Heterocycles and uses thereof

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof, and methods of using the same. The compounds and methods have a range of uses as therapeutic, diagnostic and research tools. In particular, the subject compositions and methods are used to reduce signal transduction output of oncogenic proteins.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 435,219, filed December 23, 2022, and U.S. Provisional Application No. 63 / 582,402, filed September 13, 2023, each of which is incorporated herein by reference in its entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing submitted electronically in XML format and hereby incorporated by reference in its entirety. The XML copy was created on December 19, 2023, is named 56690_763_601_SL.xml, and is 13,982 bytes in size. Background Art

[0005] Cancer (e.g., tumors, neoplasms, metastases) is the second leading cause of death worldwide, accounting for an estimated 10 million deaths annually. Many types of cancer are marked by mutations in one or more proteins involved in various signaling pathways, which lead to the uncontrolled growth of cancer cells. In some cases, it is known that approximately 25% to 30% of tumors contain rat sarcoma (Ras) mutations. In particular, mutations in the Kirsten Ras oncogene (K-Ras) are one of the most common Ras mutations detected in human cancers, including lung adenocarcinoma (LUAD) and pancreatic ductal adenocarcinoma (PDAC).

[0006] Ras proteins have long been considered "undruggable," in part due to their high affinity for their substrate guanosine-5'-triphosphate (GTP) and / or their smooth surface without any obvious targetable regions. The specific G12C Ras gene mutation has been identified as a druggable target, and a number of G12C-specific inhibitors have been developed against this target. However, the application of such therapies remains limited because the G12C mutation in Ras exhibits a much lower prevalence compared to other known Ras mutations, such as G12D and G12V. Drug resistance and lack of persistence further limit such therapies. Summary of the Invention

[0007] In view of the foregoing, there is still a considerable need for a new therapeutic and diagnostic design that can specifically target Ras (including wild-type Ras, mutants and / or related proteins of Ras) to reduce Ras signaling output. Of particular interest are inhibitors of mutant Ras proteins such as Ras G12S and / or G12C, which are used to treat Ras-related diseases (e.g., cancer). Such compositions and methods can be particularly useful for treating a variety of diseases, including but not limited to cancer and neoplasia conditions. The present disclosure meets these needs and provides additional advantages that are applicable to the diagnosis, prognosis and / or treatment of a variety of diseases.

[0008] In certain aspects, the present disclosure provides a modified Ras protein comprising a compound covalently bonded to one or more amino acid residues of the Ras protein, wherein the modified Ras protein comprises a compound of formula (I'):

[0009]

[0010] in:

[0011] Dashed lines indicate covalent bonds to amino acid residues;

[0012] R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R 20 replace;

[0013] L 1 is optionally replaced by one or more R 20 substituted 5- to 20-membered heterocycles;

[0014] L 2 Selected from 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)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-, where C1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace;

[0015] L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in a haloalkyl group;

[0016] L 3 and R 6 Together with the atoms to which they are attached, they form a 4- to 8-membered monocyclic heterocycloalkyl, a 7- to 12-membered spirocyclic heterocycloalkyl, or a 7- to 12-membered fused bicyclic heterocycloalkyl, wherein each is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted by one, two or three substituents, and wherein L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or

[0017] R 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted by one, two or three substituents, and wherein L 3 It is a key;

[0018] R 2 Selected from halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 2 and R 3 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0019] R 3 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0020] R 4、R 5 and R 6 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0021] R 19 is independently selected at each occurrence from 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);

[0022] R 20 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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)2R22 、-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 ; wherein two R connected to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 ) is substituted with a substituent;

[0023] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 carbocyclic or 3- to 12-membered heterocyclic rings, each of which is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and -OH substituents;

[0024] R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocycle); and

[0025] R 23 independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or R attached to the same nitrogen atom 22 and R 23 A 3- to 10-membered heterocyclic ring is formed.

[0026] In some embodiments, the modified Ras protein is a modified human K-Ras mutant protein comprising a compound having a structure of Formula (I) covalently bonded to a serine residue, wherein the serine residue corresponds to position 12 of SEQ ID No. 4:

[0027]

[0028] The dotted lines represent the bonds between the serine residue and alanine 11 and glycine 13 of the K-Ras mutant protein, respectively.

[0029] In some embodiments, the modified protein of Formula (I') or (I) exhibits a reduced Ras signaling output. The reduced Ras signaling output can be demonstrated by one or more outputs selected from the following: (i) an increase in the steady-state level of GDP-bound modified protein; (ii) a decrease in the steady-state level of GTP-bound modified protein; (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 Ras G12S mutant protein; and (vii) a decrease in the interaction of Ras with Ras pathway signaling proteins.

[0030] In some embodiments, the modified protein of formula (I') or (I) comprises the amino acid sequence of SEQ ID No. 4, which has the 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.

[0031] 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 retaining group and a leaving group, and wherein the contacting results in the release of the leaving group and the formation of the 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 an amino acid sequence in SEQ ID No. 1 having a serine residue corresponding to position 12 of SEQ ID No. 1, and wherein the precursor compound selectively labels the serine residue as compared to: (i) an aspartic acid residue of a K-Ras G12D mutant protein, said aspartic acid corresponding to position 12 of SEQ ID No. 2; (ii) a valine residue of a K-Ras G12V mutant protein, said valine corresponding to position 12 of SEQ ID No. 3; and / or (iii) a glycine residue of a K-Ras wild-type protein, said glycine corresponding to position 12 of SEQ ID No. 1. In some embodiments, the precursor compound selectively labels the serine residue 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 selected from or a salt or tautomer thereof, wherein R 8 and R 9 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

[0032] In certain aspects, the present disclosure provides compounds of formula (II):

[0033]

[0034] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0035] R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R20 replace;

[0036] L 1 is optionally replaced by one or more R 20 substituted 5- to 20-membered heterocycles;

[0037] L 2 Selected from 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)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-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace;

[0038] L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in a haloalkyl group;

[0039] L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted by one, two or three substituents, and wherein L 3 and R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or

[0040] R 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted with one, two or three substituents, and wherein L 3 It is a key;

[0041] R 2 Selected from halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 2and R 3 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents of a haloalkyl group;

[0042] R 3 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0043] R 4 、R 5 and R 6 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0044] R 7 Selected from

[0045] R 8 and R 9 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0046] R 19 is independently selected at each occurrence from 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);

[0047] R 20 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 ; wherein two R attached to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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(R22 )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 ) is substituted with a substituent;

[0048] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 carbocyclic or 3- to 12-membered heterocyclic rings, each of which is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and -OH substituents;

[0049] R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocycle); and

[0050] R 23 independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or R attached to the same nitrogen atom 22 and R 23 A 3- to 10-membered heterocyclic ring is formed.

[0051] In some embodiments, when R 7 When substituted with hydrogen, 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 K-Ras protein, as assessed by HTRF assay, IC 50Less than 1000 nM. 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 the Ras protein.

[0052] In some embodiments, for a compound or modified protein or the present disclosure, L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 In some embodiments, L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 In some embodiments, L 3 and R6 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (halogenated alkyl) and wherein L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine. 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted with one, two or three substituents, and wherein L 3 It is a key.

[0053] In some embodiments, the compound of formula (II) is a compound of formula (II-a):

[0054]

[0055] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0056] W 1 and W 3 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2;

[0057] W 2 Selected from N and C(R 11 );

[0058] n1 and n3 are each independently selected from 0, 1, 2, 3, 4 and 5, wherein the sum of n1 and n3 is at least 1;

[0059] R 10 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and

[0060] R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

[0061] In some embodiments, for compounds of formula (II-a), W 1 and W 3 Each is C(R 11 ) 2. In some embodiments, W2 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 2.

[0062] In some embodiments, the compound of formula (II) is a compound of formula (II-b):

[0063]

[0064] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0065] W 4 and W 5 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2;

[0066] W 2 Selected from N and C(R 11 );

[0067] n4 and n5 are each independently selected from 0, 1, 2, 3, 4 and 5;

[0068] R 10 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and

[0069] R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

[0070] In some embodiments, for compounds of formula (II-b), W 4 and W 5 Each is C(R 11 ) 2. In some embodiments, W 2 It 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.

[0071] In some embodiments, the compound of formula (II) is a compound of formula (II-c):

[0072]

[0073] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0074] W 1 、W 3 、W 4 and W 5 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2;

[0075] W 2 Selected from N and C(R 11 );

[0076] n1 and n3 are each independently selected from 0, 1, 2, 3, 4 and 5, wherein the sum of n1 and n3 is at least 2;

[0077] n4 and n5 are each independently selected from 0, 1, 2, 3, 4 and 5;

[0078] R 10 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and

[0079] R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

[0080] In some embodiments, for compounds of formula (II-c), each W 1 Independently selected from C(R 11 )2 and O. In some embodiments, n1 is 2, 3 or 4, one W 1 is O, and the rest are W 1 Each is C(R 11 ) 2. In some embodiments, W 3 It is C(R 11 ) 2. In some embodiments, W 2 Is N. In some embodiments, W 4 and W 5 Each is 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.

[0081] In some embodiments, Selected from

[0082]

[0083] wherein each is optionally replaced by one, two or three R 11 replace.

[0084] In some embodiments, the compound of formula (II) is a compound of formula (II-d):

[0085]

[0086] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0087] W 3 Selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2;

[0088] n3 is selected from 0, 1, 2, 3, 4 and 5;

[0089] R 10 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and

[0090] R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

[0091] In some embodiments, for compounds of Formula (II-d), each W 3 It is C(R 11 In some embodiments, n3 is 1, 2, or 3.

[0092] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 10 and R 11 independently selected at each occurrence from hydrogen and C 1-3 alkyl.

[0093] In some embodiments, for the compounds or modified proteins of the present disclosure, R 1 Selected from C 6-10 Aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted by one, two, three, four or five R 20 In some embodiments, R 1 is selected from naphthyl, isoquinolyl, indazolyl, benzothiazolyl, benzothienyl, phenyl and pyridyl, each of which is optionally substituted by one or more R 20 In some embodiments, R 1 One, two, three or four independently selected from halogen, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -OR 22 、-N(R 22 )(R 23 ) and C 3-6 In some embodiments, R 1 is substituted with one, two, three or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH=CH2, -CF3, -C≡C, -OH, -NH2 and -cyclopropyl. 1 Selected from

[0094]

[0095] In some embodiments, R 1 Selected from In some embodiments, R 1 yes

[0096] In some embodiments, for the compounds or modified proteins of the present disclosure, L 1 is optionally replaced by one or more R 20 In some embodiments, L 1 Is one, two, three or four R 20 In some embodiments, L1 Contains 1 to 5 nitrogen atoms. In some embodiments, L 1 yes:

[0097]

[0098] in:

[0099] W is N, C (R 17 )、N(R 17b )、C(R 17 )2, C(O), S(O) or S(O)2;

[0100] Z is N, C (R 17 )、N(R 17b )、C(R 17 )2, C(O), S(O) or S(O)2; wherein W and Z are not simultaneously selected from C(O), S(O) and S(O)2;

[0101] V and J are each independently selected from N, C(R 1 )、C(R 17 )、N(R 1 )、N(R 17b )、C(R 1 )(R 17 ) and C(R 17 )2; where exactly one of V and J is C(R 1 )、N(R 1 ) or C(R 1 )(R 17 );

[0102] U is N, C (R 17 )、N(R 17b )、C(R 17 )2, S(O), S(O)2 or C(O);

[0103] Y is N, C (R 18 )、N(R 17b )、C(R 18 )(R 17 ), S(O), S(O)2 or C(O);

[0104] X is N, C (R 17 )、N(R 17b ) or C(R 17 )2;

[0105] R 17 is independently selected at each occurrence from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 , where 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 carbon ring), -C 0-6Alkyl-(3- to 12-membered heterocyclic ring) and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring) are optionally substituted by one, two, or three R 20 replace;

[0106] R 17b is independently selected at each occurrence from hydrogen, -CN, 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 heterocyclic ring), -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)2R 12 、-S(O)(NR 12 )R 12 、-S(O)2N(R 12 )(R 13 ) and -S(=O)(=NR 12 )N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace;

[0107] R 18 Selected from 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 carbon ring), -C 0-6Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 , where 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring) are optionally substituted by one, two, or three R 20 replace;

[0108] R 12 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace;

[0109] R 13 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R attached to the same nitrogen atom 12 and R 13 Formed optionally by one, two or three R 20 substituted 3- to 10-membered heterocycle;

[0110] R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 14 Together with the carbon atoms to which they are attached, they form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring, wherein 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 heterocyclic ring), C 3-12 The carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one, two or three R 20 replace; and

[0111] represents a single or double bond such that all valences are satisfied.

[0112] In some embodiments, for the compounds or modified proteins of the present disclosure, W is C(R 17 )、C(R 17 )2 or C(O); Z is N, C(R 17 )、N(R17b ) or C(R 17 )2; 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); Z is N, CCl, N(R 17b ) or CH2; V is C(R 1 ) or N(R 1 ); and J is CF or CH2. In some embodiments, W is C(R 17 ); Z is C(R 17 ); V is C(R 1 ); and J is C(R 17 In some embodiments, W is CH; Z is CCl; V is C(R 1 ); and J is CF. In some embodiments, U is N; Y is C(R 18 ); and X is N. In some embodiments, R 18 Selected from hydrogen, C 1-3 Alkyl, -OR 12 and a 3- to 10-membered heterocyclic ring, wherein C 1-3 The alkyl group and the 3- to 10-membered heterocyclic ring are optionally replaced by one, two or three R 20 In some embodiments, R 18 Yes-OR 12 In some embodiments, R 18 Yes-O(C 1-3 alkylene) (4- to 10-membered heterocyclic ring), wherein the 4- to 10-membered heterocyclic ring is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and =C(R 21 )2 is substituted with a substituent, wherein R 21 is independently selected at each occurrence from hydrogen, halogen and C 1-3 In some embodiments, R 18 Selected from

[0113]

[0114]

[0115]

[0116] In some embodiments, R 18 Selected from

[0117] In some embodiments, for the compounds or modified proteins of the present disclosure, L 1 yes In some embodiments, R 1 -L 1 yes In some embodiments, R 1 -L 1 yes In some embodiments, L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 In some embodiments, L 2 Selected from 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-, where C 1-3 Alkylene, C 1-3 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, C 1-3 Alkyl and C 1-3 In some embodiments, L 2 It is a key.

[0118] In some embodiments, for the compounds or modified proteins of the present disclosure, R 2 Selected from C 1-6 Alkyl and C 3-6 In some embodiments, R 3 Selected from hydrogen and C 1-6 Alkyl groups, such as R 3 In some embodiments, R 4 、R 5 and R 6 are independently selected from hydrogen, C 1-3 Alkyl and -(C 1-3 alkyl)CN, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 In some embodiments, R 7 yes In some embodiments, R 8 is selected from hydrogen, halogen, -CH3, -CH2F, -CHF2 and -CF3, such as R 8In some embodiments, R 9 is selected from hydrogen, halogen, -CH3, -CH2F, -CHF2 and -CF3, such as R 9 Selected from hydrogen and chlorine.

[0119] In some embodiments, for the compounds described herein, R 1 is selected from naphthyl, isoquinolyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl and pyridinyl, each of which is optionally substituted by one or more R 20 Replace; L 1 Is one, two, three or four R 20 Substituted 10-membered bicyclic heterocycle; L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 Replace; and R 7 yes In some embodiments, R 1 -L 1 yes L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 Replace; and R 7 yes

[0120] In some embodiments, when R 7 When R is replaced by hydrogen, the compounds described herein reversibly bind to the K-Ras protein. In some embodiments, when R 7 When substituted with hydrogen, the compound reversibly binds to K-Ras protein, as assessed by HTRF assay, and IC 50 Less than 1000 nM, less than 250 nM, less than 100 nM or even lower. In some embodiments, when -C(O)R 7 When substituted with hydrogen, the compounds described herein bind reversibly to K-Ras protein. In some embodiments, when -C(O)R 7 When substituted with hydrogen, the compound reversibly binds to K-Ras protein, as assessed by HTRF assay, and IC 50 Less than 1000 nM, less than 250 nM, less than 100 nM or even lower.

[0121] In some embodiments, the present disclosure provides a compound disclosed 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.

[0122] 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 as described herein. In some embodiments, the modified Ras mutant protein exhibits a reduced Ras signaling output. The reduced Ras signaling output can be demonstrated by one or more outputs selected from the following: (i) an increase in the steady-state level of the GDP-bound modified protein; (ii) a decrease in the steady-state level of the GTP-bound modified protein; (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 the Ras G12S mutant protein; and (vii) a decrease in the interaction of Ras with Ras pathway signaling proteins. In some embodiments, the Ras mutant protein comprises an amino acid sequence selected from the group consisting of SEQ ID No. 1, SEQ ID No. 3, SEQ ID No. 5, and corresponding fragments thereof comprising the serine residue corresponding to position 12 of SEQ ID No. 1. In some embodiments, the Ras mutant protein comprises an amino acid sequence of SEQ ID No. 1, or a fragment thereof comprising the serine residue corresponding to position 12 of SEQ ID No. 1. In some embodiments, the contacting results in the release of a leaving group, such as selected from the group consisting of or a leaving group of a salt or tautomer thereof. In some embodiments, the modified Ras mutant protein comprises the amino acid sequence of SEQ ID No. 1 or a fragment thereof containing the serine residue corresponding to position 12 of SEQ ID No. 1, and wherein the compound selectively labels the serine residue compared to: (i) an aspartic acid residue of a K-Ras G12D mutant protein, the aspartic acid corresponding to position 12 of SEQ ID No. 2; (ii) a valine residue of a K-Ras G12V mutant protein, the valine corresponding to position 12 of SEQ ID No. 3; and / or (iii) a glycine residue of a K-Ras wild-type protein, the glycine corresponding to position 12 of SEQ ID No. 1. In some embodiments, the compound selectively labels the serine residue 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.

[0123] 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 as 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 comprising a Ras mutant protein, comprising modifying the Ras mutant protein of the subject by administering to the subject a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, 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, such that the modified Ras mutant protein exhibits a reduced Ras signaling output. In some embodiments, the cancer is a solid tumor or a hematological cancer. In some embodiments, the cancer comprises a K-Ras G12S mutant protein.

[0124] 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 as 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 growth, comprising administering an effective amount of a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting the growth of the cell.

[0125] Any of the methods described herein may further comprise administering an additional agent. In some embodiments, the additional agent comprises (1) an inhibitor of MEK; (2) an inhibitor of epidermal growth factor receptor (EGFR) and / or its mutants; (3) an immunotherapy agent; (4) a taxane; (5) an antimetabolite; (6) an inhibitor of FGFR1 and / or FGFR2 and / or FGFR3 and / or its mutants; (7) a mitotic kinase inhibitor; (8) an anti-angiogenic drug; (9) a topoisomerase inhibitor; (10) a platinum-containing compound; (11) c-MET and / or its mutants (12) inhibitors of BCR-ABL and / or its mutants; (13) inhibitors of ErbB2 (Her2) and / or its mutants; (14) inhibitors of AXL and / or its mutants; (15) inhibitors of NTRK1 and / or its mutants; (16) inhibitors of RET and / or its mutants; (17) inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or its mutants; (18) inhibitors of ERK and / or its mutants; (19) MDM 2 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, L Inhibitors of CK, Bcr-Abl, or AKT; (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. In some embodiments, the additional agent comprises an SHP2 inhibitor 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 SOS inhibitor selected from BI-3406, MRTX0902, BAY 293, RMC-5845, and BI-1701963.In some embodiments, the additional agent comprises an EGFR inhibitor selected from afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, and EGF-816. In some embodiments, the additional agent comprises a MEK inhibitor selected from trametinib, cobimetinib, binimetinib, selumetinib, refametinib, and AZD6244. In some embodiments, the additional agent comprises an ERK inhibitor selected from the group consisting of ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, and ravoxertinib. In some embodiments, the additional agent comprises a CDK4 / 6 inhibitor selected from palbociclib, ribociclib, and abemaciclib. In some embodiments, the additional agent comprises a BRAF inhibitor selected from sorafenib, vemurafenib, dabrafenib, encorafenib, regorafenib, and GDC-879.

[0126] Incorporation by reference

[0127] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0128] The novel features of the present invention are particularly set forth in the appended claims. A better understanding of the nature and advantages of the present invention will be obtained by reference to the following detailed description which illustrates illustrative embodiments in which the principles of the invention are utilized and the accompanying drawings, in which:

[0129] Figure 1 Depicted is a sequence alignment of various wild-type Ras proteins including K-Ras, H-Ras, N-Ras, RalA, and RalB from top to bottom. DETAILED DESCRIPTION

[0130] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. If there are multiple definitions of terms herein, those in this section shall prevail. All patents, patent applications, publications, and disclosed nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned herein are incorporated herein by reference. Chemical structures are herein referred to as in The sections and sections of the present invention are named according to the IUPAC conventions implemented in the ® software (Perkin Elmer, Inc., Cambridge, MA). The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limited. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0131] The term "C x-y ” or “C x -C y " when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl is intended to include groups containing x to y carbons in the chain. For example, the term "C x-y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight chain alkyl and branched chain alkyl groups containing x to y carbons in the chain.

[0132] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched alkyl groups. Alkyl groups may contain 1 to 12 carbon atoms (e.g., C 1-12 Alkyl), such as 1 to 8 carbon atoms (C 1-8 alkyl) or 1 to 6 carbon atoms (C 1-6 Alkyl). Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. The alkyl group is attached to the rest of the molecule by a single bond. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted with one or more substituents, such as those described herein.

[0133] "Haloalkyl" refers to an alkyl group 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.

[0134] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one double bond, including straight-chain and branched alkenyl groups. Alkenyl groups can contain 2 to 12 carbon atoms (e.g., C 2-12 alkenyl), such as 2 to 8 carbon atoms (C 2-8 alkenyl) or 2 to 6 carbon atoms (C 2-6 Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. Unless otherwise specifically stated in the specification, an alkenyl group is optionally substituted with one or more substituents, such as those described herein.

[0135] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one triple bond, including straight-chain and branched alkynyl groups. Alkynyl groups can contain 2 to 12 carbon atoms (e.g., C 2-12 Alkynyl), such as 2 to 8 carbon atoms (C 2-8 Alkynyl) or 2 to 6 carbon atoms (C 2-6 Alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted with one or more substituents, such as those described herein.

[0136] "Alkylene" or "alkylene chain" refers to a substituted or unsubstituted divalent saturated hydrocarbon radical, including straight-chain alkylene and branched-chain alkylene, containing 1 to 12 carbon atoms (e.g., C 1-12 Alkylene), such as 1 to 8 carbon atoms (C 1-8 Alkylene) or 1 to 6 carbon atoms (C 1-6 Alkylene). Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, "alkenylene" and "alkynylene" refer to alkylene groups as defined above, each containing one or more carbon-carbon double bonds or carbon-carbon triple bonds. 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 in the chain. Unless specifically stated otherwise in the specification, an alkylene, alkenylene, or alkynylene group is optionally substituted with one or more substituents, such as those described herein.

[0137] "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) carbon atoms are replaced by heteroatoms (e.g., O, N, P, Si, S, or combinations thereof). Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatom may optionally be quaternized. If given, the numerical range 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 rest of the molecule can be through a heteroatom or carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless specifically stated otherwise in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents, such as those described herein.

[0138] "Heteroalkylene", "heteroalkenylene" and "heteroalkynylene" refer to substituted or unsubstituted alkylene, alkenylene and alkynylene, respectively, wherein one or more (such as 1, 2 or 3) carbon atoms are replaced by heteroatoms (such as O, N, P, Si, S or a combination thereof). Any nitrogen, phosphorus and sulfur heteroatoms present in the chain can be optionally oxidized, and any nitrogen heteroatom can be optionally quaternized. If given, the numerical range refers to the total chain length. For example, a 3- to 8-membered heteroalkylene 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 one heteroatom or one carbon in the heteroalkylene, heteroalkenylene or heteroalkynylene chain, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon. Unless specifically stated otherwise in the specification, the heteroalkylene, heteroalkenylene or heteroalkynylene is optionally substituted with one or more substituents (such as those described herein).

[0139] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is a carbon atom. 3-10 Single ring, C 6-12 Double ring, C 7-18 Polycyclic, C 5-12 Spirocyclic and C 6-12 Each ring of the bicyclic or polycyclic carbocyclic ring can be selected from saturated rings, unsaturated rings and aromatic rings. In some embodiments, the carbocyclic ring is C 6-12 Aryl, such as C 6-10 In some embodiments, the carbocyclic ring is C 3-12 In some embodiments, the carbocyclic ring is C 5-12Cycloalkenyl. In an exemplary embodiment, an aromatic ring (e.g., phenyl) can be fused with a saturated ring or an unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). As long as valence allows, any combination of saturated rings, unsaturated rings, and aromatic bicyclics is included in the definition of carbocycle. Carbocycle can include fused rings, bridged rings, spirocycles, saturated rings, unsaturated rings, aromatic rings, or any combination thereof. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless specifically stated otherwise in the specification, carbocycle is optionally substituted with one or more substituents (e.g., those substituents described herein).

[0140] "Heterocycle" refers to a saturated ring, unsaturated ring or aromatic ring containing one or more heteroatoms, such as 1,2 or 3 heteroatoms selected from O, S and N. Heterocycle can include 3 to 10-membered monocycles, 6 to 12-membered bicyclics, 7 to 18-membered polycyclics, 5 to 12-membered spirocycles and 6 to 12-membered bridged rings. Each ring of a bicyclic or polycyclic heterocycle can be selected from a saturated ring, an unsaturated ring and an aromatic ring. If valence allows, the heterocycle can be connected to the rest of the molecule by any atom of the heterocycle (such as a carbon atom or nitrogen atom of the heterocycle). In some embodiments, the heterocycle is a 5 to 10-membered heteroaryl, such as a 5-membered or 6-membered heteroaryl. In some embodiments, the heterocycle is a 3 to 12-membered heterocycloalkyl. The heterocycle can include fused rings, bridged rings, spirocycles, saturated rings, unsaturated rings, aromatic rings or any combination thereof. In an exemplary embodiment, a heterocycle (such as a pyridyl) can be fused to a saturated ring or an unsaturated ring (such as cyclohexane, cyclopentane or cyclohexene). Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl and quinolinyl. Unless otherwise specifically stated in the specification, the heterocycle is optionally substituted with one or more substituents, such as those described herein.

[0141] "Heteroaryl" refers to an aromatic ring containing at least one heteroatom, such as 1, 2 or 3 heteroatoms selected from O, S and N. Heteroaryl groups can 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 can be selected from monocyclic or bicyclic rings, including fused ring systems, spirocyclic ring systems and bridged ring systems, wherein at least one of the rings in the ring system is aromatic. The heteroatoms in the heteroaryl group can be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. If valence permits, the heteroaryl group can be attached to the rest of the molecule through any atom of the heteroaryl group, such as a carbon or nitrogen atom of the heteroaryl group. Examples of heteroaryl groups include, but are not limited to, azepine, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydroquinolyl, thiadiazolyl, thiazolyl, and thienyl. Unless specifically stated otherwise in the specification, heteroaryl groups are optionally substituted with one or more substituents, such as those described herein.

[0142] Unless otherwise stated, hydrogen atoms are implicit in the structures depicted herein to the extent necessary to satisfy valence requirements.

[0143] Squiggly lines drawn across keys or dotted key The terms "bond breaking" and "bond joining" are used interchangeably herein to indicate where a bond breaks or joins. For example, in the structure In the case of R 1 Yes 2-fluoro-6-hydroxyphenyl in the 1 can be described as or

[0144] The term "substituted" refers to a portion of a substituent having a hydrogen replacement on one or more carbons or heteroatoms of a structure. It should be understood that "substituted" or "substituted by ... " include implicit restrictive conditions, i.e., such substitutions conform to the valence allowed for the substituted atom and substituent, and the substitution results in a stable compound, for example, one that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is intended to include all substituents allowed of an organic compound. In a broad sense, the substituents allowed include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For suitable organic compounds, the substituents allowed may be one or more and may be the same or different. For purposes of this disclosure, heteroatoms such as nitrogen may have any substituent allowed of an organic compound as described herein that satisfies the valence of a heteroatom.

[0145] The compounds disclosed herein, such as compounds of formula (I) or (II), are optionally substituted with one or more, such as 1, 2 or 3, substituents selected from:

[0146] 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 )(R23 )、-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 wherein two substituents attached to the same or adjacent atoms are optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 The carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 );

[0147] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 carbocyclic or 3- to 12-membered heterocyclic rings, each of which is optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and -OH;

[0148] R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), wherein -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocycle) is optionally independently selected from halogen and C 1-6 substituted with one, two or three groups of the alkyl group; and

[0149] R 23 independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or R attached to the same nitrogen atom 22 and R 23A 3- to 10-membered heterocyclic ring is formed.

[0150] In some embodiments, the compounds disclosed herein, such as compounds of formula (I) or (II), are optionally substituted with one or more, such as 1, 2, or 3, substituents selected from:

[0151] 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 、-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)2N(R 22 )(R 23 )-, where 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 ring), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 The carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 22 、-SR 22 、-N(R 22 )(R 23 ), =NR 22 and = C(R 21 )2;

[0152] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0153] R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), wherein -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocycle) is optionally independently selected from halogen and C 1-6 Alkyl groups are substituted by one, two or three groups;

[0154] R 23 independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or R attached to the same nitrogen atom 22 and R 23 A 3- to 10-membered heterocyclic ring is formed.

[0155] In some embodiments, the compounds disclosed herein, such as compounds of formula (I) or (II), are optionally substituted with one or more, such as 1, 2, or 3, substituents selected from the group consisting of halogen, oxo, =NH, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Carbocyclic ring, -CH2-(C 3-10 carbon ring), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, -CH2-(C 3-10 -carbocycle), 3- to 10-membered heterocycle and -CH2-(3- to 10-membered heterocycle) are optionally substituted by one, two or three groups independently selected from the group consisting of halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3 and -NHCH2CH3.

[0156] Those skilled in the art will appreciate that substituents themselves may be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are to be understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0157] Where 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., -CH2O- is also intended to encompass -OCH2-.

[0158] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, an "optionally substituted" group can be unsubstituted or substituted.

[0159] The compounds of the present disclosure also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0160] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, represented as1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). Protium is the most abundant hydrogen isotope in nature. Deuterium enrichment can provide certain therapeutic advantages, such as increasing half-life and / or exposure in vivo, or can provide compounds for studying drug elimination and metabolic pathways in vivo. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, but are not limited to 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 35 S. 36 Cl and 18 F. Of particular interest are compounds of formula (II) enriched with tritium or carbon-14, which can be used, for example, in tissue distribution studies; compounds of the present disclosure enriched with deuterium (particularly at metabolic sites), which result, for example, in compounds with greater metabolic stability; and compounds enriched with positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 Compounds of formula (II) having N, which can be used, for example, in positron emission tomography (PET) studies. Isotopically enriched compounds can be prepared by conventional techniques known to those skilled in the art.

[0161] As used herein, the phrases "formula," "having the formula," or "having the structure" are not intended to be limiting and are used in the same manner as the term "comprising" is generally used. For example, if a structure is described, it is understood that all stereoisomers and tautomeric forms are encompassed unless otherwise indicated.

[0162] Certain compounds described herein contain one or more asymmetric centers and can therefore produce enantiomers, diastereomers, and other stereoisomeric forms, whose asymmetric centers can be defined as (R)- or (S)- according to absolute stereochemistry. In some embodiments, in order to optimize the therapeutic activity of the compounds of the present disclosure, for example, to treat cancer, it may be necessary for the carbon atoms to have a specific configuration (e.g., (R, R), (S, S), (S, R) or (R, S)) or to be enriched in stereoisomeric forms having such a configuration. The compounds of the present disclosure can be provided as racemic mixtures. Therefore, unless otherwise stated, the present disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), mixtures enriched in stereoisomers, etc. When a chemical structure without any stereochemistry is described herein, it is understood that all possible stereoisomers are encompassed by such structures. Similarly, when specific stereoisomers are shown or named herein, those skilled in the art will understand that, unless otherwise indicated, minor amounts of other stereoisomers may be present in the compositions of the present disclosure, provided that the presence of such other isomers does not abrogate the utility of the composition as a whole. Individual stereoisomers can be obtained by a number of methods known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography utilizing a suitable chiral stationary phase or support, or by chemically converting them into diastereomers, separating the diastereomers by conventional means such as chromatography or recrystallization, and then regenerating the original stereoisomers.

[0163] Additionally, where applicable, all cis-trans or E / Z isomers (geometric isomers), tautomeric forms, and topoisomeric forms of the compounds described herein are included within the scope of the present disclosure unless otherwise indicated.

[0164] The term "pharmaceutically acceptable" refers to a material that is biologically or otherwise unacceptable when used in the subject composition and method. For example, the term "pharmaceutically acceptable carrier" refers to a material such as an adjuvant, excipient, glidant, sweetener, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier, which can be incorporated into the composition and applied to the patient without causing unacceptable biological effects or interacting with other components of the composition in an unacceptable manner. This type of pharmaceutically acceptable material typically meets the required standards of toxicology and production testing, and includes those materials that are determined as suitable inactive ingredients by the U.S. Food and Drug Administration.

[0165] The terms "salt" and "pharmaceutically acceptable salt" refer to salts prepared from bases or acids. Pharmaceutically acceptable salts are suitable for administration to patients such as mammals (e.g., salts with acceptable mammalian safety for a given dosage regimen). Salts can be formed from inorganic bases, organic bases, inorganic acids, and organic acids. In addition, 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 can be formed and are included in 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.

[0166] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are 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. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, etc. Salts of amino acids such as arginate, gluconate, and galacturonate are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to skilled artisans.

[0167] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared by adding inorganic or organic bases to the free acids. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metals and alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, 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, ethylenediphenylamine, N-methylglucamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al. (supra).

[0168] The term "effective amount" or "therapeutically effective amount" refers to an amount of a pharmaceutical agent sufficient to achieve a beneficial or desired result. The therapeutically effective amount can vary depending on one or more of the following: the subject and disease condition being treated, the subject's weight and age, the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. An effective amount of the active agent can be administered in a single dose or in multiple doses. A component can be described herein as having at least an effective amount or at least an effective amount, such as an amount related to a particular goal or purpose, such as any goal or purpose described herein. The term "effective amount" also applies to a dose that will provide a detectable image by an appropriate imaging method. The specific dose can vary depending on one or more of the following: the particular agent selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0169] As used herein, "treatment" refers to methods used to obtain beneficial or desired results for a disease, disorder, or medical condition (such as cancer) in a subject, including but not limited to the following: (a) preventing the disease or medical condition from occurring, e.g., preventing the recurrence of the disease or medical condition, or prophylactically treating a subject susceptible to the disease or medical condition; (b) ameliorating the disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a subject; (c) inhibiting the disease or medical condition, e.g., slowing or arresting the development of the disease or medical condition in a subject; or (d) alleviating the symptoms of the disease or medical condition in a subject. For example, "treating cancer" would include preventing the occurrence of cancer, ameliorating cancer, inhibiting cancer, and alleviating the symptoms of cancer. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, notwithstanding that the subject may still be suffering from the underlying disorder.

[0170] As used herein, the term "therapeutic effect" encompasses therapeutic benefits and / or prophylactic benefits as 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, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0171] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds that have the ability to inhibit a 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 effects of the target protein. Although preferred antagonists herein specifically interact with (e.g., bind to) a target, compounds that inhibit the biological activity of a target protein by interacting with other members of a signal transduction pathway of which the target protein is a member are also specifically included in the definition.

[0172] The term "selective inhibition" or "selectively inhibit" refers to the ability of a biologically active agent to preferentially reduce target signaling activity over off-target signaling activity via direct or indirect interaction with the target.

[0173] The terms "subject" and "patient" refer to animals, such as mammals, for example, humans. The methods described herein can be used for both human therapy and veterinary applications. In some embodiments, the subject is a mammal, such as a human. "Mammal" includes humans and livestock animals, such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), as well as non-livestock animals, such as wild animals, etc.

[0174] The terms "therapeutic agent," "therapeutic capable agent," or "treatment agent" are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. Beneficial effects include enabling a diagnostic determination; ameliorating a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder, or condition; and generally combating a disease, symptom, disorder, or pathological condition.

[0175] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may contain modified amino acids, and may be interrupted by non-amino acids. The term also encompasses amino acid polymers that have been modified (e.g., by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation to a labeling component). As used herein, the term "amino acid" refers to natural and / or non-natural or synthetic amino acids, including glycine and the D optical isomer or the L optical isomer, as well as amino acid analogs and peptide mimetics.

[0176] 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 their analogs. A polynucleotide can have any three-dimensional structure and can perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci defined by linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. Polynucleotides can comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acids (PNA), morpholino oligonucleotides and locked nucleic acids (LNA), glycerol nucleic acids (GNA), threose nucleic acids (TNA), 2'-fluoro nucleic acids, 2'-OMe nucleic acids and thiophosphate DNA. If present, the modification of the nucleotide structure can be given before or after the assembly of the polymer. The sequence of nucleotides can be interrupted by non-nucleotide components. Polynucleotides can be further modified after polymerization, such as by being put together with a labeling component or other put together targets.

[0177] As used herein, "expression" refers to the process by which a polynucleotide is transcribed from a DNA template (e.g., into mRNA or other RNA transcripts) and / or the process by which the transcribed mRNA is subsequently translated into a peptide, polypeptide, or protein. Transcripts and encoded polypeptides may be collectively referred to as "gene products." If the polynucleotide is derived from genomic DNA, expression may include splicing of mRNA in eukaryotic cells.

[0178] An "antigen" is a part or molecule that contains an epitope and therefore specifically binds to an antibody. An "antigen binding unit" can be a whole or fragment (or multiple fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. A full-length antibody can be, for example, a monoclonal antibody, a recombinant antibody, a chimeric antibody, a deimmunized antibody, a humanized antibody, and a human antibody. Examples of fragments of a full-length antibody can include, but are not limited to, a variable heavy chain (VH), a variable light chain (VL), a heavy chain found in camelids such as camels, llamas, and alpacas (VHH or VL), and a variable light chain (VL). H H), heavy chains found in sharks (V-NAR domains), single-domain antibodies (sdAbs, or "nanoantibodies") containing a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and "rIgG" (or half antibodies). Examples of modified fragments of antibodies may include, but are not limited to, scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabody, single-chain diabody, tandem diabody (Tandab), tandem di-scFv, tandem tri-scFv, minibody (e.g., (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2, and multibody (e.g., triabody or tetrabody).

[0179] The terms "antibody" and "antibodies" encompass any antigen binding unit, including but not limited to monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, and any other epitope-binding fragments.

[0180] "Prodrug" is meant to represent a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound as described herein (e.g., a compound of formula (II)). Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound. In some aspects, a prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often provide advantages in solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T. et al., "Pro-drugs 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 incorporated herein by reference in its entirety). The term "prodrug" is also meant to include any covalently bonded carriers that release the active compound in vivo when such prodrug is administered to a mammalian subject. As described herein, prodrugs of an active compound are generally prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds in which a hydroxyl, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of hydroxy functional groups, or acetamide, formamide, and benzamide derivatives of amine functional groups in the active compound, and the like.

[0181] The term "in vivo" refers to an event that occurs in the body of a subject. The term "ex vivo" refers to an event that first occurs outside of the body of a subject for subsequent application to the body of the subject in vivo. For example, an ex vivo preparation may involve preparing cells outside of the body of a subject for the purpose of introducing the prepared cells into the body of the same or a different subject. The term "in vitro" refers to an event that occurs outside of the body of a subject. For example, an in vitro assay encompasses any assay that is performed outside of the body of a subject. In vitro assays encompass cell-based assays in which live or dead cells are employed. In vitro assays also encompass cell-free assays in which intact cells are not employed.

[0182] The present disclosure also means to cover the metabolites in vivo of the disclosed compounds. Such products can be produced by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the compound administered, for example, mainly due to enzymatic processes. Therefore, the present disclosure includes compounds produced by a process comprising administering the compound disclosed herein to a mammal for a period of time sufficient to produce its metabolites. Such products are typically administered to animals (such as rats, mice, guinea pigs, monkeys, or humans) using a radiolabeled compound of the present disclosure in a detectable dose, allowing enough time for metabolism, and isolating its conversion products from urine, blood, or other biological samples for identification.

[0183] The term "Ras" or "RAS" refers to proteins in the rat sarcoma (Ras) superfamily of small GTPases, such as proteins in 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 the unclassified subfamily. In some embodiments, the Ras protein is selected from KRAS (also referred to herein interchangeably 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 selected from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

[0184] The terms "mutant Ras" and "Ras mutant" as used interchangeably herein refer to Ras proteins 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 selected from 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, two or more mutations may be continuous, non-continuous, or a combination thereof. In some embodiments, the mutation may be present at any position of Ras. In some embodiments, the mutation may be present at position 12, 13, 62, 92, 95, 96 (e.g., Y96D), or any combination thereof relative to Ras of SEQ ID No. 1 when optimally aligned. In some embodiments, the mutant Ras may comprise 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 comprise at most 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 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 less than 50 amino acids in length. In some embodiments, the mutated amino acid is a proteinogenic amino acid, a natural amino acid, a standard amino acid, a non-standard amino acid, an atypical amino acid, an essential amino acid, a non-essential amino acid, or an unnatural 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 non-polar 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 portion. In some embodiments, the substituted amino acid comprises a reactive portion. In some embodiments, the mutant Ras can be further modified, for example, by conjugation with a detectable label. In some embodiments, the mutant Ras is a full-length or truncated polypeptide. For example, the mutant Ras can be a truncated polypeptide comprising residues 1-169 or residues 11-183 (e.g., residues 11-183 of mutant RALA or mutant RALB).

[0185] As used herein, the terms "corresponding to" or "corresponds to" as applied to amino acid residues in a polypeptide sequence refer to the correspondence of such amino acids relative to a reference sequence when optimally aligned (e.g., taking into account gaps, insertions, and mismatches; wherein the alignment can be a primary sequence alignment of a folded protein or a three-dimensional structural alignment). For example, the serine residue in the K-Ras G12S mutant refers to the serine at residue 12 of SEQ ID No. 4, which can be used as a reference sequence. For example, the aspartic acid residue in the K-Ras G12D mutant refers to the aspartic acid at residue 12 of SEQ ID No. 2, which can be used as a reference sequence. When an amino acid in a mutant Ras protein corresponds to an amino acid position in a WT Ras protein, it is understood that the mutant amino acid is located at a position corresponding to the wild-type amino acid (e.g., SEQ ID No. 1), even though the amino acid in the mutant Ras protein can be a different amino acid (e.g., G12D, wherein the wild-type G at position 12 is substituted with the aspartic acid at position 12 of SEQ ID No. 1). In embodiments, the modified Ras mutant proteins disclosed herein may comprise a C-terminal truncation or an N-terminal truncation before the G12S mutant serine residue. The G12S mutant serine residue in such N-terminally truncated modified mutants is still considered to correspond to position 12 of SEQ ID No. 1. In addition, the aspartic acid residue at position 12 of SEQ ID No. 2 has corresponding residues found in SEQ ID Nos. 6 and 8.

[0186] The terms "Switch II pocket" and "Switch II binding pocket," as used interchangeably herein, refer to the binding pocket formed beneath 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-helix and α3-helix of Ras. In some embodiments, the Switch II binding pocket is located about or at least about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 nanometers (nm) or more from position 12, position 60, position 99, or any combination thereof. In some embodiments, the Switch II binding pocket is located at a distance of at most about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200 nm or more from position 12, position 60, position 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 a small molecule.

[0187] In some embodiments, the Switch II pocket of Ras comprises three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or more amino acid residues, or three to fifteen residues selected from V7, V9, G10, G12, a G12X mutant (e.g., G12C, G12S, G12D or G12V), 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 of HRAS or NRAS protein. In some embodiments, the SwitchII pocket of Ras comprises three, four, five, six, seven, eight, nine, ten, eleven or twelve amino acid residues selected from G10, G12, a G12X mutant (e.g., G12C, G12S, G12D or G12V), K16, P34, T58, A59, E62, R68, D69, H95, Q99, R102 and V103 of SEQ ID NO. 1, or the corresponding amino acid residues of HRAS or NRAS protein.

[0188] The term "leaving group" is used herein according to its well-understood meaning in chemistry and refers to an atom or group of atoms that breaks away from the rest of a molecule, taking with it the electron pair that was the bond between the leaving group and the rest of the molecule.

[0189] "Degradation enhancer" is a compound that can bind to a ubiquitin ligase protein (e.g., an E3 ubiquitin ligase protein), or a compound that can bind to a protein that can bind to a ubiquitin ligase protein to form a protein complex that can conjugate the ubiquitin protein to the target protein. In embodiments, the degradation enhancer can bind to an E3 ubiquitin ligase protein or a protein complex comprising an E3 ubiquitin ligase protein. In embodiments, the degradation enhancer can bind to an E2 ubiquitin conjugating enzyme. In embodiments, the degradation enhancer can bind to a protein complex comprising an E2 ubiquitin conjugating enzyme and an E3 ubiquitin ligase protein.

[0190] Modified proteins and compounds

[0191] In certain aspects, the present disclosure provides a modified Ras protein comprising a compound covalently bonded to an amino acid residue of the Ras protein, wherein the modified Ras protein comprises a compound of formula (I'):

[0192]

[0193] in:

[0194] Dashed lines indicate covalent bonds to amino acid residues;

[0195] R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R 20 replace;

[0196] L 1 is optionally replaced by one or more R 20 substituted 5- to 20-membered heterocycles;

[0197] L 2 Selected from 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)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-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace;

[0198] L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally substituted by one, two, or three R 20 replace;

[0199] L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally substituted by one, two, or three R 20 Replaced by L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or

[0200] R 2 and R 6 Together with the atoms to which they are attached, they form a 20 substituted 3- to 8-membered monocyclic heterocycloalkyl, wherein L 3 It is a key;

[0201] R 2 Selected from R 20 , or R 2 and R 3 Together with the carbon atom to which they are attached, they form a 20 Substituted C 3-6 Cycloalkyl;

[0202] R 3 Selected from hydrogen and R 20 ;

[0203] R 4 、R 5 and R 6 are each independently selected from hydrogen and R 20 , or R 4 and R5 Together with the carbon atom to which they are attached, they form a 20 Substituted C 3-6 Cycloalkyl;

[0204] R 19 is independently selected at each occurrence from hydrogen, -CN, 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), -OH and -O(C 1-6 alkyl), wherein 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) and -O(C 1-6 alkyl) is optionally replaced by one, two or three R 20 replace;

[0205] R 20 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 ; wherein two R connected to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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)OR22 、-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 ) is substituted with a substituent;

[0206] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring, wherein 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 heterocyclic ring), C 3-12 The carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one, two or three R 20 replace;

[0207] R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), wherein C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace; and

[0208] R 23 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R attached to the same nitrogen atom 22 and R 23 Formed optionally by one, two or three R 20 Substituted 3- to 10-membered heterocycle.

[0209] In certain aspects, the present disclosure provides a modified Ras protein comprising a compound covalently bonded to an amino acid residue of the Ras protein, wherein the modified Ras protein comprises a compound of formula (I'):

[0210]

[0211] in:

[0212] Dashed lines indicate covalent bonds to amino acid residues;

[0213] R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R 20 replace;

[0214] L 1 is optionally replaced by one or more R 20 substituted 5- to 20-membered heterocycles;

[0215] L 2 Selected from 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)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-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace;

[0216] L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in a haloalkyl group;

[0217] L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3halogenated alkyl) is substituted by one, two or three substituents, and wherein L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or

[0218] R 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted by one, two or three substituents, and wherein L 3 It is a key;

[0219] R 2 Selected from halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 2 and R 3 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0220] R 3 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0221] R 4 、R 5 and R 6 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0222] R 19 is independently selected at each occurrence from 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);

[0223] R 20 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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(R22 )(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 ; wherein two R connected to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 ) is substituted with a substituent;

[0224] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 carbocyclic or 3- to 12-membered heterocyclic rings, each of which is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and -OH substituents;

[0225] R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocycle); and

[0226] R 23 independently selected at each occurrence from hydrogen and C 1-6Alkyl; or R attached to the same nitrogen atom 22 and R 23 A 3- to 10-membered heterocyclic ring is formed.

[0227] In some embodiments, the modified protein of Formula (I') is a modified protein of Formula (I'-a), (I'-b), (I'-c), or (I'-d):

[0228] in:

[0229] W 1 、W 3 、W 4 and W 5 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2;

[0230] W 2 Selected from N and C(R 11 );

[0231] n1 and n3 are each independently selected from 0, 1, 2, 3, 4 and 5;

[0232] n4 and n5 are each independently selected from 0, 1, 2, 3, 4 and 5;

[0233] R 10 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and

[0234] R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

[0235] 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.

[0236] In certain aspects, the present disclosure provides a modified human K-Ras protein comprising a compound having a structure of Formula (I) covalently bonded to a serine residue, wherein the serine residue corresponds to position 12 of SEQ ID No. 4:

[0237]

[0238] in:

[0239] The dashed lines indicate the bonds between the serine residue and alanine 11 and glycine 13 of the K-Ras mutant protein, respectively;

[0240] R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R 20 replace;

[0241] L 1 is optionally replaced by one or more R 20 substituted 5- to 20-membered heterocycles;

[0242] L 2 Selected from 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)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-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace;

[0243] L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally substituted by one, two, or three R 20 replace;

[0244] L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally substituted by one, two, or three R 20 Replaced by L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or

[0245] R 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally substituted by one, two or three R 20 Substituted, where L 3 It is a key;

[0246] R 2 Selected from R 20 , or R 2 and R 3 Together with the carbon atom to which they are attached, they form a 20 Substituted C 3-6 Cycloalkyl;

[0247] R 3 Selected from hydrogen and R 20 ;

[0248] R 4 、R 5 and R 6 are each independently selected from hydrogen and R 20 , or R4 and R 5 Together with the carbon atom to which they are attached, they form a 20 Substituted C 3-6 Cycloalkyl;

[0249] R 19 is independently selected at each occurrence from hydrogen, -CN, 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), -OH and -O(C 1-6 alkyl), wherein 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) and -O(C 1-6 alkyl) is optionally replaced by one, two or three R 20 replace;

[0250] R 20 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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)2R22 、-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 ; wherein two R connected to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 ) is substituted with a substituent;

[0251] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring, wherein 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 heterocyclic ring), C 3-12 The carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one, two or three R 20 replace;

[0252] R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), wherein C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace; and

[0253] R 23 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R attached to the same nitrogen atom 22 and R 23 Formed optionally by one, two or three R 20 Substituted 3- to 10-membered heterocycle.

[0254] In certain aspects, the present disclosure provides a modified human K-Ras protein comprising a compound having a structure of Formula (I) covalently bonded to a serine residue, wherein the serine residue corresponds to position 12 of SEQ ID No. 4:

[0255]

[0256] in:

[0257] The dotted lines represent the bonds between the serine residue and alanine 11 and glycine 13 of the K-Ras mutant protein, respectively;

[0258] R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R 20 replace;

[0259] L 1 is optionally replaced by one or more R 20 substituted 5- to 20-membered heterocycles;

[0260] L 2 Selected from 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)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-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace;

[0261] L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in a haloalkyl group;

[0262] L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted by one, two or three substituents, and wherein L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or

[0263] R 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted by one, two or three substituents, and wherein L 3 It is a key;

[0264] R 2 Selected from halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 2 and R 3 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0265] R 3 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0266] R 4 、R 5 and R 6 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0267] R 19 is independently selected at each occurrence from 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);

[0268] R 20 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 )-、-S(=O)(=NR 22 )N(R 22 )(R 23 ) and -OCH2C(O)OR 22 ; wherein two R connected to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 ) is substituted with a substituent;

[0269] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 carbocyclic or 3- to 12-membered heterocyclic rings, each of which is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and -OH substituents;

[0270] R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocycle); and

[0271] R 23 independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or R attached to the same nitrogen atom 22 and R 23 A 3- to 10-membered heterocyclic ring is formed.

[0272] In some embodiments, the modified protein of Formula (I) is a modified protein of Formula (Ia), (Ib), (Ic), or (Id):

[0273] in:

[0274] W 1 、W 3 、W 4 and W 5 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2;

[0275] W 2 Selected from N and C(R 11 );

[0276] n1 and n3 are each independently selected from 0, 1, 2, 3, 4 and 5;

[0277] n4 and n5 are each independently selected from 0, 1, 2, 3, 4 and 5;

[0278] R 10 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and

[0279] R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

[0280] 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 the nucleophilic serine residue at position 12 corresponding to SEQ ID No: 1. In some embodiments, the modified Ras protein is formed by contacting a compound disclosed herein (e.g., a compound of Formula (II), (II-a), (II-b), (II-c), or (II-d)) with a serine residue of an unmodified Ras protein (e.g., 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 retaining group and a leaving group, and wherein the 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 selected from or a salt or tautomer thereof, wherein R 8 and R 9 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl) and -O(C 1-6 In some embodiments, the leaving group is

[0281] 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, wherein the precursor compound comprises a retaining group and a leaving group, and wherein the leaving group is separated from the remainder of the precursor compound by an electron pair that previously formed a covalent bond between the leaving group and the remainder of the precursor compound after the precursor compound was contacted with the unmodified Ras G12S mutant protein. 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, wherein the precursor compound comprises a retaining group and a leaving group, and wherein the contacting results in the release of the leaving group and the formation of the modified protein. The release of the leaving group can be determined 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:

[0282] L=[U+P]–[M]

[0283] in:

[0284] L is the molecular weight of the leaving group; U is the molecular weight of the unmodified Ras G12S mutant; P is the molecular weight of the subject precursor compound used to modify the unmodified Ras G12S mutant; and M is the molecular weight of the modified Ras G12S mutant covalently bonded to the precursor (excluding the leaving group).

[0285] The molecular weight of the modified Ras G12S mutant can be determined by mass spectrometry. In some embodiments, the subject compound, upon contact with an unmodified Ras G12S mutant protein (e.g., K-Ras G12S, H-Ras G12S, or N-Ras G12S), produces a leaving group having a molecular weight of less than about 200 Da, such as less than about 190 Da, 180 Da, 170 Da, 160 Da, 150 Da, 140 Da, 130 Da, 120 Da, 110 Da, 100 Da, 90 Da, 80 Da, 70 Da, 60 Da, 50 Da, 40 Da, 30 Da, 20 Da, or less. One or more compounds described herein (e.g., compounds in Table 1) upon contact with K-Ras G12S, produce a leaving group having a molecular weight of less than 120 Da.

[0286] In some embodiments, the modified Ras mutant proteins of the present disclosure exhibit reduced Ras signaling output. The reduction in signaling output can be determined by various methods known in the art. For example, phosphorylation of a substrate or a specific amino acid residue thereof can be detected and / or quantified using one or more techniques such as kinase activity assays, phosphorylation-specific antibodies, Western blots, enzyme-linked immunosorbent assays (ELISAs), cell-based ELISAs, intracellular flow cytometry, mass spectrometry, or multi-analyte analysis. The reduced Ras signaling output is demonstrated by one or more outputs selected from the group consisting of: (i) an increase in the steady-state level of GDP-bound modified protein; (ii) a decrease in the steady-state level of GTP-bound modified protein; (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 the Ras G12S mutant protein; and (vii) a decrease in Ras interaction with Ras pathway signaling proteins. In some embodiments, the reduction is demonstrated by 2, 3, 4, or more of items (i)-(vii). In some embodiments, the reduction in Ras signaling output can be demonstrated by any one of (i)-(vii) compared to a control unmodified corresponding Ras protein that is not covalently bonded to a compound disclosed herein. For example, a control Ras protein as described herein can be a Ras protein (e.g., wild-type or mutant) that is not complexed with a compound disclosed herein. The increase in (i) or the decrease in (ii) to (vii) 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, as compared to a control Ras protein. In some embodiments, reduced interaction of Ras with Ras pathway signaling proteins is determined by observing reduced interaction with SOS (including SOS1 and SOS2), RAF, SHC, SHP (including SHP1 and SHP2), MEK, MAPK, ERK, GRB, RASA1, and / or GNAQ.

[0287] Signaling outputs measured according to IC50 values ​​can be obtained, and the IC50 ratio of one mutant relative to another mutant can be calculated. For example, a selective reduction in K-Ras G12S signaling output can be demonstrated by a ratio greater than one. In particular, when the ratio of IC50 (for K-Ras G12D) to IC50 (for K-Ras G12S) is greater than 1, a selective reduction in K-Ras G12S signaling relative to K-Ras G12D signaling is demonstrated. One or more compounds disclosed herein (such as the compounds in Table 1) exhibit at least 1-fold selective inhibition of K-Ras G12S relative to Ras G12D, and in some cases greater than 2-fold, 3-fold, 4-fold, or 5-fold. In some embodiments, the compounds of the present disclosure exhibit an IC50 of less than 500 nM (such as less than 100 nM, 50 nM, 10 nM, or even less) for K-Ras G12S. Using one or more of the methods exemplified herein, the subject compounds can exhibit selective labeling of the Ras G12S mutant relative to the Ras G12D mutant or wild-type protein. Exemplary compounds (e.g., compounds of Table 1) can covalently label the K-Ras G12S mutant by at least 1%, 10%, 20%, 50%, or more, while no detectable labeling is observed for K-Ras G12D or K-Ras wild-type when tested under the same or comparable conditions.

[0288] In some embodiments, the modified Ras protein comprises the amino acid sequence of SEQ ID No. 4, or a fragment thereof comprising the 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 the serine residue corresponding to position 12 of SEQ ID No. 1, wherein the precursor compound selectively labels the serine residue as compared to: (i) an aspartic acid residue of a K-Ras G12D mutant protein, said aspartic acid corresponding to position 12 of SEQ ID No. 2; (ii) a valine residue of a K-Ras G12V mutant protein, said valine corresponding to position 12 of SEQ ID No. 3; and / or (iii) a glycine residue of a K-Ras wild-type protein, said glycine corresponding to position 12 of SEQ ID No. 1. In some embodiments, the precursor compound selectively labels the serine residue in SEQ ID No. 4 at least 2-fold, 3-fold, 4-fold, or 5-fold more when assayed under comparable conditions. In some embodiments, the precursor compound selectively labels the serine residue more than 5-fold when assayed under comparable conditions. It should be understood that when a compound of the present disclosure selectively labels a serine residue of a K-Ras G12S protein as compared to another K-Ras protein (e.g., WT, G12D, G12V), the compound labels the K-Ras G12S protein at a faster rate or to a greater extent, or by any other quantifiable measure, as compared to the other K-Ras protein (e.g., WT, G12D, G12V) under similar or identical reaction conditions used for the compared proteins. In some embodiments, greater labeling of K-Ras G12S compared to another K-Ras protein (e.g., WT, G12D, G12V) 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.In some embodiments, K-Ras G12S can be labeled 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 faster at a selected time point during the labeling process compared to another K-Ras protein (e.g., WT, G12D, G12V).

[0289] In some embodiments, the compounds of the present disclosure selectively label a serine residue at least 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10-fold or more compared to: (i) an aspartic acid residue of a K-Ras G12D mutant protein corresponding to position 12 of SEQ ID No. 2, and / or (ii) a valine residue of a K-Ras G12V mutant protein corresponding to position 12 of SEQ ID No. 3, when assayed under comparable conditions. In some embodiments, the compounds of the present disclosure selectively label (e.g., by covalent binding) in vitro the serine residue of an unmodified Ras G12S protein corresponding to position 12 of SEQ ID No: 4. In some embodiments, the compounds of the present disclosure selectively label (e.g., by covalent binding) in vivo the serine residue of an unmodified Ras G12S protein corresponding to position 12 of SEQ ID No: 4.

[0290] 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 K-Ras inhibitors and have a wide range of applications in therapy, diagnosis, and other biomedical research. In some embodiments, the compounds disclosed herein covalently modify Ras proteins, such as K-RasG12S proteins. In some embodiments, Ras proteins, such as K-RasG12S proteins, are contacted with compounds disclosed herein to form modified Ras proteins.

[0291] In certain aspects, the present disclosure provides compounds of formula (II):

[0292]

[0293] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0294] R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R 20 replace;

[0295] L 1 is optionally replaced by one or more R 20 substituted 5- to 20-membered heterocycles;

[0296] L 2 Selected from 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)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-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace;

[0297] L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally substituted by one, two, or three R 20 replace;

[0298] L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally substituted by one, two, or three R 20 Replaced by L 3 and R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or

[0299] R2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally substituted by one, two or three R 20 Substituted, where L 3 It is a key;

[0300] R 2 Selected from R 20 , or R 2 and R 3 Together with the carbon atom to which they are attached, they form a 20 Substituted C 3-6 Cycloalkyl;

[0301] R 3 Selected from hydrogen and R 20 ;

[0302] R 4 、R 5 and R 6 are each independently selected from hydrogen and R 20 , or R 4 and R 5 Together with the carbon atom to which they are attached, they form a 20 Substituted C 3-6 Cycloalkyl;

[0303] R 7 Selected from

[0304] R 8 and R 9 are each independently selected from hydrogen and R 20 ;

[0305] R 19 is independently selected at each occurrence from hydrogen, -CN, 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), -OH and -O(C 1-6 alkyl), wherein 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) and -O(C 1-6 alkyl) is optionally replaced by one, two or three R 20replace;

[0306] R 20 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 ; wherein two R connected to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein C 1-6Alkyl, 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 ) is substituted with a substituent;

[0307] R 21is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring, wherein 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 heterocyclic ring), C 3-12 The carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one, two or three R 20 replace;

[0308] R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace; and

[0309] R 23 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R attached to the same nitrogen atom 22 and R 23 Formed optionally by one, two or three R 20 Substituted 3- to 10-membered heterocycle.

[0310] In certain aspects, the present disclosure provides compounds of formula (II):

[0311]

[0312] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0313] R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R 20 replace;

[0314] L 1 is optionally replaced by one or more R 20 substituted 5- to 20-membered heterocycles;

[0315] L 2 Selected from 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)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-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace;

[0316] L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in a haloalkyl group;

[0317] L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted by one, two or three substituents, and wherein L 3 and R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or

[0318] R 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted with one, two or three substituents, and wherein L 3 It is a key;

[0319] R2 Selected from halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 2 and R 3 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents of a haloalkyl group;

[0320] R 3 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0321] R 4 、R 5 and R 6 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0322] R 7 Selected from

[0323] R 8 and R 9 are independently selected from hydrogen, halogen, -CN, C1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0324] R 19 is independently selected at each occurrence from 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);

[0325] R 20 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 ; wherein two R attached to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )(R23 )、-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 ) is substituted with a substituent;

[0326] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 carbocyclic or 3- to 12-membered heterocyclic rings, each of which is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and -OH substituents;

[0327] R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocycle); and

[0328] R 23 independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or R attached to the same nitrogen atom 22 and R 23 A 3- to 10-membered heterocyclic ring is formed.

[0329] In some embodiments, for the compound of formula (II) or the modified protein of formula (I') or (I), L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally substituted by one, two, or three R20 In some embodiments, for the compound of formula (II) or the modified protein of formula (I') or (I), L 3 and R 2 Together with the atoms to which they are attached, they 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 optionally substituted by one, two, or three R 20 In some embodiments, L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally substituted by one, two or three R 20 In some embodiments, L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally substituted by one, two, or three R 20 Replaced by L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine. 2 and R 6 Together with the atoms to which they are attached, they form a 20 substituted 3- to 8-membered monocyclic heterocycloalkyl, wherein L 3 In some embodiments, L 3 and R 2 , L 3 and R 6 or R 2 and R 6 The ring formed is formed by at least one R 20 (As an R 20 , two R 20 、Three R 20 , Four Rs 20 or the five R's 20 )replace.

[0330] In some embodiments, for the compound of formula (II) or the modified protein of formula (I') or (I), L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 In some embodiments, for the compound of formula (II) or the modified protein of formula (I') or (I), L 3 and R 2 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 In some embodiments, L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 In some embodiments, L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted by one, two or three substituents, and wherein L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine. 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted by one, two or three substituents, and wherein L 3 In some embodiments, L 3 With R 2 , L 3With R 6 or R 2 With R 6 The ring formed is unsubstituted. 3 With R 2 , L 3 With R 6 or R 2 With R 6 The ring formed is selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one substituent, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 In some embodiments, L 3 With R 2 , L 3 With R 6 or R 2 With R 6 The ring formed is independently selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with two substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 In some embodiments, L 3 With R 2 , L 3 With R 6 or R 2 With R 6The ring formed is independently selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted by three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 In some embodiments, L 3 With R 2 , L 3 With R 6 or R 2 With R 6 The ring formed is independently selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally substituted by one, two or three selected from R 20 In some embodiments, L 3 With R 2 , L 3 With R 6 or R 2 With R 6 The ring formed is selected from halogen, -(C 0-6 Alkyl)-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 In some embodiments, L 3 With R 2 , L 3 With R 6 or R 2 With R 6 The ring formed is independently selected from halogen, -(C0-6 Alkyl)-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 In some embodiments, L 3 With R 2 , L 3 With R 6 or R 2 With R 6 The ring formed is independently selected from halogen, -(C 0-6 Alkyl)-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 In some embodiments, the substituents are C 1-6 Alkyl groups, such as -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2 or -C(CH3)3.

[0331] In some embodiments, the compound of formula (II) is of formula (II-a), (II-b), (II-c) or (II-

[0332] A compound, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0333] W 1 、W 3 、W 4 and W 5 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2;

[0334] W 2 Selected from N and C(R 11 );

[0335] n1 and n3 are each independently selected from 0, 1, 2, 3, 4 and 5;

[0336] n4 and n5 are each independently selected from 0, 1, 2, 3, 4 and 5;

[0337] R 10 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and

[0338] R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

[0339] In some embodiments, for the compound of formula (II-a) or the modified protein of formula (I'-a) or (Ia), W 1 and W 3 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2; W 2 Selected from N and C(R 11 ); n1 and n3 are each independently selected from 0, 1, 2, 3, 4 and 5, wherein the sum of n1 and n3 is at least 1; R 10 is independently selected at each occurrence from hydrogen, -(C 1-6 Alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; and R 11 is independently selected at each occurrence from hydrogen, halogen, -(C 0-6 Alkyl)-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 haloalkyl), or two R 11 Formation C 3-6 In some embodiments, W 1 and W 3 Each is C(R 11 ) 2. In some embodiments, W 2 Is N. In some embodiments, W 1 and W 3 Each is C(R 11 )2; and W 2 Is N. In some embodiments, W 1 and W 3 Each is C(R 11 )2;W 2 is N; n1 is 2 or 3; and n3 is 1 or 2. In some embodiments, W 1 and W 3 Each is C(R 11 )2;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 Each is C(R 11 )2;W 2 is N; n1 is 2; and n3 is 1. In some embodiments, W 1 and W 3 Each is C(R 11 )2;W 2 is N; n1 is 2; and n3 is 2. In some embodiments, W 1 and W 3 Each is C(R 11 )2;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 2, 3, or 4, and n3 is 1 or 2. In some embodiments, Selected from wherein each is optionally replaced by one, two or three R 11 replace.

[0340] In some embodiments, for the compound of formula (II-b) or the modified protein of formula (I'-b) or (Ib), W 4 and W 5Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2; W 2 Selected from N and C(R 11 ); n4 and n5 are each independently selected from 0, 1, 2, 3, 4 and 5; R 10 is independently selected at each occurrence from hydrogen, -(C 0-6 Alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; and R 11 is independently selected at each occurrence from hydrogen, halogen, -(C 0-6 Alkyl)-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 haloalkyl), or two R 11 Formation C 3-6 In some embodiments, W 4 and W 5 Each is C(R 11 ) 2. In some embodiments, W 2 It is C(R 11 ). In some embodiments, W 4 and W 5 Each is C(R 11 )2; and W 2 It is C(R 11 ). In some embodiments, W 4 and W 5 Each is CH2; and W 2 Is CH. In some embodiments, W 4 and W 5 Each is C(R 11 )2;W 2 It 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 Each is C(R 11 )2;W 2 It is C(R 11 ); and the sum of n4 and n5 is 0, 1 or 2. In some embodiments, W 4 and W 5 Each is C(R 11 )2;W 2 It is C(R 11); the sum of n4 and n5 is 0, 1 or 2; and L 2 Selected from -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 Each is C(R 11 )2;W 2 It is C(R 11 ); n4 is 0; and n5 is 0. In some embodiments, L 2 Selected from C 1-3 Alkylene, 2-membered to 3-membered heteroalkylene and -N(R 19 )-. In some embodiments, L 2 Selected from 2- to 3-membered heteroalkylene and -N(R 19 )-. In some embodiments, L 2 Selected from -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene- and -N(R 19 )-. In some embodiments, L 2 Selected from -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, Selected from wherein each is optionally replaced by one, two or three R 11 replace.

[0341] In some embodiments, for the compound of formula (II-c) or the modified protein of formula (I'-c) or (Ic), W 1 、W 3 、W 4 and W 5 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2; W 2 Selected from N and C(R 11 ); n1 and n3 are each independently selected from 0, 1, 2, 3, 4 and 5, wherein 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 selected at each occurrence from hydrogen, -(C 1-6 Alkyl)-CN, C 1-6 Alkyl, C1-6 Haloalkyl and C 3-6 cycloalkyl; and R 11 is independently selected at each occurrence from hydrogen, halogen, -(C 0-6 Alkyl)-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 haloalkyl), or two R 11 Formation C 3-6 In some embodiments, each W 1 Independently selected from C(R 11 )2 and O. In some embodiments, n1 is 2, 3 or 4, one W 1 is O, and the rest are W 1 Each is C(R 11 ) 2. In some embodiments, W 3 It is C(R 11 ) 2. In some embodiments, W 2 Is N. In some embodiments, W 4 and W 5 Each is C(R 11 )2. In some embodiments, n1 is 2, 3 or 4; one W 1 Selected from C(R 11 )2 and O, and the rest W 1 Each is C(R 11 )2;W 2 is N; n3 is 1 or 2; W 3 It is C(R 11 )2; n4 is 0 or 1; W 4 It is C(R 11 )2; n5 is 0 or 1; and W 5 It is C(R 11 )2. In some embodiments, n1 is 2, 3 or 4; one W 1 Selected from C(R 11 )2 and O, and the rest W 1 Each is C(R 11 )2;W 2 is N; n3 is 1 or 2; W 3 It is C(R 11 )2; n4 is 0 or 1; W 4 It is C(R 11 )2; n5 is 0 or 1; W 5 It is C(R 11 )2; and L 2In some embodiments, n1 is 2, 3, or 4; one W 1 is selected from CH2 and O, and the rest W 1 Each is CH2; W 2 is N; n3 is 1 or 2; W 3 is CH2; n4 is 0 or 1; W 4 is CH2; n5 is 0 or 1; and W 5 is CH2. In some embodiments, the sum of n1 and n3 is 3, 4 or 5; one W 1 Selected from C(R 11 )2 and O, and the rest W 1 Each is C(R 11 )2;W 2 It is N; W 3 It is C(R 11 )2; n4 is 0; and n5 is 0. In some embodiments, n1 is 2, 3, or 4; W 1 It is C(R 11 )2;W 2 is N; n3 is 1 or 2; W 3 It is C(R 11 )2; n4 is 0 or 1; W 4 It is C(R 11 )2; n5 is 0 or 1; and W 5 It is C(R 11 )2. In some embodiments, n1 is 4; W 1 It is C(R 11 )2;W 2 is N; n3 is 1; W 3 It is C(R 11 )2; n4 is 0; and n5 is 0. In some embodiments, n1 is 3; W 1 It is C(R 11 )2;W 2 is N; n3 is 1; W 3 It is C(R 11 )2; n4 is 0; and n5 is 0. In some embodiments, n1 is 3; one selected from C(R 11 )2 and O, and the rest W 1 Each is C(R 11 )2;W 2 is N; n3 is 1; W 3 It is C(R 11 )2; n4 is 0; and n5 is 0. In some embodiments, n1 is 2; W 1 It is C(R 11 )2;W 2 is N; n3 is 1; W 3 It is C(R11 )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, Selected from

[0342] wherein each is optionally replaced by one, two or three R 11 replace.

[0343] In some embodiments, for the compound of formula (II-d) or the modified protein of formula (I'-d) or (Id), W 3 Selected from 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 selected at each occurrence from hydrogen, -(C 1-6 Alkyl)-CN, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 cycloalkyl; and R 11 is independently selected at each occurrence from hydrogen, halogen, -(C 0-6 Alkyl)-CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 In some embodiments, each W 3 It is C(R 11 ) 2. In some embodiments, W 3 It is C(R 11 )2; and n3 is 1, 2 or 3. In some embodiments, W 3 It is C(R 11 )2; n3 is 1, 2 or 3; and L 2 Selected from -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 n3 is 1, 2, or 3. In some embodiments, W 3 It is C(R11 )2; and n3 is 1. In some embodiments, W 3 It is C(R 11 )2; and n3 is 2. In some embodiments, W 3 It is C(R 11 )2; n3 is 3. In some embodiments, L 2 Selected from C 1-3 Alkylene, 2-membered to 3-membered heteroalkylene and -N(R 19 )-. In some embodiments, L 2 Selected from 2- to 3-membered heteroalkylene and -N(R 19 )-. In some embodiments, L 2 Selected from -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene- and -N(R 19 )-. In some embodiments, L 2 Selected from -N(R 19 )-, -N(CH3)CH2- and -N(CH3)CH(CH3)-. In some embodiments, n3 is 1, 2 or 3. In some embodiments, Selected from wherein each is optionally replaced by one, two or three R 11 replace.

[0344] 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 selected at each occurrence from hydrogen and C 1-3 In some embodiments, one R 10 or R 11 It is C 1-3 Alkyl, such as -CH3, -CH2CH3 or -CH(CH3)2, and any remaining R 10 and R 11 In some embodiments, two R 10 and / or R 11 Independently C 1-3 Alkyl, such as -CH3, -CH2CH3 or -CH(CH3)2, and any remaining R 10 and R 11 Each is hydrogen.

[0345] 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 Selected from C 6-10 Aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted by one, two, three, four or five R 20 In some embodiments, R 1 is selected from naphthyl, isoquinolyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl and pyridinyl, each of which is optionally substituted by one or more R 20 In some embodiments, R 1 One, two, three or four independently selected from halogen, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -OR 22 、-N(R 22 )(R 23 ) and C 3-6 In some embodiments, R 1 Substituted with one, two, three or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH=CH2, -CF3, -C≡C, -OH, -NH2 and -cyclopropyl.

[0346] 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 Selected from fused bicyclic C 4-12 Cycloalkyl, fused bicyclic C 3-11 Heterocycloalkyl, fused bicyclic C 7-12 Aryl and fused bicyclic C 3-11 Heteroaryl, wherein the fused bicyclic C 4-12 Cycloalkyl, fused bicyclic C 3-11 Heterocycloalkyl, fused bicyclic C 7-12 Aryl and fused bicyclic C 3-11 Heteroaryl is optionally substituted by one, two, three, four, five, six or seven R 20 In some embodiments, R 1 Selected from spiro bicyclic C 4-12Cycloalkyl and spirobicyclic C 3-11 Heterocycloalkyl, wherein the spirobicyclic C 4-12 Cycloalkyl and spirobicyclic C 3-11 Heterocycloalkyl is optionally substituted by one, two, three, four, five, six or seven R 20 In some embodiments, R 1 It is a multi-ring system.

[0347] 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 One, two, three or four independently selected from 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 ) is substituted by a substituent, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3-6 Cycloalkyl is optionally substituted by one, two or three independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR 22 In some embodiments, R 1 One, two, three or four independently selected from halogen, -CN, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -OR 22 and -N(R 22 )(R 23 ) is substituted with a substituent. In some embodiments, R 1 is substituted with one, two, three or four substituents independently selected from halogen, -CN, -CH3, -C≡CH, -OH and -NH2. 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 Substituted with one, two, three or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH=CH2, -CF3, -C≡C, -OH, -NH2 and -cyclopropyl.

[0348] 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 Selected from:

[0349]

[0350] in:

[0351] Q 1 , Q 3 and Q 5 independently selected from N and C(R 1d );

[0352] Q 4 and Q 6 Independently selected from O, S, C(R 1a )(R 1b ) and N(R 1c );

[0353] X 4 、X 5 、X 6 、X 9 and X 10 Independently selected from C(R 1a ) and N;

[0354] X 13 Selected from bonds, 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(R 1a )(R 1b)N(R 1c ) and N(R 1c );

[0355] X 14 、X 15 、X 17 and X 18 independently selected from C(O), C(R 1a )、N、C(R 1a )(R 1b ) and N(R 1c );

[0356] X 16 Selected from C, N and C(R 1a );

[0357] Each R 1a 、R 1b 、R 1d and R 1h independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, 3- to 10-membered heterocycle, -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 )(R13 )、-CH2C(O)N(R 12 )(R 13 )、-CH2N(R 12 )C(O)R 12 、-CH2S(O)2R 12 and -CH2S(O)2N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocyclic and 3- to 10-membered heterocyclic rings are optionally substituted by one, two or three R 20 substituted; or R bonded to the same carbon 1a With R 1b Join to form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic rings, including 3- to 10-membered heterocyclic rings and C 3-10 The carbocyclic ring is optionally substituted by one, two or three R 20 Substitution; or two R bonded to adjacent atoms 1a Join to form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic rings, including 3- to 10-membered heterocyclic rings and C 3-10 The carbocyclic ring is optionally substituted by one, two or three R 20 Substitution; or R bonded to an adjacent atom 1h and R 1a 、R 1b 、R 1c and R 1d to form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic rings, including 3- to 10-membered heterocyclic rings and C 3-10 The carbocyclic ring is optionally substituted by one, two or three R 20 replace; and

[0358] Each R 1c are independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered heterocyclic ring and C 3-10 Carbon ring, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 10-membered heterocyclic ring and C 3-10 The carbocyclic ring is optionally substituted by one, two or three R 20 replace.

[0359] In some embodiments, R 1 Selected from In some embodiments, R 1 Selected from

[0360] 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 Selected from

[0361]

[0362]

[0363] In some embodiments, R 1 yes

[0364] 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 Selected from

[0365]

[0366]

[0367]

[0368] In some embodiments, R 1 Selected from In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes In some embodiments, R 1 yes

[0369] 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 optionally replaced by one or more R 20 In some embodiments, L 1 is a 10-membered bicyclic heterocycle, which is surrounded by one, two, three or four R 20 In some embodiments, L 1 Contains 1 to 5 nitrogen atoms. In some embodiments, L 1 is optionally replaced by one or more R 20 In some embodiments, L 1 is optionally replaced by one or more R 20 substituted 12- to 20-membered polycyclic heterocycle, for example optionally substituted with one or more R 20 In some embodiments, L 1 selected from tetrahydropyridopyrimidines (e.g., 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine), pyridopyrimidines (e.g., pyrido[4,3-d]pyrimidine), pyridopyrimidones (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.

[0370] 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 for:

[0371]

[0372] in:

[0373] W is N, C (R 17 )、N(R 17b )、C(R 17 )2, C(O), S(O) or S(O)2;

[0374] Z is N, C (R 17 )、N(R 17b )、C(R17 )2, C(O), S(O) or S(O)2; wherein W and Z are not simultaneously selected from C(O), S(O) and S(O)2;

[0375] V and J are each independently selected from N, C(R 1 )、C(R 17 )、N(R 1 )、N(R 17b )、C(R 1 )(R 17 ) and C(R 17 )2; where exactly one of V and J is C(R 1 )、N(R 1 ) or C(R 1 )(R 17 );

[0376] U is N, C (R 17 )、N(R 17b )、C(R 17 )2, S(O), S(O)2 or C(O);

[0377] Y is N, C(R 18 )、N(R 17b )、C(R 18 )(R 17 ), S(O), S(O)2 or C(O);

[0378] X is N, C(R 17 )、N(R 17b ) or C(R 17 )2;

[0379] R 17 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -OR 12 、-SR 12 、-N(R 12 )(R 13 ), =NR 12 , =C(R 14 )2、-C(O)OR 12 、-OC(O)N(R12 )(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 , where 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring) are optionally substituted by one, two, or three R 20 replace;

[0380] R 17b is independently selected at each occurrence from hydrogen, -CN, 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 heterocyclic ring), -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)2R 12 、-S(O)(NR 12 )R 12 、-S(O)2N(R 12 )(R 13 ) and -S(=O)(=NR 12 )N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace;

[0381] R 18 Selected from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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)2R12 、-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 , where 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring) are optionally substituted by one, two, or three R 20 replace;

[0382] R 12 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace;

[0383] R 13 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 1-6haloalkyl; or R attached to the same nitrogen atom 12 and R 13 Formed optionally by one, two or three R 20 substituted 3- to 10-membered heterocycle;

[0384] R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 14 Together with the carbon atoms to which they are attached, they form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring, wherein 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 heterocyclic ring), C 3-12 The carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one, two or three R 20 replace; and

[0385] represents a single or double bond such that all valences are satisfied.

[0386] In certain aspects, the present disclosure provides compounds of formula (II):

[0387]

[0388] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0389] R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R 20 replace;

[0390] L 1 yes:

[0391]

[0392] in:

[0393] W is N, C (R 17 )、N(R 17b )、C(R 17 )2, C(O), S(O) or S(O)2;

[0394] Z is N, C (R 17 )、N(R 17b )、C(R 17 )2, C(O), S(O) or S(O)2; wherein W and Z are not simultaneously selected from C(O), S(O) and S(O)2;

[0395] V and J are each independently selected from N, C(R 1 )、C(R 17 )、N(R 1 )、N(R 17b )、C(R 1 )(R 17 ) and C(R 17 )2; where exactly one of V and J is C(R 1 )、N(R 1 ) or C(R 1 )(R 17 );

[0396] U is N, C (R 17 )、N(R 17b )、C(R 17 )2, S(O), S(O)2 or C(O);

[0397] Y is N, C(R 18 )、N(R 17b )、C(R 18 )(R 17 ), S(O), S(O)2 or C(O);

[0398] X is N, C(R 17 )、N(R 17b ) or C(R 17 )2;

[0399] R 17 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 , where 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring) are optionally substituted by one, two, or three R 20 replace;

[0400] R 17b is independently selected at each occurrence from hydrogen, -CN, 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 heterocyclic ring), -OR 12 、-SR12 、-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)2R 12 、-S(O)(NR 12 )R 12 、-S(O)2N(R 12 )(R 13 ) and -S(=O)(=NR 12 )N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace;

[0401] R 18 Selected from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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(R12 )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 , where 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring) are optionally substituted by one, two, or three R 20 replace;

[0402] R 12 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace;

[0403] R 13 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R attached to the same nitrogen atom 12 and R 13 Formed optionally by one, two or three R 20 substituted 3- to 10-membered heterocycle;

[0404] R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 14 Together with the carbon atoms to which they are attached, they form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring, wherein 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 heterocyclic ring), C 3-12 The carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one, two or three R 20 replace;

[0405] represents a single or double bond such that all valences are satisfied;

[0406] L 2 Selected from 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)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-, where C1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace;

[0407] L 3 and R 2 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in a haloalkyl group;

[0408] L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted by one, two or three substituents, and wherein L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or

[0409] R2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted with one, two or three substituents, and wherein L 3 It is a key;

[0410] R 2 Selected from halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 2 and R 3 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents of a haloalkyl group;

[0411] R 3 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0412] R 4 、R 5and R 6 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0413] R 7 Selected from

[0414] R 8 and R 9 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group;

[0415] R 19 is independently selected at each occurrence from 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);

[0416] R 20 is independently selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 ; wherein two R attached to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 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 ) is substituted with a substituent;

[0417] R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 carbocyclic or 3- to 12-membered heterocyclic rings, each of which is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and -OH substituents;

[0418] R 22independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocycle); and

[0419] R 23 independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or R attached to the same nitrogen atom 22 and R 23 A 3- to 10-membered heterocyclic ring is formed.

[0420] In some embodiments, W is C(R 17 )、C(R 17 )2 or C(O); Z is N, C(R 17 )、N(R 17b ) or C(R 17 ); 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); Z is N, CCl, N(R 17b ) or CH2; V is C(R 1 ) or N(R 1 ); and J is CF or CH2. In some embodiments, W is C(R 17 ); Z is C(R 17 ); V is C(R 1 ); and J is C(R 17 In some embodiments, W is CH; Z is CCl; V is C(R 1 ); and J is CF. In some embodiments, W is CH; Z is CCF3; V is C(R 1 ); and J is CF. In some embodiments, U is N; Y is C(R 18 ); and X is N. In some embodiments, W is CH; Z is N; V is C(R 1 ); and J is CF.

[0421] In some embodiments, for the compounds or modified proteins described herein, R 18 Selected from hydrogen, C 1-3 Alkyl, -OR 12 and a 3- to 10-membered heterocyclic ring, wherein C 1-3 The alkyl group and the 3- to 10-membered heterocyclic ring are optionally replaced by one, two or three R 20Substituted. In some embodiments, L 1 is substituted by C 1-3 alkyl, -OR 12 and a 3- to 10-membered heterocycle, where the C 1-3 alkyl and the 3- to 10-membered heterocycle are optionally substituted by one, two or three R 20 . In some embodiments, R 18 is -OR 12 . In some embodiments, L 1 is substituted by -OR 12 . In some embodiments, R 18 is -O(C 1-3 alkylene)(4- to 10-membered heterocycle), where the 4- to 10-membered heterocycle is optionally substituted by one, two or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and =C(R 21 )2, where R 21 is independently selected from hydrogen, halogen and C 1-3 alkyl at each occurrence. In some embodiments, L 1 is substituted by -O(C 1-3 alkylene)(4- to 10-membered heterocycle), where the 4- to 10-membered heterocycle is optionally substituted by one, two or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl and =C(R 21 )2, where R 21 is independently selected from hydrogen, halogen and C 1-3 alkyl at each occurrence.

[0422] In some embodiments, for the compounds or modified proteins described herein, R 18 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 and -N(R 12 )(R 13 ), where the C 1-6 alkyl, C 2-6 alkenyl, C 3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted by one, two or three R 20 . In some embodiments, R 18 is selected from hydrogen, -(C 0-3 alkylene)-O-(C 0-3 alkylene)-R 20 , C 1-3 alkyl and 3- to 10-membered heterocycle, where each C0-3 Alkylene, C 1-3 The alkyl group and the 3- to 10-membered heterocyclic ring are optionally replaced by one, two or three R 20 In some embodiments, R 18 Selected from hydrogen, C 1-3 Alkyl, -OR 12 and a 3- to 10-membered heterocyclic ring, wherein C 1-3 The alkyl group and the 3- to 10-membered heterocyclic ring are optionally substituted by one, two or three R 20 In some embodiments, R 18 is OR 12 In some embodiments, R 18 -O(C 1-3 alkylene) (4- to 10-membered heterocyclic ring), wherein the 4- to 10-membered heterocyclic ring is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and =C(R 21 )2 is substituted with a substituent, wherein R 21 is independently selected at each occurrence from hydrogen, halogen and C 1-3 alkyl.

[0423] In some embodiments, for the compounds or modified proteins described herein, R 18 or L 1 The substituents are selected from

[0424]

[0425]

[0426]

[0427] In some embodiments, R 18 or L 1 The substituents are selected from In some embodiments, R 18 or L 1 The substituents are selected from In some embodiments, R 18 or L 1 The substituents are selected from In some embodiments, R 18 or L 1 The substituents are selected from

[0428] In some embodiments, R 18 or L 1 The substituents are selected from In some embodiments, R18 or L 1 The substituents are selected from In some embodiments, R 18 or L 1 The substituents are selected from In some embodiments, R 18 or L 1 The substituents are selected from In some embodiments, R 18 or L 1 The substituents are selected from In some embodiments, R 18 or L 1 The substituents are selected from In some embodiments, R 18 or L 1 The substituents are selected from

[0429] In an embodiment, R B2 Selected from In some embodiments, R B2 Selected from

[0430]

[0431] 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). 1 is substituted with F and Cl. In some embodiments, L 1 By an R 18 and one or more halogens. In some embodiments, L 1 R 18 , Cl and F. In some embodiments, L 1 By one or more R 20 (such as three or more R 20 ) is substituted. In some embodiments, L 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 optionally substituted. 1is 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 halogen. 1 is substituted by Cl, F and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein the 3- to 12-membered heterocycle is substituted by halogen. 1 By Cl, F and -O(C 1-3 In some embodiments, L 1 By Cl, F and -O(C 1-3 In some embodiments, L 1 Substituted by Cl, F and -OCH2 (5- to 9-membered heterocyclic ring), wherein the 5- to 9-membered heterocyclic ring is substituted by halogen.

[0432] 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 yes In some embodiments, R 1 -L 1 yes In some embodiments, R 1 -L 1 yes like In some embodiments, R 1 -L 1 yes In some embodiments, R 1 -L 1 yes In some embodiments, R 1 -L 1 yes like In some embodiments, R 1 -L 1 yes In some embodiments, R 1 -L 1 yes like In some embodiments, R 1 -L 1 yes like In some embodiments, R 1 -L 1 yes like

[0433] 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 Selected from Each of which is represented by one or more R 20 (such as one, two, three, four or five R 20 )replace.

[0434] 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 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 In some embodiments, L 2 Selected from bond, C 1-4 Alkylene, 2-membered to 4-membered heteroalkylene, -N(R 19 )-、-C(O)-、-N(R 19 )S(O)2- and -N(R 19 )S(O)-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 In some embodiments, L 2 Selected from bond, C 1-4 Alkylene, 2-membered to 4-membered heteroalkylene and -N(R 19 )-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 In some embodiments, L 2 Selected from bond, C 1-3 Alkylene, -N(H)C 0-3 Alkylene-, -N(C 1-3 Alkyl)C 0-3Alkylene- and -N(C 3-6 Cycloalkyl)C 0-3 Alkylene-, where C 0-3 Alkylene, C 1-3 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, C 1-3 Alkyl and C 1-3 In some embodiments, L 2 Selected from 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-, where C 1-3 Alkylene, C 1-3 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, C 1-3 Alkyl and C 1-3 In some embodiments, L 2 Selected from bond, C 1-3 Alkylene, 2-membered to 3-membered heteroalkylene and -N(R 19 )-. In some embodiments, L 2 is selected from a bond, a 2-membered to 3-membered heteroalkylene group and -N(R 19 )-. In some embodiments, L 2 Selected from -N(H)C 1-3 Alkylene-, -N(C 1-3 Alkyl)C 1-3 Alkylene- and -N(R 19 )-. In some embodiments, L 2 Selected from -N(R 19 )-, -N(CH3)CH2- and -N(CH3)CH(CH3)-. In some embodiments, L 2 Selected from 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-, where C 1-3 Alkylene, C 1-3 Alkyl and C 3-6 Cycloalkyl is optionally substituted by one, two or three radicals selected from halogen, C 1-3 Alkyl and C1-3 In some embodiments, L 2 is selected from the group consisting of a bond, -N(CH3)CH2- and -N(CH3)CH(CH3)-. In some embodiments, L 2 It is a key.

[0435] 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 Selected from C 1-6 Alkyl and C 3-6 In some embodiments, R 2 Selected from -CH3, -CH2CH3, -CH(CH3)2, cyclopropyl, 1-methylcyclopropyl and cyclobutyl.

[0436] 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 Selected from hydrogen and C 1-6 In some embodiments, R 3 It's hydrogen.

[0437] 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 selected from hydrogen, C 1-3 Alkyl and -(C 1-3 alkyl)CN, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl.

[0438] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 Selected from

[0439] In some embodiments, R 7 Selected from In some embodiments, R 7 Selected from

[0440] In some embodiments, R 7 yes

[0441] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 8 is selected from hydrogen, halogen, -CH3, -CH2F, -CHF2 and -CF3. In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 is -CH3. In some embodiments, R 8 is -CH2F. In some embodiments, R 8 is -CHF2. 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 It is -CN.

[0442] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), R 9 is selected from hydrogen, halogen, -CH3, -CH2F, -CHF2 and -CF3. In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 is -CH3. In some embodiments, R 9is -CH2F. In some embodiments, R 9 is -CHF2. 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 It is -CN.

[0443] 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, isoquinolyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl and pyridinyl, each of which is optionally substituted by one or more R 20 Replace; L 1 Is one, two, three or four R 20 substituted 10-membered bicyclic heterocycle; and L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 replace.

[0444] 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),

[0445] R 1 -L 1 yes and

[0446] L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 replace.

[0447] 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),

[0448] R 1 -L 1 yes and

[0449] L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 replace.

[0450] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d),

[0451] R 1 is selected from naphthyl, isoquinolyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl and pyridinyl, each of which is optionally substituted by one or more R 20 replace;

[0452] L 1 is a 10-membered bicyclic heterocycle, which is surrounded by one, two, three or four R 20 replace;

[0453] L 2 Selected from single bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 replace; and

[0454] R 7 yes

[0455] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d),

[0456] R 1 -L 1 yes

[0457] L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 replace; and

[0458] R 7 yes

[0459] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d),

[0460] R 1 -L 1 yes

[0461] L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 replace; and

[0462] R 7 yes

[0463] In some embodiments, for compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d),

[0464] R 1 -L 1 yes

[0465] L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 replace; and

[0466] R 7 yes

[0467] In some embodiments, the compound of formula (II) is selected from

[0468] In some embodiments, the compound of formula (II) is selected from of compounds.

[0469] In some embodiments, the compound of formula (II) is selected from

[0470] In some embodiments, the compound of formula (II) is selected from of compounds.

[0471] In some embodiments, when R 7 When substituted with hydrogen, the compound of formula (II), (II-a), (II-b), (II-c) or (II-d) reversibly binds to K-Ras protein. In some embodiments, when R 7 When substituted with hydrogen, the compound reversibly binds to K-Ras protein, as assessed by HTRF assay, and IC 50 Less than 1000 nM, less than 500 nM, less than 250 nM, less than 100 nM or even lower. In some embodiments, when -C(O)R 7 When substituted with hydrogen, the compounds of Formula (II), (II-a), (II-b), (II-c) or (II-d) reversibly bind to K-Ras protein. In some embodiments, when -C(O)R 7 When substituted with hydrogen, the compound reversibly binds to K-Ras protein, as assessed by HTRF assay, and IC 50 Less than 1000 nM, less than 500 nM, less than 250 nM, less than 100 nM or even lower.

[0472] In some embodiments, the 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 an enantiomeric excess of at least 80%, such as 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%.

[0473] In some embodiments, the compounds disclosed herein, such as compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), 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). In some embodiments, the compounds disclosed herein, such as compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d), 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). 7is a triazole optionally substituted with methyl, -CH2-CN or halogen (e.g., Cl). In some embodiments, the 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), such as 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 halogen (eg, Cl); L 1 quilt Replace; and R 1 yes In some embodiments, the selective and targeted inhibition of K-Ras G12S is due to (1) a warhead (e.g., R in Formula (II), (II-a), (II-b), (II-c), or (II-d) disclosed herein) 7 ) is capable of or readily reacts 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) is linked to R 7 To L 1 These linker atoms can orient the warhead to specifically favor reaction with the serine residue at position 12 of the K-Ras G12S mutant.

[0474] In some embodiments, the subject warheads exhibit at least 1-fold, and in some cases greater than 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, or 20-fold, or even higher, selective binding to K-Ras G12S relative to K-Ras G12D or wild-type K-Ras. In some embodiments, the subject warheads exhibit selectivity and rapid engagement of K-Ras G12S, resulting in at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% or even greater 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, 9 hours, 10 hours, 20 hours, or 24 hours. In some embodiments, the selectivity and rapid engagement of K-Ras G12S is demonstrated by at least 50% engagement within 24 hours. In some embodiments, the subject compounds specifically covalently bind K-Ras G12S, with substantially no detectable labeling of K-Ras G12D, when assayed under comparable conditions.

[0475] Inclusion of the disclosed warheads can enhance the efficacy or potency of K-Ras G12S inhibition. In some embodiments, the subject compounds comprising the subject warheads inhibit K-Ras G12S with greater potency, as demonstrated 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 not comprising the warhead. In some embodiments, the subject compounds comprising the subject warheads inhibit K-Ras G12S with greater potency, as demonstrated 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 not comprising the warhead, as determined in the biochemical assay exemplified in Example 5.

[0476] Inclusion of a warhead disclosed herein can enhance the efficacy or potency of a subject compound in inhibiting the proliferation of cells expressing the K-Ras G12S mutation and / or the K-Ras G12C mutation. In some embodiments, a subject compound comprising a subject warhead inhibits the proliferation of cells expressing the K-Ras G12S mutation and / or the K-Ras G12C mutation with greater potency, as demonstrated 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 not comprising the warhead. In some embodiments, the subject compounds comprising the subject warheads inhibit proliferation of cells expressing the K-Ras G12S mutation and / or the K-Ras G12C mutation with greater potency, as demonstrated 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 not comprising the warhead, as determined in the cytostasis assay exemplified in Example 9.

[0477] In addition to cell proliferation inhibition and highly effective reduction of K-Ras signaling (particularly signaling mediated by K-Ras G12S and / or K-Ras G12C mutants), the compounds disclosed herein also exhibit favorable ADME and / or DMPK properties. Finely tuned pharmacological properties are crucial for improving the efficacy and safety of K-Ras inhibitors in therapeutic clinical applications.

[0478] In some embodiments, the compounds of the present disclosure (e.g., compounds of Formula (II), (II-a), (II-b), (II-c), or (II-d)) exhibit at least one, two, three, or more favorable pharmacological properties. Exemplary superior DMPK properties may include, but are not limited to, improved metabolic stability, reduced hERG propensity, reduced CYP inhibition, increased oral exposure, and reduced serum protein binding (thereby increasing the amount of free and available compound in the subject's blood after administration of the compound). In some embodiments, at least one, two, three, or more favorable pharmacological properties are observed in the subject 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 halogen (e.g., Cl). In some embodiments, at least one, two, three or more favorable pharmacological properties (including microsomal stability) are observed in the subject compounds of Formula (II), (II-a), (II-b), (II-c) or (II-d), wherein R 7is a triazole optionally substituted with methyl, -CH2-CN or halogen (eg Cl), wherein L 1 quilt

[0479] substituted, and wherein R 1 yes

[0480] In some embodiments, the subject compounds exhibit suitable metabolic stability, as determined by a T1 / 2 of metabolism in mouse liver microsomes of greater than 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 metabolism in human liver microsomes of greater than 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 100 minutes, 120 minutes or longer (see Example 11 for experimental procedures). In some other embodiments, a T1 / 2 of at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes or longer is observed in both mouse and human microsomal metabolism assays. It is expected that one or more compounds disclosed herein 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.

[0481] In certain aspects, the present disclosure provides a

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488] or a pharmaceutically acceptable salt or solvate thereof.

[0489] In some embodiments, the present disclosure provides atropisomers of the compounds described herein (e.g., 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 an enantiomeric excess of at least 80%, such as 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%. 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 its corresponding enantiomer or epimer. Typically, such mixtures contain a mixture of the two isomers in a ratio of at least 9:1, preferably at least 19:1. In some embodiments, the atropisomer is provided in an enantiomeric excess of at least 96%, meaning that the compound has less than 2% of the corresponding enantiomer. In some embodiments, the atropisomer is provided in a diastereomeric excess of at least 96%, meaning that the compound has less than 2% of the corresponding diastereomer.

[0490] The term "atropisomer" refers to a conformational stereoisomer that occurs when rotation about a single bond in a molecule is prevented, restricted, or greatly slowed due to steric interactions with other parts of the molecule, and wherein the substituents at either end of the single bond are asymmetric (i.e., optical activity is produced without the need for an asymmetric carbon center or stereocenter). When the barrier to rotation about a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species can be permitted. Atropisomers are enantiomers (or diastereomers) that do not have a single asymmetric atom. Atropisomers are generally considered stable if the barrier to interconversion is high enough to allow the atropisomers to undergo little or no interconversion at room temperature for at least one week (preferably at least one year). In some embodiments, when the atropisomer compound is in a substantially pure form (which is typically a solid state), the atropisomer compounds of the present disclosure do not undergo more than about 5% interconversion of their opposite atropisomer within one week at room temperature. In some embodiments, the atropisomer compounds of the present disclosure do not undergo more than about 5% interconversion with their opposite atropisomers within one year at room temperature (about 25° C.). The present chemical entities, pharmaceutical compositions, and methods are intended to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single atropisomers, and intermediate mixtures.

[0491] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0492] In some embodiments, the compounds described herein possess acidic or basic groups and therefore 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 its free form with a suitable acid or base and isolating the salt thus formed.

[0493] In some embodiments, the compounds described herein exist in the form of solvates. In some embodiments, methods of treating a disease are performed by administering such solvates. Methods of treating a disease by administering such solvates as pharmaceutical compositions are also described herein.

[0494] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. 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 an aqueous solvent / organic solvent mixture using an organic solvent, including but not limited to dioxane, tetrahydrofuran, or MeOH. In addition, provided herein are compounds that exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.

[0495] In certain aspects, the present disclosure provides a formula BL BE -E compound, wherein:

[0496] B is a monovalent form of a compound described herein;

[0497] L BE is a covalent linker bonded to B and E; and

[0498] E is the monovalent form of the degradation enhancer.

[0499] "Degradation enhancer" is a compound that can bind to a ubiquitin ligase protein (e.g., an E3 ubiquitin ligase protein), or a compound that can bind to a protein that can bind to a ubiquitin ligase protein to form a protein complex that can conjugate the ubiquitin protein to the target protein. In some embodiments, the degradation enhancer can bind to an E3 ubiquitin ligase protein or a protein complex comprising an E3 ubiquitin ligase protein. In some embodiments, the degradation enhancer can bind to an E2 ubiquitin conjugating enzyme. In some embodiments, the degradation enhancer can bind to a protein complex comprising an E2 ubiquitin conjugating enzyme and an E3 ubiquitin ligase protein.

[0500] In some embodiments, the degradation enhancer is capable of binding to a protein 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, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von-Hippel-Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MKRN1, CMA (chaperone-mediated autophagy), SCFb-TRCP (slip-retaining protein-F box (β-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAP1 (inhibitor of apoptosis protein 1), APC / C (anaphase-promoting complex / cyclin), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4 CRBN) ubiquitin ligases, 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 enhancer is capable of binding to a protein selected from the group consisting of 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 enhancer is a compound described in Ishida and Ciulli, SLAS Discovery 2021, Vol. 25(4)484-502, which is incorporated by reference in its entirety for any purpose, 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.

[0501] In some embodiments, the degradation enhancer is a compound described in US20180050021, WO2016146985, WO2018189554, WO2018119441, WO2018140809, WO2018119448, WO2018119357, WO2018118598, WO2018102067, WO201898280, WO2 01889736, WO201881530, WO201871606, WO201864589, WO201852949, WO2017223452, WO20172044 45. WO2017197055, WO2017197046, WO2017180417, WO2017176958, WO201711371, WO2018226542, WO2018223909, WO2018189554, WO2016169989, WO2016146985, CN105085620B, CN106543185B, U S10040804, US9938302, US10144745, US10145848, US9938264, US9632089, US9821068, US975852 2. US9500653, US9765019, US8507488, US8299057, US20180298027, US20180215731, US20170065719, US20170037004, US20160272639, US20150291562, or US20140356322, each of which is incorporated by reference in its entirety for any purpose.

[0502] In some embodiments, L BE Yes-L BE1 -L BE2 -L BE3 -L BE4 -L BE5 -;

[0503] L BE1 , L BE2 , L BE3 , L BE4 and 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 Alkynylidene, C 1-6 Halogenated alkylene, C 3-12 Cycloalkylene, C 1-11 Heterocycloalkylene, C 6-12 Arylene or C 1-11 Heteroarylene, wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 1-6 Halogenated alkylene, C 3-12 Cycloalkylene, C 1-11 Heterocycloalkylene, C 6-12 Arylene or C 1-11 Heteroarylene is optionally substituted by one, two or three R 20 substituted; and wherein (-OC 1-6 alkyl) z and (-C 1-6 Alkyl-O) z - Each C in 1-6 The alkyl group is optionally substituted by one, two or three R 20 replace; and

[0504] z is independently an integer from 0 to 10.

[0505] In some embodiments, L BE is -(O-C2 alkyl) z , and z is an integer from 1 to 10. In some embodiments, L BE is -(C2 alkyl-O-) z , and z is an integer from 1 to 10. In some embodiments, L BE Yes - (CH2) zz1 L BE2 (CH2O) zz2 -, where L BE2 is a bond, a 5-membered or 6-membered heterocyclic group, a phenylene group, -C 2-4 alkylene, -SO2- or -NH-; and zz1 and zz2 are independently an integer from 0 to 10. In some embodiments, L BE Yes - (CH2)zz1 (CH2O) zz2 -, wherein zz1 and zz2 are each independently an integer from 0 to 10. In some embodiments, L BE is a PEG linker (e.g., a divalent linker of 1 to 10 ethylene glycol subunits). In some embodiments, E is selected from

[0506] In one embodiment, E is selected from

[0507] The monovalent form of the compound.

[0508] Chemical entities as described herein can be synthesized according to one or more illustrative schemes and / or techniques known in the art herein. Materials used herein are commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or any specific substituents, and these schemes are for illustrative purposes. Although various steps are described and depicted in schemes 1 and 2, in some cases, these steps can be carried out in an order different from that shown in schemes 1 and 2. Various modifications can be made to these synthesis reaction schemes, and with reference to those skilled in the art of the present disclosure, various modifications will be expected. Unless otherwise noted, the numbers or R groups in each scheme are generally the same as those defined elsewhere herein.

[0509] Unless otherwise indicated, the reactions described herein are carried out at atmospheric pressure, generally in the temperature range of -10°C to 200°C. Furthermore, unless otherwise indicated, reaction times and conditions are intended to be approximate, e.g., at a temperature range of about -10°C to about 110°C, over a period of about 1 to about 24 hours, at about atmospheric pressure; reactions left to run overnight last an average of about 16 hours.

[0510] Generally speaking, the compounds of the present disclosure can be prepared by the following reaction scheme:

[0511] Solution 1

[0512]

[0513] 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 used to form a C-N bond between an appropriately 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 reveals the secondary amine 1d, which can then react with compound 1e in the presence of a suitable base (e.g., DIPEA) to provide a compound of Formula 1f.

[0514] Option 2

[0515]

[0516] 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 used to form a C-N bond between an appropriately 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 provide 2b1, 2b2, 2b3, or 2b4, respectively. Removal of the N-protecting group reveals the secondary amine 2c1, 2c2, 2c3, or 2c4, which can then be reacted with R in the presence of triphosgene (bis(trichloromethyl)carbonate (BTC)) and pyridine. 7 -H to provide compounds of Formula 2d1, 2d2, 2d3 or 2d4.

[0517] In some embodiments, compounds of the present disclosure, such as compounds of the formula 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.

[0518] Table 1

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554] The compounds of Table 1 are depicted with straight bonds, wedge-shaped bonds, and / or cut wedge-shaped bonds. It should be understood that the compounds depicted in Table 1 encompass all possible stereoisomers, including atropisomers of the compounds of Table 1. In some cases, the relative stereochemistry of one or more stereocenters of the compound has been determined; 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. Therefore, it should be understood that if two or more compound numbers in Table 1 are provided with the same illustrated structure, a different stereoisomer or mixture of stereoisomers of the illustrated structure is represented by each compound number. Provided The compound is a substantially pure single atropisomer (R).

[0555] 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 also inhibit Ras proteins, Kras proteins, or mutant forms thereof. In some embodiments, the subject compounds selectively inhibit Kras mutants relative to wild-type Kras. In some embodiments, the IC50 of the subject compounds to Kras mutants (e.g., including G12S) is less than about 5 μM, less than about 1 μM, less than about 500nM, less than about 250nM, less than about 100nM, less than about 50nM or even lower, as measured in an in vitro assay known in the art or exemplified herein. In some embodiments, the subject compounds are covalently bound to Kras mutants (e.g., KrasG12S and / or KrasG12C).

[0556] In some embodiments, the compounds of the present disclosure can reduce Ras signaling output. Such reduction can be demonstrated by one or more of the following: (i) the steady-state level of GDP-bound Ras protein increases; (ii) the steady-state level of GTP-bound Ras protein decreases; (iii) the reduction of phosphorylated AKTs473, (iv) the reduction of phosphorylated ERKT202 / y204, (v) the reduction of phosphorylated S6S235 / 236, and (vi) Ras-driven tumor cells (e.g., tumor cells derived from tumor cell lines disclosed herein) The reduction (e.g., inhibition) of cell growth. In some cases, the reduction of Ras signaling output can be demonstrated by two, three, four, five or all of the above (i)-(vi).

[0557] It should be understood that the different aspects of the present disclosure can be understood individually, collectively, or in combination with each other. Each aspect described herein can be applied to any specific application disclosed herein. The material composition comprising the compound of any chemical formula disclosed in the compound section of the present disclosure can be used in the method section, including the use and production methods disclosed herein, or vice versa.

[0558] method

[0559] The compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are Ras inhibitors that can inhibit Ras proteins, such as wild-type Ras or Ras mutant proteins from K-Ras, H-Ras, or N-Ras (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D). The compounds disclosed herein, including pharmaceutically acceptable salts or solvates thereof, have a wide range of applications in therapy, diagnosis, and other biomedical research.

[0560] 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.

[0561] In certain aspects, the present disclosure provides a method of treating cancer comprising a Ras mutant (e.g., G12S, G12C, and / or G13C) protein, the method comprising inhibiting the Ras mutant protein in the subject by administering a compound to the subject, wherein the compound is characterized in that upon contact with the Ras mutant protein, the activity or function of the Ras mutant protein is inhibited (e.g., partially inhibited or fully inhibited), such that the inhibited Ras mutant protein exhibits reduced Ras signaling output (e.g., compared to a corresponding Ras protein not contacted by the compound).

[0562] In certain aspects, the present disclosure provides a method 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.

[0563] In certain aspects, the present disclosure provides a method of inhibiting cell growth, comprising administering an effective amount of a compound as described herein or a pharmaceutically acceptable salt or solvate thereof to a cell expressing a Ras (e.g., K-Ras) protein, thereby inhibiting the growth of the cell. In some embodiments, the subject method comprises administering an additional agent to the cell.

[0564] In certain aspects, the present disclosure provides a method 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, 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 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 a 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.

[0565] In certain aspects, the present disclosure provides a method of 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 against the Ras protein of less than 10 μM, such as less than 5 μM, 1 μM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 50 pM, 10 pM or less.

[0566] In certain aspects, the present disclosure provides a method of treating Ras-mediated cancer in a subject in need thereof, comprising administering to the subject a 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 (such as a compound of formula (II)), or an embodiment thereof or a pharmaceutically acceptable salt or solvate thereof.

[0567] In some embodiments, the cancer is a solid tumor.In some embodiments, the cancer is a hematological cancer.

[0568] In practicing any of the methods disclosed herein, the Ras target to which the subject compound covalently or reversibly binds can be a Ras mutant (e.g., G12S, G12C, and / or G13C), including mutants of K-Ras, H-Ras, or N-Ras. In some embodiments, the method of treating cancer can be applied to treat solid tumors or hematological cancers. In some embodiments, the cancer treated can be, but is not limited to, prostate cancer, brain cancer, colon cancer, rectal cancer, renal cell carcinoma, liver cancer, various lung cancers including non-small cell lung cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head cancer or neck cancer, skin or intraocular malignant 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, non-Hodgkin's lymphoma, endocrine System cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, solid tumors in children, bladder cancer, kidney or ureteral cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, combinations of said cancers, and metastatic lesions of said cancers. In some embodiments, it is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer. In some embodiments, it is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from 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 (P-ALL), The invention also includes a hematological cancer comprising one or more of: a hematologic malignancy, a blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, a malignant lymphoproliferative condition, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and a preleukemia.In some embodiments, it is 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 one or more cancers selected from 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).

[0569] Any of the methods of treatment disclosed herein can be administered alone or in combination with another therapy or another agent. "Combination" means a method comprising (a) formulating a subject composition containing the subject compound and another agent, or (b) using the subject composition separately from another agent as an overall treatment regimen. "Combination" means that another therapy or agent is administered simultaneously, concurrently, or sequentially (without specific time limits) with the subject composition comprising a compound disclosed herein, wherein such combined administration provides a therapeutic effect.

[0570] In some embodiments, the subject treatment method is combined with surgery, cell therapy, chemotherapy, radiation and / or immunosuppressive agents. In addition, the compositions of the present disclosure can be combined with other therapeutic agents, such as other anticancer agents, antiallergic agents, antinausea agents (or antiemetics), analgesics, cell protectants, immunostimulants and combinations thereof. In one embodiment, the subject treatment method is combined with a chemotherapeutic agent.

[0571] 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, decarbazine, melphalan, ifosfamide, temozolomide), immune cell antibodies (e.g., alemtuzumab, gemtuzumab), Monoclonal antibody (gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab), antimetabolites (including, for example, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), TNFR glucocorticoid-induced TNFR-related protein (GITR) agonists, proteasome inhibitors (e.g., aclacinomycin A, gliotoxin or bortezomib), immunomodulators such as thalidomide or thalidomide derivatives (e.g., lenalidomide). Additional chemotherapeutic agents contemplated for use in combination include busulfan Busulfan injection cladribine Cyclophosphamide (( or ), cytarabine, cytosine arabinoside Cytarabine liposome injection daunorubicin hydrochloride Daunorubicin citrate liposome injection Dexamethasone, doxorubicin hydrochloride Etoposide Fludarabine phosphate Hydroxyurea Idarubicin Mitoxantrone Gemtuzumab Ozogamicin Anastrozole Bicalutamide bleomycin sulfate Busulfan injection Capecitabine N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin carmustine Chlorambucil Cisplatin Dacarbazine Dactinomycin (Actinomycin D, Cosmegan, dexamethasone, docetaxel) 5-Fluorouracil Flutamide Tezacitibine, gemcitabine (difluorodeoxycytidine), ifosfamide Irinotecan L-asparaginase Leucovorin calcium, melphalan 6-Mercaptopurine methotrexate Mitoxantrone Mylotarg, paclitaxel Phoenix (yttrium-90 / MX-DTPA), pentostatin, polyphenylpropanone 20, and carmustine implants Tamoxifen citrate teniposide 6-thioguanine, thiotepa, tirapazamine Topotecan Hydrochloride for Injection Vinblastine vincristine and vinorelbine

[0572] Anticancer agents of particular interest for combination with the compounds of the present disclosure include: anthracyclines; alkylating agents; antimetabolites; drugs that inhibit the calcium-dependent phosphatase calcineurin or the p70S6 kinase FK506 or inhibit p70S6 kinase; mTOR inhibitors; immunomodulators; anthracyclines; vinca alkaloids; proteasome inhibitors; GITR agonists; protein tyrosine phosphatase inhibitors; CDK4 kinase inhibitors; BTK inhibitors; MKN kinase inhibitors; DGK kinase inhibitors; or oncolytic viruses.

[0573] Exemplary antimetabolites include, but are not limited to, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors: methotrexate 5-Fluorouracil Floxuridine Cytarabine ( Tarabine PFS), 6-mercaptopurine ), 6-thioguanine (thioguanine ), fludarabine phosphate Pentostatin pemetrexed raltitrexed Cladribine clofarabine Azacitidine Decitabine and gemcitabine Preferred antimetabolites include cytarabine, clofarabine, and fludarabine.

[0574] Exemplary alkylating agents include, but are not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes: Aminouracil mustard Uracilnitrogen ), chlormethine Cyclophosphamide ( Revimmune TM ), ifosfamide Melphalan Chlorambucil Pipobroman Triethylenemelamine Triethylenethiophosphate, Temozolomide Thiotepa Busulfan Carmustine lomustine Streptozocin and dacarbazine Additional exemplary alkylating agents include, but are not limited to, oxaliplatin Temozolomide ( and ); Dactinomycin (also known as actinomycin-D, ); melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, ); Altretamine (also known as hexamethylmelamine (HMM), ); Carmustine Bendamustine Busulfan ( and ); carboplatin Lomustine (also known as CCNU, ); Cisplatin (also known as CDDP, and ) ; Chlorambucil Cyclophosphamide ( and ); Dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, ); Hexamethylmelamine (also known as hexamethylmelamine (HMM), ); ifosfamide Prednumustine; Procarbazine Dichloromethyldiethylamine (also known as nitrogen mustard, mustine, and dichloromethyldiethylamine hydrochloride, ); Streptozotocin Thiotepa (also known as thiophosphoamide, TESPA, and TSPA, ); cyclophosphamide and Bendamustine HCl

[0575] In some aspects, the compositions provided herein can be administered in combination with radiotherapy such as radiation. Whole 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 20 Gy at the most. Radiation can be whole body radiation or partial body radiation. When radiation is whole body radiation, it may be uniform or uneven. For example, when radiation may not be uniform, a narrower area of ​​the body, such as the neck, may receive a higher dose than a wider area, such as the buttocks.

[0576] When desirable, immunosuppressant can be used in conjunction with theme treatment method.Exemplary immunosuppressant includes but is not limited to cyclosporin (cyclosporin), azathioprine (azathioprine), methotrexate, mycophenolate mofetil and FK506, antibody or other immune ablative agent (immunoablative agent) such as CAMPATH, anti-CD3 antibody (for example, muromonab (muromonab), otelixizumab (otelixizumab)) or other antibody therapy, cytotoxin, fludarabine, cyclosporin, FK506, rapamycin (rapamycin), mycophenolic acid, steroid, FR901228, cytokine and irradiation, peptide vaccine and its any combination.According to the subject of the present disclosure, the various methods described above can include the administration of at least one immunomodulator. In certain embodiments, at least one immunomodulator is selected from immunostimulators, checkpoint immune blockers (e.g., immune checkpoint genes such as PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIR and CD39 blockers or inhibitors), radiotherapy agents, chemotherapy agents and combinations thereof. In some embodiments, the immunostimulator is selected from IL-12, agonist co-stimulatory monoclonal antibodies and combinations thereof. In one embodiment, the immunostimulator is IL-12. In some embodiments, the agonist costimulatory monoclonal antibody is selected from anti-4-1BB antibodies (e.g., urelumab, PF-05082566), anti-OX40 antibodies (pogalizumab, tavolixizumab, PF-04518600), anti-ICOS antibodies (BMS986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof. In one embodiment, the agonist costimulatory monoclonal antibody is an anti-4-1BB antibody. In some embodiments, the checkpoint immune blocker is selected from 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 blocker is an anti-PD-L1 antibody. In some cases, the compounds of the present disclosure can be combined with bone marrow transplantation, the use of chemotherapy agents such as fludarabine, external beam radiotherapy (XRT), cyclophosphamide or antibodies such as OKT3 or CAMPATH T cell purification therapy (for example, before, simultaneously with or after) administered to the subject. In some cases, amplified cells can be administered before or after surgery. Alternatively, the composition comprising the compound as described herein can be administered together with an immunostimulant. An immunostimulant can be a vaccine, colony stimulating agent, interferon, interleukin, virus, antigen, co-stimulator, immunogenic agent, immunomodulator or immunotherapy agent. An immunostimulant can be a cytokine such as an interleukin. One or more cytokines can be introduced together with the modified cells provided herein. Cytokines can be used to strengthen the function of modified T lymphocytes (including adoptively transferred tumor-specific cytotoxic T lymphocytes) to expand within the tumor microenvironment. In some cases, IL-2 can be used to promote the expansion of modified cells as described herein. It is also possible to use cytokines such as IL-15. It is also possible to utilize other related cytokines in the field of immunotherapy, such as IL-2, IL-7, IL-12, IL-15, IL-21 or any combination thereof. The interleukin can be IL-2 or aldesleukin (aldeskeukin). Aldesleukin can be administered in low doses or high doses. The high-dose aldesleukin regimen can be directed to administering aldesleukin intravenously every 8 hours with about 0.037mg / kg (600,000IU / kg) when tolerated, for up to about 14 doses. Immunostimulants (e.g., aldesleukin) can be administered within 24 hours after cell administration. Immunostimulants (e.g., aldesleukin) can be administered in an infusion form in about 15min about every 8 hours after cell infusion, for up to about 4 days. The immunostimulant (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 instances, 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.

[0577] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are combined or co-administered with one or more pharmacologically active agents selected from (1) inhibitors of MEK (e.g., MEK1, MEK2) or its mutants (e.g., trametinib, cometinib, bemetinib, selumetinib, rameltetinib, AZD6244); (2) inhibitors of epidermal growth factor receptor (EGFR) and / or its mutants (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, dapoxetine, tadalafil, tadalafil, seletinib, seletinib, rameltetinib, AZD6244); (3) inhibitors of epidermal growth factor receptor (EGFR) and / or its mutants (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, seletinib, seletinib, seletinib, seletinib, seletinib, AZD6244); (4) inhibitors of EGFR and / or its mutants (e.g., levofloxacin, levofloxacin, tadalafil, seletinib ... (e.g., tadalafil ... 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, such as, for example, palbociclib, ribociclib, abecilib); (8) anti-angiogenic drugs (e.g., anti-VEGF antibodies, such as, for example, bevacizumab); (9) topoisomerase inhibitors (e.g., epipodophyllotoxins, such as, for example, etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone); (10) platinum-containing compounds (e.g., cisplatin, oxaliplatin, carboplatin); (11) 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) Inhibitors of NTRK1 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); (19) inhibitors of ERK and / or its mutants (e.g., ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, ravoxertinib); (20) MDM2 inhibitors (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-BET762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645); (23) inhibitors of IGF1 / 2 and / or IGF1-R (e.g., xentuzumab, MEDI-573); (24) inhibitors of CDK9 (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B); B), AT7519, dinaciclib, SNS-032); (25) inhibitors of farnesyl transferase (e.g., tipifarnib); (26) inhibitors of the SHIP pathway, including SHIP2 inhibitors and SHIP1 inhibitors; (27) inhibitors of SRC (e.g., dasatinib); (28) inhibitors of JAK (e.g., tofacitinib);(29) PARP inhibitors (e.g., 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) KRAS Inhibitors of the G12C mutant (e.g., including but not limited to AMG510, MRTX849, and any covalent inhibitor that binds to cysteine ​​residue 12 of Kras, the structure of which is known) (e.g., as described in US20180334454, US20190144444, US20150239900, US10246424, US20180086753, WO2018143315, WO2018206539, WO201911 07519, WO2019141250, WO2019150305, US9862701, US20170197945, US20180086753, US10144724, US20190 055211, US20190092767, US20180127396, US20180273523, US10280172, US20180319775, US20180273515, U S20180282307, US20180282308, WO2019051291, WO2019213526, WO2019213516, WO2019217691, WO2019241 157. WO2019217307, WO2020047192, WO2017087528, WO2018218070, WO2018218069, WO2018218071, WO2020 027083, WO2020027084, WO2019215203, WO2019155399, WO2020035031, WO2014160200, WO2018195349, WO2018112240, WO2019204442, WO2019204449, WO2019104505, WO2016179558, WO2016176338, or Ras G12C inhibitors described in related patents and applications, each of which 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-BEZ235-AN); (38) MAR PK 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, such as SHP2 inhibitors (e.g., RMC-4630, ERAS-601, In some embodiments, the Ras inhibitors described herein (e.g., compounds, salts, or solvates of Formula (II)) are combined or co-administered with one or more checkpoint immune blockers (e.g., anti-PD-1 and / or anti-PD-L1 antibodies, anti-CLTA-4 antibodies). In some embodiments, a Ras inhibitor described herein (e.g., a compound, salt, or solvate of Formula (II)) is combined or co-administered with one or more pharmacologically active agents, including inhibitors 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 compound described herein that is capable of binding to a Ras protein (e.g., KRAS, a mutant Ras protein) to modulate the activity of such a Ras mutant (e.g., G12C, G12S, or G13C) may be combined or co-administered 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 combined or co-administered 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 combined or co-administered 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 combined or co-administered 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 combined or co-administered with a compound described herein (e.g., a compound capable of binding to a Ras protein) is selected from RMC-5845 and BI-1701963 SOS (e.g., SOS1, SOS2) inhibitors. In some embodiments, the additional pharmacologically active agent used in combination or co-administered with a compound as described herein (e.g., a compound capable of binding to a Ras protein) is an SOS (e.g., SOS1, SOS2) inhibitor described in WO2021092115, WO2018172250, WO2019201848, WO2019122129, WO2018115380, WO2021127429, WO2020180768 or WO2020180770, all of which are incorporated herein by reference in their entirety for all purposes.

[0578] In some embodiments, any compound described herein that is capable of binding to a Ras protein (e.g., Kras) to modulate the activity of such a Ras protein can be combined or co-administered with one or more checkpoint immune blockers (e.g., anti-PD-1 and / or anti-PD-L1 antibodies, anti-CLTA-4 antibodies).

[0579] In some embodiments, the compounds described herein (e.g., compounds, salts, or solvates of Formula (II)) are combined or administered in combination with one or more pharmacologically active agents comprising an inhibitor of: (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); or (3) 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); or (4) 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); or (5) 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); or (6) SHP2 or a mutant thereof (e.g., 6-(4-amino-4-methylpiperidin-1-yl)-3-(2, -13909 / BBP-398, SHP099, RMC-4550); (3) SHC or its mutants (e.g., PP2, AID371185); (4) GAB or its mutants (e.g., GAB-0001); (5) GRB or its mutants; (6) JAK or its mutants (e.g., tofacitinib); (7) A-RAF, B-RAF, C-RAF or their mutants (e.g., RAF-709, LY-3009120); (8) BRAF or its mutants (e.g., sorafenib, vemurafenib); ), dabrafenib, encorafenib, regorafenib, GDC-879; (9) MEK or its mutants (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib, AZD6244); (10) ERK or its mutants (e.g., ulixertinib, MK-8353, LTT462, AZD 0364, SCH772984, BIX02189, LY3214996, ravoxertinib); (11) PI3K or its mutants (e.g., idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, NVP-BEZ235-AN);(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, (14) c-MET or its mutants (e.g., K252a, SU11274, PHA665752, PF2341066); (15) ALK or its mutants (e.g., crizotinib, alectinib, entrectinib, brigatinib); (16) FGFR1, FGFR-2, FGFR-3, FGFR-4 or its mutants mutants (e.g., nintedanib); (17) BCR-ABL or its mutants (e.g., imatinib, dasatinib, nilotinib); (18) ErbB2 (Her2) or its mutants (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (19) AXL or its mutants (e.g., R428, amuvatinib, X L-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, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645); (26) IGF1, IGF2, IGF1R or mutants thereof (e.g., xentuzumab, MEDI-573);(27) CDK9 or its mutants (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B, AT7519, dinaciclib, SNS-032); or (28) CDK4 / 6 (e.g., palbociclib, ribociclib, abemaciclib).

[0580] In combination therapy, the compounds provided herein and the other anticancer agent can be administered simultaneously, concurrently, or sequentially without specific time limits, wherein such administration provides therapeutically effective levels of both compounds in the patient's body.

[0581] In some embodiments, the compounds of the present invention and other anticancer agents are usually administered in any order by a suitable route (such as infusion or oral). The dosage regimen can be changed according to the stage of the disease, the patient's physical health level, the safety profile of the single drug and the tolerance of the single drug, and other criteria known to the attending physician and medical practitioners of the combination. Depending on the specific cycle to be used for treatment, the compounds of the present invention and other anticancer agents can be administered within a few minutes, hours, days or even weeks apart from each other. In addition, the cycle can be included in the treatment cycle, more often administering one drug than another, and administering it with different doses each time the drug is administered.

[0582] In some cases, the treatment regimen may be administered based on the subject's weight. In subjects determined to be obese (BMI>35), actual body weight may need to be utilized. BMI is calculated as follows: BMI = weight (kg) / [height (m)] 2 .

[0583] Body weight can be calculated for males as 50 kg + 2.3 * (number of inches over 60 inches) or for females as 45.5 kg + 2.3 (number of inches over 60 inches). For subjects who are 20% over their ideal body weight, an adjusted body weight can be calculated. Adjusted body weight can be the sum of ideal body weight + (0.4 x (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 as follows: BSA (m 2 )=√height(cm)*weight(kg) / 3600.

[0584] In one aspect, a method of modulating the activity of a Ras (e.g., K-Ras) protein is provided, comprising contacting the Ras protein with an effective amount of a compound as 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 method comprises administering an additional agent or therapy.

[0585] In some embodiments, a method of modulating the activity of a Ras protein comprises contacting the Ras protein with an effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the modulation comprises inhibiting the activity of a Ras (e.g., K-Ras) protein. In some embodiments, a method of modulating the activity of a Ras protein (including Ras mutants (e.g., G12S, G12C, and / or G13C) proteins of K-Ras, H-Ras, and N-Ras) comprises contacting the Ras protein with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0586] In some embodiments, a method is provided for reducing Ras signaling output in a cell by contacting the cell with a compound described herein. 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 mutants (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 demonstrated by two, three, four, five, six, or all of the above (i)-(vii). In some embodiments, the reduction in any one or more of (i)-(vii) 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, 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-foldThe reduction in cell growth can be demonstrated using tumor cells or cell lines. Tumor cell lines can be derived from tumors in one or more tissues such as pancreas, lung, ovary, bile duct, 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, but are not limited to, A549 (e.g., K-Ras G12S), 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 G12V), and K-Ras G12F. 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 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.86.86 (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)).

[0587] In one aspect, a modified Ras mutant protein is provided, comprising a compound described herein (or a residue of a compound described herein, wherein the residue of the compound is modified by an independent compound described herein after covalent bonding to the amino acid) covalently bonded to an amino acid corresponding to position 12 or 13 of SEQ ID No: 1. In some embodiments, such covalently bonded modified Ras mutant proteins exhibit reduced Ras signaling output (e.g., compared to a corresponding unmodified Ras mutant without the covalently bonded compound). In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently bonded 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 bonded to an amino acid residue corresponding to position 12 or 13 of SEQ ID No: 1, wherein the Ras mutant protein is a human protein selected from KRasG12C, KRasG12S, KRasG13C, and KRasG13S. In some embodiments, the modified Ras mutant protein comprises a compound as described herein covalently bonded to an amino acid residue at position 12 or 13 corresponding to SEQ ID No: 1, wherein 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 as described herein covalently bonded to an amino acid residue at position 12 or 13 corresponding to SEQ ID No: 1, wherein the Ras mutant protein is a human KRas G12S protein. In some embodiments, the modified Ras mutant protein comprises a compound as described herein covalently bonded to an amino acid residue at position 12 or 13 corresponding to SEQ ID No: 1, wherein the Ras mutant protein is a human KRas G12C protein. In some embodiments, the modified Ras mutant protein includes a compound as described herein covalently bonded to a protein of SEQ ID No. 4. In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently bonded to the serine residue at position 12 of SEQ ID No. 4. In some embodiments, the modified Ras mutant protein comprises a compound described herein covalently bonded to the cysteine ​​residue at position 12 corresponding to SEQ ID No. 1, wherein 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 bonded to an amino acid residue corresponding to position 12 or 13 of SEQ ID No: 1, wherein 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 bonded to an amino acid residue corresponding to position 12 or 13 of SEQ ID No: 1, wherein the Ras mutant protein is a mammalian protein (including a human protein) selected from HRas G12C, HRas G12S, HRas G13C, and HRas G13S. It should be understood that the compounds described herein can be modified after covalently binding to an amino acid (e.g., a mutant amino acid other than G) corresponding to position 12 or 13 of human KRas (e.g., SEQ ID. No: 1). The subject compounds of the present disclosure encompass compounds described herein immediately prior to covalent bonding to a Ras mutant protein and the resulting compounds covalently bonded to a modified Ras mutant protein. For example, when the ring of the compound opens upon covalent bonding to the amino acid corresponding to position 12 or 13 of SEQ ID No: 1, the subject compounds of the present disclosure can covalently bond to the mutant Ras protein to form a modified Ras mutant protein. Compounds before and after such covalent bonding are considered subject compounds of the present disclosure.

[0588] In the embodiments of the modified Ras mutant proteins described herein, the reduced Ras signaling output is demonstrated by a reduction in one or more outputs selected from: (i) increased steady-state levels of GDP-bound modified protein; (ii) reduction in phosphorylated AKTs473, (iii) reduction in phosphorylated ERK T202 / Y204, (iv) reduction in phosphorylated S6S235 / 236, (v) decreased cell growth of tumor cells expressing the Ras mutant protein (e.g., G12C, G12S, G13C, or G13S), and (vi) reduction in Ras interaction with Ras pathway signaling proteins.

[0589] In some embodiments, the modified Ras mutant proteins described herein are 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 at position 12 corresponding to SEQ ID No: 4. In some embodiments, the compound comprises a retaining group and a leaving group, and wherein the contacting results in the release of the leaving group and the formation of the modified protein. In some embodiments, the compound selectively labels the serine residue at position 12 corresponding to SEQ ID No. 4 relative to a valine (G12V) residue or a glycine residue (wild-type Kras) at the same position (G12S mutant). In some embodiments, the compound selectively labels a serine residue at least 1, 2, 3, 4, 5, or 10 times more than (i) an aspartic acid residue of a K-Ras G12D mutant protein (the aspartic acid corresponding to residue 12 of SEQ ID NO: 2) and / or (ii) a valine residue of a K-Ras G12V mutant protein (the valine corresponding to residue 12 of SEQ ID NO: 3), when assayed under comparable conditions. In some embodiments, the compound selectively labels a cysteine ​​residue at position 12 (a K-Ras G12C mutant in which glycine is substituted with cysteine) relative to a valine residue (K-Ras G12V) or a glycine residue (wild-type K-Ras) at the same position. In some embodiments, the compound selectively labels a cysteine ​​residue or a serine residue of a K-Ras mutant (i.e., K-Ras G12C or K-Ras G12S) at least 1, 2, 3, 4, 5, or 10 times or more compared to (i) an aspartic acid residue of a K-Ras G12D mutant protein (the aspartic acid corresponding to residue 12 of SEQ ID NO:2) and / or (ii) a valine residue of a K-Ras G12V mutant protein (the valine corresponding to residue 12 of SEQ ID NO:3) when assayed under comparable conditions.

[0590] In embodiments of the modified Ras mutant proteins described herein, the compound covalently binds in vitro to the serine residue of the unmodified Ras G12S protein corresponding to position 12 of SEQ ID No: 4. In embodiments of the modified Ras mutant proteins described herein, the compound covalently binds in vivo to the serine residue of the unmodified K-Ras G12S protein corresponding to position 12 of SEQ ID No: 4. In embodiments of the modified Ras mutant proteins described herein, the compound covalently binds in vitro or in vivo to the cysteine ​​residue of the unmodified Ras G12C protein corresponding to position 12 of the K-Ras G12C mutant (in which the glycine residue is substituted with cysteine). In embodiments of the modified Ras mutant proteins described herein, the compound covalently binds in vitro or in vivo to the serine residue and cysteine ​​residue (at position 12) of the unmodified K-Ras G12S and K-Ras G12C proteins, respectively.

[0591] In one aspect, a method of 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, HRasG12S, HRas G13C, or HRas G13S) is provided, the method comprising modifying the Ras mutant protein in the subject by administering to the subject a compound described herein, 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 or 13 of SEQ ID No: 1, such that the modified Ras mutant protein exhibits reduced Ras signaling output (e.g., compared to a control, such as an unmodified Ras mutant protein that is not covalently bound to any compound, such as a compound disclosed herein)).

[0592] In some aspects, the subject compound exhibits one or more of the following characteristics: it is capable of reacting with a mutant residue of 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 covalently modifying such Ras mutant and / or it comprises a moiety that readily reacts with a nucleophilic amino acid residue at position 12 or 13 corresponding to SEQ ID No: 1 (e.g., KRas G12C, KRas G12S, KRas G13C, KRas G13S, NRas G12C, NRas G12S, NRasG13C, NRas G13S, HRas G12C, HRas G12S, HRas G13C, or HRas G13S). In some embodiments, when used to modify a Ras mutant protein, the subject compounds reduce the signaling output of the Ras protein. In some embodiments, the subject compounds exhibit an IC50 of less than 10 μM, such as less than 5 μM, 1 μM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 50 pM, 10 pM or less (for a 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), as determined by a reduction in Ras::SOS1 interaction).

[0593] In some embodiments, the modified Ras mutant proteins disclosed herein exhibit reduced Ras signaling output. The reduction in signaling output can be determined by various methods known in the art. For example, 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 analysis) can be used to detect and / or quantify the phosphorylation of a substrate or a specific amino acid residue thereof. A number of readouts can demonstrate a reduction in Ras signaling output, including but not limited to: (i) increased steady-state levels of GDP-bound modified proteins; (ii) a reduction in phosphorylated AKTs473, (iii) a reduction in phosphorylated ERK T202 / Y204, (iv) a reduction in phosphorylated S6 S235 / 236, (v) a decrease in cell growth of tumor cells expressing a Ras mutant protein (e.g., KRas G12C, KRas G12S, KRas G13C, KRas G13S, NRas G12C, NRas G12S, NRas G13C, NRasG13S, HRas G12C, HRas G12S, HRas G13C, or HRas G13S); and (vi) a reduction in Ras interaction with a Ras pathway signaling protein. In some embodiments, the reduction is demonstrated by two, three, four, or more of items (i)-(vi). In some embodiments, a reduction in Ras signaling output can be demonstrated by any of (i)-(vi) compared to a control unmodified corresponding Ras protein that is not covalently bonded to any compound disclosed herein. For example, as described herein, a control Ras protein can be a Ras protein (e.g., wild-type or mutant) that is not complexed with any of the subject compounds disclosed herein. As compared to a control Ras protein, the increase in item (i) or the decrease in items (ii) through (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. In some embodiments, reduced interaction of Ras with Ras pathway signaling proteins is established by reduced interaction with SOS (including SOS1 and SOS2), RAF, SHC, SHP (including SHP1 and SHP2), MEK, MAPK, ERK, GRB, RASA1, or GNAQ.

[0594] Signaling outputs measured as IC50 values ​​can be obtained, and a ratio of IC50 values ​​for one mutant relative to another can be calculated. For example, a selective reduction in K-Ras G12S signaling output can be demonstrated by a ratio greater than one. In particular, if the ratio of IC50 (for K-Ras G12D or wild-type) to IC50 (for K-Ras G12S) is greater than 1, then a selective reduction in K-Ras G12S signaling relative to K-Ras G12D signaling or wild-type K-Ras signaling is demonstrated.

[0595] It is understood that when a compound described herein selectively labels serine and / or cysteine ​​residues of a K-Ras G12S or K-Ras G12C protein as compared to another K-Ras protein (e.g., WT, G12D, or G12V), the compound labels the K-Ras-G12S or K-Ras-G12C protein at a greater rate or to a greater extent, or by any other quantifiable measure, under similar or identical reaction conditions as the compared proteins. In some embodiments, greater labeling of K-Ras G12S and / or K-Ras G10C compared to another K-Ras protein (e.g., WT, G12D, or G12V) 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.

[0596] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are Ras modulators (including Ras inhibitors) capable of covalently modifying Ras proteins. The modified Ras proteins can be Ras G12S mutants or G12C mutants from K-Ras, H-Ras, or N-Ras. The compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, have a wide range of applications in therapy, diagnosis, and other biomedical research.

[0597] In one aspect, a method of treating cancer in a subject comprising a Ras G12S mutant protein is provided, comprising modifying the Ras G12S mutant protein in the subject by administering to the subject a compound described herein, wherein the compound is characterized in that, upon contact with the Ras G12S mutant protein, the Ras G12S mutant protein is covalently modified at the serine residue corresponding to residue 12 of SEQ ID No: 4, such that the modified K-Ras G12S protein exhibits reduced Ras signaling output (e.g., compared to a corresponding unmodified Ras protein not bound to the covalent compound).

[0598] In one aspect, a method of treating cancer in a subject comprising a Ras G12C mutant protein is provided, comprising modifying the Ras G12C mutant protein in the subject by administering to the subject a compound described herein, wherein the compound is characterized in that, upon contact with the Ras G12C mutant protein, the Ras G12C mutant protein is covalently modified at the cysteine ​​residue corresponding to residue 12 of SEQ ID No: 1 (wherein the glycine at position 12 is substituted with cysteine), such that the modified K-Ras G12C protein exhibits reduced Ras signaling output (e.g., compared to a corresponding unmodified Ras protein not bound to the covalent compound).

[0599] In one aspect, a method for modulating the activity of a Ras protein (e.g., K-Ras, mutant K-Ras, K-Ras G12S) is provided, 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.

[0600] In practicing any of the methods disclosed herein, the Ras target to which the subject compounds covalently bind 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).

[0601] Pharmaceutical compositions and methods of administration

[0602] In one aspect, a pharmaceutical composition is provided, comprising a compound described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0603] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, are administered to a subject in a biocompatible 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 comprising 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.

[0604] In some embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein 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), which is selected based on the selected route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005)).

[0605] Thus, provided herein is a pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt as described herein and 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 is not harmful to the recipient (i.e., subject) of the composition.

[0606] In some embodiments of the methods described herein, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent to administer a pharmaceutical composition. The administration of compounds described herein and compositions can be achieved by any method enabling the compound to be delivered to the site of action. These methods include, but are not limited to, via enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories and rectal enemas), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), suction, transdermal, transmucosal, sublingual, buccal and topical (including on the skin, dermis, enema, eye drops, ear drops, intranasal, vaginal) administration to deliver, although the most suitable approach can depend on, for example, the condition and illness of the recipient. For example only, compounds described herein can be topically administered to the area in need of treatment by, for example, local infusion during surgery, local application such as cream or ointment, injection, catheter or implant. Administration can also be performed 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.

[0607] In some embodiments of the methods described herein, pharmaceutical compositions suitable for oral administration are provided as discrete units such as capsules, cachets, 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 provided as a pill, electuary, or paste.

[0608] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Tablets can be prepared by compressing or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form (such as a powder or granules) optionally mixed with a binder, an inert diluent or lubricant, a surfactant, or a dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. In some embodiments, the tablets are coated or scored and formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration should be suitable for such administration in terms of dosage. Push-fit capsules can contain the active ingredient blended with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft capsules, active compound can be dissolved or suspended in suitable liquid such as fatty oil, liquid paraffin or liquid polyethylene g...

Claims

1. A modified Ras protein comprising a compound covalently bonded to one or more amino acid residues of the Ras protein, wherein the modified Ras protein comprises a compound of formula (I'): in: Dashed lines indicate covalent bonds to the amino acid residues; R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R 20 replace; L 1 is optionally replaced by one or more R 20 substituted 5- to 20-membered heterocycles; L 2 Selected from 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)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-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace; L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in a haloalkyl group; L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted by one, two or three substituents, and wherein L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or R 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted with one, two or three substituents, and wherein L 3 It is a key; R 2 Selected from halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 2 and R 3 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group; R 3 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group; R 4 、R 5 and R 6 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group; R 19 is independently selected at each occurrence from 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 selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 ; wherein two R connected to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 ) is substituted with a substituent; R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 carbocyclic or 3- to 12-membered heterocyclic rings, each of which is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and -OH substituents; R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocycle); and R 23 independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or R attached to the same nitrogen atom 22 and R 23 A 3- to 10-membered heterocyclic ring is formed.

2. The modified Ras protein according to claim 1, wherein the modified Ras protein is a modified human K-Ras mutant protein comprising a compound having a structure of formula (I) covalently bonded to a serine residue, wherein the serine residue corresponds to position 12 of SEQ ID No. 4: The dotted lines represent the bonds between the serine residue and alanine 11 and glycine 13 of the K-Ras mutant protein, respectively.

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

4. The modified protein of claim 3, wherein the reduced Ras signaling output is demonstrated by one or more outputs selected from the group consisting of: (i) an increase in the steady-state level of GDP-bound modified protein; (ii) a decrease in the steady-state level of GTP-bound modified protein; (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 the Ras G12S mutant protein; and (vii) a decrease in the interaction of Ras with Ras pathway signaling proteins. 5 . The modified protein according to claim 1 , comprising the amino acid sequence of SEQ ID No. 4, wherein the amino acid sequence has the serine residue corresponding to position 12 of SEQ ID No.

1. 6 . The modified protein according to claim 1 , comprising the amino acid sequence of SEQ ID No. 4, or a fragment thereof having the serine residue corresponding to position 12 of SEQ ID No.

1.

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 the serine residue of an unmodified Ras G12S mutant protein, wherein the precursor compound comprises a retaining group and a leaving group, and wherein the contacting results in release of the leaving group and formation of the modified protein.

8. The modified protein according to claim 7, wherein the precursor compound is the compound according to claim 14.

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

1.

10. The modified protein according to claim 9, wherein The precursor compound selectively labels the serine residue at least 2-fold when assayed under comparable conditions.

11. The modified protein according to 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 modified protein according to any one of claims 7 to 12, wherein the leaving group is selected from or a salt or tautomer thereof, wherein R 8 and R 9 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

14. A compound of formula (II): or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 Selected from C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, each of which is optionally replaced by one or more R 20 replace; L 1 is optionally replaced by one or more R 20 substituted 5- to 20-membered heterocycles; L 2 Selected from 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)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-, where C 1-4 Alkylene and 2- to 4-membered heteroalkylene are optionally substituted by one, two or three R 20 replace; L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in a haloalkyl group; L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted by one, two or three substituents, and wherein L 3 and R 6 The 4- to 8-membered monocyclic heterocycloalkyl formed is not piperazine; or R 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 halogenated alkyl) is substituted with one, two or three substituents, and wherein L 3 It is a key; R 2 Selected from halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 2 and R 3 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents of a haloalkyl group; R 3 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group; R 4 、R 5 and R 6 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group; R 7 Selected from R 8 and R 9 are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -CN, C 1-6 Alkyl, -O(C 1-6 alkyl) and -O(C 1-6 substituted with one, two or three substituents in a haloalkyl group; R 19 is independently selected at each occurrence from 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 selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 ; wherein two R attached to the same or adjacent atoms 20 Optionally joined to form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring; wherein 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one or more independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 ) is substituted with a substituent; R 21 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 21 Together with the carbon atoms to which they are attached, they form C 3-12 carbocyclic or 3- to 12-membered heterocyclic rings, each of which is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Substitution of haloalkyl and -OH substituents; R 22 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring); R 23 independently selected at each occurrence from hydrogen and C 1-6 Alkyl; or R attached to the same nitrogen atom 22 and R 23 forming a 3- to 10-membered heterocyclic ring; and When R 7 When substituted with hydrogen, the compound reversibly binds to K-Ras protein, as assessed by HTRF assay, with IC 50 Less than 1000nM.

15. The compound, salt or solvate according to claim 14 or the modified protein according to any one of claims 1 to 13, wherein L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, C 3-8 monocyclic cycloalkyl, 7- to 12-membered spirocyclic heterocycloalkyl, or 7- to 12-membered fused bicyclic heterocycloalkyl, each of which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

16. The compound, salt, solvate or modified protein of claim 15, wherein L 3 and R 2 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

17. The compound, salt or solvate according to claim 14 or the modified protein according to any one of claims 1 to 13, wherein L 3 and R 6 Together with the atoms to which they are attached, they 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 optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted by one, two or three substituents in the haloalkyl) group, wherein L 3 With R 6 The 4- to 8-membered monocyclic heterocycloalkyl group formed is not piperazine.

18. The compound, salt or solvate according to claim 14 or the modified protein according to any one of claims 1 to 13, wherein R 2 and R 6 Together with the atoms to which they are attached, they form a 3- to 8-membered monocyclic heterocycloalkyl group, which is optionally selected from halogen, -OH, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 cycloalkyl) is substituted with one, two or three substituents, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted by one, two or three substituents, wherein L 3 It is a key.

19. The compound according to claim 14, which has the structure of formula (II-a): or a pharmaceutically acceptable salt or solvate thereof, wherein: W 1 and W 3 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2; W 2 Selected from N and C(R 11 ); n1 and n3 are each independently selected from 0, 1, 2, 3, 4 and 5, wherein the sum of n1 and n3 is at least 1; R 10 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

20. The compound, salt or solvate according to claim 19, wherein W 1 and W 3 Each is C(R 11 )2.

21. The compound, salt or solvate according to claim 19 or 20, wherein W 2 It's N.

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. 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. The compound according to claim 14, which has the structure of formula (II-b): or a pharmaceutically acceptable salt or solvate thereof, wherein: W 4 and W 5 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2; W 2 Selected from N and C(R 11 ); n4 and n5 are each independently selected from 0, 1, 2, 3, 4 and 5; R 10 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

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

26. The compound, salt or solvate according to claim 24 or 25, wherein W 2 It is C(R 11 ).

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

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

29. The compound according to claim 14, which has the structure of formula (II-c): or a pharmaceutically acceptable salt or solvate thereof, wherein: W 1 、W 3 、W 4 and W 5 Each independently selected from N(R 10 )、C(R 11 )2, C(O), O, S(O) and S(O)2; W 2 Selected from N and C(R 11 ); n1 and n3 are each independently selected from 0, 1, 2, 3, 4 and 5, wherein 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 selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

30. The compound, salt or solvate of claim 29, wherein each W 1 Independently selected from C(R 11 )2 and O.

31. The compound, salt or solvate according to claim 29 or 30, wherein n1 is 2, 3 or 4, one W 1 is O, and the rest are W 1 Each is C(R 11 )2.

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

33. A compound, salt or solvate according to any one of claims 29 to 32, wherein W 2 It's N.

34. A compound, salt or solvate according to any one of claims 29 to 33, wherein W 4 and W 5 Each is C(R 11 )2.

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

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

39. The compound, salt or solvate of claim 29, wherein Selected from wherein each is optionally replaced by one, two or three R 11 replace.

40. The compound according to claim 14, which has the structure of formula (II-d): or a pharmaceutically acceptable salt or solvate thereof, wherein: W 3 Selected from 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 selected at each occurrence from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 haloalkyl) is substituted with one, two or three substituents; and R 11 is independently selected at each occurrence from 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 Formation C 3-6 Cycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, -O(C 1-6 alkyl) and -O(C 3-6 Cycloalkyl) is optionally selected from halogen, -OH, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, -O(C 1-3 alkyl) and -O(C 1-3 substituted with one, two or three substituents in the alkyl group (e.g., alkyl halide).

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

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

43. A compound, salt or solvate according to any one of claims 19 to 42, wherein R 10 and R 11 independently selected at each occurrence from hydrogen and C 1-3 alkyl.

44. A compound, salt or solvate according to any one of claims 14 to 43 or a modified protein according to any one of claims 1 to 13, wherein R 1 Selected from C 6-10 Aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted by one, two, three, four or five R 20 replace.

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

46. ​​The compound, salt or solvate according to any one of claims 14 to 45, or the modified protein according to any one of claims 1 to 13, wherein R 1 One, two, three or four independently selected from halogen, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, -OR 22 、-N(R 22 )(R 23 ) and C 3-6 The cycloalkyl group is substituted with a substituent.

47. The compound, salt, solvate or modified protein of claim 46, wherein R 1 Substituted with one, two, three or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH=CH2, -CF3, -C≡C, -OH, -NH2 and -cyclopropyl.

48. A compound, salt or solvate according to any one of claims 14 to 43 or a modified protein according to any one of claims 1 to 13, wherein R 1 Selected from 49. A compound, salt or solvate according to any one of claims 14 to 43 or a modified protein according to any one of claims 1 to 13, wherein R 1 Selected from 50. A compound, salt or solvate according to any one of claims 14 to 43 or a modified protein according to any one of claims 1 to 13, wherein R 1 yes 51. A compound, salt or solvate according to any one of claims 14 to 50, or a modified protein according to any one of claims 1 to 13, wherein L 1 is optionally replaced by one or more R 20 Substituted 6- to 12-membered heterocycle.

52. The compound, salt, solvate or modified protein of claim 51, wherein L 1 Is one, two, three or four R 20 Substituted 10-membered bicyclic heterocycle.

53. A compound, salt or solvate according to any one of claims 14 to 52, or a modified protein according to any one of claims 1 to 13, wherein L 1 Contains 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, wherein L 1 yes: in: 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; wherein W and Z are not simultaneously selected from C(O), S(O) and S(O)2; V and J are each independently selected from N, C(R 1 )、C(R 17 )、N(R 1 )、N(R 17b )、C(R 1 )(R 17 ) and C(R 17 )2; where exactly one of V and J is C(R 1 )、N(R 1 ) or C(R 1 )(R 17 ); 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 selected at each occurrence from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 , where 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring) are optionally substituted by one, two, or three R 20 replace; R 17b is independently selected at each occurrence from hydrogen, -CN, 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), -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)2R 12 、-S(O)(NR 12 )R 12 、-S(O)2N(R 12 )(R 13 ) and -S(=O)(=NR 12 )N(R 12 )(R 13 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace; R 18 Selected from 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring), -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 , where 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 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic ring) are optionally substituted by one, two, or three R 20 replace; R 12 independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring) is optionally substituted by one, two or three R 20 replace; R 13 independently selected at each occurrence from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R attached to the same nitrogen atom 12 and R 13 Formed optionally by one, two or three R 20 substituted 3- to 10-membered heterocycle; R 14 is independently selected at each occurrence from hydrogen, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkyl-(C 3-12 carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic ring), or two R 14 Together with the carbon atoms to which they are attached, they form C 3-12 Carbocyclic or 3- to 12-membered heterocyclic ring, wherein 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 heterocyclic ring), C 3-12 The carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted by one, two or three R 20 replace; and represents a single or double bond such that all valences are satisfied.

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

56. The compound, salt, solvate or modified protein of claim 55, wherein W is CH, CH2 or C(O); Z is N, CCl, N(R 17b ) or CH2; V is C(R 1 ) or N(R 1 ); and J is CF or CH2.

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

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

59. according to the compound, salt, solvate or modified protein described in any one of claims 54 to 58, wherein U is N; Y is C (R 18 ); and X is N.

60. The compound, salt, solvate or modified protein of any one of claims 54 to 59, wherein R 18 Selected from hydrogen, C 1-3 Alkyl, -OR 12 and a 3- to 10-membered heterocyclic ring, wherein C 1-3 The alkyl group and the 3- to 10-membered heterocyclic ring are optionally replaced by one, two or three R 20 replace.

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

62. The compound, salt, solvate or modified protein of claim 60, wherein R 18 Yes-O(C 1-3 alkylene) (4- to 10-membered heterocyclic ring), wherein the 4- to 10-membered heterocyclic ring is optionally substituted by one, two or three independently selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and =C(R 21 )2 is substituted with a substituent, wherein R 21 is independently selected at each occurrence from hydrogen, halogen and C 1-3 alkyl.

63. according to the compound, salt, solvate or modified protein described in any one of claims 54 to 59, wherein R 18 Selected from 64. The compound, salt, solvate or modified protein of claim 62, wherein R 18 Selected from:

65. according to the compound, salt, solvate or modified protein, salt or solvate described in any one of claims 14 to 64 or the modified protein described in any one of claims 1 to 13, wherein L 1 yes 66. The compound, salt, solvate or modified protein of claim 65, wherein R 1 -L 1 yes 67. The compound, salt, solvate or modified protein of claim 66, wherein R 1 -L 1 yes 68. A compound, salt or solvate according to any one of claims 14 to 67, or a modified protein according to any one of claims 1 to 13, wherein L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 replace.

69. The compound, salt, solvate or modified protein of claim 68, wherein L 2 Selected from 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-, where C 1-3 Alkylene, C 1-3 Alkyl and C 3-6 Cycloalkyl is optionally selected from halogen, C 1-3 Alkyl and C 1-3 The haloalkyl group is substituted by one, two or three substituents.

70. A compound, salt or solvate according to any one of claims 14 to 67, or a modified protein according to any one of claims 1 to 13, wherein L 2 It is a key.

71. according to the compound of any one of claims 14 to 70, salt or solvate or the modified protein of any one of claims 1 to 13, wherein R 2 Selected from C 1-6 Alkyl and C 3-6 Cycloalkyl.

72. A compound, salt or solvate according to any one of claims 14 to 71, or a modified protein according to any one of claims 1 to 13, wherein R 3 Selected from hydrogen and C 1-6 alkyl.

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

74. 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, wherein R 4 、R 5 and R 6 are independently selected from hydrogen, C 1-3 Alkyl and -(C 1-3 alkyl)CN, or R 4 and R 5 Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl.

75. A compound, salt or solvate according to any one of claims 14 to 74, wherein R 7 yes 76. A compound, salt or solvate according to any one of claims 14 to 75, wherein R 8 Selected from hydrogen, halogen, -CH3, -CH2F, -CHF2 and -CF3.

77. The compound, salt or solvate of claim 76, wherein R 8 It's hydrogen.

78. A compound, salt or solvate according to any one of claims 14 to 77, wherein R 9 Selected from hydrogen, halogen, -CH3, -CH2F, -CHF2 and -CF3.

79. The compound, salt or solvate of claim 78, wherein R 9 Selected from hydrogen and chlorine.

80. The compound, salt or solvate of claim 75, wherein R 7 yes 81. The compound, salt or solvate of any one of claims 14, 19, 24, 29 or 40, wherein: R 1 is selected from naphthyl, isoquinolyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl and pyridinyl, each of which is optionally substituted by one or more R 20 replace; L 1 Is one, two, three or four R 20 substituted 10-membered bicyclic heterocycle; L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 replace; and R 7 yes 82. The compound, salt or solvate of any one of claims 14, 19, 24, 29 or 40, wherein: R 1 -L 1 yes L 2 Selected from bond, C 1-3 Alkylene and 2- to 3-membered heteroalkylene, wherein C 1-3 Alkylene and 2- to 3-membered heteroalkylene are optionally substituted by one, two or three R 20 replace; and R 7 yes 83. according to the compound, salt or solvate described in any one of claim 14 to 82, wherein when R 7 When substituted with hydrogen, the compound reversibly binds to the K-Ras protein.

84. The compound, salt or solvate of claim 83, wherein the compound inhibits K-Ras G12S mutant cell proliferation as assessed by an in vitro cell proliferation assay, IC 50 Less than 1000nM.

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

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

88. The method of claim 87, wherein the reduced Ras signaling output is demonstrated by one or more outputs selected from the group consisting of: (i) an increase in the steady-state level of GDP-bound modified protein; (ii) a decrease in the steady-state level of GTP-bound modified protein; (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 Ras G12S mutant protein; and (vii) a decrease in the interaction of Ras with Ras pathway signaling proteins.

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 having a serine residue corresponding to position 12 of SEQ ID No.

1.

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

4.

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

92. The method of claim 91, wherein the leaving group is selected from: or a salt or tautomer thereof.

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

1.

94. The method of claim 93, wherein the compound selectively labels the serine residue at least 2-fold when assayed under comparable conditions.

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

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

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

98. A method of treating cancer in a subject comprising a Ras mutant protein, the method comprising: The Ras mutant protein in the subject is modified by administering to the subject a compound according to any one of claims 14 to 84, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is characterized in that, upon contact with the Ras mutant protein, the Ras mutant protein is covalently modified at the residue corresponding to residue 12 of SEQ ID No: 4, such that the modified Ras mutant protein exhibits reduced Ras signaling output.

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

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

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

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

104. The method of claim 103, wherein the additional agent comprises (1) an inhibitor of MEK; (2) an inhibitor of epidermal growth factor receptor (EGFR) and / or its mutants; (3) an immunotherapeutic agent; (4) a taxane; (5) an antimetabolite; (6) an inhibitor of FGFR1 and / or FGFR2 and / or FGFR3 and / or their mutants; (7) a mitotic kinase inhibitor; (8) an anti-angiogenic drug; (9) a topoisomerase inhibitor; (10) a platinum-containing compound; (11) Inhibitors of c-MET and / or its mutants; (12) inhibitors of BCR-ABL and / or its mutants; (13) inhibitors of ErbB2 (Her2) and / or its mutants; (14) inhibitors of AXL and / or its mutants; (15) inhibitors of NTRK1 and / or its mutants; (16) inhibitors of RET and / or its mutants; (17) inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or its mutants; (18) inhibitors of ERK and / or 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, PDGF Inhibitors of R, LCK, Bcr-Abl, or AKT; (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 method of claim 103, wherein the additional agent comprises a medicament selected from the group consisting of RMC-4630, ERAS-601, SHP2 inhibitors.

106. The method of claim 103, wherein the additional agent comprises a SOS inhibitors of RMC-5845 and BI-1701963.

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

108. The method of claim 103, wherein the additional agent comprises a MEK inhibitor selected from trametinib, cometinib, bemetinib, selumetinib, rameltinib, and AZD6244.

109. The method of claim 103, wherein the additional agent comprises an ERK inhibitor selected from the group consisting of uritinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, and lavositinib.

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

111. The method of claim 103, wherein the additional agent comprises a BRAF inhibitor selected from sorafenib, vemurafenib, dapafenib, conferfenib, regorafenib, and GDC-879.

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