Heterocycles and their uses

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof, as well as methods for their use. The compounds and methods have a wide range of applications as therapeutic, diagnostic, and research tools. In particular, the subject compositions and methods are useful for reducing the signaling output of oncogenic proteins. In certain embodiments, the present disclosure provides modified Ras proteins comprising a compound covalently bound to one or more amino acid residues of the Ras protein, wherein the modified Ras protein comprises a compound of formula (I').

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 435,219, filed December 23, 2022, and U.S. Provisional Patent Application No. 63 / 582,402, filed September 13, 2023, each of which is incorporated herein by reference in its entirety.

[0002] (Sequence Listing) This application contains a Sequence Listing that has been submitted electronically in XML format, and is incorporated herein by reference in its entirety. The XML copy, created on December 19, 2023, is named 56690_763_601_SL.xml and is 13,982 bytes in size. [Background technology]

[0003] Cancer (e.g., tumors, neoplasms, metastases) is the second leading cause of death worldwide and is estimated to be responsible for approximately 10 million deaths each year. Many types of cancer harbor mutations in one or more proteins involved in various signaling pathways, leading to the uncontrolled proliferation of cancer cells. In some cases, approximately 25–30 percent (%) of tumors are known to harbor Rat sarcoma (Ras) mutations. In particular, mutations in K-Ras (Kirsten Ras oncogene) are one of the most frequent Ras mutations detected in human cancers, including lung adenocarcinoma (LUAD) and pancreatic ductal adenocarcinoma (PDAC).

[0004] 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 lacking any obvious target region. The specific G12C Ras gene mutation has been identified as a druggable target, with numerous G12C-specific inhibitors being developed. However, because the G12C mutation in Ras exhibits a much lower prevalence than other known Ras mutations, such as G12D and G12V, such therapeutics remain of limited use. Drug resistance and lack of durability pose further limitations to these therapeutics. Summary of the Invention [Means for solving the problem]

[0005] In light of the above, there remains a significant need for novel designs of therapeutic and diagnostic methods that can specifically target Ras, including wild-type Ras, mutant Ras and / or related proteins, and reduce Ras signaling output. Of particular note are inhibitors of mutant Ras proteins, such as Ras G12S and / or G12C, for the treatment of Ras-related diseases (e.g., cancer). Such compositions and methods may be particularly useful for treating a variety of diseases, including, but not limited to, cancer and neoplastic conditions. The present disclosure addresses these needs and provides additional advantages applicable to the diagnosis, prognosis, and / or treatment of a variety of diseases.

[0006] In certain aspects, the present disclosure provides a modified Ras protein comprising a compound covalently attached to one or more amino acid residues of the Ras protein, wherein the modified Ras protein comprises a compound of formula (I'). [ka] During the ceremony, The dashed lines represent covalent bonds to amino acid residues; R 1 is C 3-12carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 20 may be substituted with L 1 is one or more R 20 is a 5- to 20-membered heterocycle optionally substituted with L 2 is a bond, C 1-4 Alkylene, 2-4 membered heteroalkylene, -O-, -N(R 19 )-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R 19 -, -N(R 19 )S(O)2-, -N(R 19 )S(O)-, -N(R 19 )P(O)R 19 -, -S(O)2N(R 19 )-, -S(O)N(R 19 )-, -P(O)R 19 N(R 19 )-, -OS(O)2-, -OS(O)-, -OP(O)R 19 -, -S(O)2O-, -S(O)O-, and -P(O)R 19 O-, C 1-4 Alkylene and 2- to 4-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with L 3 and R 2 together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3-8 forming a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) is halogen, -OH, -CN, C1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); L 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 and R 6 is not piperazine, or R 2 and R 6 together with the atoms to which they are attached, form halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted by 1, 2, or 3 substituents selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 is a bond, R 2 is halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl or R 2 and R 3 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 4 , R 5 , and R 6 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6cycloalkyl or R 4 and R 5 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 19 is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OH, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl), R 20 is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 and two R attached to the same or adjacent atoms are selected from 20 is combined with C 3-12 may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3-12 membered heterocycle), -(2-6 membered heteroalkyl)-(3-12 membered heterocycle), C3-12 carbocycle, and 3-12 membered heterocycle are not substituted with halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(=O)(=NR 22 )N(R 22 )(R 23 and optionally substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 together with the carbon atoms to which they are attached, form C 3-12 forming a carbocyclic or 3- to 12-membered heterocyclic ring, each of which is independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl, and —OH; R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle); R 23 independently in each occurrence hydrogen and C 1-6 alkyl or R bonded to a 3- to 10-membered heterocycle of the same nitrogen atom form 22 and R 23 is.

[0007] In some embodiments, the modified Ras protein is a modified human K-Ras mutant protein comprising a compound covalently attached to a serine residue having the structure of Formula (I), wherein the serine residue corresponds to position 12 of SEQ ID NO:4: [ka] The dashed lines represent the bonds between the serine residues of the K-Ras mutant protein and alanine 11 and glycine 13, respectively.

[0008] In some embodiments, the modified protein of Formula (I') or (I) exhibits a decreased Ras signaling output, which may be evidenced by one or more outputs selected from: (i) an increased steady-state level of a GDP-bound modified protein; (ii) a decreased steady-state level of a GTP-bound modified protein; (iii) a decreased steady-state level of phosphorylated AKTs473; (iv) a decrease in phosphorylated ERK T202 / Y204; (v) a decrease in phosphorylated S6 S235 / 236; (vi) a decrease in cell proliferation of tumor cells expressing a Ras G12S mutant protein; and (vii) a decrease in Ras interaction with Ras pathway signaling proteins.

[0009] In some embodiments, the modified protein of Formula (I') or (I) comprises the amino acid sequence of SEQ ID NO: 4, with a serine residue corresponding to position 12 of SEQ ID NO: 1. In some embodiments, the modified protein comprises the amino acid sequence of SEQ ID NO: 4.

[0010] In some embodiments, the modified protein of Formula (I') or (I) is formed by contacting a precursor compound with a serine residue of an unmodified Ras G12S mutant protein, wherein the precursor compound comprises a leaving group and a leaving group, and said contacting results in release of the leaving group and formation of said modified protein. In some embodiments, the precursor compound is a compound described herein, such as a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d). In some embodiments, the modified protein comprises the amino acid sequence of SEQ ID NO:1 or a fragment thereof comprising a serine residue corresponding to position 12 of SEQ ID NO:1, and the precursor compound selectively labels serine residues relative to (i) an aspartic acid residue of a K-Ras G12D mutant protein (said aspartic acid corresponds to position 12 of SEQ ID NO:2); (ii) a valine residue of a K-Ras G12V mutant protein (said valine corresponds to position 12 of SEQ ID NO:3); and / or (iii) a glycine residue of a K-Ras wild-type protein (said glycine corresponds to position 12 of SEQ ID NO:1). In some embodiments, the precursor compound selectively labels serine residues by at least 2-fold, 3-fold, 4-fold, 5-fold, or more when assayed under comparable conditions. In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo. In some embodiments, the leaving group is [ka] or a salt or tautomer thereof; R 8 and R 9 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl).

[0011] In certain aspects, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 20 may be substituted with L 1 is one or more R 20 is a 5- to 20-membered heterocycle optionally substituted with L 2 is a bond, C 1-4 Alkylene, 2-4 membered heteroalkylene, -O-, -N(R 19 )-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R 19 -, -N(R 19 )S(O)2 - , -N(R 19 )S(O)-, -N(R19)P(O)R19-, -S(O)2N(R19)-, -S(O)N(R19)-, -P(O)R19N(R19)-, -OS(O)2-, -OS(O)-, -OP(O)R19-, -S(O)2O-, -S(O)O-, and -P(O)R 19 O-, C 1-4 Alkylene and 2- to 4-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with L 3 and R 2 together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3-8 forming a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) is halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); L 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 and R 6 is not piperazine, or R 2 and R 6 together with the atoms to which they are attached, form halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6cycloalkyl), forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted by 1, 2, or 3 substituents selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 is a bond, R 2 is halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl or R 2 and R 3 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 4 , R 5 , and R 6 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl or R 4 and R 5 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 7 teeth, [ka] is selected from R 8 and R 9 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl), and -O(C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl; R 19 is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OH, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl), R 20 is independently in each occurrence halogen, oxo, -CN, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(C 3-12 -(2- to 6-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -OR 22 , -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22 , -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R2 2)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 and two R's bonded to the same or adjacent atoms are selected from 20 is combined with C 3-12 may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3-12 membered heterocycle), -(2-6 membered heteroalkyl)-(3-12 membered heterocycle), C3-12 carbocycle, and 3-12 membered heterocycle are not substituted with halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Haloalkoxy, -OR 22 , =C(R22, -N(R22)(R23), =NR22-SR21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22 , -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R 22 )(R 23 ), and -S(=O)(=NR 22 )N(R 22 )(R 23 and optionally substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 together with the carbon atoms to which they are attached, form C 3-12 forming a carbocyclic or 3- to 12-membered heterocyclic ring, each of which is independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl, and —OH; R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle); R 23 independently in each occurrence hydrogen and C 1-6 alkyl or R bonded to a 3- to 10-membered heterocycle of the same nitrogen atom form22 and R 23 is.

[0012] In some embodiments, the subject compounds of any formula disclosed herein, including compounds of formula (II), (II-a), (II-b), (II-c), or (II-d), can be R 7 is replaced with hydrogen, it reversibly binds to K-Ras protein with an IC50 of less than 1000 nM as assessed by HTRF assay. In some embodiments, the subject compounds of any formula disclosed herein, including compounds of formula (II), (II-a), (II-b), (II-c), or (II-d), reversibly bind to the Switch II pocket of Ras protein.

[0013] In some embodiments, the compound or modified protein, or the present disclosure, 3 and R 2 together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3-8 forming a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl). In some embodiments, L 3 and R 2together with the atoms to which they are attached, form halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted by 1, 2, or 3 substituents selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 In some embodiments, L is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkoxy, alkoxy, haloalkyl, alkoxy, alkoxysilyl ... 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group consisting of halogen, -OH, CN, C1-3 alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 and R 6In some embodiments, the 4-8 membered monocyclic heterocycloalkyl formed by is not piperazine. 2 and R 6 together with the atoms to which they are attached, form halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted by 1, 2, or 3 substituents selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 is a bond.

[0014] In some embodiments, the compound of Formula (II) is a compound of Formula (II-a): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: W 1 and W 3 are each independently N(R 10 ), C(R 11 )2, C(O), O, S(O), and S(O)2; W 2 is N and C(R 11 ) and n1 and n3 are each independently selected from 0, 1, 2, 3, 4, and 5, and the sum of n1 and n3 is at least 1; R 10 independently in each occurrence, hydrogen, C1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C3-6 cycloalkyl are substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); R 11 is independently in each occurrence hydrogen, halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), or two R attached to the same carbon atom 11 Selected from C 3-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl).

[0015] In some embodiments, for compounds of formula (II-a), W 1 and W 3 are respectively C(R 11 )2. In some embodiments, W 2 is N. In some embodiments, the sum of n1 and n3 is 2, 3, 4, or 5. In some embodiments, n1 is 2, 3, or 4, and n3 is 1 or h2.

[0016] In some embodiments, the compound of Formula (II) has the formula (II-b): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: W 4 and W 5 are each independently N(R 10 ), C(R 11 )2, C(O), O, S(O), and S(O)2; W 2 is N and C(R 11 ) and n4 and n5 are each independently selected from 0, 1, 2, 3, 4, and 5; R 10 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); R 11 is independently in each occurrence hydrogen, halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), or two R attached to the same carbon atom 11 Selected from C 3-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3haloalkyl).

[0017] In some embodiments, for compounds of formula (II-b), W 4 and W 5 are respectively C(R 11 )2. In some embodiments, W 2 is C(R 11 In some embodiments, the sum of n4 and n5 is 0 or 1. In some embodiments, n4 and n5 are each 0.

[0018] In some embodiments, the compound of Formula (II) is a compound of Formula (II-c): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: W 1 , W 3 , W 4 , and W 5 are each independently N(R 10 ), C(R 11 )2, C(O), O, S(O), and S(O)2; W 2 is N and C(R 11 ) are selected from n1 and n3 are each independently selected from 0, 1, 2, 3, 4, and 5, and the sum of n1 and n3 is at least 2; n4 and n5 are each independently selected from 0, 1, 2, 3, 4, and 5; R 10 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3alkyl), and -O(C 1-3 haloalkyl); R 11 is independently in each occurrence hydrogen, halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), or two R attached to the same carbon atom 11 Selected from C 3-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl).

[0019] In some embodiments, for compounds of Formula (II-c), each W 1 are independently C(R 11 )2 and O. In some embodiments, n1 is 2, 3, or 4 and one W 1 is O and the remaining W 1 are respectively C(R 11 )2. In some embodiments, W 3 is C(R 11 )2. In some embodiments, W 2 is N. In some embodiments, W 4 and W 5 are C(R 11)2. In some embodiments, the sum of n1 and n3 is 2, 3, 4, or 5. In some embodiments, n1 is 2, 3, or 4 and n3 is 1. In some embodiments, the sum of n4 and n5 is 0 or 1. In some embodiments, n4 and n5 are each 0. In some embodiments, [ka] each of which is selected from 1, 2, or 3 R 11 may be substituted with.

[0020] In some embodiments, the compound of Formula (II) is a compound of Formula (II-d): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: W 3 is N(R 10 ), C(R 11 )2, C(O), O, S(O), and S(O)2; n3 is selected from 0, 1, 2, 3, 4, and 5; R 10 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); R 11 is independently in each occurrence hydrogen, halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C3-6 cycloalkyl), or two R attached to the same carbon atom; C 3-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl).

[0021] In some embodiments, for compounds of formula (II-d), each W 3 is C(R 11 ) 2. In some embodiments, n3 is 1, 2, or 3.

[0022] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 10 and R 11 independently in each occurrence hydrogen and C 1-3 It is alkyl.

[0023] In some embodiments, for a compound or modified protein of the disclosure, R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, each of which is selected from 1, 2, 3, 4, or 5 R 20 In some embodiments, R 1 is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is selected from one or more R 20 In some embodiments, R 1 is halogen, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 Alkenyl, C2-3 Alkynyl, -OR 22 , -N(R 22 )(R 23 ), and C 3-6 In some embodiments, R is substituted with 1, 2, 3, or 4 substituents independently selected from cycloalkyl. 1 is substituted with 1, 2, 3, or 4 substituents independently selected from halogen, —CN, —CH, —CHCH, —CH═CH, —CF, —C≡C, —OH, —NH, and -cyclopropyl. 1 teeth, [ka] [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth [ka] is.

[0024] In some embodiments, with respect to the compounds or modified proteins of the present disclosure, L 1 is one or more R 20 In some embodiments, L is a 6- to 12-membered heterocycle optionally substituted with 1 can have 1, 2, 3, or 4 R's 20 In some embodiments, L is a 10-membered bicyclic heterocycle optionally substituted with 1 contains 1 to 5 nitrogen atoms. 1 teeth: [ka] During the ceremony, W is N, C(R17), N(R17b), C(R17)2, C(O), S(O), or S(O)2; Z is N, C(R 17 ), N(R 17b ), C(R 17 )2, C(O), S(O), or S(O)2, and W and Z are not both selected from C(O), S(O), and S(O)2; V and J each independently represent N, C(R 1 ), C(R 17 ), N(R 1 ), N(R 17b ), C(R 1 )(R 17 ), and C(R 17 )2, and exactly one of V and J is selected from C(R 1 ), N(R 1 ), or C(R 1 )(R 17 ) and U is N, C(R 17 ), N(R 17b ), C(R 17 )2, S(O), S(O)2, or C(O); Y is N, C(R 18 ), N(R 17b ), C(R 18 )(R 17 ), S(O), S(O)2, or C(O); X is N, C(R 17 ), N(R 17b ), or C(R 17 )2, R 17 is independently in each occurrence hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), =NR 12 , =C(R 14 )2, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NR 12 )N(R 12 )(R 13 ), and -OCH2C(O)OR 12 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are substituted with one, two, or three R 20 may be substituted with R17b is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3-12 membered heterocycle), -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ) and -S(=O)(=NR 12 )N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle) is a heterocyclic ring having one, two, or three R 20 may be substituted with R 18 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12 , -SR 12 , -N(R 12 )(R 13 ), =NR 12 , =C(R 14 )2, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NR 12 )N(R 12 )(R 13 ), and -OCH2C(O)OR 12 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are substituted with one, two, or three R 20 may be substituted with R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 Alkyl-(3- to 12-membered heterocycle) is a heterocycle containing one, two, or three R 20 may be substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 may be one, two, or three R together with the same nitrogen atom to which they are attached. 20 forming a 3- to 10-membered heterocycle optionally substituted by R 14 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 form a 3- to 12-membered heterocyclic ring together with the carbon atoms to which they are attached, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), C 0-6 Alkyl-(3-12 membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles may contain one, two, or three R 20 and [ka] indicates a single or double bond where all valences are satisfied.

[0025] In some embodiments, for compounds or modified proteins of the present disclosure, W is C(R 17 ), C(R 17 )2, or C(O), and Z is N, C(R 17 ), N(R 17b ), or C(R 17 )2, and V is C(R 1 ) or N(R 1 ) and J is C(R 17 ) or C(R 17 )2. In some embodiments, W is CH, CH2, or C(O) and Z is N, CCl, N(R 17b ), or CH2, and V is C(R 1 ) or N(R 1 ) and J is CF or CH2. In some embodiments, W is C(R 17 ), and Z is C(R 17 ), and V is C(R 1 ), and J is C(R 17 In some embodiments, W is CH, Z is CCl, and V is C(R 1 ) and J is CF. In some embodiments, U is N and Y is C(R 18 ) and X is N. In some embodiments, R 18 is hydrogen, C 1-3 Alkyl, -OR 12 and 3- to 10-membered heterocycles, 1-3 Alkyl and 3- to 10-membered heterocycles may have one, two, or three R 20 In some embodiments, R 18 HA-OR 12’ In some embodiments, R 18 is -O(C 1-3 alkylene)(4-10 membered heterocycle), wherein the 4-10 membered heterocycle is 1-3 Alkyl, C 1-3 Haloalkyl, and =C(R 21)2, and optionally substituted with 1, 2, or 3 substituents independently selected from R 21 represents independently in each occurrence hydrogen, halogen, and C 1-3 In some embodiments, R 18 teeth, [ka] [ka] [ka] In some embodiments, R 18 teeth, [ka] is selected from.

[0026] In some embodiments, for a compound or modified protein of the disclosure, L 1 teeth [ka] In some embodiments, R 1 -L 1 teeth [ka] In some embodiments, R 1 -L 1 teeth [ka] In some embodiments, L 2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene are each selected from the group consisting of 1, 2, or 3 R 20 In some embodiments, L 2 is a bond, C 1-3Alkylene, -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene-, and -N(C 3-6 Cycloalkyl)C 1-3 alkylene- selected from C 1-3 Alkylene, C 1-3 Alkyl, and C 3-6 Cycloalkyl is halogen, C 1-3 Alkyl, and C 1-3 In some embodiments, L is optionally substituted with 1, 2, or 3 substituents selected from haloalkyl. 2 is a bond.

[0027] In some embodiments, for a compound or modified protein of the disclosure, R 2 is C 1-6 Alkyl and C 3-6 In some embodiments, R 3 is hydrogen and C 1-6 alkyl, for example, R 3 is hydrogen. In some embodiments, R 4 , R 5 , and R 6 are independently hydrogen, C 1-3 Alkyl, and -(C 1-3 alkyl)CN, or R 4 and R 5 together with the carbon atoms to which they are attached, form C 3-6 In some embodiments, R 7 teeth [ka] In some embodiments, R 8 is selected from hydrogen, halogen, —CH, —CHF, —CHF, and —CF, for example, R 8 is hydrogen. In some embodiments, R 9 is selected from hydrogen, halogen, —CH, —CHF, —CHF, and —CF, for example, R9 is selected from hydrogen and chloro.

[0028] In some embodiments, for the compounds described herein, R 1 is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is selected from one or more R 20 and L 1 can have 1, 2, 3, or 4 R's 20 and L is a 10-membered bicyclic heterocycle optionally substituted with 2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene are each selected from the group consisting of 1, 2, or 3 R 20 and R 7 teeth [ka] In some embodiments, R 1 -L 1 teeth [ka] and L 2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene can be substituted with one, two, or three R 20 and R 7 teeth [ka] is.

[0029] In some embodiments, the compounds described herein include R 7 When R is replaced with hydrogen, the compound reversibly binds to the K-Ras protein. 7In some embodiments, the compounds described herein reversibly bind to K-Ras proteins with an IC50 of less than 1000 nM, less than 250 nM, less than 100 nM, or even less, as assessed by an HTRF assay when -C(O)R is replaced with hydrogen. 7 In some embodiments, the compound binds reversibly to K-Ras proteins when -C(O)R is replaced with hydrogen. 7 is substituted with hydrogen, the IC is less than 1000 nM, less than 250 nM, less than 100 nM, or even lower as assessed by HTRF assay 50 It reversibly binds to the K-Ras protein.

[0030] In some embodiments, the present disclosure provides a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0031] In certain aspects, the present disclosure provides a method for modifying a Ras mutant protein, comprising contacting the Ras mutant protein with an effective amount of a compound, salt, or solvate described herein. In some embodiments, the modified Ras mutant protein exhibits a reduced Ras signaling output. The reduced Ras signaling output may be evidenced by one or more outputs selected from: (i) an increased steady-state level of a GDP-bound modified protein; (ii) a decreased steady-state level of a GTP-bound modified protein; (iii) a decreased steady-state level of phosphorylated AKTs473; (iv) a decreased phosphorylated ERK T202 / Y204; (v) a decreased phosphorylated S6 S235 / 236; (vi) reduced cell proliferation of tumor cells expressing a Ras G12S mutant protein; and (vii) reduced Ras interaction with Ras pathway signaling proteins. In some embodiments, the modified Ras mutant protein comprises an amino acid sequence selected from SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, and respective fragments thereof comprising a serine residue corresponding to position 12 of SEQ ID NO: 1. In some embodiments, the modified Ras mutant protein comprises the amino acid sequence of SEQ ID NO: 1, or a respective fragment thereof comprising a serine residue corresponding to position 12 of SEQ ID NO: 1. In some embodiments, the contacting comprises: [ka] In some embodiments, the modified Ras mutant protein comprises the amino acid sequence of SEQ ID NO: 1 or a fragment thereof containing a serine residue corresponding to position 12 of SEQ ID NO: 1, and the compound selectively labels the serine residue compared to (i) an aspartic acid residue of a K-Ras G12D mutant protein (the aspartic acid corresponds to position 12 of SEQ ID NO: 2); (ii) a valine residue of a K-Ras G12V mutant protein (the valine corresponds to position 12 of SEQ ID NO: 3); and / or (iii) a glycine residue of a K-Ras wild-type protein (the glycine corresponds to position 12 of SEQ ID NO: 1). In some embodiments, the compound selectively labels the serine residue by at least 2-fold, 3-fold, 4-fold, 5-fold, or more when assayed under comparable conditions. In some embodiments, the contacting occurs in vivo or in vitro.

[0032] In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a method of treating cancer in a subject containing a Ras mutant protein, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modifying the subject's Ras mutant protein, wherein the compound is characterized in that, upon contact with the Ras mutant protein, the Ras mutant protein is covalently modified at a residue corresponding to residue 12 of SEQ ID NO: 1, thereby causing the modified Ras mutant protein to exhibit reduced Ras signaling output. In some embodiments, the cancer is a solid tumor or a hematological cancer. In some embodiments, the cancer contains a K-Ras G12S mutant protein.

[0033] In certain aspects, the present disclosure provides a method for modulating the signaling output of a Ras protein, comprising contacting the Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the signaling output of the Ras protein. In certain aspects, the present disclosure provides a method for inhibiting cell proliferation, comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting proliferation of the cell.

[0034] Some of the methods described herein include administering an additional agent. In some embodiments, the additional agent is selected from the group consisting of (1) an inhibitor of MEK, (2) an inhibitor of epidermal growth factor receptor (EGFR) and / or a mutant thereof, (3) an immunotherapeutic agent, (4) a taxane, (5) an antimetabolite, (6) an inhibitor of FGFR1 and / or FGFR2 and / or FGFR3 and / or a mutant thereof, (7) a mitotic kinase inhibitor, (8) an anti-angiogenic agent, (9) a topoisomerase inhibitor, (10) a platinum-containing compound, (11) a c-MET and and / or mutants thereof, (12) inhibitors of BCR-ABL and / or mutants thereof, (13) inhibitors of ErbB2 (Her2) and / or mutants thereof, (14) inhibitors of AXL and / or mutants thereof, (15) inhibitors of NTRK1 and / or mutants thereof, (16) inhibitors of RET and / or mutants thereof, (17) inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or mutants thereof (18) inhibitors of ERK and / or its mutants, (19) MDM2 inhibitors, (20) inhibitors of mTOR, (21) inhibitors of IGF1 / 2 and / or IGF1-R, (22) inhibitors of CDK9, (23) inhibitors of farnesyltransferase, (24) inhibitors of the SHIP pathway, (25) inhibitors of SRC, (26) inhibitors of JAK, (27) PARP inhibitors, (28) ROS1 inhibitors, (29) inhibitors of the SHP pathway, (30) inhibitors of Src, FLT3, HDA In some embodiments, the additional agent comprises an inhibitor of SHP2 selected from RMC-4630, ERAS-601, TNO155, JAB-3068, IACS-13909 / BBP-398, SHP099, and RMC-4550.In some embodiments, the additional agent comprises an inhibitor of SOS selected from BI-3406, MRTX0902, BAY 293, RMC-5845, and BI-1701963. In some embodiments, the additional agent comprises an inhibitor of EGFR selected from afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, and EGF-816. In some embodiments, the additional agent comprises an inhibitor of MEK selected from trametinib, cobimetinib, binimetinib, selumetinib, refametinib, and AZD6244. In some embodiments, the additional agent comprises an inhibitor of ERK selected from ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, and lavoxertinib. In some embodiments, the additional agent comprises an inhibitor of CDK4 / 6 selected from palbociclib, ribociclib, and abemaciclib. In some embodiments, the additional agent comprises an inhibitor of BRAF selected from sorafenib, vemurafenib, dabrafenib, encorafenib, regorafenib, and GDC-879.

[0035] (Incorporated 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.

[0036] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [Brief explanation of the drawings]

[0037] [Figure 1]Figure 1 shows a top-to-bottom sequence alignment of various wild-type Ras proteins, including K-Ras, H-Ras, N-Ras, RalA, and RalB. DETAILED DESCRIPTION OF THE INVENTION

[0038] (Detailed explanation) Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event of multiple definitions for terms herein, those in this section 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. Chemical structures are named herein according to the IUPAC convention as implemented in ChemDraw® software (Perkin Elmer, Inc., Cambridge, MA). The section headings used herein are merely organizational and should not be construed as limiting the subject matter described. As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Furthermore, the use of the terms "including," as well as other forms such as "include," "includes," and "included," is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0039] When used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, "C x-y " or "C x -C y " is meant to include groups containing x to y carbons in the chain. For example, "C x-yThe term "alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched-chain alkyl groups, containing x to y carbons in the chain.

[0040] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched alkyl groups. Alkyl groups have 1 to 12 carbon atoms (e.g., C 1-12 alkyl), e.g., 1 to 8 carbon atoms (C 1-8 alkyl) or 1 to 6 carbon atoms (C 1-6 The alkyl group may contain a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise expressly stated herein, the alkyl group is optionally substituted with one or more substituents, such as those described herein.

[0041] The term "haloalkyl" refers to an alkyl group that is substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0042] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group, including straight-chain and branched alkenyl groups, containing at least one double bond. Alkenyl groups are groups containing 2 to 12 carbon atoms (e.g., C 2-12 alkenyl), e.g., 2 to 8 carbon atoms (C 2-8 alkenyl) or 2 to 6 carbon atoms (C 2-6The alkenyl group may contain an alkyl group (e.g., alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise in the specification, alkenyl groups are optionally substituted with one or more substituents, such as those described herein.

[0043] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group, including straight-chain and branched alkynyl groups, containing at least one triple bond. Alkynyl groups are groups of 2 to 12 carbon atoms (e.g., C 2-12 alkynyl), e.g., 2 to 8 carbon atoms (C 2-8 alkynyl) or 2 to 6 carbon atoms (C 2-6 The alkynyl group may contain an alkynyl group (alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, alkynyl groups are optionally substituted with one or more substituents, such as those described herein.

[0044] An "alkylene" or "alkylene chain" is an alkylene group having 1 to 12 carbon atoms (e.g., C 1-12 alkylene), e.g., 1 to 8 carbon atoms (C 1-8 alkylene) or 1 to 6 carbon atoms (C 1-6 "Alkylene" refers to a substituted or unsubstituted divalent saturated hydrocarbon group, including straight-chain alkylene groups and branched alkylene groups containing an alkylene group (alkylene). Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, "alkenylene" and "alkynylene" refer to an alkylene group, as defined above, containing one or more carbon-carbon double or triple bonds, respectively. The point of attachment of the alkylene, alkenylene, or alkynylene chain to the rest of the molecule can be through one carbon or any two carbons of the chain. Unless stated otherwise herein, an alkylene, alkenylene, or alkynylene group is optionally substituted with one or more substituents, such as those described herein.

[0045] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to substituted or unsubstituted alkyl, alkenyl, and alkynyl groups, respectively, in which one or more, e.g., 1, 2, or 3, of the carbon atoms are replaced with a heteroatom such as O, N, P, Si, S, or a combination thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may be optionally oxidized, and any nitrogen heteroatom may be quaternized. When a numerical range is specified, it refers to the total chain length. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the remainder of the molecule can be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless otherwise stated herein, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted with one or more substituents, such as those described herein.

[0046] "Heteroalkylene," "heteroalkenylene," and "heteroalkynylene" refer to substituted or unsubstituted alkylene, alkenylene, and alkynylene groups, respectively, in which one or more, e.g., 1, 2, or 3, of the carbon atoms are replaced with a heteroatom such as O, N, P, Si, S, or a combination thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may be optionally oxidized, and any nitrogen heteroatom may be optionally quaternized. When a numerical range is specified, it refers to the total chain length. For example, a 3- to 8-membered heteroalkylene group has a chain length of 3 to 8 atoms. The point of attachment of the heteroalkylene, heteroalkenylene, or heteroalkynylene chain to the rest of the molecule can be through either one heteroatom or one carbon, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkylene, heteroalkenylene, or heteroalkynylene chain. Unless stated otherwise specifically in the specification, a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted with one or more substituents, such as those described herein.

[0047] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is a carbon atom. 3-10 Monocyclic ring, C 6-12 Bicyclic ring, C 7-18 polycyclic ring, C 5-12 Spirocyclic rings, and C 6-12 It may contain bridged rings. Each ring of a bicyclic or polycyclic carbocycle may be selected from saturated rings, unsaturated rings, and aromatic rings. In some embodiments, a carbocycle is 6-10 C such as aryl 6-12 In some embodiments, the carbocycle is a C 3-12 In some embodiments, the carbocycle is a C 5-12A carbocycle is a cycloalkenyl group. In an exemplary embodiment, an aromatic ring, such as phenyl, may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as long as valence permits, is included in the definition of a carbocycle. A carbocycle may include fused rings, bridged rings, spirocyclic rings, saturated rings, unsaturated rings, aromatic rings, or any combination thereof. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantine, phenyl, indanyl, and naphthyl. Unless otherwise specified herein, a carbocycle may be substituted with one or more substituents, such as those described herein.

[0048] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms, e.g., 1, 2, or 3 heteroatoms selected from O, S, and N. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 7- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings. Each ring in a bicyclic or polycyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. A heterocycle may be attached to the remainder of the molecule through any atom of the heterocycle, such as a carbon or nitrogen atom of the heterocycle, as long as valence permits. In some embodiments, a heterocycle is a 5- to 10-membered heteroaryl group, e.g., a 5- or 6-membered heteroaryl. In some embodiments, a heterocycle is a 3- to 12-membered heterocycloalkyl group. A heterocycle may include fused, bridged, spirocyclic, saturated, unsaturated, or aromatic rings, or any combination thereof. In exemplary embodiments, heterocyclic rings, such as pyridyl, may be fused to saturated or unsaturated rings, such as cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocyclic rings include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Unless otherwise specified herein, heterocyclic rings may be substituted with one or more substituents, such as those described herein.

[0049] "Heterocycle" refers to an aromatic ring containing one or more heteroatoms, e.g., 1, 2, or 3 heteroatoms selected from O, S, and N. Heterocycles include 5- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 7- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings. As used herein, heteroaryl rings may be selected from monocyclic or bicyclic rings, including fused, spirocyclic, and bridged ring systems, where at least one of the rings in the ring system is aromatic. Heteroatoms in a heteroaryl may be oxidized. One or more nitrogen atoms, if present, may be quaternized. A heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl, such as a carbon or nitrogen atom of the heteroaryl, as valence permits. Examples of heteroaryl groups include, but are not limited to, azepinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and thienyl groups. Unless otherwise specified herein, heteroaryl can be optionally substituted with one or more substituents, such as those described herein.

[0050] Unless otherwise stated, hydrogen atoms are implied in structures drawn herein as necessary to satisfy valence requirements.

[0051] Bond or dashed bond " [ka] "A wavy line drawn across " [ka] " are used interchangeably herein to indicate where a bond break or bond occurs. For example, the structure [ka] In R 1 but, [ka] When R is 2-fluoro-6-hydroxyphenyl, 1 teeth, [ka] It can be depicted as:

[0052] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbon or heteroatoms of the structure. It is understood that "substituted" or "substituted with" includes the implicit connotation that such substitution is in accordance with the permissible valences of the replacing atom and substituent, and that the substitution results in a stable compound that does not undergo spontaneous transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term substituted is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, can have any of the permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom.

[0053] The compounds disclosed herein, for example compounds of formula (I) or (II), Halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 (Two substituents attached to the same or adjacent atoms may be bonded, and C 3-12 Forms a carbocyclic ring or a 3- to 12-membered heterocyclic ring, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles are not substituted by halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(=O)(=NR 22 )N(R 22 )(R 23 and optionally substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 together with the carbon atoms to which they are attached, form C 3-12 forming a carbocyclic or 3- to 12-membered heterocyclic ring, each of which is independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl, and —OH; R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), -C 0-6 Alkyl-(C 3-12 carbocyclic) and -C 0-6 Alkyl-(3-12 membered heterocycle) is a 3-membered heterocycle containing halogen and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 23 independently in each occurrence hydrogen and C 1-6 alkyl or R bonded to a 3- to 10-membered heterocycle of the same nitrogen atom form 22 and R 23 is.

[0054] In some embodiments, a compound disclosed herein, e.g., a compound of formula (I) or (II), Halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C3-12 carbocyclic), -(2-6 membered heteroalkyl)-(C3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR22, -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , and -S(O)N(R 22 )(R 23 )-, which may be substituted or unsubstituted, for example, 1, 2 or 3, and 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles are not substituted by halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , and =C(R 21 )2 may be substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), -C 0-6 Alkyl-(C 3-12 carbocyclic) and -C 0-6 Alkyl-(3-12 membered heterocycle) is a 3-membered heterocycle containing halogen and C 1-6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R 23 independently in each occurrence hydrogen and C 1-6 alkyl or R bonded to a 3- to 10-membered heterocycle of the same nitrogen atom form 22 and R 23 is.

[0055] In some embodiments, the compounds disclosed herein, e.g., compounds of Formula (I) or (II), may be selected from the group consisting of, for example, halogen, oxo, ═NH, —CN, —NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10carbocyclic ring), a 3- to 10-membered heterocyclic ring, -CH2- (a 3- to 10-membered heterocyclic ring), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3, and 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocycle), 3- to 10-membered heterocycle, and -CH2- (3- to 10-membered heterocycle) are optionally substituted with 1, 2, or 3 groups independently selected from halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3.

[0056] It will be understood by those skilled in the art that, where appropriate, the substituents themselves can be substituted. Unless specifically designated as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0057] When divalent substituents are designated herein by their conventional chemical formula written from left to right, they are intended to encompass the isomers resulting from writing the structure from right to left, e.g., -CHO- is also intended to encompass -OCH-.

[0058] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, an "optionally substituted" group may be either unsubstituted or substituted.

[0059] The compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0060] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but a different atomic mass or mass number from that found predominantly in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen is: 1 H (protium), 2 H (deuterium), and 3 H (tritium) has three natural isotopes. Protium is the most abundant isotope of hydrogen in nature. Enriching with deuterium may provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds useful for investigating drug elimination and metabolic pathways in vivo. Examples of isotopes that may be incorporated into the compounds of the present disclosure include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 36 Cl, and 18 Of particular note are compounds of formula (I) that are enriched in tritium or carbon-14, which may be used, for example, in tissue distribution studies, compounds of the present disclosure that are enriched in deuterium, particularly at metabolic sites, e.g., resulting in compounds with greater metabolic stability, and compounds of formula (I) that may be used, for example, in positron emission tomography (PET) studies. 11 C. 18 F, 15 O, and 13A compound of formula (I) enriched in a positron-emitting isotope such as N. Isotopically enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0061] As used herein, the phrases "of the formula," "having the formula," or "having the structure" are not intended to be limiting and are used in the same manner as the term "comprises" is commonly used. For example, when a structure is depicted, it is understood that all stereoisomers and tautomeric forms are encompassed unless otherwise specified.

[0062] Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which asymmetric centers may be defined in terms of absolute stereochemistry as (R)- or (S)-. In some embodiments, to optimize the therapeutic activity of compounds of the present disclosure, e.g., for treating fibrosis, it may be desirable for carbon atoms to have a particular configuration (e.g., (R,R), (S,S), (S,R), or (R,S)), or to be enriched in stereoisomeric forms having such configurations. Compounds of the present disclosure may be provided as racemic mixtures. Thus, the present disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated. When chemical structures are depicted herein without any stereochemistry, it is understood that all possible stereoisomers are encompassed by such structures. Similarly, where a particular stereoisomer is shown or named herein, those of skill in the art will understand that, unless otherwise indicated, small amounts of other stereoisomers may be present in the compositions of the present disclosure, provided that the utility of the composition as a whole is not obviated by the presence of such other isomers. Individual stereoisomers can be obtained by numerous methods known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using suitable chiral stationary phases or supports, or chemically converting them to diastereomers, separating the diastereomers by conventional means such as chromatography or recrystallization, and then regenerating the original stereoisomer.

[0063] Additionally, where applicable, all cis-trans or E / Z isomeric (geometric isomeric), tautomeric, and topoisomeric forms of the compounds described herein are included within the scope of the present disclosure, unless otherwise specified.

[0064] The term "pharmaceutically acceptable," as used in the subject compositions and methods, refers to a substance that is not biologically or otherwise unacceptable. For example, the term "pharmaceutically acceptable carrier" refers to a substance, such as an adjuvant, excipient, glidant, sweetener, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier, that can be incorporated into a composition and administered to a patient without producing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition. Such pharmaceutically acceptable substances typically have met the required standards of toxicological and manufacturing testing and include substances identified by the U.S. Food and Drug Administration as suitable inactive ingredients.

[0065] The terms "salt" and "pharmaceutically acceptable salt" refer to a salt prepared from a base or an acid. A pharmaceutically acceptable salt is suitable for administration to a patient, such as a mammal (e.g., a salt that has acceptable mammalian safety for a given dosing regimen). Salts can be formed from inorganic bases, organic bases, inorganic acids, and organic acids. Furthermore, when a compound contains both a basic moiety, such as an amine, pyridine, or imidazole, and an acidic moiety, such as a carboxylic acid or tetrazole, zwitterions may be formed and are included within the term "salt" as used herein. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0066] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, 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, and 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, disulfate, 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. Amino acid salts 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)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to those skilled in the art.

[0067] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and characteristics of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, 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.

[0068] 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 condition being treated, the subject's weight and age, the severity of the 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, such as those associated with a particular goal or objective, such as any described herein. The term "effective amount" also applies to a dose that will provide 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 administration regimen to be followed, whether or not it is co-administered with other compounds, the timing of administration, the tissue to be imaged, and the physical delivery system through which the agent is delivered.

[0069] As used herein, "treating" or "treatment" refers to an approach to obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition (such as cancer) in a subject, including, but not limited to: (a) preventing the onset of a disease or medical condition, e.g., preventing the recurrence of a disease or medical condition, or prophylactic treatment of a subject susceptible to a disease or medical condition; (b) ameliorating a disease or medical condition, e.g., eliminating or causing regression of a disease or medical condition in a subject; (c) inhibiting a disease or medical condition, e.g., slowing or halting the progression of a disease or medical condition in a subject; or (d) alleviating the symptoms of a disease or medical condition in a subject. For example, "treating cancer" includes preventing the onset of cancer, ameliorating cancer, inhibiting cancer, and alleviating the symptoms of cancer. A therapeutic benefit is also achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, although the subject may still be afflicted with the underlying disorder.

[0070] A "therapeutic effect," as that term is used herein, encompasses the therapeutic and / or prophylactic benefits described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0071] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds capable of inhibiting the biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., K-Ras). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target, but specifically included within this definition are compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member.

[0072] The terms "selective inhibition" or "selectively inhibit" refer to the ability of a bioactive agent to preferentially reduce target signaling activity relative to off-target signaling activity, through direct or indirect interaction with the target.

[0073] The terms "subject" and "patient" refer to animals such as mammals, e.g., humans. The methods described herein can be useful for both human therapy and veterinary applications. In some embodiments, the subject is a mammal, such as a human. "Mammal" includes humans, as well as domestic animals, both laboratory animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wildlife.

[0074] The terms "therapeutic agent," "therapeutic agent," or "treatment agent" are used interchangeably and refer to a molecule or compound that has some beneficial effect when administered to a subject. Beneficial effects include enabling a diagnostic determination, ameliorating a disease, symptom, disorder, or pathological condition, reducing or preventing the occurrence of a disease, symptom, disorder, or condition, and generally counteracting a disease, symptom, disorder, or pathological condition.

[0075] 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. The terms also encompass modified amino acid polymers, such as disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein, the term "amino acid" refers to either 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.

[0076] 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. Non-limiting examples of polynucleotides include: coding or non-coding regions of a gene or gene fragment, loci (locuses) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, small 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. Polynucleotides 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 added 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 labeling components or other binding targets.

[0077] 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. The transcript and the encoded polypeptide may be collectively referred to as a "gene product." If the polynucleotide is derived from genomic DNA, expression may also include splicing of the mRNA in a eukaryotic cell.

[0078] An "antigen" is a moiety or molecule that contains an epitope and, as such, also specifically binds to an antibody. An "antigen-binding unit" can be the entirety of a full-length antibody or a fragment (or fragments), a structural variant thereof, a functional variant thereof, or a combination thereof. Full-length antibodies can be, for example, monoclonal antibodies, recombinant antibodies, chimeric antibodies, deimmunized antibodies, humanized antibodies, and human antibodies. Examples of fragments of full-length antibodies include 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 (V-NAR domains) found in sharks, single domain antibodies (sdAbs, e.g., "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 include, but are not limited to, scFv, di-scFv, or bi(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).

[0079] The terms "antibody" and "antibodies" include any antigen-binding unit, including, but not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, and other epitope-binding fragments.

[0080] "Prodrug" is intended to refer to a compound that can be converted under physiological conditions into a biologically active compound (e.g., a compound of formula (II)) described herein by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. A prodrug is inactive when administered to a subject, but is converted into an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," (1987) ACS Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, each of which is fully incorporated herein by reference). The term "prodrug" is also meant to include any covalently bonded carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein may typically be prepared by modifying functional groups present in the active compound such that the modifications are cleaved to the parent active compound either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy group, an amino group, or a mercapto group is bonded to any group that cleaves to form a free hydroxy group, a free amino group, or a free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of a hydroxy functional group in the active compound, or acetamide, formamide, and benzamide derivatives of an amine functional group.

[0081] The term "in vivo" refers to events that occur within a subject's body. The term "ex vivo" refers to events that occur initially outside a subject's body for later application in vivo within the subject's body. For example, ex vivo preparation can involve preparing cells outside a subject's body with the intent of introducing the prepared cells into the same or a different subject. The term "in vitro" refers to events that occur outside a subject's body. For example, an in vitro assay includes any assay performed outside a subject's body. In vitro assays include cell-based assays in which live or dead cells are employed. In vitro assays include cell-free assays in which intact cells are not used.

[0082] The present disclosure is also meant to encompass in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Accordingly, the present disclosure includes compounds produced by a process comprising administering a compound disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the present disclosure to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0083] 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, the Rho subfamily, the Rab subfamily, the Rap subfamily, the Arf subfamily, the Ran subfamily, the Rheb subfamily, the RGK subfamily, the Rit subfamily, the Miro subfamily, and an unclassified subfamily. In some embodiments, the Ras protein is selected from the group consisting of KRAS (also interchangeably referred to 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, such as KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

[0084] The terms "mutant Ras" and "Ras mutant," as 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 may be an introduced mutation, a naturally occurring mutation, or a non-naturally occurring mutation. In some embodiments, the mutation may 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 may be consecutive, non-consecutive, or a combination thereof. In some embodiments, the mutation may be present at any position in Ras. In some embodiments, when optimally aligned, mutations may be present at positions 12, 13, 62, 92, 95, 96 (e.g., Y96D) of Ras relative to SEQ ID NO: 1, or any combination thereof. In some embodiments, the 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 is less than about or at most 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 50 amino acids in length. In some embodiments, the amino acid of the mutation 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 polypeptide or a 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).

[0085] As used herein, when applied to an amino acid residue in a polypeptide sequence, the term "corresponding to" or "corresponding to" refers to the correspondence of that amino acid relative to a reference sequence when optimally aligned (e.g., the alignment may be a primary sequence alignment or a three-dimensional structural alignment of a folded protein, taking into account gaps, insertions, and mismatches). For example, a serine residue in a K-Ras G12S mutant refers to the serine corresponding to residue 12 of SEQ ID NO:4, which can serve as a reference sequence. For example, an aspartic acid residue in a K-Ras G12D mutant refers to the aspartic acid corresponding to residue 12 of SEQ ID NO:2, which can serve as a reference sequence. Where an amino acid in a mutant Ras protein corresponds to an amino acid position in a wild-type Ras protein, it is understood that the amino acid in the mutant Ras protein may be a different amino acid (e.g., G12D, in which the wild-type G at position 12 is replaced with aspartic acid at position 12 of SEQ ID NO:1), but the mutant amino acid is at the position corresponding to the wild-type amino acid (e.g., in SEQ ID NO:1). In embodiments, the modified Ras mutant proteins disclosed herein may include a truncation at the C-terminus or an N-terminus preceding the G12S mutant serine residue. The G12S mutant serine residue in such an N-terminal truncated modified mutant is still considered to correspond to position 12 of SEQ ID NO:1. Furthermore, the aspartic acid residue at position 12 of SEQ ID NO:2 finds the corresponding residue in SEQ ID NOs:6 and 8.

[0086] As used interchangeably herein, the terms "Switch II pocket" and "Switch II binding pocket" refer to the binding pocket formed under the "Switch II" loop of Ras. In some embodiments, the Switch II pocket is located between the central beta sheet (β-sheet) and the alpha (α)2 and α3 helices of Ras. In some embodiments, the Switch II binding pocket is located at or at least about 5, 200 nanometers (nm) or more from positions 110, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 2, 60, 99, or any combination thereof. In some embodiments, the Switch II binding pocket is located up to about 5, 200 nm, or more from positions 110, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 2, 60, 99, or any combination thereof. In some cases, the Switch II pocket can be formed upon binding to a small molecule (e.g., a small molecule inhibitor). Alternatively, the Switch II pocket can be formed prior to binding to the small molecule.

[0087] In some embodiments, the Switch II pocket of Ras comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more amino acid residues, or 3 to 15 residues selected from the group consisting of V7, V9, G10, G12, G12X mutants (e.g., G12C, G12S, G12D, or G12V) of SEQ ID NO: 1, K14, K16, P34, T58, A59, G60, Q61, E62, E63, Y64, S65, R68, D69, M72, D92, H95, Y96, Q99, I100, R102, and V103 of SEQ ID NO: 1, or the corresponding amino acid residues in an HRAS or NRAS protein. In some embodiments, the Switch II pocket of Ras comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acid residues selected from the group consisting of G10, G12, a G12X mutant (e.g., G12C, G12S, G12D, or G12V) of SEQ ID NO: 1, K16, P34, T58, A59, E62, R68, D69, H95, Q99, R102, and the corresponding amino acid residues of V103 of SEQ ID NO: 1, or the corresponding amino acids of an HRAS or NRAS protein.

[0088] The term "leaving group" is used herein in accordance with its well-understood meaning in chemistry to refer to an atom or group of atoms that separates from the rest of a molecule, taking with it the electron pair that used to be the bond between the leaving group and the rest of the molecule.

[0089] A "degradation-promoting agent" is a compound capable of binding to a ubiquitin ligase protein (e.g., an E3 ubiquitin ligase protein) or a protein capable of binding to a ubiquitin ligase protein, forming a protein complex capable of binding the ubiquitin protein to a target protein. In embodiments, the degradation-promoting agent is capable of binding to an E3 ubiquitin ligase protein or a protein complex comprising an E3 ubiquitin ligase protein. In embodiments, the degradation-promoting agent is capable of binding to an enzyme that binds to E2 ubiquitin. In embodiments, the degradation-promoting agent is capable of binding to a protein complex comprising an enzyme that binds to E2 ubiquitin and an E3 ubiquitin ligase protein. Modified Proteins and Compounds

[0090] In certain aspects, the present disclosure provides a modified Ras protein comprising a compound covalently attached to an amino acid residue of the aforementioned Ras protein, wherein the modified Ras protein provides a compound of formula (I'). [ka] During the ceremony, The dashed lines represent covalent bonds to amino acid residues; R 1 is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 20 may be substituted with L 1 is one or more R 20 is a 5- to 20-membered heterocycle optionally substituted with L 2 is a bond, C 1-4 Alkylene, 2-4 membered heteroalkylene, -O-, -N(R 19 )-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R 19 -, -N(R 19 )S(O)2-, -N(R 19 )S(O)-, -N(R 19 )P(O)R 19 -, -S(O)2N(R19 )-, -S(O)N(R 19 )-, -P(O)R 19 N(R 19 )-, -OS(O)2-, -OS(O)-, -OP(O)R 19 -, -S(O)2O-, -S(O)O-, and -P(O)R 19 O-, C 1-4 Alkylene and 2- to 4-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with L 3 and R 2 together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3-8 form a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is substituted by one, two, or three R 20 may be substituted with L 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which may be selected from the group consisting of 1, 2, or 3 R 20 and L 3 and R 6 is not piperazine, or R 2 and R 6 together with the atoms to which they are attached, can consist of one, two, or three R 20 and forming an optionally substituted 3- to 8-membered monocyclic heterocycloalkyl, wherein L 3 is a bond, R 2 is R 20 , or R 2 and R 3 and together with the carbon atoms to which they are attached, one, two, or three R 20 C optionally substituted with 3-6 forming a cycloalkyl, R 3 is hydrogen and R 20 is selected from R 4 , R 5 , and R 6 are each independently hydrogen and R 20 or R 4 and R 5 together with the carbon atoms to which they are attached, can consist of one, two, or three R 20 C which may be substituted 3-6 forming a cycloalkyl, R 19 is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -OH, and -O(C 1-6 alkyl), and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), and -O(C 1-6 alkyl) can be one, two, or three R 20 may be substituted with R 20 is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22 , -SR 22 , -N(R22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 and two R's bonded to the same or adjacent atoms are selected from 20 is combined with C 3-12 may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2-6 membered heteroalkyl)-(C3-12 carbocyclic), -C 0-6 Alkyl-(3-12 membered heterocycle), -(2-6 membered heteroalkyl)-(3-12 membered heterocycle), C3-12 carbocycle, and 3-12 membered heterocycle are not substituted with halogen, oxo, -CN, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(=O)(=NR 22 )N(R 22 )(R 23 and optionally substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 form a 3- to 12-membered heterocyclic ring together with the carbon atoms to which they are attached, and C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), C 0-6 Alkyl-(3-12 membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles may contain one, two, or three R 20 may be substituted with R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 Alkyl-(3- to 12-membered heterocycle) is a heterocyclic ring consisting of one, two, or three R 20 may be substituted with R 23 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 22 and R 23 may be one, two, or three R together with the same nitrogen atom to which they are attached. 20 and forming a 3- to 10-membered heterocycle which may be substituted by the following:

[0091] In certain aspects, the present disclosure provides a modified Ras protein comprising a compound covalently attached to an amino acid residue of said Ras protein, wherein the modified Ras protein provides a compound of formula (I'): [ka] During the ceremony, The dashed lines represent covalent bonds to amino acid residues; R 1 is C 3-12carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 20 may be substituted with L 1 is one or more R 20 is a 5- to 20-membered heterocycle optionally substituted with L 2 is a bond, C 1-4 Alkylene, 2-4 membered heteroalkylene, -O-, -N(R 19 )-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R 19 -, -N(R 19 )S(O)2-, -N(R 19 )S(O)-, -N(R 19 )P(O)R 19 -, -S(O)2N(R 19 )-, -S(O)N(R 19 )-, -P(O)R 19 N(R 19 )-, -OS(O)2-, -OS(O)-, -OP(O)R 19 -, -S(O)2O-, -S(O)O-, and -P(O)R 19 O-, C 1-4 Alkylene and 2- to 4-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with L 3 and R 2 together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3-8 forming a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) is halogen, -OH, -CN, C1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); L 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 and R 6 is not piperazine, or R 2 and R 6 together with the atoms to which they are attached, form halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted by 1, 2, or 3 substituents selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 is a bond, R 2 is halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl or R 2 and R 3 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 4 , R 5 , and R 6 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6cycloalkyl or R 4 and R 5 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 19 is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OH, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl), R 20 is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 and two R's bonded to the same or adjacent atoms are selected from 20 is combined with C 3-12 may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles are not substituted by halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(=O)(=NR 22 )N(R 22 )(R 23 and optionally substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 together with the carbon atoms to which they are attached, form C 3-12 forming a carbocyclic or 3- to 12-membered heterocyclic ring, each of which is independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl, and —OH; R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6alkyl-(3- to 12-membered heterocycle); R 23 independently in each occurrence hydrogen and C 1-6 alkyl or R bonded to a 3- to 10-membered heterocycle of the same nitrogen atom form 22 and R 23 is.

[0092] In some embodiments, the modified protein of formula (I') is a modified protein of formula (I'-a), (I'-b), (I'-c), or (I'-d). [ka] wherein: W 1 , W 3 , W 4 , and W 5 are each independently N(R 10 ), C(R 11 )2, C(O), O, S(O), and S(O)2; W 2 is N and C(R 11 ) and n1 and n3 are each independently selected from 0, 1, 2, 3, 4, and 5; n4 and n5 are each independently selected from 0, 1, 2, 3, 4, and 5; R 10 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); R 11 is independently in each occurrence hydrogen, halogen, -OH, -CN, C1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), or two R attached to the same carbon atom 11 Selected from C 3-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl).

[0093] In some embodiments, for compounds of Formula (I'), the amino acid is selected from serine, tyrosine, cysteine, lysine, and histidine. In some embodiments, the amino acid is serine. In some embodiments, the amino acid is tyrosine. In some embodiments, the amino acid is cysteine. In some embodiments, the amino acid is lysine. In some embodiments, the amino acid is histidine. In some embodiments, the amino acid is serine or cysteine.

[0094] In certain aspects, the present disclosure provides a modified human K-Ras protein comprising a compound covalently attached to a serine residue having the structure of Formula (I), wherein the serine residue corresponds to position 12 of SEQ ID NO:4. [ka] During the ceremony, The dashed lines represent the bonds between serine residues of the K-Ras mutant protein and alanine 11 and glycine 13, respectively; R 1 is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 20may be substituted with L 1 is one or more R 20 is a 5- to 20-membered heterocycle optionally substituted with L 2 is a bond, C 1-4 Alkylene, 2-4 membered heteroalkylene, -O-, -N(R 19 )-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R 19 -, -N(R 19 )S(O)2-, -N(R 19 )S(O)-, -N(R 19 )P(O)R 19 -, -S(O)2N(R 19 )-, -S(O)N(R 19 )-, -P(O)R 19 N(R 19 )-, -OS(O)2-, -OS(O)-, -OP(O)R 19 -, -S(O)2O-, -S(O)O-, and -P(O)R 19 O-, C 1-4 Alkylene and 2- to 4-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with L 3 and R 2 together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3-8 form a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is substituted by one, two, or three R 20 may be substituted with L 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which may be selected from the group consisting of 1, 2, or 3 R 20 and L 3 and R 6 is not piperazine, or R 2 and R 6 together with the atoms to which they are attached, can consist of one, two, or three R 20 and forming an optionally substituted 3- to 8-membered monocyclic heterocycloalkyl, wherein L 3 is a bond, R 2 is R 20 , or R 2 and R 3 and together with the carbon atoms to which they are attached, one, two, or three R 20 C optionally substituted with 3-6 forming a cycloalkyl, R 3 is hydrogen and R 20 is selected from R 4 , R 5 , and R 6 are each independently hydrogen and R 20 or R 4 and R 5 together with the carbon atoms to which they are attached, can consist of one, two, or three R 20 C which may be substituted 3-6 forming a cycloalkyl, R 19 is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -OH, and -O(C 1-6 alkyl), and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), and -O(C 1-6 alkyl) can be one, two, or three R 20 may be substituted with R 20 is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 and two R's bonded to the same or adjacent atoms are selected from 20 is combined with C 3-12may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles are not substituted by halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(=O)(=NR 22 )N(R 22)(R 23 and optionally substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 form a 3- to 12-membered heterocyclic ring together with the carbon atoms to which they are attached, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), C 0-6 Alkyl-(3-12 membered heterocycle), C3-12 carbocycle, and 3-12 membered heterocycle may be selected from 1, 2, or 3 R 20 may be substituted with R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 Alkyl-(3- to 12-membered heterocycle) is a heterocyclic ring consisting of one, two, or three R 20 may be substituted with R 23 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 22 and R 23 may be one, two, or three R together with the same nitrogen atom to which they are attached.20 and forming a 3- to 10-membered heterocycle which may be substituted by the following:

[0095] In certain aspects, the present disclosure provides a modified human K-Ras protein comprising a compound covalently attached to a serine residue having the structure of Formula (I), wherein the serine residue corresponds to position 12 of SEQ ID NO:4. [ka] During the ceremony, The dashed lines represent the bonds between serine residues of the K-Ras mutant protein and alanine 11 and glycine 13, respectively; R 1 is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 20 may be substituted with L 1 is one or more R 20 is a 5- to 20-membered heterocycle optionally substituted with L 2 is a bond, C 1-4 Alkylene, 2-4 membered heteroalkylene, -O-, -N(R 19 )-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R 19 -, -N(R 19 )S(O)2-, -N(R 19 )S(O)-, -N(R 19 )P(O)R 19 -, -S(O)2N(R 19 )-, -S(O)N(R 19 )-, -P(O)R 19 N(R 19 )-, -OS(O)2-, -OS(O)-, -OP(O)R 19 -, -S(O)2O-, -S(O)O-, and -P(O)R 19 O-, C 1-4 Alkylene and 2- to 4-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with L 3 and R 2together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3-8 forming a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) is halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); L 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3haloalkyl), and L 3 and R 6 is not piperazine, or R 2 and R 6 together with the atoms to which they are attached, form halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted by 1, 2, or 3 substituents selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 is a bond, R 2 is halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl or R 2 and R 3 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 3is hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 4 , R 5 , and R 6 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl or R 4 and R 5 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 19 is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OH, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl), R 20 is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 and two R's bonded to the same or adjacent atoms are selected from 20 is combined with C 3-12 may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles are not substituted by halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(=O)(=NR 22 )N(R 22 )(R 23 and optionally substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 together with the carbon atoms to which they are attached, form C 3-12 forming a carbocyclic or 3- to 12-membered heterocyclic ring, each of which is independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl, and —OH; R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle); R 23 independently in each occurrence hydrogen and C 1-6 alkyl or R bonded to a 3- to 10-membered heterocycle of the same nitrogen atom form 22 and R 23 is.

[0096] In some embodiments, the modified protein of formula (I) is a modified protein of formula (Ia), (Ib), (Ic), or (Id). [ka] During the ceremony, W 1 , W 3 , W 4 , and W 5 are each independently N(R 10 ), C(R 11 )2, C(O), O, S(O), and S(O)2; W 2 is N and C(R 11 ) and n1 and n3 are each independently selected from 0, 1, 2, 3, 4, and 5; n4 and n5 are each independently selected from 0, 1, 2, 3, 4, and 5; R 10 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); R 11 is independently in each occurrence hydrogen, halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), or two R attached to the same carbon atom 11 Selected from C 3-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl).

[0097] In some embodiments, the modified Ras mutant proteins described herein are formed by contacting a precursor compound with a serine residue of an unmodified Ras G12S mutant protein, wherein the precursor compound comprises a moiety susceptible to reaction with a nucleophilic serine residue corresponding to position 12 of SEQ ID NO:1. In some embodiments, the modified Ras protein is formed by contacting a compound disclosed herein, such as a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), with a serine residue of an unmodified Ras protein, such as an unmodified K-Ras G12S mutant protein. In some embodiments, the modified Ras protein is formed by contacting a precursor compound with a serine residue of an unmodified Ras G12S mutant protein, wherein the precursor compound comprises a leaving group and a leaving group, and said contacting results in release of the leaving group and formation of the modified protein. In some embodiments, the precursor compound is a compound disclosed herein, such as a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d). In some embodiments, the leaving group is [ka] or a salt or tautomer thereof; R 8 and R 9 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl), and -O(C 1-6 In some embodiments, the leaving group is substituted with 1, 2, or 3 substituents selected from the group consisting of methyl, ... [ka] is.

[0098] In some embodiments, the modified K-Ras G12S protein is formed by contacting a precursor compound with a serine residue of an unmodified Ras G12S mutant protein, the precursor compound comprising a leaving group and a leaving group, wherein the leaving group separates from the remainder of the precursor compound after contacting the precursor compound with the unmodified Ras G12S mutant protein with an electron pair that previously formed a covalent bond between the leaving group and the remainder of the precursor compound. In some embodiments, the modified K-Ras G12S protein is formed by contacting a precursor compound with a serine residue of an unmodified Ras G12S mutant protein, the precursor compound comprising a leaving group and a leaving group, wherein contact results in release of the leaving group and formation of the modified protein. Release of the leaving group can be confirmed by various methods known in the art, including, but not limited to, mass spectrometry. In particular, the molecular weight of the leaving group can be determined by the following formula:

number

[0099] The molecular weight of the modified Ras G12S mutant can be confirmed by mass spectrometry. In some embodiments, when the subject compounds contact an unmodified Ras G12S mutant protein (e.g., K-Ras G12S, H-Ras G12S, or N-Ras G12S), they produce a leaving group with a molecular weight of less than about 200 Da, for example, about 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, or 20 Da. When one or more compounds described herein, such as those in Table 1, contact K-Ras G12S, they produce a leaving group with a molecular weight of less than 120 Da.

[0100] In some embodiments, the modified Ras mutant proteins disclosed herein exhibit reduced Ras signaling output. Reduced signaling output can be confirmed by a variety of methods known in the art. For example, phosphorylation of a substrate or specific amino acid residues thereof can be detected and / or quantified by one or more techniques, such as kinase activity assays, phospho-specific antibodies, Western blots, enzyme-linked immunosorbent assays (ELISAs), cell-based ELISAs, intracellular flow cytometry, mass spectrometry, and multi-analyte profiling. Reduced Ras signaling output can be evidenced by one or more outputs selected from: (i) increased steady-state levels of GDP-bound modified proteins; (ii) decreased steady-state levels of GTP-bound modified proteins; (iii) decreased steady-state levels of phosphorylated AKTs473; (iv) decreased phosphorylated ERK T202 / Y204; (v) decreased phosphorylated S6 S235 / 236; (vi) decreased cell proliferation of tumor cells expressing Ras G12S mutant proteins; and (vii) decreased Ras interaction with Ras pathway signaling proteins. In some embodiments, the reduction is evidenced by two, three, four, or more of items (i)-(vii). In some embodiments, the reduction in Ras signaling output can be evidenced by any one of items (i)-(vii) compared to a control, unmodified, corresponding Ras protein that is not covalently bound to any of the compounds disclosed herein. For example, the control Ras protein described herein can be a Ras protein (e.g., wild-type or mutant) that is not complexed with any of the subject compounds of the present disclosure. The increase in item (i) or the decrease in items (ii)-(vi) can be at least about 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more, when compared to a control Ras protein.In some embodiments, the decreased interaction of Ras with Ras pathway signaling proteins is established by decreased interaction with SOS (including SOS1 and SOS2), RAF, SHC, SHP (including SHP1 and SHP2), MEK, MAPK, ERK, GRB, RASA1, or GNAQ.

[0101] Signaling output, measured as IC50 values, can be obtained, and the ratio of the IC50 for one variant compared to another can be calculated. For example, a selective reduction in K-Ras G12S signaling output can be evidenced by a ratio greater than 1. In particular, a selective reduction in K-Ras G12S signaling compared to K-Ras G12D signaling is demonstrated by a ratio of IC50 (for K-Ras G12D) to IC50 (for K-Ras G12S) greater than 1. One or more compounds disclosed herein, such as those in Table 1, exhibit at least 1-fold, and in some instances, greater than 2-fold, 3-fold, 4-fold, or 5-fold selective inhibition of K-Ras G12S compared to K-Ras G12D. In some embodiments, compounds of the present disclosure exhibit an IC50 for K-Ras G12S of less than 500 nM, e.g., less than 100 nM, less than 50 nM, less than 10 nM, or even lower. By applying one or more of the methods exemplified herein, the subject compounds may exhibit selective labeling of Ras G12S relative to Ras G12D mutant or wild-type protein. Exemplary compounds, such as those in Table 1, may covalently label K-Ras G12S mutant at least 1%, 10%, 20%, 50%, or more, with no detectable labeling observed for K-Ras G12D or K-Ras wild-type when tested under the same or comparable conditions.

[0102] In some embodiments, the modified Ras protein comprises the amino acid sequence of SEQ ID NO:4, or a fragment thereof comprising a serine residue corresponding to position 12 of SEQ ID NO:1. In some embodiments, the modified Ras protein comprises the amino acid sequence of SEQ ID NO:4. In some embodiments, the modified protein comprises the amino acid sequence of SEQ ID NO:1, or a fragment thereof comprising a serine residue corresponding to position 12 of SEQ ID NO:1, and the precursor compound selectively labels the serine residue compared to (i) the aspartate residue of a K-Ras G12D mutant protein (the aspartate corresponds to position 12 of SEQ ID NO:2); (ii) the valine residue of a K-Ras G12V mutant protein (the valine corresponds to position 12 of SEQ ID NO:3); and / or (iii) the glycine residue of a K-Ras wild-type protein (the glycine corresponds to position 12 of SEQ ID NO:1). In some embodiments, the precursor compound selectively labels the serine residue of SEQ ID NO:4 by at least 2-fold, 3-fold, 4-fold, or 5-fold when assayed under comparable conditions. In some embodiments, the precursor compound selectively labels serine residues by more than 5-fold when assayed under comparable conditions. If a compound described herein selectively labels serine residues of a K-Ras G12S protein relative to another K-Ras protein (e.g., wild-type, G12D, or G12V), it will be understood that the compound will label the K-Ras G12D protein at a faster rate, or to a greater extent, or by any other quantifiable measure, relative to the other K-Ras protein (e.g., wild-type, G12S, G12V) under similar or identical reaction conditions for the compared proteins.In some embodiments, the greater labeling of K-Ras G12S can be 0.1x, 0.2x, 0.3x, 0.4x, 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, 1x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, 100x, 200x, 300x, 400x, 500x, 600x, 700x, 800x, 900x, 1000x, 2000x, 3000x, 4000x, 5000x, or more, compared to another K-Ras protein (e.g., wild-type, G12D, or G12V). In some embodiments, the greater labeling of K-Ras G12S can be 0.1x, 0.2x, 0.3x, 0.4x, 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, 1x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, 100x, 200x, 300x, 400x, 500x, 600x, 700x, 800x, 900x, 1000x, 2000x, 3000x, 4000x, 5000x, or more, compared to another K-Ras protein (e.g., wild-type, G12D, or G12V).

[0103] In some embodiments, compounds of the present disclosure selectively label serine residues by at least 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, or more times when assayed under equivalent conditions compared to (i) aspartic acid residues in K-Ras G12D mutant proteins (the aspartic acid corresponds to position 12 of SEQ ID NO:2) and / or (ii) valine residues in K-Ras G12V mutant proteins (the valine corresponds to position 12 of SEQ ID NO:3). In some embodiments, compounds of the present disclosure selectively label (e.g., via covalent bonding) serine residues in unmodified Ras G12S proteins corresponding to position 12 of SEQ ID NO:4 in vitro. In some embodiments, compounds of the present disclosure selectively label (e.g., via covalent bonding) serine residues in unmodified Ras G12S proteins corresponding to position 12 of SEQ ID NO:4 in vivo.

[0104] The compounds of formula (II) disclosed herein, including compounds of formula (II-a), (II-b), (II-c), and (II-d), or pharmaceutically acceptable salts or solvates thereof, are Ras inhibitors and have a wide range of uses in therapeutics, diagnostics, and other biomedical research. In some embodiments, the compounds disclosed herein covalently modify a Ras protein, such as a K-Ras G12S protein. In some embodiments, a Ras protein, such as a K-Ras G12S protein, is contacted with a compound disclosed herein to form a modified Ras protein.

[0105] In certain aspects, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 20 may be substituted with L 1 is one or more R 20 is a 5- to 20-membered heterocycle optionally substituted with L 2 is a bond, C 1-4 Alkylene, 2-4 membered heteroalkylene, -O-, -N(R 19 )-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R 19 -, -N(R 19 )S(O)2-, -N(R 19 )S(O)-, -N(R 19 )P(O)R 19 -, -S(O)2N(R 19 )-, -S(O)N(R 19 )-, -P(O)R 19 N(R 19 )-, -OS(O)2-, -OS(O)-, -OP(O)R 19 -, -S(O)2O-, -S(O)O-, and -P(O)R 19O-, C 1-4 Alkylene and 2- to 4-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with L 3 and R 2 together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3-8 form a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is substituted by one, two, or three R 20 may be substituted with L 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which may be selected from the group consisting of 1, 2, or 3 R 20 and L 3 and R 6 is not piperazine, or R 2 and R 6 together with the atoms to which they are attached, can consist of one, two, or three R 20 and forming an optionally substituted 3- to 8-membered monocyclic heterocycloalkyl, wherein L 3 is a bond, R 2 is R 20 , or R 2 and R 3 and together with the carbon atoms to which they are attached, one, two, or three R 20 C optionally substituted with 3-6 forming a cycloalkyl, R 3 is hydrogen and R 20 is selected from R 4 , R 5 , and R 6 are each independently hydrogen and R 20 or R4 and R 5 together with the carbon atoms to which they are attached, can consist of one, two, or three R 20 C optionally substituted with 3-6 forming a cycloalkyl, R 7 teeth, [ka] is selected from R 8 and R 9 are each independently hydrogen and R 20 Selected from; R 19 is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -OH, and -O(C 1-6 alkyl), and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), and -O(C 1-6 alkyl) can be one, two, or three R 20 may be substituted with R 20 is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22, -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 and two R's bonded to the same or adjacent atoms are selected from 20 is combined with C 3-12 may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C 3-12Carbocycles and 3- to 12-membered heterocycles are not substituted by halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(=O)(=NR 22 )N(R 22 )(R 23 and optionally substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21form a 3- to 12-membered heterocyclic ring together with the carbon atoms to which they are attached, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), C 0-6 Alkyl-(3-12 membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles may contain one, two, or three R 20 may be substituted with R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 Alkyl-(3- to 12-membered heterocycle) is a heterocyclic ring consisting of one, two, or three R 20 may be substituted with R 23 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 22 and R 23 may be one, two, or three R together with the same nitrogen atom to which they are attached. 20 and forming a 3- to 10-membered heterocycle which may be substituted by the following:

[0106] In certain aspects, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is C 3-12carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 20 may be substituted with L 1 is one or more R 20 is a 5- to 20-membered heterocycle optionally substituted with L 2 is a bond, C 1-4 Alkylene, 2-4 membered heteroalkylene, -O-, -N(R 19 )-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R 19 -, -N(R 19 )S(O)2-, -N(R 19 )S(O)-, -N(R 19 )P(O)R 19 -, -S(O)2N(R 19 )-, -S(O)N(R 19 )-, -P(O)R 19 N(R 19 )-, -OS(O)2-, -OS(O)-, -OP(O)R 19 -, -S(O)2O-, -S(O)O-, and -P(O)R 19 O-, C 1-4 Alkylene and 2- to 4-membered heteroalkylene are each selected from the group consisting of 1, 2, or 3 R 20 may be substituted with L 3 and R 2 together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3-8 forming a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) is halogen, -OH, -CN, C1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); L 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 and R 6 is not piperazine, or R 2 and R 6 together with the atoms to which they are attached, form halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted by 1, 2, or 3 substituents selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 is a bond, R 2 is halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl or R 2 and R 3 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C3-6 cycloalkyl are substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 4 , R 5 , and R 6 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6cycloalkyl or R 4 and R 5 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6アルキル、C1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl; R 7 teeth, [ka] is selected from R 8 and R 9 are independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, - O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 19 is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OH, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl), R 20 is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 and two R attached to the same or adjacent atoms 20 is combined with C 3-12 may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles are not substituted by halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(=O)(=NR 22 )N(R 22 )(R 23 and optionally substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 together with the carbon atoms to which they are attached, form C 3-12 forming a carbocyclic or 3- to 12-membered heterocyclic ring, each of which is independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl, and —OH; R 22 independently in each occurrence hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl 、 -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle); R 23 independently in each occurrence hydrogen and C 1-6 alkyl or R bonded to a 3- to 10-membered heterocycle of the same nitrogen atom form 22 and R 23 is.

[0107] In some embodiments, for a compound of Formula (II) or a modified protein of Formula (I') or (I), L 3 and R 2 together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3~8 form a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is substituted by one, two, or three R 20 In some embodiments, for a compound of Formula (II) or a modified protein of Formula (I') or (I), L 3 and R 2 together with the atoms to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which may be selected from the group consisting of 1, 2, or 3 R 20In some embodiments, L 3 and R 2 together with the atoms to which they are attached, can consist of one, two, or three R 20 In some embodiments, L 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which may be selected from the group consisting of 1, 2, or 3 R 20 and L 3 and R 6 In some embodiments, the 4-8 membered monocyclic heterocycloalkyl formed by is not piperazine. 2 and R 6 together with the atoms to which they are attached, can consist of one, two, or three R 20 and L 3 is a bond. In some embodiments, L 3 and R 2 , L 3 and R 6 , or R 2 and R 6 The ring formed by 20 , 2 R 20 , 3 R 20 , 4 R 20 , or five R 20 At least one R such as 20 is replaced by .

[0108] In some embodiments, for a compound of Formula (II) or a modified protein of Formula (I') or (I), L 3 and R 2 together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C 3-8forming a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 C selected from 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 In some embodiments, for a compound of Formula (II) or a modified protein of Formula (I') or (I), L is selected from the group consisting of aryl, aryl haloalkyl ... 3 and R 2 , together with the atoms to which they are attached, form a 3- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl). In some embodiments, L 3 and R2 together with the atoms to which they are attached, form halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted by 1, 2, or 3 substituents selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 In some embodiments, L is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkoxy, alkoxy, haloalkyl, alkoxy, alkoxysilyl ... 3 and R 6 together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 and R 6In some embodiments, the 4-8 membered monocyclic heterocycloalkyl formed by is not piperazine. 2 and R 6 together with the atoms to which they are attached, form halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted by 1, 2, or 3 substituents selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 is a bond. In some embodiments, L 3 and R 2 , L 3 and R 6 , or R 2 and R 6 The ring formed by L is unsubstituted. 3 and R 2 , L 3 and R 6 or R 2 and R 6 are halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl). In some embodiments, L 3 and R 2 , L 3 and R 6 or R 2 and R 6 are independently halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 In some embodiments, L is optionally substituted with 1, 2, or 3 substituents selected from alkyl. 3 and R 2 , L 3 and R 6 or R 2 and R 6 are independently halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl). In some embodiments, L 3 and R 2 , L 3 and R 6 or R 2 and R 6 are halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is R 20 In some embodiments, L is substituted with 1, 2, or 3 substituents selected from 3 and R 2 , L 3 and R 6 or R 2 and R 6 is a halogen, -(C 0-6 alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl). In some embodiments, L 3 and R 2 , L 3 and R 6 or R 2 and R 6 is a halogen, -(C 0-6 alkyl)-CN, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 In some embodiments, L is substituted with two substituents independently selected from the group consisting of aryl, aryl haloalkyl, aryl haloalkyl, and aryl haloalkyl. 3 and R 2 , L 3 and R 6 or R 2 and R 6 is a halogen, -(C 0-6 alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 In some embodiments, the substituents are C, such as -CH, -CHCH, -CHCHCH, -CH(CH), -CHCH(CH), or -C(CH). 1-6 It is alkyl.

[0109] In some embodiments, the compound of Formula (II) is a compound of Formula (II-a), (II-b), (II-c), or (II-d): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: W 1 , W 3 , W 4 , and W 5 are each independently N(R 10 ), C(R 11 )2, C(O), O, S(O), and S(O)2; W 2 is N and C(R 11 ) and n1 and n3 are each independently selected from 0, 1, 2, 3, 4, and 5; n4 and n5 are each independently selected from 0, 1, 2, 3, 4, and 5; R 10 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group consisting of halogen, -OH, -CN, C1-3 alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); R 11 is independently in each occurrence hydrogen, halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), or two R attached to the same carbon atom 11 Selected from C 3-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl).

[0110] In some embodiments, for a compound of Formula (II-a) or a modified protein of Formula (I'-a) or (Ia), W 1 and W 3 are each independently N(R 10 ), C(R 11 )2, C(O), O, S(O), and S(O)2, W 2 is N and C(R 11), n1 and n3 are each independently selected from 0, 1, 2, 3, 4, and 5, the sum of n1 and n3 is at least 1, and R 10 is independently in each occurrence hydrogen, -(C 1-6 alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, R 11 is independently in each occurrence hydrogen, halogen, -(C 0-6 alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl), or two R bonded to the same carbon atom 11 is C 3-6 In some embodiments, W 1 and W 3 are C(R 11 )2. In some embodiments, W 2 is N. In some embodiments, W 1 and W 3 are C(R 11 )2 and W 2 is N. In some embodiments, W 1 and W 3 are C(R 11 )2 and W 2 is N, n1 is 2 or 3, and n3 is 1 or 2. In some embodiments, W 1 and W 3 are C(R 11 )2 and W 2 is N, n1 is 2 or 3, n3 is 1 or 2, and L 2 is a bond. In some embodiments, W 1 and W 3 are C(R 11 )2 and W 2 is N, n1 is 2, and n3 is 1. In some embodiments, W1 and W 3 are C(R 11 )2 and W 2 is N, n1 is 2, and n3 is 2. In some embodiments, W 1 and W 3 are C(R 11 )2 and W 2 is N, n1 is 3, and n3 is 2. In some embodiments, L 2 is a bond. In some embodiments, the sum of n1 and n3 is 2, 3, 4, or 5. In some embodiments, n1 is 1, 2, 3, or 4, and n3 is 1 or 2. In some embodiments, [ka] each of which is selected from 1, 2, or 3 R 11 may be substituted with.

[0111] In some embodiments, for a compound of Formula (II-b) or a modified protein of Formula (I'-b) or (Ib), W 4 and W 5 are each independently N(R 10 ), C(R 11 )2, C(O), O, S(O), and S(O)2, W 2 is N and C(R 11 ), n4 and n5 are each independently selected from 0, 1, 2, 3, 4, and 5; R 10 is independently in each occurrence hydrogen, -(C 1-6 alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, R 11 is independently in each occurrence hydrogen, halogen, -(C 0-6 alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C1-6 haloalkyl), or two R bonded to the same carbon atom 11 is C 3-6 In some embodiments, W 4 and W 5 are C(R 11 )2. In some embodiments, W 2 is C(R 11 In some embodiments, W 4 and W 5 are C(R 11 )2 and W 2 is C(R 11 In some embodiments, W 4 and W 5 are CH2 and W 2 is CH. In some embodiments, W 4 and W 5 are C(R 11 )2 and W 2 is C(R 11 ), n4 is 0, 1, or 2, and n5 is 0, 1, or 2. In some embodiments, W 4 and W 5 are C(R 11 )2 and W 2 is C(R 11 ) and the sum of n4 and n5 is 0, 1, or 2. In some embodiments, W 4 and W 5 are C(R 11 )2 and W 2 is C(R 11 ), the sum of n4 and n5 is 0, 1, or 2, and L 2 -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene-, and -N(R 19 In some embodiments, W 4 and W 5 are C(R 11 )2 and W 2 is C(R 11), n4 is 0, and n5 is 0. In some embodiments, L 2 is C 1-3 Alkylene, 2- to 3-membered heteroalkylene, and -N(R 19 In some embodiments, L 2 is 2-3 membered heteroalkylene, and -N(R 19 In some embodiments, L 2 is -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene-, and -N(R 19 In some embodiments, L 2 is -N(R 19 )-, -N(CH3)CH2-, and -N(CH3)CH(CH3)-. In some embodiments, the sum of n4 and n5 is 0 or 1. In some embodiments, n4 and n5 are each 0. In some embodiments, [ka] each of which is selected from 1, 2, or 3 R 11 may be substituted with.

[0112] In some embodiments, for a compound of Formula (II-c) or a modified protein of Formula (I'-c) or (Ic), W 1 , W 3 , W 4 , and W 5 are each independently N(R 10 ), C(R 11 )2, C(O), O, S(O), and S(O)2, W 2 is N and C(R 11 ), n1 and n3 are each independently selected from 0, 1, 2, 3, 4, and 5, and the sum of n1 and n3 is at least 2; n4 and n5 are each independently selected from 0, 1, 2, 3, 4, and 5, and R 10 is independently in each occurrence hydrogen, -(C 1-6alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, and R 11 is independently in each occurrence hydrogen, halogen, -(C 0-6 alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl), or two R bonded to the same carbon atom 11 is C 3-6 In some embodiments, each W 1 are independently C(R 11 In some embodiments, n1 is 2, 3, or 4 and 1 W 1 is O and the remaining W 1 are respectively C(R 11 )2. In some embodiments, W 3 is C(R 11 )2. In some embodiments, W 2 is N. In some embodiments, W 4 and W 5 are C(R 11 In some embodiments, n1 is 2, 3, or 4, and one W 1 is C(R 11 )2 and O, and the remaining W 1 are respectively C(R 11 )2 and W 2 is N, n3 is 1 or 2, and W 3 is C(R 11 )2, n4 is 0 or 1, W 4 is C(R 11 )2, n5 is 0 or 1, W 5 is C(R 11 In some embodiments, n1 is 2, 3, or 4, and one W 1 is C(R 11)2 and O, and the remaining W 1 are respectively C(R 11 )2 and W 2 is N, n3 is 1 or 2, and W 3 is C(R 11 )2, n4 is 0 or 1, W 4 is C(R 11 )2, n5 is 0 or 1, W 5 is C(R 11 )2 and L 2 In some embodiments, n1 is 2, 3, or 4, and one W 1 are selected from CH2 and O, and the remaining W 1 are CH2 and W 2 is N, n3 is 1 or 2, and W 3 is CH2, n4 is 0 or 1, W 4 is CH2, n5 is 0 or 1, W 5 In some embodiments, the sum of n1 and n3 is 3, 4, or 5, and one W 1 is C(R 11 )2 and O, and the remaining W 1 are respectively C(R 11 )2 and W 2 is N and W 3 is C(R 11 ) 2, n4 is 0, and n5 is 0. In some embodiments, n1 is 2, 3, or 4, and W 1 is C(R 11 )2 and W 2 is N, n3 is 1 or 2, and W 3 is C(R 11 )2, n4 is 0 or 1, W 4 is C(R 11 )2, n5 is 0 or 1, W 5 is C(R 11 )2. In some embodiments, n1 is 4 and W 1 is C(R 11 )2 and W 2 is N, n3 is 1, and W 3is C(R 11 ) 2, n4 is 0, and n5 is 0. In some embodiments, n1 is 3 and W 1 is C(R 11 )2 and W 2 is N, n3 is 1, and W 3 is C(R 11 ) 2, n4 is 0, and n5 is 0. In some embodiments, n1 is 3 and 1 W 1 is C(R 11 )2 and O, and the remaining W 1 are C(R 11 )2 and W 2 is N, n3 is 1, and W 3 is C(R 11 ) 2, n4 is 0, and n5 is 0. In some embodiments, n1 is 2 and W 1 is C(R 11 )2 and W 2 is N, n3 is 1, and W 3 is C(R 11 )2, n4 is 0, and n5 is 0. In some embodiments, L 2 is a bond. In some embodiments, the sum of n1 and n3 is 2, 3, 4, or 5. In some embodiments, n1 is 2, 3, or 4 and n3 is 1. In some embodiments, the sum of n4 and n5 is 0 or 1. In some embodiments, n4 and n5 are each 0. In some embodiments, [ka] each of which is selected from 1, 2, or 3 R 11 may be substituted with.

[0113] In some embodiments, for a compound of Formula (II-d) or a modified protein of Formula (I'-d) or (Id), W 3 is N(R 10 ), C(R 11)2, C(O), O, S(O), and S(O)2; n3 is selected from 0, 1, 2, 3, 4, and 5; R 10 is independently in each occurrence hydrogen, -(C 1-6 alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 3-6 cycloalkyl, R 11 is independently in each occurrence hydrogen, halogen, -(C 0-6 alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl). In some embodiments, each W 3 is C(R 11 )2. In some embodiments, W3 is C(R 11 )2 and n3 is 1, 2, or 3. In some embodiments, W 3 is C(R 11 )2, n3 is 1, 2, or 3, and L 2 is -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene-, and -N(R 19 In some embodiments, W 3 is CH2 and n 3 is 1, 2, or 3. In some embodiments, W 3 is C(R 11 )2 and n3 is 1. In some embodiments, W 3 is C(R 11 )2 and n3 is 2. In some embodiments, W 3 is C(R 11 )2 and n3 is 3. In some embodiments, L 2 is C 1-3 Alkylene, 2- to 3-membered heteroalkylene, and -N(R 19 In some embodiments, L 2is 2-3 membered heteroalkylene and -N(R 19 In some embodiments, L 2 is -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene-, and -N(R 19 In some embodiments, L 2 is -N(R 19 )-, -N(CH3)CH2-, and -N(CH3)CH(CH3)-. In some embodiments, n3 is 1, 2, or 3. In some embodiments, [ka] each of which is selected from 1, 2, or 3 R 11 may be substituted with.

[0114] In some embodiments, for a compound of Formula (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'-a), (I'-b), (I'-c), (I'-d), (Ia), (Ib), (Ic), or (Id), R 10 and R 11 independently in each occurrence hydrogen and C 1-3 In some embodiments, one R 10 or R 11 is a C alkyl such as -CH, -CHCH, or -CH(CH), and any remaining R 10 and R 11 are each hydrogen. In some embodiments, two R 10 and / or R 11 are independently C alkyl, such as -CH, -CHCH, or -CH(CH), and any remaining R 10 and R 11 are hydrogen atoms.

[0115] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), R 1 is C 6-10 aryl and 5- to 10-membered heteroaryl, each of which is selected from 1, 2, 3, 4, or 5 R 20 In some embodiments, R 1 is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is selected from one or more R 20 In some embodiments, R 1 is halogen, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -OR 22 , -N(R 22 )(R 23 ), and C 3-6 In some embodiments, R is substituted with 1, 2, 3, or 4 substituents independently selected from cycloalkyl. 1 is substituted with 1, 2, 3, or 4 substituents independently selected from halogen, —CN, —CH 3 , —CH 2 CH 3 , —CH═CH 2 , —CF 3 , —C≡C, —OH, —NH 2 , and -cyclopropyl.

[0116] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), R 1 is a fused bicyclic C 4-12 Cycloalkyl, fused bicyclic C 3-11 Heterocycloalkyl, Fused Bicyclic C 7-12 Aryl, and fused bicyclic C3-11 heteroaryl, and a fused bicyclic C 4-12 Cycloalkyl, fused bicyclic C 3-11 Heterocycloalkyl, Fused Bicyclic C 7-12 Aryl, Fused Bicyclic C 3-11 Heteroaryl can have 1, 2, 3, 4, 5, 6, or 7 R 20 In some embodiments, R 1 is a spirocyclic bicyclic C 4-12 Cycloalkyl and spirocyclic bicyclic C 3-11 heterocycloalkyl; spirocyclic bicyclic C 4-12 Cycloalkyl and spirocyclic bicyclic C 3-11 Heterocycloalkyl can have 1, 2, 3, 4, 5, 6, or 7 R 20 In some embodiments, R 1 is a polycyclic ring system.

[0117] In some embodiments, R is used for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id). 1 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -OR 22 , -SR 22 , and -N(R 22 )(R 23 ) and is substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and -OR 22In some embodiments, R 1 is halogen, -CN, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -OR 22 , and -N(R 22 )(R 23 In some embodiments, R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from halogen, —CN, —CH, —C≡CH, —OH, and —NH. In some embodiments, R 1 is substituted with -F, -CN, and -NH. In some embodiments, R 1 is substituted with -F, -C≡CH, and -OH. In some embodiments, R 1 is substituted with -CF, -CH, and -NH. In some embodiments, R 1 is substituted with -CF and -NH. In some embodiments, R 1 -CF3, -CH 3、 In some embodiments, R 1 is substituted with -CF, -F, and -NH. In some embodiments, R 1 is substituted with 1, 2, 3, or 4 substituents independently selected from halogen, —CN, —CH 3 , —CH 2 CH 3 , —CH═CH 2 , —CF 3 , —C≡C, —OH, —NH 2 , and -cyclopropyl.

[0118] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), R 1 teeth, [ka] is selected from: Q 1 , Q 3 , and Q 5 are independently N and C(R 1d ) and Q 4 and Q 6 are independently O, S, C(R 1a )(R 1b ), and N(R 1c ) and X 4 , X 5 , X 6 , X 9 , X 10 are independently C(R 1a ) and N; X 13 is a bond, C(R 1a ), N, C(O), C(R 1a )(R 1b ), C(O)C(R 1a )(R 1b ), C(R 1a )(R 1b )C(R 1a )(R 1b ), C(R1 a )(R1 b )N(R 1c ), and N(R 1c ) and X 14 , X 15 , X 17 , X 18 are independently C(O), C(R 1a ), N, C(R 1a )(R 1b ), and N(R 1c ) and X 16 is C, N, and C(R 1a ) and Each R 1a , R 1b , R 1d , and R 1h are independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O)2R 12 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 12 )C(O)R 12 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle, 3- to 10-membered heterocycle may be substituted with 1, 2, or 3 R20 or R20 bonded to the same carbon. 1a and R 1b are bonded to form a 3-10 membered heterocycle or a C3-10 carbocycle, and the 3-10 membered heterocycle and the C3-10 carbocycle may be substituted with 1, 2, or 3 R20, or two R20 bonded to adjacent atoms. 1aare linked to form a 3-10 membered heterocycle or a C3-10 carbocycle, and the 3-10 membered heterocycle and the C3-10 carbocycle are optionally substituted with 1, 2, or 3 R20, or R 1h and R bonded to adjacent atoms 1a , R 1b , R 1c , and R 1d are bonded to form a 3-10 membered heterocycle or a C3-10 carbocycle, and the 3-10 membered heterocycle and the C3-10 carbocycle are bonded to one, two, or three R 20 may be substituted with Each R 1c independently in each occurrence, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocyclic rings and 3- to 10-membered heterocyclic rings, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 may be substituted with. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] is selected from.

[0119] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), R 1 teeth, [ka] [ka] In some embodiments, R 1 teeth [ka] is.

[0120] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), R 1 teeth, [ka] [ka] [ka] [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] is.

[0121] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), L 1 is one or more R 20 In some embodiments, L is a 6- to 12-membered heterocycle optionally substituted with 1 can have 1, 2, 3, or 4 R's 20 In some embodiments, L is a 10-membered bicyclic heterocycle optionally substituted with 1 contains 1 to 5 nitrogen atoms. 1 is one or more R 20 In some embodiments, L is a 6-membered monocyclic heterocycle optionally substituted with 1 is one or more R 20 12- to 20-membered polycyclic heterocycles optionally substituted with, for example, one or more R 20 In some embodiments, L is a 12- to 18-membered tricyclic heterocycle optionally substituted with 1is selected from tetrahydropyridopyrimidines (e.g., 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine), pyridopyrimidines (e.g., pyrido[4,3-d]pyrimidine), pyridopyrimidinones (e.g., pyrido[4,3-d]pyrimidin-5(6H)-one or pyrido[2,3-d]pyrimidin-2(1H)-one), pyrimidines, quinazolines, and 1,2,4-oxadiazoles.

[0122] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), L 1 is. [ka] During the ceremony, W is N, C(R 17 ), N(R 17b ), C(R 17 )2, C(O), S(O), or S(O)2; Z is N, C(R 17 ), N(R 17b ), C(R 17 )2, C(O), S(O), or S(O)2, and W and Z are not both selected from C(O), S(O), and S(O)2; V and J each independently represent N, C(R 1 ), C(R 17 ), N(R 1 ), N(R 17b ), C(R 1 )(R 17 ), and C(R 17 )2, and exactly one of V and J is selected from C(R 1 ), N(R 1 ), or C(R 1 )(R 17 ) and U is N, C(R 17 ), N(R 17b ), C(R 17)2, S(O), S(O)2, or C(O); Y is N, C(R 18 ), N(R 17b ), C(R 18 )(R 17 ), S(O), S(O)2, or C(O); X is N, C(R 17 ), N(R 17b ), or C(R 17 )2, R 17 is independently in each occurrence hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), =NR 12 , =C(R 14 )2, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O)2R 12, -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NR 12 )N(R 12 )(R 13 ), and -OCH2C(O)OR 12 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are substituted with one, two, or three R 20 may be substituted with R 17b is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3-12 membered heterocycle), -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ) and -S(=O)(=NR 12 )N(R 12 )(R13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle) is a heterocyclic ring having one, two, or three R 20 may be substituted with R 18 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), =NR 12 , =C(R 14 )2, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R12 )(R 13 ), -S(=O)(=NR 12 )N(R 12 )(R 13 ), and -OCH2C(O)OR 12 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are substituted with one, two, or three R 20 may be substituted with R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 Alkyl-(3- to 12-membered heterocycle) is a heterocycle containing one, two, or three R 20 may be substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 may be one, two, or three R together with the same nitrogen atom to which they are attached. 20 forming a 3- to 10-membered heterocycle optionally substituted by R 14 is independently in each occurrence hydrogen, halogen, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 14 form a 3- to 12-membered heterocyclic ring together with the carbon atoms to which they are attached, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), C 0-6 Alkyl-(3-12 membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles may contain one, two, or three R 20 and [ka] indicates a single or double bond where all valences are satisfied.

[0123] In certain aspects, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 20 may be substituted with L 1 teeth, [ka] During the ceremony, W is N, C(R 17 ), N(R 17b ), C(R 17 )2, C(O), S(O), or S(O)2; Z is N, C(R 17), N(R 17b ), C(R 17 )2, C(O), S(O), or S(O)2, and W and Z are not both selected from C(O), S(O), and S(O)2; V and J each independently represent N, C(R 1 ), C(R 17 ), N(R 1 ), N(R 17b ), C(R 1 )(R 17 ), and C(R 17 )2, and exactly one of V and J is selected from C(R 1 ), N(R 1 ), or C(R 1 )(R 17 ) and U is N, C(R 17 ), N(R 17b ), C(R 17 )2, S(O), S(O)2, or C(O); Y is N, C(R 18 ), N(R 17b ), C(R 18 )(R 17 ), S(O), S(O)2, or C(O); X is N, C(R 17 ), N(R 17b ), or C(R 17 )2, R 17 is independently in each occurrence hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), =NR12 , =C(R 14 )2, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NR 12 )N(R 12 )(R 13 ), and -OCH2C(O)OR 12 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are substituted with one, two, or three R 20 may be substituted with R 17b is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C3-12 carbocycle), -C 0-6 Alkyl-(3-12 membered heterocycle), -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ) and -S(=O)(=NR 12 )N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle) is a heterocyclic ring having one, two, or three R 20 may be substituted with R 18 is halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 12 , -SR 12 , -N(R 12 )(R 13 ), =NR 12 , =C(R 14 )2, -C(O)OR12 , -OC(O)N(R 12 )(R 13 ), -N(R 12 )C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)OR 12 , -N(R 12 )S(O)2R 12 , -C(O)R 12 , -S(O)R 12 , -OC(O)R 12 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 12 )C(O)R 12 , -S(O)2R 12 , -S(O)(NR 12 )R 12 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NR 12 )N(R 12 )(R 13 ), and -OCH2C(O)OR 12 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are substituted with one, two, or three R 20 may be substituted with R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6alkyl-(3- to 12-membered heterocycle), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 Alkyl-(3- to 12-membered heterocycle) is a heterocycle containing one, two, or three R 20 may be substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 may be one, two, or three R together with the same nitrogen atom to which they are attached. 20 forming a 3- to 10-membered heterocycle optionally substituted by R 14 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or R 14 together with the carbon atoms to which they are attached, C 3-12 Forms a carbocyclic or 3- to 12-membered heterocyclic ring, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), and 3- to 12-membered heterocycle can be selected from 1, 2, or 3 R 20 may be substituted with [ka] indicates a single or double bond where all valences are satisfied, L 2 is a bond, C 1-4Alkylene, 2-4 membered heteroalkylene, -O-, -N(R 19 )-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R 19 -, -N(R 19 )S(O)2-, -N(R 19 )S(O)-, -N(R 19 )P(O)R 19 -, -S(O)2N(R 19 )-, -S(O)N(R 19 )-, -P(O)R 19 N(R 19 )-, -OS(O)2-, -OS(O)-, -OP(O)R 19 -, -S(O)2O-, -S(O)O-, and -P(O)R 19 O-, C 1-4 Alkylene and 2- to 4-membered heteroalkylene are each selected from the group consisting of 1, 2, or 3 R 20 may be substituted with L 3 and R 2 together with the atoms to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which may be selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), -O(C 3-6 Cycloalkyl) is a group that is substituted with halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl); L 3 and R 6together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), and C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a halogen, -OH, CN, C1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3 haloalkyl), and L 3 and R 6 is not piperazine, or R 2 and R 6 together with the atoms to which they are attached, form halogens, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 cycloalkyl), forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted by 1, 2, or 3 substituents selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 3-6 Cycloalkyl) is a group consisting of halogen, -OH, CN, C1-3 alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl), and -O(C 1-3haloalkyl), and L 3 is a bond, R 2 is halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl or R 2 and R 3 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 4 , R 5 , and R 6 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl or R 4 and R 5 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl), and -O(C 1-6 optionally substituted with 1, 2, or 3 substituents selected from haloalkyl; R 7 teeth, [ka] is selected from R 8 and R 9 are independently hydrogen, halogen, -CN, C 1-6 Alkyl, and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl is a group that can be substituted with halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl); R 19 is independently in each occurrence hydrogen, -CN, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OH, -O(C 1-6 alkyl), and -O(C 1-6 haloalkyl), R 20 is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR 22 , -SR 22 , -N(R 22 )(R23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 )-, -S(=O)(=NR 22 )N(R 22 )(R 23 ), and -OCH2C(O)OR 22 and two R attached to the same or adjacent atoms 20 is combined with C 3-12 may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbocycle), -C 0-6 Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C 3-12 Carbocycles and 3- to 12-membered heterocycles are not substituted by halogen, oxo, -CN, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 , -SR 22 , -N(R 22 )(R 23 ), =NR 22 , =C(R 21 )2, -C(O)OR 22 , -OC(O)N(R 22 )(R 23 ), -N(R 22 )C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)OR 22 , -N(R 22 )S(O)2R 22 , -C(O)R 22 , -S(O)R 22 , -OC(O)R 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -N(R 22 )C(O)R 22 , -S(O)2R 22 , -S(O)(NR 22 )R 22 , -S(O)2N(R 22 )(R 23 ), and -S(=O)(=NR 22 )N(R 22 )(R 23 and optionally substituted with one or more substituents independently selected from R 21 is independently in each occurrence hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle), or two R 21 together with the carbon atoms to which they are attached, form C 3-12 forming a carbocyclic or 3- to 12-membered heterocyclic ring, each of which is independently selected from the group consisting of halogen, C 1-3 Alkyl, C1-3 optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl, and —OH; R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbocyclic), and -C 0-6 alkyl-(3- to 12-membered heterocycle); R 23 independently in each occurrence hydrogen and C 1-6 alkyl or R bonded to a 3- to 10-membered heterocycle of the same nitrogen atom form 22 and R 23 is.

[0124] In some embodiments, W is C(R 17 ), C(R 17 )2, or C(O), and Z is N, C(R 17 ), N(R 17b ), or C(R 17 )2, and V is C(R 1 ) or N(R 1 ) and J is C(R 17 ) or C(R 17 )2. In some embodiments, W is CH, CH2, or C(O) and Z is N, CCl, N(R 17b ), or CH2, and V is C(R 1 ) or N(R 1 ) and J is CF or CH2. In some embodiments, W is C(R 17 ), and Z is C(R 17 ), and V is C(R 1 ), and J is C(R 17 In some embodiments, W is CH, Z is CCl, and V is C(R 1 ) and J is CF. In some embodiments, W is CH, Z is CCF, and V is C(R 1 ) and J is CF. In some embodiments, U is N and Y is C(R18 ) and X is N. In some embodiments, W is CH, Z is N, and V is C(R 1 ) and J is CF.

[0125] In some embodiments, for a compound or modified protein described herein, R 18 is hydrogen, C 1-3 Alkyl, -OR 12 and 3- to 10-membered heterocycles, 1-3 Alkyl and 3- to 10-membered heterocycles may have one, two, or three R 20 In some embodiments, L 1 is C 1-3 Alkyl, -OR 12 and substituted with a 3- to 10-membered heterocycle, C 1-3 Alkyl and 3- to 10-membered heterocycles may have one, two, or three R 20 In some embodiments, R 18 HA-OR 12 In some embodiments, L 1 HA-OR 12 In some embodiments, R 18 is -O(C 1-3 alkylene)(4-10 membered heterocycle), wherein the 4-10 membered heterocycle is 1-3 Alkyl, C 1-3 Haloalkyl, and =C(R 21 )2, and optionally substituted with 1, 2, or 3 substituents independently selected from R 21 represents independently in each occurrence hydrogen, halogen, and C 1-3 In some embodiments, L is selected from alkyl. 1 is -O(C 1-3 alkylene) (4-10 membered heterocycle), and the 4-10 membered heterocycle is substituted with halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, and =C(R 21 )2, and optionally substituted with 1, 2, or 3 substituents independently selected from R 21independently in each occurrence hydrogen, halogen, and C 1-3 is selected from alkyl.

[0126] In some embodiments, for a compound or modified protein described herein, R 18 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , and -N(R 12 )(R 13 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 In some embodiments, R 18 is hydrogen l-(C 0-3 alkylene)-O-(C 0-3 alkylene)-R 20 , C 1-3 alkyl, and 3- to 10-membered heterocycle, each C 0-3 Alkylene, C 1-3 Alkyl and 3- to 10-membered heterocycles may have 1, 2, or 3 R 20 In some embodiments, R 18 is hydrogen, C 1-3 Alkyl, -OR 12 and 3- to 10-membered heterocycles, 1-3 Alkyl and 3- to 10-membered heterocycles may have one, two, or three R 20 In some embodiments, R 18 HA-OR 12’ In some embodiments, R 18 is -O(C 1-3 alkylene)(4-10 membered heterocycle), wherein the 4-10 membered heterocycle is 1-3 Alkyl, C 1-3 Haloalkyl, and =C(R 21 )2, and optionally substituted with 1, 2, or 3 substituents independently selected from R 21represents independently in each occurrence hydrogen, halogen, and C 1-3 alkyl.

[0127] In some embodiments, with respect to the compounds or modified proteins described herein, R 18 or L 1 The substituents of [ka] [ka] [ka] In some embodiments, R 18 or L 1 The substituents of [ka] In some embodiments, R 18 or L 1 The substituents of [ka] In some embodiments, R 18 or L 1 The substituents of [ka] In some embodiments, R 18 or L 1 The substituents of [ka] In some embodiments, R 18 or L 1 The substituents of [ka] In some embodiments, R 18or L 1 The substituents of [ka] In some embodiments, R 18 or L 1 The substituents of [ka] In some embodiments, R 18 or L 1 The substituents of [ka] In some embodiments, R 18 or L 1 The substituents of [ka] In some embodiments, R 18 or L 1 The substituents of [ka] In some embodiments, R 18 or L 1 The substituents of [ka] is selected from.

[0128] In embodiments, R B2 teeth, [ka] In some embodiments, R B2 teeth, [ka] [ka] is selected from.

[0129] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), L 1 is substituted with one or more halogens, such as F or Cl. In some embodiments, L 1 is substituted with F and Cl. In some embodiments, L 1 is one R 18 and substituted with one or more halogens. In some embodiments, L 1 is R 18 , Cl, and F. In some embodiments, L 1 is one or more R 20 , e.g., three or more R 20 In some embodiments, L 1 is substituted with at least one halogen and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), which is optionally substituted. 1 is substituted with at least one halogen and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein the 3- to 12-membered heterocycle is substituted with a halogen. 1 is substituted with Cl, F, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein the 3- to 12-membered heterocycle is substituted with halogen. 1 are Cl, F, and -O(C 1-3 In some embodiments, L is substituted with alkyl)-(3- to 12-membered heterocycle), and the 3- to 12-membered heterocycle is substituted with halogen. 1 are Cl, F, and -O(C 1-3 In some embodiments, L is substituted with alkyl)-(5- to 9-membered heterocycle), and the 5- to 9-membered heterocycle is substituted with halogen. 1is substituted with Cl, F, and -OCH2 (a 5- to 9-membered heterocycle), which is substituted with halogen.

[0130] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), R 1 -L 1 teeth [ka] In some embodiments, R 1 -L 1 teeth [ka] In some embodiments, R 1 -L 1 teeth [ka] for example [ka] In some embodiments, R 1 -L 1 teeth [ka] In some embodiments, R 1 -L 1 teeth [ka] In some embodiments, R 1 -L 1 teeth [ka] for example [ka] In some embodiments, R 1 -L 1 teeth [ka] In some embodiments, R 1 -L 1 teeth [ka] for example [ka] In some embodiments, R 1 -L 1 teeth [ka] for example [ka] In some embodiments, R 1 -L 1 teeth [ka] for example [ka] is.

[0131] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), R 1 -L 1 teeth [ka] each of which is selected from one or more R 20 , e.g., 1, 2, 3, 4, or 5 R 20 is replaced by .

[0132] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), L 2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene can be one, two, or three R 20 In some embodiments, L 2 is a bond, C 1-4 Alkylene, 2-4 membered heteroalkylene, -N(R 19 )-, -C(O)-, -N(R 19 )S(O)2-, and -N(R 19 )S(O)-, C 1-4 Alkylene and 2- to 4-membered heteroalkylene can be substituted with one, two, or three R 20 In some embodiments, L 2 is a bond, C 1-4 Alkylene, 2- to 4-membered heteroalkylene, and -N(R 19 )- is selected from C 1-4 Alkylene and 2- to 4-membered heteroalkylene are substituted with one, two, or three R 20 In some embodiments, L 2 is a bond, C 1-3 Alkylene, -N(H)C 0-3 Alkylene-, -N(C 1-3 Alkyl)C 0-3 Alkylene-, and -N(C 3-6 Cycloalkyl)C 0-3 alkylene- selected from C 0-3 Alkylene, C 1-3 Alkyl, and C 3-6Cycloalkyl is a halogen, C 1-3 Alkyl, and C 1-3 In some embodiments, L is optionally substituted with 1, 2, or 3 substituents selected from haloalkyl. 2 is a bond, C 1-3 Alkylene, -N(R 19 )-, -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene-, and -N(C 3-6 Cycloalkyl)C 1-3 alkylene- selected from C 1-3 Alkylene, C 1-3 Alkyl, and C 3-6 Cycloalkyl is a halogen, C 1-3 Alkyl, and C 1-3 In some embodiments, L is optionally substituted with 1, 2, or 3 substituents selected from haloalkyl. 2 is a bond, C 1-3 Alkylene, 2- to 3-membered heteroalkylene, and -N(R 19 In some embodiments, L 2 is a bond, 2- to 3-membered heteroalkylene, and -N(R 19 In some embodiments, L 2 is -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene-, and -N(R 19 In some embodiments, L 2 is -N(R 19 )-, -N(CH3)CH2-, and -N(CH3)CH(CH3)-. In some embodiments, L 2 is a bond, C 1-3 Alkylene, -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene-, and -N(C 3-6 Cycloalkyl)C 1-3 alkylene- selected from C 1-3Alkylene, C 1-3 Alkyl, and C 3-6 Cycloalkyl is halogen, C 1-3 In some embodiments, L is optionally substituted with 1, 2, or 3 substituents selected from alkyl, and C haloalkyl. 2 is selected from a bond, —N(CH3)CH2—, and —N(CH3)CH(CH3)—. In some embodiments, L 2 is a bond.

[0133] In some embodiments, for a compound of Formula (II), (II-b), or (II-c), or a modified protein of Formula (I'), (I'-b), (I'-c), (I), (Ib), or (Ic), R 2 is C 1-6 Alkyl and C 3-6 In some embodiments, R 2 is selected from -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, 1-methylcyclopropyl, and cyclobutyl.

[0134] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), R 3 is hydrogen and C 1-6 In some embodiments, R 3 is hydrogen.

[0135] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), R 4 , R 5 , and R 6 are independently hydrogen, C1-3 Alkyl, and -(C 1-3 alkyl)CN, or R 4 and R 5 together with the carbon atoms to which they are attached, form C 3-6 Forms a cycloalkyl.

[0136] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0137] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 8 is selected from hydrogen, halogen, —CH, —CHF, —CHF, and —CF. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is halogen. In some embodiments, R 8 is —CH3. In some embodiments, R 8 is -CHF. In some embodiments, R 8 is -CHF. In some embodiments, R 8 is CF3. In some embodiments, R 8 is Cl. In some embodiments, R 8 is F. In some embodiments, R 8 is -CN.

[0138] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 9 is selected from hydrogen, halogen, —CH, —CHF, —CHF, and —CF. In some embodiments, R 9 is selected from hydrogen and chloro. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is halogen. In some embodiments, R 9is —CH3. In some embodiments, R 9 is -CHF. In some embodiments, R 9 is -CHF. In some embodiments, R 9 is CF3. In some embodiments, R 9 is Cl. In some embodiments, R 9 is F. In some embodiments, R 9 is -CN.

[0139] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id), R 1 is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, pyridinyl, each of which is selected from one or more R 20 may be substituted with L 1 can have 1, 2, 3, or 4 R's 20 and L is a 10-membered bicyclic heterocycle substituted with 2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with.

[0140] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id): R 1 -L 1 teeth [ka] and L2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene can be substituted with one, two, or three R 20 may be optionally substituted with

[0141] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), or a modified protein of Formula (I'), (I'-a), (I'-b), (I'-c), (I'-d), (I), (Ia), (Ib), (Ic), or (Id): R 1 -L 1 teeth [ka] and L 2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with.

[0142] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 1 is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is selected from one or more R 20 may be substituted with L 1 can have 1, 2, 3, or 4 R's 20 is a 10-membered bicyclic heterocycle substituted with L 2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene can be substituted with one, two, or three R 20may be substituted with R 7 teeth [ka] and

[0143] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 1 -L 1 teeth [ka] and L 2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with R 7 teeth [ka] and

[0144] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 1 -L 1 teeth [ka] and L 2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with R 7 teeth [ka] and

[0145] In some embodiments, for a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 1 -L 1 teeth [ka] and L 2 is a bond, C 1-3 alkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene and 2- to 3-membered heteroalkylene can be substituted with one, two, or three R 20 may be substituted with R 7 teeth [ka] and

[0146] In some embodiments, the compound of formula (II) is [ka] In some embodiments, the compound of formula (II) is selected from: [ka] is selected from.

[0147] In some embodiments, the compound of formula (II) [ka] In some embodiments, the compound of formula (II) is selected from: [ka] is selected from.

[0148] In some embodiments, the compound of Formula (II), (II-a), (II-b), (II-c), or (II-d) is R 7 When R is replaced with hydrogen, the compound reversibly binds to the K-Ras protein. 7 IC<1000 nM, <500 nM, <250 nM, <100 nM, or even lower as assessed by HTRF assay when is replaced with hydrogen 50 In some embodiments, the compound of Formula (II), (II-a), (II-b), (II-c), or (II-d) reversibly binds to the K-Ras protein at -C(O)R 7 In some embodiments, the compound binds reversibly to K-Ras proteins when -C(O)R is replaced with hydrogen. 7 is substituted with hydrogen, an IC of less than 1000 nM, less than 500 nM, less than 250 nM, less than 100 nM, or even less as assessed by HTRF assay 50 It reversibly binds to the K-Ras protein.

[0149] In some embodiments, compounds described herein, such as compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), are provided as substantially pure stereoisomers. In some embodiments, the stereoisomers are provided in at least 80% enantiomeric excess, e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% enantiomeric excess.

[0150] In some embodiments, compounds disclosed herein, e.g., compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), selectively and potently inhibit K-Ras G12S relative to wild-type K-Ras or other K-Ras mutants (e.g., K-Ras G12V or K-Ras G12D). In some embodiments, compounds disclosed herein exhibit selective and potent inhibition of K-Ras G12S relative to wild-type K-Ras or other K-Ras mutants (e.g., K-Ras G12V or K-Ras G12D), e.g., compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), wherein R 7 is a triazole optionally substituted with methyl, -CH2-CN, or a halogen (e.g., Cl). In some embodiments, the compounds disclosed herein exhibit selective and potent inhibition of K-Ras G12S compared to wild-type K-Ras or other K-Ras mutants (e.g., K-Ras G12V or K-Ras G12D), e.g., a compound of formula (II), (II-a), (II-b), (II-c), or (II-d), wherein R 7 is triazole optionally substituted with methyl, —CH—CN, or halogen (e.g., Cl), and L 1 teeth [ka] is substituted with R 1 teeth [ka] In some embodiments, K-Ras G12S selective and on-target inhibition is achieved by (1) a reactive group (e.g., R7 of Formula (II), (II-a), (II-b), (II-c), or (II-d)) that is capable of or prone to react with a serine residue in Ras, such as the serine of SEQ ID NO:4 or the serine corresponding to position 12 of SEQ ID NO:1, and / or (2) R 7 L 1This is due to the geometry of the atoms connecting to the K-Ras G12S mutant. These bond atoms may orient the reactive group to specifically favor reaction with the serine residue at position 12 of the K-Ras G12S mutant.

[0151] In some embodiments, the subject reactive groups exhibit at least 1-fold, and in some instances greater than 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, or 20-fold or even greater selective engagement of K-Ras G12S compared to K-Ras G12D or wild-type K-Ras. In some embodiments, the subject reactive groups exhibit selective and rapid engagement of K-Ras G12S, resulting in at least 5%, 98%, or 99% or even higher engagement of G12S within 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 9 hours, 10 hours, 20 hours, or 24 hours. In some embodiments, selective and rapid engagement of K-Ras G12S is evidenced by at least 50% engagement within 24 hours. In some embodiments, the subject compounds specifically covalently engage K-Ras G12S with essentially no detectable labeling of K-Ras G12D when assayed under comparable conditions.

[0152] The inclusion of a reactive group of the present disclosure may enhance the efficacy or potency of K-Ras G12S inhibition. In some embodiments, subject compounds containing a subject reactive group inhibit K-Ras G12S with greater potency, as evidenced by an IC50 value that is at least 10%, 20%, 50%, 100%, 200%, 300%, 400%, or at least 500% lower than the IC50 value of a corresponding control compound that does not contain the reactive group. In some embodiments, subject compounds containing a subject reactive group inhibit K-Ras G12S with greater potency, as evidenced by an IC50 value that is at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, or at least 20-fold lower than the IC50 value of a corresponding control compound that does not contain the reactive group, as determined in the biochemical assay exemplified in Example 5.

[0153] The inclusion of a reactive group of the present disclosure may enhance the efficacy or potency of a subject compound in inhibiting the proliferation of cells expressing a K-Ras G12S mutation and / or a K-Ras G12C mutation. In some embodiments, a subject compound containing a subject reactive group exhibits greater potency in inhibiting the proliferation of cells expressing a K-Ras G12S mutation and / or a K-Ras G12C mutation, as evidenced by an IC50 value that is at least 10%, 20%, 50%, 100%, 200%, 300%, 400%, or at least 500% lower than the IC50 value of a corresponding control compound that does not contain the reactive group. In some embodiments, subject compounds containing the subject reactive group inhibit the proliferation of cells expressing the K-Ras G12S mutation and / or the K-Ras G12C mutation as evidenced by an IC50 value that is at least 1.1-fold, 1.2-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, or at least 20-fold lower than the IC50 value of a corresponding control compound that does not contain a warhead, as determined in a cellular inhibition assay exemplified in Example 9.

[0154] In addition to their high potency in inhibiting cell proliferation and reducing K-Ras signaling, particularly K-Ras G12S and / or K-Ras G12C mutant-mediated signaling, the compounds disclosed herein also exhibit favorable ADME and / or DMPK properties. Fine-tuned pharmacological properties are crucial for improving the efficacy and safety of K-Ras inhibitors for clinical therapeutic use.

[0155] In some embodiments, compounds of the present disclosure, such as compounds of formula (II), (II-a), (II-b), (II-c), or (II-d), exhibit at least one, two, three, or more advantageous pharmacological properties. Exemplary superior DMPK properties may include, but are not limited to, improved metabolic stability, reduced hERG impairment, reduced CYP inhibition, increased oral exposure, and reduced serum protein binding (thus increasing the amount of free and available compound circulating in the blood of a subject following administration of the compound). In some embodiments, at least one, two, three, or more advantageous pharmacological properties are observed in the subject compounds having formula (II), (II-a), (II-b), (II-c), or (II-d), wherein R 7 is a triazole optionally substituted with methyl, —CH—CN, or a halogen (e.g., Cl). In some embodiments, at least one, two, three, or more advantageous pharmacological properties (including microsomal stability) are observed in the subject compounds having formula (II), (II-a), (II-b), (II-c), or (II-d), wherein R 7 is a triazole optionally substituted with methyl, —CH—CN, or halogen (e.g., Cl), and L 1 teeth [ka] is substituted with R 1 teeth, [ka] is.

[0156] In some embodiments, the subject compounds exhibit suitable metabolic stability as determined by a T1 / 2 of mouse liver microsomal metabolism of greater than 10, 20, 30, 40, 50, 60 minutes, or longer (see Example 11 for experimental procedures). In some embodiments, the subject compounds exhibit suitable metabolic stability as determined by a T1 / 2 of human liver microsomal metabolism of greater than 10, 20, 30, 40, 50, 60, 100, 120 minutes, or longer (see Example 11 for experimental procedures). In yet some other embodiments, a T1 / 2 of at least 10, 20, 30, 40, 50, 60 minutes, or longer is observed in both mouse and human microsomal metabolism assays. One or more compounds disclosed herein are expected to exhibit suitable microsomal stability in mouse and / or human liver microsomal metabolism assays, with a T1 / 2 of greater than 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, or longer.

[0157] In some embodiments, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0158] In some embodiments, the present disclosure provides atropisomers of compounds described herein, such as compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d). In some embodiments, the atropisomers are provided in enantiomeric excess. In some embodiments, the atropisomers are provided in at least 80% enantiomeric excess, e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% enantiomeric excess. In some embodiments, the compounds of Formula (I) or (II) or modified proteins are preferably used as non-racemic mixtures, in which one atropisomer is present in excess over the corresponding enantiomer or epimer. Typically, such mixtures contain a mixture of two isomers in a ratio of at least 9:1, preferably at least 19:1. In some embodiments, the atropisomers are provided in at least 96% enantiomeric excess, meaning that the compounds have less than 2% of the corresponding enantiomer. In some embodiments, the atropisomers are provided in at least 96% diastereomeric excess, meaning that the compounds have less than 2% of the corresponding diastereomer.

[0159] The term "atropisomer" refers to a stereoisomer that occurs when rotation around a single bond within a molecule is prevented, restricted, or significantly slowed as a result of steric interactions with other parts of the molecule, and the substituents on both ends of the single bond are asymmetric (i.e., optical activity occurs without the need for an asymmetric carbon center or stereocenter). If the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species may be permitted. Atropisomers are enantiomers (or epimers) that do not contain a single asymmetric atom. Atropisomers are typically considered stable if the barrier to interconversion is high enough to allow little or no interconversion of the atropisomers at room temperature for at least one week, and preferably at least one year. In some embodiments, atropisomeric compounds of the present disclosure do not undergo more than about 5% interconversion to their opposite atropisomers at room temperature over a period of one week, when the atropisomeric compounds are in substantially pure form, typically in the solid state. In some embodiments, the atropisomeric compounds of the present disclosure do not undergo more than about 5% interconversion to their opposite atropisomers over a period of one year at room temperature (approximately 25° C.). The present chemical entities, pharmaceutical compositions, and methods are intended to encompass all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single atropisomers, and intermediate mixtures.

[0160] In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0161] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases or acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting the purified compound in free form with the appropriate acid or base and isolating the salt thus formed.

[0162] In some embodiments, the compounds described herein exist as solvates. In some embodiments, there are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0163] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the process of crystallization using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents, including but not limited to dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated and solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0164] In certain aspects, the present disclosure provides a compound of formula BL BE -E, wherein B is a monovalent form of a compound described herein; L BEis a covalent linker attached to B and E, E is a monovalent form of the decomposition accelerator.

[0165] A "degradation-promoting agent" is a compound capable of binding to a ubiquitin ligase protein (e.g., an E3 ubiquitin ligase protein) or a protein capable of binding to a ubiquitin ligase protein to form a protein complex capable of conjugating the ubiquitin protein to a target protein. In some embodiments, a degradation-promoting agent is capable of binding to an E3 ubiquitin ligase protein or a protein complex comprising an E3 ubiquitin ligase protein. In some embodiments, a degradation-promoting agent is capable of binding to an E2 ubiquitin-conjugating enzyme. In some embodiments, a degradation-promoting agent is capable of binding to a protein complex comprising an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin ligase protein.

[0166] In some embodiments, the pro-degradation agent is selected from the group consisting of E3A, mdm2, APC, EDD1, SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRI P12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von Hippel-Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MKRN1, CMA (chaperone-mediated autophagy), SCFb-TRCP (Skip-Cullin-F box (beta-TRCP) ubiquitin complex), b-TRCP (b transduction repeat-containing protein), cIAP1 (cellular inhibitor of apoptosis protein 1), APC / C (homology promoting complex / cyclosome), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4 CRBN) capable of binding a protein selected from ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885. In some embodiments, the degradation-promoting agent is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1. In some embodiments, the degradation promoter is a compound described in Ishida and Ciulli, SLAS Discovery 2021, Vol. 25(4) 484-502, such as VH032, VH101, VH298, thalidomide, bestatin, methylbestatin, nutlin, idasanutlin, bardoxolone, bardoxolone methyl, indisulam (E7070), E7820, chloroquinoxaline sulfonamide (CQS), nimbolide, KB02, ASTX660, lenalidomide, or pomalidomide, which is incorporated by reference in its entirety for all purposes.

[0167] In some embodiments, the degradation-promoting agent is any of the agents described in U.S. Patent Application Publication Nos. 20180050021, WO2016146985, WO2018189554, WO2018119441, WO2018140809, WO2018119448, WO2018119357, WO2018118598, WO2018102067, WO201898280, WO201889736, WO201881530, WO201871606, WO201864589, WO201852949, WO2017223452, WO2017204445, WO20171970 55, WO2017197046, WO2017180417, WO2017176958, WO201711371, WO2018226542, WO2018223909, WO20 18189554, WO2016169989, WO2016146985, CN105085620B, CN106543185B, US10040804, US9938302, US 10144745, US10145848, US9938264, US9632089, US9821068, US9758522, US9500653, US9765019, US85 Nos. 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488, 07488.

[0168] In some embodiments, L BE -L BE1 -L BE2 -L BE3 -L BE4 -L BE5 - and L BE1 , L BE2 , L BE3 , L BE4 , L BE5 are independently a bond, -O-, -N(R 12 )-, -C(O)-, -N(R 12 )C(O)-, -C(O)N(R 12)-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 12 )-, -S(O)N(R 12 )-, -N(R 12 )S(O)-, -N(R 12 )S(O)2-, C 1-6 Alkylene, (-OC 1-6 alkyl) z -, (-C 1-6 Alkyl-O) z -, C 2-6 Alkenylene, C 2-6 Alkynylene, C 1-6 Haloalkylene, C 3-12 Cycloalkylene, C 1-11 Heterocycloalkylene, C 6-12 Arylene, or C 1-11 Heteroarylene, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 1-6 Haloalkylene, C 3-12 Cycloalkylene, C 1-11 Heterocycloalkylene, C 6-12 Arylene, or C 1-11 Heteroarylene can be one, two, or three R 20 may be substituted with (-OC 1-6 alkyl) z - and (-C 1-6 Alkyl-O) z -Each C 1-6 Alkyl can be one, two, or three R 20 may be substituted with z is independently an integer of 0 to 10.

[0169] In some embodiments, L BE is -(O-C2 alkyl) z - and z is an integer from 1 to 10. In some embodiments, L BE -(C2 alkyl-O-) z - and z is an integer from 1 to 10. In some embodiments, L BE Ha-(CH2) zz1 L BE2(CH2O) zz2 - and L BE2 is a bond, 5- to 6-membered heterocyclene, phenylene, -C 2-4 alkynylene, -SO2-, or -NH-, and zz1 and zz2 are independently integers from 0 to 10. In some embodiments, L BE is -(CH2) zz1 (CH2O) zz2 -, and zz1 and zz2 are each independently an integer from 0 to 10. In some embodiments, L BE is a PEG linker (e.g., a bivalent linker of 1 to 10 ethylene glycol subunits). In some embodiments, E is [ka] In some embodiments, E is a monovalent form of a compound selected from: [ka] is a monovalent form of a compound selected from

[0170] The chemical compounds described herein can be synthesized according to one or more of the exemplary schemes herein and / or techniques known in the art. The materials used herein are commercially available or prepared by synthetic methods commonly known in the art. These schemes are used for illustrative purposes and are not limited to the compounds listed in the Examples or by any particular substituents. Various steps are described and illustrated in Schemes 1 and 2, although in some cases, these steps may be performed in an order different from that shown in Schemes 1 and 2. Various modifications to these synthetic reaction schemes may be made and will suggest themselves to those skilled in the art upon reading this disclosure. The numbering or R groups in each scheme typically have the same meaning as defined elsewhere herein, unless otherwise indicated.

[0171] Unless specified to the contrary, reactions described herein are conducted at atmospheric pressure and generally within a temperature range of −10° C. to 200° C. Furthermore, unless otherwise specified, reaction times and conditions are approximate and are intended to be conducted, for example, at about atmospheric pressure within a temperature range of about −10° C. to about 110° C. for a period of about 1 to about 24 hours, with reactions being left to react overnight for an average period of about 16 hours.

[0172] In general, the compounds of the present disclosure can be prepared by the following reaction schemes. [ka]

[0173] In some embodiments, compounds of formula 1f can be prepared according to Scheme 1. For example, an amination reaction (e.g., using PyBOP and DBU) can be utilized to form a C-N bond between a suitably protected amine of 1a (e.g., PG1 is Boc, Bus, Cbz, or Fmoc) and an aryl or heteroaryl alcohol or chloride of 1b to provide 1c. Removal of the N-protecting group to reveal secondary amine 1d can be followed by reaction with compound 1e in the presence of a suitable base, such as DIPEA, to provide compounds of formula 1f. [ka]

[0174] In some embodiments, compounds of formula 2d1, 2d2, 2d3, or 2d4 can be prepared according to Scheme 2. For example, an amination reaction (e.g., using PyBOP and DBU) can be utilized to form a C-N bond between a suitably protected amine of 2a1, 2a2, 2a3, or 2a4 (e.g., PG1 is Boc, Bus, Cbz, or Fmoc) and an aryl or heteroaryl alcohol or chloride of 1b to afford 2b1, 2b2, 2b3, or 2b4, respectively. Following removal of the N-protecting group to reveal secondary amine 2c1, 2c2, 2c3, or 2c4, the R 3 amine can be reacted with triphosgene (bis(trichloromethyl)carbonate (BTC)) and pyridine to form the secondary amine 2c1. 7 -H to give compounds of formula 2d1, 2d2, 2d3, or 2d4.

[0175] In some embodiments, compounds of the present disclosure, for example, compounds of the formulas given in Table 1, are synthesized according to one of the general routes outlined in Schemes 1 and 2, Example 1, or by methods generally known in the art. In some embodiments, exemplary compounds can include, but are not limited to, compounds selected from Table 1, or salts or solvates thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 [Table 1-25] [Table 1-26] [Table 1-27] The compounds in Table 1 are depicted with flat, wedge-shaped, and / or dashed wedge-shaped bonds. It is understood that the compounds depicted in Table 1 can encompass all possible stereoisomers, including atropisomers of the compounds in Table 1. In some cases, the relative stereochemistry at one or more stereocenters of the compounds has been determined, and in some cases, the absolute stereochemistry has been determined. In some cases, a single compound number represents a mixture of stereoisomers, including atropisomers. In some cases, a single compound number represents a single stereoisomer, such as a single atropisomer. Thus, when the same depicted structure is provided for two or more compound numbers in Table 1, it is understood that different stereoisomers or mixtures of stereoisomers of the depicted structure are represented by each compound number. † The compound is provided as a substantially pure single atropisomer (R).

[0176] In some embodiments, the compounds of the present disclosure exhibit one or more functional properties disclosed herein. For example, the subject compounds bind to Ras proteins, Kras proteins, or mutant forms thereof. In some embodiments, the subject compounds specifically bind to and inhibit Ras proteins, Kras proteins, or mutant forms thereof. In some embodiments, the subject compounds selectively inhibit Kras mutants compared to wild-type Kras. In some embodiments, the subject compounds have an IC50 of less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 250 nM, less than about 100 nM, less than about 50 nM, or less, as measured in in vitro assays known in the art or exemplified herein. In some embodiments, the subject compounds covalently bind to Kras mutants (e.g., KrasG12S and / or KrasG12C).

[0177] In some embodiments, the subject compounds of the present disclosure are capable of reducing Ras signaling output. Such reduction may be evidenced by one or more of the following: (i) an increase in the steady-state level of GDP-bound Ras protein, (ii) a decrease in the steady-state level of GTP-bound Ras protein, (iii) a decrease in phosphorylated AKTs473, (iv) a decrease in phosphorylated ERKT202 / y204, (v) a decrease in phosphorylated S6S235 / 236, and (vi) a reduction (e.g., inhibition) of cell growth in Ras-driven tumor cells (e.g., derived from the tumor cell lines disclosed herein). In some cases, a reduction in Ras signaling output may be evidenced by two, three, four, five, or all of the above (i)-(vi).

[0178] It is understood that the various aspects of the present invention can be evaluated individually, collectively, or in combination with one another. The various aspects of the present invention described herein can be applied to any of the specific uses disclosed herein. A composition of matter comprising a compound of any formula disclosed herein in the Compositions section of the present disclosure can be utilized in the Methods section, including the Methods of Use and Production sections disclosed herein, and vice versa. method

[0179] The compounds described herein, or their pharmaceutically acceptable salts or solvates, are Ras inhibitors that can inhibit Ras proteins such as wild-type Ras or Ras mutant proteins (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D) from K-Ras, H-Ras, or N-Ras.The compounds disclosed herein (including their pharmaceutically acceptable salts or solvates) have a wide range of uses in therapy, diagnosis, and other biomedical research.

[0180] In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0181] In certain aspects, the present disclosure provides a method of treating a cancer comprising a Ras mutant (e.g., G12S, G12C, and / or G13C) protein, comprising inhibiting a Ras mutant protein in the subject by administering to the subject a compound, wherein the compound, upon contact with the Ras mutant protein, inhibits (e.g., partially inhibits or completely inhibits) the activity or function of the Ras mutant protein, and the inhibited Ras mutant protein exhibits reduced Ras signaling output (e.g., compared to a corresponding Ras protein not contacted with the compound).

[0182] In certain aspects, the present disclosure provides methods for modulating the activity of a Ras protein (e.g., K-Ras, mutant K-Ras, G12S, G12C, and / or G13C), comprising contacting the Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.

[0183] In certain aspects, the present disclosure provides methods for inhibiting cell growth, comprising administering to cells expressing a Ras (e.g., K-Ras) protein an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting proliferation of said cells. In some embodiments, the subject methods comprise administering an additional agent to said cells.

[0184] In certain aspects, the present disclosure provides methods for treating a disease mediated at least in part by a Ras protein, such as K-Ras or a mutant thereof, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease is a cancer, such as a solid tumor or a hematological cancer. In some embodiments, the method further comprises administering to the subject an additional agent, such as an SHP2 inhibitor, an SOS inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a BRAF inhibitor, or a combination thereof.

[0185] In certain aspects, the present disclosure provides a method for inhibiting the activity of a Ras protein, such as K-Ras or a mutant thereof, comprising contacting the Ras protein with a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound exhibits an IC50 for the Ras protein of less than 10 μM, for example, 5 μM, 1 μM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 50 pM, 10 pM or less.

[0186] In certain aspects, the present disclosure provides methods of treating Ras-mediated cancer in a subject in need thereof, comprising administering to the subject an SHP2 inhibitor, an SOS inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, or a BRAF inhibitor, and an effective amount of a compound disclosed herein, e.g., a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof.

[0187] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological cancer.

[0188] In practicing any of the methods disclosed herein, the Ras target to which the subject compound is covalently bound can be a Ras mutant (e.g., G12S, G12C, and / or G13C), including mutants of K-Ras, H-Ras, and N-Ras. In some embodiments, the methods of treating cancer can be applied to treat solid tumors or hematological cancers. In some embodiments, the cancers treated include, but are not limited to, prostate cancer, brain cancer, colon cancer, rectal cancer, renal cell carcinoma, liver cancer, non-small cell lung cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, and non-Hodgkin's lymphoma. The cancer may be a cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, childhood solid tumors, cancer of the bladder, cancer of the kidney or ureter, cancer of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, combinations of the above cancers, and metastatic lesions of the above cancers. In some embodiments, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer.In some embodiments, a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasia, and leukemia. and the hematological malignancies are selected from one or more of the following: pulmonary leukemia, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell follicular lymphoma or large cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and preleukemia. In some embodiments, a method of treating cancer in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is one or more cancers selected from the group consisting of chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), and / or acute lymphoblastic leukemia (ALL).

[0189] Any of the therapies disclosed herein can be administered alone or in combination or concomitantly with another therapy or other drug. "Combination" is meant to include (a) formulating the subject compositions containing the subject compounds with another drug, and (b) using the subject compositions separately from the other drug as part of an overall therapeutic regimen. "In combination" means that the other therapy or drug is administered either concurrently, simultaneously, or sequentially with the subject compounds, including the compounds disclosed herein, without specific time restrictions, and such combined administration results in a therapeutic effect.

[0190] In some embodiments, the subject treatment methods are combined with surgery, cell therapy, chemotherapy, radiation, and / or immunosuppressants. Furthermore, the compositions of the present disclosure can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergy agents, anti-nausea (or anti-emetic) agents, analgesics, cytoprotective agents, immunostimulators, and combinations thereof. In one embodiment, the subject treatment methods are combined with chemotherapeutic agents.

[0191] Exemplary chemotherapeutic agents include anthracyclines (e.g., doxorubicin (e.g., liposomal doxorubicin)), vinca alkaloids (e.g., vinblastine, vincristine, vindesine, vinorelbine), alkylating agents (e.g., cyclophosphamide, decyl benzoate, melphalan, ifosfamide, temozolomide), immune cell antibodies (e.g., alemtuzamab, gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab, ximab), antimetabolites (including, for example, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors (e.g., fludarabine)), TNFR glucocorticoid-inducible TNFR-related protein (GITR) agonists, proteasome inhibitors (e.g., aclacinomycin A, gliotoxin, or bortezomib), immunomodulatory agents such as thalidomide or thalidomide derivatives (e.g., lenalidomide). Additional chemotherapeutic agents contemplated for use in combination include busulfan (Myleran®), busulfan injection (Busulfex®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, and doxorubicin. Hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), hydroxyurea (Hydrea®), idarubicin (Idamycin®), mitoxantrone (Novantrone®), gemtuzumab ozogamicin (Mylotarg®), anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan injection (Busulfex®),Capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), dexamethasone, docetaxel (Taxotere®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantro®), ne®), Mylotarg, paclitaxel (Taxol®), Phoenix (Yttrium 90 / MX-DTPA), pentostatin, polipheprosan 20 and carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0192] Anti-cancer agents of particular interest for combination with the compounds of the invention include anthracyclines, alkylating agents, antimetabolites, drugs that inhibit either the calcium-dependent phosphatase calcineurin or the p70S6 kinase FK506, or that inhibit p70S6 kinase, mTOR inhibitors, immunomodulators, anthracyclines, vinca alkaloids, proteosome inhibitors, GITR agonists, protein tyrosine phosphatase inhibitors, CDK4 kinase inhibitors, BTK inhibitors, MKN kinase inhibitors, DGK kinase inhibitors, or oncolytic viruses.

[0193] Exemplary antimetabolites include, but are not limited to, the following pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors: methotrexate (Rheumatrex®, Trexall®), 5-fluorouracil (Adrucil®, Efudex®, Fluoroplex®), floxuridine (FUDF®), cytarabine (Cytosar-U®, Tarabine PFS), 6-mercaptopurine (Puri-Nethol®), 6-thioguanine (Thioguanine Tabloid®), fludarabine phosphate (Fludara®), pentostatin (Nipent®), pemetrexed (Alimta®), raltitrexed (Tomudex®), cladribine (Leustatin®), clofarabine (Clofarex®, Clolar®), azacitidine (Vidaza®), decitabine, and gemcitabine (Gemzar®). Preferred antimetabolites include cytarabine, clofarabine, and fludarabine.

[0194] Exemplary alkylating agents include, but are not limited to, the following nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes: uracil mustard (Aminouracil Mustard®), Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, uracil mitrogen mustard (Uracil nitrogen mustard). mustard®), Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), chlorambucil (Leukeran®), pipobroman (Amedil®), edel®), Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and dacarbazine (DTIC-Dome®). Further exemplary alkylating agents include, but are not limited to, oxaliplatin (Eloxatin®),Temozolomide (Temodar® and Temodal®), dactinomycin (also known as actinomycin-D, Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®), altretamine (also known as hexamethylmelamine (HMM), Hexalen®), carmustine (BiCNU®), bendamustine (Treanda®), busulfan (Busulfex® and Myleran®), carboplatin (Paraplatin®), lomustine (as CCNU®), also known as CeeNU®), cisplatin (also known as CDDP, Platinol® and Platinol®-AQ), chlorambucil (Leukeran®), cyclophosphamide (Cytoxan® and Neosar®), dacarbazine (DTIC, also known as DIC and imidazolecarboxamide, DTIC-Dome®), altretamine (also known as hexamethylmelamine (HMM), Hexalen®), ifosfamide (Ifex®), Prednumustine, procarbazine (Matulane®), mechlorethamine (nitrogen mustard, mustine, and mechloroethamine hydrochloride) hydrochloride (Mustargen®), streptozocin (Zanosar®), thiotepa (also known as thiophosphamide, TESPA and TSPA, Thioplex®), cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®), and bendamustine HCl (Treanda®).

[0195] In certain embodiments, the compositions provided herein can be administered in combination with radiation therapy, such as radiation. Body radiation can be administered at 12 Gy. The radiation dose can include a cumulative dose of 12 Gy to the whole body, including healthy tissue. The radiation dose can include 5 Gy to 20 Gy. The radiation dose can be 5 Gy, 6 Gy, 7 Gy, 8 Gy, 9 Gy, 10 Gy, 11 Gy, 12 Gy, 13 Gy, 14 Gy, 15 Gy, 16 Gy, 17 Gy, 18 Gy, 19 Gy, or up to 20 Gy. The radiation can be total body radiation or partial body radiation. If the radiation is total body radiation, the radiation can be uniform or non-uniform. For example, if the radiation is non-uniform, a smaller area of ​​the body, such as the neck, may receive a higher dose than a larger area, such as the lower back.

[0196] If desired, immunosuppressants can be used in combination with the subject treatment methods. Exemplary immunosuppressants include, but are not limited to, cyclosporine, azathioprine, methotrexate, mycophenolate, and FK506, antibodies or other immunoablative agents such as CAMPATH, anti-CD3 antibodies (e.g., muromonab, otelixizumab), or other antibody therapies, cytoxin, fludarabine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation, peptide vaccines, and any combination thereof. According to the subject matter of the present disclosure, the above-mentioned various methods may include administering at least one immunomodulatory agent. In certain embodiments, the at least one immunomodulatory agent is selected from the group consisting of an immunostimulatory agent, a checkpoint immune blocker (e.g., a blocker or inhibitor of immune checkpoint genes such as, for example, PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs, and CD39), a radiotherapeutic agent, a chemotherapeutic agent, and combinations thereof. In some embodiments, the immunostimulatory agent is selected from the group consisting of IL-12, an agonistic costimulatory monoclonal antibody, and combinations thereof. In one embodiment, the immunostimulatory agent is IL-12. In some embodiments, the agonistic costimulatory monoclonal antibody is selected from the group consisting of an anti-4-1BB antibody (e.g., urelumab, PF-05082566), an anti-OX40 antibody (pogalizumab, taborixizumab, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX-2011), and a combination thereof. In one embodiment, the agonistic costimulatory monoclonal antibody is an anti-4-1BB antibody.In some embodiments, the checkpoint immune blockade is selected from the group consisting of anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab, BMS-936559), anti-CTLA-4 antibodies (e.g., tremelimumab, ipilimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab, cemiplimab), anti-LAG3 antibodies (e.g., C9B7W, 410C9), anti-B7-H3 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g., F38-2E2), and combinations thereof. In one embodiment, the checkpoint immune blockade is an anti-PD-L1 antibody. In some cases, the compounds of the present disclosure can be administered to a subject in combination with (e.g., before, simultaneously with, or after) bone marrow transplantation, T cell ablative therapy using either a chemotherapeutic agent such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide, or an antibody such as OKT3 or CAMPATH. In some cases, the expanded cells can be administered before or after surgery. Alternatively, a composition comprising a compound described herein can be administered with an immunostimulatory agent. The immunostimulatory agent can be a vaccine, colony-stimulating agent, interferon, interleukin, virus, antigen, costimulatory agent, immunogenic agent, immunomodulatory agent, or immunotherapeutic agent. The immunopotentiator can be a cytokine such as an interleukin. One or more cytokines can be introduced using the modified cells provided herein. Cytokines can be used to enhance the function of modified T lymphocytes (including adoptively transferred tumor-specific cytotoxic T lymphocytes) and allow them to proliferate within the tumor microenvironment. In some cases, IL-2 can be used to promote the proliferation of the modified cells described herein. Cytokines such as IL-15 can also be employed. Other cytokines relevant to immunotherapy, such as IL-2, IL-7, IL-12, IL-15, IL-21, or a combination thereof, can also be used. The interleukin can be IL-2 or aldesleukin. Aldesleukin can be administered in low or high doses.A high-dose aldesleukin regimen may involve up to about 14 doses of aldesleukin at about 0.037 mg / kg (600,000 IU / kg) administered intravenously every 8 hours, depending on tolerability. The immunostimulant (e.g., aldesleukin) may be administered within 24 hours after cell administration. The immunostimulant (e.g., aldesleukin) may be administered as an infusion over about 15 minutes about every 8 hours for up to about 4 days after cell infusion. The immune stimulant (e.g., aldesleukin) can be administered at a dose of about 100,000 IU / kg, 200,000 IU / kg, 300,000 IU / kg, 400,000 IU / kg, 500,000 IU / kg, 600,000 IU / kg, 700,000 IU / kg, 800,000 IU / kg, 900,000 IU / kg, or up to about 1,000,000 IU / kg. In some cases, aldesleukin can be administered at a dose of about 100,000 IU / kg to 300,000 IU / kg, 300,000 IU / kg to 500,000 IU / kg, 500,000 IU / kg to 700,000 IU / kg, 700,000 IU / kg to about 1,000,000 IU / kg.

[0197] In some embodiments, the compounds disclosed herein, or salts or solvates thereof, are used in combination with (1) inhibitors of MEK (e.g., MEK1, MEK2) or mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib, AZD6244); (2) inhibitors of epidermal growth factor receptor (EGFR) and / or mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab-panitumumab, osimertinib, olmutinib, EGF-816); (3) immunotherapeutic agents (e.g., (4) taxanes (e.g., paclitaxel, docetaxel); (5) antimetabolites (e.g., methotrexate, antifolates such as raltitrexed, pyrimidine analogs such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogs, purine and adenosine analogs such as capecitabine and gemcitabine, mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (arabinose), C), fludarabine); inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or FGFR4 and / or mutants thereof (e.g., nintedanib); antimetabolites (e.g., antifolates such as methotrexate, raltitrexed, pyrimidine analogs such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogs, purine and adenosine analogs such as capecitabine and gemcitabine, mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (arabinose), C), fludarabine); (6) inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or FGFR4 and / or their mutants (e.g., nintedanib); (7) mitotic kinase inhibitors (e.g., CDK4 / 6 inhibitors, e.g., palbociclib, ribociclib, abemaciclib, etc.); (8) antiangiogenic drugs (e.g., anti-VEGF antibodies such as bevacizumab); (9) topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone, etc.);(10) Platinum-containing compounds (e.g., cisplatin, oxaliplatin, carboplatin); (11) Inhibitors of ALK and / or its mutants (e.g., crizotinib, alectinib, entrectinib, brigatinib); (12) Inhibitors of c-MET and / or its mutants (e.g., K252a, SU11274, PHA665752, PF2341066); (13) Inhibitors of BCR-ABL and / or its mutants (e.g., imatinib, dasatinib, nilotinib); (14) Inhibitors of ErbB2 (Her2) and / or its mutants (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (15) Inhibitors of AXL and / or its mutants (e.g., R428, amuvatinib, XL-880); (16) NTR Inhibitors of K1 and / or its mutants (e.g., merestinib); (17) inhibitors of RET and / or its mutants (e.g., BLU-667, lenvatinib); (18) inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or their mutants (RAF-709, LY-3009120, sorafenib, vemurafenib, dabrafenib, encorafenib, regorafenib, GDC-879); (19) inhibitors of ERK and / or its mutants (e.g., ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, lavoxertinib); (20) inhibitors of MDM2 (e.g., HDM-201, NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115; (21) mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (22) BET inhibitors (e.g., I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645); (23) IGF1 / 2 inhibitors and / or IGF1-R inhibitors (e.g., xentuzumab, MEDI-573);(24) CDK9 inhibitors (e.g., DRB, flavopiridol, CR8, AZD5438, purvalanol B, AT7519, dinaciclib, SNS-032); (25) farnesyltransferase inhibitors (e.g., tipifarnib); (26) SHIP pathway inhibitors, including SHIP1 inhibitors as well as SHIP2 inhibitors; (27) SRC inhibitors (e.g., dasatinib); (28) JAK inhibitors (e.g., tofacitinib); (29) PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib); (30) BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib);(31) ROS1 inhibitors (e.g., entrectinib), (32) inhibitors of Src, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, or AKT, (33) inhibitors of KRAS G12C mutants (e.g., including but not limited to AMG510, MRTX849, and any covalent inhibitors that bind to cysteine ​​residue 12 of Kras, the structure of which is known) (e.g., US20180334454, US20190144444, US20150239900, US10246424, US20180086753, WO2018143315, WO2018206 539, WO20191107519, WO2019141250, WO2019150305, US9862701, US20170197945, US20180086753, US1014472 4, US20190055211, US20190092767, US20180127396, US20180273523, US10280172, US20180319775, US2018027 3515, US20180282307, US20180282308, WO2019051291, WO2019213526, WO2019213516, WO2019217691, WO2019 241157, WO2019217307, WO2020047192, WO2017087528, WO2018218070, WO2018218069, WO2018218071, WO20200 27083, WO2020027084, WO2019215203, WO2019155399, WO2020035031, WO2014160200, WO2018195349, WO2018112240, WO2019204442, WO2019204449, WO2019104505, WO2016179558, WO2016176338, or related patents and applications (each of which patents and applications is incorporated by reference in its entirety);(34) SHC inhibitors (e.g., PP2, AID371185), (35) GAB inhibitors (e.g., GAB-0001), (36) GRB inhibitors, (37) PI-3 kinase inhibitors (e.g., Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, NVP-BE1185), Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, NVP-BE Z235-AN), (38) MARPK inhibitors, (39) CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib), (40) MAPK inhibitors (e.g., VX-745, VX-702, RO-4402257, SCIO-469, BIRB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323, GW-856553, RWJ67657, BCT-197), or (41) SHP pathway inhibitors, for example, SHP2 inhibitors (e.g., RMC-4630, ERAS-601, [ka] or SHP1 inhibitors. In some embodiments, a Ras inhibitor described herein, such as a compound of Formula (II), salt, or solvate, is administered in combination with or in combination with one or more checkpoint immune blockers (e.g., anti-PD-1 antibody and / or anti-PD-L1 antibody, anti-CLTA-4 antibody). In some embodiments, a Ras inhibitor described herein, such as a compound of Formula (II), salt, or solvate, is administered in combination with one or more pharmacologically active agents, including an inhibitor against one or more targets selected from MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, mitotic kinases, topoisomerases, ALK, ALK5, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1 / 2, IGF1-R, CDK9, SHIP1, SHIP2, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, KrasG12C mutant, and ROS1. In some embodiments, any of the compounds herein that can bind to Ras proteins (e.g., KRAS, mutant Ras proteins) and regulate the activity of such Ras mutants (e.g., G12C, G12S, or G13C) can be administered in combination with or with one or more additional pharmacologically active agents, including inhibitors of SOS (e.g., SOS1, SOS2) or mutants thereof. In some embodiments, the additional pharmacologically active agent administered in combination with or with a compound described herein (e.g., a compound capable of binding to a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS2). In some embodiments, the additional pharmacologically active agent administered in combination with or with a compound described herein (e.g., a compound capable of binding to a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS2).In some embodiments, the additional pharmacologically active agent administered in combination with or in conjunction with a compound described herein (e.g., a compound capable of binding to a Ras protein) is [ka] In some embodiments, the additional pharmacologically active agent administered in combination with or in conjunction with a compound described herein (e.g., a compound capable of binding to a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS2) selected from RMC-5845, and BI-1701963. In some embodiments, the additional pharmacologically active agent administered in combination with or in conjunction with a compound described herein (e.g., a compound capable of binding to a Ras protein) is an inhibitor of SOS (e.g., SOS1, SOS2) described in WO2021092115, WO2018172250, WO2019201848, WO2019122129, WO2018115380, WO2021127429, WO2020180768, or WO2020180770, all of which are incorporated herein by reference in their entireties for all purposes.

[0198] In some embodiments, any of the compounds herein that are capable of binding to a Ras protein (e.g., Kras) and modulating the activity of such a Ras protein may be administered in combination or in conjunction with one or more checkpoint immune blockade agents (e.g., anti-PD-1 and / or anti-PD-L1 antibodies, anti-CLTA-4 antibodies).

[0199] In some embodiments, a compound described herein, such as, for example, a compound of Formula (II), salt, or solvate, is administered in combination or in conjunction with a pharmacologically active agent, including the following inhibitors: (1) SOS1 or a mutant thereof (e.g., RMC-5845, BI-3406, BAY-293, MRTX0902, BI-1701963); (2) SHP2 or a mutant thereof (e.g., 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine, TNO155, RMC-4630, ERAS-601, JAB-3068, IACS-13909 / BBP-398, SHP099, RMC-4550); (3) SHC or a mutant thereof (e.g., (4) GAB or a mutant thereof (e.g., GAB-0001); (5) GRB or a mutant thereof; (6) JAK or a mutant thereof (e.g., tofacitinib); (7) A-RAF, B-RAF, C-RAF or a mutant thereof (e.g., RAF-709, LY-3009120); (8) BRAF or a mutant thereof (e.g., sorafenib, vemurafenib, dabrafenib, encorafenib, regorafenib, GDC-879); (9) MEK or a mutant thereof (e.g., (10) ERK or its mutants (e.g., ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, ravoxertinib); (11) PI3K or its mutants (e.g., idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, NVP-BEZ235-A) N); (12) MAPK or its mutants (e.g., VX-745, VX-702, RO-4402257, SCIO-469, BIRB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323, GW-856553, RWJ67657, BCT-197); (13) EGFR or its mutants (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab-panitumumab, osimertinib, olmutinib, EGF-816);(14) c-MET or a mutant thereof (e.g., K252a, SU11274, PHA665752, PF2341066); (15) ALK or a mutant thereof (e.g., crizotinib, alectinib, entrectinib, brigatinib); (16) FGFR1, FGFR-2, FGFR-3, FGFR-4 or a mutant thereof (e.g., nintedanib); (17) BCR-ABL or a mutant thereof (e.g., imatinib, dasatinib, nilotinib); (18) ErbB2 (Her2) or a mutant thereof (19) AXL or its mutants (e.g., R428, amuvatinib, XL-880); (20) NTRK1 or its mutants (e.g., merestinib); (21) ROS1 or its mutants (e.g., entrectinib); (22) RET or its mutants (e.g., BLU-667, lenvatinib); (23) MDM2 or its mutants (e.g., HDM-201, NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115; (24) mTOR or its mutants (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (25) BET or its mutants (e.g., I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, Orionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645; (26) IGF1, IGF2, IGF1R or variants thereof (e.g., xentuzumab, MEDI-573); (27) CDK9 or variants thereof (e.g., DRB, flavopiridol, CR8, AZD5438, parvalanol B, AT7519, dinaciclib, SNS-032); or (28) CDK4 / 6 (e.g., palbociclib, ribociclib, abemaciclib).

[0200] In combination therapy, the compounds provided herein and other anti-cancer agents can be administered either concurrently, simultaneously, or sequentially without specific time restrictions, and such administration provides therapeutically effective levels of the two compounds in the patient's body.

[0201] In some embodiments, the compound of the present disclosure and other anticancer drugs are generally administered sequentially in any order by suitable routes such as infusion or oral administration.Dosage regimens can vary according to the stage of disease, the physical condition of patients, the safety profile of each drug, the tolerance of each drug, and other criteria known to the attending physician and doctor who administers the combination therapy.The compound of the present disclosure and other anticancer drugs can be administered within minutes, hours, days, or even weeks apart, depending on the specific cycle used in treatment.In addition, this cycle can also include administering one drug more frequently than the other during the treatment cycle, or administering different doses for each drug administration.

[0202] In some cases, treatment regimen can be administered according to the subject's weight.For subjects who are determined to be obese (BMI>35), it may be necessary to use actual weight.BMI is calculated as follows: BMI=weight (kg) / [height (m)] 2 It is calculated by:

[0203] Body weight can be calculated as 50 kg + 2.3 × (inches over 60 inches) for men or 45.5 kg + 2.3 (inches over 60 inches) for women. For subjects who are over 20% of their ideal body weight, a corrected body weight can be calculated. The corrected body weight can be the sum of ideal body weight + (0.4 × (actual body weight - ideal body weight)). In some cases, body surface area can be used to calculate dosage. Body surface area (BSA) can be calculated by BSA (m2) = √ height (cm) × body weight (kg) / 3600.

[0204] In certain aspects, methods are provided for modulating the activity of a Ras (e.g., K-Ras) protein, comprising contacting the Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras (e.g., K-Ras) protein. In some embodiments, the subject methods comprise administering an additional agent or therapy.

[0205] In some embodiments, a method for modulating the activity of a Ras protein is provided, comprising contacting the Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the modulating comprises inhibiting the activity of the Ras (e.g., K-Ras) protein. In some embodiments, a method for modulating the activity of K-Ras, H-Ras, and N-Ras Ras mutant (e.g., G12S, G12C, and / or G13C) proteins is provided, comprising contacting the Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0206] In some embodiments, a method for reducing Ras signaling output in cells is provided by contacting cells with a compound described herein.The reduction in Ras signaling can be demonstrated by one or more of the following: (i) an increase in the steady-state level of GDP-bound modified proteins, (ii) a decrease in the steady-state level of GTP-bound Ras proteins, (iii) a decrease in phosphorylated AKTs473, (iv) a decrease in phosphorylated ERKT202 / y204, (v) a decrease in phosphorylated S6S235 / 236, (vi) a decrease in cell growth of tumor cells expressing Ras mutant (e.g., G12S, G12C, and / or G13C) proteins, and (vii) a decrease in Ras interaction with Ras pathway signaling proteins.Non-limiting examples of Ras pathway signaling proteins include SOS (including SOS1 and SOS2), RAF, SHC, SHP (including SHP1 and SHP2), MEK, MAPK, ERK, GRB, RASA1, and GNAQ. In some embodiments, the reduction in Ras signaling output can be evidenced by two, three, four, five, six, or all of (i)-(vii) above. In some embodiments, the reduction in any one or more of (i)-(vii) is greater than or equal to 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 21-fold, 22-fold, 23-fold, 24-fold, 25-fold, 26-fold, 27-fold, 28-fold, 29-fold, 30-fold, 31-fold, 32-fold, 33-fold, 34-fold, 35-fold, 36-fold, 37-fold, 38-fold, 39-fold, 40-fold, 41-fold, 42-fold, 43-fold, 44-fold, 45-fold, 46-fold, 47-fold, 48-fold, 49-fold, 50-fold, 51-fold, 52-fold, 53-fold, 54-fold, 55-fold, 56-fold, 57-fold, 58-fold, 59-fold, 60-fold, 61-fold, 62-fold, 63-fold, 64-fold, 65-fold, 66-fold, 67-fold, 68-fold, 69-fold, 70-fold, 71-fold, 72-fold, 73-The reduction in cell proliferation can be 9x, 1x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 20x, 30x, 40x, 50x, 60x, 70x, 80x, 90x, 100x, 200x, 300x, 400x, 500x, 600x, 700x, 800x, 900x, 1000x, 2000x, 3000x, 4000x, 5000x, or more. The reduction in cell proliferation can be demonstrated by using tumor cells or cell lines. The tumor cell line can be derived from one or more tissues, such as tumors of the pancreas, lung, ovary, biliary tract, intestine (e.g., small intestine, large intestine, colon), endometrium, stomach, hematopoietic tissue (e.g., lymphoid tissue), etc. Examples of tumor cell lines with K-Ras mutations include A549 (e.g., K-Ras G12S), e.g., AGS (e.g., K-Ras G12D), ASPC1 (e.g., K-Ras G12D), Calu-6 (e.g., K-Ras Q61K), CFPAC-1 (e.g., K-Ras G12V), CL40 (e.g., K-Ras G12D), COLO678 (e.g., K-Ras G12D), COR-L23 (e.g., K-Ras G12V), DAN-G (e.g., K-Ras G12V), GP2D (e.g., K-Ras G12D), GSU ​​(e.g., K-Ras G12F), HCT116 (e.g., K-Ras G13D), HEC1A (e.g., K-Ras G12D), HEC1B (e.g., K-Ras G12F), HEC50B (e.g., K-Ras G12F), HEYA8 (e.g., K-Ras G12D or G13D), HPAC (e.g., K-Ras G12D), HPAFII (e.g., K-Ras G12D), HUCCT1 (e.g., K-Ras G12D), KARPAS620 (e.g., K-Ras G13D), KOPN8 (e.g., K-Ras G13D), KP-3 (e.g., K-Ras G12V), KP-4 (e.g., K-Ras G12D), L3.3 (e.g., K-Ras G12D), LoVo (e.g., K-Ras G13D), LS180 (e.g., K-Ras G12D), LS513 (e.g., K-Ras G12D), MCAS (e.g., K-Ras G12D), NB4 (e.g., K-Ras A18D), NCI-H1355 (e.g., K-Ras G13C), NCI-H1573 (e.g., K-Ras G12A), NCI-H1944 (e.g., K-Ras G13D), NCI-H2009 (e.g., K-Ras G12A), NCI-H441 (e.g., K-Ras G12V), NCI-H747 (e.g., K-Ras G13D), NOMO-1 (e.g., K-Ras G12D), OV7 (e.g., K-Ras G12D), PANC0203 (e.g., K-Ras G12D), PANC0403 (e.g., K-Ras G12D), PANC0504 (e.g., K-Ras G12D), PANC0813 (e.g., K-Ras G12D), PANC1 (e.g., K-Ras G12D), Panc-10.05 (e.g., K-Ras G12D), PaTu-8902 (e.g., K-Ras G12V), PK1 (e.g., K-Ras G12D), PK45H (e.g., K-Ras G12D), PK59 (e.g., K-Ras G12D), SK-CO-1 (e.g., K-Ras G12V), SKLU1 (e.g., K-Ras G12D), SKM-1 (e.g., K-Ras K117N), SNU1 (e.g., K-Ras G12D), SNU1033 (e.g., K-Ras G12D), SNU1197 (e.g., K-Ras G12D), SNU407 (e.g., K-Ras G12D), SNU410 (e.g., K-Ras G12D), SNU601 (e.g., K-Ras G12D), SNU61 (e.g., K-Ras G12D), SNU8 (e.g., K-Ras G12D), SNU869 (e.g., K-Ras G12D), SNU-C2A (e.g., K-Ras G12D), SU.86.Examples of such antibodies include, but are not limited to, K-Ras G12D (e.g., K-Ras G12D), SUIT2 (e.g., K-Ras G12D), SW1990 (e.g., K-Ras G12D), SW403 (e.g., K-Ras G12V), SW480 (e.g., K-Ras G12V), SW620 (e.g., K-Ras G12V), SW948 (e.g., K-Ras Q61L), T3M10 (e.g., K-Ras G12D), TCC-PAN2 (e.g., K-Ras G12R), TGBC11TKB (e.g., K-Ras G12D), and MIA Pa-Ca (e.g., MIA Pa-Ca 2 (e.g., K-Ras G12C)).

[0207] In one aspect, a modified Ras mutant protein is provided that comprises a compound described herein (or a residue of a compound described herein, wherein the residue of the compound is modified from the compound described herein alone upon covalent attachment to the amino acid) covalently attached to an amino acid corresponding to position 12 or 13 of SEQ ID NO: 1. In some embodiments, such covalently modified Ras mutant proteins exhibit reduced Ras signaling output (e.g., compared to a corresponding unmodified Ras mutant in the absence of the covalently attached compound). In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently attached to an amino acid residue corresponding to position 12 or 13 of SEQ ID NO: 1. In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently attached to an amino acid residue corresponding to position 12 or 13 of SEQ ID NO: 1, and the Ras mutant protein is a human protein selected from KRas G12C, KRas G12S, KRas G13C, and KRas G13S. In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently linked to an amino acid residue corresponding to position 12 or 13 of SEQ ID NO:1, and the Ras mutant protein is a human KRAS mutant protein (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D). In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently linked to an amino acid residue corresponding to position 12 or 13 of SEQ ID NO:1, and the Ras mutant protein is a human KRas G12S protein. In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently linked to an amino acid residue corresponding to position 12 or 13 of SEQ ID NO:1, and the Ras mutant protein is a KRas G12C protein. In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently linked to a protein of SEQ ID NO:4. In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently linked to a serine residue at position 12 of SEQ ID NO:4.In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently attached to a cysteine ​​residue corresponding to position 12 of SEQ ID NO: 1, where the wild-type glycine at position 12 is mutated to cysteine. In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently attached to an amino acid residue corresponding to position 12 or 13 of SEQ ID NO: 1, where the Ras mutant protein is a mammalian Ras protein (including a human protein) selected from NRas G12C, NRas G12S, NRas G13C, and NRas G13S. In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently attached to an amino acid residue corresponding to position 12 or 13 of SEQ ID NO: 1, where the Ras mutant protein is a mammalian protein (including a human protein) selected from HRas G12C, Hras G12S, Hras G13C, and HRas G13S. It will be understood that the compounds described herein can be modified by covalently attaching an amino acid corresponding to position 12 or 13 of human KRas (e.g., SEQ ID NO: 1) (e.g., a mutant amino acid other than G). The subject compounds of the present disclosure include the compounds described herein immediately before covalently binding a Ras mutant protein, as well as the resulting compounds after covalently binding to a modified Ras mutant protein. For example, the subject compounds of the present disclosure can be covalently bound to a mutant Ras protein to form a modified Ras mutant protein when covalently bound to the amino acid corresponding to position 12 or 13 of SEQ ID NO: 1 to open the ring of the compound. All compounds before and after such covalent binding are considered to be subject compounds of the present invention.

[0208] In embodiments of the modified Ras mutant proteins described herein, the decreased Ras signaling output is evidenced by (i) an increase in steady-state levels of GDP-bound modified proteins, (ii) a decrease in phosphorylated AKTs473, (iii) a decrease in phosphorylated ERK T202 / Y204, (iv) a decrease in phosphorylated S6 S235 / 236, (v) a decrease in cell growth of tumor cells expressing the Ras mutant protein (e.g., G12C, G12S, G13C, or G13S), and (vi) a decrease in the interaction of Ras with Ras pathway signaling proteins.

[0209] In some embodiments, the modified Ras mutant protein described herein is formed by contacting a compound described herein with a serine residue of an unmodified Ras G12S mutant protein, wherein the compound comprises a moiety susceptible to reaction with a nucleophilic serine residue corresponding to position 12 of SEQ ID NO:4. In some embodiments, the compound comprises a leaving group and a leaving group, and said contacting results in release of the leaving group and formation of said modified protein. In some embodiments, the compound selectively labels the serine residue corresponding to position 12 of SEQ ID NO:4 (G12S mutant) relative to the valine residue (G12V) or glycine residue (wild-type Kras) at the same position. In some embodiments, the compound selectively labels the serine residue relative to (i) the aspartate residue of a K-Ras G12D mutant protein (the aspartate corresponds to residue 12 of SEQ ID NO:2) and / or (ii) the valine residue of a K-Ras G12V mutant protein (the valine corresponds to residue 12 of SEQ ID NO:3). In some embodiments, the compound selectively labels the cysteine ​​residue at position 12 (K-Ras G12C mutant, where glycine is substituted with cysteine) relative to the valine residue (K-Ras G12V) or glycine residue (wild-type K-Ras) at the same position. In some embodiments, the compound selectively labels the cysteine ​​or serine residue of a K-Ras mutant (i.e., K-Ras G12C or K-Ras G12S) by at least 1, 2, 3, 4, 5, 10, or more times when assayed under equivalent conditions compared to (i) the aspartic acid residue of a K-Ras G12D mutant protein (wherein the aspartic acid corresponds to residue 12 of SEQ ID NO:2) and / or (ii) the valine residue of a K-Ras G12V mutant protein (wherein the valine corresponds to residue 12 of SEQ ID NO:3).

[0210] In embodiments of modified Ras mutant proteins described herein, a compound covalently binds in vitro to a serine residue of an unmodified Ras G12S protein corresponding to position 12 of SEQ ID NO: 4. In embodiments of modified Ras mutant proteins described herein, a compound contacts in vivo a serine residue of an unmodified K-Ras G12S protein corresponding to position 12 of SEQ ID NO: 4. In embodiments of modified Ras mutant proteins described herein, a compound covalently binds in vitro or in vivo to a cysteine ​​residue of an unmodified Ras G12C protein corresponding to position 12 of a K-Ras G12C mutant (in which the glycine residue is replaced with cysteine). In embodiments of modified Ras mutant proteins described herein, a compound covalently binds in vitro or in vivo to both the serine and cysteine ​​residues of unmodified K-Ras G12S and K-Ras G12C proteins, respectively, at position 12 of the respective proteins.

[0211]

[0014] In one aspect, methods are provided for treating cancer in a subject comprising a Ras mutant protein (e.g., KRas G12C, KRas G12S, KRas G13C, KRas G13S, NRas G12C, NRas G12S, NRas G13C, NRas G13S, HRas G12C, HRas G12S, HRas G13C, or HRas G13S), comprising modifying the subject's Ras mutant protein by administering to the subject a compound described herein, wherein the compound, upon contact with the Ras mutant protein, covalently modifies the Ras mutant protein at a residue corresponding to residue 12 or 13 of SEQ ID NO: 1, whereby the modified Ras mutant protein exhibits reduced Ras signaling output (e.g., compared to a control, such as an unmodified Ras mutant protein not covalently bound with any compound, such as a compound disclosed herein).

[0212] In some embodiments, the subject compounds exhibit one or more of the following characteristics: they are capable of reacting with mutant residues of Ras mutant proteins (e.g., KRas G12C, KRas G12S, KRas G13C, KRas G13S, NRas G12C, NRas G12S, NRas G13C, NRas G13S, HRas G12C, HRas G12S, HRas G13C, or HRas G13S) to covalently modify such Ras mutants, and / or they contain a moiety that is susceptible to reacting with a nucleophilic amino acid residue corresponding to positions 12 or 13 of SEQ ID NO:1 (e.g., KRas G12C, KRas G12S, KRas G13C, KRas G13S, NRas G12C, NRas G12S, NRas G13C, NRas G13S, HRas G12C, HRas G12S, HRas G13C, or HRas G13S). In some embodiments, the subject compounds, when used to modify a Ras mutant protein, reduce the signaling output of the Ras protein. In some embodiments, the subject compounds exhibit an IC50 (as determined by a reduction in Ras::SOS1 interaction) against mutant Ras (e.g., KRas G12C, KRas G12S, KRas G13C, KRas G13S, NRas G12C, NRas G12S, NRas G13C, NRas G13S, HRas G12C, HRas G12S, HRas G13C, or HRas G13S) of 10 μM or less, e.g., 5 μM or less, 1 μM or less, 500 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, 5 nM or less, 1 nM or less, 500 pM or less, 50 pM or less, or 10 pM or less.

[0213] In some embodiments, the modified Ras mutant proteins disclosed herein exhibit reduced Ras signaling output. Reduced signaling output can be confirmed by a variety of methods known in the art. For example, phosphorylation of a substrate or its specific amino acid residues can be detected and / or quantified by one or more techniques, such as kinase activity assay, phospho-specific antibody, Western blot, enzyme-linked immunosorbent assay (ELISA), cell-based ELISA, intracellular flow cytometry, mass spectrometry, and multi-analysis profiling. A decrease in Ras signaling output can be evidenced by a number of readouts, including, but not limited to, (i) an increase in steady-state levels of GDP-bound modified proteins, (ii) a decrease in phosphorylated AKTs473, (iii) a decrease in phosphorylated ERK T202 / Y204, (iv) a decrease in phosphorylated S6 S235 / 236, and (v) a decrease in cell growth of primary cells expressing a Ras mutant protein (e.g., KRas G12C, KRas G12S, KRas G13C, KRas G13S, NRas G12C, NRas G12S, NRas G13C, NRas G13S, HRas G12C, HRas G12S, HRas G13C, or HRas G13S), and (vi) a decrease in the interaction of Ras with Ras pathway signaling proteins. In some embodiments, a decrease is evidenced by two, three, four, or more of items (i)-(vi). In some embodiments, the reduction in Ras signaling output can be evidenced by any one of (i)-(vi) compared to a control, unmodified, corresponding Ras protein that is not covalently bound to any of the compounds disclosed herein. For example, the control Ras protein described herein can be a Ras protein (e.g., wild-type or mutant) that is not complexed with any of the subject compounds of the present disclosure.The increase in item (i) or the decrease in items (ii)-(vi) can be at least about 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more, when compared to a control Ras protein. In some embodiments, the decreased interaction of Ras with Ras pathway signaling proteins is established by decreased interaction with SOS (including SOS1 and SOS2), RAF, SHC, SHP (including SHP1 and SHP2), MEK, MAPK, ERK, GRB, RASA1, or GNAQ.

[0214] Signaling output measured as IC50 values ​​can be obtained, and the ratio of the IC50 for one variant compared to another can be calculated. For example, a selective reduction in K-Ras G12S signaling output can be evidenced by a ratio greater than 1. In particular, a selective reduction in K-Ras G12S signaling relative to K-Ras G12D signaling or wild-type K-Ras signaling is evidenced by a ratio of IC50 (for K-Ras G12D or wild-type) to IC50 (for K-Ras G12S) greater than 1.

[0215] It will be understood that when a compound described herein selectively labels serine and / or cysteine ​​residues of a K-Ras G12S or K-Ras G12C protein relative to another K-Ras protein (e.g., wild-type, G12D, or G12V), the compound will label the K-Ras G12S or K-Ras G12C protein at a faster rate, or to a greater extent, or by any other quantifiable measure, relative to the other K-Ras protein (e.g., wild-type, G12D, G12V) under similar or identical reaction conditions for the compared proteins. In some embodiments, the greater labeling of K-Ras G12S and / or K-Ras G12C can be 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more, compared to another K-Ras protein (e.g., wild-type, G12D, or G12V).

[0216] In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, are Ras regulators (including Ras inhibitors) that can covalently modify Ras proteins. The modified Ras proteins can be K-Ras, H-Ras, or Ras G12S mutants or G12C mutants derived from N-Ras. The compounds disclosed herein, their pharmaceutically acceptable salts, or solvates have a wide range of applications in therapy, diagnosis, and other biomedical research.

[0217] In one aspect, a method is provided for treating cancer in a subject containing a Ras G12S mutant protein, comprising modifying the subject's Ras G12S mutant protein by administering to the subject a compound described herein, wherein upon contact with the Ras G12S mutant protein, the compound covalently modifies the Ras G12S mutant protein at a serine residue corresponding to residue 12 of SEQ ID NO: 4, whereby the modified K-Ras G12S protein is characterized by exhibiting reduced Ras signaling output (e.g., compared to a corresponding unmodified Ras protein not covalently bound to the compound).

[0218] In one aspect, a method is provided for treating cancer in a subject containing a Ras G12C mutant protein, comprising modifying the subject's Ras G12C mutant protein by administering to the subject a compound described herein, wherein upon contact with the Ras G12C mutant protein, the compound covalently modifies the Ras G12C mutant protein at a cysteine ​​residue corresponding to residue 12 of SEQ ID NO: 1 (wherein the glycine at position 12 is replaced with cysteine), thereby characterizing the modified K-Ras G12C protein as exhibiting a reduced Ras signaling output (e.g., compared to a corresponding unmodified Ras protein not covalently bound to the compound).

[0219] In one aspect, provided is a method of modulating the activity of a Ras protein (e.g., K-Ras, mutant K-Ras, K-Ras G12S), comprising contacting the Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.

[0220] In practicing any of the methods disclosed herein, the Ras target to which the subject compounds are covalently bound can be a Ras mutant (e.g., KRas G12C, KRas G12S, KRas G13C, KRas G13S, NRas G12C, NRas G12S, NRas G13C, NRas G13S, HRas G12C, HRas G12S, HRas G13C, or HRas G13S). Pharmaceutical Compositions and Methods of Administration

[0221] 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.

[0222] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are administered to a subject in a biologically compatible form suitable for administration to treat or prevent a disease, disorder, or condition. Administration of the compounds described herein can be in any pharmacological form, including a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with a pharmaceutically acceptable carrier.

[0223] In some embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are administered as pure chemicals, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 2011). st The compositions are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected based on the chosen route of administration and standard pharmaceutical practice, as described in (Ed. Mack Pub. Co., Easton, PA (2005)).

[0224] Thus, provided herein are pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients. An excipient (or carrier) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject) of the composition.

[0225] In some embodiments of the methods described herein, the compounds described herein are administered in the form of a pharmaceutical composition, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent. Administration of the compounds and compositions described herein can be effected by any method that allows the compound to be delivered to the site of action. These methods include, but are not limited to, enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including transdermal, dermal, enema, eye drops, ear drops, intranasal, and vaginal) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient. By way of example only, the compounds described herein can be administered locally to the site in need of treatment, for example, by local infusion during surgery, topical application such as a cream or ointment, injection, catheter, or implant. Administration can also be by direct injection at the site of the diseased tissue or organ. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are administered orally.

[0226] In some embodiments of the methods described herein, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0227] Orally usable pharmaceutical compositions include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer such as glycerin or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide delayed or controlled release of the active ingredient therein. All formulations intended for oral administration should be in dosages suitable for such administration. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. The sugar-coated core is provided with a suitable coating. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or sugar-coated coatings for identification or to characterize different combinations of active compound dosages.

[0228] In some embodiments of the methods described herein, the pharmaceutical compositions are formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations may be presented in unit dosage form, such as ampoules or multi-dose containers, with added preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The compositions may be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder or freeze-dried (lyophilized) form, requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described above.

[0229] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0230] Pharmaceutical compositions can also be formulated as depot preparations. Such long-acting preparations can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compound can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or can be formulated as sparingly soluble derivatives, for example, as sparingly soluble salts. [Example]

[0231] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. Unless otherwise specified, all materials, including reagents, starting materials, and solvents, were purchased from commercial sources, such as Sigma-Aldrich and VWR, and used without further purification. Unless otherwise specified, reactions were carried out under a nitrogen atmosphere. Reaction progress was monitored by thin-layer chromatography (TLC), analytical high-performance liquid chromatography (analytical HPLC), and mass spectrometry, details of which may be provided in specific examples.

[0232] The reactions proceeded as specifically described for each preparation, and in common, the reaction mixtures were purified by extraction and other purification methods, such as crystallization and precipitation, depending on the temperature and solvent. Additionally, reaction mixtures were routinely purified by preparative HPLC, for example, using Microsorb C18 or Microsorb BDS column packings and conventional eluents. Reaction progress was typically monitored by liquid chromatography-mass spectrometry (LCMS). Characterization of isomers was typically performed by nuclear Overhauser effect spectroscopy (NOE). Characterization of reaction products was performed by mass spectrometry and / or 1 H-NMR spectroscopy was routinely performed. For NMR measurements, samples were dissolved in deuterated solvents (CD3OD, CDCl3, or DMSO-d6).

[0233] Example 1a: Synthesis of (4R)-2-amino-4-(6-chloro-4-(1-ethyl-2-(1H-1,2,4-triazole-1-carbonyl)-2,6-diazaspiro[3.4]octan-6-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (123) [ka]

[0234] Step A: A mixture of 1-1 (5 g, 41.3 mmol), 1-2 (12 g, 206.6 mmol), and MgSO (24.8 g, 206.6 mmol) in DCM (50 mL) was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column (PE / EA = 2 / 1) to give compound 1-3 (5.4 g, yield: 81.8%) as a colorless oil. ESI-MS m / z: (M+H) + =161.0.

[0235] Step B: n-Butyllithium (2.5 M in hexane, 12.4 mL, 31.0 mmol) was added dropwise to a solution of diisopropylamine (3.14 g, 31.0 mmol) in dry THF (30 mL) at 0 °C, and the resulting solution was stirred at 0 °C for 0.5 h. The reaction mixture was then cooled to -78 °C, followed by the dropwise addition of a THF solution (40 mL) of 1-4 (5.7 g, 24.8 mmol). The resulting mixture was stirred at -78 °C for 1 h, after which a solution of (i-PrO)TiCl (37.2 mL, 37.2 mmol) was added dropwise, and the reaction mixture was stirred for 1 h. A solution of 1-3 (2 g, 12.4 mmol) in THF (5 mL) was then added dropwise, and the reaction mixture was stirred for an additional 1 h. The reaction mixture was diluted with NHCl (aq) (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column (PE / EA=3 / 1) to give compound 1-5 (3 g, yield: 62.5%) as a colorless oil. ESI-MS m / z: (M+H) + =391.4.

[0236] Step C: To a solution of 1-5 (3 g, 7.69 mmol) in dry THF (30 mL) was added LiAlH (15.3 mL, 15.3 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h, and then 10H O·NaSO was added. The mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 1-6 (2.4 g, yield: 86.3%) as a colorless oil. ESI-MS m / z: (M+H) + =363.6.

[0237] Step D: To a solution of 1-6 (1 g, 2.76 mmol) and TsCl (0.787 g, 4.14 mmol) in dry THF (10 mL) was added NaH (60% dispersion in mineral oil, 0.552 g, 13.8 mmol) at 0 °C. After stirring at 25 °C for 3 h, the reaction mixture was diluted with NHCl (aq) (20 mL) and extracted with EA (20 mL × 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA = 3 / 1) to give compound 1-7 as a colorless oil (200 mg, yield: 21%). ESI-MS m / z: (M+H) + =345.2.

[0238] Step E: To a solution of 1-7 (150 mg, 0.43 mmol) in DCM (2 mL) was added TFA (0.4 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h, and then the solvent was removed under reduced pressure...

Claims

1. A modified Ras protein comprising a compound covalently attached to one or more amino acid residues of said Ras protein, said modified Ras protein comprising a compound of formula (I'): 【Chemistry 146】 During the ceremony, The dashed lines represent covalent bonds to amino acid residues. R １ is C ３－１２ carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R ２０ may be substituted with L １ is one or more R ２０ is a 5- to 20-membered heterocycle optionally substituted with L ２ is a bond, C １－４ Alkylene, 2- to 4-membered heteroalkylene, —O—, —N(R １９ )-, -C(O)-, -S-, -S(O) ２ -, -S(O)-, -P(O)R １９ -, -N(R １９ ) S (O) ２ -, -N(R １９ )S(O)-,-N(R １９ ) P(O)R １９ -, -S(O) ２ N (R １９ ) --, -S(O)N(R １９ )-, -P(O)R １９ N (R １９ ) -, -OS(O) ２ -, -OS(O)-, -OP(O)R １９ -, -S(O) ２ -O-, -S(O)O-, and -P(O)R １９ O-, C １－４ Alkylene and 2-4 heteroalkylene are 1, 2, or 3 R ２０ may be substituted with L ３ and R ２ together with the atom to which they are attached, represent a 3- to 8-membered monocyclic heterocycloalkyl, C ３－８ forming a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl), and C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), —O(C ３－６ cycloalkyl) is halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl); L ３ and R ６ together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl), and C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ Cycloalkyl) is a group that includes halogen, —OH, CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl), and L ３ and R ６ is not piperazine, or R ２ and R ６ together with the atoms to which they are attached, halogens, -OH, -CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted with 1, 2, or 3 substituents selected from C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ Cycloalkyl) is a group that includes halogen, —OH, CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl), and L ３ is a bond, R ２ is halogen, -CN, C １－６ Alkyl, and C ３－６ cycloalkyl, or R ２ and R ３ together with the carbon atoms to which they are attached, form C ３－６ Forms a cycloalkyl, C １－６ Alkyl and C ３－６ Cycloalkyl is a group containing halogen, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C １－６ haloalkyl); R ３ is hydrogen, halogen, -CN, C １－６ Alkyl, and C ３－６ cycloalkyl; １－６ Alkyl and C ３－６ Cycloalkyl is a group containing halogen, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C １－６ haloalkyl); R ４ , R ５ , and R ６ are each independently hydrogen, halogen, —CN, C １－６ Alkyl, and C ３－６ cycloalkyl, or R ４ and R ５ together with the carbon atoms to which they are attached, form C ３－６ Forms a cycloalkyl, C １－６ Alkyl and C ３－６ Cycloalkyl is a group containing halogen, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C １－６ optionally substituted with 1, 2, or 3 substituents selected from haloalkyl; R １９ is independently in each occurrence hydrogen, —CN, C １－６ Alkyl, C ３－６ Carbocyclic ring, 3- to 6-membered heterocyclic ring, —OH, —O(C １－６ alkyl), and —O(C １－６ haloalkyl); R ２０ is independently in each occurrence halogen, oxo, —CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), -(2- to 6-membered heteroalkyl)-(C ３－１２ carbocycle), -C ０－６ alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR ２２ , -SR ２２ , -N(R ２２ ) (R ２３ ), =NR ２２ , = C(R ２１ ) ２ , -C(O)OR ２２ , -OC(O)N(R ２２ ) (R ２３ ), -N(R ２２ )C(O)N(R ２２ ) (R ２３ ), -N(R ２２ )C(O)OR ２２ , -N(R ２２ ) S (O) ２ R ２２ , -C(O)R ２２ , -S(O)R ２２ , -OC(O)R ２２ , -C(O)N(R ２２ ) (R ２３ ), -C(O)C(O)N(R ２２ ) (R ２３ ), -N(R ２２ ) C(O)R ２２ , -S(O) ２ R ２２ , -S(O)(NR ２２ ) R ２２ , -S(O) ２ N (R ２２ ) (R ２３ )-, -S(=O)(=NR ２２ ) N (R ２２ ) (R ２３ ), and -OCH ２ C(O)OR ２２ and two R bonded to the same or adjacent atoms are selected from: ２０ is combined with C ３－１２ may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, —C ０～６ Alkyl-(C ３～１２ carbocyclic ring), -(2- to 6-membered heteroalkyl)-(C ３～１２ carbocycle), -C ０～６ alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C ３～１２ Carbocycles and 3- to 12-membered heterocycles are substituted with halogen, oxo, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ haloalkoxy, -OR ２２ , -SR ２２ , -N(R ２２ ) (R ２３ ), =NR ２２ , = C(R ２１ ) ２ , -C(O)OR ２２ , -OC(O)N(R ２２ ) (R ２３ ), -N(R ２２ )C(O)N(R ２２ ) (R ２３ ), -N(R ２２ )C(O)OR ２２ , -N(R ２２ ) S (O) ２ R ２２ , -C(O)R ２２ , -S(O)R ２２ , -OC(O)R ２２ , -C(O)N(R ２２ ) (R ２３ ), -C(O)C(O)N(R ２２ ) (R ２３ ), -N(R ２２ ) C(O)R ２２ , -S(O) ２ R ２２ , S(O)(NR ２２ ) R ２２ , -S(O) ２ N (R ２２ ) (R ２３ ), and —S(═O)(═NR ２２ ) N (R ２２ ) (R ２３ and optionally substituted with one or more substituents independently selected from R ２１ is independently in each occurrence hydrogen, halogen, C １－６ Alkyl, C １－６ Haloalkyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), and -C ０－６ alkyl-(3- to 12-membered heterocycle), or two R ２１ together with the carbon atoms to which they are attached, form C ３－１２ form a carbocyclic or 3- to 12-membered heterocyclic ring, each of which may be selected from the group consisting of halogen, C １－３ Alkyl, C １－３ optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl, and —OH; R ２２ is independently in each occurrence hydrogen, C １－６ Alkyl, C １－６ Haloalkyl 、 -C ０－６ Alkyl-(C ３－１２ carbocyclic ring), and -C ０－６ alkyl-(3- to 12-membered heterocycle); R ２３ is independently in each occurrence hydrogen and C １－６ alkyl or R bonded to a 3- to 10-membered heterocycle in the same nitrogen atom form ２２ and R ２３ A modified Ras protein,

2. the modified Ras protein is a modified human K-Ras mutant protein comprising a compound covalently attached to a serine residue having the structure of formula (I), wherein the serine residue corresponds to position 12 of SEQ ID NO:4; 【Chemistry 147】 The modified Ras protein of claim 1, wherein the dashed lines represent bonds between the serine residue of the K-Ras mutant protein and alanine 11 and glycine 13, respectively.

3. The modified protein of claim 1 or 2, wherein the modified Ras protein exhibits reduced Ras signaling output.

4. 4. The modified protein of claim 3, wherein the reduced Ras signaling output can be evidenced by one or more outputs selected from: (i) an increase in steady-state levels of GDP-bound modified proteins; (ii) a decrease in steady-state levels of GDP-bound modified proteins; (iii) a decrease in steady-state levels of phosphorylated AKTs473; (iv) a decrease in phosphorylated ERK T202 / Y204; (v) a decrease in phosphorylated S6 S235 / 236; (vi) a decrease in cell proliferation of tumor cells expressing a Ras G12S mutant protein; and (vii) a decrease in Ras interaction with Ras pathway signaling proteins.

5. 5. The modified protein of any one of claims 1 to 4, comprising the amino acid sequence of SEQ ID NO: 4 with the serine residue corresponding to position 12 of SEQ ID NO:

1.

6. 6. The modified protein of any one of claims 1 to 5, comprising the amino acid sequence of SEQ ID NO: 4, or a fragment thereof having a serine residue corresponding to position 12 of SEQ ID NO:

1.

7. 7. The modified protein of any one of claims 1 to 6, wherein the modified Ras protein is formed by contacting a precursor compound with a serine residue of an unmodified Ras G12S mutant protein, the precursor compound comprising a leaving group and a leaving group, and wherein said contacting liberates said leaving group to form the modified protein.

8. The modified protein of claim 7, wherein the precursor compound is a compound of claim 14.

9. 9. The modified protein of claim 7 or 8, wherein the modified protein comprises the amino acid sequence of SEQ ID NO: 4 or a fragment thereof comprising a serine residue corresponding to position 12 of SEQ ID NO: 4, and the precursor compound selectively labels serine residues compared to (i) aspartic acid residues of K-Ras G12D mutant protein (the aspartic acid corresponds to position 12 of SEQ ID NO: 2); (ii) valine residues of K-Ras G12V mutant protein (the valine corresponds to position 12 of SEQ ID NO: 3); and / or (iii) glycine residues of K-Ras wild-type protein (the glycine corresponds to position 12 of SEQ ID NO: 1).

10. 10. The modified protein of claim 9, wherein the precursor compound selectively labels the serine residue at least two-fold when assayed under comparable conditions.

11. 10. The modified protein of claim 9, wherein the precursor compound selectively labels the serine residue at least 5-fold when assayed under comparable conditions.

12. The modified protein of any one of claims 7 to 11, wherein the contacting occurs in vivo.

13. The leaving group is 【Chemistry 148】 or a salt or tautomer thereof, wherein R ８ and R ９ are each independently hydrogen, halogen, —CN, C １－６ Alkyl, and C ３－６ cycloalkyl; １－６ Alkyl and C ３－６ Cycloalkyl is halogen, —CN, C １－６ Alkyl, —O(C １－６ alkyl), and —O(C １－６ The modified protein of any one of claims 7 to 12, optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkyl haloalkyl, alkoxy, alkoxysilyl ...

14. Compound of formula (II): 【Chemistry 149】 or a pharmaceutically acceptable salt or solvate thereof, wherein: R １ is C ３－１２ carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R ２０ may be substituted with L １ is one or more R ２０ is a 5- to 20-membered heterocycle optionally substituted with L ２ is a bond, C １－４ Alkylene, 2- to 4-membered heteroalkylene, —O—, —N(R １９ )-, -C(O)-, -S-, -S(O) ２ -, -S(O)-, -P(O)R １９ -, -N(R １９ ) S (O) ２ -, -N(R １９ )S(O)-,-N(R １９ ) P(O)R １９ -, -S(O) ２ N (R １９ )-,-S(O)N(R １９ )-, -P(O)R １９ N (R １９ ) -, -OS(O) ２ -, -OS(O)-, OP(O)R １９ -, -S(O) ２ -O-, -S(O)O-, and -P(O)R １９ O-, C １－４ Alkylene and 2-4 heteroalkylene are 1, 2, or 3 R ２０ may be substituted with L ３ and R ２ together with the atom to which they are attached, represent a 3- to 8-membered monocyclic heterocycloalkyl, C ３－８ forming a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl), and C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), —O(C ３－６ cycloalkyl) is halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl); L ３ and R ６ together with the atoms to which they are attached form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl), and C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ Cycloalkyl) is a group that includes halogen, —OH, CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl), and L ３ and R ６ is not piperazine, or R ２ and R ６ together with the atoms to which they are attached, halogens, -OH, -CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted with 1, 2, or 3 substituents selected from C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ Cycloalkyl) is a group that includes halogen, —OH, CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl), and L ３ is a bond, R ２ is halogen, -CN, C １－６ Alkyl, and C ３－６ cycloalkyl, or R ２ and R ３ together with the carbon atoms to which they are attached, form C ３－６ Forms a cycloalkyl, C １－６ Alkyl and C ３－６ Cycloalkyl is a group containing halogen, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C １－６ haloalkyl); R ３ is hydrogen, halogen, -CN, C １－６ Alkyl, and C ３－６ cycloalkyl; １－６ Alkyl and C ３－６ Cycloalkyl is a group containing halogen, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C １－６ haloalkyl); R ４ , R ５ , and R ６ are each independently hydrogen, halogen, —CN, C １－６ Alkyl, and C ３－６ cycloalkyl, or R ４ and R ５ together with the carbon atoms to which they are attached, form C ３－６ Forms a cycloalkyl, C １－６ Alkyl and C ３－６ Cycloalkyl is a group containing halogen, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C １－６ optionally substituted with 1, 2, or 3 substituents selected from haloalkyl; R ７ teeth, [Chemical 150] is selected from R ８ and R ９ are each independently hydrogen, halogen, —CN, C １－６ Alkyl, and C ３－６ cycloalkyl; １－６ Alkyl and C ３－６ Cycloalkyl is a group containing halogen, —CN, C １－６アルキル、 -O(C １－６ alkyl), and —O(C １－６ optionally substituted with 1, 2, or 3 substituents selected from haloalkyl; R １９ is independently in each occurrence hydrogen, —CN, C １－６ Alkyl, C ３－６ Carbocyclic ring, 3- to 6-membered heterocyclic ring, —OH, —O(C １－６ alkyl), and —O(C １－６ haloalkyl); R ２０ is independently in each occurrence halogen, oxo, —CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), -(2- to 6-membered heteroalkyl)-(C ３－１２ carbocycle), -C ０－６ alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR ２２ , -SR ２２ , -N(R ２２ ) (R ２３ ), =NR ２２ , = C(R ２１ ) ２ , -C(O)OR ２２ , -OC(O)N(R ２２ ) (R ２３ ), -N(R ２２ )C(O)N(R ２２ ) (R ２３ ), -N(R ２２ )C(O)OR ２２ , -N(R ２２ ) S (O) ２ R ２２ , -C(O)R ２２ , -S(O)R ２２ , -OC(O)R ２２ , -C(O)N(R ２２ ) (R ２３ ), -C(O)C(O)N(R ２２ ) (R ２３ ), -N(R ２２ ) C(O)R ２２ , -S(O) ２ R ２２ , -S(O)(NR ２２ ) R ２２ , -S(O) ２ N (R ２２ ) (R ２３ )-, -S(=O)(=NR ２２ ) N (R ２２ ) (R ２３ ), and -OCH ２ C(O)OR ２２ and two R bonded to the same or adjacent atoms are selected from ２０ is combined with C ３－１２ may form a carbocyclic ring or a 3- to 12-membered heterocyclic ring, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, —C ０－６ alkyl-(C3-12 carbocyclic ring), -(2- to 6-membered heteroalkyl)-(C ３－１２ carbocycle), -C ０－６ Alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are substituted with halogen, oxo, —CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ haloalkoxy, -OR ２２ , -SR ２２ , -N(R ２２ ) (R ２３ ), =NR ２２ , = C(R ２１ ) ２ , -C(O)OR ２２ , -OC(O)N(R ２２ ) (R ２３ ), -N(R ２２ )C(O)N(R ２２ ) (R ２３ ), -N(R ２２ )C(O)OR ２２ , -N(R ２２ ) S (O) ２ R ２２ , -C(O)R ２２ , -S(O)R ２２ , -OC(O)R ２２ , -C(O)N(R ２２ ) (R ２３ ), -C(O)C(O)N(R ２２ ) (R ２３ ), -N(R ２２ ) C(O)R ２２ , -S(O) ２ R ２２ , S(O)(NR ２２ ) R ２２ , -S(O) ２ N (R ２２ ) (R ２３ ), and —S(═O)(═NR ２２ ) N (R ２２ ) (R ２３ and optionally substituted with one or more substituents independently selected from R ２１ is independently in each occurrence hydrogen, halogen, C １－６ Alkyl, C １－６ Haloalkyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), and -C ０－６ alkyl-(3- to 12-membered heterocycle), or two R ２１ together with the carbon atoms to which they are attached, form C ３－１２ form a carbocyclic or 3- to 12-membered heterocyclic ring, each of which may be selected from the group consisting of halogen, C １－３ Alkyl, C １－３ optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl, and —OH; R ２２ is independently in each occurrence hydrogen, C １－６ Alkyl, C １－６ハロアルキル、 -C ０－６ Alkyl-(C ３－１２ carbocyclic ring), and -C ０－６ alkyl-(3- to 12-membered heterocycle); R ２３ is independently in each occurrence hydrogen and C １－６ alkyl or R bonded to a 3- to 10-membered heterocycle in the same nitrogen atom form ２２ and R ２３ forms a 3- to 10-membered heterocyclic ring, R ７ IC of less than 1000 nM when assessed by HTRF assay when is replaced with hydrogen ５０ A compound or a pharmaceutically acceptable salt or solvate thereof, which reversibly binds to K-Ras protein at the .beta.-receptor group.

15. L ３ and R ２ together with the atom to which they are attached form a 3- to 8-membered monocyclic heterocycloalkyl, C ３－８ forming a monocyclic cycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl), and C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl) is halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ 15. The compound, salt or solvate of claim 14, or the modified protein of any one of claims 1 to 13, optionally substituted with 1, 2 or 3 substituents selected from:

16. L ３ and R ２ together with the atoms to which they are attached, halogens, -OH, -CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted with 1, 2, or 3 substituents selected from C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl) is halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ 16. The compound, salt, solvate, or modified protein of claim 15, optionally substituted with 1, 2, or 3 substituents selected from:

17. L ３ and R ６ together with the atoms to which they are attached, each of which is a halogen, -OH, -CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, each optionally substituted by 1, 2, or 3 substituents selected from C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), —O(C ３－６ cycloalkyl) is halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl), and L ３ and R ６ 15. The compound, salt, or solvate of claim 14, or the modified protein of any one of claims 1 to 13, wherein the 4-8 membered monocyclic heterocycloalkyl formed by

18. R ２ and R ６ together with the atoms to which they are attached, halogens, -OH, -CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ forming a 3- to 8-membered monocyclic heterocycloalkyl optionally substituted with 1, 2, or 3 substituents selected from C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), —O(C ３－６ cycloalkyl) is halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl), and L ３ The compound, salt, or solvate of claim 14, or the modified protein of any one of claims 1 to 13, wherein is a bond.

19. Structure of formula (II-a): 【Chemistry 151】 or a pharmaceutically acceptable salt or solvate thereof, wherein: W １ and W ３ are each independently N(R １０ ), C(R １１ ) ２ , C(O), O, S(O), and S(O) ２ is selected from W ２ is N, and C(R １１ ) are selected from n1 and n3 are each independently selected from 0, 1, 2, 3, 4, and 5, and the sum of n1 and n3 is at least 1; R １０ is independently in each occurrence hydrogen, C １－６ Alkyl, and C ３－６ cycloalkyl; １－６ Alkyl and C ３－６ Cycloalkyl is a group that includes halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl); R １１ is independently in each occurrence hydrogen, halogen, —OH, —CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl), or two R １１ is selected from C ３－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ Cycloalkyl) is a group that includes halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ 15. The compound of claim 14, substituted with 1, 2, or 3 substituents selected from: alkyl, haloalkyl;

20. W １ and W ３ are C(R １１ ) ２ 20. The compound, salt, or solvate of claim 19, wherein:

21. W ２ 21. The compound, salt, or solvate of claim 19 or 20, wherein is N.

22. 22. The compound, salt, or solvate of any one of claims 19 to 21, wherein the sum of n1 and n3 is 2, 3, 4, or 5.

23. 23. The compound, salt, or solvate of any one of claims 19 to 22, wherein n1 is 2, 3, or 4, and n3 is 1 or 2.

24. Structure of formula (II-b): 【Chemistry 152】 or a pharmaceutically acceptable salt or solvate thereof, wherein: W ４ and W ５ are each independently N(R １０ ), C(R １１ ) ２ , C(O), O, S(O), and S(O) ２ is selected from W ２ is N and C(R １１ ) are selected from n4 and n5 are each independently selected from 0, 1, 2, 3, 4, and 5; R １０ is independently in each occurrence hydrogen, C １－６ Alkyl, and C ３－６ cycloalkyl; １－６ Alkyl and C ３－６ Cycloalkyl is a group that includes halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl); R １１ is independently in each occurrence hydrogen, halogen, —OH, —CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl), or two R １１ is selected from C １－６ Alkyl, C ３－ 6 cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ Cycloalkyl) is a group that includes halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ 15. The compound of claim 14, substituted with 1, 2, or 3 substituents selected from: alkyl, haloalkyl;

25. W ４ and W ５ are C(R １１ ) ２ 25. The compound, salt, or solvate of claim 24, wherein:

26. W ２ is C(R １１ 26. The compound, salt, or solvate of claim 24 or 25, wherein

27. The compound, salt, or solvate of any one of claims 24 to 26, wherein n4 and n5 are 0 or 1.

28. 28. The compound, salt, or solvate of any one of claims 24 to 27, wherein n4 and n5 are each 0.

29. Structure of Formula (II-C): 【Chemistry 153】 or a pharmaceutically acceptable salt or solvate thereof, wherein: W １ , W ３ , W ４ , and W ５ are each independently N(R １０ ), C(R １１ ) ２ , C(O), O, S(O), and S(O) ２ is selected from W ２ is N and C(R １１ ) are selected from n1 and n3 are each independently selected from 0, 1, 2, 3, 4, and 5, and the sum of n1 and n3 is at least 2; n4 and n5 are each independently selected from 0, 1, 2, 3, 4, and 5; R １０ is independently in each occurrence hydrogen, C １－６ Alkyl, and C ３－６ cycloalkyl; １－６ Alkyl and C ３－６ Cycloalkyl is a group that includes halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl); R １１ is independently in each occurrence hydrogen, halogen, —OH, —CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl), or two R １１ is selected from C ３－６ Cycloalkyl, C １－６ Alkyl, C ３－ 6 cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ Cycloalkyl) is a group that includes halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ and optionally substituted with 1, 2, or 3 substituents selected from haloalkyl.

30. W １ But C(R １１ ) ２ 30. The compound, salt, or solvate of claim 29, wherein the compound, salt, or solvate is selected from:

31. n1 is 2, 3, or 4, and one W １ is O and the remaining W １ are respectively C(R １１ ) ２ 31. The compound, salt, or solvate of claim 29 or 30, wherein:

32. W ３ is C(R １１ ) ２ 32. The compound, salt, or solvate of any one of claims 29 to 31, wherein:

33. W ２ The compound, salt, or solvate of any one of claims 29 to 32, wherein is N.

34. W ４ and W ５ are C(R １１ ) ２ 34. The compound, salt, or solvate of any one of claims 29 to 33, wherein:

35. 35. The compound, salt, or solvate of any one of claims 29 to 34, wherein the sum of n1 and n3 is 2, 3, 4, or 5.

36. 36. The compound, salt, or solvate of any one of claims 29 to 35, wherein n1 is 2, 3, or 4, and n3 is 1.

37. 37. The compound, salt, or solvate of any one of claims 29 to 36, wherein n4 and n5 are 0 or 1.

38. 38. The compound, salt, or solvate of any one of claims 29 to 37, wherein n4 and n5 are each 0.

39. 【Chemistry 154】 each of which is selected from 1, 2, or 3 R １１ 30. The compound, salt, or solvate of claim 29, optionally substituted with:

40. Structure of formula (II-d): 【Chemistry 155】 or a pharmaceutically acceptable salt or solvate thereof, wherein: W ３ is N(R １０ ), C(R １１ ) ２ , C(O), O, S(O), and S(O) ２ is selected from n3 is selected from 0, 1, 2, 3, 4, and 5; R １０ is independently in each occurrence hydrogen, C １－６ Alkyl, and C ３－６ cycloalkyl; １－６ Alkyl and C ３－６ Cycloalkyl is a group that includes halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl); R １１ is independently in each occurrence hydrogen, halogen, —OH, —CN, C １－６ Alkyl, C ３－６ cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ cycloalkyl), or two R １１ is selected from C １－６ Alkyl, C ３－ 6 cycloalkyl, —O(C １－６ alkyl), and —O(C ３－６ Cycloalkyl) is a group that includes halogen, —OH, —CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ cycloalkyl, —O(C １－３ alkyl), and —O(C １－３ haloalkyl).

41. W ３ is C(R １１ ) ２ 41. The compound, salt, or solvate of claim 40, wherein:

42. 42. The compound, salt, or solvate of claim 40 or 41, wherein n3 is 1, 2, or 3.

43. R １０ and R １１ independently in each occurrence hydrogen and C １－３ 43. The compound, salt, or solvate of any one of claims 19 to 42, wherein the alkyl is selected from:

44. R １ But C ６－１０ aryl and 5- to 10-membered heteroaryl, each of which is selected from 1, 2, 3, 4, or 5 R ２０ 44. The compound, salt, or solvate of any one of claims 14 to 43, or the modified protein of any one of claims 1 to 13, optionally substituted with

45. R １ is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is selected from one or more R ２０ 45. The compound, salt, or solvate of any one of claims 14 to 44, or the modified protein of any one of claims 1 to 13, optionally substituted with

46. R １ But halogen, -CN, C １－３ Alkyl, C １－３ Haloalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, -OR ２２ , -N(R ２２ ) (R ２３ ), and C ３－６ 46. ​​The compound, salt, or solvate of any one of claims 14 to 45, or the modified protein of any one of claims 1 to 13, substituted with 1, 2, 3, or 4 substituents independently selected from cycloalkyl.

47. R １ is halogen, -CN, -CH ３ , -CH ２ CH ３ , -CH=CH ２ , -CF ３ , -C≡C, -OH, -NH ２ 47. The compound, salt, solvate, or modified protein of claim 46, substituted with 1, 2, 3, or 4 substituents independently selected from: -cyclopropyl; ...

48. R １ but, 【Chemistry 156-1】 【Chemistry 156-2】 44. The compound, salt, or solvate of any one of claims 14 to 43, or the modified protein of any one of claims 1 to 13, selected from:

49. R １ but, 【Chemistry 157】 44. The compound, salt, or solvate of any one of claims 14 to 43, or the modified protein of any one of claims 1 to 13, selected from:

50. R １ but 【Chemistry 158】 44. The compound, salt, or solvate of any one of claims 14 to 43, or the modified protein of any one of claims 1 to 13, wherein:

51. L １ But there are one or more R ２０ 51. The compound, salt, or solvate of any one of claims 14 to 50, or the modified protein of any one of claims 1 to 13, wherein R is a 6- to 12-membered heterocycle optionally substituted by

52. L1 is 1, 2, or 3 R ２０ 52. The compound, salt, solvate, or modified protein of claim 51 , wherein R is a 10-membered bicyclic heterocyclyl optionally substituted with R.

53. L １ 53. The compound, salt, or solvate of any one of claims 14 to 52, or the modified protein of any one of claims 1 to 13, wherein comprises 1 to 5 nitrogen atoms.

54. A compound, salt, or solvate according to any one of claims 14 to 53, or a modified protein according to any one of claims 1 to 13, comprising L １ but, 【Chemistry 159】 During the ceremony, W is N, C (R １７ ), N(R １７ｂ ), C(R １７ ) ２ , C(O), S(O), or S(O) ２ and Z is N, C(R １７ ), N(R １７ｂ ), C(R １７ ) ２ , C(O), S(O), or S(O) ２ and both W and Z are C(O), S(O), and S(O) ２ There is no selection from V and J each independently represent N, C(R １ ), C(R １７ ), N(R １ ), N(R １７ｂ ), C(R １ ) (R １７ ), and C(R １７ ) ２ and exactly one of V and J is selected from C(R １ ), N(R １ ), or C(R １ ) (R １７ ) and U is N, C (R １７ ), N(R １７ｂ ), C(R １７ ) ２ , S(O), S(O) ２ or C(O), Y is N, C(R １８ ), N(R １７ｂ ), C(R １８ ) (R １７ ), S(O), S(O) ２ or C(O), X is N, C(R １７ ), N(R １７ｂ ), or C(R １７ ) ２ and R １７ is independently in each occurrence hydrogen, halogen, —CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), -(2- to 6-membered heteroalkyl)-(C ３－１２ carbocycle), -C ０－６ alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), =NR １２ , = C(R １４ ) ２ , -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １２ )C(O)N(R １２ ) (R １３ ), -N(R １２ )C(O)OR １２ , -N(R １２ ) S (O) ２ R １２ , -C(O)R １２ , -S(O)R １２ , -OC(O)R １２ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １２ ) C(O)R １２ , -S(O) ２ R １２ , -S(O) ２ R １２ , -S(O)(NR １２ ) R １２ , -S(O) ２ N (R １２ ) (R １３ ), -S(=O)(=NR １２ ) N (R １２ ) (R １３ ), and -OCH ２ C(O)OR １２ is selected from C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), -(2- to 6-membered heteroalkyl)-(C ３－１２ carbocycle), -C ０－６ Alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are substituted with one, two, or three R ２０ may be substituted with R １７ｂ is independently in each occurrence hydrogen, —CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C ０－６ Alkyl-(C ３－１２ carbocycle), -C ０－６ alkyl-(3- to 12-membered heterocycle), —OR １２ , -SR １２ , -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -C(O)R １２ , -S(O)R １２ , -OC(O)R １２ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -S(O) ２ R １２ , -S(O)(NR １２ ) R １２ , -S(O) ２ N (R １２ ) (R13) and —S(═O)(═NR １２ ) N (R １２ ) (R １３ ) and C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C ０－６ Alkyl-(C ３－１２ carbocycle), -C ０－６ Alkyl-(3- to 12-membered heterocycle) is a heterocycle having one, two, or three R ２０ may be substituted with R １８ is halogen, -CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), -(2- to 6-membered heteroalkyl)-(C ３－１２ carbocycle), -C ０－６ alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR １２ , -SR １２ , -N(R １２ ) (R １３ ), =NR １２ , = C(R １４ ) ２ , -C(O)OR １２ , -OC(O)N(R １２ ) (R １３ ), -N(R １２ )C(O)N(R １２ ) (R １３ ), -N(R １２ )C(O)OR １２ , -N(R １２ ) S (O) ２ R １２ , -C(O)R １２ , -S(O)R １２ , -OC(O)R １２ , -C(O)N(R １２ ) (R １３ ), -C(O)C(O)N(R １２ ) (R １３ ), -N(R １２ ) C(O)R １２ , -S(O) ２ R １２ , -S(O)(NR １２ ) R １２ , -S(O) ２ N (R １２ ) (R １３ ), -S(=O)(=NR １２ ) N (R １２ ) (R １３ ), and -OCH ２ C(O)OR １２ is selected from C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 2- to 6-membered heteroalkyl, 2- to 6-membered heteroalkenyl, 2- to 6-membered heteroalkynyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), -(2- to 6-membered heteroalkyl)-(C ３－１２ carbocycle), -C ０－６ Alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are substituted with one, two, or three R ２０ may be substituted with R １２ is independently in each occurrence hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), and -C ０－６ alkyl-(3- to 12-membered heterocycle), １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), and -C ０－６ Alkyl-(3- to 12-membered heterocycle) is a heterocycle having one, two, or three R ２０ may be substituted with R １３ is independently in each occurrence hydrogen, C １－６ Alkyl, and C １－６ haloalkyl, or R １２ and R １３ may be one, two, or three R together with the same nitrogen atom to which they are attached. ２０ forming a 3- to 10-membered heterocyclic ring optionally substituted by R １４ is independently in each occurrence hydrogen, halogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C ０－６ Alkyl-(C ３－１２ carbocyclic ring), and C ０－６ alkyl-(3- to 12-membered heterocycle), or two R １４ together with the carbon atoms to which they are attached form a 3- to 12-membered heterocyclic ring, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, —C ０－６ Alkyl-(C ３－１２ carbon ring), C ０－６ alkyl-(3- to 12-membered heterocycle), C ３－１２ Carbocycles and 3- to 12-membered heterocycles may contain one, two, or three R ２０ and [Chemical 160] represents a single or double bond such that all valences are satisfied, or a compound, salt, or solvate, or modified protein, wherein:

55. W is C(R １７ ), C(R17) ２ , or C(O), and Z is N, C(R １７ ), N(R １７ｂ ), or C(R １７ ) ２ and V is C(R １ ) or N(R １ ) and J is C(R １７ ) or C(R １７ ) ２ 55. The compound, salt, solvate, or modified protein of claim 54, wherein:

56. W is CH, CH ２ or C(O), and Z is N, CCl, N(R １７ｂ ), or CH ２ and V is C(R １ ) or N(R １ ) and J is CF or CH ２ 56. The compound, salt, solvate, or modified protein of claim 55, wherein:

57. W is C (R １７ ), and Z is C(R １７ ) and V is C(R １ ) and J is C(R １７ 55. The compound, salt, solvate, or modified protein of claim 54, wherein

58. W is CH, Z is CCl, and V is C(R １ 58. The compound, salt, solvate, or modified protein of claim 57, wherein J is CF.

59. U is N and Y is C(R １８ 59. The compound, salt, solvate, or modified protein of any one of claims 54 to 58, wherein X is N.

60. R18 is hydrogen, C １－３ Alkyl, -OR １２ and 3- to 10-membered heterocycles, １－３ Alkyl and 3- to 10-membered heterocycle are each selected from 1, 2, or 3 R ２０ 60. The compound, salt, solvate, or modified protein according to any one of claims 54 to 59, optionally substituted with:

61. R １８ Ga-OR １２ 61. The compound, salt, solvate, or modified protein of claim 60, wherein:

62. R １８ But -O(C １－３ alkylene) (4- to 10-membered heterocycle), wherein the 4- to 10-membered heterocycle is １－３ Alkyl, C １－３ haloalkyl, and ═C(R ２１ ) ２ and R ２１ independently in each occurrence hydrogen, halogen, and C １－３ 61. The compound, salt, solvate, or modified protein of claim 60, wherein the compound, salt, solvate, or modified protein is selected from alkyl.

63. R １８ but, 【Chemistry 161-1】 【Chemistry 161-2】 【Chemistry 161-3】 60. The compound, salt, solvate, or modified protein of any one of claims 54 to 59, wherein:

64. R １８ 63. The compound, salt, solvate, or modified protein of claim 62, wherein: 【Chemistry 162】

65. L １ but 【Chemistry 163】 65. The compound, salt, solvate, or modified protein, salt, or solvate of any one of claims 14 to 64, or the modified protein of any one of claims 1 to 13, which is

66. R １ -L １ but 【Chemistry 164】 66. The compound, salt, solvate, or modified protein of claim 65, wherein:

67. R １ -L １ but 【Chemistry 165】 67. The compound, salt, solvate of claim 66, which is: Or a modified protein.

68. L ２ is bond, C １－３ alkylene, and 2- to 3-membered heteroalkylene; １－３ Alkylene and 2- to 3-membered heteroalkylene are selected from the group consisting of 1, 2, or 3 R ２０ 68. The compound, salt, or solvate of any one of claims 14 to 67, or the modified protein of any one of claims 1 to 13, optionally substituted with

69. L ２ is bond, C １－３ Alkylene, —N(H)C １－３ Alkylene-, -N(C １－３ alkyl) C １－３ Alkylene-, and -N(C ３－６ Cycloalkyl)C １－３ alkylene-, １－３ Alkylene, C １－３ Alkyl, and C ３－６ Cycloalkyl is halogen, C １－３ Alkyl, and C １－３ 69. The compound, salt, solvate, or modified protein of claim 68, optionally substituted with 1, 2, or 3 substituents selected from haloalkyl.

70. L ２ 68. The compound, salt, or solvate of any one of claims 14 to 67, or the modified protein of any one of claims 1 to 13, wherein is a bond.

71. R ２ But C １－６ Alkyl and C ３－６ 71. A compound, salt, or solvate according to any one of claims 14 to 70, wherein the compound is selected from the group consisting of cycloalkyl, ... １－１３ 1. The modified protein according to any one of claims 1 to 9.

72. R ３ is hydrogen and C １－６ 72. The compound, salt, or solvate of any one of claims 14 to 71, or the modified protein of any one of claims 1 to 13, wherein the compound, salt, or solvate is selected from alkyl.

73. R ３ 73. The compound, salt, solvate, or modified protein of claim 72, wherein is hydrogen.

74. R ４ , R ５ , and R ６ are independently hydrogen, C １－３ alkyl, and -(C １－３ alkyl)CN, or R ４ and R ５ together with the carbon atoms to which they are attached, C ３－６ A compound, salt, or solvate according to any one of claims 14 to 73, or a modified protein according to any one of claims 1 to 13, which forms a cycloalkyl.

75. R ７ but 【Chemistry 166】 75. The compound, salt, or solvate of any one of claims 14 to 74, wherein:

76. R ８ is hydrogen, halogen, -CH ３ , -CH ２ F, -CHF ２ , and -CF ３ 76. The compound, salt, or solvate of any one of claims 14 to 75, selected from:

77. R ８ 77. The compound, salt, or solvate of claim 76, wherein is hydrogen.

78. R ９ is hydrogen, halogen, -CH ３ , -CH ２ F, -CHF ２ , and -CF ３ 78. The compound, salt, or solvate of any one of claims 14 to 77, which is selected from:

79. R ９ 79. The compound, salt, or solvate of claim 78, wherein is selected from hydrogen and chloro.

80. R ７ but 【Chemistry 167】 76. The compound, salt, or solvate of claim 75, wherein:

81. 41. A compound, salt, or solvate according to claim 14, 19, 24, 29, or 40, R １ is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is selected from one or more R ２０ may be substituted with L １ is 1, 2, 3, or 4 R ２０ is a 10-membered bicyclic heterocycle substituted with L ２ is bond, C １－３ alkylene, and 2- to 3-membered heteroalkylene; １－３ Alkylene and 2- to 3-membered heteroalkylene are selected from the group consisting of 1, 2, or 3 R ２０ may be substituted with R ７ but 【Chemical 168】 A compound, salt, or solvate thereof, wherein

82. 41. A compound, salt, or solvate according to claim 14, 19, 24, 29, or 40, R １ -L １ but 【Chemistry 169】 and L ２ is bond, C １－３ alkylene, and 2- to 3-membered heteroalkylene; １－３ Alkylene and 2- to 3-membered heteroalkylene are selected from the group consisting of 1, 2, or 3 R ２０ may be substituted with R ７ but 【Chemistry 170】 A compound, salt, or solvate thereof, wherein

83. R ７ 83. The compound, salt, or solvate of any one of claims 14 to 82, wherein when is replaced with hydrogen, the compound reversibly binds to K-Ras protein.

84. The compound has an IC of less than 1000 nM when evaluated by an in vitro cell proliferation assay. ５０ 84. The compound, salt, or solvate of claim 83, which inhibits K-Ras G12S mutant cell proliferation at

85. 85. A pharmaceutical composition comprising a compound according to any one of claims 14 to 84, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

86. 85. A method of modifying a Ras mutant protein, comprising contacting said Ras mutant protein with an effective amount of a compound, salt, or solvate of any one of claims 14 to 84.

87. 87. The method of claim 86, wherein the modified Ras mutant protein exhibits reduced Ras signaling output.

88. 88. The method of claim 87, wherein the reduced Ras signaling output is evidenced by one or more outputs selected from: (i) an increase in steady-state levels of GDP-bound modified proteins, (ii) a decrease in steady-state levels of GTP-bound modified proteins, (iii) a decrease in phosphorylated AKTs473, (iv) a decrease in phosphorylated ERK T202 / Y204, (v) a decrease in phosphorylated S6 S235 / 236, (vi) a decrease in cell growth of tumor cells expressing a Ras G12S mutant protein, and (vii) a decrease in Ras interaction with Ras pathway signaling proteins.

89. 89. The method of any one of claims 86 to 88, wherein the Ras mutant protein comprises the amino acid sequence of SEQ ID NO: 4 with a serine residue corresponding to position 12 of SEQ ID NO:

1.

90. 89. The method of any one of claims 86 to 88, wherein the Ras mutant protein comprises the amino acid sequence of SEQ ID NO:

4.

91. 91. The method of any one of claims 86 to 90, wherein said contacting results in release of a leaving group.

92. The leaving group is 【Chemistry 171】 92. The method of claim 91 , wherein the compound is a salt or tautomer thereof.

93. 93. The method of any one of claims 86-92, wherein the modified Ras mutant protein comprises the amino acid sequence of SEQ ID NO:1 or a fragment thereof comprising a serine residue corresponding to position 12 of SEQ ID NO:1, and the compound selectively labels serine residues relative to (i) aspartic acid residues of K-Ras G12D mutant protein (the aspartic acid corresponds to position 12 of SEQ ID NO:2); (ii) valine residues of K-Ras G12V mutant protein (the valine corresponds to position 12 of SEQ ID NO:3); and / or (iii) glycine residues of K-Ras wild-type protein (the glycine corresponds to position 12 of SEQ ID NO:1).

94. 94. The method of claim 93, wherein the compound selectively labels the serine residue at least two-fold when assayed under equivalent conditions.

95. 94. The method of claim 93, wherein the compound selectively labels the serine residue at least 5-fold when assayed under comparable conditions.

96. 96. The method of any one of claims 86 to 95, wherein said contacting occurs in vivo.

97. 85. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 14 to 84, or a pharmaceutically acceptable salt or solvate thereof.

98. A method for treating cancer in a subject containing a Ras mutant protein, comprising modifying the subject's Ras mutant protein by administering to the subject a compound described in any one of claims 14 to 84, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound, when contacted with the Ras mutant protein, covalently modifies the Ras mutant protein at a residue corresponding to residue 12 of SEQ ID NO: 4, such that the modified Ras mutant protein exhibits reduced Ras signaling output.

99. 99. The method of claim 97 or 98, wherein the cancer is a solid tumor or a hematological cancer.

100. 100. The method of any one of claims 97 to 99, wherein the cancer comprises a K-Ras G12S mutant protein.

101. 85. A method of modulating the signaling output of a Ras protein, comprising contacting the Ras protein with an effective amount of a compound of any one of claims 14 to 84, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the signaling output of the Ras protein.

102. 85. A method of inhibiting cell growth, comprising administering to a cell expressing a Ras protein an effective amount of a compound of any one of claims 14 to 84, or a pharmaceutically acceptable salt or solvate thereof, thereby inhibiting growth of said cell.

103. 103. The method of any one of claims 86 to 102, comprising administering an additional agent.

104. The additional agent may be (1) an inhibitor of MEK, (2) an inhibitor of epidermal growth factor receptor (EGFR) and / or a mutant thereof, (3) an immunotherapeutic agent, (4) a taxane, (5) an antimetabolite, (6) an inhibitor of FGFR1 and / or FGFR2 and / or FGFR3 and / or a mutant thereof, (7) a mitotic kinase inhibitor, (8) an anti-angiogenic agent, (9) a topoisomerase inhibitor, (10) a platinum-containing compound, or (11) an inhibitor of c-MET and / or a mutant thereof. (12) inhibitors of BCR-ABL and / or mutants thereof, (13) inhibitors of ErbB2 (Her2) and / or mutants thereof, (14) inhibitors of AXL and / or mutants thereof, (15) inhibitors of NTRK1 and / or mutants thereof, (16) inhibitors of RET and / or mutants thereof, (17) inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or mutants thereof, (18) inhibitors of ERK and / or or inhibitors of its mutants, (19) MDM2 inhibitors, (20) mTOR inhibitors, (21) IGF1 / 2 and / or IGF1-R inhibitors, (22) CDK9 inhibitors, (23) farnesyltransferase inhibitors, (24) SHIP pathway inhibitors, (25) SRC inhibitors, (26) JAK inhibitors, (27) PARP inhibitors, (28) ROS1 inhibitors, (29) SHP pathway inhibitors, (30) Src, FLT3, HDAC, VEGFR, PDGFR , LCK, Bcr-Abl or AKT inhibitors, (31) inhibitors of KrasG12C, (32) SHC inhibitors (e.g., PP2, AID371185), (33) GAB inhibitors, (34) PI-3 kinase inhibitors, (35) MARPK inhibitors, (36) CDK4 / 6 inhibitors, (37) MAPK inhibitors, (38) SHP2 inhibitors, (39) checkpoint immune blockers, (40) SOS1 inhibitors, or (41) SOS2 inhibitors.

105. The additional drug is RMC-4630, ERAS-601, 【Chemistry 172】 104. The method of claim 103, comprising an inhibitor of SHP2 selected from:

106. Additional drugs are 【Chemistry 173】 104. The method of claim 103, comprising an inhibitor of SOS selected from RMC-5845, and BI-1701963.

107. 104. The method of claim 103, wherein the additional agent comprises an inhibitor of EGFR selected from afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, and EGF-816.

108. 104. The method of claim 103, wherein the additional agent comprises an inhibitor of MEK selected from trametinib, cobimetinib, binimetinib, selumetinib, refametinib, and AZD6244.

109. 104. The method of claim 103, wherein the additional agent comprises an inhibitor of ERK selected from ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, and lavoxertinib.

110. 104. The method of claim 103, wherein the additional agent comprises an inhibitor of CDK4 / 6 selected from palbociclib, ribociclib, and abemaciclib.

111. 104. The method of claim 103, wherein the additional agent comprises an inhibitor of BRAF selected from sorafenib, vemurafenib, dabrafenib, encorafenib, regorafenib, and GDC-879.

Images