EP-4739661-A1 - GTPASE INHIBITORS AND USES THEREOF

Abstract

Described herein, inter alia , are GTPase inhibitors and uses thereof.

Inventors

• SHOKAT, KEVAN M.
• ZHENG, Qinheng

Assignees

• The Regents of University of California

Dates

Publication Date

20260513

Application Date

20240705

Claims (1)

1. WHAT IS CLAIMED IS: 1 1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: (I); wherein ding Pocket binding moiety; L 1 is a bond or divalent linker; and wherein gen, -CX 2 3, -CHX 2 2, -CH2X 2 , -OCX 2 3, -OCH2X 2 , -OCHX 2 2 , -CN, -SO n2 R 2D , -SO v2 NR 2A R 2B , ^NR 2C NR 2A R 2B , ^ONR 2A R 2B , ^NHC(O)NR 2C NR 2A R 2B , -NHC(O)NR 2A R 2B , -N(O)m2, -NR 2A R 2B , -C(O)R 2C , -C(O)OR 2C , -C(O)NR 2A R 2B , -OR 2D , -SR 2D , -NR 2A SO2R 2D , -NR 2A C(O)R 2C , -NR 2A C(O)OR 2C , -NR 2A OR 2C , -PR 2A R 2B , -P(O)R 2A R 2B , -OP(O)OR 2A OR 2B , ^SiR 2A R 2B R 2C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2A , R 2B , R 2C , and R 2D are independently hydrogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH 2 , -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2A and R 2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X 2 is independently –F, -Cl, -Br, or –I; n2 is an integer from 0 to 4; m2 and v2 are independently 1 or 2; and wherein the compound is not: O O N N N N N N 27 , 28 1 2. The compound of claim 1, wherein R is hydrogen, halogen, -CCl 3 , -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ^NHNH 2 , ^ONH 2 , ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 3. The compound of claim 1, wherein R 2 is hydrogen, -CX 2 3, -SO2R 2D , -P(O)R 2A R 2B , ^SiR 2A R 2B R 2C , unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, or substituted or unsubstituted phenyl. 4. The compound of claim 1, wherein R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH2CH(CH3)2, -CF3, -Si(CH3)3, -P(O)(CH3)2, -S(O)2CH3, unsubstituted phenyl, , . , . 6. The compound of claim 1, wherein L 1 is –L 101 -L 102 -L 103 -; L 101 is connected directly to E; L 101 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 101 -, -C(O)NR 101 -, -NR 101 C(O)-, -NR 101 C(O)O-, -OC(O)NR 101 -, -NR 101 C(O)NR 101 -, -NR 101 C(NH)NR 101 -, -S(O)2-, -NR 101 S(O)2-, -S(O)2NR 101 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 102 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 102 -, -C(O)NR 102 -, -NR 102 C(O)-, -NR 102 C(O)O-, -OC(O)NR 102 -, -NR 102 C(O)NR 102 -, -NR 102 C(NH)NR 102 -, -S(O)2-, -NR 102 S(O)2-, -S(O)2NR 102 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 103 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 103 -, -C(O)NR 103 -, -NR 103 C(O)-, -NR 103 C(O)O-, -OC(O)NR 103 -, -NR 103 C(O)NR 103 -, -NR 103 C(NH)NR 103 -, -S(O)2-, -NR 103 S(O)2-, -S(O)2NR 103 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and each R 101 , R 102 , and R 103 is independently hydrogen, halogen, -CCl3, -CBr3, -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , COOH CONH2 NO2 SH SO3H OSO3H SO2NH2 ^NHNH2 ^ONH2 ^NHC(O)NHNH 2 , ^NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 7. The compound of claim 1, wherein L 1 is a bond. 8. The compound of claim 1, wherein L 1 is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene. 9. The compound of claim 1, wherein L 1 is a spirocyclic substituted or unsubstituted 3 to 8 membered heterocycloalkylene. 10. The compound of claim 6, wherein L 1 is or l, -CH2Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I, -OCHCl 2 , -OCHBr 2 , -OCHF 2 , -OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R 3 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z3 is an integer from 0 to 9. 11. The compound of claim 10, wherein L 1 is N N . L 10 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 100 -, -C(O)NR 100 -, -NR 100 C(O)-, -NR 100 C(O)O-, -OC(O)NR 100 -, -NR 100 C(O)NR 100 -, -NR 100 C(NH)NR 100 -, -S(O)2-, -NR 100 S(O)2-, -S(O)2NR 100 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 100 is independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I, -OCHCl 2 , -OCHBr 2 , -OCHF 2 , -OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10 is hydrogen, halogen, -CX 10 3 , -CHX 10 2 , -CH 2 X 10 , -OCX 10 3 , -OCH 2 X 10 , -OCHX 10 2, -CN, -SOn10R 10D , -SOv10NR 10A R 10B , ^NR 10C NR 10A R 10B , ^ONR 10A R 10B , ^NHC(O)NR 10C NR 10A R 10B , -NHC(O)NR 10A R 10B , -N(O) m10 , -NR 10A R 10B , -C(O)R 10C , -C(O)OR 10C , -C(O)NR 10A R 10B , -OR 10D , -SR 10D , -NR 10A SO 2 R 10D , -NR 10A C(O)R 10C , -NR 10A C(O)OR 10C , -NR 10A OR 10C , -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10A , R 10B , R 10C , and R 10D are independently hydrogen, -CCl 3 , -CBr 3 , -CF 3 , -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH 2 , -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10A and R 10B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; X 10 is independently –F, -Cl, -Br, or –I; n10 is an integer from 0 to 4; and m10 and v10 are independently 1 or 2. 13. The compound of claim 1, wherein R 1 is , , or CI3, -CH2Cl, -CH2Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I, -OCHCl 2 , -OCHBr 2 , -OCHF 2 , -OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 6 is independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 11; z5 is an integer from 0 to 9; and z6 is an integer from 0 to 9. 14. The compound of claim 13, wherein R 4 is independently a halogen, -CF3, -OH, unsubstituted C1-C4 alkyl, substituted 2 to 6 membered heteroalkyl, or substituted 5 to 6 membered heteroaryl. 15. The compound of claim 13, wherein R 4 is independently –F, -Cl, -CF 3 , -OH, or unsubstituted methyl. 16. The compound of claim 13, wherein R 4 is independently a 2 to 6 membered heteroalkyl, substituted with substituted heterocycloalkyl or unsubstituted fused heterocycloalkyl. 17. The compound of claim 13, wherein R 4 is independently . 18. The compound of claim 13, wherein R 4 is independently a substituted pyridyl. 19. The compound of claim 13, wherein z4 is 1, 2, or 3. 20. The compound of claim 13, wherein R 5 is independently a halogen, -CF3, -CN, -OH, -NH2, unsubstituted C1-C4 alkyl, or unsubstituted C2-C4 alkynyl. 21. The compound of claim 13, wherein R 5 is independently –F, -Cl, -CF3, -CN, -OH, -NH 2 , unsubstituted methyl, or unsubstituted ethynyl. 22. The compound of claim 13, wherein z5 is 1, 2, or 3. 23. The compound of claim 13, wherein R 6 is independently a halogen or unsubstituted C1-C4 alkyl. 24. The compound of claim 13, wherein R 6 is independently –Cl or unsubstituted methyl. 25. The compound of claim 13, wherein z6 is 1 or 2. 26. The compound of claim 1, wherein R 1 is , , , , F F N , . e compoun o c a m , avng e ormu a: . 28. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof. 29. A method of treating cancer in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 -L 1 -H is capable of binding to Ras(G12D) with a K d of less than 1 µM. 30. The method of claim 29, wherein the cancer is pancreatic cancer, colorectal cancer, lung cancer, leukemia, thyroid cancer, bladder cancer, or ovarian cancer. 31. The method of claim 29, wherein the cancer is pancreatic ductal adenocarncinoma, colorectal adenocarcinoma, colorectal carcinoma, rectal carcinoma, rectal adenocarcinoma, colon adenocarcinoma, plasma cell myeloma, bile duct carcinoma, chronic myelomonocytic leukemia, acute myeloid leukemia, lung adenocarcinoma, non-small cell lung carcinoma, squamous cell lung carcinoma, rhabdomyosarcoma, endometrium carcinoma, thyroid carcinoma, bladder carcinoma, ovarian carcinoma, or myelodysplastic syndrome. 32. A method of treating a K-Ras(G12D)-associated disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 -L 1 -H is capable of binding to K- Ras(G12D) with a K d of less than 1 µM. 33. A method of treating an H-Ras(G12D)-associated disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 -L 1 -H is capable of binding to H- Ras(G12D) with a K d of less than 1 µM. 34. The method of claim 33, wherein said H-Ras(G12D)-associated disease is Costello syndrome. 35. A method of treating an N-Ras(G12D)-associated disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 -L 1 -H is capable of binding to N- Ras(G12D) with a K d of less than 1 µM. 36. A method of modulating the level of activity of a K-Ras protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 -L 1 -H is capable of binding to K-Ras with a Kd of less than 1 µM. 37. The method of claim 36, wherein said modulating of said activity comprises modulating GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, K-Ras subcellular localization, K-Ras post-translational processing, or K- Ras post-translational modifications. 38. The method of claim 36, wherein said modulating is increasing the activity of said K-Ras protein. 39. The method of claim 36, wherein said modulating is reducing the activity of said K-Ras protein. 40. The method of claim 36, wherein said K-Ras protein is a human K-Ras protein. 41. The method of claim 40, wherein said human K-Ras protein contains a G12D mutation. 42. A method of modulating the level of activity of an H-Ras protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 -L 1 -H is capable of binding to H-Ras with a K d of less than 1 µM. 43. The method of claim 42, wherein said modulating of said activity comprises modulating GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, H-Ras subcellular localization, H-Ras post-translational processing, or H- Ras post-translational modifications. 44. The method of claim 42, wherein said modulating is increasing the activity of said H-Ras protein. 45. The method of claim 42, wherein said modulating is reducing the activity of said H-Ras protein. 46. The method of claim 42, wherein said H-Ras protein is a human H-Ras protein. 47. The method of claim 46, wherein said human H-Ras protein contains a G12D mutation. 48. A method of modulating the level of activity of an N-Ras protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 -L 1 -H is capable of binding to N-Ras with a Kd of less than 1 µM. 49. The method of claim 48, wherein said modulating of said activity comprises modulating GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, N-Ras subcellular localization, N-Ras post-translational processing, or N- Ras post-translational modifications. 50. The method of claim 48, wherein said modulating is increasing the activity of said N-Ras protein. 51. The method of claim 48, wherein said modulating is reducing the activity of said N-Ras protein. 52. The method of claim 48, wherein said N-Ras protein is a human K-Ras protein. 53. The method of claim 52, wherein said human N-Ras protein contains a G12D mutation. 54. A K-Ras protein covalently bound to a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein said compound is covalently bound to an aspartate residue of said K-Ras protein. 55. The covalently modified K-Ras protein of claim 54, wherein said compound is reversibly covalently bound to an aspartate residue of said K-Ras protein. 56. The covalently modified K-Ras protein of claim 54, wherein said compound is irreversibly covalently bound to an aspartate residue of said K-Ras protein. 57. The covalently modified K-Ras protein of claim 54, wherein said covalently modified K-Ras protein has a modulated activity relative to a control, wherein said activity is selected from GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, K-Ras subcellular localization, K-Ras post-translational processing, and K-Ras post-translational modifications. 58. The covalently modified K-Ras protein of claim 54, wherein said K- Ras protein contains a G12D mutation. 59. The covalently modified K-Ras protein of claim 58, wherein said compound is covalently bonded to aspartate residue 12. 60. An H-Ras protein covalently bound to a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein said compound is covalently bound to an aspartate residue of said H-Ras protein. 61. The covalently modified H-Ras protein of claim 60, wherein said compound is reversibly covalently bound to an aspartate residue of said H-Ras protein. 62. The covalently modified H-Ras protein of claim 60, wherein said compound is irreversibly covalently bound to an aspartate residue of said H-Ras protein. 63. The covalently modified H-Ras protein of claim 60, wherein said covalently modified H-Ras protein has a modulated activity relative to a control, wherein said activity is selected from GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, H-Ras subcellular localization, H-Ras post-translational processing, and H-Ras post-translational modifications. 64. The covalently modified H-Ras protein of claim 60, wherein said H- Ras protein contains a G12D mutation. 65. The covalently modified H-Ras protein of claim 64, wherein said compound is covalently bonded to aspartate residue 12. 66. An N-Ras protein covalently bound to a compound of one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein said compound is covalently bound to an aspartate residue of said N-Ras protein. 67. The covalently modified N-Ras protein of claim 66, wherein said compound is reversibly covalently bound to an aspartate residue of said N-Ras protein. 68. The covalently modified N-Ras protein of claim 66, wherein said compound is irreversibly covalently bound to an aspartate residue of said N-Ras protein. 69. The covalently modified N-Ras protein of claim 66, wherein said covalently modified H-Ras protein has a modulated activity relative to a control, wherein said activity is selected from GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, N-Ras subcellular localization, N-Ras post-translational processing, and N-Ras post-translational modifications. 70. The covalently modified N-Ras protein of claim 66, wherein said H- Ras protein contains a G12D mutation. 71. The covalently modified N-Ras protein of claim 70, wherein said compound is covalently bonded to aspartate residue 12.

Description

GTPase INHIBITORS AND USES THEREOF CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No.63/525,118, filed July 5, 2023, which is incorporated herein by reference in its entirety and for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (048536- 768001WO_Sequence_Listing_ST26.xml; Size: 5,334 bytes; and Date of Creation: June 26, 2024) is hereby incorporated by reference in its entirety. BACKGROUND [0003] Oncogenic mutations of Ras are one of the most common genetic alterations in human cancer, with an estimated disease burden of >3 million patients per year worldwide. In the KRAS gene, a GGT to GAT nucleotide transition at codon 12 (c.35 G>A) gives rise to KRAS G12D, the most frequent Ras mutation accounting for about 23% of Ras-driven cancers. Selective targeting of KRAS G12D while sparing wild type KRAS is a highly desirable therapeutic goal, as it would enable a large therapeutic window for cancer treatment. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY [0004] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: (I). [0005] R1 is a Switch II Binding Pocket binding moiety. [0006] L1 is a bond or divalent linker. [0007] . [0008] R2 is hydrogen, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -CN, -SOn2R2D, -SOv2NR2AR2B, ^NR2CNR2AR2B, ^ONR2AR2B, ^NHC(O)NR2CNR2AR2B, -NHC(O)NR2AR2B, -N(O)m2, -NR2AR2B, -C(O)R2C, -C(O)OR2C, -C(O)NR2AR2B, -OR2D, -SR2D, -NR2ASO2R2D, -NR2AC(O)R2C, -NR2AC(O)OR2C, -NR2AOR2C, -PR2AR2B, -P(O)R2AR2B, -OP(O)OR2AOR2B, ^SiR2AR2BR2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0009] R2A, R2B, R2C, and R2D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0010] X2 is independently –F, -Cl, -Br, or –I. The symbol n2 is an integer from 0 to 4. The symbols m2 and v2 are independently 1 or 2. [0011] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0012] In an aspect is provided a method of treating cancer in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to Ras(G12D) with a Kd of less than 1 µM, wherein R1 and L1 are as described herein, including in embodiments. [0013] In an aspect is provided a method of treating a K-Ras(G12D)-associated disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to K-Ras(G12D) with a Kd of less than 1 µM, wherein R1 and L1 are as described herein, including in embodiments. [0014] In an aspect is provided a method of treating an H-Ras(G12D)-associated disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to H-Ras(G12D) with a Kd of less than 1 µM, wherein R1 and L1 are as described herein, including in embodiments. [0015] In an aspect is provided a method of treating an N-Ras(G12D)-associated disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, R1-L1-H is capable of binding to N-Ras(G12D) with a Kd of less than 1 µM, wherein R1 and L1 are as described herein, including in embodiments. [0016] In an aspect is provided a method of modulating the level of activity of a K-Ras protein in a cell, the method including contacting the cell with an effective amount of a compound described herein, o