula (Ia); wherein R4’ is hydrogen or R4. 3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the compound is of Formula (Ib): Formula (Ib); wherein R4’ is hydrogen or R4. 4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the compound is of Formula (Ic): wherein R4’ is hydrogen or R4. 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is heterocycloalkyl. 6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is monocyclic heterocycloalkyl. 7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is bicyclic heterocycloalkyl. 8. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is 4- to 8-membered heterocycloalkyl. 9. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is 5- to 8-membered heterocycloalkyl. 10. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is 5- to 6-membered heterocycloalkyl. 11. The compound of any one of claims 5-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the heterocycloalkyl comprises 1 to 4 heteroatoms selected from the group consisting of O, S, and N. 12. The compound of any one of claims 5-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the heterocycloalkyl comprises 1 to 3 heteroatoms selected from the group consisting of O, S, and N. 13. The compound of any one of claims 5-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the heterocycloalkyl comprises 1 to 3 heteroatoms selected from the group consisting of O and N. 14. The compound of any one of claims 5-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the heterocycloalkyl comprises 1 to 2 heteroatoms selected from the group consisting of O and N. 15. The compound of any one of claims 5-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the heterocycloalkyl comprises 1 to 2 heteroatoms that are N. 16. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl. 17. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is pyrrolidinyl or piperidinyl. 18. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is pyrrolidinyl. 19. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is piperidinyl. 20. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein Ring A is 6-azaspiro[3.4]octanyl, 7-azaspiro[3.5]nonanyl, 6- azaspiro[2.5]octanyl, 2-azaspiro[4.4]nonanyl, 8-oxa-2-azaspiro[4.5]decanyl, 2-azaspiro[3.4]octanyl, 2-oxa-7-azaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, or 2-azaspiro[3.3]heptanyl. 21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein L is -[C(R3)2]m-. 22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R3 is independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R3 are taken together to form a cycloalkyl. 23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R3 is independently hydrogen, deuterium, halogen, -OH, C1-C6alkyl, or C1-C6haloalkyl; or two R3 are taken together to form a cycloalkyl. 24. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R3 is independently hydrogen, halogen, -OH, or C1-C6alkyl; or two R3 are taken together to form a cycloalkyl. 25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R3 is independently hydrogen or C1-C6alkyl. 26. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R3 is hydrogen. 27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein m is 1 or 2. 28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein m is 1. 29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein m is 2. 30. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein L is -CH2-, -CH2CH2-, or -CH2CH2CH2-. 31. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein L is -CH2-. 32. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein L is -CH2CH2-. 33. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein L is -CH2CH2CH2-. 34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R4 is independently deuterium, halogen, C1-C6alkyl, or C1-C6haloalkyl. 35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R4 is independently deuterium or halogen. 36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein p is 0 or 1. 37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein p is 0. 38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein p is 1. 39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein W is N. 40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1 is independently deuterium, halogen, -CN, -OH, -ORa, - NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R1a. 41. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1 is independently deuterium, halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R1a. 42. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1 is independently deuterium, halogen, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R1a. 43. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1 is independently halogen, -OH, -ORa, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, or cycloalkyl. 44. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1 is independently halogen, C1-C6alkyl, or C1-C6haloalkyl. 45. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1 is independently halogen or C1-C6alkyl. 46. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1 is independently C1-C6alkyl. 47. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1 is independently C1-C6alkyl optionally substituted with one or more R1a. 48. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1 is independently C1-C6alkyl. 49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1a is independently deuterium, halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. 50. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1a is independently deuterium, halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. 51. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1a is independently deuterium, halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 52. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1a is independently halogen, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 53. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1a is independently -NRcRd, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 54. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein each R1a is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein n is 0-2. 56. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein n is 0 or 1. 57. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein n is 0. 58. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein n is 1. 59. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is selected from a compound of table 1 or 2. 60. A pharmaceutical composition comprising a compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient. 61. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 62. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of claim 60. 63. The method of claim 61 or 62, further comprising administering an additional therapeutic agent. 64. The method of claim 63, wherein the additional therapeutic agent is an immunotherapeutic agent. 65. The method of claim 64, wherein the immunotherapeutic agent is an anti-PD-1 antibody, an anti- PD-L1 antibody, or an anti-CTLA-4 antibody. 66. A method of treating type-2 diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 67. A method of treating type-2 diabetes in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of claim 60. 68. A method of treating and/or controlling obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 69. A method of treating and/or controlling obesity in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of claim 60. 70. A method of treating a metabolic disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 71. A method of treating a metabolic disease in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of claim 60. |
[0065] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is , , some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring compound of Formula (I) or (Ia)-(Ic), Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring . [0066] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is ,
, . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring . [0068] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -O-, -S-, -S(=O)-, -S(=O) 2 -, - NR 2 -, -[C(R 3 )2]m-, -O[C(R 3 )2]m-, -NR 2 [C(R 3 )2]m-, -[C(R 3 )2]mO-, or -[C(R 3 )2]mNR 2 -. [0069] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -[C(R 3 )2]m-. [0070] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R 3 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R 3 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen, halogen, -OH, or C 1 -C 6 alkyl; or two R 3 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), two R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), two R 3 are taken together to form a cycloalkyl optionally substituted with one or more R. [0071] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 3 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 3 is hydrogen. [0072] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), m is 1-3. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), m is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), m is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), m is 2. [0073] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -CH2-, -CH2CH2-, or - CH2CH2CH2-. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -CH2-. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -CH2CH2-. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -CH 2 CH 2 CH 2 -. [0074] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -O-. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -S-, -S(=O)-, or -S(=O)2-. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -NR 2 -. [0075] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -NR 2 C(=O)- or -C(=O)NR 2 -. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -NR 2 S(=O)2- or -S(=O)2NR 2 -. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -O[C(R 3 )2]m-, -NR 2 [C(R 3 )2]m-, -[C(R 3 )2]mO-, or -[C(R 3 )2]mNR 2 -. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -O[C(R 3 )2]m- or - NR 2 [C(R 3 )2]m-. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), L is -[C(R 3 )2]mO- or - [C(R 3 )2]mNR 2 -. [0076] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R 2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R 2 is hydrogen or C 1 -C 6 alkyl. [0077] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 4 is independently deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 4 is independently deuterium or halogen. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 4 is independently halogen. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 4 is independently -OR a or C 1 -C 6 alkyl. [0078] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), p is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), p is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), p is 1. [0079] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), W is N. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), W is CR W . [0080] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R W is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R W is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R W is hydrogen. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R W is C 1 -C 6 alkyl. [0081] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R 1a . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R 1a . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently deuterium, halogen, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R 1a . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently halogen, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)- (Ic), each R 1 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently C 1 -C 6 alkyl optionally substituted with one or more R 1a . [0082] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , - C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R 1a . [0083] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , - C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R 1a . In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently deuterium, halogen, -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I) or (Ia)- (Ic), each R 1 is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), two R 1 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), two R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), two R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R. [0084] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1a is independently halogen, -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1a is independently -NR c R d , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1a is independently cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. [ 0085] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R 1 is independently fluoro, [0086] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-8. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-7. In some embodiments of a compound of Formula (I) or (Ia)- (Ic), n is 0-6. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-5. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-4. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-3. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0. In some embodiments of a compound of Formula (I) or (Ia)- (Ic), n is 1-8. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1-7. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1-6. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1-5. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1-4. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1-3. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 3. In some embodiments of a compound of Formula (I) or (Ia)- (Ic), n is 4. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 5. In some embodiments of
, [0091] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (II), wherein: Ring B is a cycloalkyl, heterocycloalkyl, or heteroaryl; each R 1 is independently deuterium, halogen, -CN, -NO 2 , -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , - C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R 1a ; or two R 1 on the same atom are taken together to form an oxo; or two R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; each R 1a is independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , - C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or two R 1a on the same atom are taken together to form an oxo; n is 1-11; R 2 is hydrogen, -C(=O)R a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R 3 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R; or two R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; m is 1-4; each R 4 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 0-2; W is CR W or N; R W is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , - C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -OC 1 -C 3 alkyl, -OC 1 -C 3 haloalkyl, -S(=O)C 1 -C 3 alkyl, -S(=O) 2 C 1 - C 3 alkyl, -S(=O) 2 NH 2 , -S(=O) 2 NHC 1 -C 3 alkyl, -S(=O) 2 N(C 1 -C 3 alkyl) 2 , -NH 2 , -NHC 1 -C 3 alkyl, -N(C 1 - C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, - C(=O)N(C 1 -C 3 alkyl) 2 , C 1 -C 3 alkyl, C 1 -C 3 deuteroalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 1 - C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; or two R on the same atom form an oxo. [0092] In some embodiments of a compound of Formula (II), the compound is of Formula (IIa): Formula (IIa); wherein R 4’ is hydrogen or R 4 . [0093] In some embodiments of a compound of Formula (II), the compound is of Formula (IIb): Formula (IIb); wherein R 4’ is hydrogen or R 4 . [0094] In some embodiments of a compound of Formula (II), the compound is of Formula (IIc): wherein R 4’ is hydrogen or R 4 . [0095] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 4- to 8-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5- to 8- membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heterocycloalkyl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heterocycloalkyl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heterocycloalkyl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heterocycloalkyl comprising 1 heteroatom that is N. [0096] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is cycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 4- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5- to 8-membered cycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5- to 6-membered cycloalkyl. [0097] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heteroaryl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 5-membered heteroaryl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is 6-membered heteroaryl. [0098] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heteroaryl comprising 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heteroaryl comprising 1 to 2 heteroatoms selected from the group consisting of O and N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heteroaryl comprising 1 to 2 heteroatoms that are N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), Ring B is heteroaryl comprising 1 heteroatom that is N. [0099] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -O-, -S-, -S(=O)-, - S(=O) 2 -, -NR 2 -, -[C(R 3 ) 2 ] m -, -O[C(R 3 ) 2 ] m -, -NR 2 [C(R 3 ) 2 ] m -, -[C(R 3 ) 2 ] m O-, or -[C(R 3 ) 2 ] m NR 2 -. [00100] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -[C(R 3 )2]m-. [00101] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -CH2-, -CH2CH2-, or - CH 2 CH 2 CH 2 -. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -CH 2 -. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -CH 2 CH 2 -. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -CH2CH2CH2-. [00102] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -O-. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -S-, -S(=O)-, or -S(=O)2-. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -NR 2 -. [00103] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -NR 2 C(=O)- or - C(=O)NR 2 -. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -NR 2 S(=O) 2 - or - S(=O)2NR 2 -. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -O[C(R 3 )2]m-, - NR 2 [C(R 3 )2]m-, -[C(R 3 )2]mO-, or -[C(R 3 )2]mNR 2 -. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -O[C(R 3 ) 2 ] m - or -NR 2 [C(R 3 ) 2 ] m -. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), L is -[C(R 3 )2]mO- or -[C(R 3 )2]mNR 2 -. [00104] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R 3 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R 3 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 3 is independently hydrogen, halogen, -OH, or C 1 -C 6 alkyl; or two R 3 are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), two R 3 are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), two R 3 are taken together to form a cycloalkyl optionally substituted with one or more R. [00105] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 3 is independently hydrogen, deuterium, halogen, -OH, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 3 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 3 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 3 is hydrogen. [00106] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 1-3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 1. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), m is 2. [00107] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R 2 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R 2 is hydrogen or C 1 -C 6 alkyl. [00108] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 4 is independently deuterium, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 4 is independently deuterium or halogen. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 4 is independently halogen. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 4 is independently -OR a or C 1 -C 6 alkyl. [00109] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), p is 0 or 1. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), p is 0. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), p is 1. [00110] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), W is N. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), W is CR W . [00111] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R W is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R W is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R W is hydrogen. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), R W is C 1 -C 6 alkyl.In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , - S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R 1a . [00112] In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , - C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R 1a . In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 1 is independently deuterium, halogen, -CN, -OH, -OR a , -S(=O) 2 R a , -S(=O) 2 NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 1 is independently deuterium, halogen, -S(=O)2R a , -S(=O)2NR c R d , -C(=O)R a , -C(=O)OR b , - C(=O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 1 is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), each R 1 is independently C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), two R 1 on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), two R 1 on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), two R 1 on the different atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-8. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-7. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-6. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-5. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-4. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1-3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1 or 2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 1. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 2. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 3. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 4. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 5. In some embodiments of a compound of Formula (II) or (IIa)-(IIc), n is 6. [00113] In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. [00114] In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl independently and optionally substituted with one or more R. [00115] In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; wherein each alkyl and cycloalkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; wherein each alkyl is independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 alkyl independently and optionally substituted with one or more R. In some embodiments of a compound disclosed herein, R c is cycloalkyl and R d hydrogen. [00116] In some embodiments of a compound disclosed herein, R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound disclosed herein, R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl. [00117] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, - OH, -OC 1 -C 3 alkyl, -OC 1 -C 3 haloalkyl, NH 2 , -NHC 1 -C 3 alkyl, -N(C 1 -C 3 alkyl) 2 , C 1 -C 3 alkyl, C 1 -C 3 deuteroalkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3alkyl, - OC 1 -C 3 haloalkyl, NH 2 , C 1 -C 3 alkyl, C 1 -C 3 deuteroalkyl, or C 1 -C 3 haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3alkyl, NH2, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen, C1- C 3 alkyl, or C 1 -C 3 haloalkyl. [00118] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [00119] In some embodiments, the compound disclosed herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. TABLE 1 * Stereochemistry arbitrarily assigned [00120] In some embodiments, the compound disclosed herein is a compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Table 2
Further Forms of Compounds Disclosed Herein Isomers/Stereoisomers [00121] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds [00122] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. [00123] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts [00124] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [00125] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. [00126] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, HEWAMNASE& HEWXME'*&/'DINASE& HXDQNWXBEMYNASE& \'HXDQNWXBTSXQASE& HXDQNCHKNQIDE& HXDQNBQNLIDE& hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate and xylenesulfonate. [00127] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct- 2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1 -carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts. [00128] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-4 alkyl)4, and the like. [00129] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen- containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates [00130] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. [00131] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Tautomers [00132] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Method of Treatment [00133] Disclosed herein are methods of treatment of a disease in which inhibition of PTPN1/ PTPN2 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00134] Disclosed herein are methods of treatment of a disease in which inhibition of PTPN1 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN1 is beneficial is cancer or a metabolic disease. [00135] Disclosed herein are methods of treatment of a disease in which inhibition of PTPN2 is beneficial, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN2 is beneficial is cancer. Cancer [00136] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is used to treat cancer. [00137] As used herein, “cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas (e.g., papillary adenocarcinomas), lymphomas, leukemias, melanomas, etc., including solid and lymphoid cancers. [00138] The term “leukemia” refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, chronic leukemia, acute nonlymphocytic leukemia, acute lymphocytic leukemia, B-cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, erythroleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblasts leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, polycythemia vera, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia. [00139] The term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, endotheliosarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, osteogenic sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma. [00140] The term “carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bile duct carcinoma, bladder carcinoma, breast carcinoma, Brenner carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchiogenic carcinoma, cerebriform carcinoma, cervical carcinoma, cholangiocellular carcinoma, chordoma, chorionic carcinoma, clear cell carcinoma, colloid carcinoma, colon carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, cystadenocarcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, endometrioid carcinoma, epiermoid carcinoma, epithelial carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lung carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, nonpapillary renal cell carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, ovarian carcinoma, pancreatic ductal carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, sebaceous gland carcinoma, seminoma, serous carcinoma, signet- ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, sweat gland carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, undifferentiated carcinoma, verrucous carcinoma, or carcinoma villosum. [00141] In some embodiments, the cancer is acoustic neuroma, adrenal cortical cancer, adrenal gland cancer, astrocytoma, benign monoclonal gammopathy, biliary tract cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchus cancer, cancer of the hematological tissues, cancer of the hepatic stellate cells, cancer of the oral cavity or pharynx, cancer of the pancreatic stellate cells, carcinoma, central nervous system cancer, cervical cancer, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma, endocrine system cancer, endometrial cancer, ependymoma, epithelial ovarian cancer, esophageal cancer, gastric cancer, genitourinary tract cancer, glioblastoma multiforme, glioma, gynecologic cancers, head and neck cancer, hemangioblastoma, Hodgkin's Disease, immunocytic amyloidosis, kidney cancer, laryngeal cancer, leukemia, liver cancer (including hepatocarcinoma), lobular carcinoma, lung cancer, lymphoma , malignant carcinoid, malignant hypercalcemia, malignant pancreatic insulanoma, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloma, neoplasms of the endocrine or exocrine pancreas, neuroblastoma, non-Hodgkin's Lymphoma, oligodendroglioma, oral cancer, ovarian cancer, Paget' s Disease of the Nipple, pancreatic cancer, papillary thyroid cancer, peripheral nervous system cancer, Phyllodes Tumors, pinealoma, premalignant skin lesions, primary macroglobulinemia, primary thrombocytosis, prostate cancer, renal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small bowel or appendix cancer, stomach cancer, testicular cancer, thyroid cancer, urinary bladder cancer, uterine cancer, Waldenstrom’s macroglobulinemia. Metabolic Diseases [00142] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is used to treat a metabolic disease. [00143] As used herein, the term “metabolic disease” refers to a disease or condition affecting a metabolic process in a subject. Exemplary metabolic diseases include non-alcoholic steatohepatitis (NASH), non- alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease. In some embodiments, a compound disclosed herein, is used to treat a metabolic disease (e.g., a metabolic disease described herein) by decreasing or eliminating a symptom of the disease. In some embodiments, the method of treatment comprises decreasing or eliminating a symptom comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like. Dosing [00144] In certain embodiments, the compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial. [00145] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition. [00146] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). [00147] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms. [00148] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. [00149] In some embodiments, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In some embodiments, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. Routes of Administration [00150] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections. [00151] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. Pharmaceutical Compositions/Formulations [00152] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals. [00153] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. [00154] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof. [00155] The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. Combination [00156] Disclosed herein are methods of treating cancer using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent. [00157] In some embodiments, the additional therapeutic agent is an anticancer agent. [00158] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein. [00159] In some embodiments, the additional therapeutic agent is an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti- CTLA-4 antibody. Example 1: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylpyrrolidin-3-yl)methyl)phe nyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide Step 1: Synthesis of compound 1-2 [00160] To a solution of 1-1 (100 g, 420.1 mmol, 1 eq) in THF (1.5 L) was added benzyl alcohol (47.7 g, 441.2 mmol, 45.8 mL, 1.05 eq) followed by dropwise addition of 1M t-BuOK (441 mL, 1.05 eq) at -78°C and then allowed to stir for 0.5 h. To the resulting reaction mixture was then added to H2O (1.5 L) then extracted with ethyl acetate (1 L×3). The combined organic layers were washed with brine (2 L), dried with Na 2 SO 4 , then filtered and concentrated under reduced pressure to give a crude. The crude was recrystallized in heptane to give 1-2 (131 g, 1.21 mol, 95% yield) as a yellow solid. *H NMR (400 MHz, DMSO-t/s) 5 7.62 (d, J- 1.6 Hz, 1H), 7.56 (dd, J- 9.2, 1.6 Hz, 1H), 7.41 (m, 5H), 5.35 (s, 2H).
Step 2: Synthesis of compound 1-3
[00161] To a solution of 1-2 (90 g, 275.97 mmol, 1 eq) in THF (500 mL) and MeOH (500 mL) was added Zn (90.2 g, 1.38 mol, 5 eq) portion-wise, followed by slow addition of sat. NH4CI (aq ) (54.67 g, 275.97 mmol, 100 mL, 27% purity, 1 eq) then allowed to stir for 3 h at 25 °C. The reaction mixture was filtered, then poured into water (1 L) and extracted with ethyl acetate (500 mL*4). The combined organic layers were washed with brine (1 L), dried with Na2SO4, then filtered and concentrated under reduced pressure to give 1- 3 (78 g, 95% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.48 (m, 2H), 7.39 (m, 2H), 7.31 (m, 1H), 5.16 (s, 2H), 4.84 (s, 2H).
Step 3: Synthesis of compound 1-5
[00162] To a solution 1-3 (103 g, 347.81 mmol, 1 eq) in DMF (1.5 L) was added K2CO3 (144 g, 1.04 mol, 3 eq), H2O (6.2 mL) and 1-4 (74.6 g, 382 mmol, 56.5 mL, 1.1 eq) then heated to 60 °C and allowed to stir for 72 h. To the resulting reaction mixture was added H2O (1 L) then extracted with ethyl acetate (500 mL*4). The combined organic layers were washed with brine (500 mL), dried withNa2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography on silica gel eluting with petroleum ether/ ethyl acetate- 1 : 0 to 10:1 to give crude 1-5 ( 160 g, crude product) as a brown oil. LCMS (ESI+): m/z = 356.0/354. 1 (M-/Bu+H) .
Step 4: Synthesis of compound 1-6
[00163] To a solution of 7V-(oxomethylene)sulfamoyl chloride (43.1 g, 304 mmol, 26.4 mL, 2.5 eq) in CH 2 Cl 2 (210 mL) was added prop-2-en-l-ol (17.7 g, 304 mmol, 20.7 mL, 2.5 eq) and allowed to stir for 0.5 h at 0 °C. To this was then added a solution of 1-5 (50 g, 121.87 mmol, 1 eq) and triethylamine (37 g, 365.61 mmol, 50.89 mL, 3 eq) in CH 2 Cl 2 (280 mL) and allowed to stir for an additional 0.5 h. The reaction mixture was then allowed to warm to 25°C and stirred for an additional 1 h. The resulting reaction mixture was added to H2O (600 mL) then extracted with CH 2 Cl 2 (600 mL*3). The combined organic layer was washed with brine (600 mL), dried with Na 2 SO 4 . then filtered and concentrated under reduced pressure to give 1-6 (510 g, crude) as a yellow solid which was used in next step without purification. 1 H NMR (400 MHz, DMSO-t/s) 5 11.68 (s, 1H), 7.47-7.39 (m, 4H), 7.38-7.34 (m, 1H), 7.30-7.25 (m, 2H), 5.76-5.73 (m, 1H), 5.26-5.23 (m, 1H), 5.19 (d, J= 1.7 Hz, 1H), 5.18-5.13 (m, 2H), 4.59 (d, J= 17.5 Hz, 1H), 4.31-4.12 (m, 3H), 1.34 (s, 9H).
Step 5: Synthesis of compound 1-7 A
[00164] To a solution of 1-6 (50 g, 87 mmol, 1 eq) in MeOH (500 mL) was added NaOMe (78.5 g, 435 mmol, 30% purity in THF, 5 eq) and Pd(PPli3)4 (3.02 g, 2.62 mmol, 0.03 eq) then heated to 60 °C and allowed to stir for 1 h. The resulting reaction mixture was filtered, and the filtrate was isolated. To the filtrate was then added to IM HC1 (2 L) then extracted with ethyl acetate (3 L*3). The combined organic layer was washed with brine (1 L), dried with Na2SOi. then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give 1-7 A (196 g, 472 mmol, 54% yield) as a yellow solid. 1 H NMR (400 MHz, CD3<5% [ 0(-2'0(-- $L& +7%& 0(-)'0(,, $L& ,7%& 0(++ $S& J = 1.8 Hz, 1H), 7.12 (dd, J = 2.0, 8.8 Hz, 1H), 5.17 (s, 2H), 4.40 (s, 2H). Step 6: Synthesis of compound 1-9A [00165] To a solution of 0.5M 9-BBN (180 mL, 1.5 eq) was added 1-8 (16.5 g, 90.3 mmol, 1.5 eq) then heated to 60 °C and allowed to stir 1 h. The reaction mixture was then allowed to cool to 20 °C. To this was then added a solution of 1-7 (25 g, 60.2 mmol, 1 eq), K 2 CO 3 (12.4 g, 90.3 mmol, 1.5 eq) and Pd(dppf)Cl 2 - CH2Cl2 (4.92 g, 6.02 mmol, 0.1 eq) in DMF (250 mL) and H2O (25 mL) then heated to 60 °C and allowed to stir for an additional 12 h. The resulting reaction mixture was filtered, and the filtrate was isolated. To the filtrate was then added to H 2 O (200 mL) then extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give 1-9A (22 g, 42.3 mmol, 70.33% yield) as a brown solid. 1 H NMR (400 MHz, CD 3 <5% [ 0(.* $D& J = 7.4 Hz, 2H), 7.41-7.22 (m, 3H), 6.78 (s, 1H), 6.69 (br d, J = 10.3 Hz, 1H), 5.19 (s, 2H), 4.27 (s, 2H), 3.47-3.36 (m, 2H), 3.27-3.15 (m, 1H), 2.95 (br t, J = 8.5 Hz, 1H), 2.75-2.56 (m, 2H), 2.49-2.33 (m, 1H), 1.86 (br d, J = 5.9 Hz, 1H), 1.60-1.50 (m, 1H), 1.45 (s, 9H). Step 7: Synthesis of compound 1-10 [00166] A solution of 1-9A (13 g, 25 mmol, 1 eq) in 4M HCl/ethyl acetate (200 mL) was allowed to stir for 2 h at 25 °C. The reaction mixture was then concentrated under reduced pressure to give 1-10 (15.7 g, HCl salt, crude) as a brown solid. 1 H NMR (400 MHz, CD3<5% [ 0(-1 $BQ D& J = 7.0 Hz, 2H), 7.40-7.30 (m, 3H), 6.90 (s, 1H), 6.79 (dd, J = 0.8, 10.1 Hz, 1H), 5.21 (s, 2H), 4.42 (s, 2H), 3.45-3.34 (m, 1H), 3.23 (br s, 1H), 2.85 (br s, 1H), 2.78 (br dd, J = 3.7, 7.4 Hz, 2H), 2.65-2.53 (m, 1H), 2.13-2.00 (m, 2H), 1.75-1.56 (m, 1H). Step 8: Synthesis of compound 1-11A [00167] To a solution of 1-10 (250 mg, 548 µmol, 1 eq) in MeOH (3 mL) was added formaldehyde (82 mg, 1.1 mmol, 75 µL, 2 eq) and AcOH (82 mg, 1.3 mmol, 78 µL, 2.5 eq) and allowed to stir for 0.5 h at 0 °C. To this was then added NaBH4 (130 mg, 3.4 mmol, 6.27 eq) and allowed to stir for an additional 2 h at 0 °C. The resulting reaction mixture was added to H 2 O (50 mL) then extracted with ethyl acetate (5 mL×3). The combined organic layer was washed with brine, dried with Na2SO4, then filtered and concentrated under reduced pressure to give 1-11A as a crude. LCMS (ESI-): m/z = 432.4 (M-H)-. Step 9: Synthesis of compound Example 1 [00168] To a solution of 1-11A (150 mg, 319 µmol, 1 eq) in MeOH (5 mL) was added Pd/C (100 mg, 5% purity) then degassed and purged with H2 (15 psi) several times. The reaction mixture was then allowed to stir for 12 h at 15 °C. The resulting reaction mixture was filtered then concentrated under reduced pressure to give a crude. The crude was purified by HPLC to give Example 1 (6 mg, 98% purity). LCMS (ESI-): m/z = 342.2 (M-H)-. 1 H NMR (400 MHz, CD3<5% [ /(/* $L& +7%& -(+, $R& +7%& +(1* $L& -7%& +(/2 $L& ,7%& +(+* (m, 1H), 1.78 (m, 1H), 1.32 (m, 1H). Examples 2-30 were prepared according to the procedures described in Example 1 using the appropriate intermediates. Example 31: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylpiperidin-3-yl)methyl)phen yl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide Step 1: Synthesis of compound 31-2 [00169] To 31-1 (17.8 g, 90.3 mmol, 1.5 eq) was added to 0.5M 9-BBN (180 mL, 1.5 eq) then heated to 60 °C and allowed to stir for 1 h. The reaction mixture was then cooled to 20 °C and added to a solution of 1- 7A (1 eq), K2CO3 (12.48 g, 90.31 mmol, 1.5 eq) and Pd(dppf)Cl2-CH2Cl2 (4.92 g, 6.02 mmol, 0.1 eq) in DMF (250 mL) and H2O (25 mL) then heated to 60 °C and allowed to stir for an additional 12 h. To the resulting reaction mixture was then added to H 2 O (200 mL) then extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (300 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give 31-2 (35 g, crude) as a brown oil. 1 H NMR (CD 3 <5% [ 0(-2 $D& J = 7.3 Hz, 2H), 7.37-7.32 (m, 2H), 7.29 (br d, J = 7.3 Hz, 1H), 6.81 (s, 1H), 6.70 (d, J = 10.1 Hz, 1H), 5.19 (s, 2H), 4.33 (br s, 2H), 3.94-3.75 (m, 2H), 2.91-2.76 (m, 1H), 2.61-2.47 (m, 3H), 1.75-1.61 (m, 4H), 1.41 (br s, 9H), 1.20 (br d, J = 16.9 Hz, 1H). Step 2: Synthesis of compound 31-3 [00170] A mixture of 31-2 (33 g, 61.84 mmol, 1 eq) in 4M HCl/ethyl acetate (350 mL) was degassed and purged with N2 for 3 times, then allowed to stir for 2 h at 25 °C. The reaction mixture was then concentrated under reduced pressure and purified by HPLC to give 31-3 (11 g, 23.4 mmol, 37% yield) as a white solid. 1 H NMR (CD3<5% [ 0(-2 $D& J = 7.3 Hz, 2H), 7.38-7.32 (m, 2H), 7.28 (s, 1H), 6.78 (s, 1H), 6.69 (dd, J = 1.5, 10.1 Hz, 1H), 5.17 (s, 2H), 4.28 (s, 2H), 3.33 (br d, J = 1.6 Hz, 1H), 3.23-3.15 (m, 1H), 2.86 (dt, J = 3.2, 13.0 Hz, 1H), 2.68-2.60 (m, 2H), 2.59-2.51 (m, 1H), 1.98 (ddd, J = 3.9, 7.6, 11.4 Hz, 1H), 1.93-1.86 (m, 1H), 1.85-1.74 (m, 1H), 1.72-1.57 (m, 1H), 1.23 (br dd, J = 3.3, 12.6 Hz, 1H). Step 3: Synthesis of compound 31-4A [00171] To a solution of formaldehyde (259 mg, 3.2 mmol, 237 µL, 3 eq) in acetonitrile (5 mL) was added 31-3 (0.5 g, 1.06 mmol, 1 eq) and acetic acid (159 mg, 2.66 mmol, 152 µL, 2.5 eq) and allowed to stir for 1 h at 15 °C. To this was then added NaBH 3 CN (74 mg, 1.17 mmol, 1.1 eq) and allowed to stir for an additional 1 h. The resulting reaction mixture was concentrated under reduced pressure to give 31-4A (0.5 g, crude) as a yellow solid. LCMS (ESI-): m/z = 446.4(M-H)-. Step 4: Synthesis of compound Example 31 [00172] To a solution of 31-4A (150 mg, 319 mol, 1 eq) in MeOH (5 mL) was added 5% Pd/C (100 mg) then degassed and purged with H2 (15 psi) several times. The reaction mixture was then allowed to stir for 12 h at 15 °C. The resulting reaction mixture was filtered over celite and concentrated under reduced pressure to give a crude. The crude was purified by HPLC to give Example 31 (6 mg). LCMS (ESI-): m/z = 356.2 (M-H)-. 1 H NMR (400 MHz, CD3<5% [ /(.2 $R& *7%& /(./ $D& J = 10.7 Hz, 1H), 4.24 (s, 2H), 3.41 (br d, J = 12.3 Hz, 1H), 3.28 (br s, 1H), 2.89-2.83 (m, 1H), 2.80 (s, 3H), 2.71-2.57 (m, 2H), 2.55-2.45 (m, 1H), 2.11-2.00 (m, 1H), 1.99-1.90 (m, 1H), 1.89-1.81 (m, 1H), 1.79-1.65 (m, 1H), 1.15 (d, J = 2.3 Hz, 1H). Examples 32 – 54 were prepared according to the procedures described in Example 31 using the appropriate intermediates.
Example 55: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylazepan-3-yl)methyl)phenyl) -1,2,5- thiadiazolidin-3-one 1,1-dioxide Step 1: Synthesis of compound 55-2A [00173] To a solution of 0.5M 9-BBN (3.18 mL, 1.5 eq) was added 55-1 (244 mg, 1.16 mmol, 1.2 eq) then heated to 60 °C and allowed to stir 1 h. The reaction mixture was then allowed to cool to 20 °C. To this was then added a solution of 1-7A (400 mg, 963 µmol, 1 eq), K 2 CO 3 (200 mg, 1.44 mmol, 1.5 eq) and Pd(dppf)Cl2-CH2Cl2 (78 mg, 96 µmol, 0.1 eq) in DMF (4 mL) and H2O (0.4 mL) then heated to 60 °C and allowed to stir for an additional 12 h. To the reaction mixture was added H 2 O (10 mL) then extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL), dried with Na 2 SO 4 , then filtered and concentrated under reduced pressure to give 55-2A (500 mg, 913 µmol, 94% yield) as a yellow oil. LCMS (ESI-): m/z = 546.4 (M-H)-. 1 H NMR (400 MHz, CD3<5% [ 0(-2 $R& +7%& 0(,1'0(,, $L& 2H), 7.29 (s, 1H), 6.75 (s, 1H), 6.66 (dd, J = 1.4, 10.2 Hz, 1H), 5.19 (s, 2H), 4.33 (s, 2H), 3.61-3.46 (m, 1H), 3.43-3.34 (m, 2H), 3.20-3.05 (m, 1H), 2.53 (s, 2H), 1.91-1.57 (m, 5H), 1.45 (d, J = 6.8 Hz, 9H), 1.38-1.28 (m, 1H), 1.20-1.06 (m, 1H) Step 2: Synthesis of compound 55-3A [00174] To a mixture 55-2A (470 mg, 858 µmol, 1 eq) in THF (10 mL) was added 10% Pd/C (20 mg) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times then allowed to stir for 2 h at 25 °C. The resulting reaction mixture was filtered over celite and then concentrated under reduced pressure to give 55-3A (370 mg, 808 µmol, 94% yield) as a colorless oil. LCMS (ESI-): m/z = 456.3 (M-H)-. Step 3: Synthesis of compound Example 55 [00175] To a solution of 55-3 (370 mg, 808 µmol, 1 eq) in ethyl acetate (2 mL) added 4M HCl/ethyl acetate (20 mL) and allowed to stir for 20 min at 25 °C. The reaction mixture was concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give Example 55 (94 mg, 263 µmol, 32% yield). LCMS (ESI+): m/z = 358.1 (M+H) + . 1 H NMR (400 MHz, CD3<5% [ /(//'/(-0 $L& +7%& 4.23 (s, 2H), 3.22-3.11 (m, 3H), 2.86 (dd, J = 10.3, 13.6 Hz, 1H), 2.67-2.58 (m, 1H), 2.54-2.45 (m, 1H), 2.21-2.05 (m, 1H), 1.97-1.75 (m, 4H), 1.62-1.50 (m, 1H), 1.47-1.34 (m, 1H). Example 56: Synthesis of 5-(2-fluoro-6-hydroxy-4-((1-methylazepan-3-yl)methyl)phenyl) -1,2,5- thiadiazolidin-3-one 1,1-dioxide [00176] Compound 56-1 was prepared according to the procedure described for Example 55. To a solution of 56-1 (50 mg, 140 µmol, 1 eq) and formaldehyde (218 mg, 2.7 mmol, 0.2 mL, 19.2 eq) in MeOH (20 mL) was added 10% Pd/C (20 mg, 139 µmol) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times then allowed to stir for 2 h at 20 °C. The resulting reaction mixture was filtered over celite and then concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give Example 56 (2 mg, 5.2 µmol, 3% yield). LCMS (ESI-): m/z = 370.1 (M-H)-. 1 H NMR (400 MHz, CD3<5% [ /(//'/(.+ $L& +7%& -(+- $R& +7%& ,(,)',()/ $L& -7%& +(1, $R& ,7%& +(//'+(-1 $L& 2H), 2.24 (br d, J = 7.4 Hz, 1H), 2.02-1.83 (m, 4H), 1.67-1.58 (m, 1H), 1.52-1.38 (m, 1H). Examples 57 – 60 were prepared according to the procedures described in Examples 55 and 56 using the appropriate intermediates. Example 61: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(1-methylpyrrolidin-3-yl)ethyl)ph enyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide Step 1: Synthesis of compound 61-2 [00177] To a solution of 0.5M 9-BBN (14.4 mL, 1.5 eq) was added 61-1 (1.4 g, 7.2 mmol, 1.5 eq) then heated to 60 °C and allowed to stir 1 h. The reaction mixture was then allowed to cool to 20 °C. To this was then added a solution of 1-7A (2 g, 4.82 mmol, 1 eq), K2CO3 (998 mg, 7.2 mmol, 1.5 eq) and Pd(dppf)Cl2- CH 2 Cl 2 (393 mg, 481 µmol, 0.1 eq) in DMF (20 mL) and H 2 O (10 mL) then heated to 60 °C and allowed to stir for an additional 12 h. To the reaction mixture was added H2O (50 mL) then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give 61-2 (1.5 g, 2.8 mmol, 58% yield) as a white solid. Step 2: Synthesis of compound 61-3 A solution of 61-2 (470 mg, 880 µmol, 1 eq) in 4M HCl/ethyl acetate (10 mL) was allowed to stir for 0.5 h at 25 °C. The reaction mixture was concentrated under reduced pressure to give 61-3 (400 mg, crude) as a yellow solid. Step 3: Synthesis of compound 61-4A series [00178] To a solution of 61-3 (100 mg, 230 µmol, 1 eq), formaldehyde (14 mg, 461 µmol, 13 µL, 2 eq) in acetonitrile (2 mL) was added acetic acid (34 mg, 576 µmol, 33 µL, 2.5 eq) and allowed to stir for 0.5 h at 25 °C. To this was then added NaBH 3 CN (29 mg, 461 µmol, 2 eq) and allowed to stir for an additional 1 h. To the reaction mixture was added H2O (5 mL) then extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (10 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give 61-4A (70 mg, crude) as a white solid. LCMS (ESI+): m/z = 448.3 (M+H) + . Step 4: Synthesis of compound Example 61 [00179] To a solution of 61-4A (70 mg, 156 µmol, 1 eq) in MeOH (3 mL) was added 10% Pd/C (50 mg) under N 2 . The suspension was degassed under vacuum and purged with H 2 (15 psi) 3 times then allowed to stir for 12 h at 25 °C. The resulting reaction mixture was filtered over celite and then concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give Example 61 (6 mg, 15 µmol, 10% yield). LCMS (ESI-): m/z =356.1 (M-H)-. 1 H NMR (D 2 <% [ /(.1'/(-. $L& +7%& -(,, $R& +7%& 3.46-3.26 (m, 2H), 2.93-2.80 (m, 4H), 2.65-2.49 (m, 2H), 2.41-2.16 (m, 2H), 1.81-1.64 (m, 3H), 1.22 (t, J = 7.3 Hz, 1H). Example 62 - 64 were prepared according to the procedures described in Example 61 using the appropriate intermediates. Example 65: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(1-methylpyrrolidin-3-yl)ethyl)ph enyl)-1,2,5- Step 1: Synthesis of compound 65-2 [00180] To a solution of 0.5M 9-BBN (3.61 mL, 1.5 eq) was added 65-1 (356 mg, 1.8 mmol, 1.5 eq) then heated to 60 °C and allowed to stir 1 h. The reaction mixture was then allowed to cool to 20 °C. To this was then added a solution of 1-7A (500 mg, 1.20 mmol, 1 eq), K2CO3 (249 mg, 1.81 mmol, 1.5 eq) and Pd(dppf)Cl2-CH2Cl2 (98 mg, 120 µmol, 0.1 eq) in DMF (5 mL) and H2O (0.5 mL) then heated to 60°C and allowed to stir for an additional 12 h. To the reaction mixture was added H 2 O (50 mL) then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give 65-2 (230 mg, 431 µmol, 35% yield) as a yellow solid. Step 2: Synthesis of compound 65-3 [00181] A solution of 65-2 (230 mg, 431 µmol, 1 eq) in 4M HCl/ethyl acetate (10 mL) was allowed to stir for 0.5 h at 25 °C. The reaction mixture was concentrated under reduced pressure to give 65-3 (250 mg, crude) as a white solid. Step 3: Synthesis of compound 65-4A [00182] To a solution of 65-3 (100 mg, 213 µmol, 1 eq), formaldehyde (34 mg, 425 µmol, 31 µL, 2 eq) in 1,2-dichloroethane (2 mL) was added diisopropylethylamine (30 mg, 234 µmol, 40 µL, 1.1 eq) and allowed to stir for 0.5 h at 25 °C. To this was then added NaBH(OAc)3 (139 mg, 638 µmol, 3 eq) and allowed to stir for an additional 1 h. To the reaction mixture was added H 2 O (5 mL) then extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with brine (10 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give 65-4A (70 mg, crude) as a white solid. LCMS (ESI-): m/z = 446.4 (M-H)-. Step 4: Synthesis of compound Example 65 [00183] To a solution of 65-4A (20 mg, 44 µmol, 1 eq) in MeOH (3 mL) was added 10% Pd/C (10 mg) under N 2 . The suspension was degassed under vacuum and purged with H 2 (15 psi) 3 times then allowed to stir for 12 h at 25 °C. The resulting reaction mixture was filtered over celite and then concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give Example 65 (2 mg, 5.4 µmol, 12% yield). LCMS (ESI-): m/z = 356.1 (M-H)-. 1 H NMR (400 MHz, D 2 <% [ /(0.'/(// $L& +7%& -(,- (s, 2H), 3.68-3.57 (m, 1H), 3.26-3.15 (m, 1H), 3.07 (br d, J = 9.3 Hz, 1H), 2.83 (s, 3H), 2.76 (ddd, J = 5.6, 8.6, 14.1 Hz, 1H), 2.67-2.55 (m, 1H), 2.39-2.17 (m, 2H), 2.12-1.69 (m, 4H). Examples 66 - 68 were prepared according to the procedures described in Example 65 using the appropriate intermediates.
Example 69: Synthesis of 5-(4-(azetidin-3-ylmethyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-t hiadiazolidin-3- one 1,1-dioxide Step 1: Synthesis of compound 69-2 [00184] To a solution of 0.5M 9-BBN (3.18 mL, 1.65 eq) was added 69-1 (293 mg, 1.4 mmol, 1.5 eq) then heated to 60 °C and allowed to stir 1 h. The reaction mixture was then allowed to cool to 20 °C. To this was then added a solution of 1-7A (400 mg, 963 µmol, 1 eq), K2CO3 (200 mg, 1.4 mmol, 1.5 eq) and Pd(dppf)Cl2-CH2Cl2 (78.67 mg, 96.33 µmol, 0.1 eq) in DMF (4mL) and H2O (0.4 mL) then heated to 60 °C and allowed to stir for an additional 12 h. To the reaction mixture was added H 2 O (10 mL) then extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give 69-2 (150 mg, 278 µmol, 28% yield) as a red solid. Step 2: Synthesis of compound Example 69 [00185] To a solution of 69-2 (130 mg, 240 µmol, 1 eq) in THF (10 mL) was added 10% Pd/C (50 mg) under N 2 . The suspension was degassed under vacuum and purged with H 2 (15 psi) 3 times then allowed to stir for 2 h at 25 °C. The resulting reaction mixture was filtered over celite and then concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give Example 69 (3.6 mg, 11.4 µmol, 5% yield). 1 H NMR (400 MHz, CD3<5% [ /(/*'/(.+ $L& +7%& -(++ $R& +7%& -()2'-()+ $L& +7%& ,(11' 3.79 (m, 2H), 3.27-3.16 (m, 1H), 2.89 (d, J = 7.8 Hz, 2H). Example 70: Synthesis of 5-(2-fluoro-6-hydroxy-4-((2-propylpyrrolidin-1-yl)methyl)phe nyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide
Step 1: Synthesis of compound 70-1 [00186] To a solution of 1-7A (2 g, 4.82 mmol, 1 eq), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.42 g, 48.17 mmol, 8.17 mL, 10 eq) and K2CO3 (2.0 g, 14.4 mmol, 3 eq) in DMF (20 mL) and H2O (2 mL) was added Pd(dppf)Cl 2 -CH 2 Cl 2 (393 mg, 481 µmol, 0.1 eq) then heated to 80 °C and allowed to stir for 12 h. To the reaction mixture was added H2O (30 mL) then extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (40 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiO 2 , ethyl acetate/methanol=100/1 to 5/1) to give 70-1 (1.4 g, 3.86 mmol, 80% yield) as a yellow oil. 1 H NMR (400 MHz, CD3<5% [ 0(., $BQ D& J = 7.5 Hz, 2H), 7.38-7.32 (m, 2H), 7.31-7.24 (m, 1H), 7.00 (s, 1H), 7.03-6.96 (m, 1H), 6.91 (br d, J = 10.6 Hz, 1H), 6.68 (br dd, J = 10.8, 17.3 Hz, 1H), 5.81 (br d, J = 17.6 Hz, 1H), 5.32 (br d, J = 10.9 Hz, 1H), 5.20 (s, 2H), 4.28 (s, 2H). Step 2: Synthesis of compound 70-2 [00187] To a solution of 70-1 (1.4 g, 3.86 mmol, 1 eq) and 2,6-dimethylpyridine (827 mg, 7.7 mmol, 900 µL, 2 eq) in 1,4-dioxane (40 mL) and H2O (10 mL) was added NaIO4 (3.31 g, 15.45 mmol, 856 µL, 4 eq) slowly and allowed to stir for 2 h at 0 °C under N2. To this was then added potassium osmate (VI) dihydrate (71 mg, 193 µmol, 0.05 eq) and allowed to warm to 20 °C and stirred for an additional 10 h. To the reaction mixture was added sat. NaHCO3 (aq) (100 mL) then extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (50 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by prep-TLC (CH2Cl2/methanol=5:1, Rf=0.13) to give 70-2 (800 mg, 2.2 mmol, 56% yield) as a white solid. 1 H NMR (400 MHz, CD3<5% [ 2(2) $D& J = 1.5 Hz, 1H), 7.57 (d, J = 7.9 Hz, 7H), 5.28 (s, 2H), 4.33 (s, 2H). Step 3: Synthesis of compound 70-4A [00188] To a solution of 70-2 (100 mg, 274 µmol, 1 eq) in CH 2 Cl 2 (4 mL) was added diisopropylethylamine (35 mg, 274 µmol, 47 µL, 1 eq) and 4A MS (100 mg) at 25 °C then was allowed to stir for 0.5 h. To this was then added 70-3 (49 mg, 329 µmol, 1.2 eq) and allowed to stir for an additional 2 h. To the reaction mixture was then added NaBH(OAc)3 (174 mg, 823 µmol, 3 eq) and allowed to stir for an additional 12 h. To the reaction mixture was added H 2 O (5 mL) then extracted with CH 2 Cl 2 (5 mL×3). The combined organic layers were washed with brine (10 mL), dried with Na 2 SO 4 , then filtered and concentrated under reduced pressure to give 70-4A (110 mg, crude) as a yellow oil. LCMS (ESI-): m/z = 460.1 (M-H)-. Step 4: Synthesis of compound Example 70 [00189] To a solution of 70-4A (100 mg, 216 µmol, 1 eq) in THF (20 mL) was added 10% Pd/C (50 mg) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times then allowed to stir for 2 h at 25 °C. The resulting reaction mixture was filtered over celite and then concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give Example 70 (5 mg, 13 µmol, 6% yield). LCMS (ESI-): m/z = 370.1 (M-H)-. 1 H NMR (400 MHz, CD3<5% [ 0())'/(/2 $L& +7%& 4.44 (br d, J = 12.9 Hz, 1H), 4.26 (s, 2H), 4.04 (br d, J = 12.9 Hz, 1H), 3.48-3.35 (m, 2H), 3.24-3.10 (m, 1H), 2.41-2.28 (m, 1H), 2.16-2.03 (m, 1H), 2.03-1.92 (m, 1H), 1.91-1.83 (m, 1H), 1.81-1.70 (m, 1H), 1.60- 1.29 (m, 3H), 1.06-0.93 (m, 3H). Example 71 – 73 were prepared according to the procedures described in Example 70 using the appropriate intermediates. Example 74: Synthesis of 5-(2-fluoro-6-hydroxy-3-((1-methylpiperidin-2-yl)methyl)phen yl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide
Step 1: Synthesis of compound 74-2 [00190] To a solution of 2-bromopyridine (5 g, 31.6 mmol, 3.01 mL, 1 eq) in THF (50 mL) was added 2.5M n-BuLi (12.6 mL, 1 eq) dropwise at -78 °C under N2 and allowed to stir for 1 h. To this was then added a solution of 74-1 (4.43 g, 31.6 mmol, 1 eq) in THF (5 mL) and allowed to stir for an additional 0.5 h. The resulting reaction mixture was quenched with a mixture of sat. NH 4 Cl (aq) (80 mL) and allowed to stir for 5 minutes at 25 °C. The resulting reaction mixture was then extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiO2, petroleum ether/ethyl acetate=4/1 to 0/1) to give 74-2 (2.56 g, 11.6 mmol, 37% yield) as a light pink solid. 1 H NMR (400 MHz, DMSO-d6% [ 2(01 $BQ R& *7%& 1(-2'1(,. $L& *7%& 0(01 $DS& J = 1.8, 7.7 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.22 (ddd, J = 1.0, 4.8, 7.4 Hz, 1H), 7.13 (t, J = 8.6 Hz, 1H), 6.55 (dd, J = 2.3, 8.5 Hz, 1H), 6.47 (dd, J = 2.3, 12.0 Hz, 1H), 5.96 (d, J = 4.6 Hz, 1H), 5.83 (d, J = 4.4 Hz, 1H). Step 2: Synthesis of compound 74-3 [00191] To a solution of 74-2 (2.46 g, 11.22 mmol, 1 eq) in TFA (25 mL) was added Et3SiH (6.52 g, 56.1 mmol, 9 mL, 5 eq) then heated to 60 °C and allowed to stir for 12 h. To the reaction mixture was added sat. NaHCO 3 (aq) (100 mL) then extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (300 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiO2, petroleum ether/ethyl acetate=3/1 to 2/1) to give 74-3 (1.6 g, 7.8 mmol, 70% yield) as yellow solid. 1 H NMR (400 MHz, CDCl3% [ 1(20 $BQ D& J = 1.4 Hz, 1H), 8.55 (d, 4.2 Hz, 1H), 7.72 (dt, J = 1.7, 7.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.23 (dd, J = 5.4, 7.0 Hz, 1H), 6.87 (t, J = 8.6 Hz, 1H), 6.39-6.24 (m, 2H), 4.09 (s, 2H). Step 3: Synthesis of compound 74-4 [00192] To a solution of 74-3 (1.5 g, 7.38 mmol, 1 eq) in THF (50 mL) was added 1M HCl (1.66 mL) and PtO 2 (300 mg) under N 2 . The suspension was degassed under vacuum and purged with H 2 (200 psi) then allowed to stir for 8 h at 25 °C. The resulting reaction mixture was filtered over celite and then concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=1/1 to ethyl acetate/methanol=10/1) to give 74-4 (870 mg, 4.16 mmol, 56% yield) as a yellow solid. 1 H NMR (400 MHz, CD3<5% [ 0(), $S& J = 8.6 Hz, 1H), 6.60-6.47 (m, 2H), 3.15 (br dd, J = 1.9, 12.4 Hz, 1H), 2.99-2.87 (m, 1H), 2.79-2.64 (m, 3H), 1.86-1.78 (m, 1H), 1.77-1.67 (m, 2H), 1.60- 1.47 (m, 1H), 1.41 (tq, J = 3.3, 12.6 Hz, 1H), 1.33-1.21 (m, 1H). Step 4: Synthesis of compound 74-5 [00193] To a solution of 74-4 (820 mg, 3.9 mmol, 1 eq) in THF (8.2 mL) was added triethylamine (594 mg, 5.88 mmol, 818 µL, 1.5 eq) and Boc 2 O (1.28 g, 5.88 mmol, 1.35 mL, 1.5 eq) at 20 °C and allowed to stir for 1 h. To the reaction mixture was added H2O (15 mL) then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (45 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiO2, petroleum ether/ethyl acetate=7/1 to 5/1) to give 74-5 (800 mg, 2.6 mmol, 66% yield) as a yellow oil. 1 H NMR (400 MHz, CD3<5% [ /(21 $BQ S& J = 8.6 Hz, 1H), 6.54-6.41 (m, 2H), 4.50- 4.35 (m, 1H), 3.96 (br d, J = 12.1 Hz, 1H), 3.01 (dt, J = 2.1, 13.3 Hz, 1H), 2.95-2.65 (m, 2H), 1.80-1.57 (m, 5H), 1.44-1.35 (m, 1H), 1.26 (br s, 9H). Step 5: Synthesis of compound 74-6 [00194] To a solution of 74-5 (800 mg, 2.6 mmol, 1 eq) in DMF (8 mL) was added K 2 CO 3 (1.07 g, 7.76 mmol, 3 eq) and BnBr (884 mg, 5.17 mmol, 614 µL, 2 eq) at 20 °C and allowed to stir for 1 h. To the reaction mixture was added H2O (15 mL) then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (30 mL×5), dried with Na 2 SO 4 , then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 9/1) to give 74-6 (960 mg, 2.4 mmol, 94% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 % [ 0(-0'0(+2 $L& .7%& 0(). $BQ D& J = 7.5 Hz, 1H), 6.74-6.61 (m, 2H), 5.02 (s, 2H), 4.43 (br s, 1H), 4.11-3.99 (m, 1H), 3.00-2.86 (m, 1H), 2.81 (br d, J = 7.5 Hz, 2H), 1.71-1.60 (m, 3H), 1.57 (br d, J = 4.9 Hz, 2H), 1.48-1.39 (m, 1H), 1.31 (s, 8H). Step 6: Synthesis of compound 74-7 [00195] To a solution of 74-6 (710 mg, 1.78 mmol, 1 eq) in THF (7 mL) was added 2.5M n-BuLi (1.07 mL, 1.5 eq) at -78 °C and allowed to stir for 1 h under N2. To this was added a solution of I2 (676 mg, 2.67 mmol, 537 µL, 1.5 eq) in THF (7 mL) and allowed to stir for an additional 1 h. The resulting suspension was quenched with a mixture of sat. NH4Cl (aq) and 1M Na2S2O3 (aq) (1:1, 15 mL) and allowed to stir for 5 minutes at 25 °C. The resulting reaction mixture was then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na 2 SO 4 , then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 to 8/1) to give 74-7 (650 mg, 1.24 mmol, 70% yield) as a white solid. 1 H NMR (400 MHz, CDCl3% [ 0(.+'0(-/ $L& +7%& 0(-) $S& J = 7.5 Hz, 2H), 7.36-7.30 (m, 1H), 7.12-6.99 (m, 1H), 6.58 (d, J = 8.4 Hz, 1H), 5.14 (s, 2H), 4.45 (br s, 1H), 4.17-3.95 (m, 1H), 2.99- 2.74 (m, 3H), 1.77-1.52 (m, 5H), 1.49-1.40 (m, 1H), 1.28 (br s, 9H). Step 7: Synthesis of compound 74-8 [00196] A solution of 74-7 (650 mg, 1.24 mmol, 1 eq), tert-butyl 2-aminoacetate (243 mg, 1.86 mmol, 1.5 eq) and Cs2CO3 (1.21 g, 3.71 mmol, 3 eq) in 1,4-dioxane (6.5 mL) was degassed and purged with N2 for 3 times. To this was then added XPhos (66 mg, 123 µmol, 0.1 eq) and BrettPhos Pd G3 (112 mg, 123 µmol, 0.1 eq) and again degassed and purged with N 2 for 3 times, then heated to 90 °C and allowed to stir for 24 h. To the reaction mixture was added H2O (15 mL) then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (50 mL), dried with Na 2 SO 4 , then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=1/0 to 7/1) to give 74-8 (560 mg, 1.06 mmol, 85% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 % [ 0(-/'0(,) $L& .7%& /(/+'/(./ $L& *7%& /(., $BQ D& J = 5.9 Hz, 1H), 5.08 (s, 2H), 4.41 (br s, 1H), 4.00 (t, J = 2.1 Hz, 2H), 2.97-2.70 (m, 3H), 1.69-1.51 (m, 6H), 1.45 (s, 9H), 1.35 (s, 9H). Step 8: Synthesis of compound 74-9 [00197] To a solution of N-(oxomethylene)sulfamoyl chloride (225 mg, 1.6 mmol, 138 µL, 1.5 eq) in CH 2 Cl 2 (6 mL) was added prop-2-en-1-ol (100 mg, 1.7 mmol, 117 µL, 1.63 eq) at 0 °C under N 2 and allowed to stir for 0.5 h. To this was then added a solution of 74-8 (560 mg, 1.06 mmol, 1 eq) and triethylamine (214 mg, 2.1 mmol, 295 µL, 2 eq) in CH 2 Cl 2 (6 mL) and allowed to stir for an additional 0.5 h. To the reaction mixture was added H 2 O (20 mL) then extracted with CH 2 Cl 2 (15 mL×3). The combined organic layers were washed with brine (40 mL), dried with Na2SO4, then filtered and concentrated under reduced pressure to give 74-9 (786 mg, crude) as yellow oil. 1 H NMR (400 MHz, CDCl3% [ 0(.)'0(,) $L& .7%& 0(*/'0()* $L& 1H), 6.75-6.62 (m, 1H), 5.97-5.79 (m, 1H), 5.43-5.23 (m, 3H), 5.15-4.96 (m, 2H), 4.57-4.51 (m, 2H), 3.20 (q, J = 7.4 Hz, 1H), 2.96-2.76 (m, 3H), 1.69-1.51 (m, 6H), 1.41 (d, J = 8.4 Hz, 9H), 1.33-1.24 (m, 9H). Step 9: Synthesis of compound 74-10 [00198] To a solution of 74-9 (776 mg, 1.12 mmol, 1 eq) in MeOH (8 mL) was added NaOMe (606 mg, 3.37 mmol, 3 eq) and Pd(PPh3)4 (26 mg, 22 µmol, 0.02 eq) under N2 then heated to 60 °C for 0.5 h. To the reaction mixture was added 1M HCl (15 mL) then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (45 mL), dried with Na 2 SO 4 , then filtered and concentrated under reduced pressure to give 74-10 (540 mg, crude) as yellow oil. 1 H NMR (400 MHz, CDCl3% [ 0(.)'0(-/ $L& 1H), 7.43-7.39 (m, 2H), 7.39-7.32 (m, 2H), 7.25-7.00 (m, 1H), 6.76 (dd, J = 1.3, 8.7 Hz, 1H), 5.16-5.09 (m, 2H), 4.47-4.36 (m, 2H), 2.98-2.73 (m, 3H), 1.75-1.48 (m, 6H), 1.34-1.26 (m, 9H). Step 10: Synthesis of compound 74-11 [00199] To 74-10 (540 mg, 1.01 mmol, 1 eq) was added 4M HCl/ethyl acetate (10 mL) at 20 °C and allowed to stir for 0.5 h. The reaction mixture was then concentrated under reduced pressure to give 1-11 (472 mg, crude) as a yellow solid. 1 H NMR (400 MHz, CD 3 <5% [ 0(.2'0(.* $L& *7%& 0(-1 $BQ D& J = 6.9 Hz, 1H), 7.42-7.33 (m, 3H), 7.32-7.28 (m, 1H), 7.06-6.97 (m, 1H), 5.25-5.15 (m, 2H), 4.49-4.38 (m, 2H), 3.41- 3.33 (m, 2H), 3.00-2.86 (m, 3H), 1.95-1.86 (m, 3H), 1.66 (br dd, J = 3.3, 11.7 Hz, 1H), 1.58-1.47 (m, 2H). Step 11: Synthesis of compound 74-12A [00200] To a solution of 74-11 (200 mg, 425 µmol, 1 eq), formaldehyde (107 mg, 1.3 mmol, 98 µL, 3.1 eq) in acetonitrile (2 mL) was added acetic acid (64 mg, 1.06 mmol, 61 µL, 2.5 eq) at 20 °C and allowed to stir for 0.5 h. To this was then added NaBH 3 CN (29 mg, 468 µmol, 1.1 eq) and allowed to stir for an additional 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to give 74- 12A (190 mg, crude) as colorless oil. LCMS (ESI-): m/z = 446.1 (M-H)-. Step 12: Synthesis of compound Example 74 To a solution of 74-12A (170 mg, 380 µmol, 1 eq) in MeOH (15 mL) was added 10% Pd/C (170 mg) under N2. The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times then allowed to stir for 12 h at 25 °C. The resulting reaction mixture was filtered over celite and then concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give Example 74 (22 mg, 62 µmol, 16% yield). LCMS (ESI-): m/z = 356.1 (M-H)-. 1 H NMR (400 MHz, D2<% [ 7.12 (t, J = 8.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 4.35 (s, 2H), 3.50-3.00 (m, 5H), 2.92 (br s, 3H), 2.81-2.67 (m, 1H), 1.86-1.73 (m, 3H), 1.54-1.35 (m, 2H). Examples 75 - 80 were prepared according to the procedures described in Example 74 using the appropriate intermediates.
Example 83: Synthesis of 5-(2-fluoro-6-hydroxy-4-(2-(pyrrolidin-l-yl)ethyl)phenyl)-l, 2,5- thiadiazolidin-3-one 1,1-dioxide
Step 1: Synthesis of compound 83-2B
[00201] To a solution of 1-7B (4.4 g, 10.65 mmol, 1 eq) in DME (44 mL) and H2O (4.4 mL) was added Pd(dppf)Ch (779 mg, 1.06 mmol, 0.1 eq), K2CO3 (4.41 g, 31.94 mmol, 3 eq) and 83-1 (4.22 g, 21.30 mmol, 2 eq) then heated to 95 °C and allowed to stir for 2 h. To the resulting reaction mixture was then added to H2O (50 mL) then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (50 mL), dried with Na2SC>4, then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by column chromatography on silica gel eluting ethyl acetate/methanol=99/l to 80/20 to give 83-2B (5 g, crude yield). *H NMR (CDCI3) 5 6.95 (br d, J- 12.84 Hz, 1 H) 6.78 (br s, 1 H) 6.58 (br d, J= 10.51 Hz, 1 H) 5.65 (br d, J= 12.59 Hz, 1 H) 5.09-5.37 (m, 2 H) 4.21 (br s, 2 H) 3.85 (q, J = 6.77 Hz, 2 H) 3.75 (br s, 2 H) 3.44 (br s, 2 H) 3.26 (s, 3 H) 1.31 (br t, J- 6.97 Hz, 3 H).
Step 2: Synthesis of compound 83-3B
[00202] To a solution of 83-2B (200 mg, 494 pmol, 1 eq) in CH2CI2 (4 mL) was added TFA (308 mg, 2.70 mmol, 200 pL, 5.4 eq) and allowed to stir for 0.5 h at 0 °C. The resulting reaction mixture was then neutralized with diethylamine to reach a pH=8-9. This was then concentrated under reduced pressure to give 83-3B. LCMS (ESI-): m/z - 375.2(M-H)".
Step 3: Synthesis of compound 83-5A
[00203] To a solution of 83-3B (500 mg, 1.3 mmol, 1 eq) in CH2CI2 (2 mL) was added 83-4 (188 mg, 2.66 mmol, 220 pL, 2 eq) and diisopropylethylamine (515 mg, 4 mmol, 694 pL, 3 eq) and allowed to stir for 0.5 h at 25 °C. To this was then added NaBH3CN (250 mg, 4 mmol, 3 eq) and allowed to stir for an additional 0.5 h. To the resulting reaction mixture was then added to H 2 O (10 mL) then extracted with CH 2 Cl 2 (10 mL×3). The combined organic layers were washed with brine (10 mL), dried with Na 2 SO 4 , then filtered and concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give 83-5A (210 mg, 36.6% yield) as a yellow oil. LCMS (ESI+): m/z = 432.2(M+H) + . Step 4: Synthesis of compound Example 83 [00204] To a solution of 83-5A (0.02 g, 46.14 µmol, 1 eq) in THF (1 mL) was added 4M HCl/dioxane (1 mL) and allowed to stir for 1 h at 0 °C. The reaction mixture was then concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give Example 83 (2.16 mg, 100% purity). LCMS (ESI-): m/z = 342.2 (M-H)-. 1 H NMR (400 MHz, D2<% [ /(0, $L& +7%& -(,. $R& +7%& ,(-/ $L& ,7%& ,(,* $L& 3H), 2.98 (m, 2H), 2.02 (s, 4H). Example 84: Synthesis of 5-(4-(2-(2-ethylpyrrolidin-1-yl)ethyl)-2-fluoro-6-hydroxyphe nyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide [00205] Compound 83-5C was prepared according to the procedure described for 83-5A. To a solution of 83-5C (0.02 g, 46.14 µmol, 1 eq) in MeOH (1 mL) was added Pd/C (0.02 g, 10% purity) under N 2 . The suspension was degassed under vacuum and purged with H2 (15 psi) 3 times. This was then allowed to stir for 1 h at 40 °C. The resulting reaction mixture was filtered over celite and the filtrate was concentrated under reduced pressure to give a crude. The crude was then purified by HPLC to give Example 84 (2 mg). LCMS (ESI+): m/z = 372.2 (M+H) + . 1 H NMR (400 MHz, D2<% [ /(0. $L& +7%& -(,. $R& +7%& ,(/, $L& +7%& 3.27-3.15 (m, 3H), 3.04-2.98 (m, 2H), 2.31 (m, 1H), 2.07-1.96 (m, 3H), 1.73 (m, 1 H), 1.52 (m, 1H), 0.96- 0.92 (t, 3H). Example 85 – 128 were prepared according to the procedures described in Example 83 using the appropriate intermediates.
Example A: Enzymatic Assay used to determine potency of PTPN2 Inhibitors [00206] Compound activity was determined in an in vitro enzymatic assay using untagged, full-length human PTPN2 (TC45) (1-387) protein. PTPN2 was produced in E. coli as a GST-TEV fusion and the GST was removed by TEV digestion, followed by additional purification to yield full-length PTPN2 (SEQ ID 1). PTPN2 enzyme was diluted in assay buffer (50mM HEPES pH7.5, 0.2mM EDTA, 1mM DTT, 0.02% Brij- 35, 0.02% BSA) to a final concentration of 0.5 nM and added to black 384-well non-binding plates (Greiner, 781900). Compounds were subsequently added using a Tecan D300e dispenser. Following a 10 min incubation at room temperature, DiFMUP substrate (ThermoFisher, D22065) was added to a final concentration of 100 µM. Plates were transferred to a SpectraMax plate reader (Molecular Devices) and fluorescence intensity was measured (ex 358, em 455) after a 30 min incubation at room temperature. Each plate included a 100% inhibition control (no enzyme) and a 0% inhibition control (DMSO) from which % inhibition for test compounds was calculated. A four-parameter curve fit was used to determine IC50 values from % inhibition data. Example B: B16F10 Cellular Growth Inhibition Assay [00207] 4NLONTMD ACSIUISX VAR DESEQLIMED TRIMG AM IMSEQFEQNM GALLA $86;\%'IMDTCED CEKKTKAQ GQNVSH inhibition assay with the murine B16F10 melanoma cell line on an Agilent xCELLigence Real-Time Cell Analysis platform (RTCA). RTCA E-Plate View 96 plates (Agilent, 300601010) were pre-equilibrated with 50 µL of assay media (DMEM+10% FBS, Gibco 10566-024, Gibco 10082-147) at 37°C in a humidified incubator before taking an initial measurement of impedance (sweep). B16F10 cells cultured in assay media were dissociated with TrypLE Express (Gibco 12605-010) for five minutes at 37°C, diluted in 3 volumes of assay buffer, centrifuged for 5 minutes at 500xg at room temperature before diluting cells to 7,700 cells/mL in assay media, plating 130 µL/well (1,000 cells/well) in the inner 60 wells of the assay plate, and adding 150 µL of assay media to the outer wells of the plate. Cells were incubated at room temperature for 20 min to allow cells to settle before placing them in the xCELLigence reader and incubating overnight at 37°C, sweeping wells every 15 minutes. After 24 hours, well readings were paused, plates were removed from the incubator and compounds were added using a Tecan D300e dispenser. All wells were normalized to a final CNMCEMSQASINM NF )(." 5:?<( 6NKKNVIMG A ,) LIM IMCTBASINM AS ,0Z4& QECNLBIMAMS LNTRE 86;\ $>#5 Systems™ 485MI100) was diluted to 10 ng/mL in assay media and 20 µL was added to assay wells (1 ng/mL final concentration). Assay plates were placed in the xCELLigence reader and swept every 15 minutes. After 48 hours, well readings were normalized to the time point immediately preceding compound addition and the area under the growth curve (AUC) was calculated by the RTCA software and exported. A four-parameter curve fit was used to determine compound IC50 values using % inhibition for each compound CNMCEMSQASINM CAKCTKASED TRIMG SHE 5:?< UEHICKE VISH 86;\ SQEASLEMS AR BAREKIME $)" IMHIBISINM% AMD A ONRISIUE CNMSQNK =@=;+ IMHIBISNQ VISH 86;\ SQEASLEMS AR *))" IMHIBISINM( The data from Example A and Example B is shown in table 3. TABLE 3
NT: not tested