Heterocyclic compounds and uses thereof

Abstract

The present disclosure provides compounds and their pharmaceutically acceptable salts, as well as methods of using them.The compounds and methods have various usefulness as therapeutic agents, diagnostic agents, and research tools.In particular, the compositions and methods are useful for reducing the signaling output of oncogenic proteins.In one aspect, a pharmaceutical composition is provided that contains the compounds described herein, or their pharmaceutically acceptable salts or solvates, and pharmaceutically acceptable excipients.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 147,712 (filed February 9, 2021), U.S. Provisional Patent Application No. 63 / 191,910 (filed May 21, 2021), U.S. Provisional Patent Application No. 63 / 147,713 (filed February 9, 2021), U.S. Provisional Patent Application No. 63 / 166,224 (filed March 25, 2021), and U.S. Provisional Patent Application No. 63 / 176,866 (filed April 19, 2021), each of which is incorporated by reference in its entirety herein. [Background technology]

[0002] background Cancer (e.g., tumors, neoplasms, metastases) is the second leading cause of death worldwide, estimated to be responsible for approximately 10 million deaths annually. Many types of cancer are characterized by mutations in one or more proteins involved in various signaling pathways that lead to unregulated proliferation of cancerous cells. In some cases, approximately 25–30 percent (%) of tumors are known to harbor Rat sarcoma (Ras) mutations. In particular, mutations in the Kirsten Ras oncogene (K-Ras) gene are one of the most frequent Ras mutations detected in human cancers, including lung adenocarcinoma (LUAD) and pancreatic ductal adenocarcinoma (PDAC).

[0003] Kras is known to be a driver of oncogenesis, but to date, there are no clinically approved targeted therapies for Ras-mutated cancers. Ras proteins have long been considered "undruggable," in part due to their high affinity for their substrate, guanosine-5'-triphosphate (GTP), and / or their smooth surface without obvious targeting regions. Recently, the specific G12C Ras gene mutation has been identified as a druggable target. However, such therapeutic approaches remain limited because the G12C mutation in Ras has a low prevalence (e.g., approximately 3% in PDAC) compared with other known Ras mutations, including G12D, G12V, and G12S mutations. Summary of the Invention [Means for solving the problem]

[0004] overview In view of the above, there is still a great need for new therapeutic and diagnostic agent designs that can specifically target Ras mutants and / or Ras-related proteins to reduce Ras pathway signaling.Such compositions and methods can be particularly useful for treating various diseases, including but not limited to cancer and neoplastic conditions.The present disclosure addresses these needs and provides additional advantages that can be applied to the diagnosis, prognosis and treatment of a wide variety of diseases.

[0005] In one aspect, the compound of formula (I-1): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: [ka] is a 7- or 8-membered monocyclic heterocycloalkyl ring; X is C or N; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R4 are independently halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a or two R on the same carbon atom 4 together, one, two, or three R 20a C substituted as needed 3~6 form a cycloalkyl; or two R on adjacent carbon atoms 4 Together, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 forming a heteroaryl, wherein the C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0006] In one aspect, the compound of formula (I-2): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: [ka] is a 7- or 8-membered monocyclic heterocycloalkyl ring; X is C or N; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15, -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a or two R on the same carbon atom 4 together, one, two, or three R 20a C substituted as needed 3~6 form a cycloalkyl; or two R on adjacent carbon atoms 4 Together, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 forming a heteroaryl, wherein the C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0007] In embodiments, p is 2, 3, 4, or 5.

[0008] In embodiments, J is C(R 17 )

[0009] In embodiments, R 2 is halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b has been substituted as necessary.

[0010] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the formula (I'): [ka] having the structure where X 1 is selected from C, N, O, S, S(O), and S(O)2; X 1a is selected from N and C(H); and q is 1 or 2.

[0011] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the formula (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig): [ka] having a structure selected from where X 1 is selected from C, N, O, S, S(O), and S(O)2; and q is 1 or 2.

[0012] In one aspect, the compound of formula (I''-1): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: X is C or N; X 1 is C(R 4 )(R 6 ), N(R 12 ), N(R 6 ), O, S, S(O), and S(O)2; Y is C(R 7 ), S(O), S(O)2, C(O), or N; Y 1 is selected from CH2, N(H), O, S, S(O), and S(O)2; Y 2 is selected from CH2, N(H), O, S, S(O), and S(O)2; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; R 4 is halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 Ha-L 2 -R 5 and; R 7 is halogen, -CN, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 15 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b or R 7 can be one, two, or three R 20b C replaced with 1~6 is alkyl; R 8is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; and [ka] indicates a single or double bond such that all valences are satisfied.

[0013] In one aspect, the compound of formula (I''-2): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: X is C or N; X 1 is C(R 4 )(R 6 ), N(R 12 ), N(R 6 ), O, S, S(O), and S(O)2; Y is C(R 7 ), S(O), S(O)2, C(O), or N; Y 1 is selected from CH2, N(H), O, S, S(O), and S(O)2; Y 2 is selected from CH2, N(H), O, S, S(O), and S(O)2; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; R 4 is halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 Ha-L 2 -R 5 and; R 7 is halogen, -CN, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 15 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 2~6Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b or R 7 can be one, two, or three R 20b C replaced with 1~6 is alkyl; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; and [ka] indicates a single or double bond such that all valences are satisfied.

[0014] In an embodiment, Y 2 is a bond. In embodiments, Y 2 is CH2. In an embodiment, Y 1 is CH. In an embodiment, X is N; Y is C; U is N; and Z is C(R 8 ) and V is C(R 16 ) and J is C(R 17 ) and W is C(R 18 In an embodiment, X is N; Y is C(O); U is N; and Z is C(R8 ) and V is N; J is C(R 17 ) and W is C(R 18 In an embodiment, X is N; Y is N; U is C(O); and Z is C(R 8 ) and V is C(R 16 ) and J is C(R 17 ) and W is C(R 18 In an embodiment, X is N; Y is C; U is N; Z is N; V is N; J is C(R 17 ) and W is C(R 18 In an embodiment, X is N; Y is C; U is N; and Z is C(R 8 ) and V is C(R 16 ) and J is C(R 17 ) and W is N. In an embodiment, X is N; Y is C; U is N; Z is C(R 8 ) and V is N; J is C(R 17 ) and W is C(R 18 )

[0015] In one aspect, the compound of formula (II-1): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: [ka] is a 7- or 8-membered monocyclic heterocycloalkyl ring; X is C or N; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; W is N or C(R 18 ) and; Z 1 is N or C(R 6 ) and; Z2 is N(R 7 ) or C(R 8 )(R 9 ) and; Z 3 does not exist; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a or two R on the same carbon atom 4 together, one, two, or three R 20aC substituted as needed 3~6 form a cycloalkyl; or two R on adjacent carbon atoms 4 Together, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 forming a heteroaryl, wherein the C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 is hydrogen and C 1~6 alkyl; R 7 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -S(O)N(R 12 )(R 13 )-, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9Heteroaryl can be one, two, or three R 20c with substitution as necessary; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; R 9 is hydrogen and C 1~6 alkyl; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15, -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R20d , R 20e , R 20f , R 20g , R 20h , R 20i , and R 20j each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0016] In one aspect, the compound of formula (II-2): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: [ka] is a 7- or 8-membered monocyclic heterocycloalkyl ring; X is C or N; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; W is N or C(R 18 ) and; Z 1 is N or C(R 6 ) and; Z 2 is N(R 7 ) or C(R 8 )(R 9 ) and; Z 3 does not exist; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a or two R on the same carbon atom 4 together, one, two, or three R 20a C substituted as needed 3~6 form a cycloalkyl; or two R on adjacent carbon atoms 4 Together, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 forming a heteroaryl, wherein the C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 is hydrogen and C 1~6 alkyl; R 7 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -S(O)N(R 12 )(R 13 )-, where C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; R 9 is hydrogen and C 1~6 alkyl; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , and R 20j each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0017] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the formula (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIl), and (IIm): [ka] [ka] having a structure selected from: And here X 1 is selected from C, N, O, S, S(O), and S(O)2; X 1a is selected from N and C(H); and q is 1 or 2.

[0018] In one aspect, the compound of formula (IIIa-3), (IIIb-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (IIIh-3), or (IIIi-3): [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof; where: X is C or N; X 1 is C(R 4 )(R 6 ), N(R 4 ), N(R 6 ), O, S, S(O), and S(O)2; X 2 is X 3 , -CH2-, -X 3 CH2-, -CH2X 3 -, -CH2CH2-, -C(H)(R 4 )-, -C(H)(R 4 )-, -X 3 C(H)(R 4 )-, -C(H)(R 4 )X 3 -, -C(H)(R 4 )CH2-, -C(H)(R 4 )C(H)(R 4 )-, -C(R 4 )2-, -X 3 C(R 4 )2-, -C(R 4 )2X 3 -, -C(H)C(R4 )2-, -C(R 4 )C(H)-, and -C(R 4 )2C(R 4 )2-selected; X 3 is N(R 1 ), O, S, S(O), and S(O)2; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; Each R 1 are independently hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 )-, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15, -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 Ha-L 2 -R 5 and; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0019] In one aspect, the compound of formula (IIIa-4), (IIIb-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), or (IIIi-4): [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof; where: X is C or N; X 1 is C(R4 )(R 6 ), N(R 4 ), N(R 6 ), O, S, S(O), and S(O)2; X 2 is X 3 , -CH2-, -X 3 CH2-, -CH2X 3 -, -CH2CH2-, -C(H)(R 4 )-, -C(H)(R 4 )-, -X 3 C(H)(R 4 )-, -C(H)(R 4 )X 3 -, -C(H)(R 4 )CH2-, -C(H)(R 4 )C(H)(R 4 )-, -C(R 4 )2-, -X 3 C(R 4 )2-, -C(R 4 )2X 3 -, -C(H)C(R 4 )2-, -C(R 4 )C(H)-, and -C(R 4 )2C(R 4 )2-selected; X 3 is N(R 1 ), O, S, S(O), and S(O)2; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14)-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; Each R 1 are independently hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 Ha-L 2 -R 5 and; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14)C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0020] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIa-3) or (IIIa-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIb-3) or (IIIb-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIId-3) or (IIId-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIe-3) or (IIIe-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIf-3) or (IIIf-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIg-3) or (IIIg-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIh-3) or (IIIh-4). In an embodiment, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of formula (IIIi-3) or (IIIi-4). 2 is selected from -CH2- and -CH2CH2-.

[0021] In one aspect, the compound of formula (IVa-1), (IVb-1), or (IVc-1): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: X is C or N; X 4 is N(R1 ), O, S, S(O), S(O)2, -CH2-, -C(H)(R 4 )-, -C(R 4 )2-, and C(H)(-L 2 -R 5 ) are selected from; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; Each R 1 are independently hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 )-, C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 from heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; Each R 5are independently hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15, -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; s is 0, 1, 2, 3, or 4; t is 1, 2, 3, 4, or 5; where s+t≧2; and [ka] indicates a single or double bond such that all valences are satisfied.

[0022] In one aspect, the compound of formula (IVa-2), (IVb-2), or (IVc-2): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: X is C or N; X 4 is N(R 1 ), O, S, S(O), S(O)2, -CH2-, -C(H)(R 4 )-, -C(R 4 )2-, and C(H)(-L 2 -R5 ) are selected from; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; Each R 1 are independently hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 from heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15, -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; Each R 5 is independently an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20cwith substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; s is 0, 1, 2, 3, or 4; t is 1, 2, 3, 4, or 5; where s+t≧2; and [ka] indicates a single or double bond such that all valences are satisfied.

[0023] In an embodiment, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of formula (IVa-1) or (IVa-2). In an embodiment, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of formula (IVb-1) or (IVb-2). In an embodiment, s is 1 or 2. In an embodiment, t is 1 or 2. In an embodiment, X 4 is N(R 1 In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of formula (IVc-1) or (IVc-2):

[0024] In one aspect, the compound of formula (Va-1), (Vb-1), or (Vc-1): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: X is C or N; X 5 is N(R 1 ), O, S, S(O), and S(O)2; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; Z 1 is C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 1 is hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R12 )(R 13 )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 2 -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20awith substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14)S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; u is 0, 1, 2, 3, or 4; v is 0, 1, 2, 3, or 4; and [ka] indicates a single or double bond such that all valences are satisfied.

[0025] In one aspect, the compound of formula (Va-2), (Vb-2), or (Vc-2): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: X is C or N; X 5 is N(R 1 ), O, S, S(O), and S(O)2; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; Z 1 is C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 1 is hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 2 -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15, -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12, -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21, -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; u is 0, 1, 2, 3, or 4; v is 0, 1, 2, 3, or 4; and [ka] indicates a single or double bond such that all valences are satisfied.

[0026] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Va-1) or (Va-2). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Vb-1) or (Vb-2). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (Vc-1) or (Vc-2). In embodiments, u is 0 or 1. In embodiments, v is 0 or 1. In embodiments, X 5 is N(R 1 In an embodiment, R 1 is hydrogen. In embodiments, R 1 Ha-L 2 -R 5 is.

[0027] In one aspect, the compound of formula (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (IIIh-3), or (IIIi-3): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: X is C or N; X 1 is C(R 4 )(R 6 ), N(R 4 ), N(R 6 ), O, S, S(O), and S(O)2; X 2 is X 3 , -CH2-, -X 3 CH2-, -CH2X 3 -, -CH2CH2-, -C(H)(R 4 )-, -C(H)(R 4 )-, -X 3 C(H)(R 4 )-, -C(H)(R 4 )X 3 -, -C(H)(R 4 )CH2-, -C(H)(R 4 )C(H)(R 4 )-, -C(R 4 )2-, -X 3 C(R 4 )2-, -C(R 4 )2X 3 -, -C(H)C(R 4 )2-, -C(R 4 )C(H)-, and -C(R 4 )2C(R 4 )2-selected; X 3 is N(R 1 ), O, S, S(O), and S(O)2; X 4 is X 5 , -CH2-, -X 5 CH2-, -CH2X 5 -, -CH2CH2-, -C(H)(R 4 )-, -C(H)(R 4 )-, -X 5 C(H)(R 4)-, -C(H)(R 4 )X 5 -, -C(H)(R 4 )CH2-, -C(H)(R 4 )C(H)(R 4 )-, -C(R 4 )2-, -X 5 C(R 4 )2-, -C(R 4 )2X 5 -, -C(H)C(R 4 )2-, -C(R 4 )C(H)-, and -C(R 4 )2C(R 4 )2-selected; X 5 is N(R 1 ), S, S(O), and S(O)2; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; Each R 1 are independently hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12, -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 Ha-L 2 -R 5 and; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0028] In one aspect, the compound of formula (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), or (IIIi-4): [ka] or a pharmaceutically acceptable salt or solvate thereof; where: X is C or N; X 1 is C(R 4 )(R 6 ), N(R 4 ), N(R 6 ), O, S, S(O), and S(O)2; X 2 is X 3 , -CH2-, -X 3 CH2-, -CH2X 3 -, -CH2CH2-, -C(H)(R 4 )-, -C(H)(R 4 )-, -X 3 C(H)(R 4 )-, -C(H)(R 4 )X 3 -, -C(H)(R 4 )CH2-, -C(H)(R 4 )C(H)(R 4 )-, -C(R 4 )2-, -X 3 C(R 4 )2-, -C(R 4 )2X 3 -, -C(H)C(R 4 )2-, -C(R 4 )C(H)-, and -C(R 4 )2C(R 4 )2-selected; X 3 is N(R 1 ), O, S, S(O), and S(O)2; X 4 is X 5 , -CH2-, -X 5 CH2-, -CH2X 5 -, -CH2CH2-, -C(H)(R 4 )-, -C(H)(R 4 )-, -X 5 C(H)(R 4 )-, -C(H)(R 4 )X5 -, -C(H)(R 4 )CH2-, -C(H)(R 4 )C(H)(R 4 )-, -C(R 4 )2-, -X 5 C(R 4 )2-, -C(R 4 )2X 5 -, -C(H)C(R 4 )2-, -C(R 4 )C(H)-, and -C(R 4 )2C(R 4 )2-selected; X 5 is N(R 1 ), S, S(O), and S(O)2; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; Each R 1are independently hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 Ha-L 2 -R 5 and; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0029] In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIa-3) or (IIIa-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIb-3) or (IIIb-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIId-3) or (IIId-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIe-3) or (IIIe-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIf-3) or (IIIf-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIg-3) or (IIIg-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of Formula (IIIh-3) or (IIIh-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of formula (IIIi-3) or (IIIi-4). In embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, has the structure of formula (IIIc-3) or (IIIc-4).

[0030] In an embodiment, X 4 is -NH-. In an embodiment, Y is C. In an embodiment, Y is N. In an embodiment, Y is C(O). In an embodiment, X is C. In an embodiment, X is N. In an embodiment, U is C. In an embodiment, U is N. In an embodiment, U is C(O). In an embodiment, Z is C(R 8 In an embodiment, R 8 is hydrogen. In an embodiment, Z is N. In an embodiment, V is C(R 16 In an embodiment, V is C(H). In an embodiment, V is N. In an embodiment, J is C(R 17 In an embodiment, W is C(R 18In an embodiment, W is C(H). In an embodiment, W is N. In an embodiment, R 2 is C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , and -N(R 12 )(R 13 ), where C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b In an embodiment, R 2 -OR 12 , -SR 12 , and C 1~6 alkyl, wherein C 1~6 Alkyl can be one, two, or three R 20b In an embodiment, R 2 HA-OR 12 In an embodiment, R 12 is C 1~6 Alkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d In an embodiment, R 12 can be one, two, or three R20d C substituted as needed 1~6 In embodiments, R 12 can be one, two, or three R 20d C substituted as needed 2~9 In embodiments, R 12 can be one, two, or three R 20d optionally substituted with -CH2-C 2~9 In embodiments, each R 20d are independently halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9Heteroaryl is substituted with halogen, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -S(O)R 25 , and -S(O)N(R 22 )(R 23 ) optionally substituted with 1, 2, or 3 groups independently selected from 20d are independently halogen, C 1~6 Alkyl, and -OR 21 is selected from, where C 1~6 Alkyl is halogen, oxo, C 1~6 Alkyl, -OR 21 , and -N(R 22 )(R 23 ) optionally substituted with 1, 2, or 3 groups independently selected from

[0031] In embodiments, R 2 teeth, [ka] [ka] is selected from.

[0032] In an embodiment, L 1 is a bond. In embodiments, L 1 is O. In an embodiment, R 19 can be one, two, or three R 20i C substituted as needed 1~9 In an embodiment, R 19 can be one, two, or three R 20i C substituted as needed6~10 In embodiments, L is aryl. 2 is selected from a bond, C1-C6 alkyl, and -C(O)-. 2 is a bond. In embodiments, L 2 is C1-C6 alkyl. In an embodiment, R 5 is hydrogen. In embodiments, R 5 is a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein. 5 is an electrophilic moiety capable of forming a covalent bond with residue at position 12 of the KRAS protein, for example, the cysteine ​​residue at position 12 of the KRAS protein. 5 teeth, [ka] and; and m, if present, is 0, 1, 2, or 3.

[0033] Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (I Id), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (II In some embodiments of the present compounds of formula Ih-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , or -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a and optionally substituted with the following: Formula (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (II In some embodiments of the present compounds of formula Ih-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 heteroaryl, -OH, -SH, -NH2, -C(O)OH, -OC(O)NH2, -NHC(O)NH2, -NHC(O)OH, -NHS(O)2H, -C(O)H, -S(O)H, -OC(O)H, -C(O)NH2, -C(O)C(O)NH2, -NHC(O)H, -S(O)2H, -S(O)2NH2-, S(=O)(=NH)NH2, -CH2C(O)NH2, -CH2NHC(O)H, -CH2S(O)2H, or -CH2S(O)2NH2, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a and optionally substituted with the following: Formula (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (II In some embodiments of the present compounds of formula Ih-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5are independently halogen. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (I In further embodiments of the present compounds of formula IIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently -CN. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), In an embodiment of the present compound (IIIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5are independently —OH. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (II In some embodiments of the present compounds of formula Ih-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently -NH2. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (I In further embodiments of the present compounds of formula IIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5are independently —C(O)OH. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (IIIh-3), (IIIi-3), (IIIa-4) In select embodiments of the present compounds of formula (I), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5are independently —OC(O)NH2. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), In an embodiment of the present compound (IIIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently —NHC(O)NH2. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), In an embodiment of the present compound (IIIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5are independently —NHC(O)OH. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (II In some embodiments of the present compounds of formula Ih-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently -NHS(O)2H. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), In an embodiment of the present compound (IIIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5are independently —C(O)NH2. Formulas (I-1), (I'), (I''-1), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), ( In some embodiments of the present compounds of formula IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (IIIh-3), (IIIi-3), (IVa-1), (IVb-1), (IVc-1), (Va-1), (Vb-1), or (Vc-1), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independent of each R 5 are independently hydrogen. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), In an embodiment of the present compound (IIIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5is independently oxo. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (I In further embodiments of the present compounds of formula IIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently 1, 2, or 3 R 20a C substituted as needed 1~6It is an alkyl. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (I Id), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (II In select embodiments of the present compounds of formula Ih-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently 1, 2, or 3 R 20a C substituted as needed 3~6The formula (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), In an embodiment of the present compound (IIIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently 1, 2, or 3 R 20a C substituted as needed 2~9Heterocycloalkyl. Formula (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3) ), (IIIg-3), (IIIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt thereof. In some embodiments of the compound, each R 5 are independently 1, 2, or 3 R 20a C substituted as needed 6~10It is an aryl. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (I Id), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (I In further embodiments of the present compounds of formula IIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independent of each R 5 are independently 1, 2, or 3 R 20a C substituted as needed 1~9Heteroaryl. Formula (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (II In select embodiments of the present compounds of formula Ih-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently -OR 12 It is. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), ( IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), In an embodiment of the present compound (IIIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5are independently -N(R 12 )(R 13 ). Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (I Id), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (II In select embodiments of the present compounds of formula Ih-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independent and N(R 14 )S(O)2R 15It is. Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (I Id), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (II In select embodiments of the present compounds of formula Ih-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (IIIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), or (Vc-2), or a pharmaceutically acceptable salt or solvate thereof, each R 5 are independently -S(O)R 15 In embodiments, each R 20a are independently halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; each R 23 are independently H and C 1~6 alkyl; each R 24 are independently H and C 1~6 alkyl; each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 In an embodiment, each R 20a are independently halogen, -CN, -OR 21 , and -N(R 22 )(R 23 In embodiments, each R 20a is independently selected from halogen, —CN, —OH, and —NH. In an embodiment, each R20a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is halogen, oxo, -CN , C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 In an embodiment, each R 20a independently, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 In an embodiment, R is selected from heteroaryl. 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, and -CH2-C 2~9 heterocycloalkyl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, and -CH2-C 2~9 Heterocycloalkyl can have one, two, or three R 20d In an embodiment, R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 In an embodiment, R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 In an embodiment, R15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, and C 2~9 heterocycloalkyl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, and C 2~9 Heterocycloalkyl can have one, two, or three R 20f has been substituted as necessary.

[0034] In one aspect, there is provided a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0035] In one aspect, a method for treating cancer in a subject in need thereof is provided, comprising administering to the subject a therapeutically effective amount of the compound disclosed herein, or its pharmaceutically acceptable salt or solvate.In an embodiment, the cancer is a solid tumor.In an embodiment, the cancer is a solid tumor or a blood cancer.

[0036] In one aspect, a method for modulating the activity of a Ras protein is provided, comprising contacting the Ras protein with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.

[0037] In embodiments, modulating comprises inhibiting Ras protein activity. In embodiments, the Ras protein is a K-Ras protein. In embodiments, the Ras protein is a G12D, G12S, G12C, G13D, G13C, or G12V mutant K-Ras. In embodiments, the method includes administering an additional agent or treatment. In embodiments, the additional agent or treatment is selected from the group consisting of a chemotherapeutic agent, a radioactive agent, and an immunomodulatory agent. In embodiments, modulating occurs in vitro or in vivo.

[0038] In one aspect, a method for inhibiting cell proliferation is provided, comprising administering an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, to cells expressing Ras protein, thereby inhibiting the proliferation of these cells.In an embodiment, this method comprises administering an additional agent to the cells.In an embodiment, this additional agent is a chemotherapeutic agent, a radioactive agent, or an immunomodulatory agent.

[0039] In one aspect, provided is a Ras protein regulated by the compound disclosed herein.In yet another aspect, provided is a Ras protein bound by the compound disclosed herein, or its pharmaceutically acceptable salt or solvate, wherein the activity of the Ras protein is reduced compared to the Ras protein that is not bound by the compound.

[0040] In one aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: [ka] Provide; where: [ka] is a 7- or 8-membered monocyclic heterocycloalkyl ring; X is C or N; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15, and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a or two R on the same carbon atom 4 together, one, two, or three R 20a C substituted as needed 3~6 form a cycloalkyl; or two R on adjacent carbon atoms 4 Together, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 forming a heteroaryl, wherein the C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14)C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0041] In some embodiments, the structure of formula (I'), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (I) having the formula: where X 1 is selected from C, N, O, S, S(O), and S(O)2; X 1a is selected from N and C(H); and q is 1 or 2.

[0042] In some embodiments, the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (I) having the formula: where X 1 is selected from C, N, O, S, S(O), and S(O)2; and q is 1 or 2.

[0043] In some embodiments, the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (I) having the formula:

[0044] In some embodiments, the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (I) having the formula:

[0045] In some embodiments, the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (I) having the formula:

[0046] In some embodiments, the structure of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (I) having the formula:

[0047] In some embodiments, the structure of formula (If), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (I) having the formula:

[0048] In some embodiments, the structure of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (I) having the formula:

[0049] In another aspect, the present disclosure provides a compound of formula (I″), or a pharmaceutically acceptable salt or solvate thereof: [ka] Provide; where: X is C or N; X 1 is C(R 4 )(R 6 ), N(R 12 ), N(R 6 ), O, S, S(O), and S(O)2; Y is C(R 7 ), S(O), S(O)2, C(O), or N; Y 1 is selected from CH2, N(H), O, S, S(O), and S(O)2; Y 2 is selected from CH2, N(H), O, S, S(O), and S(O)2; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15, and -S(O)N(R 12 )(R 13 ) are selected from; R 4 is halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 Ha-L 2 -R 5 and; R 7 is halogen, -CN, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 15 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b or R 7 can be one, two, or three R 20b C replaced with 1~6 is alkyl; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; and [ka] indicates a single or double bond such that all valences are satisfied.

[0050] In some embodiments, Y 2is a bond. 2 is CH. In some embodiments, Y 1 is CH. In some embodiments, X 1 is N(H), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, X 1 is N(R 4 In some embodiments, X is a compound of formula (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt or solvate thereof. 1 is N(-L 2 -R 5 In some embodiments, X is a compound of formula (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt or solvate thereof. 1 is O, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, X 1 is S, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, X 1 is S(O)2. In some embodiments, X is a compound of formula (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt or solvate thereof. 1is CH2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, X 1 is C(H)(R 4 In some embodiments, X is a compound of formula (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt or solvate thereof. 1 is C(R 4 In some embodiments, X is a compound of formula (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein X is 1 is C(H)(-L 2 -R 5 or a pharmaceutically acceptable salt or solvate thereof.

[0051] In some embodiments, the compound is of Formula (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the compound is of Formula (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0052] In some embodiments, V is C(R 16In some embodiments, V is C(H), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, V is N, or a pharmaceutically acceptable salt or solvate thereof.

[0053] In some embodiments, W is C(R 18 In some embodiments, W is C(H), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, W is N, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, W is N, or a pharmaceutically acceptable salt or solvate thereof.

[0054] In some embodiments, Z is C(R 8In some embodiments, the compound is of Formula (I), (I'), (I"), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(H). In some embodiments, the compound is of Formula (I), (I'), (I"), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.

[0055] In another aspect, the present disclosure provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof: [ka] Provide; where: [ka] is a 7- or 8-membered monocyclic heterocycloalkyl ring; X is C or N; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; W is N or C(R 18 ) and; Z 1 is N or C(R 6 ) and; Z 2 is N(R 7 ) or C(R 8 )(R 9 ) and; Z 3 does not exist or is N(R 26 ), or C(R 27 )(R 28 ) and; L 1 and L2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a or two R on the same carbon atom 4 together, one, two, or three R 20a C substituted as needed 3~6 form a cycloalkyl; or two R on adjacent carbon atoms 4 Together, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C1~9 forming a heteroaryl, wherein the C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, or C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 is hydrogen and C 1~6 alkyl; R 7 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -S(O)N(R 12 )(R 13 )-, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; R9 is hydrogen and C 1~6 alkyl; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12)(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , R 20i , and R 20j each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; R 26 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -S(O)N(R 12 )(R 13 )-, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20j with substitution as necessary; R 27 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20j with substitution as necessary; R 28is hydrogen and C 1~6 alkyl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0056] In some embodiments, the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula:

[0057] In some embodiments, the structure of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula:

[0058] In some embodiments, the structure of formula (IIc'), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula: where X 1 is selected from C, N, O, S, S(O), and S(O)2; X 1a is selected from N and C(H); and q is 1 or 2.

[0059] In some embodiments, the structure of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula: where X 1 is selected from C, N, O, S, S(O), and S(O)2; and q is 1 or 2.

[0060] In some embodiments, the structure of formula (IId'), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula: where X 1 is selected from C, N, O, S, S(O), and S(O)2; X 1a is selected from N and C(H); and q is 1 or 2.

[0061] In some embodiments, the structure of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula: where X 1 is selected from C, N, O, S, S(O), and S(O)2; and q is 1 or 2.

[0062] In some embodiments, X 1 is N(H), or a pharmaceutically acceptable salt or solvate thereof. 1 is N(R 4 In some embodiments, X is a compound of formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof. 1 is N(-L 2 -R 5In some embodiments, X is a compound of formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof. 1 is O, or a pharmaceutically acceptable salt or solvate thereof. 1 is S, or a pharmaceutically acceptable salt or solvate thereof. 1 is S(O)2, or a pharmaceutically acceptable salt or solvate thereof. 1 is CH2, or a pharmaceutically acceptable salt or solvate thereof. 1 is C(H)(R 4 In some embodiments, X is a compound of formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof. 1 is C(R 4 In some embodiments, X is a compound of formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is C(H)(-L 2 -R 5 or a pharmaceutically acceptable salt or solvate thereof.

[0063] In some embodiments, the compound is of Formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments, the compound is of Formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.

[0064] In some embodiments, Z 3 is a compound of formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein

[0065] In some embodiments, Z 2 is C(R 8 )(R 9 or a pharmaceutically acceptable salt or solvate thereof.

[0066] In some embodiments, R 9 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

[0067] In some embodiments, the compound is of Formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C. In some embodiments, the compound is of Formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0068] In some embodiments, the compound is of Formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C. In some embodiments, the compound is of Formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N. In some embodiments, the compound is of Formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C(O).

[0069] In some embodiments, the compound is of Formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein U is C. In some embodiments, the compound is of Formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein U is N. In some embodiments, the compound is of Formula (II), (IIa), (IIb), (IIc'), (IIc), (IId'), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein U is C(O).

[0070] In some embodiments, the structure of Formula (IIe), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula:

[0071] In some embodiments, the structure of formula (IIf), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula:

[0072] In some embodiments, the structure of Formula (IIg), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula:

[0073] In some embodiments, the structure of Formula (IIh), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula:

[0074] In some embodiments, the structure of Formula (IIi), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula:

[0075] In some embodiments, the structure of Formula (IIj), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula:

[0076] In some embodiments, the structure of Formula (IIk), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula:

[0077] In some embodiments, the structure of Formula (IIm), or a pharmaceutically acceptable salt or solvate thereof: [ka] is a compound of formula (II) having the formula:

[0078] In another aspect, the present disclosure provides a compound of formula (IIIa)-(IIIi), or a pharmaceutically acceptable salt or solvate thereof: [ka] [ka] Provide; where: X is C or N; X 1 is C(R 4 )(R 6 ), N(R 4 ), N(R 6 ), O, S, S(O), and S(O)2; X 2 is X 3 , -CH2-, -X 3 CH2-, -CH2X 3 -, -CH2CH2-, -C(H)(R 4 )-, -C(H)(R 4 )-, -X 3 C(H)(R 4 )-, -C(H)(R 4 )X 3 -, -C(H)(R 4 )CH2-, -C(H)(R 4 )C(H)(R 4 )-, -C(R 4 )2-, -X 3 C(R 4 )2-, -C(R 4 )2X 3 -, -C(H)C(R 4 )2-, -C(R 4 )C(H)-, and -C(R 4 )2C(R 4 )2-selected; X 3 is N(R 1 ), O, S, S(O), and S(O)2; X4 is X 5 , -CH2-, -X 5 CH2-, -CH2X 5 -, -CH2CH2-, -C(H)(R 4 )-, -C(H)(R 4 )-, -X 5 C(H)(R 4 )-, -C(H)(R 4 )X 5 -, -C(H)(R 4 )CH2-, -C(H)(R 4 )C(H)(R 4 )-, -C(R 4 )2-, -X 5 C(R 4 )2-, -C(R 4 )2X 5 -, -C(H)C(R 4 )2-, -C(R 4 )C(H)-, and -C(R 4 )2C(R 4 )2-selected; X 5 is N(R 1 ), S, S(O), and S(O)2; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15, and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15, -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 Ha-L 2 -R 5 and; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0079] In some embodiments, the structure of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0080] In some embodiments, the structure of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0081] In some embodiments, the structure of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0082] In some embodiments, the structure of Formula (IIIe), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0083] In some embodiments, the structure of formula (IIIf), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0084] In some embodiments, the structure of Formula (IIIg), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0085] In some embodiments, the structure of Formula (IIIh), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0086] In some embodiments, the structure of formula (IIIi), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0087] In some embodiments, the structure of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0088] In some embodiments, X 4 is selected from —CH 2 — and —CH 2 CH 2 —, or a pharmaceutically acceptable salt or solvate thereof.

[0089] In some embodiments, X 2is selected from —CH— and —CHCH—, or a pharmaceutically acceptable salt or solvate thereof.

[0090] In another aspect, the present disclosure provides a compound of formula (IIIa)-(IIIi), or a pharmaceutically acceptable salt or solvate thereof: [ka] [ka] Provide; where: X is C or N; X 1 is C(R 4 )(R 6 ), N(R 4 ), N(R 6 ), O, S, S(O), and S(O)2; X 2 is X 3 , -CH2-, -X 3 CH2-, -CH2X 3 -, -CH2CH2-, -C(H)(R 4 )-, -C(H)(R 4 )-, -X 3 C(H)(R 4 )-, -C(H)(R 4 )X 3 -, -C(H)(R 4 )CH2-, -C(H)(R 4 )C(H)(R 4 )-, -C(R 4 )2-, -X 3 C(R 4 )2-, -C(R 4 )2X 3 -, -C(H)C(R 4 )2-, -C(R 4 )C(H)-, and -C(R 4 )2C(R 4 )2-selected; X3 is N(R 1 ), O, S, S(O), and S(O)2; X 4 is X 5 , -CH2-, -X 5 CH2-, -CH2X 5 -, -CH2CH2-, -C(H)(R 4 )-, -C(H)(R 4 )-, -X 5 C(H)(R 4 )-, -C(H)(R 4 )X 5 -, -C(H)(R 4 )CH2-, -C(H)(R 4 )C(H)(R 4 )-, -C(R 4 )2-, -X 5 C(R 4 )2-, -C(R 4 )2X 5 -, -C(H)C(R 4 )2-, -C(R 4 )C(H)-, and -C(R 4 )2C(R 4 )2-selected; X 5 is N(R 1 ), S, S(O), and S(O)2; Each R 1 are independently hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 2 is hydrogen, halogen, -CN, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 Ha-L 2 -R 5 and; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14)S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and [ka] indicates a single or double bond such that all valences are satisfied.

[0091] In some embodiments, the structure of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof: [ka] A compound having the formula (IIIa), wherein J, U, V, W, X, Y, Z, X 1 , X 2 , L 2 , R 2 , R 3 ,n,R 4 , p, and R 5 is as described herein.

[0092] In some embodiments, the structure of Formula (IIIb), or a pharmaceutically acceptable salt or solvate thereof: [ka] A compound having the formula (IIIb), wherein J, U, V, W, X, Y, Z, X 1 , X 2 , L 2 , R 2 , R 3 ,n,R 4 , p, and R 5 is as described herein.

[0093] In some embodiments, the structure of Formula (IIId), or a pharmaceutically acceptable salt or solvate thereof: [ka] A compound having the formula (IIId), wherein J, U, V, W, X, Y, Z, X 1 , X 2 , L 2 , R 2 , R 3 ,n,R 4, p, and R 5 is as described herein.

[0094] In some embodiments, the structure of Formula (IIIe), or a pharmaceutically acceptable salt or solvate thereof: [ka] A compound having the formula (IIIe), wherein J, U, V, W, X, Y, Z, X 1 , X 2 , L 2 , R 2 , R 3 ,n,R 4 , p, and R 5 is as described herein.

[0095] In some embodiments, the structure of formula (IIIf), or a pharmaceutically acceptable salt or solvate thereof: [ka] A compound having the formula (IIIf), wherein J, U, V, W, X, Y, Z, X 1 , X 2 , L 2 , R 2 , R 3 ,n,R 4 , p, and R 5 is as described herein.

[0096] In some embodiments, the structure of Formula (IIIg), or a pharmaceutically acceptable salt or solvate thereof: [ka] A compound having the formula (IIIg), wherein J, U, V, W, X, Y, Z, X 1 , X 2 , L 2 , R 2 , R 3 ,n,R 4 , p, and R 5is as described herein.

[0097] In some embodiments, the structure of Formula (IIIh), or a pharmaceutically acceptable salt or solvate thereof: [ka] A compound having the formula (IIIh), wherein J, U, V, W, X, Y, Z, X 1 , X 2 , L 2 , R 2 , R 3 ,n,R 4 , p, and R 5 is as described herein.

[0098] In some embodiments, the structure of formula (IIIi), or a pharmaceutically acceptable salt or solvate thereof: [ka] A compound having the formula (IIIi), wherein J, U, V, W, X, Y, Z, X 1 , X 2 , L 2 , R 2 , R 3 ,n,R 4 , p, and R 5 is as described herein.

[0099] In some embodiments, the structure of Formula (IIIc), or a pharmaceutically acceptable salt or solvate thereof: [ka] A compound having the formula (IIIc), wherein J, U, V, W, X, Y, Z, X 1 , X 4 , L 2 , R 2 , R 3 ,n,R 4 , p, and R 5 is as described herein.

[0100] In another aspect, the present disclosure provides a compound of formula (IVa), (IVb), or (IVc), or a pharmaceutically acceptable salt or solvate thereof: [ka] Provide; where: X is C or N; X 4 is N(R 1 ), O, S, S(O), S(O)2, -CH2-, -C(H)(R 4 )-, -C(R 4 )2-, and C(H)(-L 2 -R 5 ) are selected from; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; Each R 1 are independently hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 from heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12, -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 8 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14)C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12)(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22, and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; s is 0, 1, 2, 3, or 4; t is 1, 2, 3, 4, or 5; where s+t≧2; and [ka] indicates a single or double bond such that all valences are satisfied.

[0101] In some embodiments, the structure of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0102] In some embodiments, the structure of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0103] In some embodiments, the compound is of Formula (IVa) or (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein s is 1.

[0104] In some embodiments, t is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

[0105] In some embodiments, X 4 is N(R 1 or a pharmaceutically acceptable salt or solvate thereof.

[0106] In some embodiments, the structure of Formula (IVc), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0107] In another aspect, the present disclosure provides a compound of formula (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof: [ka] Provide; where: X is C or N; X 5 is N(R 1), O, S, S(O), and S(O)2; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; Z 1 is C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 1 is hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 )-, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 2 -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20b with substitution as necessary; Each R 3 are independently hydrogen, halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -OR 12 , -N(R 12 )(R 13 ), -CN, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from; Each R 4 are independently hydrogen, halogen, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20a with substitution as necessary; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 8is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C1~9 Heteroaryl can be one, two, or three R 20c with substitution as necessary; Each R 12 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d with substitution as necessary; Each R 13 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; or R 12 and R 13 means that together with the nitrogen to which they are attached, they form one, two, or three R 20e C substituted as needed 2~9 forming a heterocycloalkyl ring; Each R 14 are independently hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; Each R 15 are independently selected C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20f with substitution as necessary; R 16 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20g with substitution as necessary; R 17 Ha-L 1 -R 19 and; R 18 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ), where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20h with substitution as necessary; R 19 is C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20i with substitution as necessary; R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i each independently represents a halogen, —CN, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, -CH2-C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl is a group containing halogen, oxo, -CN, C 1~6 Alkyl, C1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 optionally substituted with 1, 2, or 3 groups independently selected from Each R 21 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; Each R 22 are independently H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9heteroaryl; Each R 23 are independently H and C 1~6 alkyl; Each R 24 are independently H and C 1~6 alkyl; Each R 25 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; u is 0, 1, 2, 3, or 4; v is 0, 1, 2, 3, or 4; and [ka] indicates a single or double bond such that all valences are satisfied.

[0108] In some embodiments, the structure of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0109] In some embodiments, the structure of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0110] In some embodiments, the structure of Formula (Vc), or a pharmaceutically acceptable salt or solvate thereof: [ka] It is a compound having the formula:

[0111] In some embodiments, u is 0 or 1, or a pharmaceutically acceptable salt or solvate thereof.

[0112] In some embodiments, v is 0 or 1, or a pharmaceutically acceptable salt or solvate thereof.

[0113] In some embodiments, X 5 is N(R 1 or a pharmaceutically acceptable salt or solvate thereof.

[0114] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 Ga-L 2 -R 5 In some embodiments, R is a compound of formula (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein 1 is hydrogen. In some embodiments, R is a compound of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof. 1 Ga-L 2 -R 5In some embodiments, X is a compound of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof. 4 is —NH—; or a pharmaceutically acceptable salt or solvate thereof.

[0115] In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C. In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N. In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C(O).

[0116] In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C. In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0117] In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein U is C. In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein U is N. In some embodiments, U is C(O), a compound of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof.

[0118] In some embodiments, Z is C(R 8or a pharmaceutically acceptable salt or solvate thereof.

[0119] In some embodiments, R 8 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

[0120] In some embodiments, Z is N, or a pharmaceutically acceptable salt or solvate thereof.

[0121] In some embodiments, V is C(R 16In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein C(H). In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, V is N, or a pharmaceutically acceptable salt or solvate thereof.

[0122] In some embodiments, J is C(R 17 or a pharmaceutically acceptable salt or solvate thereof.

[0123] In some embodiments, W is C(R 18In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein W is C(H). In some embodiments, the compound is of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, W is N, or a pharmaceutically acceptable salt or solvate thereof.

[0124] In some embodiments, R 2 But hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , and -N(R 12 )(R 13 ), where C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20bIn some embodiments, R is a compound of Formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 2 But, -OR 12 , -SR 12 , and C 1~6 alkyl, wherein C 1~6 Alkyl can be one, two, or three R 20b In some embodiments, R is a compound of Formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 2 -OR 12or a pharmaceutically acceptable salt or solvate thereof.

[0125] In some embodiments, R 12 But C 1~6 Alkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 heteroaryl, wherein C 1~6 Alkyl, C 2~9 Heterocycloalkyl, -CH2-C 2~9 Heterocycloalkyl, C 6~10 Aryl, -CH2-C 6~10 Aryl, and C 1~9 Heteroaryl can be one, two, or three R 20d In some embodiments, R is a compound of Formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, optionally substituted with 12 but one, two, or three R20d C substituted as needed 1~6 In some embodiments, R is a compound of Formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R is alkyl. 12 but one, two, or three R 20d C substituted as needed 2~9 In some embodiments, R is a compound of Formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R is a heterocycloalkyl. 12 but one, two, or three R 20d optionally substituted with -CH2-C 2~9heterocycloalkyl; or a compound of Formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof.

[0126] In some embodiments, each R 20d are independently halogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 is selected from, where C1~6 Alkyl, C 3~6 Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl is substituted with halogen, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -S(O)R 25 , and -S(O)N(R 22 )(R 23 and R is a substituted or unsubstituted aryl group; ... 20d are independently halogen, C 1~6 Alkyl, and -OR 21 is selected from, where C 1~6 Alkyl is halogen, oxo, C 1~6 Alkyl, -OR 21 , and -N(R 22 )(R 23or a pharmaceutically acceptable salt or solvate thereof.

[0127] In some embodiments, R 2 but, [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0128] In some embodiments, L 1is a bond. In some embodiments, L is a compound of Formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, L is a bond. 1 is O; or a pharmaceutically acceptable salt or solvate thereof.

[0129] In some embodiments, R 19 but one, two, or three R 20i C substituted as needed 1~9In some embodiments, R is a compound of Formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R is a compound of Formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (I ... or a pharmaceutically acceptable salt or solvate thereof. 19 but one, two, or three R 20i C substituted as needed 6~10 and R is aryl; or a pharmaceutically acceptable salt or solvate thereof.

[0130] In some embodiments, L 2is selected from a bond, C1-C6 alkyl, and —C(O)—, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, L 2 is a bond. In some embodiments, L is a compound of Formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, L is a bond. 2 is C1-C6 alkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0131] In some embodiments, R 5is hydrogen; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R 5 is a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of a KRAS protein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R 5 but, [ka] and; and m, if present, is 0, 1, 2, or 3; A compound of formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof.

[0132] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0133] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, is provided. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological cancer.

[0134] In another aspect, the present disclosure provides a method for modulating the activity of a Ras protein, comprising administering a Ras protein to an effective amount of a compound of formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (I

[0014] Provided are methods for modulating the activity of a Ras protein, comprising contacting a subject with a compound of formula Ik), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of a Ras protein. In some embodiments, the modulation comprises inhibiting Ras protein activity. In some embodiments, the Ras protein is a K-Ras protein. In some embodiments, the Ras protein is a G12D or G12V mutant K-Ras. In some embodiments, the method comprises administering an additional agent or treatment. In some embodiments, the additional agent or treatment is selected from the group consisting of a chemotherapeutic agent, a radioactive agent, and an immunomodulatory agent. In some embodiments, the modulation occurs in vitro or in vivo.

[0135] In another aspect, the present disclosure provides a method for inhibiting cell proliferation, the method comprising administering to a cell expressing a Ras protein an effective amount of a compound of formula (I), (I'), (I''), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc'), (IIc), (IId'), (IId), (IIe), (IIf), (IIg), (IIh), (IIi The method includes administering a compound of Formula (II), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, to the cells, thereby inhibiting proliferation of the cells. In some embodiments, the method includes administering an additional agent to the cells. In some embodiments, the additional agent is a chemotherapeutic agent, a radioactive agent, or an immunomodulatory agent.

[0136] In another aspect, the present disclosure provides a compound of formula (I), (I′), (I″), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II), (IIa), (IIb), (IIc′), (IIc), (IId′), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa), (IIIb), (IIIc), (IIId), Provided is a Ras protein bound to a compound of formula (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IVa), (IVb), (IVc), (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt or solvate thereof, wherein the activity of the Ras protein is reduced compared to a Ras protein not bound to the compound.

[0137] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0138] Detailed Description The practice of some embodiments disclosed herein will employ, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics, and recombinant DNA, within the skill of one of ordinary skill in the art. See, e.g., Sambrook and Green, Molecular Cloning: A Laboratory Manual, 4th Edition (2012); the series Current Protocols in Molecular Biology (eds. F.M.A.usubel et al.); the series Methods in Enzymology (Academic Press, Inc.), PCR 2: A Practical Approach (eds. M.J. MacPherson, B.D. Hames, and G.R. Taylor (1995)); Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual; and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition (ed. R.I. Freshney (2010)).

[0139] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter belongs. In the event that there are multiple definitions for terms in this specification, the definitions in this section shall prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned herein are incorporated by reference. When referring to a URL or other such identifier or address, it is understood that such identifiers may change and specific information on the Internet may come and go, but that equivalent information can be found by searching the Internet. Reference thereto evidences the availability and public dissemination of such information.

[0140] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed subject matter. In this application, the use of the singular includes the plural unless expressly stated otherwise. It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including" and other forms such as "include," "includes," and "included" is not limiting.

[0141] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0142] Definitions of standard chemical terms may be found in reference works including, but not limited to, Carey and Sundberg, Advanced Organic Chemistry, 4th Edition, Volumes A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used.

[0143] Unless specific definitions are provided, the nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry described herein are art-recognized. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and patient treatment. Standard techniques (e.g., electroporation, lipofection) can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation. Reactions and purification techniques can be performed, for example, using kits according to manufacturer specifications, or as commonly accomplished in the art, or as described herein. The foregoing techniques and procedures can generally be performed in a conventional manner and as described in the various general and more specific references cited and discussed throughout this specification.

[0144] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0145] As used herein, C1-C x is C1~C2, C1~C3...C1~C x Includes C1~C xrefers to the number of carbon atoms that make up the moiety it designates (excluding optional substituents).

[0146] An "alkyl" group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation. In some embodiments, an "alkyl" group can have 1 to 6 carbon atoms. (Whenever it appears herein, a numerical range such as "1 to 6" refers to each integer within the given range; for example, "1 to 6 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on up to and including 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" without a specified numerical range.) The alkyl group of the compounds described herein may be designated as "C1-C6 alkyl" or similar designation. By way of example only, "C1-C6 alkyl" indicates that there are 1 to 6 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and hexyl. The alkyl group can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (ie, an alkylene group).

[0147] "Alkoxy" refers to an "-O-alkyl" group, where alkyl is as defined herein.

[0148] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms and containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2, and -C(CH3)=CHCH3. In some embodiments, an alkenyl group can have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, alkenyl groups can be monoradicals or diradicals (i.e., alkenylene groups).

[0149] The term "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms and containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -C≡CCH2CH2CH3. In some embodiments, alkynyl groups can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, alkynyl groups can be monoradicals or diradicals (i.e., alkynylene groups).

[0150] "Amino" refers to the group -NH2.

[0151] The term "alkylamine" or "alkylamino" refers to an -N(alkyl) group, where alkyl is as defined herein and x and y are selected from the group: x=1, y=1, and x=2, y=0. x H y "Dialkylamino" refers to the group -N(alkyl)2, where alkyl is as defined herein. When x=2, the alkyl groups, together with the nitrogen to which they are attached, can optionally form a cyclic ring system. "Dialkylamino" refers to the group -N(alkyl)2, where alkyl is as defined herein.

[0152] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons (where n is an integer). Aromatic rings can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. Aromatics can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0153] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be formed by 5, 6, 7, 8, 9, or more than 9 carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. Depending on the structure, the aryl group can be a monoradical or a diradical (i.e., an arylene group). In embodiments, the aryl radical is a monocyclic, bicyclic, or tricyclic ring system. In some embodiments, the aryl ring is fused to a cycloalkyl ring or a heterocycloalkyl ring, making it a "fused-ring aryl."

[0154] "Carboxy" refers to -COH. In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties to a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to a carboxylic acid group. A compound having a carboxylic acid moiety can have the carboxylic acid moiety replaced with a carboxylic acid bioisostere and have similar physical and / or biological properties compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere ionizes at physiological pH to about the same extent as a carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to: [ka] Examples include:

[0155] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. A cycloalkyl can be saturated or partially unsaturated. In some embodiments, a cycloalkyl ring is fused to an aryl, heteroaryl, heterocycloalkyl, or second cycloalkyl ring. In some embodiments, a cycloalkyl ring is a spirocyclic cycloalkyl ring. In some embodiments, a cycloalkyl group includes groups having 3 to 10 ring atoms. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., a cycloalkylene group).

[0156] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, or tricyclic ring system in which at least one of the rings in the ring system is fully unsaturated. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group). In some embodiments, a heteroaryl ring is fused to a cycloalkyl ring or a heterocycloalkyl ring, making it a "fused-ring heteroaryl."

[0157] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group in which at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl can be saturated or partially unsaturated. In some embodiments, the heterocycloalkyl ring is fused to an aryl, heteroaryl, cycloalkyl, or second heterocycloalkyl ring. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocycloalkyl ring is a spirocyclic heterocycloalkyl ring. In some embodiments, the heterocycloalkyl ring is a bridged heterocycloalkyl ring. Unless otherwise specified, a heterocycloalkyl has 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number (including heteroatoms) of atoms comprising the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).

[0158] The term "halo" or alternatively "halogen" means fluoro, chloro, bromo and iodo.

[0159] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. The halogens can be the same or different. Non-limiting examples of haloalkyls include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, and the like.

[0160] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl include -CF, -CHF, -CHF, -CHCF, -CFCF, -CFCF, -CF(CH), and the like. Non-limiting examples of fluoroalkoxy groups include -OCF, -OCHF, -OCHF, -OCHCF, -OCFCF, -OCFCF, -OCF(CH), and the like.

[0161] The term "heteroalkyl" refers to an alkyl radical in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) can be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Additionally, up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A "heteroalkyl" may have 1 to 6 carbon atoms, excluding the number of heteroatoms.

[0162] The term "oxo" refers to the =O radical.

[0163] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are considered to be part of a larger substructure.

[0164] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often a recognized chemical entity embedded in or appended to a molecule.

[0165] As used herein, the substituent "R" appearing alone and without a number designation refers to a substituent selected from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0166] "Optionally" or "as needed" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0167] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C-C alkylalkyne, halo, acyl, acyloxy, -COH, -CO-alkyl, nitro, haloalkyl, fluoroalkyl, and amino (including mono- and di-substituted amino groups (e.g., -NH, -NHR, -N(R)), and protected derivatives thereof). By way of example, an optional substituent is L s R s (In the formula, each L s is independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O)2-, —NH—, —NHC(O)—, —C(O)NH-, S(═O)2NH-, —NHS(═O)2, —OC(O)NH-, —NHC(O)O—, —(C1-C6 alkyl)-, or —(C2-C6 alkenyl)-; each R sand (C1-C6 alkyl), (C3-C8 cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C1-C6 heteroalkyl). Protecting groups that may form the protective derivatives of the above substituents can be found in sources such as Greene and Wuts, above.

[0168] "Pharmaceutically acceptable salt" includes both acid addition salts and base addition salts.The pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0169] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, and the like, which retain the biological effectiveness and properties of the free base, and which are not biologically or otherwise undesirable. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Salts of amino acids, such as arginate, gluconate, and galacturonate, are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques well known to those skilled in the art.

[0170] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0171] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. These terms also encompass modified amino acid polymers; for example, disulfide bond formation, glycosylation, lipid modification, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein, the term "amino acid" refers to natural and / or unnatural or synthetic amino acids, including glycine and both D- and L-optical isomers, as well as amino acid analogs and peptidomimetics.

[0172] The terms "polynucleotide," "nucleotide," "nucleotide sequence," "nucleic acid," and "oligonucleotide" are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides can have any three-dimensional structure and can perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may contain one or more modified nucleotides, such as methylated nucleotides, and nucleotide analogs, such as peptide nucleic acids (PNAs), morpholinos and locked nucleic acids (LNAs), glycol nucleic acids (GNAs), threose nucleic acids (TNAs), 2'-fluoro, 2'-OMe, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. Polynucleotides may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.

[0173] As used herein, "expression" refers to the process by which a polynucleotide is transcribed from a DNA template (such as into mRNA or other RNA transcripts) and / or the process by which the transcribed mRNA is subsequently translated into a peptide, polypeptide, or protein. Transcription products and encoded polypeptides may be collectively referred to as "gene products." If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in eukaryotic cells.

[0174] The terms "subject," "individual," and "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Also included are tissues, cells, and their progeny of biological entities obtained in vivo or cultured in vitro.

[0175] The terms "therapeutic agent," "therapeutic agent," or "treatment agent" are used interchangeably and refer to a molecule or compound that provides some beneficial effect upon administration to a subject. Beneficial effects include enabling a diagnosis; ameliorating a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder, or condition; and generally combating a disease, symptom, disorder, or pathological condition.

[0176] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms during treatment. For prophylactic benefit, the composition may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject who may not yet have the disease, condition, or symptom, but who reports one or more physiological symptoms of the disease. Typically, prophylactic benefit involves reducing the incidence and / or worsening of one or more diseases, conditions, or symptoms during treatment (e.g., between a treated and an untreated population, or between the treated and untreated states of a subject, etc.).

[0177] The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to produce a beneficial or desired result. A therapeutically effective amount may vary depending on one or more of the subject and disease condition being treated, the subject's weight and age, the severity of the disease condition, the mode of administration, etc., and can be easily determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or multiple doses. A component may be described herein as having at least an effective amount, or at least an effective amount related to a particular goal or purpose, such as any of those described herein. The term "effective amount" also applies to a dose that provides an image for detection by an appropriate imaging method. The specific dose may vary depending on one or more of the particular agent selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to be imaged, and the physical delivery system in which it is delivered.

[0178] An "antigen" is a moiety or molecule that contains an epitope and therefore also specifically binds to an antibody.

[0179] An "antigen-binding unit" can be a whole or fragment (or multiple fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. A full-length antibody can be, for example, a monoclonal antibody, a recombinant antibody, a chimeric antibody, a deimmunized antibody, a humanized antibody, and a human antibody. Examples of fragments of full-length antibodies include, but are not limited to, variable heavy chains (VH), variable light chains (VL), heavy chains (VHH or VL) found in camelids, such as camels, llamas, and alpacas. H H), heavy chains found in sharks (V-NAR domains), single domain antibodies (sdAb or "nanobodies") containing a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and "r IgG" (or half antibodies). Examples of modified antibody fragments may include, but are not limited to, scFv, di-scFv or bis(s)scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), and multibodies (e.g., triabodies or tetrabodies).

[0180] The terms "antibody" and "antibodies" encompass any antigen-binding unit, including, but not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, and any other epitope-binding fragment.

[0181] The term "in vivo" refers to events that take place inside a subject's body.

[0182] The term "ex vivo" refers to an event that initially occurs outside of a subject's body for subsequent in vivo application within the subject's body. For example, ex vivo preparation can involve preparing cells outside of a subject's body with the intent of introducing the prepared cells into the same or a different subject's body.

[0183] The term "in vitro" refers to an event that occurs outside of a subject's body. For example, an in vitro assay encompasses any assay that is performed outside of a subject's body. An in vitro assay encompasses cell-based assays in which live or dead cells are used. An in vitro assay also encompasses cell-free assays in which intact cells are not used.

[0184] The term "Ras" or "RAS" refers to proteins of the Rat sarcoplasmic reticulum (Ras) superfamily of small GTPases, such as the Ras subfamily. The Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and the unclassified subfamily. In some embodiments, the Ras protein is selected from the group consisting of KRAS (also used interchangeably herein as K-Ras, K-ras, or Kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, e.g., KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

[0185] The terms "mutant Ras" and "Ras mutant," when used interchangeably herein, refer to a Ras protein having one or more amino acid mutations relative to a common reference sequence, such as a wild-type (WT) sequence. In some embodiments, the mutant Ras is selected from mutant KRAS, mutant HRAS, mutant NRAS, mutant MRAS, mutant ERAS, mutant RRAS2, mutant RALA, mutant RALB, mutant RIT1, and any combination thereof, such as mutant KRAS, mutant HRAS, mutant NRAS, mutant RALA, mutant RALB, and any combination thereof. In some embodiments, the mutation can be an introduced mutation, a naturally occurring mutation, or a non-naturally occurring mutation. In some embodiments, the mutation can be a substitution (e.g., a substituted amino acid), an insertion (e.g., an addition of one or more amino acids), or a deletion (e.g., a removal of one or more amino acids). In some embodiments, the two or more mutations can be consecutive, non-consecutive, or a combination thereof. In some embodiments, the mutation can be present at any position in Ras. In some embodiments, mutations may be present at positions 12, 13, 62, 92, 95, or any combination thereof of Ras relative to SEQ ID NO: 1 when optimally aligned. In some embodiments, mutant Ras may contain about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, the mutant Ras may contain up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations.In some embodiments, the mutant Ras can be about or up to about 500, 400, 300, 250, 240, 233, 230, 220, 219, 210, 208, 206, 204, 200, 195, 190, 189, 188, 187, 186, 185, 180, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 160, 155, 150, 125, 100, 90, 80, 70, 60, 50, or less than 50 amino acids in length. In some embodiments, the mutated amino acid is a proteinogenic amino acid, a naturally occurring amino acid, a standard amino acid, a non-standard amino acid, a non-canonical amino acid, an essential amino acid, a non-essential amino acid, or a non-naturally occurring amino acid. In some embodiments, the mutated amino acid has a positively charged side chain, a negatively charged side chain, a polar uncharged side chain, a nonpolar side chain, a hydrophobic side chain, a hydrophilic side chain, an aliphatic side chain, an aromatic side chain, a cyclic side chain, an acyclic side chain, a basic side chain, or an acidic side chain. In some embodiments, the mutation comprises a reactive moiety. In some embodiments, the replacement amino acid comprises a reactive moiety. In some embodiments, the mutant Ras can be further modified, such as by conjugation with a detectable label. In some embodiments, the mutant Ras is a full-length or truncated polypeptide. For example, the mutant Ras can be a truncated polypeptide comprising residues 1-169 or residues 11-183 (e.g., residues 11-183 of mutant RALA or mutant RALB).

[0186] compound Formulas (I-1), (I-2), (I'), (I''-1), (I''-2), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (II-1), (II-2), (IIa), (IIb), (IIc'), (IIc), (IId'), (I Id), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), (IIm), (IIIa-1), (IIIb-1), (IIIc-1), (IIId-1), (IIIe-1), (IIIf-1), (IIIg-1), (I IIh-1), (IIIi-1), (IIIa-2), (IIIb-2), (IIIc-2), (IIId-2), (IIIe-2), (IIIf-2), (IIIg-2), (IIIh-2), (IIIi-2), (IIIa-3), (IIIb-3), (I IIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (IIIh-3), (IIIi-3), (IIIa-4), (IIIb-4), (IIIc-4), (IIId-4), (IIIe-4), (IIIf-4), (I IIg-4), (IIIh-4), (IIIi-4), (IVa-1), (IVb-1), (IVc-1), (IVa-2), (IVb-2), (IVc-2), (Va-1), (Vb-1), (Vc-1), (Va-2), (Vb-2), (Vc-2), (X I-1), (XI-2), (XIa), (XIb), (XIc), (XId), (XIe), (XIf), (XII-1), (XII-2), (XIIa), (XIIb), (XIIc), (XIId), (XXI-1), (XXI-2), (XXIa), (X Compounds of Formula XIb), (XXIc), (XXII-1), (XXII-2), (XXIIa-1), (XXIIa-2), (XXIIb-1), (XXIIb-2), (XXIIc), (XXIId), (XXIIe), (XXIIf), (XXIIg), (XXIII-1), (XXIII-2), (XXIV-1), or (XXIV-2), or pharmaceutically acceptable salts or solvates thereof, are Ras modulators (including Ras inhibitors) and have a wide range of uses in therapy, diagnosis, and other biomedical research.

[0187] In one aspect, a compound of formula (I-1), or a pharmaceutically acceptable salt or solvate thereof: [ka] is provided; where: [ka] is a 7- or 8-membered monocyclic heterocycloalkyl ring; X is C or N; Y is C, S(O), S(O), C(O), or N; U is C, S(O), S(O), C(O), or N; Z is N or C(R 8 ) and; V and J are independently N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ) and; W is N or C(R 18 ) and; L 1 and L 2 are independently a bond, C1-C6 alkyl, -O-, -N(R 14 )-, -C(O)-, -N(R 14 )C(O)-, -C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-, -S(O)N(R 14 )-, -N(R 14 )S(O)-, -N(R 14 )S(O)2-, -OCON(R 14 )-, -N(R 14 )C(O)O-, and -N(R 14 )C(O)N(R 14 )-selected from; R 2 is hydrogen, halogen, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6Cycloalkyl, C 2~9 Heterocycloalkyl, C 6~10 Aryl, C 1~9 Heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 )-, S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ...

Claims

1. Formula (IVa-1), (IVb-1), or (IVc-1): 【Chemistry 1137】 or a pharma- ceutically acceptable salt or solvate thereof; X is C or N; X 4 is selected from N(R 1 ), O, S, S(O), S(O) 2 , —CH 2 —, —C(H)(R 4 )—, —C(R 4 ) 2 —, and C(H)(-L 2 -R 5 ); Y is C, S(O), S(O)2, C(O), or N; U is C, S(O), S(O)2, C(O), or N; Z is N or C(R 8 ); V and J are independently selected from N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ); W is N or C(R 18 ); L 1 and L 2 are independently selected from a bond, C 1 -C 6 alkyl, —O—, —N(R 14 )—, —C(O)—, —N(R 14 )C(O)—, —C(O)N(R 14 )—, —S—, —S(O) 2 —, —S(O)—, —S(O) 2 N(R 14 )—, —S(O)N(R 14 )—, —N(R 14 )S(O)—, —N(R 14 )S(O) 2 —, —OCON(R 14 )—, —N(R 14 )C(O)O—, and —N(R 14 )C(O)N(R 14 )—; Each R 1 is independently selected from hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , -S(O) 2 N(R 12 )(R 13 )-, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20a ; R 2 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 )-, S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20b ; each R 3 is independently selected from hydrogen, halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 12 , —N(R 12 )(R 13 ), —CN, —C(O)OR 12 , —OC(O)N(R 12 )(R 13 ), —C(O)R 15 , —S(O) 2 R 15 , and —S(O) 2 N(R 12 )(R 13 ); each R 4 is independently hydrogen, halogen, oxo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , —OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 )—, S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20a ; each R 5 is independently hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 8 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 )-, S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20c ; Each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl. The heteroaryl is optionally substituted with 1, 2, or 3 R 20d ; each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 12 and R 13 together with the nitrogen to which they are attached form a C 2-9 heterocycloalkyl ring optionally substituted with 1, 2, or 3 R 20e ; each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20f ; R 16 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 )-, S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20g ; R 17 is -L 1 -R 19 ; R 18 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 )-, S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20h ; R 19 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, where C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20i ; Each of R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i are each independently selected from halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, —CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, —CH 2 -C 6-10 aryl, C 1-9 heteroaryl, —OR 21 , —SR 21 , —N(R 22 )(R 23 ), —C(O)OR 22 , —C(O)N(R 22 )(R 23 ), —C(O)C(O)N(R 22 )(R 23 ), —OC(O)N(R 22 )(R 23 ), —N(R 24 )C(O)N(R 22 )(R 23 ), —N(R 24 )C(O)OR 25 , —N(R 24 )C(O)R 25 , —N(R 24 )S(O) 2 R 25 , —C(O)R 25 , —S(O) 2 R 25 , —S(O) 2 N(R 22 )(R 23 ), —OCH 2 C(O)OR 22 , and —OC(O)R 25 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl are halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24) C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O) 2 R 25 , -C(O)R 25 , -S(O) 2 R 25 , -S(O) 2 N(R 22)(R 23 ), and -OC(O)R 25 ; each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 23 is independently selected from H and C 1-6 alkyl; each R 24 is independently selected from H and C 1-6 alkyl; each R 25 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; s is 0, 1, 2, 3, or 4; t is 1, 2, 3, 4, or 5; where s+t≧2; and 【Chemistry 1138】 indicates a single or double bond such that all valences are satisfied, or a compound, or a pharma- ceutically acceptable salt or solvate thereof.

2. Formula: 【Chemical 1146】 10. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt or solvate thereof; wherein: Z is N or C(R 8 ); L 2 is selected from a bond, C 1 -C 6 alkyl, and —C(O)—; R 2 is —OR 12 ; each R 4 is independently hydrogen, halogen, oxo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , —OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 ), —S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20a ; R 5 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, where C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20a ; R 8 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 ), —S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20c ; Each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl. The heteroaryl is optionally substituted with 1, 2, or 3 R 20d ; each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 12 and R 13 together with the nitrogen to which they are attached form a C 2-9 heterocycloalkyl ring optionally substituted with 1, 2, or 3 R 20e ; each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 15 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20f ; R 16 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 ), —S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20g ; R 17 is -L 1 -R 19 ; L 1 is a bond; R 19 is selected from C 6-10 aryl, and C 1-9 heteroaryl, where C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20i ; R 20a , R 20c , R 20d , R 20e , R 20f , R 20g and R 20i are each independently selected from halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, —CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, —CH 2 -C 6-10 aryl, C 1-9 heteroaryl, —OR 21 , —SR 21 , —N(R 22 )(R 23 ), —C(O)OR 22 , —C(O)N(R 22 )(R 23 ), —C(O)C(O)N(R 22 )(R 23 ), —OC(O)N(R 22 )(R 23 ), —N(R 24 )C(O)N(R 22 )(R 23 ), —N(R 24 )C(O)OR 25 , —N(R 24 )C(O)R 25 , —N(R 24 )S(O) 2 R 25 , —C(O)R 25 , —S(O) 2 R 25 , —S(O) 2 N(R 22 )(R 23 ), —OCH 2 C(O)OR 22 , and —OC(O)R 25 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl are halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O) 2 R 25 , -C(O)R 25 , -S(O) 2 R 25 , -S(O) 2 N(R 22 )(R 23), and optionally substituted with 1, 2, or 3 groups independently selected from -OC(O)R 25 ; each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 23 is independently selected from H and C 1-6 alkyl; each R 24 is independently selected from H and C 1-6 alkyl; each R 25 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; p is 1, 2, 3, 4, or 5; s is 0 or 1; t is 1 or 2; A compound, or a pharma- ceutically acceptable salt or solvate thereof, wherein s+t≧2.

3. R 2 is 【Chemical 1147】 【Chemistry 1148】 【Chemical 1149】 2. The compound of claim 1, selected from:

4. R 19 is 【Chemistry 1150】 and Q 3 is C(R 1d ); Q4 is S; X 14 , X 15 , X 6 , X 9 , X 10 , X 11 , and X 12 are independently selected from C(R 1a ) and N; each R 1a is independently selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -OH, and -NH 2 ; R 1d is -CN; 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein R 1h is --NH 2 .

5. R 19 is 【Chemistry 1151】 【Chemistry 1152】 【Chemistry 1153】 2. The compound of claim 1, selected from:

6. A compound represented by the formula (IIIa-3), (IIIb-3), (IIIc-3), (IIId-3), (IIIe-3), (IIIf-3), (IIIg-3), (IIIh-3), or (IIIi-3): 【Chemistry 1141】 or a pharma- ceutically acceptable salt or solvate thereof; X is C or N; X 1 is selected from C(R 4 )(R 6 ), N(R 4 ), N(R 6 ), O, S, S(O), and S(O) 2 ; X 2 is X 3 , —CH 2 —, —X 3 CH 2 —, —CH 2 X 3 —, —CH 2 CH 2 —, —C(H)(R 4 )—, —C(H)(R 4 )—, —X 3 C(H)(R 4 )—, —C(H)(R 4 )X 3 —, —C(H)(R 4 )CH 2 —, —C(H)(R 4 )C(H)(R 4 )—, —C(R 4 ) 2 —, —X 3 C(R 4 ) 2 —, —C(R 4 ) 2 X 3 —, —C(H)C(R 4 ) 2 —, —C(R 4 ) 2 C(H)—, and —C(R 4 ) 2 C(R 4 ) 2 -; X 3 is selected from N(R 1 ), O, S, S(O), and S(O) 2 ; X 4 is X 5 , —CH 2 —, —X 5 CH 2 —, —CH 2 X 5 —, —CH 2 CH 2 —, —C(H)(R 4 )—, —C(H)(R 4 )—, —X 5 C(H)(R 4 )—, —C(H)(R 4 )X 5 —, —C(H)(R 4 )CH 2 —, —C(H)(R 4 )C(H)(R 4 )—, —C(R 4 ) 2 —, —X 5 C(R 4 ) 2 —, —C(R 4 ) 2 X 5 —, —C(H)C(R 4 ) 2 —, —C(R 4 ) 2 C(H)—, and —C(R 4 ) 2 C(R 4 ) 2 -; X 5 is selected from N(R 1 ), S, S(O), and S(O) 2 ; Y is C, S(O), S(O)2, C(O), or N; U is C, S(O), S(O)2, C(O), or N; Z is N or C(R 8 ); V and J are independently selected from N, C(R 16 ), and C(R 17 ), where one of V and J is C(R 17 ); W is N or C(R 18 ); L 1 and L 2 are independently selected from a bond, C 1 -C 6 alkyl, —O—, —N(R 14 )—, —C(O)—, —N(R 14 )C(O)—, —C(O)N(R 14 )—, —S—, —S(O) 2 —, —S(O)—, —S(O) 2 N(R 14 )—, —S(O)N(R 14 )—, —N(R 14 )S(O)—, —N(R 14 )S(O) 2 —, —OCON(R 14 )—, —N(R 14 )C(O)O—, and —N(R 14 )C(O)N(R 14 )—; Each R 1 is independently selected from hydrogen, -L 2 -R 5 , -C(O)OR 12 , -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , -S(O) 2 N(R 12 )(R 13 )-, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20a ; R 2 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 )-, S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20b ; each R 3 is independently selected from hydrogen, halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 12 , —N(R 12 )(R 13 ), —CN, —C(O)OR 12 , —OC(O)N(R 12 )(R 13 ), —C(O)R 15 , —S(O) 2 R 15 , and —S(O) 2 N(R 12 )(R 13 ); each R 4 is independently hydrogen, halogen, oxo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , —OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 )—, S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20a ; R 5 is hydrogen or a group other than an electrophilic moiety capable of forming a covalent bond with the cysteine ​​residue at position 12 of the KRAS protein; R 6 is -L 2 -R 5 ; R 8 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 )-, S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20c ; Each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl. The heteroaryl is optionally substituted with 1, 2, or 3 R 20d ; each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 12 and R 13 together with the nitrogen to which they are attached form a C 2-9 heterocycloalkyl ring optionally substituted with 1, 2, or 3 R 20e ; each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 15 is independently selected C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20f ; R 16 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 )-, S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20g ; R 17 is -L 1 -R 19 ; R 18 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 )-, S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20h ; R 19 is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, where C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20i ; Each of R 20a , R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i are each independently selected from halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, —CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, —CH 2 -C 6-10 aryl, C 1-9 heteroaryl, —OR 21 , —SR 21 , —N(R 22 )(R 23 ), —C(O)OR 22 , —C(O)N(R 22 )(R 23 ), —C(O)C(O)N(R 22 )(R 23 ), —OC(O)N(R 22 )(R 23 ), —N(R 24 )C(O)N(R 22 )(R 23 ), —N(R 24 )C(O)OR 25 , —N(R 24 )C(O)R 25 , —N(R 24 )S(O) 2 R 25 , —C(O)R 25 , —S(O) 2 R 25 , —S(O) 2 N(R 22 )(R 23 ), —OCH 2 C(O)OR 22 , and —OC(O)R 25 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl are halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24) C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O) 2 R 25 , -C(O)R 25 , -S(O) 2 R 25 , -S(O) 2 N(R 22)(R 23 ), and -OC(O)R 25 ; each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 23 is independently selected from H and C 1-6 alkyl; each R 24 is independently selected from H and C 1-6 alkyl; each R 25 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; n is 0, 1, or 2; p is 1, 2, 3, 4, or 5; and 【Chemistry 1142】 indicates a single or double bond such that all valences are satisfied, or a compound, or a pharma- ceutically acceptable salt or solvate thereof.

7. Formula: 【Chemical 1154】 7. The compound of claim 6 having the structure: or a pharma- ceutically acceptable salt or solvate thereof; wherein: Z is N or C(R 8 ); R 2 is 【Chemistry 1155】 【Chemistry 1156】 【Chemistry 1157】 Selected from: each R 4 is independently hydrogen, halogen, oxo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , —OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 ), —S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20a ; R 5 is an electrophilic moiety capable of forming a covalent bond with the residue at position 12 of the KRAS protein; 【Chemistry 1158】 each R b is independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6 alkoxy, and C 1 -C 6 alkyl, or two R b optionally taken together form a heterocycle having 3 to 12 ring atoms or a C 3 -C 6 cycloalkyl; R 8 is hydrogen, halogen, C 1-6 alkyl, or —OR 12 , where C 1-6 alkyl is optionally substituted with 1, 2, or 3 R 20c ; Each R 12 is independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl. The heteroaryl is optionally substituted with 1, 2, or 3 R 20d ; each R 13 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; or R 12 and R 13 together with the nitrogen to which they are attached form a C 2-9 heterocycloalkyl ring optionally substituted with 1, 2, or 3 R 20e ; each R 14 is independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; each R 15 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20f ; R 16 is hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , —C(O)N(R 12 )(R 13 ), —C(O)C(O)N(R 12 )(R 13 ), —N(R 14 )C(O)R 15 , —S(O) 2 R 15 , —S(O) 2 N(R 12 )(R 13 ), —S(═O)(═NH)N(R 12 )(R 13 ), —CH 2 C(O)N(R 12 )(R 13 ), —CH 2 N(R 14 )C(O)R 15 , —CH 2 S(O) 2 R 15 , and —CH 2 S(O) 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20g ; R 17 is -L 1 -R 19 ; L 1 is a bond; R 19 is selected from C 6-10 aryl, and C 1-9 heteroaryl, where C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1, 2, or 3 R 20i ; R 20a , R 20c , R 20d , R 20e , R 20f , R 20g and R 20i are each independently selected from halogen, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, —CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, —CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, —CH 2 -C 6-10 aryl, C 1-9 heteroaryl, —OR 21 , —SR 21 , —N(R 22 )(R 23 ), —C(O)OR 22 , —C(O)N(R 22 )(R 23 ), —C(O)C(O)N(R 22 )(R 23 ), —OC(O)N(R 22 )(R 23 ), —N(R 24 )C(O)N(R 22 )(R 23 ), —N(R 24 )C(O)OR 25 , —N(R 24 )C(O)R 25 , —N(R 24 )S(O) 2 R 25 , —C(O)R 25 , —S(O) 2 R 25 , —S(O) 2 N(R 22 )(R 23 ), —OCH 2 C(O)OR 22 , and —OC(O)R 25 , wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-10 aryl, -CH 2 -C 6-10 aryl, and C 1-9 heteroaryl are halogen, oxo, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O) 2 R 25 , -C(O)R 25 , -S(O) 2 R 25 , -S(O) 2 N(R 22 )(R 23), and optionally substituted with 1, 2, or 3 groups independently selected from -OC(O)R 25 ; each R 21 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 22 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; each R 23 is independently selected from H and C 1-6 alkyl; each R 24 is independently selected from H and C 1-6 alkyl; each R 25 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl; and A compound, or a pharma- ceutically acceptable salt or solvate thereof, wherein p is 1, 2, 3, 4, or 5.

8. R 19 is 【Chemical 1159】 and Q 3 is C(R 1d ); Q4 is S; X 14 , X 15 , X 6 , X 9 , X 10 , X 11 , and X 12 are independently selected from C(R 1a ) and N; each R 1a is independently selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, -OH, and -NH 2 ; R 1d is -CN; 7. The compound of claim 6, or a pharma- ceutically acceptable salt or solvate thereof, wherein R 1h is --NH 2 .

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

10. A composition for use in treating cancer in a subject in need of such treatment, comprising a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt or solvate thereof.

11. A composition for use in modulating the activity of a Ras protein, comprising a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt or solvate thereof.

12. A composition for use in inhibiting cell proliferation of cells expressing a Ras protein, comprising a compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt or solvate thereof.

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