Inhibitors and degraders of pip4k protein

Abstract

Provided are compounds and compositions of Formula (I'): which modulate the level or activity of PIP4K2A, PIP4K2B, or PIP4K2C. Also provided are methods for treating diseases or conditions by modulating (e.g., reducing) the level or activity of PIP4K2A, PIP4K2B, or PIP4K2C, comprising administering the compounds and compositions.

Description

Compounds and compositions of formula (I') are provided: (I') which modulate the level or activity of PIP4K2A, PIP4K2B, or PIP4K2C. A method of treating a disease or ailment by modulating (e.g., reducing) the level or activity of PIP4K2A, PIP4K2B, or PIP4K2C is also provided, comprising administering said compound and composition. Abstract

Claims

220232001540 CLAIMS What is claimed is: Claim 1. A compound of Formula (I’)or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: R is halo; Ring 4 is optional, and when present is a monocyclic ring selected from the group consisting of 3- to 6-membered cycloalkyl optionally substituted with one or more R4a, 4- to 6-membered heterocyclyl optionally substituted with one or more R4a, phenyl optionally substituted with one or more R4b, and 5- to 6-membered heteroaryl optionally substituted with one or more R4b; Ring 3 is a monocyclic ring selected from the group consisting of 3- to 6-membered cycloalkyl optionally substituted with one or more R3a; 4- to 6-membered heterocyclyl optionally substituted with one or more R3a; phenyl optionally substituted with one or more R3b; or 5- to 6-membered heteroaryl optionally substituted with one or more R3b; Ring 1 is a 4- to 8-membered cycloalkyl or saturated 4- to 8-membered heterocyclyl, each of which is optionally substituted with one or more R1; V is a bond, -C1-4alkylene-, -C(O)-, -C(O)O-#, -OC(O)# -C1-4alkylene-C(O)-#, - C(O)N(RV)-#, -N(RV)C(O)-#, -OC(O)N(RV)-#, -N(RV)-C(O)O#, -C1-4alkylene-C(O)N(RV)-# or -C1-4alkylene-N(RV)C(O)-#, wherein # indicates the point of attachment to Ring 1; and Q is RQ, or Ring 5, wherein Ring 5 is selected from the group consisting of 3- to 10-membered cycloalkyl optionally substituted with one or more R5a, 4- to 12-membered heterocyclyl optionally substituted with one or more R5a, and 5- to 12-membered heteroaryl optionally substituted with one or more R5b; or Q is of Formula (i)wherein: 1426 ny-2730225220232001540 Ring A is selected from the group consisting, each of which is optionally substituted with one or more C1-4alkyl or halo; X is a bond, -O-, -NH-, or -NHC(O)-;which is optionally substituted with one or more halo, C1-4alkyl, C1-4haloalkyl, or OH, and wherein RDis H or C1-4alkyl, wherein # indicates attachment to X; W is a bond, -O-, -NH-, or -NHC(O)-; Ring C is optional, and when present is 4- to 12-membered heterocyclyl optionally substituted with one or more RC; Linker is a bond, -O-, C1-10alkylene, C1-10alkylene-N(Ry), C(O)C1-10alkylene, C(O)C1-10alkylene-N(Ry), C(O)N(Ry)C1-10alkylene, C(O)N(Ry)C1-10alkylene-N(Ry), C1-6alkylene-C(O)C1-10alkylene, C1-6alkylene-C(O)C1-10alkylene-N(Ry), C1-6alkylene-C(O)N(Ry)-C1-10alkylene, C1-6alkylene-C(O)N(Ry)-C1-10alkylene-N(Ry), or is of the formula *-L1-L2-L3-**, wherein * indicates the point of attachment to Ring C when Ring C is present, and * indicates the point of attachment to W when Ring C is absent; and ** indicates the point of attachment to U when Ring 2 is present, and ** indicates the point of attachment to V when Ring 2 is absent; L1is a bond or C1-6alkylene; L2is a 3- to 10-membered cycloalkyl or 4- to 12-membered heterocyclyl optionally substituted with one or more RL; and 1427 ny-2730225220232001540 L3is C1-10 alkylene, C1-10 alkylene-N(Ry), C(O)-C1-10alkylene, C(O)-C1- 10alkylene-N(Ry), C(O)N(Ry)-C1-10alkylene, or C(O)N(Ry)-C1-10alkylene-N(Ry); U is absent when Ring 2 is absent, and is a bond or C(O) when Ring 2 is present; Ring 2 is optional, and when present is selected from the group consisting of 3- to 10-membered cycloalkyl optionally substituted with one or more R2a, 4- to 12-membered heterocyclyl optionally substituted with one or more R2a, 6- to 12-membered aryl optionally substituted with one or more R2b, and 5- to 12-membered heteroaryl optionally substituted with one or more R2b; each R1is independently oxo, halo, C1-4alkyl, C1-4haloalkyl, OH, C1-4alkoxy, C1-4haloalkoxy, C(O)C1-4alkyl, C(O)N(Ry)(Rz), CN, N(Ry)C(O)C1-4alkyl, N(Ry)C(O)C1-4haloalkyl, SO2Rx, SO2N(Ry)(Rz), C1-4alkylene-O-C1-4alkyl, C1-4alkylene- N(Ry)-C1-4alkyl, or C1-4alkylene-S(O)n-C1-4alkyl; each R2a, R3a, R4a, and R5ais independently halo, C1-4alkyl, C1-4haloalkyl, OH, C1-4alkoxy, C1-4haloalkoxy, C(O)C1-4alkyl, C(O)Rw, C(O)N(Ry)(R,z), CN, N(Ry)C(O)C1-4alkyl, N(Ry)C(O)C1-4haloalkyl, S(O)nRx, S(O)nN(Ry)(Rz), C1-4alkylene-O- C1-4alkyl, C1-4alkylene-N(Ry)-C1-4alkyl, C1-4alkylene-S(O)nRx, or oxo; each R2b, R3b, R4b, and R5bis independently halo, C1-4alkyl, C1-4haloalkyl, OH, C1-4alkoxy, C1-4haloalkoxy, C(O)C1-4alkyl, C(O)Rw, C1-4hydroxyalkyl, C(O)N(Ry)(Rz), CN, N(Ry)C(O)C1-4alkyl, N(Ry)C(O)C1-4haloalkyl, S(O)nRx, S(O)nN(Ry)(Rz), C1-4alkylene-O- C1-4alkyl, C1-4alkylene-N(Ry)-C1-4alkyl, or C1-4alkylene-S(O)nRx; each RCis independently halo, OH, C1-4alkyl, or C1-4haloalkyl; each RLis independently halo, OH, C1-4alkyl, or C1-4haloalkyl; each RQis independently H, halo, OH, C1-4alkyl, or C1-4haloalkyl; each RVis independently H, halo, OH, C1-4alkyl, or C1-4haloalkyl; each Rwis independently 3- to 10-membered cycloalkyl, phenyl optionally substituted with halo, or 4- to 12-membered heterocyclyl optionally substituted with hydroxyl, C1-4hydroxyalkyl, or C1-4aminoalkyl; each Rxis independently C1-4alkyl, C1-4haloalkyl, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-N(Ry)-C1-4alkyl, or C1-4alkylene-S(O)n-C1-4alkyl; each Ryand Rzis independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-NH-C1-4alkyl, C1-4alkylene-N(C1-4alkyl)-C1-4alkyl, 3- to 10-membered cycloalkyl, or C1-4alkylene-S(O)n-C1-4alkyl; and each n is independently 0, 1, or 2; 1428 ny-2730225220232001540 wherein: (a) Ring 1 comprises an intraannular amide, or (b) V comprises an amide or carbamate, or (c) V is taken together with an atom of Ring 1, Ring 2, or Ring 5 to which it is attached, to form an amide or carbamate; and wherein: when Ring 3 is 5-membered heteroaryl, Ring 4 is present and is not cycloalkyl or tetrahydropyranyl; and when Ring 1 is 8-membered heterocyclyl, Ring 3 is phenyl substituted with CN, Ring 4 is absent, Q is RQ, and V is -OC(O)#, then RQis not tert-butyl. Claim 2. The compound of claim 1, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: V is a bond, -C1-4alkylene-, -C(O)-, -C1-4alkylene-C(O)-#, -C(O)N(RV)-#, -N(RV)C(O)-#, -C1- 4alkylene-C(O)N(RV)-# or -C1-4alkylene-N(RV)C(O)-#, wherein # indicates the point of attachment to Ring 1; Linker is a bond, C1-10alkylene, C1-10alkylene-N(Ry), C(O)C1-10alkylene, C(O)C1-10alkylene-N(Ry), C(O)N(Ry)C1-10alkylene, C(O)N(Ry)C1-10alkylene-N(Ry), C1-6alkylene-C(O)C1-10alkylene, C1-6alkylene-C(O)C1-10alkylene-N(Ry), C1-6alkylene-C(O)N(Ry)-C1-10alkylene, C1-6alkylene-C(O)N(Ry)-C1-10alkylene-N(Ry), or is of the formula *-L1-L2-L3-**, each R2a, R3a, R4a, and R5ais independently halo, C1-4alkyl, C1-4haloalkyl, OH, C1-4alkoxy, C1-4haloalkoxy, C(O)C1-4alkyl, C(O)N(Ry)(Rz), CN, N(Ry)C(O)C1-4alkyl, N(Ry)C(O)C1-4haloalkyl, S(O)nRx, S(O)nN(Ry)(Rz), C1-4alkylene-O-C1-4alkyl, C1-4alkylene- N(Ry)-C1-4alkyl, C1-4alkylene-S(O)nRx, or oxo; each R2b, R3b, R4b, and R5bis independently halo, C1-4alkyl, C1-4haloalkyl, OH, C1-4alkoxy, C1-4haloalkoxy, C(O)C1-4alkyl, C(O)N(Ry)(Rz), CN, N(Ry)C(O)C1-4alkyl, N(Ry)C(O)C1-4haloalkyl, S(O)nRx, S(O)nN(Ry)(Rz), C1-4alkylene-O-C1-4alkyl, C1-4alkylene- N(Ry)-C1-4alkyl, or C1-4alkylene-S(O)nRx; each RVis independently halo, OH, C1-4alkyl, or C1-4haloalkyl; 1429 ny-2730225220232001540 each Ryand Rzis independently H, C1-4alkyl, C1-4haloalkyl, C1-4alkylene-O-C1-4alkyl, C1-4alkylene-NH-C1-4alkyl, C1-4alkylene-N(C1-4alkyl)-C1-4alkyl, or C1-4alkylene-S(O)n- C1-4alkyl; and each n is independently 0, 1, or 2; wherein: (a) Ring 1 comprises an intraannular amide, or (b) V comprises an amide, or (c) V is taken together with an atom of Ring 1, Ring 2, or Ring 5 to which it is attached, to form an amide; and wherein: when Ring 3 is 5-membered heteroaryl, Ring 4 is present and is not cycloalkyl or tetrahydropyranyl; and when Ring 1 is 8-membered heterocyclyl, Ring 3 is phenyl substituted with CN, Ring 4 is absent, Q is RQ, and V is -OC(O)#, then RQis not tert-butyl. Claim 3. The compound of claim 1 or 2, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: Ring 1 is a 4- to 8-membered cycloalkyl, saturated 4- to 8-membered heterocyclyl comprising at least one annular ether, saturated 4- to 8-membered heterocyclyl comprising at least one annular amine, or saturated 4- to 8-membered heterocyclyl comprising an annular amide, each of which is optionally substituted with one or more R1; and wherein: (i) when Ring 1 is a 4- to 8-membered heterocyclyl ring comprising at least one annular amine, optionally substituted with one or more R1, then V is attached to an annular nitrogen atom of Ring 1 and is -C(O)- or -C1-4alkylene-C(O)-#, wherein # indicates the point of attachment to Ring 1; (ii) when Ring 1 is a 4- to 8-membered heterocyclyl ring comprising at least one annular amide, optionally substituted with one or more R1, then V is attached to an annular nitrogen atom of Ring 1 and is a bond or -C1-4alkylene-; and (iii) when Ring 1 is C4-8cycloalkyl or a 4- to 8-membered heterocyclyl ring comprising at least one annular ether and no annular amine or annular amide, each of which is optionally substituted with one or more R1, then: 1430 ny-2730225220232001540 (a) V is -C(O)N(RV)-#, -N(RV)C(O)-#, -C1-4alkylene-C(O)N(RV)-# or -C1- 4alkylene-N(RV)C(O)-#, wherein # indicates the point of attachment to Ring 1; or (b) Ring 5 is 4- to 12-membered heterocyclyl optionally substituted with one or more R5a, and V is -C(O)- and is attached to an annular nitrogen atom of Ring 5; or (c) Ring 2 is 4- to 12-membered heterocyclyl optionally substituted with one or more R2a, and V is -C(O)- and is attached to an annular nitrogen atom of Ring 2. Claim 4. The compound of any of claims 1-3, wherein R is chloro. Claim 5. The compound of any of claims 1-3, wherein R is fluoro. Claim 6. The compound of any of claims 1-5, wherein Ring 3 is 4- to 6-membered heterocyclyl optionally substituted with one or more R3a. Claim 7. The compound of claim 6, wherein Ring 3 is, or, each of which is optionally substituted with one or more R3a. Claim 8. The compound of any of claims 1-5, wherein Ring 3 is phenyl optionally substituted with one or more R3b. Claim 9. The compound of any of claims 1-5, wherein Ring 3 is 5- to 6-membered heteroaryl optionally substituted with one or more R3bClaim 10. The compound of claim 9, wherein Ring 3 is, , each of which is optionally substituted with one or more R3b. Claim 11. The compound of any of claims 1-8, wherein Ring 4 is absent. Claim 12. The compound of any of claims 1-8, wherein Ring 4 is 3- to 6-membered cycloalkyl. 1431 ny-2730225220232001540 Claim 13. The compound of claim 12, wherein Ring 4 is cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with one or more R4a. Claim 14. The compound of any of claims 1-10, wherein Ring 4 is 4- to 6-membered heterocyclyl optionally substituted with one or more R4a. Claim 15. The compound of claim 14, wherein Ring 4 is, each of which is optionally substituted with one or more R4a. Claim 16. The compound of any of claims 1-10, wherein Ring 4 is phenyl optionally substituted with one or more R4b. Claim 17. The compound of any of claims 1-10, wherein Ring 4 is 5- to 6-membered heteroaryl optionally substituted with one or more R4b. Claim 18. The compound of claim 17, wherein Ring 4 isoptionally substituted with one or more R4b. Claim 19. The compound of any of claims 1-5, wherein Ring 3 is phenyl optionally substituted by R3b, and Ring 4 is phenyl optionally substituted by R4b. Claim 20. The compound of any of claims 1-5, wherein Ring 3 is phenyl optionally substituted by R3b, or Ring 4 is phenyl optionally substituted by R4b. Claim 21. The compound of any of claims 1-5, wherein Ring 3 is selected from the group consisting of 3- to 6-membered cycloalkyl optionally substituted with one or more R3a, 4- to 6-membered heterocyclyl optionally substituted with one or more R3a, and 5- to 6-membered heteroaryl optionally substituted with one or more R3b; and 1432 ny-2730225220232001540 Ring 4 is selected from the group consisting of 3- to 6-membered cycloalkyl optionally substituted with one or more R4a, 4- to 6-membered heterocyclyl optionally substituted with one or more R4a, and 5- to 6-membered heteroaryl optionally substituted with one or more R4b. Claim 22. The compound of any of claims 1-10 or 14-21, wherein Ring 1 is,substituted with one or more R1, wherein # indicates attachment to V. Claim 23. The compound of claim 22, wherein Ring, each of which is optionally substituted with one or more R1; and V is -C(O)N(RV)-, -N(RV)C(O)-, -C1-4alkylene-C(O)N(RV)-#, or -C1-4alkylene- N(RV)C(O)-#, wherein ## indicates the point of attachment to Ring 1. Claim 24. The compound of claim 22, wherein Ringeach of which is optionally substituted with one or more R1, wherein # indicates attachment to V; and V is -C(O)- or -C1-4alkylene-C(O)-#, wherein # indicates attachment to Ring 1. Claim 25. The compound of claim 22, wherein Ring, each of which is optionally substituted with one or more R1, wherein # indicates attachment to V; and V is bond or -C1-4alkylene-. 1433 ny-2730225220232001540 Claim 26. The compound of any of claims 1-10 or 14-25, wherein Q is RQ. Claim 27. The compound of claim 26, wherein RQis H, methyl, or acetyl. Claim 28. The compound of any of claims 1-10 or 14-25, wherein Q is Ring 5 and the compound is of Formula (II):or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Claim 29. The compound of any of claims 1-10 or 14-25, wherein Q is of Formula (i) and the compound is of Formula (IV):or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Claim 30. The compound of claim 29, wherein Ring A is, optionally substituted with C1-4alkyl or halo. Claim 31. The compound of claim 29 or 30, wherein X is a bond or -NH-. 1434 ny-2730225220232001540 Claim 32. The compound of any of claims 29-31, wherein Ring B is ,,, each of which is optionally substituted with one or more halo or OH, wherein RDis H or C1-4alkyl. Claim 33. The compound of any of claims 29-32, wherein W is a bond or -O-. Claim 34. The compound of any of claims 29-33, wherein Ring C is absent. Claim 35. The compound of any of claims 29-33, wherein Ring C is,each of which is optionally substituted with one or more RC. Claim 36. The compound of any of claims 29-35, wherein Linker is a bond, C1-10alkylene, or C(O)C1-10alkylene. Claim 37. The compound of any of claims 29-36, wherein Ring 2 is present and U is a bond. Claim 38. The compound of any of claims 29-37, wherein Ring 2 is 4- to 12-membered heterocyclyl optionally substituted with one or more R2a. Claim 39. The compound of any of claims 1-23 or 26-38, wherein RVis H. Claim 40. The compound of any of claims 29-37 or 39, wherein Ring 2 is 3- to 10- membered cycloalkyl optionally substituted with one or more R2a. 1435 ny-2730225220232001540 Claim 41. The compound of any of claims 29-39, wherein Ring 2 is,each of which is optionally substituted with one or more R2a, wherein # indicates attachment to V. Claim 42. The compound of any of claims 29-39 or 41, wherein Ring 2 is,each of which is optionally substituted with one or more R2a, wherein # indicates attachment to V. Claim 43. The compound of claim 42, wherein Ring 2 is. Claim 44. The compound of claim 43, wherein V is -C(O)- and Ring 1 is piperidinyl. Claim 45. The compound of claim 41 or 42, wherein Ring, each of which is optionally substituted with one or more R2a, wherein # indicates attachment to V. Claim 46. The compound of claim 45, wherein V is -C(O)- and Ring 1 is cyclohexyl. Claim 47. The compound of claim 45, wherein V is -C1-4alkyl-C(O)- and Ring 1 is piperidinyl. Claim 48. The compound of any of claims 27-35, wherein Ring 2, V, and Ring 1 are taken together to form: 1436 ny-2730225220232001540Claim 49. The compound of claim 48, wherein Ring 2, V, and Ring 1 are taken together to form: ,. Claim 50. The compound of claim 40, wherein Ring 2 is cyclohexyl optionally substituted with one or more R2a. Claim 51. The compound of claim 50, wherein Ring 2 isoptionally substituted with one or more R2a. Claim 52. The compound of claim 50 or 51, wherein V is -C(O)N(RV)-#, wherein # indicates the point of attachment to Ring 1, and wherein Ring 1 is cyclohexyl. Claim 53. The compound of any of claims 50-52, wherein Ring 2, V, and Ring 1 are takenClaim 54. The compound of claim 1, wherein the compound is selected from the compounds provided in Table 1 and Table 2, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 1437 ny-2730225220232001540 Claim 55. The compound of claim 54, wherein the compound is selected from the compounds provided in Table 1, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Claim 56. The compound of claim 54, wherein the compound is selected from the compounds provided in Table 2, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Claim 57. A pharmaceutical composition, comprising a compound of any of claims 1-56, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient. Claim 58. The pharmaceutical composition of claim 57, wherein the compound is a compound of any of claims 26-28 or 55, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient. Claim 59. The pharmaceutical composition of claim 57, wherein the compound is a compound of any of claims 29-53 or 56, a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient. Claim 60. A method of treating a disease or disorder associated with PIP4K2C, comprising administering to a subject a compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 57. Claim 61. A method of treating a disease or disorder by modulating the level or activity of PIP4K2C, comprising administering to a subject a compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 57. 1438 ny-2730225220232001540 Claim 62. The method of claim 61, wherein the method modulates the activity of PIP4K2C, and wherein the method comprises administering to the subject a compound of any of claims 26-28 or 55, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 58. Claim 63. The method of claim 61, wherein the method modulates the level of PIP4K2C, and wherein the method comprises administering to the subject a compound of any of claims 29-53 or 56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 59. Claim 64. The method of any one of claims 60-63, wherein the disease or disorder is a cancer, immune deficiency, autoimmune disease, infectious disease, or a combination thereof. Claim 65. The method of claim 64, wherein the cancer is brain cancer, bladder cancer, breast cancer, triple negative breast cancer, cervical cancer, colorectal carcinoma, colorectal carcinoma with MSI, colorectal carcinoma with MSS, gastric cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, leukemia, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, melanoma, Merkel cell carcinoma, multiple myeloma, pancreatic ductal carcinoma, or renal cell carcinoma. Claim 66. The method of claim 65, wherein the cancer is brain cancer, breast cancer, triple negative breast cancer, colorectal carcinoma, colorectal carcinoma with MSI, colorectal carcinoma with MSS, or non-small cell lung cancer. Claim 67. The method of any of claims 60-63, wherein the disease or disorder is a neurodegenerative disease. Claim 68. A method of treating a viral infection by modulating the level of PIP4K2C, comprising administering to a subject a compound of any of claims 29-53 or 56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 59. 1439 ny-2730225220232001540 Claim 69. A method of treating necrotizing soft tissue infection (NSTI), comprising administering to a subject a compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 57. Claim 70. A method of modulating the level or activity of at least one of PIP4K2A, PIP4K2B, and PIP4K2C, comprising administering to a subject a compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 57. Claim 71. A compound of any of claims 1-56, or the pharmaceutical composition of claim 57, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use in treating a disease or disorder associated with PIP4K2C in a subject in need thereof. Claim 72. A compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 57, for use in treating a disease or disorder by modulating the level or activity of PIP4K2C in a subject in need thereof. Claim 73. The compound for use of claim 72, wherein the compound for use modulates the activity of PIP4K2C, and wherein the compound for use is a compound of any of claims 26- 28 or 55, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 58. Claim 74. The compound for use of claim 72, wherein the compound for use modulates the level of PIP4K2C, and wherein the compound for use is a compound of any of claims 29-53 or 56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 59. Claim 75. The compound for use of any one of claims 71-74, wherein the disease or disorder is a cancer, immune deficiency, autoimmune disease, infectious disease, or a combination thereof. 1440 ny-2730225220232001540 Claim 76. The compound for use of claim 75, wherein the cancer is brain cancer, bladder cancer, breast cancer, triple negative breast cancer, cervical cancer, colorectal carcinoma, colorectal carcinoma with MSI, colorectal carcinoma with MSS, gastric cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, leukemia, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, melanoma, Merkel cell carcinoma, multiple myeloma, pancreatic ductal carcinoma, or renal cell carcinoma. Claim 77. The compound for use of claim 76, wherein the cancer is brain cancer, breast cancer, triple negative breast cancer, colorectal carcinoma, colorectal carcinoma with MSI, colorectal carcinoma with MSS, or non-small cell lung cancer. Claim 78. The compound for use of any of claims 71-74, wherein the disease or disorder is a neurodegenerative disease. Claim 79. A compound of any of claims 29-53 or 56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 59, for use in treating a viral infection by modulating the level of PIP4K2C in a subject in need thereof. Claim 80. A compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 57, for use in treating necrotizing soft tissue infection (NSTI) in a subject in need thereof. Claim 81. A compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 57, for use in modulating the level or activity of at least one of PIP4K2A, PIP4K2B, and PIP4K2C in a subject in need thereof. Claim 82. Use of a compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a 1441 ny-2730225220232001540 medicament for treating a disease or disorder associated with PIP4K2C in a subject in need thereof. Claim 83. Use of a compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a medicament for treating a disease or disorder by modulating the level or activity of PIP4K2C in a subject in need thereof. Claim 84. The use of claim 83, wherein the use modulates the activity of PIP4K2C, and wherein the compound is a compound of any of claims 26-28 or 55, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Claim 85. The use of claim 83, wherein the use modulates the level of PIP4K2C, and wherein the compound is a compound of any of claims 29-53 or 56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Claim 86. The use of any one of claims 82-85, wherein the disease or disorder is a cancer, immune deficiency, autoimmune disease, infectious disease, or a combination thereof. Claim 87. The use of claim 86, wherein the cancer is brain cancer, bladder cancer, breast cancer, triple negative breast cancer, cervical cancer, colorectal carcinoma, colorectal carcinoma with MSI, colorectal carcinoma with MSS, gastric cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, leukemia, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, melanoma, Merkel cell carcinoma, multiple myeloma, pancreatic ductal carcinoma, or renal cell carcinoma. Claim 88. The use of claim 87, wherein the cancer is brain cancer, breast cancer, triple negative breast cancer, colorectal carcinoma, colorectal carcinoma with MSI, colorectal carcinoma with MSS, or non-small cell lung cancer. Claim 89. The use of any of claims 82-85, wherein the disease or disorder is a neurodegenerative disease. 1442 ny-2730225220232001540 Claim 90. Use of a compound of any of claims 29-53 or 56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a medicament for treating a viral infection by modulating the level of PIP4K2C in a subject in need thereof. Claim 91. Use of a compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a medicament for treating necrotizing soft tissue infection (NSTI) in a subject in need thereof. Claim 92. Use of a compound of any of claims 1-56, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a medicament for modulating the level or activity of at least one of PIP4K2A, PIP4K2B, and PIP4K2C in a subject in need thereof. Claim 93. A kit, comprising (i) a compound of any of claims 1-56, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 57, and (ii) instructions for use in treating an PIP4K- mediated disease, disorder, or condition in an individual in need thereof. Claim 94. The method of claim 65 or 66, wherein the cancer is brain cancer. Claim 95. The method of any of claims 65, 66, or 94 wherein the brain cancer is glioma or glioblastoma. Claim 96. The method of any of claims 65, 66, or 94, wherein the brain cancer is brain stem glioma, gestational trophoblastic tumor glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, or visual pathway or hypothalamic glioma. Claim 97. The method of claim 65 or 66, wherein the cancer is colorectal cancer. Claim 98. The method of any of claims 65, 66, or 97, wherein the colorectal cancer is colorectal carcinoma, colorectal carcinoma with MSI, or colorectal carcinoma with MSS. 1443 ny-2730225220232001540 Claim 99. The method of any of claims 65, 66, or 97, wherein the colorectal cancer is associated with a hereditary syndrome. Claim 100. The method of claim 65 or 66, wherein the cancer is non-small cell lung cancer. Claim 101. The compound for use of claim 76 or 77, wherein the cancer is brain cancer. Claim 102. The compound for use of any of claims 76, 77, or 101, wherein the brain cancer is glioma or glioblastoma. Claim 103. The compound for use of any of claims 76, 77, or 101, wherein the brain cancer is brain stem glioma, gestational trophoblastic tumor glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, or visual pathway or hypothalamic glioma. Claim 104. The compound for use of claim 76 or 77, wherein the cancer is colorectal cancer. Claim 105. The compound for use of any of claims 76, 77, or 104, wherein the colorectal cancer is colorectal carcinoma, colorectal carcinoma with MSI, or colorectal carcinoma with MSS. Claim 106. The compound for use of any of claims 76, 77, or 104, wherein the colorectal cancer is associated with a hereditary syndrome. Claim 107. The compound for use of claim 76 or 77, wherein the cancer is non-small cell lung cancer. Claim 108. The use of claim 87 or 88, wherein the cancer is brain cancer. Claim 109. The use of any of claims 87, 88, or 108, wherein the brain cancer is glioma or glioblastoma. Claim 110. The use of any of claims 87, 88, or 108, wherein the brain cancer is brain stem glioma, gestational trophoblastic tumor glioma, cerebellar astrocytoma, cerebral 1444 ny-2730225220232001540 astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, or visual pathway or hypothalamic glioma. Claim 111. The use of claim 87 or 88, wherein the cancer is colorectal cancer. Claim 112. The use of claim 87, 88, or 111, wherein the colorectal cancer is colorectal carcinoma, colorectal carcinoma with MSI, or colorectal carcinoma with MSS. Claim 113. The use of claim 87, 88, or 111, wherein the colorectal cancer is associated with a hereditary syndrome. Claim 114. The use of claim 87 or 88, wherein the cancer is non-small cell lung cancer. Claim 115. The method of any one of claims 60-63, wherein the disease or disorder is related to loss-of-function mutations of the phosphoinositide phosphatase FIG4. Claim 116. The method of claim 115, wherein the disease or disorder is Charcot-Marie- Tooth. Claim 117. The method of claim 115 or 116, wherein the disease or disorder is Charcot- Marie-Tooth Type 4J. Claim 118. The compound for use of any one of claims 71-74, wherein the disease or disorder is related to loss-of-function mutations of the phosphoinositide phosphatase FIG4. Claim 119. The compound for use of claim 118, wherein the disease or disorder is Charcot- Marie-Tooth. Claim 120. The compound for use of claim 118 or 119, wherein the disease or disorder is Charcot-Marie-Tooth Type 4J. Claim 121. The use of any one of claims 82-85, wherein the disease or disorder is related to loss-of-function mutations of the phosphoinositide phosphatase FIG4. Claim 122. The use of claim 121, wherein the disease or disorder is Charcot-Marie-Tooth. 1445 ny-2730225220232001540 Claim 123. The use of claim 121 or 122, wherein the disease or disorder is Charcot-Marie- Tooth Type 4J. Claim 124. The method of claim 68, wherein the compound, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is administered in combination with a vaccine for viral infections to enhance the immune response. Claim 125. The compound for use of claim 79, wherein the compound, or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, is administered in combination with a vaccine for viral infections to enhance the immune response. Claim 126. The use of claim 90, wherein the medicament is administered in combination with a vaccine for viral infections to enhance the immune response. 1446 ny-2730225

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