Ras inhibitors

Abstract

This invention relates to RAS inhibitors. This disclosure provides macrocyclic compounds capable of inhibiting Ras protein, pharmaceutical compositions thereof, protein complexes thereof, and their use in cancer treatment.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511545860.8 (22) Application Date 2020.11.04 (30) Priority Data 62 / 930355 2019.11.04 US 62 / 951652 2019.12.20 US 63 / 000357 2020.03.26 US 63 / 011636 2020.04.17 US 63 / 043588 2020.06.24 US (62) Divisional Application Data 202080076129.4 2020.11.04 (71) Applicant: Ruixin Pharmaceutical Company, California, USA (72) Inventors: J. Craig, Y. Liu (74) Patent Agency: China Patent Agency (Hong Kong) Limited, 72001 Patent Attorneys: Yu Miao, Peng Chang (51) Int.Cl. C07D 401 / 04 (2006.01) C07F 7 / 18 (2006.01) C07F 5 / 02 (2006.01) (54) Invention Title: RAS Inhibitor (57) Abstract: This invention relates to RAS inhibitors. This disclosure provides macrocyclic compounds capable of inhibiting Ras protein, pharmaceutical compositions thereof, and protein complexes thereof, and their use in cancer treatment. Claims 4 pages, Description 479 pages, Drawings 6 pages, CN 121974884 A 2026.05.05 CN 1 21 97 48 84 A 1. A compound having the structure of formula Int-1: or a salt thereof, wherein: Q is hydrogen, -B(OH)2, or a halogen; Z is hydrogen or an optionally substituted C1-C6 alkyl group; Y is a halogen, -B(OH)2, -CO2H, -CO2-(C1-C6 alkyl) or -CN; E is, , or; and PNG is a protecting group. 2. The compound of claim 1, wherein E is. 3. The compound of claim 1, wherein E is. 4. The compound of claim 3, wherein E is. 5. The compound of claim 1, wherein E is. 6. The compound of claim 1, wherein E is. 7. The compound of claim 1, wherein the compound has the structure of formula Int-1a: . 8. The compound of claim 1, wherein the compound has the structure of formula Int-1b: . 9. The compound of claim 1, wherein the compound has the structure of formula Int-1c: . Claims 1 / 4 page 2 CN 121974884 A . 10. The compound of claim 1, wherein the compound has the structure of formula Int-1d: .11. The compound of claim 1, wherein the compound has the structure of formula Int-1e: . 12. The compound of claim 1, wherein the compound has the structure of formula Int-1f: . 13. The compound of any one of claims 1 to 12, wherein Q is H. 14. The compound of any one of claims 1 to 12, wherein Q is a halogen. 15. The compound of any one of claims 1 to 12, wherein Z is H or an optionally halogen-substituted C1-C6 alkyl group. 16. The compound of any one of claims 1 to 12, wherein Z is H or an optionally substituted ethyl group. 17. The compound of claim 16, wherein Z is . 18. The compound of claim 16, wherein Z is . 19. The compound of claim 13, wherein Z is H. 20. The compound of claim 13, wherein Z is an optionally substituted C1-C6 alkyl group. 21. The compound of any one of claims 1 to 6, wherein: Z is H or an optionally substituted ethyl group; Q is H or a halogen; and Y is Br, -B(OH)2, or . 22. The compound of claim 1, wherein: AZ is H, or ; Q is H; and Y is Br. 23. The compound of any one of claims 1 to 6, wherein Y is Br, -B(OH)2, or . 24. The compound of claim 6, 11, or 12, wherein PNG is Ac, TBS, or TBDPS. 25. A compound selected from the following: , , , , and . 26. The compound of claim 25, wherein the compound is: . 27. The compound of claim 25, wherein the compound is: . 28. The compound of claim 25, wherein the compound is: . 29. The compound of claim 25, wherein the compound is: . 30. The compound of claim 25, wherein the compound is: . 31. A compound selected from the following: , , , , , , and . Claims 4 / 4 pages 5 CN 121974884 A RAS Inhibitor

[0001] This application is a divisional application of the invention patent application filed on July 22, 2022, with application number 202080076129.4 and entitled "RAS Inhibitor".

[0002] Cross-Reference to Related Applications This application claims U.S. Application No. 62 / 930,355, filed November 4, 2019; filed December 20, 2019Priority interests in U.S. Application No. 62 / 951,652, filed March 26, 2020; U.S. Application No. 63 / 000,357, filed April 17, 2020; and U.S. Application No. 63 / 011,636, filed June 24, 2020, all of which are hereby incorporated by reference in their entirety. Background Art

[0003] The vast majority of small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the activity of said proteins. For example, cholesterol-lowering drugs known as statins bind to the active site of HMG-CoA reductase, thereby preventing said enzyme from binding to its substrate. The fact that many such drug / target interactions are known may mislead some into believing that small molecule regulators targeting most (if not all) proteins can be discovered, which provides a reasonable amount of time, effort, and resources. But this is far from the case. Currently, it is estimated that only about 10% of all human proteins can be targeted by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019). The other 90% are currently considered incurable or intractable for the aforementioned small molecule drug discoveries. Such targets are often referred to as “undruggable.” These undruggable targets comprise a vast and largely unexplored reservoir of medically important human proteins. Therefore, there is great interest in discovering new molecular modalities that can modulate the function of such undruggable targets.

[0004] It is well established in the literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play crucial roles in a variety of human cancers and are therefore suitable targets for anticancer therapies. In fact, approximately 30% of all human cancers in the United States are caused by Ras protein mutations, many of which are fatal. Dysregulation of Ras proteins through activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations in Ras are frequently found in human cancers. For example, an activating mutation at codon 12 in the Ras protein significantly biases the Ras mutant protein population towards the "on" (GTP-binding) state (Ras(ON)) by inhibiting GTPase-activated protein (GAP) dependence and intrinsic GTP hydrolysis rate, leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, and can be activated even in the presence of such low nucleotide concentrations. Mutations at codon 13 (e.g., G13D) and codon 61 (e.g., Q61K) in Ras have also caused oncogenic activity in some cancers.

[0005] Despite extensive drug discovery efforts targeting Ras over the past decades, no drugs directly targeting Ras have been approved. Further efforts are needed to discover other drugs for cancers driven by various Ras mutations. Summary of the Invention

[0006] This document provides Ras inhibitors. The methods described herein require the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: a target protein (e.g., Ras), and a cytosolic chaperone protein (presenting protein) (e.g., cyclophilin A) that is widely expressed in the cell. More specifically, in some embodiments, the Ras inhibitors described herein induce a new binding pocket in Ras by driving the formation of a high-affinity triple complex or conjugate between the Ras protein and the widely expressed cytosolic chaperone protein cyclophilin A (CYPA). Unbound by theory, the inventors believe that one way the compounds of the present invention and the complexes or conjugates thereto exert an inhibitory effect on Ras is by spatially blocking the interaction sites between Ras and downstream effector molecules such as RAF and PI3K required for the propagation of carcinogenic signals.

[0007] Accordingly, in some embodiments, this disclosure provides a compound of structural formula I or a pharmaceutically acceptable salt thereof: wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to a carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 10-membered heterocyclic arylene; B is absent, is -CH(R9)-, >C=CR9R9' or >CR9R9', wherein the carbon is bonded to a carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heterocyclic arylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; an optionally substituted C1-C4 heteroalkylene group; or a 3- to 8-membered heteroaryl group; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylacetone, haloacetal, or acetylacetonate; X1 is an optionally substituted C1-C2 alkylene group, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2;R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; Specification 2 / 479 pages 7 CN 121974884 A R1 is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocycloalkyl. R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl. R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with their attached carbon atoms to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with their attached carbon atoms to form C=CR7'R8'. C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl;R7a and R8a are independently hydrogen, halogroup, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl. R9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; or R9 and L combined with the atoms they are attached to form optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9' combined with the atoms they are attached to form 3- to 6-membered cycloalkyl or 3- to 6-membered heteroalkyl; R10 is hydrogen, a halogroup, a hydroxyl group, a C1-C3 alkoxy group, or a C1-C3 alkyl; R10a is hydrogen or a halogroup; R11 is hydrogen or a C1-C3 alkyl; and R21 is hydrogen or a C1-C3 alkyl (e.g., methyl).

[0008] Pharmaceutical compositions are also provided comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (See page 3 / 479 of the specification, CN 121974884 A)

[0009] Further provided is a conjugate or a salt thereof comprising the structure of formula IV: M-L-P Formula IV where L is a linker; P is a monovalent organic moiety; and M has the structure of formula V: where the dashed line represents zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered aryl; or optionally substituted 5 to 6-membered heteroaryl; B is absent, is -CH(R9)-, >C=CR9R9' or >CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; Optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenyl; optionally substitutedC1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; X1 is optionally substituted C1-C2 heteroalkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' Independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered alkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl or optionally substituted 5 to 10-membered heteroaryl, or R1 and R2 combined with the atoms to which they are attached to form optionally substituted 3 to 14-membered heterocycloalkyl; R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl. R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl.Optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocyclic alkyl; R7a and R8a are independently hydrogen, halogroup, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl. R9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R9 and L combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9' combined with the atoms to which they are attached to form 3- to 6-membered cycloalkyl or 3- to 6-membered heteroalkyl; R10 is hydrogen, a halogroup, a hydroxyl group, a C1-C3 alkoxy group, or a C1-C3 alkyl; R10a is hydrogen or a halogroup; R11 is hydrogen or a C1-C3 alkyl; and R21 is H or a C1-C3 alkyl.

[0010] A method of treating a subject with cancer is also provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof. Specification 5 / 479 pages 10 CN 121974884 A

[0011] In some embodiments, a method of treating a subject with Ras protein-related conditions is provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0012] Further, a method of inhibiting Ras protein in cells is provided, the method comprising contacting the cells with an effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0013] Specifically, any limitations discussed with respect to one embodiment of the invention may be applied to any aspect of the invention.Other embodiments. Furthermore, any compound or composition of the present invention can be used in any method of the present invention, and any method of the present invention can be used to produce or utilize any compound or composition of the present invention. Brief Description of the Drawings

[0014] Figures 1A and 1B: These figures illustrate a paired analysis of the potency of certain compounds of the present invention (formula BB) (dots on the right) and compounds of the corresponding formula AA (dots on the left) in two different cell-based assays where H is replaced by (S)Me. The y-axis represents pERK EC50 (Figure 1A) or CTG IC50 (Figure 1B) as measured in the H358 cell line.

[0015] Figures 2A and 2B: In an NSCLC (KRAS G12C) xenograft model, the compound of the present invention, namely compound A, caused significant regression in vivo. Some animals exhibited a complete response (CR) = 3 consecutive tumor measurements ≤ 30 mm3. Figure 2A shows that daily oral administration of 100 mg / kg of compound A via tube feeding induced tumor regression in the NCI-H358 KRASG12C xenograft model, a model sensitive to KRASG12C inhibition alone. A spaghetti titer plot showing individual tumor growth (Figure 2B) is shown after the tumor volume plot (Figure 2A).

[0016] Figures 3A and 3B: In the NSCLC (KRASG12C) model, the combination of the compound of the present invention, compound B, with the MEK inhibitor cobimetinib induced tumor xenograft regression. Figure 3A shows that intermittent intravenous administration of 50 mg / kg of compound B plus daily oral administration of 2.5 mg / kg of cobimetinib induced tumor regression, while each single drug induced tumor growth inhibition. The study outcome is shown as a waterfall plot (Figure 3B), indicating that 6 out of 10 mice showed tumor regression in the combination group, while no tumor regression was recorded in any of the single drug groups.

[0017] Figures 4A and 4B: In an NSCLC (KRAS G12C) model, weekly administration of the compound of the present invention, compound C, combined with daily administration of the SHP2 inhibitor RMC-4550 induced xenograft regression. Figure 4A shows the combined activity of weekly intravenous administration of 60 mg / kg of compound C plus daily oral administration of 30 mg / kg of the SHP2 inhibitor. The study end response in individual tumors is plotted as a waterfall graph (Figure 4B).

[0018] Figure 5: In a long-term cell growth NSCLC (KRAS G12C) model, the combination of the compound of the present invention, compound D, and the MEK inhibitor trametinib persistently inhibited in vitro growth.

[0019] Definitions and Chemical TermsIn this application, unless explicitly stated otherwise from the context, (i) the term “a” means “one or more”; (ii) the term “or” is used to mean “and / or” unless explicitly indicated that the term refers to an alternative that is unique or that the alternatives are mutually exclusive, however, the definition supported by this disclosure refers to a unique alternative and “and / or”; (iii) the terms “comprising” and “including” should be understood to encompass the listed components or steps, whether presenting the component or step alone or in combination with one or more additional components or steps; and (iv) when providing a range, endpoints are included.

[0020] As used herein, the term “about” is used to indicate that a value includes the standard deviation of the error of the apparatus or method used to determine the value. In some embodiments, the term “about” refers to a value ranging from 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or lower in any direction, unless otherwise specified or otherwise apparent from the context (e.g., when the number would exceed 100% of the possible value). Specification 6 / 479 pages 11 CN 121974884 A

[0021] As used herein, in the case of describing adjacent atoms, the term “adjacent” means a divalent atom directly connected by a covalent bond.

[0022] As used herein, “compounds of the invention” and similar terms, whether explicitly indicated or not, refer to the Ras inhibitors described herein, including compounds of formula I and its sub-formulas, as well as the compounds in Tables 1 and 2, and their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including transisomers), and tautomers.

[0023] The term “wildtype” refers to an entity having the structure or activity seen in nature in a “normal” state or condition (as opposed to mutation, disease, alteration, etc.). Those skilled in the art will understand that wildtype genes and polypeptides typically exist in a variety of different forms (e.g., alleles).

[0024] Those skilled in the art will understand that certain compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, transisomers, tautomers) or isotopic forms (e.g., one or more atoms are substituted with different isotopes of said atoms, e.g., hydrogen is substituted with deuterium). Unless otherwise indicated or clearly apparent from the context, the depicted structures are to be understood as representing any such isomeric or isotopic forms, individually or in combination.

[0025] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are covered. Carbon atoms containing asymmetric substitutions...The compounds of this disclosure can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., are also present in the compounds described herein, and all such stable isomers are covered in this disclosure. Cis and trans geometric isomers of the compounds of this disclosure have been described and can be isolated in mixtures of isomers or in separate isomeric forms.

[0026] In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. It will be clear from the context that, unless explicitly excluded, references to such compounds cover all such tautomeric forms. In some embodiments, the tautomeric form is obtained by exchanging a single bond with an adjacent double bond and accompanied by proton migration. In some embodiments, the tautomeric form may be a proton-transfer tautomeric form, which is an isomer with the same empirical formula and total charge as the reference form. Examples of portions having proton-transfer tautomerism include keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, amide-imine pairs, enamine-imine pairs, and cyclic forms, in which the proton may occupy two or more positions in the heterocyclic system, such as 1H-imidazolium and 3H-imidazolium, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. In some embodiments, the tautomerism may be in equilibrium or spatially locked into one form by appropriate substitution. In some embodiments, the tautomerism is obtained by interconversion of acetals.

[0027] Unless otherwise specified, the structures described herein are also intended to include compounds that differ only by the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I. Isotope-labeled compounds (e.g., compounds labeled with 3H and 14C) can be used in compound or substrate tissue distribution assays. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are available due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium (i.e., 2H), can provide certain therapeutic benefits due to enhanced metabolic stability (e.g., increased in vivo half-life or reduced dose requirement). In some embodiments, one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by carbon enriched with 13C or 14C. Positron-emitting isotopes, such as...15O, 13N, 11C, and 18F can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by following a procedure similar to that disclosed in the specification 7 / 479, page 12, CN 121974884 A, for the compounds of the invention described herein, by replacing unlabeled reagents with isotopically labeled reagents.

[0028] As is known in the art, many chemical entities can be presented in a variety of different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the invention can be used in any of these forms, including any solid form. In some embodiments, the compounds described or depicted herein can be provided in hydrate or solvate form.

[0029] Throughout this specification, substituents of the compounds disclosed herein are disclosed by group or by scope. Specifically, this disclosure is intended to include every individual combination of members of such groups and scopes. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound comprises multiple positions, and where substituents are disclosed as groups or ranges at said positions, unless otherwise indicated, this disclosure is intended to cover individual compounds and groups of compounds (e.g., species and subclasses) containing members at each position.

[0030] The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl is optionally substituted”). It is not intended to mean that the characteristic “X” (e.g., alkyl) itself is optional. As described herein, certain target compounds may contain one or more “optionally substituted” moieties. Generally, the term “substituted”, whether or not preceded by the term “optionally”, means that one or more hydrogens of the specified moieties are replaced by suitable substituents, such as any of the substituents or groups described herein. Unless otherwise indicated, a “optionally substituted” group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure may be substituted by more than one substituent selected from the specified group. For example, in the term “optionally substituted C1-C6 alkyl-C2-C9 heteroaryl,” the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The combinations of substituents contemplated in this disclosure are preferably combinations of substituents that form stable or chemically viable compounds. As used herein, the term “stable” means that a compound remains stable even after undergoing permissible changes.The conditions under which it is generated, detected, and, in some embodiments, recovered, purified, and used for one or more purposes disclosed herein remain substantially unchanged.

[0031] Suitable monovalent substituents on the substituted carbon atoms of the “optionally substituted” group may independently be deuterium; halogen; -(CH2)O-4R°; -(CH2)O-4OR°; -O(CH2)O-4R°; -O-(CH2)O-4C(O)OR°; -(CH2)O-4CH(OR°)2; - (CH2)0-4SR°; -(CH2)0-4Ph, which can be substituted by R°; -(CH2)0-4O(CH2)0-1Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2)0-4O(CH2)0-1-pyridyl, which can be substituted by R°; 4-8 membered saturated or unsaturated heterocyclic alkyl (e.g., pyridyl); 3-8 membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)NR°2; -N(R°)C(S) NR°2;‑(CH2)0‑4N(R°)C(O)OR°;‑N(R°)N(R°)C(O)R°;‑N(R°)N(R°)C(O)NR°2;‑N(R°)N(R°)C (O)OR°;‑(CH2)0‑4C(O)R°;‑C(S)R°;‑(CH2)0‑4C(O)OR°;‑(CH2)0‑4‑C(O)‑N(R°)2;‑(CH2)0‑4‑C (O)‑N(R°)‑S(O)2‑R°;‑C(NCN)NR°2;‑(CH2)0‑4C(O)SR°;‑(CH2)0‑4C(O)OSiR°3;‑(CH2)0‑4OC(O) R°;‑OC(O)(CH2)0‑4SR°;‑SC(S)SR°;‑(CH2)0‑4SC(O)R°;‑(CH2)0‑4C(O)NR°2;‑C(S)NR°2;‑C(S) SR°;‑(CH2)0‑4OC(O)NR°2;‑C(O)N(OR°)R°;‑C(O)C(O)R°;‑C(O)CH2C(O)R°;‑C(NOR°)R°; (CH2)0‑4SSR°;‑(CH2)0‑4S(O)2R°;‑(CH2)0‑4S(O)2OR°;‑(CH2)0‑4OS(O)2R°;‑S(O)2NR°2; (CH2)0‑4S(O)R°;‑N(R°)S(O)2NR°2;‑N(R°)S(O)2R°;‑N(OR°)R°;‑C(NOR°)NR°2;‑C(NH)NR°2;P(O)2R°;-P(O)R°2;-P(O)(OR°)2;-OP(O)R°2;-OP(O)(OR°)2;-OP(O)(OR°)R°;-SiR°3;-(C1-4 straight-chain or branched alkylene)O-N(R°)2;or-(C1-4 straight-chain or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted and independently of hydrogen, -C1-6 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, -CH2- (5-6 membered heteroaryl ring), or 3-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Or, despite the above definition, two independently existing R° together with their inserted atoms form a 3-12 saturated, partially unsaturated or aryl monocyclic or bicyclic ring with 0-4 independently selected heteroatoms from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0032] Suitable monovalent substituents on R° (or a ring formed by two independently existing R° and their inserted atoms) can independently be halogens, -(CH2)O-2R●, -(halogen R●), -(CH2)O-2OH, -(CH2)O-2OR●, -(CH2)O-2CH(OR●)2, -O(halogen R●), -CN, -N3, -(CH2)O-2C(O)R●, -(CH2)O-2C(O)OH, -(CH2)O-2C(O)OR●, -(CH2)O-2SR●, -(CH2)O-2SH, -(CH2)O-2NH2, -(CH2)O-2NHR●, -(CH2)O-2NR●2, -NO2, -SiR●3, -OSiR●3, -C(O)SR●, - (C1-4 straight-chain or branched alkylene)C(O)OR● or -SSR●, wherein each R● is unsubstituted or, if preceded by a "halogen group", substituted by only one or more halogens, and is independently selected from C1-4 aliphatic groups, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0033] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O- or -S(C(R*2))2-3S-, wherein R* is selected from hydrogen each time it appears independently; C1-6 aliphatic groups, which may be substituted as defined below; or havingAn unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the adjacent substituted carbon of the "optionally substituted" group include: -O(CR*2)2-3O-, wherein R* is selected from hydrogen each time it appears independently; a C1-6 aliphatic group that may be substituted as defined below; or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur.

[0034] Suitable substituents on the aliphatic group of R* include halogen, -R●, -(halogen R●), -OH, -OR●, -O(halogen R●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2 or -NO2, wherein each R● is unsubstituted or substituted with only one or more halogens when preceded by "halogen", and is independently a C1-4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph or a 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0035] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R†, -NR†2, -C(O)R†, -C(O)OR†, -C(O)C(O)R†, -C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, -C(S)NR†2, -C(NH)NR†2 or -N(R†)S(O)2R†; wherein each R† is independently hydrogen; a C1-6 aliphatic group, which may be substituted as defined below; unsubstituted - OPh; or an unsubstituted 3-6 saturated, partially unsaturated or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independently existing R† together with their inserted atoms form a 3-12 saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur.

[0036] Suitable substituents on the aliphatic group of R† are independently halogens, -R●, -(halogen R●), -OH, -OR●, -O(halogen R●), -CN, -C(O)OH, -C(O)OR●, -NH2, -NHR●, -NR●2, or -NO2, wherein each R● is unsubstituted or substituted with only one or more halogens when preceded by "halogen", and is independently a C1-4 aliphatic group, -CH2Ph, -O(CH2)O-1Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R† include =O and =S.

[0037] The term "acetyl" as used herein refers to the group -C(O)CH3.

[0038] As used herein, the term "alkoxy" refers to an -O-C1-C20 alkyl group, wherein the alkoxy group is attached to the remainder of the compound via an oxygen atom.

[0039] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10 or 1 to 6) carbon atoms. In some embodiments, the alkyl group is unbranched (i.e., straight-chain); in some embodiments, the alkyl group is branched. Alkyl groups are, for example, but not limited to, methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0040] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight-chain or branched saturated hydrocarbon, and examples include methylene, ethylene, isopropylene, etc. The term "Cx-Cy alkylene" refers to an alkylene group having between x and y carbon atoms. Exemplary x values ​​are 1, 2, 3, 4, 5, and 6, and exemplary y values ​​are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C10, C2-C20, C2-C6, C2-C10, or C2-C20 alkylene groups). In some embodiments, the alkylene group may be further substituted with 1, 2, 3, or 4 substituents as defined herein.

[0041] Unless otherwise specifically stated, the term “alkenyl” as used herein refers to a monovalent straight-chain or branched group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds, and examples of such groups are vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl groups include cis and trans isomers. Unless otherwise specifically stated, the term “alkenyl” as used herein refers to a divalent straight-chain or branched group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0042] The term “alkynyl” as used herein refers to a monovalent straight-chain or branched group having 2 to 20 carbons (e.g., 2 to 4, 2 to 6 or 2 to 10 carbons) containing carbon-carbon triple bonds, and examples of which are ethynyl and 1-propynyl.

[0043] The term “alkynyl sulfone” as used herein refers to a group containing a structure, wherein R is any chemically feasible substituent described herein.

[0044] The term “amino” as used herein refers to -N(R†)2, such as -NH2 and -N(CH3)2.

[0045] The term “aminoalkyl” as used herein refers to an alkyl moiety in which one or more carbon atoms are substituted by one or more amino moieties.

[0046] As described herein, the term "amino acid" refers to an amino acid having a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H).A molecule in which the amino acid is attached to a parent molecule group via a side chain, amino group, or acid group (e.g., a side chain). The term "amino acid" as used herein refers in the broadest sense to any compound or substance that can be incorporated into a polypeptide chain, for example, by forming one or more peptide bonds. In some embodiments, the amino acid has the universal structure H₂N-C(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a synthetic amino acid; in some embodiments, the amino acid is a D-amino acid; in some embodiments, the amino acid is an L-amino acid. "Standard amino acid" refers to any one of the twenty standard L-amino acids commonly found in naturally occurring peptides. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxyl valine, isoleucine, leucine, lysine, methionine, valine, ornithine, phenylalanine, proline, pyrrolidone, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0047] As used herein, the term “aryl” refers to a monovalent monocyclic, bicyclic, or polycyclic system formed of carbon atoms, wherein the ring attached to a side group is an aromatic ring. Examples of aryl are phenyl, naphthyl, phenanthryl, and anthracene. An aromatic ring may be attached to its side group at any heteroatom or carbocyclic atom that produces a stable structure, and unless otherwise specifically stated, any ring atom may optionally be substituted.

[0048] As used herein, the term “CO” denotes a bond. For example, a portion of the term -N(C(O)-(C0-C5 alkylene-H)- includes -N(C(O)-(C0 alkylene-H)-, which is also represented as -N(C(O)-H)-.

[0049] As used herein, the terms "carbocyclic" and "carbocyclic group" refer to a monovalent, optionally substituted C3-C12 monocyclic, bicyclic, or tricyclic structure, which may be a bridging ring, a fused ring, or a spirocyclic ring, wherein all rings are formed of carbon atoms and at least one ring is a non-aromatic ring. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloynyl. Examples of carbocyclic groups are cyclohexyl, cyclohexenyl, and cycloalkyl. (See specification 10 / 479 pages 15 CN 121974884 A) Octynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indene, dihydroindene, decahydronaphthyl, etc. The carbocyclic ring may be attached to its side group at any ring atom that produces a stable structure, and any ring atom may optionally be substituted unless otherwise specifically stated.

[0050] As used herein, the term "carbonyl" refers to a C(O) group, which may also be represented as C=O.

[0051] As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH, or its unprotonated counterpart.

[0052] As used herein, the term "cyano" refers to a -CN group.

[0053] As used herein, the term “cycloalkyl” refers to a monovalent saturated cyclic hydrocarbon group, which, unless otherwise specified, can be a bridging ring, fused ring, or spirocyclic ring having three to eight cyclic carbons, and examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0054] As used herein, the term “cycloalkenyl” refers to a monovalent, non-aromatic saturated cyclic hydrocarbon group, which, unless otherwise specified, can be a bridging ring, fused ring, or spirocyclic ring having three to eight cyclic carbons and containing one or more carbon-carbon double bonds.

[0055] As used herein, the term “diastereomer” means stereoisomers that are not mirror images of each other and are not superimposed on each other.

[0056] As used herein, the term “enantiomer” means each individual optically active form of the compound of the invention having at least 80% (i.e., at least 90% of one enantiomer and at most 10% of another enantiomer), preferably at least 90%, and more preferably at least 98% optical purity or enantiomeric excess (as determined by standard methods in the art).

[0057] The term “guanidinyl” means a group having the structure: , wherein each R is independently any chemically feasible substituent described herein.

[0058] As used herein, the term “guanidinylalkylalkyl” means an alkyl moiety in which one or more carbon atoms are substituted by one or more guanidinyl moieties.

[0059] As used herein, the term “haloacetyl” means an acetyl group in which at least one hydrogen atom is replaced by a halogen.

[0060] As used herein, the term “haloalkyl” means an alkyl moiety in which one or more carbon atoms are substituted by one or more identical or different halogen moieties.

[0061] As used herein, the term “halogen” means a halogen selected from bromine, chlorine, iodine, or fluorine.

[0062] As used herein, the term “heteroalkyl” means an alkyl group as defined herein in which at least one carbon atom is replaced by a heteroatom (e.g., O, N, or S atom). The heteroatom may appear in the middle or at the end of the group.

[0063] As used herein, the term “heteroaryl” refers to a monovalent, monocyclic, or polycyclic structure containing at least one fully aromatic ring: that is, they contain 4n+2 π electrons within the monocyclic or polycyclic system and contain at least one cyclic heteroatom selected from N, O, or S in the aromatic ring. Exemplary unsubstituted heteroaryls have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term “heteroaryl” includes any of the above-described heteroaryl rings fused to one or more aromatic or carbon rings (e.g., phenyl or cyclohexane rings) in bicyclic, tricyclic, and tetracyclic groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl. The heteroaryl ring can be located at any ring atom that produces a stable structure.The ring atom may be optionally substituted, unless otherwise specifically stated. In some embodiments, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents.

[0064] The term “heterocyclic alkyl” as used herein means that at least one ring is a non-aromatic ring and that the non-aromatic ring described in this specification (page 11 / 479, CN 121974884 A) contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and is a monovalent, monocyclic, bicyclic, or polycyclic system, which may be a bridging ring, a fused ring, or a spirocyclic ring. The 5-membered ring has zero to two double bonds, and the 6-membered and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocyclic alkyl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heterocyclic alkyl" also refers to a heterocyclic compound having a bridged polycyclic structure, wherein one or more carbon atoms or heteroatoms bridge a non-adjacent member of a monocyclic ring, such as a quinine cycloyl group. The term "heterocyclic alkyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the aforementioned heterocycles is fused with one or more aromatic rings, carbocyclic rings, heteroaromatic rings, or heterocyclic rings, such as aryl rings, cyclohexane rings, cyclohexene rings, cyclopentane rings, cyclopentene rings, pyridine rings, or pyrrolidine rings. Examples of heterocyclic alkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthidyl. Heterocyclic alkyl rings may be attached to their side groups at any ring atom that produces a stable structure, and unless otherwise specifically stated, any ring atom may optionally be substituted.

[0065] The term "hydroxyl" as used herein refers to an -OH group.

[0066] The term "hydroxyalkyl" as used herein refers to an alkyl moiety in which one or more carbon atoms are substituted by one or more -OH portions.

[0067] As used herein, the term “isomer” means any tautomer, stereoisomer, transisomer, enantiomer, or diastereomer of any compound of the present invention. It should be understood that compounds of the present invention may have one or more chiral centers or double bonds, and therefore exist in stereoisomeric form, such as double-bonded isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures described herein and therefore the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms, as well as mixtures of enantiomers and stereoisomers, such as racemates. The enantiomers and stereoisomers of the compounds of the present invention can typically be obtained by well-known methods, such as chiral gas chromatography, chiral high-performance liquid chromatography, or by complexing the compounds with chiral salts.The compound is resolved into its component enantiomers or stereoisomers by crystallization in physical form or by crystallization in a chiral solvent. Enantiomers and stereoisomers can also be obtained by well-known asymmetric synthetic methods from stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts.

[0068] As used herein, the term "connector" refers to linking part B of a compound of formula I to part W, such that the resulting compound can obtain a divalent organic moiety with an IC50 of 2 μM or lower in the Ras-RAF disruption assay provided in the following examples and the Ras-RAF disruption assay provided herein: The purpose of this biochemical assay is to measure the ability of the test compound to promote the formation of a ternary complex between a nucleotide-loaded Ras isoform and a cyclic protein A; the resulting ternary complex disrupts binding to the BRAFRBD construct, inhibiting Ras signal transduction via the RAF effector.

[0069] Label-free cyclophilin A, His6-K-Ras-GMPPNP (or other Ras variants), and GST-BRAFRBRIBD were combined in a assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl2 at final concentrations of 25 µM, 12.5 nM, and 50 nM, respectively, into a 384-well assay plate. The compounds present in the wells were initially at a final concentration of 30 µM, followed by 10-fold serial dilutions. After incubation at 25°C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the assay wells to final concentrations of 10 nM and 50 nM, respectively, and the reaction was incubated for another 1.5 hours. TR-FRET signals were read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promote the destruction of the Ras:RAF complex were identified as compounds that cause a decrease in the TR-FRET ratio relative to the DMSO control well.

[0070] In some embodiments, the connector contains 20 or fewer linear atoms. In some embodiments, the connector contains 15 or fewer linear atoms. In some embodiments, the connector contains 10 or fewer linear atoms. In some embodiments, the molecular weight of the connector is less than 500 g / mol. In some embodiments, the molecular weight of the connector is less than 400 g / mol. In some embodiments, the molecular weight of the connector is less than 300 g / mol. In some embodiments, the molecular weight of the connector is less than 200 g / mol. In some embodiments, the molecular weight of the connector is less than 100 g / mol. In some embodiments, the molecular weight of the connector is less than 50 g / mol.

[0071] As used herein, the "monovalent organic fraction" is less than 500 kDa. In some embodiments, the "monovalent organic fraction" is less than 400 kDa. In some embodiments, the "monovalent organic fraction" is less than 300 kDa. In some embodiments, the "monovalent organic fraction" is less than 200 kDa. In some embodiments, the "monovalent organic fraction" is less than 100 kDa. In some embodiments, the "monovalent organic fraction" is less than 50 kDa. In some embodiments, the "monovalent organic fraction" is less than 25 kDa. In some embodiments, the "monovalent organic fraction" is less than 20 kDa. In some embodiments, the "monovalent organic fraction" is less than 15 kDa. In some embodiments, the "monovalent organic fraction" is less than 10 kDa. In some embodiments, the "monovalent organic fraction" is less than 1 kDa. In some embodiments, the "monovalent organic fraction" is less than 500 g / mol. In some embodiments, the "monovalent organic fraction" is in the range between 500 g / mol and 500 kDa.

[0072] As used herein, the term “stereoisomer” means that a compound (e.g., any compound of the formula described herein) may have all possible different isomers and conformations, particularly all possible stereochemical and conformational isomers of the basic molecular structure, all diastereomers, enantiomers, or conformations, including trans-isomers. Some compounds of the present invention may exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0073] As used herein, the term “sulfonyl” refers to a -S(O)2- group.

[0074] As used herein, the term “thiocarbonyl” refers to a -C(S)- group.

[0075] As used herein, the term “vinyl ketone” refers to a group comprising a carbonyl group directly attached to a carbon-carbon double bond.

[0076] As used herein, the term “vinyl sulfone” refers to a group comprising a sulfonyl group directly attached to a carbon-carbon double bond.

[0077] As used herein, the term “acetylenone” refers to a group comprising a structure, wherein R is any chemically feasible substituent described herein.

[0078] Those skilled in the art will understand upon reading this disclosure that certain compounds described herein may be provided or utilized in any of a variety of forms, such as salt forms, protected forms, prodrug forms, ester forms, isomer forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a particular form of the compound. In some embodiments, reference to a particular compound may refer to the compound in any form. In some embodiments, for example, a formulation of a single stereoisomer of a compound may be considered as a different form of the compound rather than a racemic mixture of the compound; a particular salt of a compound may be considered as a different form from another salt of the compound.Formulations containing one conformational isomer ((Z) or (E)) of a double bond may be considered as different from formulations containing another conformational isomer ((E) or (Z)) of the double bond; formulations with one or more isotopes different from those present in a reference formulation may be considered as different. Detailed Description

[0079] Compounds Ras inhibitors are provided herein. The methods described herein require the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: Target protein (e.g., Ras), and a cytosolic chaperone protein (presenting protein) (e.g., cyclophilin A) widely expressed in the cell. More specifically, in some embodiments, the Ras inhibitors described herein induce a new binding pocket in Ras by driving the formation of a high-affinity triple complex between the Ras protein and the widely expressed cytosolic chaperone protein cyclophilin A (CYPA). Unbound by theory, the inventors believe that one way in which the compounds of the present invention, and the complexes or conjugates thereform, exert an inhibitory effect on Ras is by spatially blocking the interaction sites between Ras and downstream effector molecules such as RAF required for the propagation of oncogenic signals.

[0080] Unbound by theory, the inventors hypothesize that covalent and non-covalent interactions between the compounds of the present invention and Ras and chaperone proteins (e.g., cyclophilin A) can contribute to the inhibition of Ras activity. In some embodiments, the compounds of the present invention form covalent adducts with the side chains of Ras proteins (e.g., the thiohedral side chain of cysteine ​​at position 12 or 13 of the mutant Ras protein). Covalent adducts may also be formed with other side chains of Ras. Alternatively or additionally, non-covalent interactions may play a role: for example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, and combinations thereof, can contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors. Therefore, the compounds of the present invention can inhibit a variety of Ras proteins (e.g., K-Ras, N-Ras, H-Ras and mutants thereof with mutations at positions 12, 13, and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, as well as other mutants described herein).

[0081] Methods for determining covalent adduct formation are known in the art. One method for determining covalent adduct formation is to perform a “crosslinking” assay, such as an assay performed under these conditions (Note: The following protocol describes a procedure for monitoring the crosslinking of K-Ras G12C (GMP-PNP) with the compounds of the present invention. This protocol can also be implemented in place of other Ras proteins or nucleotides).

[0082] The purpose of this biochemical assay is to measure the ability of the test compound to covalently label a K-Ras isoform carrying a nucleotide. A stock solution of 5 µM K-Ras (1-169) G12C carrying GMP-PNP was diluted 10-fold to a final concentration of 0.5 µM in an assay buffer containing 12.5 mM HEPES pH 7.4, 75 mM NaCl, 1 mM MgCl2, 1 mM BME, 5 µM cyclic protein A, and 2 µM of the test compound; the final sample volume was 100 µL.

[0083] The sample was incubated at 25°C for up to 24 hours, followed by quenching with 10 µL of 5% formic acid. The quenched sample was centrifuged at 15,000 rpm for 15 minutes in a benchtop centrifuge, and then 10 µL aliquots were injected into a reversed-phase C4 column and eluted to a mass spectrometer using an increasing acetonitrile gradient in the mobile phase. Analysis of the raw data can be performed using Waters MassLynx MS software, where the binding percentage is calculated from the deconvolution of protein peaks from labeled and unlabeled K-Ras.

[0084] Therefore, this document provides a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof: wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to a carbon atom of -CH(R10)-; optionally a 3- to 6-membered heterocyclic alkyl group replaced by the specification 14 / 479 pages 19 CN 121974884 A; optionally a substituted 3- to 6-membered heterocyclic alkyl group; optionally a substituted 6-membered aryl group; or optionally a substituted 5- to 10-membered heteroaryl group; B is absent, is -CH(R9)-, >C=CR9R9' or >CR9R9', wherein the carbon is bonded to a carbonyl carbon of -N(R11)C(O)-; Optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3- to 8-membered heteroarylene; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylacetone, haloacetal, or acetylacetonate; X1 is optionally substituted C1-C2 alkylene, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally degradedThe C2-C4 alkynyl group, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocycloalkyl. R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl. R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with their attached carbon atoms to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with their attached carbon atoms to form C=CR7'R8'. ; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halogroup, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl group;R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl. R9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R9 and L combined with the atoms they are attached to form optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9' combined with the atoms they are attached to form 3- to 6-membered cycloalkyl or 3- to 6-membered heteroalkyl; R10 is hydrogen, a halogroup, a hydroxyl group, a C1-C3 alkoxy group, or a C1-C3 alkyl; R10a is hydrogen or a halogroup; R11 is hydrogen or a C1-C3 alkyl; and R21 is hydrogen or a C1-C3 alkyl (e.g., methyl).

[0085] In some embodiments, R9 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl.

[0086] In some embodiments, R21 is hydrogen.

[0087] In some embodiments, this document provides a compound having the structure of formula Ia, or a pharmaceutically acceptable salt thereof: wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to a carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered aryl; or optionally substituted 5 to 10-membered heterocyclic aryl; specification 16 / 479 pages 21 CN 121974884 AB is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to a carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 To a 6-membered cycloalkylene group; optionally substituted 3- to 6-membered heteroalkylene group; optionally substituted 6-membered arylene group; or 5- to 6-membered heteroarylene group; G is optionally substituted C1-C4 alkylene group; optionally substituted C1-C4 alkenyl group; optionally substitutedC1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylacetone, haloacetal or acetylacetone; X1 is optionally substituted C1-C2 heteroalkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R1 is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocycloalkyl. R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl. R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl.Optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocyclic alkyl; R7a and R8a are independently hydrogen, halogroup, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl. R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R9 and L combined with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, a halogroup, a hydroxyl group, a C1-C3 alkoxy group, or a C1-C3 alkyl group; R10a is hydrogen or a halogroup; and R11 is hydrogen or a C1-C3 alkyl group.

[0088] In some embodiments, this disclosure provides a compound having structural formula Ib, or a pharmaceutically acceptable salt thereof: wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to a carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heterocyclic arylene; B is -CH(R9)-, wherein the carbon is bonded to a carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heterocyclic arylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 alkenyl group.C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L is absent or is a linker; Specification 18 / 479 pages 23 CN 121974884 AW is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylacetone, haloacetal or acetylacetone; X1 is optionally substituted C1-C2 heteroalkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered alkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms to which they are attached, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl; R4 is absent, or is hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens. R5 is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano, a hydroxyl, or a C1-C4 alkoxy group, a cyclopropyl, or a cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, a halogen, or a C1-C3 alkyl group optionally substituted, or R6 and R7 combined with the carbon atoms they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, a halogen, a hydroxyl, a cyano, an optionally substituted C1-C3 alkoxy group, an optionally substituted C1-C3 alkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 alkynyl group, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 3- to 14-membered heterocycloalkyl group, an optionally substituted 5- to 10-membered heteroaryl group, or an optionally substituted 6- to 10-membered aryl group, orR7 and R8 combine with the carbon atoms they are attached to to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; Specification 19 / 479 pages 24 CN 121974884 A R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0089] In some embodiments of the compounds of the present invention, G is optionally a substituted C1-C4 heteroalkylene.

[0090] In some embodiments, compounds having the structure of formula Ic, or pharmaceutically acceptable salts thereof, are provided: wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered aryl; or optionally substituted 5- to 6-membered heterocyclic aryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heterocyclic aryl; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N;Y2, Y3, Y4, and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally... (See page 25 of the specification, 20 / 479) CN 121974884 A A substituted 3- to 14-membered heterocyclic alkyl group; R4 is absent, is hydrogen, halogen, cyano, or methyl group optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atoms they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocyclic alkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl. Optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocyclic alkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl.R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0091] In some embodiments of the compounds of the present invention, X2 is NH. In some embodiments, X3 is CH. In some embodiments, R11 is hydrogen. In some embodiments, R11 is C1-C3 alkyl. In some embodiments, R11 is methyl.

[0092] In some embodiments, the compounds of the present invention have the structure of formula Id, or a pharmaceutically acceptable salt thereof: wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally replaced 3 to 6-membered cycloalkylene; optionally replaced 3 to 6-membered heterocyclic alkylene; optionally replaced 6-membered aryl; or optionally replaced 5 to 6-membered heterocyclic aryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally replaced 3 to 6-membered cycloalkylene; optionally replaced 3 to 6-membered heterocyclic alkylene; optionally replaced 6-membered aryl; or 5 to 6-membered heterocyclic aryl; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 and Y6 are independently CH or N. R1 is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered alkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally...The substituted 3- to 14-membered heterocyclic alkyl group; R4 is absent, is hydrogen, halogen, cyano, or methyl group optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atoms they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocyclic alkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl. Optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocyclic alkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; Specification 22 / 479 pages 27 CN 121974884 A R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.

[0093] In some embodiments of the compounds of the present invention, X1 is an optionally substituted C1-C2 alkylene. In some embodiments, X1 is methylene. In some embodiments, X1 is methylene substituted with a C1-C6 alkyl or halogen. In some embodiments, X1 is -CH(Br)-. In some embodiments, X1 is -CH(CH3)-. In some embodiments, R5 is hydrogen. In some embodiments, R5 is an optionally substituted C1-C4 alkyl. In some embodiments, R5 is methyl.In some embodiments, Y4 is C. In some embodiments, R4 is hydrogen. In some embodiments, Y5 is CH.

[0094] In some embodiments, Y6 is CH. In some embodiments, Y1 is C. In some embodiments, Y2 is C. In some embodiments, Y3 is N. In some embodiments, R3 is absent. In some embodiments, Y7 is C.

[0095] In some embodiments, the compounds of the present invention have the structure of formula Ie, or a pharmaceutically acceptable salt thereof: wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered aryl; or optionally substituted 5- to 6-membered heterocyclic aryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heterocyclic aryl; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R1 is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered alkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms to which they are attached, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl. R5 is hydrogen, optionally halogenated C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atoms to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 7-membered cycloalkyl.A 10-membered aryl group, or R7 and R8, combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl. R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.

[0096] In some embodiments of the compounds of the present invention, R6 is hydrogen. In some embodiments, R2 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heteroalkyl. In some embodiments, R2 is an optionally substituted C1-C6 alkyl. In some embodiments, R2 is fluoroalkyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is -CH2CF3. In some embodiments, R2 is C2-C6 alkynyl. In some embodiments, R2 is -CHC≡CH. In some embodiments, R2 is -CH2C≡CCH3. In some embodiments, R7 is an optionally substituted C1-C3 alkyl group. In some embodiments, R7 is a C1-C3 alkyl group. In some embodiments, R8 is an optionally substituted C1-C3 alkyl group. In some embodiments, R8 is a C1-C3 alkyl group.

[0097] In some embodiments, the compounds of the present invention have the structure of formula If, or a pharmaceutically acceptable salt thereof: wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloene alkyl group; optionally substituted 3- to 6-membered heterocycloene alkyl group; optionally substituted 6-membered aryl group; or optionally substituted 5- to 6-membered heterocycloene alkyl group; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloene alkyl group.alkyl; optionally substituted 3- to 6-membered heterocyclic alkyl; optionally substituted 6-membered aryl; or 5- to 6-membered heterocyclic aryl; Specification 24 / 479 pages 29 CN 121974884 AL is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylenone or acetylenyl sulfone; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocyclic alkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is a C1-C3 alkyl; and R9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl.

[0098] In some embodiments of the compounds of the present invention, R1 is an optionally substituted 6- to 10-membered aryl, an optionally substituted 3- to 6-membered cycloalkenyl, or an optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R1 is an optionally substituted 6-membered aryl, an optionally substituted 6-membered cycloalkenyl, or an optionally substituted 6-membered heteroaryl.

[0099] In some embodiments of the compounds of the present invention, R1 is, , , , , , , , or, or, a stereoisomer thereof (e.g., a transisomer). In some embodiments of the compounds of the present invention, R1 is, or, a stereoisomer thereof (e.g., a transisomer). In some embodiments of the compounds of the present invention, R1 is.

[0100] In some embodiments, the compounds of the present invention have the structure of formula Ig, or a pharmaceutically acceptable salt thereof: Specification 25 / 479 pages 30 CN 121974884 A Wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or optionally substituted 5 to 6-membered heterocyclic arylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heterocyclic arylene; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylenone, or acetylenyl sulfone; R2 is a C1-C6 alkyl, C1-C6 fluoroalkyl, or 3- to 6-membered cycloalkyl; R7 is a C1-C3 alkyl; R8 is a C1-C3 alkyl; andR9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; Xe and Xf are independently N or CH; and R12 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 6-membered heterocyclic alkylene.

[0101] In some embodiments of the compounds of the present invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0102] In some embodiments of the compounds of the present invention, R12 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R12 is, , , , , , , or. In some embodiments, R12 is.

[0103] In some embodiments, the compounds of the present invention have the structure of formula VI, or a pharmaceutically acceptable salt thereof: Specification 26 / 479 pages 31 CN 121974884 A Wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered aryl (e.g., phenyl or phenol); or optionally substituted 5 to 10-membered heteroalkylene; B is absent, is -CH(R9)-, >C=CR9R9' or >CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; Optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3- to 8-membered heteroarylene; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylacetone, haloacetal, or acetylacetonate; X1 is optionally substituted C1-C2 alkylene, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R'Independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; R3 is absent, or R2 and R3 combined with the atoms they are attached to form optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl; Specification 27 / 479 pages 32 CN 121974884 A R4 is absent, or is hydrogen, halogen, cyano, or a methyl group optionally substituted with one to three halogens; R5 is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or an optionally substituted C1-C3 alkyl group, or R6 and R7 combined with the carbon atoms they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, an optionally substituted C1-C3 alkoxy, an optionally substituted C1-C3 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted 3- to 8-membered cycloalkyl. Optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocyclic alkyl; R7a and R8a are independently hydrogen, halogroup, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl.R9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; or R9 and L combined with the atoms they are attached to form optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9' combined with the atoms they are attached to form 3- to 6-membered cycloalkyl or 3- to 6-membered heteroalkyl; R10 is hydrogen, halogroup, hydroxyl group, C1-C3 alkoxy group, or C1-C3 alkyl; R10a is hydrogen or halogroup; R11 is hydrogen or C1-C3 alkyl; R21 is hydrogen or C1-C3 alkyl (e.g., methyl); and Xe and Xf are independently N or CH.

[0104] In some embodiments, the compounds of the present invention have the structure of formula VIa, or a pharmaceutically acceptable salt thereof: Specification 28 / 479 pages 33 CN 121974884 A Wherein A is a optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered aryl (e.g., phenyl or phenol) or optionally substituted 5- to 6-membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heteroaryl; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylenone or acetylenyl sulfone; X1 is an optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; R2 is C1-C6 alkyl, C1-C6 fluoroalkyl, or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heteroalkyl; Xe and Xf are independently N or CH; R11 is hydrogen or a C1-C3 alkyl group; and R21 is hydrogen or a C1-C3 alkyl group.

[0105] In some embodiments of the compounds of the present invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0106] In some embodiments, the compounds of the present invention have the structure of formula VIb, or a pharmaceutically acceptable salt thereof:Page 34 of document 29 / 479 CN 121974884 A Wherein A is a substituted 3 to 6-membered cycloalkylene, a substituted 3 to 6-membered heterocycloalkylene, a substituted 6-membered aryl (e.g., phenyl or phenol) or a substituted 5 to 6-membered heterocycloalkylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; a substituted 3 to 6-membered cycloalkylene; a substituted 3 to 6-membered heterocycloalkylene; a substituted 6-membered aryl; or a 5 to 6-membered heterocycloalkylene; R9 is a substituted C1-C6 alkylene, a substituted C1-C6 heteroalkylene, a substituted 3 to 6-membered cycloalkyl or a substituted 3 to 7-membered heterocycloalkyl; L is absent or is a linker; and W is a crosslinking group comprising vinyl ketone, vinyl sulfone, alkynone or alkynyl sulfone. In some embodiments of the compounds of the present invention, A is an optionally substituted 6-membered arylene.

[0107] In some embodiments, the compounds of the present invention have the structure of formula VIc (corresponding to formula BB of Figures 1A and 1B), or a pharmaceutically acceptable salt thereof: wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered aryl (e.g., phenyl or phenol); or optionally substituted 5- to 10-membered heterocyclic aryl; B is absent, is -CH(R9)-, >C=CR9R9', or >CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered aryl (details 30 / 479) Page 35 CN 121974884 A arylene; or 5 to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenyl; optionally substituted C1-C4 heteroarylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroarylene; or 3 to 8-membered heteroarylene; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylacetone, haloacetal or acetylacetone; X1 is an optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally replacedThe substituted C2-C4 alkynyl group, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl. R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with their attached carbon atoms to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with their attached carbon atoms to form C=CR7'R8'. C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted... (See specification 31 / 479, page 36, CN 121974884 A) The 5- to 10-membered heteroaryl group or optionally substituted 6- to 10-membered aryl group, orR7' and R8', together with the carbon atoms they are attached to, form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; or R9 and L, together with the atoms they are attached to, form optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9', together with the atoms they are attached to, form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R10 is hydrogen, a halogroup, a hydroxyl group, a C1-C3 alkoxy group, or a C1-C3 alkyl group; R10a is hydrogen or a halogroup; R11 is hydrogen or a C1-C3 alkyl group; and R21 is hydrogen or a C1-C3 alkyl group (e.g., methyl).

[0108] In some embodiments, A has the following structure: wherein R13 is hydrogen, a halogroup, a hydroxyl group, an amino group, an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 heteroalkyl group; and R13a is hydrogen or a halogroup. In some embodiments, R13 is hydrogen. In some embodiments, R13 and R13a are each hydrogen. In some embodiments, R13 is hydroxyl, methyl, fluorine, or difluoromethyl.

[0109] In some embodiments, A is an optionally substituted 5- or 6-membered heteroaryl group. In some embodiments, A is: (See specification 32 / 479 pages 37 CN 121974884 A).

[0110] In some embodiments, A is an optionally substituted C1-C4 heteroalkyl group. In some embodiments, A is: (See specification 32 / 479 pages 37 CN 121974884 A). In some embodiments, A is: (See specification 32 / 479 pages 37 CN 121974884 A). In some embodiments, A is: (See specification 32 / 479 pages 37 CN 121974884 A). In some embodiments, A is: (See specification 32 / 479 pages 37 CN 121974884 A). In some embodiments, A is: (See specification 32 / 479 pages 37 CN 121974884 A). In some embodiments, A is: (See specification 32 / 479 pages 37 CN 121974884 A).

[0111] In some embodiments of the compounds of the present invention, B is -CHR9-. In some embodiments, R9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl. In some embodiments, R9 is: . In some embodiments, R9 is: . In some embodiments, R9 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl.

[0112] In some embodiments of the compounds of the present invention, B is optionally substituted 6-membered arylene. In some embodiments, B is 6-membered arylene. In some embodiments, B is: .

[0113] In some embodiments of the compounds of the present invention, R7 is methyl. Specification 33 / 479 pages 38 CN121974884 A

[0114] In some embodiments of the compounds of the present invention, R8 is methyl.

[0115] In some embodiments, R21 is hydrogen.

[0116] In some embodiments of the compounds of the present invention, the connector is a structure of formula II: wherein A1 is a bond between the connector and B; A2 is a bond between W and the connector; B1, B2, B3 and B4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S and NRN; RN is hydrogen, optionally substituted C1-4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3 to 14-membered heterocyclic alkyl, optionally substituted 6 to 10-membered aryl or optionally substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, sulfur Carbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; and D1 is an optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkyneene, optionally substituted 3- to 14-membered heterocyclic alkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 8-membered heterocyclic alkylene, optionally substituted 6- to 10-membered arylene, optionally substituted C2-C10 polyethylene glycol, or optionally substituted C1-C10 heteroalkylene, or a chemical bond connecting A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j-(B4)k–A2. In some embodiments, the linker is an acyclic linker. In some embodiments, the connector has the structure of formula IIa: wherein Xa is absent or is N; R14 is absent, is hydrogen or optionally substituted C1-C6 alkyl; and L2 is absent, is -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene, wherein at least one of Xa, R14 or L2 is present. In some embodiments, the connector has the following structure: .

[0117] In some embodiments, the connector is or comprises a cyclic portion. In some embodiments, the connector has the structure of formula IIb: where o is 0 or 1; R15 is hydrogen or optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloene alkyl, or optionally substituted 3- to 8-membered heterocycloene alkyl; X4 is absent, optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 heterocycloene alkyl; Cy is optionally substituted 3- to 8-membered cycloene alkyl, optionally substituted 3- to 8-membered heterocycloene alkyl, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heterocycloene alkyl; andL3 is absent, is -SO2-, optionally substituted C1-C4 alkylene, or optionally substituted C1-C4 heteroalkylene.

[0118] In some embodiments, the connector has the structure of formula IIb-1: where o is 0 or 1; R15 is hydrogen or optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heteroalkylene; Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heteroalkylene, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; and L3 is absent, is -SO2-, optionally substituted C1-C4 alkylene, or optionally substituted C1-C4 heteroalkylene.

[0119] In some embodiments, the connector has the structure of formula IIc: wherein R15 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocyclic alkylene; and R15a, R15b, R15c, R15d, R15e, R15f, and R15g are independently hydrogen, halogen, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or, or R15b and R15d combined with the carbon to which they are attached to form optionally substituted 3- to 8-membered cycloalkylene or optionally substituted 3- to 8-membered heterocyclic alkylene.

[0120] In some embodiments, the connector has the following structure: Specification 35 / 479 pages 40 CN 121974884 A.

[0121] In some embodiments, the connector has the following structure: (See page 36 / 479, CN 121974884 A; page 37 / 479, CN 121974884 A; page 38 / 479, CN 121974884 A; page 39 / 479, CN 121974884 A).

[0122] In some embodiments, the connector has a structure.

[0123] In some embodiments, the connector has a structure. In some embodiments of the compounds of the present invention, W is a crosslinking group comprising vinyl ketone. In some embodiments, W has the structure of formula IIIa: wherein R16a, R16b, and R16c are independently hydrogen; -CN; halogen; or -C1-C3 alkyl optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or 4 to 7-membered saturated heterocyclic alkyl. In some embodiments, W is: (Specification 40 / 479 pages 45 CN 121974884 A)In some embodiments, W is a crosslinking group comprising an acetylacetonate. In some embodiments, W has the structure of formula IIIb: wherein R17 is hydrogen; a -C1-C3 alkyl group optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or a 4- to 7-membered saturated heterocyclic alkyl group; or a 4- to 7-membered saturated heterocyclic alkyl group. In some embodiments, W is: Specification 41 / 479 pages 46 CN 121974884 A. In some embodiments, W is Specification 42 / 479 pages 47 CN 121974884 A.

[0124] In some embodiments, W is a crosslinking group comprising vinyl sulfone. In some embodiments, W has the structure of formula IIIc: wherein R18a, R18b, and R18c are independently hydrogen; -CN; or -C1-C3 alkyl optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or 4 to 7-membered saturated heterocyclic alkyl. In some embodiments, W is: or. In some embodiments, W is a crosslinking group comprising an alkynyl sulfone. In some embodiments, W has the structure of formula IIId: wherein R19 is hydrogen; -C1-C3 alkyl optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or 4 to 7-membered saturated heterocyclic alkyl; or 4 to 7-membered saturated heterocyclic alkyl. In some embodiments, W is: or. In some embodiments, W has the structure of formula IIIe: where Xe is a halogen; and R20 is hydrogen; a -C1-C3 alkyl group optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or 4 to 7-membered saturated heterocyclic alkyl. In some embodiments, W is a haloacetal. In some embodiments, W is not a haloacetal.

[0125] In some embodiments, the compounds of the present invention are selected from Table 1, or pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the compounds of the present invention are selected from Table 1, or pharmaceutically acceptable salts or transisomers thereof.

[0126] Table 1: Some compounds of the present invention (Pages 44 / 479, CN 121974884 A, Pages 45 / 479, CN 50)121974884 A Instruction Manual 46 / 479 pages 51 CN 121974884 A Instruction Manual 47 / 479 pages 52 CN 121974884 A Instruction Manual 48 / 479 pages 53 CN 121974884 A Instruction Manual 49 / 479 pages 54 CN 121974884 A Instruction Manual 50 / 479 pages 55 CN 121974884 A Instruction Manual 51 / 479 pages 56 CN 121974884 A Instruction Manual 52 / 479 pages 57 CN 121974884 A Instruction Manual 53 / 479 pages 58 CN 121974884 A Instruction Manual 54 / 479 pages 59 CN 121974884 A Instruction Manual 55 / 479 pages 60 CN 121974884 A Instruction manual 56 / 479 pages 61 CN 121974884 A Instruction manual 57 / 479 pages 62 CN 121974884 A Instruction manual 58 / 479 pages 63 CN 121974884 A Instruction manual 59 / 479 pages 64 CN 121974884 A Instruction manual 60 / 479 pages 65 CN 121974884 A Instruction manual 61 / 479 pages 66 CN 121974884 A Instruction manual 62 / 479 pages 67 CN 121974884 A Instruction manual 63 / 479 pages 68 CN 121974884 A Instruction manual 64 / 479 pages 69 CN 121974884 A Instruction manual 65 / 479 pages 70 CN 121974884 A Instruction manual 66 / 479 pages 71 CN 121974884 A Instruction Manual 67 / 479 pages 72 CN 121974884 A Instruction Manual 68 / 479 pages 73 CN 121974884 A Instruction Manual 69 / 479 pages 74 CN 121974884 A Instruction Manual 70 / 479 pages 75 CN 121974884 A Instruction Manual 71 / 479 pages 76 CN 121974884 A Instruction Manual 72 / 479 pages 77 CN 121974884 A Instruction Manual 73 / 479 pages 78 CN 121974884 A Instruction Manual 74 / 479 pages 79 CN 121974884 A Instruction Manual 75 / 479 pages 80 CN 121974884A Instruction Manual 76 / 479 pages 81 CN 121974884 A Instruction Manual 77 / 479 pages 82 CN 121974884 A Instruction Manual 78 / 479 pages 83 CN 121974884 A Instruction Manual 79 / 479 pages 84 CN 121974884 A Instruction Manual 80 / 479 pages 85 CN 121974884 A Instruction Manual 81 / 479 pages 86 CN 121974884 A Instruction Manual 82 / 479 pages 87 CN 121974884 A Instruction Manual 83 / 479 pages 88 CN 121974884 A Instruction Manual 84 / 479 pages 89 CN 121974884 A Instruction Manual 85 / 479 pages 90 CN 121974884 A Instruction Manual 86 / 479 pages 91 CN 121974884 A Instruction Manual 87 / 479 pages 92 CN 121974884 A Instruction Manual 88 / 479 pages 93 CN 121974884 A Instruction Manual 89 / 479 pages 94 CN 121974884 A Instruction Manual 90 / 479 pages 95 CN 121974884 A Instruction Manual 91 / 479 pages 96 CN 121974884 A Instruction Manual 92 / 479 pages 97 CN 121974884 A Instruction Manual 93 / 479 pages 98 CN 121974884 A Instruction Manual 94 / 479 pages 99 CN 121974884 A Instruction Manual 95 / 479 pages 100 CN 121974884 A Instruction Manual 96 / 479 pages 101 CN 121974884 A Instruction manual 97 / 479 pages 102 CN 121974884 A; Instruction manual 98 / 479 pages 103 CN 121974884 A; Instruction manual 99 / 479 pages 104 CN 121974884 A; Instruction manual 100 / 479 pages 105 CN 121974884 A; Instruction manual 101 / 479 pages 106 CN 121974884 A; Instruction manual 102 / 479 pages 107 CN 121974884 A; Instruction manual 103 / 479 pages 108 CN 121974884 A; Instruction manual 104 / 479 pages 109 CN 121974884 A; Instruction manual 105 / 479 pages 110 CN121974884 A Instruction Manual 106 / 479 Page 111 CN 121974884 A Instruction Manual 107 / 479 Page 112 CN 121974884 A Instruction Manual 108 / 479 Page 113 CN 121974884 A Instruction Manual 109 / 479 Page 114 CN 121974884 A Instruction Manual 110 / 479 Page 115 CN 121974884 A Instruction Manual 111 / 479 Page 116 CN 121974884 A Instruction Manual 112 / 479 Page 117 CN 121974884 A Instruction Manual 113 / 479 Page 118 CN 121974884 A Instruction Manual 114 / 479 Page 119 CN 121974884 A Instruction Manual 115 / 479 Page 120 CN 121974884 A Instruction Manual 116 / 479 Page 121 CN 121974884 A Instruction Manual 117 / 479 Page 122 CN 121974884 A Instruction Manual 118 / 479 Page 123 CN 121974884 A Instruction Manual 119 / 479 Page 124 CN 121974884 A Instruction Manual 120 / 479 Page 125 CN 121974884 A Instruction Manual 121 / 479 Page 126 CN 121974884 A Instruction Manual 122 / 479 Page 127 CN 121974884 A Instruction Manual 123 / 479 Page 128 CN 121974884 A Instruction Manual 124 / 479 Page 129 CN 121974884 A Instruction Manual 125 / 479 pages 130 CN 121974884 A Instruction Manual 126 / 479 pages 131 CN 121974884 A Instruction Manual 127 / 479 pages 132 CN 121974884 A Instruction Manual 128 / 479 pages 133 CN 121974884 A Instruction Manual 129 / 479 pages 134 CN 121974884 A Instruction Manual 130 / 479 pages 135 CN 121974884 A Instruction Manual 131 / 479 pages 136 CN 121974884 A Instruction Manual 132 / 479 pages 137 CN 121974884 A Instruction Manual 133 / 479 pages 138 CN 121974884 APages 134 / 479, 139 CN 121974884 A, Instruction Manual; Pages 135 / 479, 140 CN 121974884 A, Instruction Manual; Pages 136 / 479, 141 CN 121974884 A, Instruction Manual; Pages 137 / 479, 142 CN 121974884 A, Instruction Manual; Pages 138 / 479, 143 CN 121974884 A, Instruction Manual; Pages 139 / 479, 144 CN 121974884 A, Instruction Manual; Pages 140 / 479, 145 CN 121974884 A, Instruction Manual; Pages 141 / 479, 146 CN 121974884 A, Instruction Manual; Pages 142 / 479, 147 CN 121974884 A, Instruction Manual; Pages 143 / 479, 148 CN 121974884 A Instruction Manual 144 / 479 Pages 149 CN 121974884 A Instruction Manual 145 / 479 Pages 150 CN 121974884 A Instruction Manual 146 / 479 Pages 151 CN 121974884 A Instruction Manual 147 / 479 Pages 152 CN 121974884 A Instruction Manual 148 / 479 Pages 153 CN 121974884 A Instruction Manual 149 / 479 Pages 154 CN 121974884 A Instruction Manual 150 / 479 Pages 155 CN 121974884 A Instruction Manual 151 / 479 Pages 156 CN 121974884 A Instruction Manual 152 / 479 Pages 157 CN 121974884 A Instruction Manual 153 / 479 Page 158 CN 121974884 A Instruction Manual 154 / 479 Page 159 CN 121974884 A Instruction Manual 155 / 479 Page 160 CN 121974884 A Instruction Manual 156 / 479 Page 161 CN 121974884 A Instruction Manual 157 / 479 Page 162 CN 121974884 A Instruction Manual 158 / 479 Page 163 CN 121974884 A Instruction Manual 159 / 479 Page 164 CN 121974884 A Instruction Manual 160 / 479 Page 165 CN 121974884 A Instruction Manual 161 / 479 Page 166 CN 121974884 A Instruction Manual 162 / 479 Page 167 CN121974884 A Instruction Manual 163 / 479 Pages 168 CN 121974884 A Instruction Manual 164 / 479 Pages 169 CN 121974884 A Instruction Manual 165 / 479 Pages 170 CN 121974884 A Instruction Manual 166 / 479 Pages 171 CN 121974884 A Instruction Manual 167 / 479 Pages 172 CN 121974884 A Instruction Manual 168 / 479 Pages 173 CN 121974884 A Instruction Manual 169 / 479 Pages 174 CN 121974884 A Instruction Manual 170 / 479 Pages 175 CN 121974884 A Instruction Manual 171 / 479 Pages 176 CN 121974884 A Instruction Manual 172 / 479 Page 177 CN 121974884 A Instruction Manual 173 / 479 Page 178 CN 121974884 A Instruction Manual 174 / 479 Page 179 CN 121974884 A Instruction Manual 175 / 479 Page 180 CN 121974884 A Instruction Manual 176 / 479 Page 181 CN 121974884 A Instruction Manual 177 / 479 Page 182 CN 121974884 A Instruction Manual 178 / 479 Page 183 CN 121974884 A Instruction Manual 179 / 479 Page 184 CN 121974884 A Instruction Manual 180 / 479 Page 185 CN 121974884 A Instruction Manual 181 / 479 Page 186 CN 121974884 A Specification 182 / 479 pages 187 CN 121974884 A Specification 183 / 479 pages 188 CN 121974884 A Note that bonds in some compounds are shown as straight lines or wedges. In some cases, the relative stereochemistry of the stereoisomers has been determined; in some cases, the absolute stereochemistry has been determined. In some cases, a single example number corresponds to a mixture of stereoisomers. All stereoisomers of the compounds in the table above are covered in this invention. In certain embodiments, the transisomers of the compounds in the table above are covered.

[0127] Parentheses should be ignored.

[0128] *The activity of such stereoisomers is actually attributable to the presence of a small number of stereoisomers in the (S) configuration at the -NC(O)-CH(CH3)2-N(CH3)- position.

[0129] In some embodiments, compounds from Table 2 are provided, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of the present invention are selected from Table 2, or pharmaceutically acceptable salts or stereoisomers thereof.

[0130] Table 2: Some of the compounds of the present invention Specification 184 / 479 pages 189 CN 121974884 A Specification 185 / 479 pages 190 CN 121974884 A Specification 186 / 479 pages 191 CN 121974884 A Specification 187 / 479 pages 192 CN 121974884 A Specification 188 / 479 pages 193 CN 121974884 A Specification 189 / 479 pages 194 CN 121974884 A Specification 190 / 479 pages 195 CN 121974884 A Specification 191 / 479 pages 196 CN 121974884 A Specification 192 / 479 pages 197 CN 121974884 A Specification 193 / 479 Page 198 CN 121974884 A Instruction Manual 194 / 479 Page 199 CN 121974884 A Instruction Manual 195 / 479 Page 200 CN 121974884 A Instruction Manual 196 / 479 Page 201 CN 121974884 A Instruction Manual 197 / 479 Page 202 CN 121974884 A Instruction Manual 198 / 479 Page 203 CN 121974884 A Instruction Manual 199 / 479 Page 204 CN 121974884 A Instruction Manual 200 / 479 Page 205 CN 121974884 A Instruction Manual 201 / 479 Page 206 CN 121974884 A Instruction Manual 202 / 479 Page 207 CN 121974884 A Instruction manual 203 / 479 pages 208 CN 121974884 A Instruction manual 204 / 479 pages 209 CN 121974884 A Instruction manual 205 / 479 pages 210 CN 121974884 A Instruction manual 206 / 479 pages 211 CN 121974884 A Instruction manual 207 / 479 pages 212 CN 121974884 A Instruction manual 208 / 479 pages 213 CN 121974884 A Instruction manual 209 / 479 pages 214 CN 121974884 ASpecification 210 / 479 pages 215 CN 121974884 A Specification 211 / 479 pages 216 CN 121974884 A Specification 212 / 479 pages 217 CN 121974884 A Specification 213 / 479 pages 218 CN 121974884 A Specification 214 / 479 pages 219 CN 121974884 A Specification 215 / 479 pages 220 CN 121974884 A Specification 216 / 479 pages 221 CN 121974884 A Specification 217 / 479 pages 222 CN 121974884 A Specification 218 / 479 pages 223 CN 121974884 A Specification 219 / 479 pages 224 CN 121974884 A Instruction Manual 220 / 479 pages 225 CN 121974884 A Instruction Manual 221 / 479 pages 226 CN 121974884 A Instruction Manual 222 / 479 pages 227 CN 121974884 A Instruction Manual 223 / 479 pages 228 CN 121974884 A Instruction Manual 224 / 479 pages 229 CN 121974884 A Instruction Manual 225 / 479 pages 230 CN 121974884 A Instruction Manual 226 / 479 pages 231 CN 121974884 A Instruction Manual 227 / 479 pages 232 CN 121974884 A Instruction Manual 228 / 479 pages 233 CN 121974884 A Instruction Manual 229 / 479 Page 234 CN 121974884 A Instruction Manual 230 / 479 Page 235 CN 121974884 A Instruction Manual 231 / 479 Page 236 CN 121974884 A Instruction Manual 232 / 479 Page 237 CN 121974884 A Instruction Manual 233 / 479 Page 238 CN 121974884 A Instruction Manual 234 / 479 Page 239 CN 121974884 A Instruction Manual 235 / 479 Page 240 CN 121974884 A Instruction Manual 236 / 479 Page 241 CN 121974884 A Instruction Manual 237 / 479 Page 242 CN 121974884 A Instruction Manual 238 / 479 Page 243 CN121974884 A Instruction Manual 239 / 479 Page 244 CN 121974884 A Instruction Manual 240 / 479 Page 245 CN 121974884 A Instruction Manual 241 / 479 Page 246 CN 121974884 A Instruction Manual 242 / 479 Page 247 CN 121974884 A Instruction Manual 243 / 479 Page 248 CN 121974884 A Instruction Manual 244 / 479 Page 249 CN 121974884 A Instruction Manual 245 / 479 Page 250 CN 121974884 A Instruction Manual 246 / 479 Page 251 CN 121974884 A Instruction Manual 247 / 479 Page 252 CN 121974884 A Instruction Manual 248 / 479 Page 253 CN 121974884 A Specification 249 / 479 Page 254 CN 121974884 A Specification 250 / 479 Page 255 CN 121974884 A Specification 251 / 479 Page 256 CN 121974884 A Specification 252 / 479 Page 257 CN 121974884 A.

[0131] It should be noted that bonds in some compounds are shown as straight lines or wedges. In some cases, the relative stereochemistry of the stereoisomers has been determined; in some cases, the absolute stereochemistry has been determined. All stereoisomers of the compounds in the table above are covered in this invention. In certain embodiments, the transisomers of the compounds in the table above are covered.

[0132] In some embodiments, the compounds of the present invention are or are used as prodrugs, for example for administration to cells or to a subject in need.

[0133] Pharmaceutical compositions are also provided comprising the compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0134] A conjugate or salt thereof is further provided comprising the structure of formula IV: wherein L is a linker; P is a monovalent organic moiety; and M has the structure of formula Va: wherein the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered aryl; or optionally substituted 5 to 6-membered heteroaryl; B is absent, is -CH(R9)-, >C=CR9R9', or >CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-;Optionally substituted 3- to 6-membered cycloalkylene; Optionally substituted 3- to 6-membered heterocycloalkylene; Optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; Specification 253 / 479 pages 258 CN 121974884 AG is an optionally substituted C1-C4 alkylene; Optionally substituted C1-C4 alkenylene; Optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; Optionally substituted C1-C4 heteroalkylene; or 3- to 8-membered heteroarylene; X1 is an optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R1 is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocycloalkyl. R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl. R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl.R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, or optionally substituted C2-C6 alkenyl. R9 and L are either 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; or R9 and L, together with the atoms to which they are attached, form optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9', together with the atoms to which they are attached, form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R10 is hydrogen, a halogroup, a hydroxyl group, a C1-C3 alkoxy group, or a C1-C3 alkyl group; R10a is hydrogen or a halogroup; and R11 is hydrogen or a C1-C3 alkyl group.

[0135] In some embodiments, the conjugate or its salt comprises a structure of formula IV: wherein L is a linker; P is a monovalent organic moiety; and M has a structure of formula Vb: wherein the dashed line represents zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to a carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered aryl; or optionally substituted 5- to 6-membered heteroalkylene;B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein the C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein the C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3- to 8-membered heteroarylene; Specification 255 / 479 pages 260 CN 121974884 A X1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R1 is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocycloalkyl. R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms they are attached to, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, is hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, orR6 and R7, together with the carbon atoms to which they are attached, form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7 and R8, together with the carbon atoms to which they are attached, form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halogroup, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R9 and L combined with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, a halogroup, a hydroxyl group, a C1-C3 alkoxy group, or a C1-C3 alkyl group; R10a is hydrogen or a halogroup; and R11 is hydrogen or a C1-C3 alkyl group.

[0136] In some embodiments, the conjugate has the structure of formula IV: where L is a linker; P is a monovalent organic moiety; and M has the structure of formula Vc: where the dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered aryl; or optionally substituted 5- to 6-membered heteroalkylene;B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein the C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein the C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3- to 8-membered heteroarylene; X1 is optionally substituted C1-C2 alkylene, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; Specification 257 / 479, page 262, CN 121974884. AR is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered alkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms to which they are attached, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl; R4 is absent, or is hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens. R5 is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano, a hydroxyl or a C1-C4 alkoxy group, a cyclopropyl or a cyclobutyl group; R6 is hydrogen or methyl; R7 is hydrogen, a halogen or an optionally substituted C1-C3 alkyl group, or R6 and R7 combined with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group; R8 is hydrogen, a halogen, a hydroxyl, a cyano, an optionally substituted C1-C3 alkoxy group, an optionally substituted C1-C3 alkyl group.R7 and R8, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atoms to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0137] In some embodiments, the compounds of the present invention have the structure of formula IV: Specification 258 / 479 pages 263 CN 121974884 A where L is a linker; P is a monovalent organic moiety; and M has the structure of formula Vd: where A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered aryl (e.g., phenyl or phenol) or optionally substituted 5- to 6-membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocycloalkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heteroaryl; X1 is an optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl;R2 is a C1-C6 alkyl, C1-C6 fluoroalkyl, or 3- to 6-membered cycloalkyl; R7 is a C1-C3 alkyl; R8 is a C1-C3 alkyl; and R9 is optionally a substituted C1-C6 alkyl, optionally a substituted C1-C6 heteroalkyl, optionally a substituted 3- to 6-membered cycloalkyl, or optionally a substituted 3- to 7-membered heteroalkyl; Xe and Xf are independently N or CH; R11 is hydrogen or C1-C3 alkyl; and R21 is hydrogen or C1-C3 alkyl.

[0138] In some embodiments of the compounds of the present invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0139] In some embodiments, the compounds of the present invention have the structure of formula IV: Specification 259 / 479 pages 264 CN 121974884 A where L is a linker; P is a monovalent organic moiety; and M has the structure of formula Ve: where A is an optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered aryl (e.g., phenyl or phenol) or optionally substituted 5 to 6-membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heteroalkylene; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl.

[0140] In some embodiments of the conjugates of the present invention, the connector has the structure of Formula II: Wherein A1 is the bond between the connector and B; A2 is the bond between P and the connector; B1, B2, B3, and B4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl. The C1 and C2 groups are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl groups; f, g, h, i, j, and k are each independently 0 or 1; and D1 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 ynynyl, optionally substituted 3- to 14-membered heterocyclic alkylene, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 6- to 10-membered aryl, optionally substituted C2-C10 alkylene...Polyethylene glycol or optionally substituted C1-C10 heteroalkylene groups, or a chemical bond connecting A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j-(B4)k–A2.

[0141] In some embodiments of the conjugates of the present invention, the monovalent organic moiety is a protein, such as Ras protein. In some embodiments, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras proteins are described herein. In some embodiments, the linker is attached to the monovalent organic moiety via a bond to a sulfhydryl group in an amino acid residue of the monovalent organic moiety. In some embodiments, the linker is bonded to the monovalent organic moiety via a bond to the carboxyl group of an amino acid residue of the monovalent organic moiety.

[0142] Further, a method of treating a subject with cancer is provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof. The cancer may be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or squamous cell lung cancer. In some embodiments, the cancer comprises a Ras mutation, such as K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras mutations are described herein.

[0143] Further, a method of treating a subject with Ras protein-related conditions is provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0144] A method for inhibiting Ras protein in cells is further provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras proteins are described herein. The cells may be cancer cells, such as pancreatic cancer cells, colorectal cancer cells, non-small cell lung cancer cells, acute myeloid leukemia cells, multiple myeloma cells, thyroid adenocarcinoma cells, myelodysplastic syndrome cells, or squamous cell lung cancer cells. Other cancer types are described herein. The cells may be in vivo or in vitro.

[0145] For the compounds of the present invention, one stereoisomer may exhibit inhibitory activity superior to another stereoisomer.For example, one transisomer may exhibit inhibitory activity, while another transisomer may exhibit very low or no inhibitory activity.

[0146] In some embodiments, the methods or uses described herein may also include administration of additional anticancer therapies. In some embodiments, said additional anticancer therapies are HER2 inhibitors, EGFR inhibitors, second Ras inhibitors, SHP2 inhibitors, SOS1 inhibitors, Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors, mTORC1 inhibitors, BRAF inhibitors, PD-L1 inhibitors, PD-1 inhibitors, CDK4 / 6 inhibitors, or combinations thereof. In some embodiments, said additional anticancer therapies are SHP2 inhibitors. Other additional anticancer therapies are described herein.

[0147] Synthetic Methods The compounds described herein may be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes.

[0148] The compounds of the present invention may be prepared by a variety of methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described in the following schemes, as well as synthetic methods known in the field of synthetic organic chemistry or modifications of the methods as understood by those skilled in the art. These methods include, but are not limited to, the methods described in the following schemes.

[0149] Scheme 1. General Synthesis of Macrocyclic Esters 261 / 479 pages 266 CN 121974884 A Scheme 1 outlines the general synthesis of macrocyclic esters. Appropriately substituted aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylprop-1-ol (1) can be prepared in three steps from protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylprop-1-ol and appropriately substituted boric acid as starting materials, including palladium-mediated coupling, alkylation and deprotection reactions. The amino-hexahydropyridazine-3-carboxylate-boronate (2) can be prepared in three steps, including protection, iridium catalyst-mediated boronization, and coupling with (S)-hexahydropyridazine-3-carboxylate methyl ester.

[0150] Appropriately substituted acetylpyrrolidine-3-carbonyl-N-methyl-L-valine (or alternative amino acid derivative) (4) can be prepared by coupling a methyl-L-valine ester with protected (S)-pyrrolidine-3-carboxylic acid, followed by deprotection, coupling with a carboxylic acid containing an appropriately substituted Michael acceptor, and hydrolysis.

[0151] The final macrocyclic ester can be prepared by coupling amino-hexahydropyridazine-3-carboxylate-boronate (2) with aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylprop-1-ol (1) in the presence of a Pd catalyst, followed byHydrolysis and macrocyclic lactone esterification steps are performed to obtain a suitably protected macrocyclic intermediate (5). Deprotection and coupling with a suitably substituted intermediate 4 yield a macrocyclic product. Additional deprotection and / or functionalization steps may be required to prepare the final compound.

[0152] Scheme 2. Alternatives to macrocyclic esters General Synthesis Specification 262 / 479 pages 267 CN 121974884 A Alternatively, macrocyclic esters may be prepared as described in Scheme 2. A suitably protected bromo-indole group (6) is coupled with a borate ester (3) in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. Subsequently, coupling with (S)-hexahydropyridazine-3-carboxylate, followed by hydrolysis and macrocyclic lactone esterification, yields an iodine intermediate (7). Coupling with a suitably substituted borate ester and alkylation in the presence of a Pd catalyst yields a fully protected macrocycle (5). Additional deprotection or functionalization steps are required to prepare the final compound.

[0153] Furthermore, those skilled in the art will understand that the compounds disclosed herein can be synthesized using the methods described in the following examples, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof. These methods include, but are not limited to, the methods described in the following examples. For example, those skilled in the art will be able to attach the desired -B-L-W group to a macrocyclic ester of formula (I), wherein B, L, and W are as defined herein, including by using the methods exemplified in the Examples section of this document.

[0154] The compounds in Table 1 herein are prepared using the methods disclosed herein, or using the methods disclosed herein in combination with the knowledge of those skilled in the art. The compounds in Table 2 can be prepared using the methods disclosed herein, or using the methods disclosed herein in combination with the knowledge of those skilled in the art.

[0155] Scheme 3. General Synthesis of Macrocyclic Esters 263 / 479 pages 268 CN 121974884 A Alternative general synthesis of macrocyclic esters is outlined in Scheme 3. Appropriately substituted indole boronic acid esters (8) can be prepared in four steps using protected 3-(5-bromo-2-iodo-1H-indole-3-yl)-2,2-dimethylprop-1-ol and appropriately substituted boronic acid as starting materials, including palladium-mediated coupling, alkylation, deprotection and palladium-mediated borylation.

[0156] Methyl amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (10) can be prepared by coupling (S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid (9) with methyl (S)-hexahydropyridazine-3-carboxylate.

[0157] The final macrocyclic ester can be prepared by coupling methyl amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (10) with a suitably substituted indole borate ester (8) in the presence of a Pd catalyst, followed by hydrolysis andA macrocyclic lactone step is performed to obtain a suitably protected macrocyclic intermediate (11). Deprotection and coupling with a suitably substituted intermediate 4 yield a macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 13 or 14.

[0158] Scheme 4. General Synthesis of Macrocyclic Esters Scheme 4 outlines alternative general synthesis of macrocyclic esters. A suitably substituted morpholine or alternative heterocyclic intermediate (pages 264 / 479, CN 121974884 A (15)) can be coupled with a suitably protected intermediate 1 via palladium-mediated coupling. Ester hydrolysis and coupling with piperazoic ester yield intermediate 16.

[0159] Macrocyclic esters can be prepared by hydrolysis, deprotection, and macrocyclic processes. Deprotection and coupling with intermediate 4 (or the like) yield a suitably substituted final macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 17.

[0160] Scheme 5. General Synthesis of Macrocyclic Esters Scheme 5 outlines alternative general synthesis of macrocyclic esters. A suitably substituted macrocycle (20) can be prepared from a suitably protected borate ester 18 and a bromoindole intermediate (19) as starting materials, including palladium-mediated coupling, hydrolysis, coupling with a piperazine ester, hydrolysis, deprotection, and macrocyclization steps. Subsequently, it is coupled with a suitably substituted protected amino acid, followed by palladium-mediated coupling to give intermediate 21. Additional deprotection and derivatization steps, including alkylation, may be required at this point.

[0161] The final macrocyclic ester can be prepared by coupling intermediate (22) with a suitably substituted carboxylic acid intermediate (23). Additional deprotection or functionalization steps may be required to prepare the final compound (24).

[0162] Furthermore, the compounds of this disclosure can be synthesized using the methods described in the following examples, as well as synthetic methods known in the field of synthetic organic chemistry, or modifications of the methods as understood by those skilled in the art. These methods include, but are not limited to, the methods described in the following examples. For example, those skilled in the art will be able to attach the desired -B-L-W group to a macrocyclic ester of formula (I), wherein B, L, and W are as defined herein, including by using the methods exemplified in the Examples section herein.

[0163] Pharmaceutical Compositions and Methods of Use Pharmaceutical Compositions and Methods of Administration The compounds involved in this invention are Ras inhibitors and can be used to treat cancer. Therefore, one embodiment of the invention provides pharmaceutical compositions comprising the compounds of the invention or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients, and methods for preparing such compositions using the compounds of the invention.

[0164] As used herein, the term "pharmaceutical composition" refers to a compound formulated with a pharmaceutically acceptable excipient, such as the compounds of the invention or pharmaceutically acceptable salts thereof.

[0165] In some embodiments, the compound is present in the drug composition in an amount suitable for a unit dose to be administered in a treatment regimen, as per the drug information sheet 265 / 479, page 270, CN 121974884 A, which shows a statistically significant likelihood of achieving the intended therapeutic effect when administered to the relevant population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for administration in the following ways: oral administration, such as solutions (aqueous or non-aqueous solutions or suspensions), tablets (e.g., tablets targeted for absorption via the buccal, sublingual, and systemic routes), pills, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions, or sustained-release formulations; surface administration, such as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or mouth; intravaginal or rectal administration, such as pessaries, creams, or foams; sublingual administration; ocular administration; transdermal administration; or nasal, lung, and other mucosal surfaces.

[0166] As used herein, “pharmaceuticalally acceptable excipient” means any inactive ingredient (e.g., a medium capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in the body of a subject. Typical excipients include, for example: anti-adhesion agents, antioxidants, adhesives, coating agents, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavoring agents, fragrances, flow enhancers, lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners or water for hydration. Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, croscarmellose, croscarmellose, citric acid, croscarmellose, cysteine, ethyl cellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. A variety of reagents and materials are well known to those skilled in the art as excipients. See, for example, Ansel et al., Ansel's Physical Data Storage Forms and Data Delivery SystemsPhiladelphia: Lippincott, Williams & Wilkins, 2004; Gennaro et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0167] Unless expressly stated otherwise, the compounds described herein may be provided or utilized in salt form, such as pharmaceutically acceptable salt form, whether explicitly stated otherwise. As used herein, the term "pharmaceutically acceptable salt" means a salt of the compound described herein that, within the limits of reasonable medical judgment, is suitable for use in contact with human tissues without excessive toxicity, irritation, anaphylactic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (edited by PHStahl and CGWermuth), Wiley-VCH, 2008. These salts may be prepared in situ during the final separation and purification of the compounds described herein, or separated by reacting the free base group with a suitable organic acid.

[0168] The compounds of the present invention may have ionizable groups, thereby enabling their preparation into pharmaceutically acceptable salt forms. These salts may be acid addition salts involving inorganic or organic acids, or, in the case of compounds of the present invention in acid form, the salts may be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared or used in pharmaceutically acceptable salt forms, which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as acids (sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid) used to form acid addition salts; and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, etc., used to form base salts. Methods for preparing suitable salts are recognized in the art.

[0169] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disaccharide, dodecyl sulfate, ethanesulfonate, transbutenedioate, glucono-heptahydrate, glyceryl phosphate, hemisulfate, heptahydrate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-optionally substituted hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectinate. Persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0170] As used herein, the term “subject” means any member of the animal kingdom. In some embodiments, “subject” means a human being at any developmental stage. In some embodiments, “subject” means a human patient. In some embodiments, “subject” means a non-human animal. In some embodiments, a non-human animal is a mammal (e.g., rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cattle, primate, or pig). In some embodiments, a subject includes, but is not limited to, mammals, birds, reptiles, amphibians, fish, or insects. In some embodiments, the subject may be a transgenic animal, a genetically engineered animal, or a clone.

[0171] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (e.g., the compound of the present invention) to be administered to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, this amount is an amount (or a whole portion thereof) of a unit dose suitable for administration according to a dosing regimen that is determined to be associated with a desired or beneficial outcome when administered to a relevant population (i.e., according to a therapeutic dosing regimen). Those skilled in the art will understand that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0172] As used herein, the term "dosing regimen" refers to a set of unit doses (typically more than one unit dose) administered individually to a subject, said unit doses typically spaced at intervals. In some embodiments, a given therapeutic compound (e.g., the compound of the present invention) has a recommended dosing regimen that may involve one or more doses. In some embodimentsIn some embodiments, the dosing regimen comprises multiple doses, each dose being spaced at equal intervals between them; in some embodiments, the dosing regimen comprises multiple doses and at least two distinct time intervals separating the individual doses. In some embodiments, all doses within the dosing regimen are amounts of the same unit dose. In some embodiments, the different doses within the dosing regimen are different amounts. In some embodiments, the dosing regimen comprises a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose different from the first dose. In some embodiments, the dosing regimen comprises a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose identical to the first dose. In some embodiments, the dosing regimen, when administered to a relevant population (i.e., a therapeutic dosing regimen), is associated with a desired or beneficial outcome.

[0173] A “treatment regimen” refers to a dosing regimen administered in a relevant population that is associated with a desired or beneficial therapeutic outcome.

[0174] The term “treatment” (“treatment / treat / treating”) in its broadest sense refers to any application of a substance (e.g., the compounds of the present invention) that partially or completely relieves, improves, reduces, or inhibits one or more symptoms, features, or causes of a particular disease, condition, or disorder; delays its onset; reduces its severity; or reduces its occurrence. In some embodiments, this treatment may be administered to a subject who does not exhibit signs of the relevant disease, condition, or disorder, or to a subject who exhibits only early signs of the disease, condition, or disorder. Alternatively or additionally, in some embodiments, the treatment may be administered to a subject who exhibits one or more identified signs of the relevant disease, condition, or disorder. In some embodiments, the treatment may be used to a subject who has been diagnosed with the relevant disease, condition, or disorder. In some embodiments, the treatment may be used to a subject known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, condition, or disorder.

[0175] The term "therapeuticly effective amount" means an amount sufficient to treat a disease, condition, or disorder when administered according to a therapeutic dosing regimen to a population suffering from or susceptible to such a disease, condition, or disorder. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence or severity of one or more symptoms of the disease, condition, or disorder, or delays its onset. Those skilled in the art will understand that the term "therapeuticly effective amount" does not actually require achieving the desired successful treatment in a particular individual. In fact, a therapeutically effective amount can be an amount that provides a specific desired pharmacological response in a substantial number of subjects when administered to patients who require this treatment. It is particularly important to understand that a particular subject may actually be "therapeuticly effective" and "refractory."In some embodiments, the therapeutically effective amount mentioned may refer to an amount measured in one or more specific tissues (e.g., tissues affected by a disease, symptom, or ailment) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, the therapeutically effective amount may be formulated as a single dose or administered in a single dose. In some embodiments, the therapeutically effective amount may be formulated as multiple doses, for example, as part of a dosing regimen, or administered in multiple doses.

[0176] For use as treatment of a subject, the compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as pharmaceutical compositions or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the desired type of treatment, such as prevention, treatment, or therapy, the compounds or pharmaceutically acceptable salts thereof are formulated in a manner consistent with these parameters. An overview of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J. C. Boylan, 1988–1999, Marcel Dekker, New York, each incorporated herein by reference.

[0177] The compositions may be prepared according to conventional mixing, granulation, or coating methods, and the pharmaceutical compositions of the present invention may contain, by weight or volume, about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the compounds of the present invention or pharmaceutically acceptable salts thereof. In some embodiments, the presence of the compounds described herein or pharmaceutically acceptable salts thereof may be 1–95% by weight of the total amount of the composition, such as the pharmaceutical composition.

[0178] The composition may be provided in dosage forms suitable for administration as follows: intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, skin, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, sac-like, intraurethral, ​​intrathecal, epidural, ear- or eye-borne, or by injection, inhalation, or direct contact with the mucous membranes of the nose, genitourinary, genital, or oral cavity. Therefore, the pharmaceutical composition may be, for example, in the form of tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, liquids, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, formulations suitable for iontophoresis delivery, or aerosols. The composition may be formulated according to conventional pharmaceutical practice.

[0179] As used herein, the term “administration” means the application of a composition (e.g., a compound or comprising as described herein) to a substance.The formulation of the compound is administered to a subject or system. Administration to animal subjects (e.g., to humans) can be performed via any suitable route. For example, in some embodiments, administration can be by bronchial (including bronchial infusion), buccal, intestinal, interdermal, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intrasacral, transmucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including intratracheal infusion), transdermal, vaginal, or vitreous administration.

[0180] The formulation can be prepared in a manner suitable for systemic or topical / topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or those prepared for transdermal, transmucosal, or oral administration. The formulation will typically include a diluent, and in some cases, adjuvants, buffers, preservatives, etc. The compound or a pharmaceutically acceptable salt thereof may also be administered in liposome compositions or as a microemulsion.

[0181] For injection, the formulation may be prepared in conventional forms, such as liquid solutions or suspensions, or in solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or in emulsion forms. Suitable excipients include, for example, water, physiological saline, dextran, glycerol, etc. Such compositions may also contain a certain amount of nontoxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitol monolaurate, etc.

[0182] Various sustained-release drug systems have also been designed. See, for example, U.S. Patent No. 5,624,677.

[0183] Systemic administration may also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or pharmaceutically acceptable salts thereof. It will be understood in the art that suitable forms include syrups, capsules, and tablets.

[0184] Each compound or pharmaceutically acceptable salt thereof described herein can be formulated in a variety of ways known in the art. For example, the first and second agents in a combination therapy can be formulated together or separately. Other modalities of combination therapy are also described herein.

[0185] Individual or separately formulated agents can be packaged together in a pillbox form. Non-limiting examples include, but are not limited to, pillboxes containing, for example, two pills, one pill and powder, suppositories or liquids in vials, two topical creams, etc. The pillbox may include optional components to facilitate the administration of a unit dose to a subject, such as vials for reconstitution of powder form, syringes, custom IV delivery systems, inhalers, etc. Additionally, the unit dose pillbox may contain instructions for the preparation and administration of the composition. The pillbox may be manufactured for a single unit dose for one subject, for multiple uses for a specific subject (at a constant dose, or where the potency of individual compounds or pharmaceutically acceptable salts thereof may vary with treatment).(subject to change as treatment progresses); or the kit may contain multiple doses suitable for administration to multiple subjects (“integrated package”). The kit assembly may be assembled in a carton, blister pack, bottle, tube, etc.

[0186] Formulations for oral use include tablets containing a mixture of the active ingredient and a non-toxic, pharmaceutically acceptable excipient. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives, including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginate, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methyl cellulose, optionally substituted hydroxypropyl methyl cellulose, ethyl cellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0187] Two or more compounds may be mixed together in tablets, capsules, or other media, or may be separated. In one example, the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that the majority of the second compound is released before the first compound is released.

[0188] Formulations for oral use may also be provided in the form of chewable tablets, or in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin); or in the form of soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and fine granules may be prepared using the ingredients mentioned above with respect to tablets and capsules, in a conventional manner, using, for example, a mixer, a fluid bed apparatus, or a spray drying device. Instructions for Use, pages 269 / 479, 274, CN 121974884 A

[0189] Controlled release of dissolution or diffusion can be achieved by appropriately coating the compound with tablets, capsules, fine granules or granules, or by incorporating the compound or a pharmaceutically acceptable salt thereof into a suitable matrix. Controlled release coatings may include one or more of the above-mentioned coating substances, such as shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethyl methacrylate, etc.2-Optionally substituted hydroxymethyl methacrylate, methyl methacrylate, 2-optionally substituted hydroxymethyl methacrylate, methyl methacrylate hydrogel, 1,3-butanediol, ethylene glycol methacrylate, or polyethylene glycol. In controlled-release matrix formulations, matrix materials may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0190] Liquid forms of compounds or pharmaceutically acceptable salts and compositions thereof that can be incorporated into the present invention for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical carriers.

[0191] Generally, when administered to humans, the oral dose of any compound of the present invention or a pharmaceutically acceptable salt thereof will depend on the nature of the compound and can be readily determined by those skilled in the art. The dosage may be, for example, about 0.001 mg to about 2000 mg daily, about 1 mg to about 1000 mg daily, about 5 mg to about 500 mg daily, about 100 mg to about 1500 mg daily, about 500 mg to about 1500 mg daily, about 500 mg to about 2000 mg daily, or any range derived therefrom.

[0192] In some embodiments, the pharmaceutical composition may also contain additional compounds having antiproliferative activity. Depending on the administration method, the compound or a pharmaceutically acceptable salt thereof will be formulated into a suitable composition for easy delivery. Each compound or a pharmaceutically acceptable salt thereof in the combination therapy may be formulated in a variety of ways known in the art. For example, the first and second agents in the combination therapy may be formulated together or separately. Ideally, the first and second agents are formulated together for simultaneous or near-simultaneous administration of the agents.

[0193] It should be understood that the compound and pharmaceutical compositions of the present invention can be formulated and used in combination therapies, that is, the compound and pharmaceutical compositions can be formulated together with one or more other desired therapeutic agents or medical procedures or administered concurrently with, before or after the administration of one or more other desired therapeutic agents or medical procedures. Specific combinations of the therapies (therapeutic agents or procedures) used in a combination regimen should take into account the compatibility of the desired therapeutic agent or procedure with the desired therapeutic effect to be achieved. It should also be understood that the therapies used may achieve the desired effect for the same condition, or they may achieve different effects (e.g., control any adverse effects).

[0194] As described herein, the administration of each drug in a combination therapy can be independent, from once to four times daily, for one day to one year, and even for the subject's lifetime. Chronic long-term administration may be required.

[0195] Method of UseIn some embodiments, the present invention discloses a method for treating a disease or condition characterized by abnormal Ras activity caused by a Ras mutant. In some embodiments, the disease or condition is cancer.

[0196] Therefore, a method for treating cancer in a subject in need is also provided, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary site, endometrial cancer, esophageal and gastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal cancer, endometrial cancer, or melanoma. Also provided is a method for treating Ras protein-related conditions in a subject requiring the instructions (pages 270 / 479, 275 CN 121974884 A), the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0197] In some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising such a compound or salt, and the methods provided herein can be used to treat a variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compound of the present invention or a salt thereof, pharmaceutical compositions comprising such a compound or salt, and methods include, but are not limited to, the following tumor types: astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral cavity, ovarian, prostate, and thyroid carcinomas and sarcomas. Other cancers include, for example: Heart cancers such as: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung cancers such as: bronchogenic carcinomas (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancers such as: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet tumor, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma), leiomyosarcoma, hemangioma, lipoma, etc. Neurofibroma, fibroma); colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital tract, such as: kidney (adenocarcinoma, Wilms' tumor).Tumors (including nephroblastoma, lymphoma, and leukemia); bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma); prostate (adenocarcinoma and sarcoma); testes (seminomatous tumor, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, and lipoma); liver, such as hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bile ducts, such as gallbladder cancer, ampullary cancer, and bile duct cancer; bones, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, and malignant giant cell tumor. Chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumors; Nervous system, such as: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma; Gynecological diseases, such as: uterus (endometrial cancer, uterine cancer, endometrial cancer), cervix (cervical cancer, cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (cancer); Hematopoietic system diseases, such as: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodyplasia syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Instruction manual 271 / 479 pages 276 CN 121974884 A Skin, such as: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands, such as: neuroblastoma.

[0198] In some embodiments, the Ras protein is wild-type (RasWT). Therefore, in some embodiments, the present inventionThe compounds of this invention are used in methods of treating patients with cancers containing RasWT (e.g., K-RasWT, H-RasWT, or N-RasWT). In some embodiments, the Ras protein is a Ras amplification (e.g., K-Rasamp). Therefore, in some embodiments, the compounds of this invention are used in methods of treating patients with cancers containing Rasamp (K-Rasamp, H-Rasamp, or N-Rasamp). In some embodiments, the cancer contains a Ras mutation, such as the Ras mutation described herein. In some implementations, the mutation is selected from: (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R, and combinations thereof; and (c) the following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, and combinations thereof; or any combination thereof. In some embodiments, the cancer comprises a K-Ras mutation selected from the group consisting of: G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L. In some embodiments, the cancer comprises an N-Ras mutation selected from the group consisting of: G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer comprises an H-Ras mutation selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V.Mutations: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit more than one Ras mutant. For example, the compounds can inhibit both K-Ras G12C and K-Ras G13C. The compounds can inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, the compounds can inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, the compounds can inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the compounds can inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the compounds of the present invention inhibit RasWT and one or more additional Ras mutations (e.g., K-, H-, or N-RasWT and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K-, H-, or N-RasWT and H-Ras Q61R, G13R, Q61K, ...). G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R; or K, H or N-RasWT and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T. In some embodiments, the compounds of the present invention inhibit Rasamp and one or more additional Ras mutations (e.g., K-, H-, or N-Rasamp and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K-, H-, or N-Rasamp and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, Specification 272 / 479 pages)277 CN 121974884 A G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R; or K, H or N-Rasamp and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T).

[0199] Methods for detecting Ras mutations are known in the art. Such methods include, but are not limited to, direct sequencing and the use of highly sensitive diagnostic assays (using CE-IVD markers), such as those described in Domagala et al., Pol J Pathol 3: 145-164 (2012), which are incorporated herein by reference in their entirety, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreenPyro. See also, for example, WO 2020 / 106640.

[0200] In some embodiments, the cancer is non-small cell lung cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is colorectal cancer and the Ras mutation includes a K-Ras mutation, such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is pancreatic cancer and the Ras mutation includes a K-Ras mutation, such as K-Ras G12D or K-Ras G12V. In some embodiments, the cancer is pancreatic cancer and the Ras mutation includes an N-Ras mutation, such as N-Ras G12D. In some embodiments, the cancer is melanoma and the Ras mutation includes an N-Ras mutation, such as N-Ras Q61R or N-Ras Q61K. In some embodiments, the cancer is non-small cell lung cancer and the Ras protein is K-Rasamp. In any of the foregoing, unless otherwise specified, the compound may also inhibit RasWT (e.g., K-, H-, or N-RasWT) or Rasamp (e.g., K-, H-, or N-Rasamp).

[0201] In some embodiments, the cancer comprises a Ras mutation and mutations in STK11LOF, KEAP1, EPHA5, or NF1. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises both a K-Ras G12C mutation and an STK11LOF mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises both a K-Ras G12C mutation and an STK11LOF mutation. In some embodiments, the cancer comprises a K-Ras G13C Ras mutation and mutations in STK11LOF, KEAP1, EPHA5, or NF1. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12V mutation. In some embodiments, the cancer is colorectal cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and contains a K-Ras G12C or K-Ras G12D mutation. In some embodiments, the cancer is pancreatic cancer and contains a K-Ras G12V mutation. In some embodiments, the cancer is endometrial cancer, ovarian cancer, bile duct cancer, or mucinous appendix cancer and contains a K-Ras G12C mutation. In some embodiments, the cancer is gastric cancer and contains a K-Ras G12C mutation. In any of the foregoing, the compound may also inhibit RasWT (e.g., K-, H-, or N-RasWT) or Rasamp (e.g., K-, H-, or N-Rasamp).

[0202] A method for inhibiting Ras protein in cells is also provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. A method for inhibiting RAF-Ras binding is also provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The cells may be cancer cells. The cancer cells may belong to any type of cancer described herein. The cells may be in vivo or in vitro.

[0203] Combination Therapy: The method of the present invention may include the compounds of the present invention used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). When administered alone, the dose of one or more of the additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may be reduced relative to a standard dose. For example, the dose may be determined empirically based on the combination and arrangement of drugs or inferred by isoradiometric analysis (e.g., Black et al., Neurology 65: S3-S6 (2005)). Specification 273 / 479 pages 278 CN 121974884 A

[0204] The compounds of the present invention may be administered before, after, or simultaneously with one or more of such additional therapies. When combined, the dose of the compound of the present invention and the dose of the one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). The compounds of the present invention and additional therapies, such as anticancer agents, may be administered together, for example, as a single pharmaceutical composition, or separately, and when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close or distant in time.

[0205] In some embodiments, the additional therapy is the administration of a side effect limiter (e.g., an agent designed to reduce the occurrence or severity of treatment side effects). For example, in some embodiments, the compounds of the present invention may also be used in combination with a therapeutic agent for treating nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0206] In some embodiments, the one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies include therapeutic agents (e.g., compounds or biologics as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, the one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biologics as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, the one or more additional therapies include two therapeutic agents. In yet another embodiment, the one or more additional therapies include three therapeutic agents. In some embodiments, the one or more additional therapies include four or more therapeutic agents.

[0207] In this combination therapy section, all references are incorporated by reference for the purposes described, whether or not so explicitly stated.

[0208] Non-pharmacological therapies Examples of non-pharmacological treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical resection of tumor tissue), and T-cell acceptor metastasis (ACT) therapy.

[0209] In some embodiments, the compounds of the present invention can be used as postoperative adjuvant therapy. In some embodiments, the compounds of the present invention can be used as preoperative neoadjuvant therapy.

[0210] Radiotherapy can be used to inhibit abnormal cell growth or treat hyperproliferative conditions, such as cancer, in subjects (e.g., mammals, such as humans). Techniques for administering radiotherapy are known in the art. Radiotherapy can be administered via...One or a combination of methods may be used, including but not limited to external beam therapy, internal radiation therapy, implantation radiation, stereotactic radiosurgery, whole-body radiation therapy, radiotherapy, and sustained or transient interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by means of a radioactive material inserted into or near a site of tumor or other proliferative tissue disease in the body. The term is intended, but not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu). Suitable radioactive sources used as the cell conditioning agents of the present invention include solids and liquids. As a non-limiting example, the radioactive source may be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides emitting photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material may also be a fluid made from any radionuclide solution, such as a solution of I-125 or I-131, or the radioactive fluid may be prepared from a slurry of a suitable fluid containing solid radionuclide microparticles, such as Au-198 or Y-90. Furthermore, the radionuclide may be embedded in a gel or radioactive microsphere.

[0211] In some embodiments, the compounds of the present invention can make abnormal cells more sensitive to radiotherapy to kill or inhibit the growth of such cells. Therefore, the present invention also relates to a method for making abnormal cells in a mammal sensitive to radiotherapy, the method comprising administering to the mammal a certain amount of the compound of the present invention, said amount effectively making the abnormal cells sensitive to radiotherapy. The amount of the compound in this method may be determined according to the manner used to determine the effective amount of such compounds described herein. In some embodiments, the compounds of the present invention may be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0212] In some embodiments, the non-pharmacological treatment is T-cell acceptor transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The source of the T cells is obtained from a subject before the T cells are expanded and genetically modified. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of the invention,Various T cell lines available in the art can be used. In some embodiments, the T cells are autologous T cells. Before or after the T cells are genetically modified to express a desired protein (e.g., CAR), the T cells can typically be activated and expanded using methods described, for example, in the following U.S. patents: 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041.

[0213] Therapeutic Agent Therapeutic agents may be compounds used to treat cancer or related symptoms.

[0214] For example, therapeutic agents may be steroids. Thus, in some embodiments, the one or more additional therapies include steroids. Suitable steroids may include, but are not limited to, acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, and cortivazol. Deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl.Fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurand renolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, methylprednisone, mometasone furoate furoate), paramethasone, prednicarbate, prednisolone, 2,5-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone (instructions 275 / 479, 280 CN 121974884 A), and their salts or derivatives.

[0215] Other examples of therapeutic agents that can be used in combination therapy with the compounds of the present invention include compounds described in the following patents: U.S. Patents Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885; and International Patent Applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089, and WO00 / 02871.

[0216] The therapeutic agent may be a biological agent (e.g., a cytokine (e.g., interferon or interleukin, such as IL-2)) for treating cancer or related symptoms. In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that arouses a target to stimulate an anticancer response or antagonizes an antigen that is important for cancer. Antibody-drug conjugates are also included.

[0217] The therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PDL-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PDL-2 inhibitor or antagonist (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor) (e.g., a PDL-2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, etc. BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0218] Therapeutic agents may be anti-TIGIT antibodies, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0219] Therapeutic agents may be agents for treating cancer or related symptoms (e.g., cytotoxic agents, non-peptide small molecules, or other compounds that can be used to treat cancer or related symptoms, collectively referred to as "anticancer agents"). Anticancer agents may be, for example, chemotherapeutic agents or targeted therapies.

[0220] Anticancer agents include mitosis inhibitors, insertion antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted urea, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progesterone, estrogens, antiestrogens, androgens, antiandrogens and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, the one or more additional therapies includeTwo or more anticancer agents. The two or more anticancer agents may be used in a mixture for combined administration or separately. Suitable dosing regimens for combined anticancer agents are known in the art and described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0221] Other non-limiting examples of anticancer agents include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® Gefitinib; alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; azacyclopropanes, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and tris(hydroxymethylmelamine); polyacetyl (especially bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (Including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189, and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin; nitrogen mustard, such as chlorambucil.(chlorambucil), chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, calicheamicin γ-II and calicheamicin ω-II). (See, for example, Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin, such as dynemicin A; bisphosphonates, such as clodronate; esperamicin; neocarzinostatin chromophore and related chromogens, aclacinomysin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin C, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, actinomycin D) (dactinomycin), daunorubicin (instructions for use, pages 277 / 479, CN 121974884 A), detorubicin, 6-diazo-5-oxo-L-leucine, adenomycin(adriamycin) (doxorubicin), morpholine doxorubicin, cyanomorpholine doxorubicin, 2-pyrrolinyl-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (such as mitomycin C), mycophenolic acid Drugs containing: nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, pteropterin, and trimetrexate; and purine analogs, such as fludarabine. Rabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azouridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; and antiadrenergics, such as aminoglutethimide, mitotane. Trilostane; folic acid supplements, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid(aminolevulinic acid); eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone, e, epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids. Examples include maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentos ta tin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; and tenuazonic acid. acid); triaziquone; 2,2',2''-trichlorotriethylamine; trichothecene, such as T-2 toxin, verracurin A, roridin A, and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide;Thiotepa; taxoids, such as Taxol® (paclitaxel), Abraxane® (a nanoparticle formulation of paclitaxel without polyoxyethylene hydrogenated castor oil and engineered from albumin), and Taxotere® (docetaxel); chloranbucil; tamoxifen (Nolvadex™); raloxifene; aromatase inhibitor 4(5)-imidazole; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene (Fareston, product information 278 / 479, page 283, CN 121974884 A®) Flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; Ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; esperamicins; capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the above.

[0222] Additional non-limiting examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, and Arimidex.®, ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, demethoxygeldanamycin, alpharadin, alvocidib, thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antitumor drugs (e.g., cell cycle nonspecific antitumor agents and other antitumor agents described herein), antitumor herbs, apaziquone, atipremod, azathioprine, belotecone, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, butthionine sulfoximine, CBV (chemotherapy), calyculin, dichloroacetic acid, discormolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE Chemotherapy regimens, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pisacentonePixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatintetranitrate, tri(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0223] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vincristine, vinorelbine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., actinomycin D, donomycin, and idarubicin), anthracycline, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, and enzymes (e.g., specification 279 / 479, page 284, CN 121974884). AL-asparaginase, which systemically metabolizes L-asparagine and removes cells that cannot synthesize asparagine, antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., methomyl mustard, cyclophosphamide and analogues, melphalan and chlorambucil), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors, such as abemaciclib, ribociclib, palbociclib, seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519). RGB286638 and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogues, and streptozocin), and trazenes-dacarbazinine.(DTIC), antiproliferative / antimitotic antimetabolites (e.g., folic acid analogs), pyrimidine analogs (e.g., fluorouracil, azuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole) and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoyl anilidehydroamic acid, vorinostat, LBH) 589. Romidesin, ACY-1215, and panobinostat; mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus); KSP (Eg5) inhibitors (e.g., Array 520); DNA binding agents (e.g., Zalypsis®); PI3K inhibitors such as PI3K δ inhibitors (e.g., GS-1101 and TGR-1202); (PI3K δ and γ) Inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; multi-kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogens), and hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38)), anti-CS1 (e.g., elotuzumab), and HSP90 inhibitors (e.g., 17AAG and KOS 953). P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors(e.g., enzastaurin), FTI (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targets (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)) and BCL-2 antagonists.

[0224] In some embodiments, the anticancer agent is selected from methicillin, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analogue or derivative variant thereof.

[0225] In some embodiments, the anticancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies, such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327.

[0226] In some embodiments, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib (page 285, CN 121974884 A, 280 / 479, CN 121974884 A), brigatinib, entrectinib, ensartinib (X-396), lorlatinib, ASP3026, CEP-37440, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0227] In some embodiments, the anticancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., SHP2 inhibitors (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, RLY-1971), SOS1 inhibitors (e.g., BI-1701963, BI-3406), Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors, or mTOR inhibitors (e.g., mTORC1 inhibitors or mTORC2 inhibitors). In some embodiments, the anticancer agent is JAB-3312. In some embodiments, the anticancer agent is an additional Ras inhibitor (e.g., AMG 510, MRTX1257, MRTX849, JNJ-74699157 (ARS-3248), LY3499446). (ARS-853 or ARS-1620) or Ras vaccines or other therapeutic modalities designed to directly or indirectly reduce the carcinogenic activity of Ras. Other examples of Ras inhibitors that can be combined with the Ras inhibitors of the present invention are provided in the following patents (which are incorporated herein by reference in their entirety): WO 2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO 2019150305, WO 2019110751、WO 2019099524、WO 2019051291、WO 2018218070、WO 2018217651、WO 2018218071、WO 2018218069、WO 2018206539、WO 2018143315、WO 2018140600、WO 2018140599、WO 2018140598、WO 2018140514、WO 2018140513、WO 2018140512、WO 2018119183、WO 2018112420、WO 2018068017、WO 2018064510、WO 2017201161、WO 2017172979、WO 2017100546、WO 2017087528、WO 2017058807、WO 2017058805、WO 2017058728、WO 2017058902、WO2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659 and WO 2013155223.

[0228] In some embodiments, therapeutic agents that can be combined with the compounds of the present invention are MAP kinase (MAPK) pathway inhibitors (or “MAPK inhibitors”). MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancer (Basel) Sep 2015; 7(3): 1758–1784. For example, MAPK inhibitors may be selected from one or more of the following: trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasetib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, described in PLoS One) .25 November 2014; 9(11) in); and GSK1120212 (or JTP-74057, described in Clin Cancer Res .1 March 2011; 17(5):989-1000 in). MAPK inhibitors may be PLX8394, LXH254, GDC-5573 or LY3009120.

[0229] In some embodiments, the anticancer agent is a disruptor or inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway. PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758–1784. For example, the PI3K / AKT inhibitor may be selected from one of the followingOne or more: NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0230] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist. Specification 281 / 479 pages 286 CN 121974884 A

[0231] In some embodiments, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapy. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0232] IGF-1R inhibitors include linsitinib or a pharmaceutically acceptable salt thereof.

[0233] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by natural ligands. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77: 639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. EGFR inhibitors may be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, ibid.) or Mab C225 (ATCC accession number HB-8508) or antibodies or antibody fragments that have binding specificity to them.

[0234] Small molecule antagonists of EGFR include gefitinib (Iressa®) and erlotinib (Tarceva®).® and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some implementations, the EGFR inhibitor is osimertinib (Tagrisso®). Other non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in the following patent disclosures, and all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO96 / 33980; U.S. Patent No. 5,747,498; WO96 / 30347; EP 0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP 837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE 19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; EP 682027; WO97 / 02266; WO97 / 27199; WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642. Other non-limiting examples of small molecule EGFR inhibitors include Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-Any EGFR inhibitor described in 1625. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family includes HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0235] MEK inhibitors include, but are not limited to, pimasiteti, selmetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and bimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation selected from the following Class I MEK1 mutations: D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is selected from the following Class II MEK1 mutations: ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N.

[0236] PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs as described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thiophene (also known as pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4,5-c]quinoline-1-yl]phenyl]propionitrile (also known as BEZ) 235 or NVP-BEZ 235, and described in WO06 / 122806); (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyprop-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholino)-8-phenyl-4H-l-benzopyran-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinopyridino[3',2':4,5]furano[3,2-d]pyrimidin-2-yl]phenol hydrochloride (available from Axon Medchem); PIK 75 (2-Methyl-5-nitro-2-[(6-bromoimidazolo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazine-benzenesulfonic acid monohydrochloride) (available from Axon)Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one (available from Axon Medchem); XL-765; and XL-147. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0237] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibiting Akt1) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); Akt-1-1,2 (inhibits Akl and 2) (Barnett et al., Biochem.J. 2005, 385(Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91: 1808-12); 1-H-imidazo[4,5-c]pyridyl compounds (e.g., WO 05 / 011700); indole-3-methanol and its derivatives (e.g., US Patent No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Supplement): 3493S-3498S); perifoxine (e.g., interferes with Akt membrane localization; Dasmahapatra et al., Clin. Cancer Res. 2004, 10(15):5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI label).Reference: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9).

[0238] mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including: temsirolimus (Torisel®); everolimus (Afinitor®). ; WO94 / 09010); deforolimus (also known as defoliomus or AP23573); rapalogs, such as those disclosed in WO98 / 02441 and WO01 / 14387, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapalog; 40-[3-hydroxy(hydroxymethyl)methylpropionate]-rapalog (also known as CC1) 779); 40-epio-(tetrazolyl)-rapamycin (also known as ABT578); 32-deoxyrapamycin; 16-pentyneoxy-32(S)-dihydrorapamycin; derivatives disclosed in WO05 / 005434; U.S. Patents 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842 and 5,256, Derivatives disclosed in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, for example, WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552. Specification 283 / 479 pages 288 CN 121974884 A

[0239] BRAF inhibitors that can be used in combination with the compounds of the present invention include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF may contain class 3 BRAF mutations. In some embodiments,Type 3 BRAF mutations are selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R; and A762E.

[0240] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance to targeted therapies, including not only conventional chemotherapy but also BCL-2 inhibitors such as ABT-263.

[0241] In some embodiments, the additional therapeutic agent is an SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which contributes to a variety of cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in a stable, inactive, self-inhibiting conformation through a binding network involving residues from the N-SH2 and PTP domains. Stimulation with cytokines or growth factors, such as those acting via receptor tyrosine kinases (RTKs), exposes the catalytic site, leading to enzymatic activation of SHP2.

[0242] SHP2 is involved in signal transduction via the RAS-mitogen-activated protein kinase (MAPK) pathway, namely JAK-STAT or phosphatidylinositol 3-kinase-AKT. Mutations in the PTPN11 gene and subsequently SHP2 have been identified in several human developmental disorders, such as Noonan Syndrome and Leopard Syndrome, and human cancers, such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancer. Some of these mutations destabilize the self-inhibitory conformation of SHP2 and promote its self-activation or enhanced growth factor-driven activation. Therefore, SHP2 represents a particularly promising target for developing novel therapies for various diseases, including cancer. It has been shown that combinations of SHP2 inhibitors (e.g., RMC-4550 or SHP099) with RAS pathway inhibitors (e.g., MEK inhibitors) can inhibit various cancer cell lines in vitro (e.g., [examples of inhibitors]).Proliferation in cancers such as pancreatic cancer, lung cancer, ovarian cancer, and breast cancer. Therefore, combination therapy involving SHP2 inhibitors and RAS pathway inhibitors can be a general strategy for preventing tumor resistance in various malignancies.

[0243] Non-limiting examples of such SHP2 inhibitors known in the art include: Chen et al., Mol Pharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; and PCT applications: WO2015107493; WO2015107494; WO201507495; WO2016203404; WO2016203405; WO2016203406; WO2011022440; WO2017156397; WO2017079723; WO2017211303; WO2012041524; WO2017211303; WO2019051084; WO2017211303; US20160030594; US20110281942; WO2010011666; WO2014113584; WO2014176488; WO2017100279; WO2019051469; US8637684; WO2007117699; WO2015003094; WO2005094314; WO2008124815; WO2009049098; WO2009135000; WO2016191328; WO2016196591; WO2017078499; WO2017210134; WO2018013597; WO2018129402; WO2018130928; WO20181309928; WO2018136264; WO2018136265; WO2018160731; WO2018172984; and WO2010121212 are each incorporated into this paper by reference.

[0244] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a hybrid irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, such as a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor, for example, targeting sites located outside the phosphatase active site. (See page 284 / 479 of the specification, CN 121974884 A)Inhibitors of cysteine ​​residues (C333). In some embodiments, the SHP2 inhibitor is a reversible inhibitor. In some embodiments, the SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RMC-4630. In some embodiments, the SHP2 inhibitor is JAB-3068. In some embodiments, the SHP2 inhibitor is RLY-1971.

[0245] In some embodiments, the additional therapeutic agent is selected from the group consisting of: MEK inhibitors, HER2 inhibitors, SHP2 inhibitors, CDK4 / 6 inhibitors, mTOR inhibitors, SOS1 inhibitors, and PD-L1 inhibitors. In some embodiments, the additional therapeutic agent is selected from the group consisting of: MEK inhibitors, SHP2 inhibitors, and PD-L1 inhibitors. See, for example, Hallin et al., Cancer Discovery, DOI: 10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575:217 (2019). In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PDL-1 inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PDL-1 inhibitor and an SHP2 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer and treatment comprises administration of a combination of the Ras inhibitor of the present invention and a second or third therapeutic agent.

[0246] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0247] Immunotherapy includes, but is not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA4 agents, anti-LAG1 agents, and anti-OX40 agents.

[0248] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that regulate immune responses) containing imide groups.IMiD drugs include thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0249] Exemplary anti-PD-1 antibodies and their methods of use are described in Goldberg et al., Blood 2007, 110(1): 186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6): 1757-1761; and WO06 / 121168 A1), and are also described elsewhere herein.

[0250] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Patent No. 6,111,090, U.S. Patent No. 8,586,023, WO2010 / 003118, and WO2011 / 090754; or, for example, U.S. Patent No. 7,025,962, EP 1947183, U.S. Patent No. 7,812,135; U.S. Patent No. 8,388,967; U.S. Patent No. 8,591,886; U.S. Patent No. 7,618,632, EP 1866339, and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, Anti-GITR antibodies as described in WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0251] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof synthesized in vitro. Anti-angiogenic agents may be agonists, antagonists, allosteric modulators, toxins, or more generally may be used to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), thereby promoting cell death or arresting cell growth. In some embodiments, one or more additional therapies include an anti-angiogenic agent.

[0252] Anti-angiogenic agents may be MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors (see specification 285 / 479 pages 290 CN 121974884 A), and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin and tebuconazole.Rolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578 and US20090012085, as well as U.S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are inhibitors with very low or no MMP-1 inhibitory activity. More preferably are inhibitors that selectively inhibit MMP-2 or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors include AG-3340, RO 32-3555, and RS 13-0830.

[0253] Other exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding domains that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen-binding domains that specifically bind to VEGF (e.g., bevacizumab) or soluble VEGF receptors or their ligand-binding domains), such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding domains that specifically bind to VEGF receptors), EGFR inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to EGFR), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen-binding domains that specifically bind to Angle and Ang2 or their receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to Tie2 kinase). Other anti-angiogenic agents include Campath, IL-8, β-FGF, and Tek antagonists (US2003 / ).0162712; US6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen-binding regions, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM unintegrin domains that antagonize the binding of integrins to their ligands (US 2002 / 0042368), specifically binding anti-eph receptor or anti-pterygium antibodies or antigen-binding regions (US Patent No. 5,981, Patents Nos. 245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, and 6,057,124 and their family members, and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands), and antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to PDGFR kinases). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US5892112); emaxanib (Pfizer, USA, US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands); DAC anti-angiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland)EP 0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); Fibrinogen-E fragment (BioActa, UK); Angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); Maspin (Sosei, Japan); 2-Methoxyestradiol (Instructions for Use 286 / 479 pages, 291 CN 121974884 A, Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); Platelet-4 (RepliGen, USA, EP 407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); Second-generation α5β3 integrin MAb (Applied Molecular Evolution, USA and Medlmmune, USA); Enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 And BPI-derived anti-angiogenic agents (XOMA, USA); PI 88 (Progen, Australia); Cilengilide (Merck KGaA, Germany; Munich Technical University, Germany, ScrippsClinic)and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (BostonChildrens Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston C hildrens Hospital, USA); USA); ZD 6 4 7 4 (Astra Zeneca, UK); ZD 6 1 2 6 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue factor pathway inhibitor (EntreMed, USA); Pinn (Gilead Sciences, USA); Xanthorrhizol (Yonsei University, South Korea); Gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California, San Diego, USA); PX 478 (ProlX, USA); METASTATIN (EntreMed, USA); Troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); Motuporamine C (British Columbia University, USA).Canada); CDP 791 (Celltech Group, UK); Atiprimod (pINN) (Glaxo Smith Kline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); Angiogenesis vaccine (EntreMed, USA); Urokinase plasminogen activator inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); InKine (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology) , South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); Drug delivery system, intraocular 2-methoxyestradiol; Angnex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-alpha inhibitor; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, USA and EntreMed,USA); MAb, KDR (ImClone Systems, USA); MAb, α5β (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); cobretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); Irsogladine (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); Squalamine (Genaera, USA); RPI 4610 (Sirna, USA); Heparinase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); and Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE-cadherin-2 antagonist (ImClone)Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thromboprotein 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0254] Other examples of therapeutic agents that can be used in combination with the compounds of the present invention include agents that specifically bind to and inhibit the activity of growth factors (e.g., antibodies, antigen-binding domains, or soluble receptors), such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding domains that specifically bind to receptor c-Met.

[0255] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolium carboxamide riboside (AICAR), squalene, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vincristine. Additionally, antisense or siRNAs that inhibit the expression of proteins including, but not limited to, ATG5 (involved in autophagy) may also be used. In some embodiments, the one or more additional therapies include autophagy inhibitors.

[0256] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an antitumor agent. In some embodiments, the one or more additional therapies include an antitumor agent. Non-limiting examples of antitumor agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, aifostine, amrubicin, amsacrine, anagrelide, anastrozole, ancer, and others.ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabineocfosfate, DA 3030 (Dong-A), daclizumab, denileukin Diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac (HIT), interferon-alpha, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, ethirimol (288 / 479 pages, 293 CN 121974884 A), epirubicin, beta-epoetin, etoposide phosphate Phosphate), exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, formustin, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, imiquimod, interferon alpha, natural interferon alpha, interferon alpha-2, interferon alpha-2a.Interferon α-2b, Interferon α-N1, Interferon α-n3, Compound Interferon-1, Natural Interferon α, Interferon β, Interferon β-1a, Interferon β-1b, Interferon γ, Natural Interferon γ-1a, Interferon γ-1b, Interleukin-1β, Iobenguane, Irinotecan, Isogradine, Lanreotide, LC 9018 (Yakult), Leflunomide, Lenograstim, Lentinan Sulfate, Letrozole, Leukocyte Alpha Interferon, Leuprorelin, Levamisole + Fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoxohydrazone, dibromoceroxyl, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, niluamide, noscapine, erythropoiesis-stimulating protein, NSC 631570 Octreotide, Oprelvekin, Osaterone, Oxaliplatin, Pacific Paclitaxel, Pamidronic Acid, Pegaspargase, Pegylated Interferon Alpha-2b, Pentosan Polysulfate Sodium, Pentostatin, Picibanil, Birubicin, Rabbit Anti-thymocyte Polyclonal Antibody, Pegylated Interferon Alpha-2a, Porfimer Sodium, Raloxifene, Raltitrexed, Rasburi Embryo, Rhenium Estradiol Re 186, Retinamide (RII), Rituximab, Romotide, Lecithin (153)Sm)(samarium lexidronam), sargramostim, sizofiran, sobuzoxane, sonermin, strontium chloride-89, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131) Trastuzumab, treosulfan, retinoic acid, trilostane, trimetrexate, triptorelin, natural tumor necrosis factor α, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysis product vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony stimulating factor (granulocyte-macrophage colony stimulating factor), histamine dihydrochloride, tiimomab(ibritumomab tiuxetan), ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine-131 MAb (Techni clone), polymorphic epithelial mucin-yttrium-90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 Galderma, nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyletiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysis product vaccine (New York Medical Center) College), viral melanoma cell lysis product vaccine (Royal Newcastle Hospital) or valspodar.

[0257] Additional examples of therapeutic agents that can be used in combination with the compounds of the present invention include ipilimumab (Yervoy®); [unclear text - possibly a specific brand or product]Nivolumab (also known as BMS-936558, Opdivo®); Pembrolizumab (Keytruda®); Averumab (Bavencio®); AMP224; BMS-936559; MPDL3280A (also known as RG7446); MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; Anti-OX40 (Providence Health) Services); huMAbOX40L; atacivib; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); ado-trastuzumab bemtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®) Baliximab (Simulect®); Benlysta®; Brentuximab vedotin (Adcetris®); Canakinumab (Ilaris®); Cimzia® (Certolizumabpegol); Zenapax®; Daratumumab (Darzalex®); Denosumab (Prolia®); Eculizumab (Soliris®); Efalizumab (Raptiva®); Gemtuzumab ozogamicin (Mylotarg®) Golimumab (Simponi®); Ibrimomab tiuxetan(Zevalin®); infliximab (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumumab (Arzerra®); omalizumab (Xolair®); palivizumab (Synagis®); pertuzumab (Perjeta®); pertuzumab (Perjeta®); ranibizumab (Lucentis®); raxibacumab (Abthrax®); tocilizumab (Actemra®) ®); tositumomab; tositumomab-i-131; tositumomab and tositumomab-i-131 (Bexxar®); Utec product information 290 / 479 pages 295 CN 121974884 A monoclonal antibody (ustekinumab) (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0258] Depending on the disease being treated, the compounds described herein may be used in combination with the agents disclosed herein or other suitable agents. Thus, in some embodiments, one or more compounds of this disclosure will be co-administered with other therapies described herein. When used in combination therapy, the compounds described herein may be administered simultaneously or separately with a second agent. Such combined administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any agents described herein may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention and any therapy described herein may be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, the compounds of this disclosure may be administered first and then followed by any therapy described herein, or vice versa. In some embodiments of the separate administration regimen, the compounds of the present invention and any therapy described herein are administered at intervals of minutes, hours, or days.

[0259] In some embodiments of any of the methods described herein, a first therapy (e.g., the compounds of the present invention) and one or more additional therapies are administered simultaneously or sequentially in any order. The first therapeutic agent may be administered after one or more of the above methods.Administered immediately before or after various additional therapies, for up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1–7 days, 1–14 days, 1–21 days, or 1–30 days.

[0260] The present invention also provides a kit comprising (a) a pharmaceutical composition including the agents described herein (e.g., compounds of the present invention) and (b) a packaging insert with instructions on performing any of the methods described herein. In some embodiments, the pillbox includes (a) a pharmaceutical composition comprising the agents described herein (e.g., compounds of the present invention), (b) one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents), and (c) a packaging insert with instructions on performing any of the methods described herein.

[0261] Since one aspect of the invention covers the treatment of diseases or related symptoms with combinations of separately administerable pharmaceutically active compounds, the invention also relates to combining individual pharmaceutical compositions in the form of a pillbox. The pillbox may contain two individual pharmaceutical compositions: the compounds of the present invention and one or more additional therapies. The pillbox may contain a container for containing the individual compositions, such as a dispensing bottle or dispensing foil packaging. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the pillbox may contain instructions on the use of the individual components. The pillbox form is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dosing intervals, or when a prescribing healthcare professional wishes to adjust the individual components in the combination.

[0262] Numbered embodiments [1] A compound or a pharmaceutically acceptable salt thereof having the structure of formula I: Specification 291 / 479 pages 296 CN 121974884 A Wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered aryl; or optionally substituted 5 to 10-membered heteroaryl; B is absent, is -CH(R9)-, >C=CR9R9' or >CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; Optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene;G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; an optionally substituted C1-C4 heteroalkylene group; or a 3- to 8-membered heteroaryl group; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylenone, or acetylenyl sulfone; X1 is an optionally substituted C1-C2 alkylene group, NR, O, or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R1 is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered alkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or R1 and R2 combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heterocycloalkyl; R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted cyano, optional ... The substituted C2-C6 alkynyl group, optionally substituted 3- to 6-membered cycloalkyl group, optionally substituted 3- to 7-membered heterocycloalkyl group, optionally substituted 6-membered aryl group, optionally substituted 5- or 6-membered heteroaryl group; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3- to 8-membered cycloalkyl group or optionally substituted 3- to 14-membered heterocycloalkyl group; R4 is absent, is hydrogen, halogen, cyano, or methyl group optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted C1-C4 alkyl group, cyano, hydroxyl, or C1-C4 alkoxy group, cyclopropyl, or cyclobutyl group; R6 is hydrogen or methyl group; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl group, or R6 and R7 are combined with the carbon atoms to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl group or optionally substituted 3- to 7-membered heterocycloalkyl group;R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl. R9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R9 and L combined with the atoms to which they are attached to form optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9' combined with the atoms to which they are attached to form 3- to 6-membered cycloalkyl or 3- to 6-membered heteroalkyl; R10 is hydrogen, halogroup, hydroxyl group, C1-C3 alkoxy group, or C1-C3 alkyl; R10a is hydrogen or halogroup; R11 is hydrogen or C1-C3 alkyl; and R21 is H or C1-C3 alkyl.

[0263] [2] The compound as described in paragraph [1] or a pharmaceutically acceptable salt thereof, wherein G is optionally substituted C1-C4 heteroalkylene.

[0264] [3] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [1] or [2], wherein the compound has the structure of formula Ic: Specification 293 / 479 pages 298 CN 121974884 A Wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally, is takenThe substituted 3- to 6-membered heterocyclic alkyl group; optionally substituted 3- to 6-membered heterocyclic alkyl group; optionally substituted 6-membered aryl group; or optionally substituted 5- to 6-membered heteroaryl group; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3- to 6-membered heterocyclic alkyl group; optionally substituted 3- to 6-membered heterocyclic alkyl group; optionally substituted 6-membered aryl group; or 5- to 6-membered heteroaryl group; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylacetone or acetylacetone; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered alkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3, together with the atoms to which they are attached, form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl; R4 is absent, or is hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens. R5 is hydrogen, optionally halogenated C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl.Optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocyclic alkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0265] [4] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [3], wherein X2 is NH.

[0266] [5] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [4], wherein X3 is CH.

[0267] [6] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [5], wherein R11 is hydrogen.

[0268] [7] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [5], wherein R11 is C1-C3 alkyl.

[0269] [8] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [7], wherein R11 is methyl.

[0270] [9] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [6], wherein the compound has the structure of formula Id: Specification 295 / 479 pages 300 CN 121974884 A wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5 to 6-membered heteroalkylene;B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered aryl; or 5- to 6-membered heteroaryl; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, alkynyl ketone, or alkynyl sulfone; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered alkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl ... R3 is absent, or R2 and R3 combined with the atoms to which they are attached form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 14-membered heterocycloalkyl; R4 is absent, is hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atoms to which they are attached form an optionally substituted 3 to 6-membered cycloalkyl or an optionally substituted 3 to 7-membered heterocycloalkyl. R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl)R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atoms to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocyclic alkyl; R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.

[0271]

[10] The compound of any one of paragraphs [1] to [9] or a pharmaceutically acceptable salt thereof, wherein X1 is an optionally substituted C1-C2 alkylene.

[0272]

[11] The compound of any one of paragraphs

[10] or a pharmaceutically acceptable salt thereof, wherein X1 is methylene.

[0273]

[12] The compound of any one of paragraphs [1] to

[11] or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen.

[0274]

[13] The compound of any one of paragraphs [1] to

[11] or a pharmaceutically acceptable salt thereof, wherein R5 is an optionally halogen-substituted C1-C4 alkyl.

[0275]

[14] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[13] , wherein R5 is methyl.

[0276]

[15] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[14] , wherein Y4 is C.

[0277]

[16] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[15] , wherein R4 is hydrogen.

[0278]

[17] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[16] , wherein Y5 is CH.

[0279]

[18] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[17] , wherein Y6 is CH.

[0280]

[19] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[18] , wherein Y1 is C.

[0281]

[20] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[19] , wherein Y2 isC.

[0282]

[21] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[20] , wherein Y3 is N.

[0283]

[22] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[21] , wherein R3 is absent.

[0284]

[23] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[22] , wherein Y7 is C.

[0285]

[24] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [6] or [9] to

[23] , wherein the compound has the structure of formula Ie: Specification 297 / 479 Page 302 CN 121974884 A Wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 6-membered heterocyclic arylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cycloene alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or 5 to 6-membered heterocyclic arylene; L is absent or is a linker; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynyl ketone, or alkynyl sulfone; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered alkenyl, optionally substituted 3- to 6-membered heteroalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heteroalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heteroalkyl. R5 is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano, a hydroxyl or a C1-C4 alkoxy group, a cyclopropyl or a cyclobutyl group; R6 is hydrogen or methyl; R7 is hydrogen, a halogen or an optionally substituted C1-C3 alkyl group, or R6 and R7 combined with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl group or an optionally substituted 3- to 7-membered heterocycloalkyl group; R8 is hydrogen, a halogen, a hydroxyl, a cyano, an optionally substituted C1-C3 alkoxy group, an optionally substituted C1-C3 alkyl group.R7 and R8, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl or optionally substituted 6- to 10-membered aryl, or R7 and R8 combined with the carbon atoms to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl. R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.

[0286]

[25] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [3] to

[24] , wherein R6 is hydrogen.

[0287]

[26] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[25] , wherein R2 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heteroalkyl.

[0288]

[27] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[26] , wherein R2 is an optionally substituted C1-C6 alkyl.

[0289]

[28] The compound as described in paragraph

[27] or a pharmaceutically acceptable salt thereof, wherein R2 is an ethyl group.

[0290]

[29] The compound as described in any one of paragraphs [1] to

[28] or a pharmaceutically acceptable salt thereof, wherein R7 is an optionally substituted C1-C3 alkyl group.

[0291]

[30] The compound as described in paragraph 29 or a pharmaceutically acceptable salt thereof, wherein R7 is a C1-C3 alkyl group.

[0292]

[31] The compound as described in any one of paragraphs [1] to 30 or a pharmaceutically acceptable salt thereof, wherein R8 is an optionally substituted C1-C3 alkyl group.

[0293]

[32] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[31] , wherein R8 is a C1-C3 alkyl group.

[0294]

[33] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[32] , wherein the compound has the structure of formula If: wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cyclohexane; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 6-membered heterocyclic arylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cyclohexane; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or 5 to 6-membered heterocyclic arylene; L is absent or is a linker; Specification 299 / 479 pages 304 CN 121974884 AW is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynyl ketone, or alkynyl sulfone; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0295]

[34] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[33] , wherein R1 is a optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 6-membered cycloalkenyl, or optionally substituted 5- to 10-membered heteroaryl.

[0296]

[35] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[34] , wherein R1 is a optionally substituted 6-membered aryl, optionally substituted 6-membered cycloalkenyl, or optionally substituted 6-membered heteroaryl.

[0297]

[36] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[35] , wherein R1 is.

[0298]

[37] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[36] , wherein R1 is.

[0299]

[38] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[37] , wherein the compound has the structure of formula Ig: Specification 300 / 479 pages 305 CN 121974884 AWherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heterocyclic arylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heterocyclic arylene; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylenone, or acetylenyl sulfone; R2 is a C1-C6 alkyl, C1-C6 fluoroalkyl, or 3- to 6-membered cycloalkyl; R7 is a C1-C3 alkyl; R8 is a C1-C3 alkyl; and R9 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; Xe and Xf are independently N or CH; and R12 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heteroalkyl.

[0300]

[39] The compound as described in paragraph

[38] or a pharmaceutically acceptable salt thereof, wherein Xe is N and Xf is CH.

[0301]

[40] The compound as described in paragraph

[38] or a pharmaceutically acceptable salt thereof, wherein Xe is CH and Xf is N.

[0302]

[41] The compound as described in any one of paragraphs

[38] to

[40] or a pharmaceutically acceptable salt thereof, wherein R12 is an optionally substituted C1-C6 heteroalkyl.

[0303]

[42] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[38] to

[41] , wherein R12 is.

[0304]

[43] The compound as described in paragraph [1] or [2] or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula VI: Specification 301 / 479 Page 306 CN 121974884 A Wherein the dashed line represents zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered aryl; or optionally substituted 5 to 10-membered heteroaryl; B is absent, is -CH(R9)-, >C=CR9R9' or >CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; Optionally substituted 3- to 6-membered cycloalkylene groups; Optionally substituted 3- to 6-membered heteroalkylene groups; Optionally substituted 6-membered...arylene; or 5 to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenyl; optionally substituted C1-C4 heteroarylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroarylene; or 3 to 8-membered heteroarylene; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylacetone, haloacetal or acetylacetonate; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH, or N; Y2, Y3, Y4, and Y7 are independently C or N; Y5 is CH, CH2, or N; Y6 is C(O), CH, CH2, or N; R2 is absent, is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3 combined with the atoms they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 is absent, is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally substituted with halogens, C1-C4 alkyl, cyano, hydroxyl, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl. R6 is hydrogen or methyl; R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7 combined with the carbon atoms they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1- to 3-alkoxy, optionally substituted C1- to 3-alkyl, optionally substituted C2- to 6-alkenyl, optionally substituted C2- to 6-alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8.Combined with the carbon atom to which it is attached, it forms C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R7a and R8a are independently hydrogen, halogroup, optionally substituted C1-C3 alkyl, or combined with the carbon atom to which they are attached to form a carbonyl group; R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl. R9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl; or R9 and L combined with the atoms they are attached to form optionally substituted 3- to 14-membered heteroalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; or R9 and R9' combined with the atoms they are attached to form 3- to 6-membered cycloalkyl or 3- to 6-membered heteroalkyl; R10 is hydrogen, halogroup, hydroxyl group, C1-C3 alkoxy group, or C1-C3 alkyl; R10a is hydrogen or halogroup; R11 is hydrogen or C1-C3 alkyl; R21 is hydrogen or C1-C3 alkyl (e.g., methyl); and Xe and Xf are independently N or CH.

[0305]

[44] The compound as described in paragraph

[43] or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula VIa: Specification 303 / 479 Page 308 CN 121974884 A Wherein A is a substituted 3 to 6-membered cycloalkylene, a substituted 3 to 6-membered heterocycloalkylene, a substituted 6-membered aryl or a substituted 5 to 6-membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; a substituted 3 to 6-membered cycloalkylene; a substituted 3 to 6-membered heterocycloalkylene; a substituted 6-membered aryl; or a 5 to 6-membered heteroaryl; L is absent or is a linker; W is a crosslinking group comprising vinyl ketone, vinyl sulfone, acetylacetone or acetylacetone; X1 is a substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; n is 0, 1, or 2;R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; R2 is C1-C6 alkyl, C1-C6 fluoroalkyl, or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl; Xe and Xf are independently N or CH; R11 is hydrogen or a C1-C3 alkyl group; and R21 is hydrogen or a C1-C3 alkyl group.

[0306]

[45] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[43] or

[44] , wherein the compound has the structure of formula VIb: Specification 304 / 479 Page 309 CN 121974884 A wherein A is a substituted 3 to 6-membered cycloalkylene, a substituted 3 to 6-membered heterocycloalkylene, a substituted 6-membered aryl or a substituted 5 to 6-membered heterocycloalkylene; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; a substituted 3 to 6-membered cycloalkylene; a substituted 3 to 6-membered heterocycloalkylene; a substituted 6-membered aryl; or a 5 to 6-membered heterocycloalkylene; R9 is a substituted C1-C6 alkylene, a substituted C1-C6 heteroalkylene, a substituted 3 to 6-membered cycloalkyl or a substituted 3 to 7-membered heterocycloalkylene; L is absent or is a linker; and W is a crosslinking group comprising vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone.

[0307]

[46] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[45] , wherein A is an optionally substituted 6-membered aryl group.

[0308]

[47] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[46] , wherein A has the following structure: wherein R13 is hydrogen, a halogroup, a hydroxyl group, an amino group, an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 heteroalkyl group; and R13a is hydrogen or a halogroup.

[0309]

[48] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[47] , wherein R13 and R13a are each hydrogen.

[0310]

[49] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[47] , wherein R13 is hydroxyl, methyl, fluorine, or difluoromethyl.

[0311]

[50] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[45] , wherein A isOptionally substituted 5- to 6-membered heteroalkylene groups.

[0312]

[51] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[50] , wherein A is: (See specification 305 / 479, page 310, CN 121974884 A).

[0313]

[52] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[45] , wherein A is an optional substituted C1-C4 heteroalkylene group.

[0314]

[53] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[52] , wherein A is: .

[0315]

[54] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[45] , wherein A is an optional substituted 3- to 6-membered heterocyclic alkylene group.

[0316]

[55] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[54] , wherein A is: .

[0317]

[56] The compound as described in paragraph

[55] or a pharmaceutically acceptable salt thereof, wherein A is.

[0318]

[57] The compound as described in any one of paragraphs [1] to

[56] or a pharmaceutically acceptable salt thereof, wherein B is - CHR9-. Specification 306 / 479 pages 311 CN 121974884 A

[0319]

[58] The compound as described in paragraph

[57] or a pharmaceutically acceptable salt thereof, wherein R9 is F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl.

[0320]

[59] The compound as described in paragraph

[58] or a pharmaceutically acceptable salt thereof, wherein R9 is: .

[0321]

[60] The compound as described in paragraph

[59] or a pharmaceutically acceptable salt thereof, wherein R9 is: .

[0322]

[61] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[56] , wherein B is an optionally substituted 6-membered arylene.

[0323]

[62] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[61] , wherein B is a 6-membered arylene.

[0324]

[63] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[61] , wherein B is: .

[0325]

[64] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[63] , wherein R7 is methyl.

[0326]

[65] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[64] , wherein R8 is methyl.

[0327]

[66] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[65] , wherein the connector is a structure of formula II:Wherein A1 is the bond between the connector and B; A2 is the bond between W and the connector; B1, B2, B3, and B4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, sulfur, etc. Carbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; and D1 is an optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkyne, optionally substituted 3- to 14-membered heterocyclic alkylene, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 3- to 8-membered heterocyclic alkylene, optionally substituted 6- to 10-membered aryl, optionally substituted C2-C10 polyethylene glycol or optionally substituted C1- to C10 heteroalkylene, or a chemical bond connecting A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j-(B4)k–A2.

[0328]

[67] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[66] , wherein the connector is acyclic.

[0329]

[68] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[67] , wherein the connector has the structure of formula IIa: Specification 307 / 479 Page 312 CN 121974884 A Wherein Xa is absent or is N; R14 is absent, is hydrogen or optionally substituted C1-C6 alkyl; and L2 is absent, is -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene, wherein at least one of Xa, R14 or L2 is absent.

[0330]

[69] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[68] , wherein the connector has the following structure: .

[0331]

[70] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[66] , wherein the linker is or comprises a cyclic moiety.

[0332]

[71] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[70] , wherein the linker has the structure of formula IIb: wherein o is 0 or 1; R15 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heteroalkylene; X4 is absent, optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 heteroalkylene.Cy is a substituted 3- to 8-membered cycloalkylene, a substituted 3- to 8-membered heterocycloalkylen...

Claims

1. Compounds having the structure of formula Int-1: Or its salt, wherein: Q represents hydrogen, -B(OH)2. Or halogen; Z is hydrogen or an optionally substituted C1-C6 alkyl group; Y is a halogen, -B(OH)2. -CO2H, -CO2-(C1-C6 alkyl) or -CN; E is , , or ; and PNG is a protecting group.

2. The compound of claim 1, wherein E is .

3. The compound of claim 1, wherein E is .

4. The compound of claim 3, wherein E is .

5. The compound of claim 1, wherein E is .

6. The compound of claim 1, wherein E is .

7. The compound of claim 1, wherein the compound has the structure of formula Int-1a: 。 8. The compound of claim 1, wherein the compound has the structure of formula Int-1b: 。 9. The compound of claim 1, wherein the compound has the structure of formula Int-1c: 。 10. The compound of claim 1, wherein the compound has the structure of formula Int-1d: 。 11. The compound of claim 1, wherein the compound has the structure of formula Int-1e: 。 12. The compound of claim 1, wherein the compound has the structure of formula Int-1f: 。 13. The compound of any one of claims 1 to 12, wherein Q is H.

14. The compound of any one of claims 1 to 12, wherein Q is a halogen.

15. The compound of any one of claims 1 to 12, wherein Z is H or optionally a C1-C6 alkyl group substituted with a halogen.

16. The compound of any one of claims 1 to 12, wherein Z is H or an optionally substituted ethyl group.

17. The compound of claim 16, wherein Z is .

18. The compound of claim 16, wherein Z is .

19. The compound of claim 13, wherein Z is H.

20. The compound of claim 13, wherein Z is an optionally substituted C1-C6 alkyl group.

21. The compound according to any one of claims 1 to 6, wherein: Z is H or an ethyl group with optional substitution; Q is H or a halogen; and Y is Br, -B(OH)2, or .

22. The compound of claim 1, wherein: Z is H, or ; Q is H; and Y is Br.

23. The compound according to any one of claims 1 to 6, wherein Y is Br, -B(OH)2, or .

24. The compound of claim 6, 11 or 12, wherein PNG is Ac, TBS or TBDPS.

25. A compound selected from those consisting of: , , , and .

26. The compound of claim 25, wherein the compound is: 。 27. The compound of claim 25, wherein the compound is: 。 28. The compound of claim 25, wherein the compound is: 。 29. The compound of claim 25, wherein the compound is: 。 30. The compound of claim 25, wherein the compound is: 。 31. A compound selected from those consisting of: , , , , , and .

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