# US 2025/0084079 A1 · Compositions and methods for inhibition of ras > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2025/0084079 A1 - Document ID: US20250084079A1 - Status: Published application - Kind: A1 - Application number: 18/726,861 - Filed: 2023-01-05 - Published: 2025-03-13 - Earliest claimed: 2022-01-06 - Assignees: TheRas, Inc.; Leidos Biomedical Research, Inc.; Lawrence Livermore National Security, LLC - Applicants: TheRas, Inc.; Leidos Biomedical Research, Inc.; Lawrence Livermore National Security, LLC - Inventors: Bin Wang; Rui Xu; Eli Wallace; Zuhui Zhang; Felice Lightstone; Yue Yang; David Michael Turner; Anna Elzbieta Maciag; Dhirendra Kumar Simanshu; Albert Hay Wah Chan - Web page: https://patentgrep.com/patent/US20250084079A1 ## CPC - C07D 417/14: containing three or more hetero rings - C07D 471/04: Ortho-condensed systems - A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine - A61K 31/519: ortho- or peri-condensed with heterocyclic rings - A61P 35/00: Antineoplastic agents - C07D 487/04: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Provided herein are compounds, or salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers thereof, as well as pharmaceutical compositions comprising the same. Also provided herein are methods of using the same in modulating (e.g., inhibiting) KRAS (e.g., KRAS having a G12D or G12V mutation or wild-type KRAS) and treating diseases or disorders such as cancers in subjects in need thereof. ## Claims ### Claim 1 A compound according to Formula I: or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein: R1 is selected from —OR7, and a 4-6 membered heterocycle comprising a nitrogen atom, wherein the heterocycle is unsubstituted or substituted with one or more R15; R2 is a 4-11 membered heterocycle containing one or more nitrogen atoms, wherein the heterocycle is unsubstituted or is substituted with one or more R8; R3 is H; R4 is selected from H, halogen, —CN, —OR12, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R11; R5 is a bicyclic heteroaryl substituted with one or more R9; R6 is selected from halogen, —OR12, —CN, and H; R7 is selected from a heterocycle and an alkylheterocycle, wherein any heterocycle comprises 4-8 members and is unsubstituted or is substituted with one or more Ra or Rb, and wherein an alkyl moiety of any alkylheterocycle is selected from C1-6 alkyl; each R8 is independently selected from halogen and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R11; each R9 is independently selected from halogen, N(R12)2, —CN, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13; each R11 is independently selected from halogen, —OR12, and —CN; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6alkyl or C2-6 alkenyl is unsubstituted or substituted with one or more R13; each R13 is independently selected from —OR14, —CN, —N(R14)2, and halogen; each R14 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H; each R15 is independently selected from halogen, —N(R14)2, C1-6alkyl, —OR14, and a 3-6 membered heterocycle, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13, and any heterocycle is unsubstituted or substituted with one or more R16; each R16 is independently selected from —OH, —OC1-6alkyl, —CN, —NH2, —NHC1-6alkyl, and halogen; R17 is a 3-6 membered heterocycle including one or more heteroatoms selected from N, O, and S, wherein the heterocycle is unsubstituted or substituted with one or more R18; each R18 is independently selected from C1-6alkyl and halogen; and each Ra and Rb is independently selected from halogen, C1-6 alkyl, —OR12, and H, wherein an W and Rb optionally join together to form a 3-6 membered carbocycle or heterocycle, and wherein any C1-6alkyl or 3-6 membered carbocycle or heterocycle is unsubstituted or is substituted with one or more R13. ### Claim 2 (depends on 1) The compound of claim 1, wherein R2 is a 4-6 membered heterocycle containing one nitrogen atom, wherein the heterocycle is unsubstituted or is substituted with one or more R8. ### Claim 3 (depends on 2) The compound of claim 2, wherein R2 is a heterocycle selected from azetidine and pyrrolidine, wherein the heterocycle is unsubstituted or is substituted with one or more R8. ### Claim 4 (depends on 1) The compound of claim 1, wherein R2 is a bridged heterocycle containing one nitrogen atom, wherein the heterocycle is unsubstituted or is substituted with one or more R8. ### Claim 5 (depends on 1) The compound of claim 1, wherein R2 is a spirocyclic heterocycle containing one or more nitrogen atoms, wherein the heterocycle is unsubstituted or substituted with one or more R8. ### Claim 6 (depends on 1) The compound of claim 1, wherein R2 is a spirocycle including a first ring that is a carbocycle and a second ring that is a heterocycle containing a nitrogen atom, wherein the spirocycle is unsubstituted or is substituted with one or more R8. ### Claim 7 (depends on 1, 2, 3, 4, 5, 6) The compound of any one of claims 1-6, wherein R2 is unsubstituted. ### Claim 8 (depends on 1, 2, 3, 4, 5, 6) The compound of any one of claims 1-6, wherein R2 is substituted with one or more R8, wherein the one or more R8 are each independently selected from halogen and C1-6alkyl, wherein any C1-6alkyl is unsubstituted. ### Claim 9 (depends on 1) The compound of claim 1, wherein the compound is a compound according to Formula IA: or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein: n is 1, 2, or 3; m is 0, 1, 2, 3, or 4; each R9 is independently selected from halogen and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R11, or two R8, together with the atoms to which they are attached, join to form a 5-7 membered ring; Rh is selected from H and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R11. ### Claim 10 (depends on 9) The compound of claim 9, wherein the compound has the structure: or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 11 (depends on 9) The compound of claim 9, wherein the compound has the structure: or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 12 (depends on 9) The compound of claim 9, wherein the compound has the structure: or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 13 (depends on 9) The compound of claim 9, wherein the compound has the structure: or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 14 (depends on 9) The compound of claim 9, wherein the compound has the structure: or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 15 (depends on 9, 10, 11, 12, 13, 14) The compound of any one of claims 9-14, wherein R1 is H. ### Claim 16 (depends on 9, 10, 11, 12, 13, 14, 15) The compound of any one of claims 9-15, wherein m is 1 or 2, and each Rg is independently selected from halogen and C1-6alkyl, wherein any C1-6alkyl is unsubstituted. ### Claim 17 (depends on 1) The compound of claim 1, wherein the compound is a compound according to Formula IB: or a salt (e.g., a pharmaceutically acceptable salt) thereof, wherein: m and q are each independently selected from 0, 1, 2, 3, and 4; n and p are each independently selected from 1 and 2; r and s are each independently selected from 1 and 2; each R9 is independently selected from halogen and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R11; and Rh is selected from H and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R11. ### Claim 18 (depends on 17) The compound of claim 17, wherein the compound has the structure: or a salt (e.g., a pharmaceutically acceptable salt) thereof. ### Claim 19 (depends on 17) The compound of claim 17, wherein the compound has the structure: or a salt (e.g., a pharmaceutically acceptable salt) thereof. ### Claim 20 (depends on 17) The compound of claim 17, wherein the compound has the structure: or a salt (e.g., a pharmaceutically acceptable salt) thereof. ### Claim 21 (depends on 17, 18, 19, 20) The compound of any one of claims 17-20, wherein Rh is H. ### Claim 22 (depends on 17, 18, 19, 20, 21) The compound of any one of claims 17-21, wherein m and q are 0. ### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22) The compound of any one of claims 1-22, wherein R1 is —OR7. ### Claim 24 (depends on 23) The compound of claim 23, wherein R1 is: wherein Ra and Rb are each independently selected from halogen, C1-6alkyl, —OR12, and H, wherein any C1-6alkyl is unsubstituted or is substituted with one or more R13. ### Claim 25 (depends on 24) The compound of claim 24, wherein Rb is H. ### Claim 26 (depends on 24) The compound of claim 24, wherein R1 is selected from: ### Claim 27 (depends on 23) The compound of claim 23, wherein R1 is selected from: wherein each Ra and Rb is independently selected from halogen, C1-6 alkyl, —OR12, and H; and Rc is selected from C1-6 alkyl, wherein an Ra and Rb or Rc optionally join together to form a 3-6 membered carbocycle or heterocycle, wherein any C1-6 alkyl or 3-6 membered carbocycle or heterocycle is unsubstituted or is substituted with one or more R13. ### Claim 28 (depends on 27) The compound of claim 27, wherein R1 is selected from: ### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22) The compound of any one of claims 1-22, wherein R1 is ### Claim 30 (depends on 29) The compound of claim 29, wherein R1 is selected from: ### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22) The compound of any one of claims 1-22, wherein R1 is a 4-6 membered heterocycle comprising a nitrogen atom, wherein the heterocycle is unsubstituted or substituted with one or more R15. ### Claim 32 (depends on 31) The compound of claim 31, wherein R1 is selected from: ### Claim 33 (depends on 1) The compound of claim 1, wherein the compound is a compound according to Formula IC: or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 34 (depends on 33) The compound of claim 33, wherein Ra is a halogen or —OR12. ### Claim 35 (depends on 33, 34) The compound of claim 33 or 34, wherein Rb is H. ### Claim 36 (depends on 33, 34, 35) The compound of any one of claims 33-35, wherein R2 is a 4-6 membered heterocycle containing one nitrogen atom, wherein the heterocycle is unsubstituted or is substituted with one or more R8. ### Claim 37 (depends on 36) The compound of claim 36, wherein R2 is a heterocycle selected from azetidine, pyrrolidine, and piperidine, wherein the heterocycle is unsubstituted or is substituted with one or more R8. ### Claim 38 (depends on 33, 34, 35) The compound of any one of claims 33-35, wherein R2 is a bridged heterocycle containing one nitrogen atom, wherein the heterocycle is unsubstituted or is substituted with one or more R8. ### Claim 39 (depends on 33, 34, 35) The compound of any one of claims 33-35, wherein R2 is a spirocyclic heterocycle containing one or more nitrogen atoms, wherein the heterocycle is unsubstituted or substituted with one or more R8. ### Claim 40 (depends on 39) The compound of claim 39, wherein R2 is a spirocycle including a first ring that is a carbocycle and a second ring that is a heterocycle containing a nitrogen atom, wherein the spirocycle is unsubstituted or is substituted with one or more R8. ### Claim 41 (depends on 33, 34, 35, 36, 37, 38, 39, 40) The compound of any one of claims 33-40, wherein R2 is unsubstituted. ### Claim 42 (depends on 33, 34, 35, 36, 37, 38, 39, 40) The compound of any one of claims 33-40, wherein R2 is substituted with one or more R8. ### Claim 43 (depends on 42) The compound of claim 42, wherein the one or more R8 are each independently selected from C1-6alkyl, wherein any C1-6alkyl is unsubstituted. ### Claim 44 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43) The compound of any one of claims 1-43, wherein R4 is H. ### Claim 45 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43) The compound of any one of claims 1-43, wherein R4 is selected from halogen, —CN, —OR12, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R1. ### Claim 46 (depends on 45) The compound of claim 45, wherein R4 is —CN. ### Claim 47 (depends on 45) The compound of claim 45, wherein R4 is a halogen. ### Claim 48 (depends on 45) The compound of claim 45, wherein R4 is C1-6alkyl that is substituted with one or more R11. ### Claim 49 (depends on 48) The compound of claim 48, wherein R4 is C1-6alkyl that is substituted with one or more halogens or —CN. ### Claim 50 (depends on 49) The compound of claim 49, wherein R4 is selected from —CF2H, —CF3, —CF2CH3, and —CH2CN. ### Claim 51 (depends on 50) The compound of claim 50, wherein R4 is —CF3. ### Claim 52 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51) The compound of any one of claims 1-51, wherein R6 is selected from halogen, —CN, and H. ### Claim 53 (depends on 52) The compound of claim 52, wherein R6 is a halogen. ### Claim 54 (depends on 52) The compound of claim 52, wherein R6 is —CN. ### Claim 55 (depends on 52) The compound of claim 52, wherein R6 is H. ### Claim 56 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55) The compound of any one of claims 1-55, wherein R5 is: wherein: X is selected from N and C—CN; Y is selected from O and S; R23 is selected from —N(R12)2, C1-6alkyl, and C1-6alkyl-N(R14)2, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13; and R24, R25, and R26 are independently selected from H, halogen, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13. ### Claim 57 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55) The compound of any one of claims 1-55, wherein R5 is selected from: any of which is substituted with one or more R9. ### Claim 58 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55) The compound of any one of claims 1-55, wherein R5 is selected from: ### Claim 59 (depends on 58) The compound of claim 58, wherein R5 is selected from: ### Claim 60 A compound according to Formula II: or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein: each dashed line represents a single or double bond; X, Y, and Z are selected from N and C, wherein one and only one of X, Y, and Z is N; R1 is selected from —OR7, and a 4-6 membered heterocycle comprising a nitrogen atom, wherein the heterocycle is unsubstituted or substituted with one or more R15; R2 is a 4-6 membered heterocycle containing one or more nitrogen atoms, wherein the heterocycle is unsubstituted or is substituted with one or more R8; when X is C, R3 is H, and when X is N, R3 is absent; when Y is C, R4 is selected from H, halogen, —CN, —OR12, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R11, and when Y is N, R4 is absent; R5 is a bicyclic heteroaryl substituted with one or more R9; when Z is C, R6 is selected from halogen, —OR12, —CN, and H, and when Z is N, R6 is absent; R7 is selected from a heterocycle and an alkylheterocycle, wherein any heterocycle comprises 4-8 members and is unsubstituted or is substituted with one or more Ra or Rb, and wherein an alkyl moiety of any alkylheterocycle is selected from C1-6 alkyl; each R8 is selected from halogen and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R11; each R9 is independently selected from halogen, —N(R12)2, —CN, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13; each R11 is independently selected from halogen, —OR12, and —CN; each R12 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H, wherein any C1-6alkyl or C2-6 alkenyl is unsubstituted or substituted with one or more R13; each R13 is independently selected from —OR14, —CN, —N(R14)2, and halogen; each R14 is independently selected from C1-6 alkyl, C2-6 alkenyl, and H; each R15 is independently selected from halogen, —N(R14)2, C1-6alkyl, —OR14, and a 3-6 membered heterocycle, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13, and any heterocycle is unsubstituted or substituted with one or more R16; each R16 is independently selected from —OH, —OC1-6alkyl, —CN, —NH2, —NHC1-6alkyl, and halogen; R17 is a 3-6 membered heterocycle including one or more heteroatoms selected from N, O, and S, wherein the heterocycle is unsubstituted or substituted with one or more R18; each R18 is independently selected from C1-6alkyl and halogen; and each Ra and Rb is independently selected from halogen, C1-6 alkyl, —OR12, and H, wherein an Ra and Rb optionally join together to form a 3-6 membered carbocycle or heterocycle, and wherein any C1-6alkyl or 3-6 membered carbocycle or heterocycle is unsubstituted or is substituted with one or more R13. ### Claim 61 (depends on 60) The compound of claim 60, wherein X is N, and Y and Z are C, and the compound is a compound according to Formula IIA: or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 62 (depends on 61) The compound of claim 61, wherein R4 is H. ### Claim 63 (depends on 61) The compound of claim 61, wherein R4 is selected from halogen, —CN, —OR12, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R11. ### Claim 64 (depends on 63) The compound of claim 63, wherein R4 is halogen (e.g., Cl or F). ### Claim 65 (depends on 63) The compound of claim 63, wherein R4 is C1-6alkyl that is substituted with one or more halogens or —CN. ### Claim 66 (depends on 65) The compound of claim 65, wherein R4 is selected from —CF2H, —CF3, —CF2CH3, and —CH2CN. ### Claim 67 (depends on 66) The compound of claim 66, wherein R4 is —CF3. ### Claim 68 (depends on 61, 62, 63, 64, 65, 66, 67) The compound of any one of claims 61-67, wherein R6 is selected from halogen, —CN, and H. ### Claim 69 (depends on 68) The compound of claim 68, wherein R6 is halogen (e.g., Cl or F). ### Claim 70 (depends on 68) The compound of claim 68, wherein R6 is H. ### Claim 71 (depends on 60) The compound of claim 60, wherein Y is N, and X and Z are C, and the compound is a compound according to Formula IIB: or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 72 (depends on 71) The compound of claim 71, wherein R6 is selected from halogen, —CN, and H. ### Claim 73 (depends on 72) The compound of claim 72, wherein R6 is a halogen (e.g., Cl or F). ### Claim 74 (depends on 72) The compound of claim 72, wherein R6 is H. ### Claim 75 (depends on 60) The compound of claim 60, wherein Z is N, and X and Y are C, and the compound is a compound according to Formula IIC: or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 76 (depends on 75) The compound of claim 75, wherein R4 is H. ### Claim 77 (depends on 75) The compound of claim 75, wherein R4 is selected from halogen, —CN, —OR12, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R11. ### Claim 78 (depends on 77) The compound of claim 77, wherein R4 is halogen (e.g., Cl or F). ### Claim 79 (depends on 77) The compound of claim 77, wherein R4 is C1-6alkyl that is substituted with one or more halogens or —CN. ### Claim 80 (depends on 79) The compound of claim 79, wherein R4 is selected from —CF2H, —CF3, —CF2CH3, and —CH2CN. ### Claim 81 (depends on 80) The compound of claim 80, wherein R4 is —CF3. ### Claim 82 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81) The compound of any one of claims 60-81, wherein R2 is a 4-6 membered heterocycle containing one nitrogen atom, wherein the heterocycle is unsubstituted or is substituted with one or more R8. ### Claim 83 (depends on 82) The compound of claim 82, wherein R2 is a heterocycle selected from azetidine, pyrrolidine, and piperidine, wherein the heterocycle is unsubstituted or is substituted with one or more R8. ### Claim 84 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83) The compound of any one of claims 60-83, wherein R2 is unsubstituted. ### Claim 85 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83) The compound of any one of claims 60-83, wherein R2 is substituted with one or more R8. ### Claim 86 (depends on 85) The compound of claim 85, wherein the one or more R8 are each independently selected from C1-6alkyl, wherein any C1-6alkyl is unsubstituted. ### Claim 87 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86) The compound of any one of claims 60-86, wherein R1 is —OR7. ### Claim 88 (depends on 87) The compound claim 87, wherein R1 is: wherein Ra and Rb are each independently selected from halogen, C1-6alkyl, —OR12, and H, wherein any C1-6alkyl is unsubstituted or is substituted with one or more R13. ### Claim 89 (depends on 88) The compound of claim 88, wherein Rb is H. ### Claim 90 (depends on 88) The compound of claim 88, wherein R1 is selected from: ### Claim 91 (depends on 87) The compound of claim 87, wherein R1 is selected from: wherein each Ra and Rb is independently selected from halogen, C1-6 alkyl, —OR12, and H; and Rc is selected from C1-6 alkyl, wherein an Ra and Rb or Rc optionally join together to form a 3-6 membered carbocycle or heterocycle, wherein any C1-6 alkyl or 3-6 membered carbocycle or heterocycle is unsubstituted or is substituted with one or more R13. ### Claim 92 (depends on 91) The compound of claim 91, wherein R1 is selected from: ### Claim 93 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86) The compound of any one of claims 60-86, wherein R1 is ### Claim 94 (depends on 93) The compound of claim 93, wherein R1 is selected from: ### Claim 95 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86) The compound of any one of claims 60-86, wherein R1 is a 4-6 membered heterocycle comprising a nitrogen atom, wherein the heterocycle is unsubstituted or substituted with one or more R15. ### Claim 96 (depends on 95) The compound of claim 95, wherein R1 is selected from: ### Claim 97 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96) The compound of any one of claims 60-96, wherein R5 is wherein: X is selected from N and C—CN; Y is selected from O and S; R23 is selected from —N(R12)2, C1-6alkyl, and C1-6alkyl-N(R14)2, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13; and R24, R25, and R26 are independently selected from H, halogen, and C1-6alkyl, wherein any C1-6alkyl is unsubstituted or substituted with one or more R13. ### Claim 98 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97) The compound of any one of claims 60-97, wherein R5 is selected from: any of which is substituted with one or more R9. ### Claim 99 (depends on 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98) The compound of any one of claims 60-98, wherein R5 is selected from: ### Claim 100 (depends on 99) The compound of claim 99, wherein R5 is selected from: ### Claim 101 A compound shown in Table 2, or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 102 A compound shown in Table 3, or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 103 (depends on 1, 102) A pharmaceutical composition comprising a compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, and a pharmaceutically acceptable excipient. ### Claim 104 (depends on 1, 102) A compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt) thereof, for use as a medicament. ### Claim 105 (depends on 104) The compound of claim 104, wherein the medicament is useful in the prevention or treatment of a disease, disorder, or condition ameliorated by the inhibition of KRAS having a G12D mutation. ### Claim 106 (depends on 104) The compound of claim 104, wherein the medicament is useful in the prevention or treatment of a disease, disorder, or condition ameliorated by the inhibition of KRAS having a G12V mutation. ### Claim 107 (depends on 104) The compound of claim 104, wherein the medicament is useful in the prevention or treatment of a disease, disorder, or condition ameliorated by the inhibition of wild-type KRAS. ### Claim 108 (depends on 104, 105, 106, 107) The compound of any one of claims 104-107, wherein the medicament is useful in the prevention or treatment of a cancer. ### Claim 109 (depends on 108) The compound of claim 108, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer. ### Claim 110 (depends on 1, 102) A compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt) thereof, for use in the treatment of a disease, disorder, or condition. ### Claim 111 (depends on 110) The compound of claim 110, wherein the disease, disorder, or condition is a cancer. ### Claim 112 (depends on 111) The compound of claim 111, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer. ### Claim 113 (depends on 110, 111, 112) The compound of any one of claims 110-112, wherein the compound is used in the treatment of a disease, disorder, or condition in a subject in need thereof. ### Claim 114 (depends on 1, 102) A compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt) thereof, for use in the manufacture of a medicament. ### Claim 115 (depends on 114) The compound of claim 114, wherein the medicament is useful in the prevention or treatment of a disease, disorder, or condition ameliorated by the inhibition of KRAS having a G12D mutation. ### Claim 116 (depends on 114) The compound of claim 114, wherein the medicament is useful in the prevention or treatment of a disease, disorder, or condition ameliorated by the inhibition of KRAS having a G12V mutation. ### Claim 117 (depends on 114) The compound of claim 114, wherein the medicament is useful in the prevention or treatment of a disease, disorder, or condition ameliorated by the inhibition of wild-type KRAS. ### Claim 118 (depends on 114, 115, 116, 117) The compound of any one of claims 114-117, wherein the medicament is useful in the treatment of a cancer. ### Claim 119 (depends on 118) The compound of claim 118, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer. ### Claim 120 (depends on 1, 102) A method, comprising administering a therapeutically effective amount of a compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt) thereof, to a subject in need thereof. ### Claim 121 (depends on 120) The method of claim 120, wherein the subject has a disease, disorder, or condition ameliorated by the inhibition of KRAS having a G12D mutation. ### Claim 122 (depends on 120) The method of claim 120, wherein the subject has a disease, disorder, or condition ameliorated by the inhibition of KRAS having a G12V mutation. ### Claim 123 (depends on 120) The method of claim 120, wherein the subject has a disease, disorder, or condition ameliorated by the inhibition of wild-type KRAS. ### Claim 124 (depends on 120, 121, 122, 123) The method of any one of claims 120-123, wherein the subject has a cancer. ### Claim 125 (depends on 124) The method of claim 124, wherein the subject was previously diagnosed with the cancer. ### Claim 126 (depends on 124) The method of claim 124, wherein the subject has previously undergone a treatment regimen for the cancer. ### Claim 127 (depends on 124) The method of claim 124, wherein the subject has previously entered remission from the cancer. ### Claim 128 (depends on 124, 125, 126, 127) The method of any one of claims 124-127, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer. ### Claim 129 (depends on 120, 121, 122, 123, 124, 125, 126, 127, 128) The method of any one of claims 120-128, wherein the compound, or the salt thereof, is administered in combination with an additional therapeutic agent. ### Claim 130 (depends on 1, 102) The use of a compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt) thereof, for the manufacture of a medicament for the treatment of a cancer. ### Claim 131 (depends on 130) The use of claim 130, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer. ### Claim 132 (depends on 1, 102) A method, comprising contacting a KRAS protein with a compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 133 (depends on 132) The method of claim 132, wherein contacting the KRAS protein with the compound modulates KRAS. ### Claim 134 (depends on 132, 133) The method of claim 132 or 133, wherein the KRAS protein has a G12D mutation. ### Claim 135 (depends on 132, 133) The method of claim 132 or 133, wherein the KRAS protein has a G12V mutation. ### Claim 136 (depends on 132, 133) The method of claim 132 or 133, wherein the KRAS protein is wild-type KRAS. ### Claim 137 (depends on 132, 133, 134, 135, 136) The method of any one of claims 132-136, wherein the KRAS protein is in an active (GTP-bound) state. ### Claim 138 (depends on 132, 133, 134, 135, 136) The method of any one of claims 132-136, wherein the KRAS protein is in an inactive (GDP-bound) state. ### Claim 139 (depends on 132, 133, 134, 135, 136, 137, 138) The method of any one of claims 132-138, wherein the KRAS protein is located within a cell. ### Claim 140 (depends on 139) The method of claim 139, wherein the cell is located within a subject. ### Claim 141 (depends on 140) The method of claim 140, wherein the subject is a human. ### Claim 142 (depends on 140, 141) The method of claim 140 or 141, wherein the subject has a cancer. ### Claim 143 (depends on 142) The method of claim 142, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer. ### Claim 144 (depends on 1, 102) A method of inhibiting the function of a KRAS protein having a G12D mutation, comprising contacting the KRAS protein with a compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 145 (depends on 1, 102) A method of inhibiting the function of a KRAS protein having a G12V mutation, comprising contacting the KRAS protein with a compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 146 (depends on 1, 102) A method of inhibiting the function of a wild-type KRAS protein, comprising contacting the KRAS protein with a compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt) thereof. ### Claim 147 (depends on 144, 145, 146) The method of any one of claims 144-146, wherein the KRAS protein is in an active (GTP-bound) state. ### Claim 148 (depends on 144, 145, 146) The method of any one of claims 144-146, wherein the KRAS protein is in an inactive (GDP-bound) state. ### Claim 149 (depends on 144, 145, 146, 147, 148) The method of any one of claims 144-148, wherein the KRAS protein is located within a cell. ### Claim 150 (depends on 149) The method of claim 149, wherein the cell is located within a subject. ### Claim 151 (depends on 150) The method of claim 150, wherein the subject is a human. ### Claim 152 (depends on 150, 151) The method of claim 150 or 151, wherein the subject has a cancer. ### Claim 153 (depends on 152) The method of claim 152, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer. ### Claim 154 (depends on 1, 102) A compound of any one of claims 1-102, or a salt (e.g., pharmaceutically acceptable salt) thereof, wherein the compound: (i) has KD of ≤0.1 μM, or 0.1 μM