Ras inhibitors

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof, and methods of using the same. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic protein.

Description

[0001] RAS INHIBITORS

[0002] CROSS-REFERENCE

[0003]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 582,318, filed September 13, 2023, U.S. Provisional Application No. 63 / 582,327, filed September 13, 2023, U.S. Provisional Application No. 63 / 582,343, filed September 13, 2023, U.S. Provisional Application No. 63 / 582,351, filed September 13, 2023, U.S. Provisional Application No. 63 / 582,374, filed September 13, 2023, U.S. Provisional Application No. 63 / 582,377, filed September 13, 2023, U.S. Provisional Application No. 63 / 582,420, filed September 13, 2023, U.S. Provisional Application No. 63 / 582,435, filed September 13, 2023, U.S. Provisional Application No. 63 / 582,445, filed September 13, 2023, and U.S. Provisional Application No. 63 / 582,391, filed September 13, 2023, each incorporated herein by reference in its entirety.

[0004] SEQUENCE LISTING

[0005]

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 5, 2024, is named 56690_795_601_SL.xml and is 15,006 bytes in size.

[0006] BACKGROUND

[0007]

[0003] A majority of small molecule drugs act by binding a functionally important pocket on a target protein, thereby modulating the activity of that protein. For example, cholesterol-lowering drugs known as statins bind the enzyme active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrates. Some may have been misled into believing that a small molecule modulator could be discovered for most proteins provided a reasonable amount of resources, time, and effort, given the fact that many such drug / target interacting pairs are known. This is far from the case. Current estimates are that only about 10% of all human proteins are targetable by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019). The other 90% are currently considered refractory or intractable toward small molecule drug discovery and are commonly referred to as “undruggable”. These undruggable targets include a vast and largely untapped reservoir of medically important human proteins. Thus, there exists a great deal of interest in discovering new molecular modalities capable of modulating the function of such undruggable targets.

[0008]

[0004] It has been well established in literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play an essential role in various human cancers and are therefore appropriate targets for anticancer therapy, especially since mutations in Ras proteins account for approximately 30% of all human cancers in the United States, many of which are fatal. Dysregulation of Ras proteins by overexpression, upstream activation, or activating mutations is common in human tumors, and activating mutations in Ras are frequently found in human cancer. For example, activating mutations at codon 12 in Ras proteins function by inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of Ras mutant proteins to the “on” (GTP -bound) state, leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, enabling Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61K) of Ras are also responsible for oncogenic activity in some cancers.

[0009]

[0005] Despite extensive drug discovery efforts against Ras during the last several decades, only two agents targeting the K-Ras G12C mutant have been approved in the U.S. (sotorasib and adagrasib). Additional efforts are needed to uncover additional medicines for cancers driven by dysregulation of Ras proteins, including by the various Ras mutations. SUMMARY

[0006] In view of the foregoing, there remains a considerable need for a new design of therapeutics and diagnostics that can specifically target Ras, including wildtype Ras, mutants and / or associated proteins of Ras to reduce Ras signaling output. Of particular interest are Ras inhibitors, including pan Ras inhibitors capable of inhibiting two or more Ras mutants and / or wildtype Ras, as well as mutant-selective inhibitors targeting mutant Ras proteins such as Ras G12D, G12C, G12S, G13D, and / or G12V, for the treatment of Ras-associated diseases (e.g., cancer). Such compositions and methods can be particularly useful for treating a variety of diseases including, but not limited to, cancers and neoplasia conditions. The present disclosure addresses these needs, and provides additional advantages applicable for diagnosis, prognosis, and / or treatment for a wide diversity of diseases.

[0007] In certain aspects, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L2or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)-, -S(O)-, -S(O)2-, -P(O)R12-, -P(O)R12O-, - C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; A and B are independently selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; C is selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; and R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle.

[0008] In some embodiments, for a compound of Formula (I), C is selected from hydrogen, halogen, -CN, C1-3 alkyl, C3-5 cycloalkyl, C1-3 haloalkyl, -CH2CN, -CH(CN)CH3, -CH2OH, and -CH(OH)CH3. In some embodiments, A and B are independently selected from optionally substituted indazolyl.

[0009] In some embodiments, the compound of Formula (I) is a compound of Formula (II): or a pharmaceutically acceptable salt or solvate thereof.

[0010] In some embodiments, for a compound of Formula (I) or (II), L1is selected from a bond, C1-6 alkyl, 2- to 6- membered heteroalkyl, -C(O)-, and -C(O)N(R12)-, wherein C1-6alkyl and 2- to 6-membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6- membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is selected from a bond and C1-3alkyl. In some embodiments, L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle.

[0011] In some embodiments, for a compound of Formula (I) or (II), -L2-L3-C(O)R19is selected from: a1, b1, b3, and b4 are independently 1, 2, 3, 4, or 5; a2, a3, and b2 are independently 0, 1, 2, 3, 4, or 5; c1, c2, c3, c4, d1, d2, e1, and e2 are independently 0, 1, 2, 3, or 4; wherein the sum of a1, a2, and a3 is less than 9; the sum of b1, b2, b3, and b4 is less than 9; the sum of c1, c2, c3, and c4 is less than 8; the sum of d1 and d2 is less than 6; and the sum of e1 and e2 is less than 6; T is independently selected at each occurrence from N(R35), C(R36)2, C(O), O, S(O), and S(O)2; T2and T3are independently selected at each occurrence from N and C(R36); R31, R32, R33, and R36are independently selected at each occurrence from hydrogen and R40; R34and R35are independently selected at each occurrence from hydrogen and R41; R40is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein two R40attached to the same carbon atom optionally join to form =NR12, =C(R14)2, or =O; wherein two R40and the atom(s) to which they are attached optionally form C3-12carbocycle or 3- to 12-membered heterocycle; wherein R40and R41and the atoms to which they are attached optionally form 3- to 12-membered heterocycle; and wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R41is independently selected at each occurrence from -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6- membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0012] In some embodiments, R40is independently selected at each occurrence from halogen, -CN, C1-6alkyl, and C3-6cycloalkyl, or two R40attached to the same carbon atom form C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). In some embodiments, R41is independently selected at each occurrence from C1-6alkyl and C3-6cycloalkyl, each of which is optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, -O(C1-6alkyl), and -O(C1-6haloalkyl).

[0013] In some embodiments, the compound of Formula (I) is: , or a pharmaceutically acceptable salt or solvate thereof.

[0014] In some embodiments, for a compound of Formula (I) or (II), R19is selected from 1,2,3-triazol-1-yl, 1,2,3- triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol-4-yl, each of which is optionally substituted. In some embodiments, R19is optionally substituted imidazol-1-yl. In some embodiments, R19is optionally substituted with one or two substituents independently selected from halogen, -CN, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, -CN, C1-6 alkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl).

[0015] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0016] In certain aspects, the present disclosure provides a method of modifying a Ras mutant protein, comprising contacting the Ras mutant protein with an effective amount of a compound disclosed herein, or a salt or solvate thereof. In some embodiments, the modified Ras mutant protein exhibits a reduced Ras signaling output. In some embodiments, the reduced Ras signaling output is evidenced by one or more output selected from (i) an increase in steady state level of GDP-bound modified protein; (ii) a reduction in steady state level of GTP-bound modified protein; (iii) a reduction of phosphorylated AKTs473; (iv) a reduction of phosphorylated ERK T202 / Y204; (v) a reduction of phosphorylated S6 S235 / 236; (vi) a reduction of cell growth of a tumor cell expressing a Ras G12S mutant protein; and (vii) a reduction in Ras interaction with a Ras-pathway signaling protein. In some embodiments, the Ras mutant protein comprises an amino acid sequence in SEQ ID No.4 having a serine residue corresponding to position 12 of SEQ ID No.1. In some embodiments, the Ras mutant protein comprises an amino acid sequence of SEQ ID No.4. In some embodiments, the modified Ras mutant protein comprises an amino acid sequence of SEQ ID No. 1, or a fragment thereof that comprises the serine residue corresponding to position 12 of SEQ ID No.1, and wherein the compound selectively labels the serine residue as compared to (i) an aspartate residue of a K-Ras G12D mutant protein, said aspartate corresponding to position 12 of SEQ ID No.2; (ii) a valine residue of a K-Ras G12V mutant protein, said valine corresponding to position 12 of SEQ ID No.3; and / or (iii) a glycine residue of a K-Ras wildtype protein, said glycine corresponding to position 12 of SEQ ID No.1. In some embodiments, the compound selectively labels the serine residue by at least 2-fold when assayed under comparable conditions. In some embodiments, the compound selectively labels the serine residue by at least 5-fold when assayed under comparable conditions. In some embodiments, the contacting occurs in vivo.

[0017] In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In certain aspects, the present disclosure provides a method of treating cancer in a subject comprising a Ras mutant protein, the method comprising: inhibiting the Ras mutant protein of said subject by administering to said subject a compound disclosed herein, wherein the compound is characterized in that upon contacting the Ras mutant protein, said Ras mutant protein exhibits reduced Ras signaling output. In certain aspects, the present disclosure provides a method of modulating signaling output of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the signaling output of the Ras protein. In certain aspects, the present disclosure provides a method of inhibiting cell growth, comprising administering an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.

[0018] In practicing any of the subject methods, the cancer may be a solid tumor or a hematological cancer. In some embodiments, the cancer comprises a K-Ras G12S mutant protein. A method of the present disclosure may further comprise administering an additional agent. INCORPORATION BY REFERENCE

[0019] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0021] FIG.1 depicts a sequence alignment of various wild type Ras proteins including K-Ras, H-Ras, N-Ras, RalA, and RalB, from top to bottom. DETAILED DESCRIPTION

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Chemical structures are named herein according to IUPAC conventions as implemented in ChemDraw®software (Perkin Elmer, Inc., Cambridge, MA). The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes”, and “included”, is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0023] The term “Cx-y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl, is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-y alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups, that contain from x to y carbons in the chain.

[0024] “Alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups. An alkyl group may contain from one to twelve carbon atoms (e.g., C1-12 alkyl), such as one to eight carbon atoms (C1-8alkyl) or one to six carbon atoms (C1-6alkyl). Exemplary alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0025] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2- fluoropropyl, and 1,2-dibromoethyl.

[0026] “Alkenyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkenyl groups, containing at least one double bond. An alkenyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkenyl), such as two to eight carbon atoms (C2-8 alkenyl) or two to six carbon atoms (C2-6 alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0027] “Alkynyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkynyl groups, containing at least one triple bond. An alkynyl group may contain from two to twelve carbon atoms (e.g., C2-12alkynyl), such as two to eight carbon atoms (C2-8alkynyl) or two to six carbon atoms (C2-6alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0028] “Alkylene” or “alkylene chain” refers to substituted or unsubstituted divalent saturated hydrocarbon groups, including linear alkylene and branched alkylene groups, that contain from one to twelve carbon atoms (e.g., C1-12 alkylene), such as one to eight carbon atoms (C1-8 alkylene) or one to six carbon atoms (C1-6 alkylene). Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, “alkenylene” and “alkynylene” refer to alkylene groups, as defined above, which comprise one or more carbon-carbon double or triple bonds, respectively. The points of attachment of the alkylene, alkenylene or alkynylene chain to the rest of the molecule can be through one carbon or any two carbons of the chain. Unless stated otherwise specifically in the specification, an alkylene, alkenylene, or alkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0029] “Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” refer to substituted or unsubstituted alkyl, alkenyl and alkynyl groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quaternized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0030] “Heteroalkylene”, “heteroalkenylene” and “heteroalkynylene” refer to substituted or unsubstituted alkylene, alkenylene and alkynylene groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quaternized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8- membered heteroalkylene group has a chain length of 3 to 8 atoms. The points of attachment of the heteroalkylene, heteroalkenylene or heteroalkynylene chain to the rest of the molecule can be through either one heteroatom or one carbon, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkylene, heteroalkenylene or heteroalkynylene chain. Unless stated otherwise specifically in the specification, a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0031] “Nitrene” refers to an unsubstituted divalent group of the general formula -NH- and its R-substituted derivatives of the general formula -N(R)-. Unless stated otherwise specifically in the specification, a nitrene group is optionally substituted, such as by a substituent described herein. Exemplary nitrene groups include -NH-, -N(CH3)-, -N(CH2CH3)-, -N(CH2CH2CH3), -N(CH(CH3)2)-, -N(CH2CH(CH3)2)-, -N(C(CH3)3), -N(CH2F)-, -N(CHF2)-, - N(CF3)-, -N(cyclopropyl)-, -N(cyclobutyl)-, and -N(cyclopentyl)-.

[0032] “Carbocycle” refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom. Carbocycle may include C3-10 monocyclic rings, C5-12 bicyclic rings, C5-18 polycyclic rings, C5-12 spirocyclic rings, and C5-12bridged rings. Each ring of a bicyclic or polycyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. A polycyclic carbocycle contains a number or rings equal to the minimum number of scissions required to convert the carbocycle into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). In some embodiments, the carbocycle is a C6-12 aryl group, such as C6-10 aryl. In some embodiments, the carbocycle is a C3-12cycloalkyl group. In some embodiments, the carbocycle is a C5-12cycloalkenyl group. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic rings, as valence permits, are included in the definition of carbocycle. A carbocycle may comprise a fused ring, a bridged ring, a spirocyclic ring, a saturated ring, an unsaturated ring, an aromatic ring, or any combination thereof. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantly, phenyl, indanyl, and naphthyl. Unless state otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0033] “Heterocycle” refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms, for example 1, 2, 3, or 4 heteroatoms selected from O, S, P, and N. Heterocycle may include 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 5- to 12-membered bridged rings. Each ring of a bicyclic or polycyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. A polycyclic heterocycle contains a number or rings equal to the minimum number of scissions required to convert the heterocycle into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a 5- to 10-membered heteroaryl group, such as 5- or 6-membered heteroaryl. In some embodiments, the heterocycle is a 3- to 12-membered heterocycloalkyl group. A heterocycle may comprise a fused ring, a bridged ring, a spirocyclic ring, a saturated ring, an unsaturated ring, an aromatic ring, or any combination thereof. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, benzothienyl, benzoxazolyl, and quinolinyl. Unless stated otherwise specifically in the specification, a heterocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0034] “Heteroaryl” refers to an aromatic ring that comprises at least one heteroatom, for example 1, 2, 3, or 4 heteroatoms selected from O, S and N. Heteroaryl may include 5- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, 6- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 6- to 12- membered bridged rings. As used herein, the heteroaryl ring may be selected from monocyclic, bicyclic, or polycyclic—including fused, spirocyclic and bridged ring systems—wherein at least one of the rings in the ring system is aromatic and comprises at least one heteroatom. A polycyclic heteroaryl contains a number or rings equal to the minimum number of scissions required to convert the heteroaryl into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). The heteroatom(s) in the heteroaryl may optionally be oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryl groups include, but are not limited to, azepinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and thienyl groups. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted by one or more substituents such as those substituents described herein.

[0035] Unless stated otherwise, hydrogen atoms are implied in structures depicted herein as necessary to satisfy the valence requirement.

[0036] A waved line “ ” drawn across or at the end of a bond or a dashed bond “ are used interchangeably herein to denote where a bond disconnection or attachment occurs. For example, in the structure , if R19is

[0037] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0038] A compound disclosed herein, such as a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), is optionally substituted by one or more—such as 1, 2 or 3—substituents selected from: halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3- 12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23)-, and - S(=O)(=NR22)N(R22)(R23); wherein two substituents attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23), and - S(=O)(=NR22)N(R22)(R23); R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH; R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein -C0-6 alkyl-(C3-12 carbocycle) and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; and R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle.

[0039] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), is optionally substituted by one or more—such as 1, 2 or 3—substituents selected from: halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, and -S(O)2N(R22)(R23)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, and =C(R21)2; R21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl; R22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein -C0-6 alkyl-(C3-12 carbocycle) and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle.

[0040] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), is optionally substituted by one or more—such as 1, 2 or 3—substituents selected from halogen, oxo, =NH, -CN, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, -CH2-(C3-10 carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and - NHCH2CH3, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10- membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, - OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3.

[0041] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted”, references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0042] Where bivalent substituent groups are specified herein by their conventional chemical formulae, written from left to right, they are intended to encompass the isomer that would result from writing the structure from right to left, e.g., -CH2O- is also intended to encompass -OCH2-.

[0043] “Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, an “optionally substituted” group may be either unsubstituted or substituted.

[0044] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0045] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted1H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Examples of isotopes that may be incorporated into compounds of the present disclosure include, but are not limited to,2H,3H,13C,14C,15N,18O,17O,35S,36Cl, and18F. Of particular interest are compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV) enriched in tritium or carbon-14, which can be used, for example, in tissue distribution studies; compounds of the disclosure enriched in deuterium—especially at a site of metabolism—resulting, for example, in compounds having greater metabolic stability; and compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV) enriched in a positron emitting isotope, such as11C,18F,15O and13N, which can be used, for example, in Positron Emission Topography (PET) studies. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0046] As used herein, the phrase “of the formula”, “having the formula” or “having the structure” is not intended to be limiting and is used in the same way that the term “comprising” is commonly used. For example, if one structure is depicted, it is understood that all stereoisomer and tautomer forms are encompassed, unless stated otherwise.

[0047] Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. In some embodiments, in order to optimize the therapeutic activity of the compounds of the disclosure, e.g., to treat cancer, it may be desirable that the carbon atoms have a particular configuration (e.g., (R,R), (S,S), (S,R), or (R,S)) or are enriched in a stereoisomeric form having such configuration. The compounds of the disclosure may be provided as racemic mixtures. Accordingly, the disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated. When a chemical structure is depicted herein without any stereochemistry, it is understood that all possible stereoisomers are encompassed by such structure. Similarly, when a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions of the disclosure unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of such other isomers. Individual stereoisomers may be obtained by numerous methods that are known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using a suitable chiral stationary phase or support, or by chemically converting them into diastereomers, separating the diastereoisomers by conventional means such as chromatography or recrystallization, then regenerating the original stereoisomer.

[0048] Additionally, where applicable, all cis-trans or E / Z isomers (geometric isomers), tautomeric forms and topoisomeric forms of the compounds described herein are included with the scope of the disclosure unless otherwise specified.

[0049] The term “pharmaceutically acceptable” refers to a material that is not biologically or otherwise unacceptable when used in the subject compositions and methods. For example, the term “pharmaceutically acceptable carrier” refers to a material—such as an adjuvant, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier—that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition. Such pharmaceutically acceptable materials typically have met the required standards of toxicological and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U.S. Food and Drug Administration.

[0050] The terms “salt” and “pharmaceutically acceptable salt” refer to a salt prepared from a base or an acid. Pharmaceutically acceptable salts are suitable for administration to a patient, such as a mammal (for example, salts having acceptable mammalian safety for a given dosage regime). Salts can be formed from inorganic bases, organic bases, inorganic acids and organic acids. In addition, when a compound contains both a basic moiety, such as an amine, pyridine or imidazole, and an acidic moiety, such as a carboxylic acid or tetrazole, zwitterions may be formed and are included within the term “salt” as used herein. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0051] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0052] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0053] The term “effective amount” or “therapeutically effective amount” refers to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or in multiple doses. A component may be described herein as having at least an effective amount, or at least an amount effective, such as that associated with a particular goal or purpose, such as any described herein. The term “effective amount” also applies to a dose that will provide an image for detection by an appropriate imaging method. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0054] As used herein, “treating” or “treatment” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition (such as cancer) in a subject, including but not limited to the following: (a) preventing the disease or medical condition from occurring, e.g., preventing the reoccurrence of the disease or medical condition or prophylactic treatment of a subject that is pre-disposed to the disease or medical condition; (b) ameliorating the disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a subject; (c) suppressing the disease or medical condition, e.g., slowing or arresting the development of the disease or medical condition in a subject; or (d) alleviating symptoms of the disease or medical condition in a subject. For example, “treating cancer” would include preventing cancer from occurring, ameliorating cancer, suppressing cancer, and alleviating the symptoms of cancer. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.

[0055] A “therapeutic effect”, as that term is used herein, encompasses a therapeutic benefit and / or prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0056] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., K-Ras). Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0057] The term “selective inhibition” or “selectively inhibit” refers to the ability of a biologically active agent to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.

[0058] The terms “subject” and “patient” refer to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, such as a human. “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non- domestic animals such as wildlife and the like.

[0059] The terms “therapeutic agent”, “therapeutic capable agent” or “treatment agent” are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. The beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.

[0060] The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein the term “amino acid” refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.

[0061] The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non- coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), morpholino and locked nucleic acid (LNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), 2’-fluoro, 2’-OMe, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.

[0062] As used herein, “expression” refers to the process by which a polynucleotide is transcribed from a DNA template (such as into an mRNA or other RNA transcript) and / or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides may be collectively referred to as “gene product.” If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell.

[0063] An “antigen” is a moiety or molecule that contains an epitope, and, as such, also specifically binds to an antibody. An “antigen binding unit” may be whole or a fragment (or fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. A full-length antibody may be, for example, a monoclonal, recombinant, chimeric, deimmunized, humanized and human antibody. Examples of a fragment of a full-length antibody may include, but are not limited to, variable heavy (VH), variable light (VL), a heavy chain found in camelids, such as camels, llamas, and alpacas (VHH or VHH), a heavy chain found in sharks (V-NAR domain), a single domain antibody (sdAb, e.g., “nanobody”) that comprises a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and “r IgG” (or half antibody). Examples of modified fragments of antibodies may include, but are not limited to scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL- CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), and multibodies (e.g., triabodies or tetrabodies).

[0064] The term “antibody” and “antibodies” encompass any antigen binding units, including without limitation: monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, and any other epitope-binding fragments.

[0065] “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV)). Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some aspects, a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” (1987) A.C.S. Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press each of which is incorporated in full by reference herein). The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound, and the like.

[0010]

[0066] The term “in vivo” refers to an event that takes place in a subject’s body. The term “ex vivo” refers to an event that first takes place outside of the subject’s body for a subsequent in vivo application into a subject’s body. For example, an ex vivo preparation may involve preparation of cells outside of a subject’s body for the purpose of introduction of the prepared cells into the same or a different subject’s body. The term “in vitro” refers to an event that takes place outside of a subject’s body. For example, an in vitro assay encompasses any assay run outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

[0011]

[0067] The disclosure is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a process comprising administering a compound disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0012]

[0068] The term “Ras” or “RAS” refers to a protein in the Rat sarcoma (Ras) superfamily of small GTPases, such as in the Ras subfamily. The Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and Unclassified subfamily. In some embodiments, a Ras protein is selected from the group consisting of KRAS (also used interchangeably herein as K-Ras, K-ras, or Kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

[0013]

[0069] The terms “mutant Ras” and “Ras mutant”, as used interchangeably herein, refer to a Ras protein with one or more amino acid mutations, such as with respect to a common reference sequence such as a wild-type (WT) sequence. In some embodiments, a mutant Ras is selected from a mutant KRAS, mutant HRAS, mutant NRAS, mutant MRAS, mutant ERAS, mutant RRAS2, mutant RALA, mutant RALB, mutant RIT 1 , and any combination thereof, such as from a mutant KRAS, mutant HRAS, mutant NRAS, mutant RALA, mutant RALB, and any combination thereof. In some embodiments, a mutation can be an introduced mutation, a naturally occurring mutation, or a non-naturally occurring mutation. In some embodiments, a mutation can be a substitution (e.g., a substituted amino acid), insertion (e.g., addition of one or more amino acids), or deletion (e.g., removal of one or more amino acids). In some embodiments, two or more mutations can be consecutive, non-consecutive, or a combination thereof. In some embodiments, a mutation can be present at any position of Ras. In some embodiments, a mutation can be present at position 12, 13, 62, 92, 95, 96 (e.g., Y96D), or any combination thereof of Ras relative to SEQ ID No. 1 when optimally aligned. In some embodiments, a mutant Ras may comprise about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, a mutant Ras may comprise up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations. In some embodiments, the mutant Ras is about or up to about 500, 400, 300, 250, 240, 233, 230, 220, 219, 210, 208, 206, 204, 200, 195, 190, 189, 188, 187, 186, 185, 180, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 160, 155, 150, 125, 100, 90, 80, 70, 60, 50, or fewer than 50 ammo acids in length. In some embodiments, an amino acid of a mutation is a proteinogenic, natural, standard, non-standard, non- canonical, essential, non-essential, or non-natural amino acid. In some embodiments, an amino acid of a mutation has a positively charged side chain, a negatively charged side chain, a polar uncharged side chain, a non-polar side chain, a hydrophobic side chain, a hydrophilic side chain, an aliphatic side chain, an aromatic side chain, a cyclic side chain, an acyclic side chain, a basic side chain, or an acidic side chain. In some embodiments, a mutation comprises a reactive moiety. In some embodiments, a substituted amino acid comprises a reactive moiety. In some embodiments, a mutant Ras can be further modified, such as by conjugation with a detectable label. In some embodiments, a mutant Ras is a full-length or truncated polypeptide. For example, a mutant Ras can be a truncated polypeptide comprising residues 1-169 or residues 11-183 (e.g., residues 11-183 of a mutant RALA or mutant RALB).

[0014]

[0070] As used herein, the term “corresponding to” or “corresponds to” as applied to an amino acid residue in a polypeptide sequence refers to the correspondence of such amino acid relative to a reference sequence when optimally aligned (e.g., taking into consideration of gaps, insertions and mismatches; wherein alignment may be primary sequence alignment or three-dimensional structural alignment of the folded proteins). For instance, the serine residue in a K-Ras G12S mutant refers to the serine corresponding to residue 12 of SEQ ID No. 4, which can serve as a reference sequence. For instance, the aspartate residue in a K-Ras G12D mutant refers to the aspartate corresponding to residue 12 of SEQ ID No. 2, which can serve as a reference sequence. When an amino acid of a mutant Ras protein corresponds to an amino acid position in the WT Ras protein, it will be understood that although the mutant Ras protein amino acid may be a different amino acid (e.g., G12D, wherein the wildtype G at position 12 is replaced by an aspartate at position 12 of SEQ ID. No. 1), the mutant amino acid is at the position corresponding to the wildtype amino acid (e.g., of SEQ ID No. 1). In some embodiments, a modified Ras mutant protein disclosed herein may comprise truncations at the C-terminus, or truncations at the N-terminal end preceding the serine residue. The serine residue in such N-terminal truncated modified mutant is still considered corresponding to position 12 of SEQ ID No. 1. In addition, an aspartate residue at position 12 of SEQ ID No. 2 finds a corresponding residue in SEQ ID Nos. 6 and 8.

[0071] As used herein, the term “leaving group” refers to an atom or group that becomes detached from an atom in the residual or main part of the substrate in a specified reaction. The residual or main part of the substrate is also referred to herein as the “staying group”. Compounds of Formula (I) and (II)

[0072] In certain aspects, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L2or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)-, -S(O)-, -S(O)2-, -P(O)R12-, -P(O)R12O-, - C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; A and B are independently selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; C is selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; and R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle.

[0073] In some embodiments, for a compound of Formula (I), C is selected from hydrogen, halogen, -CN, C1-3 alkyl, C3-5 cycloalkyl, C1-3 haloalkyl, -CH2CN, -CH(CN)CH3, -CH2OH, and -CH(OH)CH3. In some embodiments, A and B are independently selected from optionally substituted indazolyl.

[0074] In certain aspects, the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L2or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)-, -S(O)-, -S(O)2-, -P(O)R12-, -P(O)R12O-, - C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; and R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted.

[0075] In some embodiments, the compound of Formula (I) is: , or a pharmaceutically acceptable salt or solvate thereof.

[0076] In some embodiments, for a compound of Formula (I) or (II), L is -L1-L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-, wherein L1is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is a bond.

[0077] In some embodiments, for a compound of Formula (I) or (II), L1is selected from a bond, C1-6alkyl, 2- to 6- membered heteroalkyl, -C(O)-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-, wherein C1-6 alkyl and 2- to 6- membered heteroalkyl are optionally substituted. In some embodiments, L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -C(O)-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-. In some embodiments, L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -C(O)-, and -C(O)N(R12)-, wherein C1-6alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is a bond. In some embodiments, L1is 2- to 6-membered heteroalkyl, such as -CH2NH- or -CH2N(CH3)-. In some embodiments, L1is selected from a bond and 2- to 6-membered heteroalkyl. In some embodiments, L1is selected from a bond and C1-3alkyl. In some embodiments, L1is C1-3alkyl.

[0078] In some embodiments, for a compound of Formula (I) or (II), L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted. In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 6- to 12- membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycloalkyl.

[0079] In some embodiments, for a compound of Formula (I) or (II), L3is selected from a bond, 2- to 6-membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle), wherein 2- to 6-membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted. In some embodiments, L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L3is optionally substituted nitrene, such as -NH-, -N(CH3)-, -N(CH2CH3)-, or -N(CH(CH3)2)-. In some embodiments, L3is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L3is a bond.

[0080] In some embodiments, for a compound of Formula (I) or (II), L1is selected from a bond, C1-6alkyl, 2- to 6- membered heteroalkyl, -C(O)-, and -C(O)N(R12)-, wherein C1-6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6- membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond and optionally substituted 3- to 12- membered heterocycle; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L1is a bond; L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle.

[0081] In certain aspects, the present disclosure provides a compound selected from: stereoisomer, or prodrug thereof.

[0082] In general, compounds of the disclosure may be prepared by the following reaction scheme: Scheme 1

[0083] In some embodiments, a compound of Formula 1f may be prepared according to Scheme 1. For example, an appropriate halogenated heteroaromatic compound (1a) such as 3-iodo-5-methyl-1H-pyrazole may be alkylated with X-L(N-PG), wherein L comprises a suitably protected nitrogen atom (e.g., wherein PG is Boc, Cbz, or Fmoc), in the presence of a base to provide 1b. Addition of a halogenating agent can provide di-halogenated pyrazole 1c, which can undergo a cross-coupling reaction—such as a Stille or Suzuki reaction with a suitable aryl or heteroaryl coupling partner (Ar2-M)—to provide Ar2-substituted pyrazole 1d. A second cross-coupling reaction with Ar1-M can similarly provide corresponding Ar1-substituted derivative 1e. Removal of the N-protecting group can be followed by reaction with R19-H in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine to provide a compound of Formula 1f.

[0084] Synthetic procedures for certain intermediates, such as a compound of Formula 1a, may be found in WO 2021 / 124222 and WO 2021 / 120890, each of which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein. Compounds of Formula (III) and (IV)

[0085] In certain aspects, the present disclosure provides a compound of Formula (III): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -O-, -N(R12)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -P(O)R12-, - P(O)R12O-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -N(R12)P(O)R12-, -OP(O)R12-, -C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; Z is -(CR6aR6b)n-; X is =C(R15)- or -N(R15)-; R15and R16, together with the atoms to which they are attached, form C5-7 cycloalkyl or 5- to 7-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from C1-4alkyl, C1-4haloalkyl, and halogen; W is -N= or -CH=; V is -N= or -CH=; U is -N= or -C(R11)=; ring A is selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, and triazole; n is 0, 1, or 2; p is 0, 1, 2, or 3; R1a, R1b, R2a, R2b, R6a, and R6bare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; optionally wherein one of R1aor R1band one of R2aor R2b, together with the carbon atoms to which they are attached form a cyclopropane ring; and optionally wherein R6aand R6b, together with the carbon atom to which they are attached, form a cyclopropane ring; R4is selected from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), - N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), - N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R5is selected from halogen, -OC1-6alkyl substituted with optionally substituted 3- to 12-membered heterocycle, and optionally substituted 3- to 12-membered heterocycle; R11is selected from hydrogen, halogen, and C1-4 alkoxy; R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted; and R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle.

[0086] In certain aspects, the present disclosure provides a compound of Formula (IV): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -O-, -N(R12)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -P(O)R12-, - P(O)R12O-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -N(R12)P(O)R12-, -OP(O)R12-, -C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; W is -N= or -CH=; V is -N= or -CH=; U is -N= or -C(R11)=; ring A is selected from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, and triazole; R5is selected from halogen, -OC1-6 alkyl substituted with optionally substituted 3- to 12-membered heterocycle, and optionally substituted 3- to 12-membered heterocycle; R11is selected from hydrogen, halogen, and C1-4alkoxy; and R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted.

[0087] In some embodiments, for a compound of Formula (III) or (IV), ring A is selected from pyrazole, isoxazole, and 1,2,3-triazole. In some embodiments, ring A is pyrazole. In some embodiments, ring A is isoxazole. In some embodiments, ring A is 1,2,3-triazole.

[0088] In some embodiments, the compound of Formula (III) is: , or a pharmaceutically acceptable salt or solvate thereof.

[0089] In some embodiments, for a compound of Formula (III) or (IV), W is -N=, V is -CH=, and U is -N=. In some embodiments, W is -N=, V is -N=, and U is -CH=. In some embodiments, W is -N=, V is -N=, and U is -N=. In some embodiments, R5is selected from -OC1-3alkyl substituted with optionally substituted 5- to 10-membered

[0090] In some embodiments, the compound of Formula (III) is: , or a pharmaceutically acceptable salt or solvate thereof.

[0091] In some embodiments, for a compound of Formula (III) or (IV), L is -L1-L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-, wherein L1is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea.

[0092] In some embodiments, for a compound of Formula (III) or (IV), L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -O-, -N(R12)-, -C(O)-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -C(O)N(R12)-, - S(O)N(R12)-, and -S(O)2N(R12)-, wherein C1-6alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -O-, -N(R12)-, -C(O)-, - N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-. In some embodiments, L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -N(R12)-, -C(O)-, -N(R12)C(O)-, and - C(O)N(R12)-, wherein C1-6alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is a bond. In some embodiments, L1is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L1is selected from a bond, 2- to 6-membered heteroalkyl, and -N(R12)-.

[0093] In some embodiments, for a compound of Formula (III) or (IV), L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted. In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 6- to 12- membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycloalkyl.

[0094] In some embodiments, for a compound of Formula (III) or (IV), L3is selected from a bond, 2- to 6- membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted. In some embodiments, L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L3is optionally substituted nitrene, such as -NH-, -N(CH3)-, -N(CH2CH3)-, or -N(CH(CH3)2)-. In some embodiments, L3is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L3is a bond.

[0095] In some embodiments, for a compound of Formula (III) or (IV), L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -N(R12)-, -C(O)-, -N(R12)C(O)-, and -C(O)N(R12)-, wherein C1-6 alkyl and 2- to 6- membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12- membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond and optionally substituted 3- to 12-membered heterocycle; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L1is a bond; L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle.

[0096] In certain aspects, the present disclosure provides a compound selected from: pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0097] In general, compounds of the disclosure may be prepared by the following reaction scheme: Scheme 2

[0098] In some embodiments, a compound of Formula 2i may be prepared according to Scheme 2. For example, ketone 2a can be treated with magnesium bromide ethyl etherate, then methyl ester 2b added with a suitable base to form 2c. Following cyclization of ring A to give 2d, R5substitution and deprotection of the ketone can provide 2e. The 2-amino-3-cyano thiophene can be formed and the amino group protected to provide 2f. Following a deprotection step, the resulting alcohol can be treated with 2g—wherein L comprises an unprotected primary or secondary amine, and further wherein L comprises a suitably protected nitrogen atom (e.g., wherein PG is Boc, Cbz, or Fmoc)—in the presence of PyBop and a suitable base to provide the aminated product (2h). Deprotection can be followed by reaction with R19-H in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine and a second deprotection step to provide a compound of Formula 2i.

[0099] Synthetic procedures for certain intermediates may be found in WO 2023 / 099623, which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein. Compounds of Formula (V) and (VI)

[0100] In certain aspects, the present disclosure provides a compound of Formula (V): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -O-, -N(R12)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -P(O)R12-, - P(O)R12O-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -N(R12)P(O)R12-, -OP(O)R12-, -C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; E is selected from a bond and optionally substituted -C(O)-phen-1,4-diyl-; one of B1and B3is C and the other is N; B2is N or C(RB), wherein RBis selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl; ring Aais absent or 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S; X1, X2, X3, X4, and X5are independently selected from N and C, with the proviso that no more than two of X1, X2, X3, X4, and X5are N; R5, R6, R7, and RLare independently selected at each occurrence from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, - N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, - S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; and optionally wherein two geminally substituted RLsubstituents together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered spirocyclic ring containing 0 to 1 heteroatoms selected from N, O, and S; A1is selected from -CH2-, -CH2N(RL)-, -C(O)N(RL)-, -CH2O-, -CH(RL)-, -NH-, -N(RL)-, -S-, -S(O)-, and - O-; n, q, r, and s are independently 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0101] In certain aspects, the present disclosure provides a compound of Formula (VI): L is -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -O-, -N(R12)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -P(O)R12-, - P(O)R12O-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -N(R12)P(O)R12-, -OP(O)R12-, -C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; E is selected from a bond and optionally substituted -C(O)-phen-1,4-diyl-; R6aand R6bare independently selected from hydrogen and R6; R5, R6, and RLare independently selected at each occurrence from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; A1is selected from -CH2-, -CH2N(RL)-, -C(O)N(RL)-, -CH2O-, -CH(RL)-, -NH-, -N(RL)-, -S-, -S(O)-, and - O-; R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0102] In some embodiments, the compound of Formula (V) or (VI) is selected from: a pharmaceutically acceptable salt or solvate thereof.

[0103] In some embodiments, for a compound of Formula (V) or (VI), A1is selected from -N(RL)-, -S-, -S(O)-, and -O-. In some embodiments, A1is selected from -N(CH3)-, -S-, and -O-. In some embodiments, A1is -N(CH3)-. In some embodiments, A1is -S-. In some embodiments, A1is -O-.

[0104] In some embodiments, for a compound of Formula (V) or (VI), R5is selected from -CH3, -CF3, -OCH3, and -OCHF2. In some embodiments, R5is selected from -CF3 and -OCH3. In some embodiments, R5is -CH3. In some embodiments, R5is -CF3. In some embodiments, R5is -OCH3. In some embodiments, R5is -OCHF2.

[0105] In some embodiments, for a compound of Formula (V) or (VI), R6is selected from -CH3, -CH2OCH3, and - CH2CH2OCH3. In some embodiments, R6is -CH3. In some embodiments, R6is -CH2OCH3. In some embodiments, R6is -CH2CH2OCH3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0106] In some embodiments, for a compound of Formula (VI), R6aand R6bare independently selected from hydrogen, -CH3, -CH2OCH3, and -CH2CH2OCH3. In some embodiments, R6ais selected from hydrogen, -CH3, and - CH2CH2OCH3; and R6bis selected from hydrogen, -CH3, and -CH2OCH3. In some embodiments, R6ais -CH3 and R6bis hydrogen. In some embodiments, R6ais -CH2CH2OCH3and R6bis hydrogen. In some embodiments, R6ais - some embodiments, R6ais -CH3and R6bis -CH3. In some embodiments, R6ais -

[0107] In some embodiments, for a compound of Formula (V) or (VI), L is -L1-L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-, wherein L1is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is a bond.

[0108] In some embodiments, for a compound of Formula (V) or (VI), L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -O-, -N(R12)-, -C(O)-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -C(O)N(R12)-, - S(O)N(R12)-, and -S(O)2N(R12)-, wherein C1-6alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -O-, -N(R12)-, -C(O)-, - N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-. In some embodiments, L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -N(R12)-, -C(O)-, -N(R12)C(O)-, and - C(O)N(R12)-, wherein C1-6alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is a bond. In some embodiments, L1is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L1is selected from a bond, 2- to 6-membered heteroalkyl, and -N(R12)-.

[0109] In some embodiments, for a compound of Formula (V) or (VI), L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted. In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 6- to 12- membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycloalkyl.

[0110] In some embodiments, for a compound of Formula (V) or (VI), L3is selected from a bond, 2- to 6- membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted. In some embodiments, L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L3is optionally substituted nitrene, such as -NH-, -N(CH3)-, -N(CH2CH3)-, or -N(CH(CH3)2)-. In some embodiments, L3is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L3is a bond.

[0111] In some embodiments, for a compound of Formula (V) or (VI), L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -N(R12)-, -C(O)-, -N(R12)C(O)-, and -C(O)N(R12)-, wherein C1-6 alkyl and 2- to 6- membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12- membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond and optionally substituted 3- to 12-membered heterocycle; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L1is a bond; L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle.

[0112] In certain aspects, the present disclosure provides a compound selected from: thereof.

[0113] In general, compounds of the disclosure may be prepared by the following reaction schemes: Scheme 3

[0114] In some embodiments, a compound of Formula 3c may be prepared according to Scheme 3. For example, ammonolysis of aryl fluoride 3a can provide aniline 3b. Addition of R19-H to 3b in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine can provide a compound of Formula 3c. Scheme 4

[0115] In some embodiments, a compound of Formula 4i may be prepared according to Scheme 4. For example, a cross-coupling reaction, such as a Suzuki reaction between 4a and 4b, can provide compound 4c (wherein L of compound 4c comprises a suitably protected nitrogen atom (e.g., wherein PG is Boc, Cbz, or Fmoc)). Following conversion of 4c to dioxaborinane 4d, a second cross-coupling reaction, such as a Suzuki reaction with 4e, can provide 4f. Halogenation, optionally using NIS, can be followed by a third cross-coupling reaction, such as a Suzuki reaction with 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, to provide 4g. Ring closure can be accomplished in the presence of a suitable reducing agent and acid (e.g., NaBH(OAc)3and TFA), then the resulting secondary amine can optionally be substituted with RL(e.g., via a reductive amination with HCHO) to provide 4h. Deprotection can be followed by reaction with R19-H in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine to provide a compound of Formula 4i.

[0116] Synthetic procedures for certain intermediates may be found in WO 2022 / 232318, which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein. Compounds of Formula (VII) and (VIII)

[0117] In certain aspects, the present disclosure provides a compound of Formula (VII): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L2or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -O-, -N(R12)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -P(O)R12-, - P(O)R12O-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -N(R12)P(O)R12-, -OP(O)R12-, -C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; A is selected from 2- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted; B is selected from a bond, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted; G is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)O-CH(R6)-, -C(O)NHCH(R6)-, C3-12carbocycle, and 3- to 12- membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted; X1is selected from NR9, O, S(O), S(O)2, and optionally substituted C1-2alkylene; X2is selected from NH and O; X3is selected from N and CH; Y1is selected from C, CH, and N; Y2, Y3, Y4, and Y7are independently selected from C and N; Y5is selected from CH, CH2, and N; Y6is selected from C(O), CH, CH2, and N; R1is selected from -CN, C1-6 alkyl, 2- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C1-6alkyl, 2- to 6-membered heteroalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted; or R1and R2, together with the atoms to which they are attached, form optionally substituted 3- to 12-membered heterocycle; R2is absent or is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted; R3is absent; or R2and R3, together with the atom to which they are attached, form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted; R4is absent or is selected from hydrogen, halogen, -CN, C1-3alkyl, and C1-3haloalkyl; R5is selected from hydrogen, C1-6alkyl, and C3-6carbocycle, wherein C1-6alkyl and C3-6carbocycle are optionally substituted; R6is selected from hydrogen and methyl; R7is selected from hydrogen, halogen, and optionally substituted C1-3alkyl; or R6and R7, together with the carbon atoms to which they are attached, form C3-6carbocycle or 3- to 7- membered heterocycle, each of which is optionally substituted; R8is selected from hydrogen, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12- membered heterocycle are optionally substituted; or R7and R8, together with the carbon atom to which they are attached, form C=CR7′R8′, C=N(OH), C=N(O- C1-3 alkyl), C=O, C=S, C=NH, C3-6 carbocycle, or 3- to 7-membered heterocycle, wherein C3-6 carbocycle and 3- to 7-membered heterocycle are optionally substituted; R7aand R8aare independently selected from hydrogen, halogen, and optionally substituted C1-6alkyl; or R7aand R8a, together with the carbon atom to which they are attached, form C=O; R7′is selected from hydrogen, halogen, and optionally substituted C1-6 alkyl; R8′is selected from hydrogen, halogen, -OR12, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12- membered heterocycle are optionally substituted; or R7′and R8′, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 7- membered heterocycle, each of which is optionally substituted; R9is selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R10is selected from hydrogen, halogen, -OR12, and optionally substituted C1-3alkyl; R10ais selected from hydrogen and halogen; R11is selected from hydrogen and optionally substituted C1-3 alkyl; R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; R34is selected from hydrogen and optionally substituted C1-3alkyl; and indicates a single or double bond such that all valences are satisfied.

[0118] In certain aspects, the present disclosure provides a compound of Formula (VIII): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L2or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -O-, -N(R12)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -P(O)R12-, - P(O)R12O-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -N(R12)P(O)R12-, -OP(O)R12-, -C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; A is selected from 2- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted; B is selected from a bond, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted; R1is selected from -CN, C1-6 alkyl, 2- to 6-membered heteroalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C1-6alkyl, 2- to 6-membered heteroalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted; R2is absent or is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted; and R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted.

[0119] In some embodiments, for a compound of Formula (VII) or (VIII), R1is selected from C6-10carbocycle and 6- to 10-membered heterocycle, each of which is optionally substituted. In some embodiments, R1is selected from C6 carbocycle and 5- to 6-membered heterocycle, each of which is optionally substituted. In some embodiments, R1is selected from C6 aryl and 6-membered heteroaryl, each of which is optionally substituted. In some embodiments, R1is substituted pyridyl, such as substituted pyrid-3-yl. In some embodiments, R1is optionally substituted pyrid-3- yl. In some embodiments, R1is 2-(1-methoxyethyl)pyridin-3-yl. In some embodiments, R1is 2-(1- methoxyethyl)pyridin-3-yl substituted with optionally substituted 3- to 8-membered heterocycle. In some embodiments, R1is selected from .

[0120] In some embodiments, for a compound of Formula (VII) or (VIII), R1is substituted with one or two substituents. In some embodiments, R1is substituted with one or more substituents independently selected from C1-6 alkyl, 2- to 6-membered heteroalkyl, and optionally substituted 3- to 8-membered heterocycle. In some embodiments, R1is substituted with one or more substituents independently selected from -CH(CH3)OCH3, - CH2OCH3, 4-methylpiperazin-1-yl, and 4-cyclopropylpiperazin-1-yl. In some embodiments, R1is substituted with - CH(CH3)OCH3. In some embodiments, R1is substituted with -CH(CH3)OCH3 and optionally substituted piperazine. In some embodiments, R1is substituted with -CH(CH3)OCH3and piperazine, wherein the piperazine is substituted at the 4-position with C1-6alkyl or C3-6carbocycle. In some embodiments, R1is substituted with -CH(CH3)OCH3 and either 4-methylpiperazin-1-yl or 4-cyclopropylpiperazin-1-yl.

[0121] In some embodiments, for a compound of Formula (VII) or (VIII), R2is selected from C1-6 alkyl, C1-6 fluoroalkyl, and C3-6cycloalkyl. In some embodiments, R2is selected from C1-2alkyl and C1-2haloalkyl. In some embodiments, R2is selected from -CH2CH3and -CH2CF3. In some embodiments, R2is -CH2CH3. In some embodiments, R2is -CH2CF3.

[0122] In some embodiments, for a compound of Formula (VII) or (VIII), A is selected from C5-8 carbocycle, and 5- to 8-membered heterocycle, each of which is optionally substituted. In some embodiments, A is optionally substituted phenyl. In some embodiments, A is selected from 6-membered heterocycloalkyl and 6-membered heterocycloalkenyl. In some embodiments, A is selected from 6-membered heteroaryl. In some embodiments, A is selected from phenyl, phenolyl, pyridyl, 1,2,3,6-tetrahydropyridyl, thiazolyl, morpholinyl, and oxazolyl. In some embodiments, A is selected from 1,2,3,6-tetrahydropyrid-1,5-diyl, thiazol-2,4-diyl, morpholin-2,4-diyl, 5- hydroxyphen-1,3-diyl, and oxazol-2,5-diyl.

[0123] In some embodiments, for a compound of Formula (VII) or (VIII), B is selected from a bond, C1-6 alkyl, and 3- to 12-membered heterocycle, wherein C1-6 alkyl and 3- to 12-membered heterocycle are optionally substituted. In some embodiments, B is selected from C1-6alkyl and 3- to 12-membered heterocycle, each of which is optionally substituted. In some embodiments, B is selected from a bond, C1-3alkyl, and C2-3alkenyl, wherein C1-3alkyl and C2-3 alkenyl are optionally substituted. In some embodiments, B is selected from C1-3 alkyl and C2-3 alkenyl, each of which is optionally substituted. In some embodiments, B is a bond. In some embodiments, B is - CHRB-, wherein RBis selected from halogen, C1-6alkyl, C1-6haloalkyl, 2- to 6-membered heteroalkyl, C3-6cycloalkyl, and 3- to 7-membered heterocycloalkyl. In some embodiments, B is -CHRB-, wherein RBis selected from C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl. In some embodiments, B is -CHRB-, wherein RBis selected from isopropyl and cyclopentyl. In some embodiments, B is selected from -CH(CH(CH3)2)- and -CH(cyclopentyl)-. , , pharmaceutically acceptable salt or solvate thereof. In some embodiments, RBis selected from halogen, C1-6alkyl, C1-6haloalkyl, 2- to 6-membered heteroalkyl, C3-6cycloalkyl, and 3- to 7-membered heterocycloalkyl. In some embodiments, RBis selected from C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl. In some embodiments, RBis selected from -CH(CH3)2 and cyclopentyl.

[0125] In some embodiments, for a compound of Formula (VII) or (VIII), L is -L1-L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-, wherein L1is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is a bond.

[0126] In some embodiments, for a compound of Formula (VII) or (VIII), L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -O-, -N(R12)-, -C(O)-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -C(O)N(R12)-, - S(O)N(R12)-, and -S(O)2N(R12)-, wherein C1-6alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -O-, -N(R12)-, -C(O)-, - N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-. In some embodiments, L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -N(R12)-, -C(O)-, -N(R12)C(O)-, and - C(O)N(R12)-, wherein C1-6alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is a bond. In some embodiments, L1is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L1is selected from a bond, 2- to 6-membered heteroalkyl, and -N(R12)-.

[0127] In some embodiments, for a compound of Formula (VII) or (VIII), L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted. In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 6- to 12- membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycloalkyl.

[0128] In some embodiments, for a compound of Formula (VII) or (VIII), L3is selected from a bond, 2- to 6- membered heteroalkyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted. In some embodiments, L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L3is optionally substituted nitrene, such as -NH-, -N(CH3)-, -N(CH2CH3)-, or -N(CH(CH3)2)-. In some embodiments, L3is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L3is a bond.

[0129] In some embodiments, for a compound of Formula (VII) or (VIII), L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -N(R12)-, -C(O)-, -N(R12)C(O)-, and -C(O)N(R12)-, wherein C1-6alkyl and 2- to 6- membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12- membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond and optionally substituted 3- to 12-membered heterocycle; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L1is a bond; L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle.

[0130] In certain aspects, the present disclosure provides a compound selected from:

[0015] prodrug thereof.

[0016]

[0131] In general, compounds of the disclosure may be prepared by the following reaction scheme:

[0017] Scheme 5

[0018]

[0132] In some embodiments, a compound of Formula 5d may be prepared according to Scheme 5. For example, a peptide coupling reaction between amine 5a and carboxylic acid 5b, wherein L of compound 5b comprises a suitably protected nitrogen atom (e.g., wherein PG is Boc, Cbz, or Fmoc), can provide the corresponding amide. Removal of the N-protecting group to provide 5c can be followed by reaction with R19-H in the presence of triphosgene bis(tri chloromethyl) carbonate (BTC) and pyridine to provide a compound of Formula 5d.

[0133] Synthetic procedures for certain intermediates, such as a compound of Formula 5a, may be found in WO 2020 / 132597, WO 2021 / 091956, WO 2021 / 091967, WO 2021 / 091982, WO 2022 / 060836, WO 2022 / 235864, WO 2022 / 235870, WO 2023 / 060253, and WO 2023 / 133543 each of which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein. Compounds of Formula (IX) and (X)

[0134] In certain aspects, the present disclosure provides a compound of Formula (IX): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is selected from a bond and -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)-, -S(O)-, -S(O)2-, -P(O)R12-, -P(O)R12O-, - C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; or L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; P is selected from O, NH, and NRm; R42is selected from -C(O)- and optionally substituted -C1-3 alkyl-; Y1is C and X1is selected from hydrogen and R10; or Y1is N and X1is absent; E1is selected from N and CR5; E2is selected from N and CR6; provided that Y1, E1, and E2are not simultaneously N; Ar is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; R0is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; Rmis selected from C1-6 alkyl and C1-6 deuteroalkyl, each of which is optionally substituted; R5and R6are independently selected from hydrogen and R10; R9is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R10is selected from halogen, -CN, -NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0135] In some embodiments, for a compound of Formula (IX), P is NRm; R42is -C(O)-; Y1is C and X1is halogen; E1is N; E2is CH; Ar is 3-fluoro-1-hydroxy-phen-2-yl; R0is selected from optionally substituted 5- to 6- membered heteroaryl; and Rmis selected from CH3and CD3.

[0136] In certain aspects, the present disclosure provides a compound of Formula (X): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is selected from a bond and -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)-, -S(O)-, -S(O)2-, -P(O)R12-, -P(O)R12O-, - C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; or L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; Rmis selected from C1-6 alkyl and C1-6 deuteroalkyl, each of which is optionally substituted; R9is selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0137] In some embodiments, the compound of Formula (IX) is selected from: , pharmaceutically acceptable salt or solvate thereof.

[0138] In some embodiments, for a compound of Formula (IX) or (X), L is -L1-L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-, wherein L1is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea.

[0139] In some embodiments, for a compound of Formula (IX) or (X), L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -C(O)-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-, wherein C1-6 alkyl and 2- to 6- membered heteroalkyl are optionally substituted. In some embodiments, L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -C(O)-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-. In some embodiments, L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -C(O)-, and -C(O)N(R12)-, wherein C1-6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is a bond. In some embodiments, L1is 2- to 6-membered heteroalkyl, such as -CH2NH- or -CH2N(CH3)-. In some embodiments, L1is selected from a bond and 2- to 6-membered heteroalkyl. In some embodiments, L1is selected from a bond and optionally substituted 2- to 6-membered heteroalkyl.

[0140] In some embodiments, for a compound of Formula (IX) or (X), L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted. In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 6- to 12- membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycloalkyl.

[0141] In some embodiments, for a compound of Formula (IX) or (X), L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 5- to 8-membered monocyclic heterocycle, such as optionally substituted 5- to 8-membered monocyclic heterocycloalkyl. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 6- to 12-membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycle.

[0142] In some embodiments, for a compound of Formula (IX) or (X), L3is selected from a bond, 2- to 6- membered heteroalkyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted. In some embodiments, L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L3is optionally substituted nitrene, such as -NH-, -N(CH3)-, -N(CH2CH3)-, or -N(CH(CH3)2)-. In some embodiments, L3is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L3is a bond.

[0143] In some embodiments, for a compound of Formula (IX) or (X), L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -C(O)-, and -C(O)N(R12)-, wherein C1-6alkyl and 2- to 6-membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3- 12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6- membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond and optionally substituted 3- to 12- membered heterocycle; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L1is a bond; L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle. In some embodiments, L1is a bond; L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle; and L3is selected from a bond and optionally substituted nitrene.

[0144] In some embodiments, the compound of Formula (IX) is:

[0019] or a pharmaceutically acceptable salt or solvate thereof, wherein: X is selected from CH and N; R2is selected from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein two R2and the atom(s) to which they are attached optionally form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted; and m is 0, 1, 2, or 3.

[0145] In some embodiments, for a compound of Formula (IX), R2is selected from halogen, -CN, C1-6 alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O(C1-6alkyl), and -O(C1-6haloalkyl). In some embodiments, R2is selected from -CH3, and -CH2CN. In some embodiments, R2is selected from halogen, - CN, C1-6 alkyl, and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O(C1-6 alkyl), and - O(C1-6haloalkyl); and m is 1 or 2. In some embodiments, R2is selected from -CH3, and -CH2CN; and m is 1 or 2. In some embodiments, m is 0. In some embodiments, X is N and L3is a bond. In some embodiments, X is CH and L3is optionally substituted nitrene.

[0146] In certain aspects, the present disclosure provides a compound selected from:

[0147] In general, compounds of the disclosure may be prepared by the following reaction scheme: Scheme 6

[0020]

[0148] In some embodiments, a compound of Formula 6g may be prepared according to Scheme 6. For example, amine 6c can be formed from chloride 6a via a nucleophilic aromatic substitution reaction with amine 6b (wherein L of compound 6b comprises a suitably protected nitrogen atom (e.g., wherein PG is Boc, Cbz, or Fmoc)). Ring closure to 6d can be followed by an optional alkylation reaction of the amide with Rmto provide 6e. Substitution of the aryl bromide with a suitable boronic ester can provide the corresponding Ar-substituted compound (6f). Deprotection can be followed by reaction with R19-H in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine to provide a compound of Formula 6g.

[0149] Synthetic procedures for certain intermediates may be found in WO 2021 / 083167 and US Pub. No. 2023 / 0084095, each of which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein. Compounds of Formula (XI) and (XII)

[0150] In certain aspects, the present disclosure provides a compound of Formula (XI): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L2or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -O-, -N(R12)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -P(O)R12-, - P(O)R12O-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -N(R12)P(O)R12-, -OP(O)R12-, -C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) wherein 2 to 6 membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; R1, R2, R3, R4, R5, R7, and R8are independently selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R6is selected from C1-14alkyl, C2-14alkenyl, C2-14alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted; R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted; and R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle.

[0151] In some embodiments, for a compound of Formula (XI), R1, R2, R3, R4, and R5are independently selected from halogen, -NH2, -OH, and -CF3. In some embodiments, R1is -NH2 and R2, R3, R4, and R5are each -F. In some embodiments, R7is -Cl and R8is hydrogen.

[0152] In certain aspects, the present disclosure provides a compound of Formula (XII): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L2or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -O-, -N(R12)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -P(O)R12-, - P(O)R12O-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -N(R12)P(O)R12-, -OP(O)R12-, -C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; and R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted.

[0153] In some embodiments, for a compound of Formula (XI) or (XII), L is -L1-L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-, wherein L1is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea.

[0154] In some embodiments, for a compound of Formula (XI) or (XII), L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -O-, -N(R12)-, -C(O)-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -C(O)N(R12)-, - S(O)N(R12)-, and -S(O)2N(R12)-, wherein C1-6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -O-, -N(R12)-, -C(O)-, - N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-. In some embodiments, L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -N(R12)-, -C(O)-, -N(R12)C(O)-, and - C(O)N(R12)-, wherein C1-6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is a bond. In some embodiments, L1is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L1is selected from a bond, 2- to 6-membered heteroalkyl, and -N(R12)-.

[0155] In some embodiments, for a compound of Formula (XI) or (XII), L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted. In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 6- to 12- membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycloalkyl.

[0156] In some embodiments, for a compound of Formula (XI) or (XII), L3is selected from a bond, 2- to 6- membered heteroalkyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted. In some embodiments, L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L3is optionally substituted nitrene, such as -NH-, -N(CH3)-, -N(CH2CH3)-, or -N(CH(CH3)2)-. In some embodiments, L3is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L3is a bond.

[0157] In some embodiments, for a compound of Formula (XI) or (XII), L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -N(R12)-, -C(O)-, -N(R12)C(O)-, and -C(O)N(R12)-, wherein C1-6alkyl and 2- to 6- membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12- membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond and optionally substituted 3- to 12-membered heterocycle; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L1is a bond; L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle.

[0158] In some embodiments, the compound of Formula (XI) is: , or a pharmaceutically acceptable salt or solvate thereof, wherein: X is selected from CH and N; R10is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein two R10and the atom(s) to which they are attached optionally form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; and m is 0, 1, 2, or 3.

[0159] In some embodiments, for a compound of Formula (XI), R10is selected from halogen, -CN, C1-6 alkyl, and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O(C1-6alkyl), and -O(C1-6haloalkyl). In some embodiments, R10is selected from -CH3, and -CH2CN. In some embodiments, R10is selected from halogen, - CN, C1-6 alkyl, and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O(C1-6 alkyl), and - O(C1-6haloalkyl); and m is 1 or 2. In some embodiments, R10is selected from -CH3, and -CH2CN; and m is 1 or 2. In some embodiments, m is 0. In some embodiments, X is N and L3is a bond. In some embodiments, X is CH and L3is optionally substituted nitrene.

[0160] In certain aspects, the present disclosure provides a compound selected from: acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0161] In general, compounds of the disclosure may be prepared by the following reaction scheme: Scheme 7

[0162] In some embodiments, a compound of Formula 7d may be prepared according to Scheme 7. For example, alcohol 7a can be treated with 7b—wherein L comprises an unprotected primary or secondary amine, and further wherein L comprises a suitably protected nitrogen atom (e.g., wherein PG is Boc, Cbz, or Fmoc)—in the presence of PyBop and a suitable base to provide the aminated product (7c). Substitution of the aryl bromide with a suitable boronic ester can provide the corresponding Ar-substituted compound (7d). Deprotection can be followed by reaction with R19-H in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine to provide a compound of Formula 7e.

[0163] Synthetic procedures for certain intermediates may be found in WO 2021 / 121367 and WO 2022 / 237815, each of which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein. Compounds of Formula (XIII), (XIV), and (XV)

[0164] In certain aspects, the present disclosure provides a compound of Formula (XIII): or a pharmaceutically acceptable salt or solvate thereof, wherein: W is O, NR1a, S, SO2, or an optionally substituted 4- to 7-membered heterocycle; R1is hydrogen, optionally substituted C1-4 alkyl, or -L1b-R1b, L1bis absent or an optionally substituted C1-4alkylene, optionally substituted 2- to 4- membered heteroalkylene, optionally substituted C3-6carbocycle, or optionally substituted 4- to 7-membered heterocycle, R1bis hydrogen, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4alkynyl, -NR21R22, -OR23, or optionally substituted 4- to 7 membered heterocycle, or W-R1is hydrogen, –COOH, -COOR1e, -CONR1cR1d, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, or C3-6 carbocycle, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocycle is optionally substituted, each of R1a, R1cand R1dat each occurrence is independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted C2-4alkenyl, optionally substituted C2-4alkynyl, optionally substituted 2- to 4-membered heteroalkyl, optionally substituted C3-6carbocycle, optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; R1eat each occurrence is independently hydrogen, an optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted 2- to 4-membered heteroalkyl, optionally substituted C3-6carbocycle, optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group; each of A1, A2, A3, A5, and A8is independently CR30or N, R30at each occurrence is independently hydrogen, -F, -Cl, C1-4 alkyl, or C1-4 alkoxyl; or R1, W, and A1together form an optionally substituted heterocycle; L is -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -O-, -N(R12)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -P(O)R12-, - P(O)R12O-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -N(R12)P(O)R12-, -OP(O)R12-, -C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-15 carbocycle and 3- to 15-membered heterocycle, wherein C3-15 carbocycle and 3- to 15-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; R6is hydrogen, halogen, -CN, C3-4carbocycle, optionally substituted C1-4alkyl, optionally substituted C2-4alkenyl, optionally substituted C2-4alkynyl, or optionally substituted C1-4alkoxyl; R7is selected from optionally substituted C3-12 carbocycle and optionally substituted 3- to 12-membered heterocycle; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; and R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle.

[0165] In some embodiments, for a compound of Formula (XIII), W-R1is hydrogen, -COOH, -COOR1e, - CONR1cR1d, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 carbocycle, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, or C3-6carbocycle is optionally substituted with 1-3 groups independently selected from -F, -OH, protected -OH, and C1-6alkoxy.

[0166] In some embodiments, for a compound of Formula (XIII), L is a 4- to 15-membered heterocycle, wherein 4- to 15-membered heterocycle is optionally substituted with 1-3 groups independently selected from C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-4carbocycle, 3- to 4-membered heterocycle, fluorine substituted C1-4alkyl, hydroxyl substituted C1-4alkyl, and cyano substituted C1-4alkyl.

[0167] In certain aspects, the present disclosure provides a compound of Formula (XIV): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L2or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -O-, -N(R12)-, -C(O)-, -S-, -S(O)-, -S(O)2-, -P(O)R12-, - P(O)R12O-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -N(R12)P(O)R12-, -OP(O)R12-, -C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-15carbocycle and 3- to 15-membered heterocycle, wherein C3-15carbocycle and 3- to 15-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; and R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted.

[0168] In some embodiments, for a compound of Formula (XIII) or (XIV), L is -L1-L2-L3-, wherein L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-, wherein L1is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea.

[0169] In some embodiments, for a compound of Formula (XIII) or (XIV), L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -O-, -N(R12)-, -C(O)-, -N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -C(O)N(R12)-, - S(O)N(R12)-, and -S(O)2N(R12)-, wherein C1-6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -O-, -N(R12)-, -C(O)-, - N(R12)C(O)-, -N(R12)S(O)-, -N(R12)S(O)2-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-. In some embodiments, L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -N(R12)-, -C(O)-, -N(R12)C(O)-, and - C(O)N(R12)-, wherein C1-6alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is a bond. In some embodiments, L1is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L1is selected from a bond, 2- to 6-membered heteroalkyl, and -N(R12)-.

[0170] In some embodiments, for a compound of Formula (XIII) or (XIV), L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted. In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycloalkyl.

[0171] In some embodiments, for a compound of Formula (XIII) or (XIV), L3is selected from a bond, 2- to 6- membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted. In some embodiments, L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L3is optionally substituted nitrene, such as -NH-, -N(CH3)-, -N(CH2CH3)-, or -N(CH(CH3)2)-. In some embodiments, L3is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L3is a bond.

[0172] In some embodiments, for a compound of Formula (XIII) or (XIV), L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -N(R12)-, -C(O)-, -N(R12)C(O)-, and -C(O)N(R12)-, wherein C1-6 alkyl and 2- to 6- membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12- membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond and optionally substituted 3- to 12-membered heterocycle; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L1is a bond; L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle.

[0173] In some embodiments, the compound of Formula (XIII) is: , or a pharmaceutically acceptable salt or solvate thereof, wherein: X is selected from CH and N; R10is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein two R10and the atom(s) to which they are attached optionally form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; m is 0, 1, 2, or 3; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0174] In some embodiments, for a compound of Formula (XIII), R10is independently selected from halogen, - CN, C1-6 alkyl, and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O(C1-6 alkyl), and - O(C1-6haloalkyl); and m is 1 or 2. In some embodiments, R10is -CH3. In some embodiments, m is 2.

[0175] In some embodiments, for a compound of Formula (XIII), X is N and L3is a bond. In some embodiments, X is CH and L3is optionally substituted nitrene.

[0176] In certain aspects, the present disclosure provides a compound selected from: , pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0177] In certain aspects, the present disclosure provides a compound of Formula (XV): or a pharmaceutically acceptable salt or solvate thereof, wherein: X is -CH- and L is -N(R12)-, or X is N and L is a bond; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; and R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted.

[0178] In some embodiments, for a compound of Formula (XV), X is -CH- and L is –N(R12)-. In some embodiments, X is N and L is a bond.

[0179] In certain aspects, the present disclosure provides a compound selected from: , pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0180] In certain aspects, the present disclosure provides a compound selected from:

[0021] ,

[0022] , pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0181] In general, compounds of the disclosure may be prepared by the following reaction schemes: Scheme 8

[0182] In some embodiments, a compound of Formula 8e may be prepared according to Scheme 8. For example, 8a, including a suitable leaving group (LG, e.g., halide or sulfonate leaving group), can be treated with 8b—wherein L comprises an unprotected primary or secondary amine, and further wherein L comprises a suitably protected nitrogen atom (e.g., wherein PG is Boc, Cbz, or Fmoc), in the presence of a suitable base to provide the aminated product (8c). Substitution of the aryl bromide with a suitable boronic ester can provide the corresponding R7- substituted compound (8d). Deprotection can be followed by reaction with R19-H in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine to provide a compound of Formula 8e. Scheme 9

[0183] In some embodiments, similar reaction conditions and methods may be used following Scheme 9 above.

[0184] Synthetic procedures for certain intermediates may be found in WO 2020 / 233592 and WO 2018 / 217651, each of which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein. Compounds of Formula (XVI), (XVII), and (XVIII)

[0185] In certain aspects, the present disclosure provides a compound of Formula (XVI): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is a bond and X is N; or L is -N(R12)- and X is CH; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; R10is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein two R10and the atom(s) to which they are attached optionally form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; m is 0, 1, 2, or 3; L2is selected from a bond, -O-, -N(R2a)-, and -S-; R2ais selected from hydrogen and C1-3alkyl, wherein C1-3alkyl is optionally substituted; R2is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), halogen, -CN, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), and - S(=O)(=NR12)N(R12)(R13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted; R6and R8are each independently selected from hydrogen, -F, -Cl, C1-4 alkyl, C1-4 haloalkyl, and C1-4alkoxyl; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0186] In some embodiments, the compound of Formula (XVI) is a compound of Formula (XVII): or a pharmaceutically acceptable salt or solvate thereof.

[0187] In some embodiments, for a compound of Formula (XVI) or (XVII), R6is -Cl and R8is -F. In some embodiments, L2is -O-. In some embodiments, R2is -C0-6alkyl-(3- to 12-membered heterocycle), wherein -C0-6alkyl-(3- to 12-membered heterocycle) is optionally substituted. . , optionally substituted with one or more R20. In some embodiments, -L2-R2is , . In some embodiments, -L2-R2is . , . In some embodiments, -L2-R2is . some embodiments, - . some embodiments, -L2-R2is . In some embodiments, -L2-R2 . , .

[0189] In some embodiments, for a compound of Formula (XVI) or (XVII), X is CH and L is -N(R12)-. In some embodiments, X is CH and L is -N(CH3)-. In some embodiments, X is N and L is a bond.

[0190] In some embodiments, for a compound of Formula (XVI) or (XVII), R10is independently selected from halogen, -CN, C1-6 alkyl, and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, - O(C1-6alkyl), and -O(C1-6haloalkyl); and m is 1 or 2. In some embodiments, R10is -CH3.

[0191] In certain aspects, the present disclosure provides a compound of Formula (XVIII): or a pharmaceutically acceptable salt or solvate thereof, wherein: X is CH and L is selected from -N(CH3)- and -NH-; or X is N and L is a bond; and R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted.

[0192] In certain aspects, the present disclosure provides a compound selected from: pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0193] In certain aspects, the present disclosure provides a compound selected from: H , pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0194] In general, compounds of the disclosure may be prepared by the following reaction scheme: Scheme 10

[0195] In some embodiments, a compound of Formula 10f may be prepared according to Scheme 10. For example, alcohol 10a can be treated with 10b—wherein L comprises an unprotected primary or secondary amine, and further wherein L comprises a suitably protected nitrogen atom (e.g., wherein PG is Boc, Cbz, or Fmoc)—in the presence of PyBop and a suitable base to provide the aminated product (10c). A cross-coupling reaction, such as a Stille reaction with a suitably-substituted pyridine, can provide the corresponding 7-substituted quinazoline. To the product is added N-iodosuccinimide and p-toluenesulfonic acid monohydrate in N,N-dimethylformamide, and the mixture is stirred. To the product is added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate and cuprous iodide in N,N- dimethylacetamide with stirring followed by purification. To the product is added R2-L2-H, a solution of sodium hydride in THF, and the mixture is stirred and concentrated. Deprotection can be followed by reaction with R19-H in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine to provide a compound of Formula 10f.

[0196] Synthetic procedures for certain intermediates may be found in WO 2020 / 097537, which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein. Compounds of Formula (XIX), (XX), (XXI), and (XXII)

[0197] In certain aspects, the present disclosure provides a compound of Formula (XIX): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is selected from a bond and -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)-, -S(O)-, -S(O)2-, -P(O)R12-, -P(O)R12O-, - C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; or L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; A is selected from -OCH(R5)- and -N(R5)CH(R5)-; B is selected from -CH2- and -C(O)-; C is selected from -C(R3)=, -C(R3)2-, -N=, -N(R3)-, and C(O)- D is selected from -C(R8)=, -C(R8)2-, -N=, -N(R8)-, and C(O)- wherein -C D- is selected from -C(R3)=C(R8)-, -C(R3)=N-, -N=C(R8)-, -C(O)N(R8)-, -C(R3)2-N(R8)-, - N(R3)-C(R8)2-, -C(R3)2-C(R8)2-, or -N(R3)C(O)-; R3and R8are each independently selected from hydrogen, halogen, CN, -OR12, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; or R3and R8are joined to form, together with the atoms to which they are attached, a C5-6 carbocycle or 5- to 6-membered heterocycle wherein the C5 6carbocycle and 5- to 6-membered heterocycle are optionally substituted R5is independently selected from hydrogen and C1-6 alkyl; wherein C1-6 alkyl is optionally substituted; R6is selected from hydrogen, halogen,-CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and -O-C1-6 alkyl, wherein - C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and -O-C1-6alkyl are optionally substituted with one or more halogen; R7is independently selected from C3-12carbocycle, monocyclic 5- to 6-membered heterocycle, bicyclic 9- membered heterocycle comprising two or more ring nitrogen atoms, and bicyclic 10-membered heterocycle; wherein C3-12 carbocycle, monocyclic 5- to 6-membered heterocycle, bicyclic 9-membered heterocycle comprising two or more ring nitrogen atoms, and bicyclic 10-membered heterocycle are each optionally substituted; R9is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0198] In some embodiments, for a compound of Formula (XIX), R3is selected from hydrogen, halogen, -CN, - O(C1-6 alkyl), -O(C1-6 deuteroalkyl), -O(C1-6 haloalkyl), -O(C3-6 carbocycle), C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; wherein C1-6 alkyl is optionally substituted with -O(C1-6 alkyl); C2-6alkynyl is optionally substituted with -N(C1-6alkyl)2or -O(C1-6alkyl); -O(C1-6alkyl) is optionally substituted with -N(C1-6alkyl)2, -O(C1-6alkyl), or (3- to 12-membered heterocycle); and C3-12carbocycle and 3- to 12-membered heterocycle are each optionally substituted. In some embodiments, R3is hydrogen.

[0199] In some embodiments, for a compound of Formula (XIX), R7is optionally substituted phenyl. In some embodiments, R7is optionally substituted naphthyl. In some embodiments, R7is optionally substituted quinolinyl. In some embodiments, R7is optionally substituted isoquinolinyl. In some embodiments, R7is optionally substituted indazolyl. In some embodiments, R7is optionally substituted benzoimidazolyl. In some embodiments, R7is optionally substituted pyridyl. In some embodiments, R7is optionally substituted C3-12 carbocycle. In some embodiments, R7is optionally substituted monocyclic 5- to 6-membered heterocycle. In some embodiments, R7is optionally substituted bicyclic 9-membered heterocycle comprising two or more ring nitrogen atoms. In some embodiments, R7is optionally substituted bicyclic 10-membered heterocycle.

[0200] In some embodiments, for a compound of Formula (XIX), R7is selected from , , or a pharmaceutically acceptable salt or solvate thereof, wherein: L is selected from a bond and -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)-, -S(O)-, -S(O)2-, -P(O)R12-, -P(O)R12O-, - C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; or L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; R8is selected from hydrogen, halogen, CN, -OR12, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R9is selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0202] In some embodiments, for a compound of Formula (XIX) or (XX), R8is selected from hydrogen, halogen, - CN, -O(C1-6 alkyl), -O(C1-6 deuteroalkyl), -O(C1-6 haloalkyl), -O(C3-6 carbocycle), C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C3-12carbocycle, and 3- to 12-membered heterocycle; wherein C1-6alkyl is optionally substituted with - O(C1-6alkyl); C2-6alkynyl is optionally substituted with -N(C1-6alkyl)2or -O(C1-6alkyl); -O(C1-6alkyl) is optionally substituted with -N(C1-6 alkyl)2, -O(C1-6 alkyl), or (3- to 12-membered heterocycle); and C3-12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted. In some embodiments, R8is C2-4 alkynyl. In some embodiments, R8is -CCCH3. In some embodiments, R8is hydrogen.

[0203] In some embodiments, for a compound of Formula (XIX) or (XX), L is -L1-L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-, wherein L1is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-, wherein L2is bound to - C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L3-, wherein L3is bound to - C(O)R19via a nitrogen atom, thereby forming a urea.

[0204] In some embodiments, for a compound of Formula (XIX) or (XX), L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -C(O)-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-, wherein C1-6alkyl and 2- to 6- membered heteroalkyl are optionally substituted. In some embodiments, L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -C(O)-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-. In some embodiments, L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -C(O)-, and -C(O)N(R12)-, wherein C1-6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is a bond. In some embodiments, L1is 2- to 6-membered heteroalkyl, such as -CH2NH- or -CH2N(CH3)-. In some embodiments, L1is selected from a bond and 2- to 6-membered heteroalkyl. In some embodiments, L1is selected from a bond and optionally substituted 2- to 6-membered heteroalkyl.

[0205] In some embodiments, for a compound of Formula (XIX) or (XX), L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted. In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 6- to 12- membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycloalkyl.

[0206] In some embodiments, for a compound of Formula (XIX) or (XX), L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 5- to 8-membered monocyclic heterocycle, such as optionally substituted 5- to 8-membered monocyclic heterocycloalkyl. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 6- to 12-membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycle.

[0207] In some embodiments, for a compound of Formula (XIX) or (XX), L3is selected from a bond, 2- to 6- membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted. In some embodiments, L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L3is optionally substituted nitrene, such as -NH-, -N(CH3)-, -N(CH2CH3)-, or -N(CH(CH3)2)-. In some embodiments, L3is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L3is a bond.

[0208] In some embodiments, for a compound of Formula (XIX) or (XX), L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -C(O)-, and -C(O)N(R12)-, wherein C1-6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6- membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond and optionally substituted 3- to 12- membered heterocycle; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L1is a bond; L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle. In some embodiments, L1is a bond; L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle; and L3is selected from a bond and optionally substituted nitrene.

[0209] In some embodiments, the compound of Formula (XIX) is: , or a pharmaceutically acceptable salt or solvate thereof, wherein X is selected from CH and N. In some embodiments, X is N and L3is a bond. In some embodiments, X is CH and L3is optionally substituted nitrene.

[0210] In certain aspects, the present disclosure provides a compound selected from: pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0211] In certain aspects, the present disclosure provides a compound selected from: , acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0212] In an aspect is provided a compound of Formula (XXI): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is a bond and X is N; or L is -N(R12)- and X is CH; X-L is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; R7is selected from a phenyl and pyridyl; wherein the phenyl and pyridyl are optionally substituted; R10is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, - OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, - S(O)2N(R12)(R13), -S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein two R10and the atom(s) to which they are attached optionally form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; m is 0, 1, 2, or 3; R6is hydrogen, -CN, halogen, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxyl; R8is hydrogen, halogen, C1-4 alkyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 alkoxyl; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0213] In some embodiments, the compound of Formula (XXI) is a compound of Formula (XXII): pharmaceutically acceptable salt or solvate thereof.

[0214] In some embodiments, for a compound of Formula (XXI) or (XXII), X is CH and L is -N(R12)-. In some embodiments, X is N and L is a bond.

[0215] In some embodiments, for a compound of Formula (XXI) or (XXII), R10is independently selected from halogen, -CN, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). In some embodiments, R10is -CH3.

[0216] In some embodiments, for a compound of Formula (XXI) or (XXII), X is selected from CH and N; L is selected from a bond, -N(CH3)-, and -NH-; and R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2- yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol-4-yl, each of which is optionally substituted.

[0217] In some embodiments, for a compound of Formula (XIX) or (XXI), R7is selected from a phenyl and pyridyl; wherein the phenyl and pyridyl are optionally substituted. In some embodiments, R7is an optionally substituted phenyl. In some embodiments, R7is an optionally substituted pyridyl. In some embodiments, R7is In some embodiments, R7is . In some embodiments, R7is .

[0218] In certain aspects, the present disclosure provides a compound selected from: , pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0219] In certain aspects, the present disclosure provides a compound selected from: or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0220] In general, compounds of the disclosure may be prepared by the following reaction schemes: Scheme 11

[0221] In some embodiments, a compound of Formula 11e may be prepared according to Scheme 11. For example, to a solution of compound 11a is added tetrachloromethane and triphenylphosphine in DCE and the resulting 11b is purified. To a solution of 11b is added N-Chlorosuccinimide in MeCN and the resulting 11c is purified. To a solution of 11c is added RuPhos-Pd-G3, R7-boronic acid, potassium carbonate, dicyclohexyl(2’,6’- diisopropoxy-[1,1’-biphenyl]-2-yl)phosphane in 1,4-dioxane / water under nitrogen and the resulting 11d is purified. Following deprotection of 11d, pyridine and a solution of R19-H in pyridine with BTC is added to the resulting solution under nitrogen. After completion, the mixture is poured into water and is purified to provide a compound of Formula 11e. Scheme 12

[0222] In some embodiments, a compound of Formula 12f may be prepared according to Scheme 12. For example, to a solution of compound 12a is added NaH and DMF and the resulting compound 12b is purified. To a solution of 12b is added N-iodosuccinimide and H2SO4, and the resulting compound 12c is purified. To a solution of 12c is added trimethyl(R8)silane, Pd(PPh3)4, CuI, NEt3, TBAF in THF, and toluene; and the resulting compound 12d is purified. To a solution of 12d is added R7-boronic acid, RuPhos-G3, RuPhos, NaCO3, dioxane, and the resulting compound 12e is purified. Following deprotection of 12e, pyridine and a solution of R19-H in pyridine with BTC is added to the resulting solution under nitrogen. After completion, the mixture is poured into water and purified to provide a compound of Formula 12f. Scheme 13

[0223] In some embodiments, a compound of Formula 13f may be prepared according to Scheme 13. For example, coupling of amine 13a (wherein L of compound 13a comprises a suitably protected nitrogen atom (e.g., wherein PG is Boc, Cbz, or Fmoc)) with methyl ester 13b and subsequent cyclization can give tricycle 13c using a suitable base, such as cesium carbonate, in solvent (e.g., DMF) with heating. Addition of borane-THF complex in THF to 13c with stirring, followed by quenching in MeOH, can provide compound 13d. Substitution of the aryl bromide can proceed via a Suzuki reaction with 13e. Global deprotection of the resulting compound can be followed by reaction with R19-H in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine to provide a compound of Formula 13f.

[0224] Synthetic procedures for certain intermediates may be found in WO 2019 / 215203, WO 2020 / 178282, or J. Med. Chem.2023, 66, 13, 9147–9160, each of which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein. Compounds of Formula (XXIII) and (XXIV)

[0225] In certain aspects, the present disclosure provides a compound of Formula (XXIII): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is selected from a bond and -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)-, -S(O)-, -S(O)2-, -P(O)R12-, -P(O)R12O-, - C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; or L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; A is selected from -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, and -CH2N(R6)CH2-; B is selected from -CH2- and -C(O)-; Y is selected from -C(CN)- and -N-; R3and R5are each independently selected from hydrogen, halogen, -C0-3alkyl-cyclopropyl, -C1-6alkyl, and -O-C1-6 alkyl, wherein -C1-6 alkyl and -O-C1-6 alkyl are optionally substituted with one, two, or three R10; R4is selected from hydrogen, halogen, and -C1-6 alkyl optionally substituted with one, two, or three R10; R6is selected from hydrogen and C1-6alkyl optionally substituted with one, two, or three R10; R9is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R10is independently selected at each occurrence from halogen, =O, hydroxy, -C1-4alkyl, and -O-C1-4alkyl. R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0226] In certain aspects, the present disclosure provides a compound of Formula (XXIV): or a pharmaceutically acceptable salt or solvate thereof, wherein: L is selected from a bond and -L1-L2-L3-, wherein L1, L2, or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)-, -S(O)-, -S(O)2-, -P(O)R12-, -P(O)R12O-, - C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; or L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; R9is selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

[0227] In some embodiments, the compound of Formula (XXIII) is selected from: pharmaceutically acceptable salt or solvate thereof.

[0228] In some embodiments, for a compound of Formula (XXIII) or (XXIV), L is -L1-L2-L3-, wherein L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-L2-, wherein L2is bound to -C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-L3-, wherein L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L1-, wherein L1is bound to -C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L2-, wherein L2is bound to -C(O)R19via a nitrogen atom, thereby forming a urea. In some embodiments, L is -L3-, wherein L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea.

[0229] In some embodiments, for a compound of Formula (XXIII) or (XXIV), L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -C(O)-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-, wherein C1-6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -C(O)-, -C(O)N(R12)-, -S(O)N(R12)-, and -S(O)2N(R12)-. In some embodiments, L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -C(O)-, and -C(O)N(R12)-, wherein C1-6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted. In some embodiments, L1is a bond. In some embodiments, L1is 2- to 6-membered heteroalkyl, such as -CH2NH- or -CH2N(CH3)-. In some embodiments, L1is selected from a bond and 2- to 6-membered heteroalkyl. In some embodiments, L1is selected from a bond and optionally substituted 2- to 6-membered heteroalkyl.

[0230] In some embodiments, for a compound of Formula (XXIII) or (XXIV), L2is selected from C3-12carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted. In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2is optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycloalkyl.

[0231] In some embodiments, for a compound of Formula (XXIII) or (XXIV), L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 3- to 7-membered monocyclic heterocycle, such as optionally substituted 3- to 7-membered monocyclic heterocycloalkyl. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 5- to 8-membered monocyclic heterocycle, such as optionally substituted 5- to 8-membered monocyclic heterocycloalkyl. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 6- to 12-membered spirocyclic heterocycle, such as optionally substituted 6- to 12-membered spirocyclic heterocycloalkyl. In some embodiments, L2, R9, and the atoms to which they are attached form optionally substituted 7- to 12-membered fused bicyclic heterocycle, such as optionally substituted 7- to 12-membered fused bicyclic heterocycle.

[0232] In some embodiments, for a compound of Formula (XXIII) or (XXIV), L3is selected from a bond, 2- to 6- membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted. In some embodiments, L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6- membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L3is optionally substituted nitrene, such as -NH-, -N(CH3)-, -N(CH2CH3)-, or -N(CH(CH3)2)-. In some embodiments, L3is 2- to 6-membered heteroalkyl, such as -CH2NH-, -CH2N(CH3)-, -NHCH2-, or -N(CH3)CH2-. In some embodiments, L3is a bond.

[0233] In some embodiments, for a compound of Formula (XXIII) or (XXIV), L1is selected from a bond, C1-6alkyl, 2- to 6-membered heteroalkyl, -C(O)-, and -C(O)N(R12)-, wherein C1-6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond, C3-12 carbocycle and 3- to 12-membered heterocycle, wherein C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is selected from a bond and optionally substituted 3- to 12-membered heterocycle; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted. In some embodiments, L1is a bond; L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond. In some embodiments, L1is a bond; L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene. In some embodiments, L2is optionally substituted 6- to 12-membered spirocyclic heterocycle. In some embodiments, L1is a bond; L2, R9, and the atoms to which they are attached form optionally substituted 3- to 12-membered heterocycle; and L3is selected from a bond and optionally substituted nitrene.

[0234] In some embodiments, the compound of Formula (XXIII) is: , or a pharmaceutically acceptable salt or solvate thereof, wherein: X is selected from CH and N; and R2is selected from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), =NR12, =C(R14)2, =O, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted.

[0235] In some embodiments, for a compound of Formula (XXIII), R2is selected from hydrogen, halogen, -CN, C1-6 alkyl, and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). In some embodiments, R2is selected from hydrogen, -CH3, and -CH2CN. In some embodiments, R2is hydrogen. In some embodiments, X is N and L3is a bond. In some embodiments, X is CH and L3is optionally substituted nitrene.

[0236] In certain aspects, the present disclosure provides a compound selected from: pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0237] In general, compounds of the disclosure may be prepared by the following reaction schemes: Scheme 14

[0238] In some embodiments, a compound of Formula 14b may be prepared according to Scheme 14. For example, reaction of amine 14a with R19-H in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine can provide a compound of Formula 14b. Scheme 15

[0239] In some embodiments, a compound of Formula 15e may be prepared according to Scheme 15. For example, coupling of amine 15a (wherein L of compound 15a comprises a suitably protected nitrogen atom (e.g., wherein PG is Boc, Cbz, or Fmoc)) with methyl ester 15b and subsequent cyclization can give tricycle 15c using a suitable base, such as cesium carbonate, in solvent (e.g., DMF) with heating. Substitution of the aryl bromide can proceed via a Suzuki reaction with 15d. Global deprotection of the resulting compound can be followed by reaction with R19-H in the presence of triphosgene bis(trichloromethyl) carbonate (BTC) and pyridine to provide a compound of Formula 15e.

[0240] Synthetic procedures for certain intermediates, such as a compound of Formula 14a, may be found in WO 2021 / 118877, which is incorporated herein by reference in its entirety, including any synthetic methods, recitations of compound variables, combination therapies, and methods of use disclosed therein. Additional Compound Embodiments

[0241] In some embodiments, for a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), a1, b1, b3, and b4 are independently 1, 2, 3, 4, or 5; a2, a3, and b2 are independently 0, 1, 2, 3, 4, or 5; c1, c2, c3, c4, d1, d2, e1, and e2 are independently 0, 1, 2, 3, or 4; wherein the sum of a1, a2, and a3 is less than 9; the sum of b1, b2, b3, and b4 is less than 9; the sum of c1, c2, c3, and c4 is less than 8; the sum of d1 and d2 is less than 6; and the sum of e1 and e2 is less than 6; T is independently selected at each occurrence from N(R35), C(R36)2, C(O), O, S(O), and S(O)2; T2and T3are independently selected at each occurrence from N and C(R36); R31, R32, R33, and R36are independently selected at each occurrence from hydrogen and R40; R34and R35are independently selected at each occurrence from hydrogen and R41; R40is independently selected at each occurrence from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein two R40attached to the same carbon atom optionally join to form =NR12, =C(R14)2, or =O; wherein two R40and the atom(s) to which they are attached optionally form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein R40and R41and the atoms to which they are attached optionally form 3- to 12-membered heterocycle; and wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R41is independently selected at each occurrence from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6- membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted. [ a1, b1, b3, and b4 are independently 1, 2, 3, 4, or 5; a2, a3, and b2 are independently 0, 1, 2, 3, 4, or 5; c1, c2, c3, c4, d1, d2, e1, and e2 are independently 0, 1, 2, 3, or 4; wherein the sum of a1, a2, and a3 is less than 8; the sum of b1, b2, b3, and b4 is less than 8; the sum of c1, c2, c3, and c4 is less than 7; the sum of d1 and d2 is less than 6; and the sum of e1 and e2 is less than 6; T is independently selected at each occurrence from N(R35), C(R36)2, C(O), O, S(O), and S(O)2; T3is independently selected at each occurrence from N and C(R36); R31, R32, R33, and R36are independently selected at each occurrence from hydrogen and R40; R34and R35are independently selected at each occurrence from hydrogen and R41; R40is independently selected at each occurrence from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein two R40attached to the same carbon atom optionally join to form =NR12, =C(R14)2, or =O; wherein two R40and the atom(s) to which they are attached optionally form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein R40and R41and the atoms to which they are attached optionally form 3- to 12-membered heterocycle; and wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; and R41is independently selected at each occurrence from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6- membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted.

[0243] In some embodiments, R40is independently selected at each occurrence from halogen, -CN, C1-6 alkyl, and C3-6 cycloalkyl, or two R40attached to the same carbon atom form C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O(C1-6alkyl), and -O(C1-6haloalkyl). In some embodiments, R41is independently selected at each occurrence from C1-6 alkyl and C3-6 cycloalkyl, each of which is optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl).

[0244] In some embodiments, R31is selected from hydrogen, halogen, -CN, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). In some embodiments, R31is selected from hydrogen and C1-6alkyl. In some embodiments, R31is hydrogen.

[0245] In some embodiments, R32is selected from hydrogen, halogen, -CN, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). In some embodiments, R32is selected from hydrogen and C1-6alkyl. In some embodiments, R32is hydrogen.

[0246] In some embodiments, R33is selected from hydrogen, halogen, -CN, C1-6alkyl, and C3-6cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). In some embodiments, R33is selected from hydrogen and C1-6alkyl. In some embodiments, R33is hydrogen.

[0247] In some embodiments, R36is independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). In some embodiments, R36is independently selected at each occurrence from hydrogen and C1-6 alkyl. In some embodiments, R36is hydrogen.

[0248] In some embodiments, R34is selected from hydrogen, C1-6alkyl and C3-6cycloalkyl, each of which is optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, - O(C1-6 alkyl), and -O(C1-6 haloalkyl). In some embodiments, R34is selected from hydrogen and C1-6 alkyl. In some embodiments, R34is hydrogen. In some embodiments, R34is C1-6alkyl.

[0249] In some embodiments, R35is independently selected at each occurrence from hydrogen, C1-6alkyl and C3-6cycloalkyl, each of which is optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). In some embodiments, R34is independently selected at each occurrence from hydrogen and C1-6alkyl. In some embodiments, R34is hydrogen.

[0250] In some embodiments, for a compound described herein, such as a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R19is selected from 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol-4-yl, each of which is optionally substituted. In some embodiments, R19is 1,2,3-triazol-1-yl. In some embodiments, R19is 1,2,3-triazol-2-yl. In some embodiments, R19is 1,2,4-triazol-1-yl. In some embodiments, R19is 1,2,4-triazol-4-yl. In some embodiments, R19is optionally substituted imidazol-1-yl.

[0251] In some embodiments, for a compound described herein, such as a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R19is optionally substituted with one or two substituents independently selected from halogen, -CN, C1-6 alkyl, and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, -CN, C1-6 alkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl). In some embodiments, R19is optionally substituted with one or two substituents independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl. In some embodiments, R19is substituted with one or two substituents independently selected from halogen, -CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R19is unsubstituted.

[0252] In some embodiments, for a compound described herein, such as a compound of Formula (I), (II), (III),

[0253] Unless stated otherwise, an optionally substituted group of the present disclosure may be unsubstituted or substituted with one or more, such as one, two, three, four, or five, substituents independently selected from R20. In some embodiments, an optionally substituted group of the present disclosure is unsubstituted or substituted with one, two, or three substituents independently selected from R20. In some embodiments, R20is independently selected at each occurrence from: halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3- 12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(=O)(=NR22)N(R22)(R23), and -OCH2C(O)OR22; wherein two R20attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23), and - S(=O)(=NR22)N(R22)(R23); R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH; R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle); and R23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle.

[0254] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), exhibits selective and potent inhibition of K-Ras G12S and / or K-Ras G12C relative to wildtype K-Ras or other K-Ras mutants (e.g., K-Ras G12V or K-Ras G12D). In some embodiments, a subject warhead exhibits selective engagement of K-Ras G12S and / or K-Ras G12C relative to K-Ras G12D or wildtype K- Ras by at least 1-fold, and in some instances greater than 2-, 3-, 4-, 5-, 10-, 15-, or 20-fold, or even higher. In some embodiments, a subject warhead exhibits a selective and rapid engagement of K-Ras G12S and / or K-Ras G12C yielding at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or even higher engagement of G12S and / or K-Ras G12C within, 10 mins, 20 mins, 30 mins, 1 hr, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, 7 hrs, 8 hrs, 9 hrs, 10 hrs, 20 hrs, or 24 hours. In some embodiments, a selective and rapid engagement of K-Ras G12S and / or K-Ras G12C is evidenced by at least 50% engagement within 24 hours. In some embodiments, subject compounds specifically engage K-Ras G12S and / or K- Ras G12C covalently with essentially no detectable labeling of K-Ras G12D when assayed under comparable conditions.

[0255] The inclusion of a warhead of the present disclosure may enhance the efficacy or potency of K-Ras G12S and / or K-Ras G12C inhibition. In some embodiments, a subject compound comprising a subject warhead inhibits K- Ras G12S and / or K-Ras G12C with higher potency as evidenced by an IC50 value that is at least 10%, 20%, 50%, 100%, 200%, 300%, 400%, or at least 500% lower than the IC50 value of a corresponding control compound that does not comprise the warhead. In some embodiments, a subject compound comprising a subject warhead inhibits K-Ras G12S and / or K-Ras G12C with higher potency as evidenced by an IC50 value that is at least 1.1-times, 1.2- times, 1.5-times, 2-times, 3-times, 4-times, 5-times, 6-times, 7-times, 8-times, 9-times, 10-times, 15-times, or at least 20-times lower than the IC50 value of a corresponding control compound that does not comprise the warhead, as ascertained in a biochemical assay exemplified in Example 4.

[0256] The inclusion of a warhead of the present disclosure may enhance the efficacy or potency with which a subject compound inhibits the proliferation of cells that express a K-Ras G12S mutation and / or a K-Ras G12C mutation. In some embodiments, a subject compound comprising a subject warhead inhibits the proliferation of cells that express a K-Ras G12S mutation and / or a K-Ras G12C mutation with higher potency as evidenced by an IC50 value that is at least 10%, 20%, 50%, 100%, 200%, 300%, 400%, or at least 500% lower than the IC50 value of a corresponding control compound that does not comprise the warhead. In some embodiments, a subject compound comprising a subject warhead inhibits the proliferation of cells that express a K-Ras G12S mutation and / or a K-Ras G12C mutation with higher potency as evidenced by an IC50 value that is at least 1.1-times, 1.2-times, 1.5-times, 2- times, 3-times, 4-times, 5-times, 6-times, 7-times, 8-times, 9-times, 10-times, 15-times, or at least 20-times lower than the IC50 value of a corresponding control compound that does not comprise the warhead, as ascertained in a cellular inhibition assay exemplified in Example 8.

[0257] In some embodiments, a compound described herein, such as a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), is provided as a substantially pure stereoisomer. In some embodiments, the stereoisomer is provided in at least 80% enantiomeric excess, such as at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% enantiomeric excess.

[0258] In some embodiments, the present disclosure provides an atropisomer of a compound described herein, such as a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV). In some embodiments, the atropisomer is provided in enantiomeric excess. In some embodiments, the atropisomer is provided in at least 80% enantiomeric excess, such as at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% enantiomeric excess. In some embodiments, the compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV) is preferably used as a non-racemic mixture, wherein one atropisomer is present in excess of its corresponding enantiomer or epimer. Typically, such mixture contains a mixture of the two isomers in a ratio of at least 9:1, preferably at least 19:1. In some embodiments, the atropisomer is provided in at least 96% enantiomeric excess, meaning the compound has less than 2% of the corresponding enantiomer. In some embodiments, the atropisomer is provided in at least 96% diastereomeric excess, meaning the compound has less than 2% of the corresponding diastereomer.

[0259] The term “atropisomers” refers to conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, restricted, or greatly slowed as a result of steric interactions with other parts of the molecule and wherein the substituents at both ends of the single bond are asymmetrical (i.e., optical activity arises without requiring an asymmetric carbon center or stereocenter). Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted. Atropisomers are enantiomers (or epimers) without a single asymmetric atom. Atropisomers are typically considered stable if the barrier to interconversion is high enough to permit the atropisomers to undergo little or no interconversion at room temperature for a least a week, preferably at least a year. In some embodiments, an atropisomeric compound of the disclosure does not undergo more than about 5% interconversion to its opposite atropisomer at room temperature during one week when the atropisomeric compound is in substantially pure form, which is generally a solid state. In some embodiments, an atropisomeric compound of the disclosure does not undergo more than about 5% interconversion to its opposite atropisomer at room temperature (approximately 25 °C) during one year. The present chemical entities, pharmaceutical compositions, and methods are meant to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single atropisomers, and intermediate mixtures.

[0260] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0261] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases or inorganic or organic acids to form a pharmaceutically acceptable salt. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0262] In some embodiments, the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0263] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0264] The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and / or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in Schemes 1-15, the steps in some cases may be performed in a different order than the order shown in Schemes 1-15. Various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the present disclosure. Numberings or R groups in each scheme typically have the same meanings as those defined elsewhere herein unless otherwise indicated.

[0265] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from -10 °C to 200 °C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10 °C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.

[0266] In some embodiments, the compounds of the present disclosure exhibit one or more functional characteristics disclosed herein. For example, a subject compound binds to a Ras protein, KRAS protein or a mutant form thereof. In some embodiments, a subject compound binds specifically and also inhibits a Ras protein, KRAS protein or a mutant form thereof. In some embodiments, a subject compound selectively inhibits a KRAS mutant relative to a wildtype KRAS. In some embodiments, the IC50 of a subject compound for a KRAS mutant (e.g., G12S and / or G12C) is less than about 5 µM, less than about 1 µM, less than about 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, or even less, as measured in an in vitro assay known in the art or exemplified herein. In some embodiments, a subject compound covalently binds to a KRAS mutant (e.g., KRAS G12S and / or KRAS G12C).

[0267] In some embodiments, a compound of the present disclosure is capable of reducing Ras signaling output. Such reduction may be evidenced by one or more of the following: (i) an increase in steady state level of GDP- bound Ras protein; (ii) a reduction in steady state level of GTP-bound Ras protein; (iii) a reduction of phosphorylated AKTs473, (iv) a reduction of phosphorylated ERKT202 / y204, (v) a reduction of phosphorylated S6S235 / 236, and (vi) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line disclosed herein). In some cases, the reduction in Ras signaling output can be evidenced by two, three, four, five, or all of (i)-(vi) above.

[0268] It shall be understood that different aspects of the disclosure can be appreciated individually, collectively, or in combination with each other. Various aspects described herein may be applied to any of the particular applications disclosed herein. The compositions of matter, including compounds of any formulae disclosed in the compound section, of the present disclosure may be utilized in the method section, including methods of use and production disclosed herein, or vice versa. Methods

[0269] The compounds described herein, or a pharmaceutically acceptable salt or solvate thereof, are Ras inhibitors capable of inhibiting a Ras protein, such as wild-type Ras or a Ras mutant protein (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D) from K-Ras, H-Ras or N-Ras. Compounds, including pharmaceutically acceptable salts or solvates thereof, disclosed herein have a wide range of applications in therapeutics, diagnostics, and other biomedical research.

[0270] In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0271] In certain aspects, the present disclosure provides a method of treating a cancer comprising amplified wildtype Ras or a Ras mutant (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D) protein in a subject, comprising inhibiting amplified wildtype Ras or the Ras mutant protein of said subject by administering to said subject a compound, wherein the compound is characterized in that upon contacting the Ras protein, the Ras protein activity or function is inhibited (e.g., partially inhibited or completely inhibited), such that said inhibited Ras protein exhibits reduced Ras signaling output (e.g., compared to a corresponding Ras protein not contacted by the compound).

[0272] In certain aspects, the present disclosure provides a method of modulating activity of a Ras protein (e.g., K- Ras, mutant K-Ras, K-Ras G12S, K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13C, and / or K-Ras G13D), comprising contacting a Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras protein.

[0273] In certain aspects, the present disclosure provides a method of inhibiting cell growth, comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras (e.g., K-Ras) protein, thereby inhibiting growth of said cells. In some embodiments, the subject method comprises administering an additional agent to said cell.

[0274] In certain aspects, the present disclosure provides a method of treating a disease mediated at least in part by a Ras protein, such as K-Ras or a mutant thereof, in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease is cancer, such as a solid tumor or a hematological cancer. In some embodiments, the method further comprises administering an additional agent to the subject, such as a SHP2 inhibitor, a SOS inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, a BRAF inhibitor, or a combination thereof.

[0275] In certain aspects, the present disclosure provides a method of inhibiting activity of a Ras protein, such as K-Ras or a mutant thereof, comprising contacting the Ras protein with a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound exhibits an IC50 against the Ras protein of less than 10 µM, such as less than 5 µM, 1 µM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 50 pM, 10 pM or less.

[0276] In certain aspects, the present disclosure provides a method of treating a Ras-mediated cancer in a subject in need thereof, comprising administering to the subject a SHP2 inhibitor, a SOS inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a CDK4 / 6 inhibitor, or a BRAF inhibitor and an effective amount of a compound disclosed herein, such as a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematological cancer.

[0277] In practicing any of the methods disclosed herein, the Ras target to which a subject compound binds, either covalently or reversibly, can be a Ras mutant (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D), including a mutant of K-Ras, H-Ras, or N-Ras. In some embodiments, the methods of treating cancer can be applied to treat a solid tumor or a hematological cancer. In some embodiments, the cancer being treated can be, without limitation, prostate cancer, brain cancer, colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, various lung cancers including non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, non-Hodgkin’s lymphoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi’s sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers, combinations of said cancers, and metastatic lesions of said cancers. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematological cancer selected from one or more of chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T- cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt’s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and pre-leukemia. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is one or more cancers selected from the group consisting of chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), B cell acute lymphoblastic leukemia (B- ALL), and / or acute lymphoblastic leukemia (ALL).

[0278] Any of the treatment methods disclosed herein can be administered alone or in combination or in conjunction with another therapy or another agent. By “combination” it is meant to include (a) formulating a subject composition containing a subject compound together with another agent, or (b) using the subject composition separate from the another agent as an overall treatment regimen. By “conjunction” it is meant that the another therapy or agent is administered either simultaneously, concurrently or sequentially with a subject composition comprising a compound disclosed herein, with no specific time limits, wherein such conjunctive administration provides a therapeutic effect.

[0279] In some embodiments, a subject treatment method is combined with surgery, cellular therapy, chemotherapy, radiation, and / or immunosuppressive agents. Additionally, compositions of the present disclosure can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunostimulants, and combinations thereof. In one embodiment, a subject treatment method is combined with a chemotherapeutic agent.

[0280] Exemplary chemotherapeutic agents include an anthracycline (e.g., doxorubicin (e.g., liposomal doxorubicin)), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), an immune cell antibody (e.g., alemtuzamab, gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab), an antimetabolite (including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), a TNFR glucocorticoid induced TNFR related protein (GITR) agonist, a proteasome inhibitor (e.g., aclacinomycin A, gliotoxin or bortezomib), an immunomodulator such as thalidomide or a thalidomide derivative (e.g., lenalidomide). Additional chemotherapeutic agents contemplated for use in combination include busulfan (Myleran®), busulfan injection (Busulfex®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), mitoxantrone (Novantrone®), Gemtuzumab Ozogamicin (Mylotarg®), anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), dexamethasone, docetaxel (Taxotere®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6- thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0281] Anti-cancer agents of particular interest for combinations with a compound of the present disclosure include: anthracyclines; alkylating agents; antimetabolites; drugs that inhibit either the calcium dependent phosphatase calcineurin or the p70S6 kinase FK506 or inhibit the p70S6 kinase; mTOR inhibitors; immunomodulators; anthracyclines; vinca alkaloids; proteosome inhibitors; GITR agonists; protein tyrosine phosphatase inhibitors; a CDK4 kinase inhibitor; a BTK inhibitor; a MKN kinase inhibitor; a DGK kinase inhibitor; or an oncolytic virus.

[0282] Exemplary antimetabolites include, without limitation, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors: methotrexate (Rheumatrex®, Trexall®), 5-fluorouracil (Adrucil®, Efudex®, Fluoroplex®), floxuridine (FUDF®), cytarabine (Cytosar-U®, Tarabine PFS), 6-mercaptopurine (Puri-Nethol®)), 6-thioguanine (Thioguanine Tabloid®), fludarabine phosphate (Fludara®), pentostatin (Nipent®), pemetrexed (Alimta®), raltitrexed (Tomudex®), cladribine (Leustatin®), clofarabine (Clofarex®, Clolar®), azacitidine (Vidaza®), decitabine and gemcitabine (Gemzar®). Preferred antimetabolites include, cytarabine, clofarabine and fludarabine.

[0283] Exemplary alkylating agents include, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes: uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine (DTIC-Dome®). Additional exemplary alkylating agents include, without limitation, Oxaliplatin (Eloxatin®); Temozolomide (Temodar® and Temodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®); Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane®); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine HCl (Treanda®).

[0284] In certain aspects, compositions provided herein can be administered in combination with radiotherapy, such as radiation. Whole body radiation may be administered at 12 Gy. A radiation dose may comprise a cumulative dose of 12 Gy to the whole body, including healthy tissues. A radiation dose may comprise from 5 Gy to 20 Gy. A radiation dose may be 5 Gy, 6 Gy, 7 Gy, 8 Gy, 9 Gy, 10 Gy, 11 Gy, 12, Gy, 13 Gy, 14 Gy, 15 Gy, 16 Gy, 17 Gy, 18 Gy, 19 Gy, or up to 20 Gy. Radiation may be whole body radiation or partial body radiation. In the case that radiation is whole body radiation it may be uniform or not uniform. For example, when radiation may not be uniform, narrower regions of a body such as the neck may receive a higher dose than broader regions such as the hips.

[0285] Where desirable, an immunosuppressive agent can be used in conjunction with a subject treatment method. Exemplary immunosuppressive agents include but are not limited to cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies (e.g., muromonab, otelixizumab) or other antibody therapies, cytoxin, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation, peptide vaccine, and any combination thereof. In accordance with the presently disclosed subject matter, the above-described various methods can comprise administering at least one immunomodulatory agent. In certain embodiments, the at least one immunomodulatory agent is selected from the group consisting of immunostimulatory agents, checkpoint immune blockade agents (e.g., blockade agents or inhibitors of immune checkpoint genes, such as, for example, PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39), radiation therapy agents, chemotherapy agents, and combinations thereof. In some embodiments, the immunostimulatory agents are selected from the group consisting of IL-12, an agonist costimulatory monoclonal antibody, and combinations thereof. In one embodiment, the immunostimulatory agent is IL-12. In some embodiments, the agonist costimulatory monoclonal antibody is selected from the group consisting of an anti-4-lBB antibody (e.g., urelumab, PF-05082566), an anti-OX40 antibody (pogalizumab, tavolixizumab, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX- 2011), and combinations thereof. In one embodiment, the agonist costimulatory monoclonal antibody is an anti-4-l BB antibody. In some embodiments, the checkpoint immune blockade agents are selected from the group consisting of anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab, BMS-936559), anti-CTLA-4 antibodies (e.g., tremelimumab, ipilimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab, cemiplimab), anti-LAG3 antibodies (e.g., C9B7W, 410C9), anti-B7-H3 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g., F38-2E2), and combinations thereof. In one embodiment, the checkpoint immune blockade agent is an anti-PD-Ll antibody. In some cases, a compound of the present disclosure can be administered to a subject in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In some cases, expanded cells can be administered before or following surgery. Alternatively, compositions comprising a compound described herein can be administered with immunostimulants. Immunostimulants can be vaccines, colony stimulating agents, interferons, interleukins, viruses, antigens, co- stimulatory agents, immunogenicity agents, immunomodulators, or immunotherapeutic agents. An immunostimulant can be a cytokine such as an interleukin. One or more cytokines can be introduced with modified cells provided herein. Cytokines can be utilized to boost function of modified T lymphocytes (including adoptively transferred tumor-specific cytotoxic T lymphocytes) to expand within a tumor microenvironment. In some cases, IL-2 can be used to facilitate expansion of the modified cells described herein. Cytokines such as IL-15 can also be employed. Other relevant cytokines in the field of immunotherapy can also be utilized, such as IL-2, IL-7, IL-12, IL-15, IL-21, or any combination thereof. An interleukin can be IL-2, or aldesleukin. Aldesleukin can be administered in low dose or high dose. A high dose aldesleukin regimen can involve administering aldesleukin intravenously every 8 hours, as tolerated, for up to about 14 doses at about 0.037 mg / kg (600,000 IU / kg). An immunostimulant (e.g., aldesleukin) can be administered within 24 hours after a cellular administration. An immunostimulant (e.g., aldesleukin) can be administered in as an infusion over about 15 minutes about every 8 hours for up to about 4 days after a cellular infusion. An immunostimulant (e.g., aldesleukin) can be administered at a dose from about 100,000 IU / kg, 200,000 IU / kg, 300,000 IU / kg, 400,000 IU / kg, 500,000 IU / kg, 600,000 IU / kg, 700,000 IU / kg, 800,000 IU / kg, 900,000 IU / kg, or up to about 1,000,000 IU / kg. In some cases, aldesleukin can be administered at a dose from about 100,000 IU / kg to 300,000 IU / kg, from 300,000 IU / kg to 500,000 IU / kg, from 500,000 IU / kg to 700,000 IU / kg, from 700,000 IU / kg to about 1,000,000 IU / kg.

[0286] In some embodiments, a compound described herein, such as a compound, salt, or solvate of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), is administered in combination or in conjunction with one or more pharmacologically active agents selected from (1) an inhibitor of MEK (e.g., MEK1, MEK2) or of mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib, AZD6244); (2) an inhibitor of epidermal growth factor receptor (EGFR) and / or of mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, EGF-816); (3) an immunotherapeutic agent (e.g., checkpoint immune blockade agents, as disclosed herein); (4) a taxane (e.g., paclitaxel, docetaxel); (5) an anti-metabolite (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); (6) an inhibitor of FGFR1 and / or FGFR2 and / or FGFR3 and / or FGFR4 and / or of mutants thereof (e.g., nintedanib); (7) a mitotic kinase inhibitor (e.g., a CDK4 / 6 inhibitor, such as, for example, palbociclib, ribociclib, abemaciclib); (8) an anti-angiogenic drug (e.g., an anti-VEGF antibody, such as, for example, bevacizumab); (9) a topoisomerase inhibitor (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone); (10) a platinum-containing compound (e.g. cisplatin, oxaliplatin, carboplatin); (11) an inhibitor of ALK and / or of mutants thereof (e.g. crizotinib, alectinib, entrectinib, brigatinib); (12) an inhibitor of c-MET and / or of mutants thereof (e.g., K252a, SU11274, PHA665752, PF2341066); (13) an inhibitor of BCR-ABL and / or of mutants thereof (e.g., imatinib, dasatinib, nilotinib); (14) an inhibitor of ErbB2 (Her2) and / or of mutants thereof (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (15) an inhibitor of AXL and / or of mutants thereof (e.g., R428, amuvatinib, XL-880); (16) an inhibitor of NTRK1 and / or of mutants thereof (e.g., merestinib); (17) an inhibitor of RET and / or of mutants thereof (e.g., BLU-667, Lenvatinib); (18) an inhibitor of A-Raf and / or B-Raf and / or C-Raf and / or of mutants thereof (RAF-709, LY-3009120, sorafenib, vemurafenib, dabrafenib, encorafenib, regorafenib, GDC-879); (19) an inhibitor of ERK and / or of mutants thereof (e.g., ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, ravoxertinib); (20) an MDM2 inhibitor (e.g., HDM-201, NVP-CGM097, RG- 7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115); (21) an inhibitor of mTOR (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (22) an inhibitor of BET (e.g., I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645); (23) an inhibitor of IGF1 / 2 and / or of IGF1-R (e.g., xentuzumab, MEDI-573); (24) an inhibitor of CDK9 (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B, AT7519, dinaciclib, SNS-032); (25) an inhibitor of farnesyl transferase (e.g., tipifarnib); (26) an inhibitor of SHIP pathway including SHIP2 inhibitor, as well as SHIP1 inhibitors; (27) an inhibitor of SRC (e.g., dasatinib); (28) an inhibitor of JAK (e.g. tofacitinib); (29) a PARP inhibitor (e.g. Olaparib, Rucaparib, Niraparib, Talazoparib), (30) a BTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Zanubrutinib), (31) a ROS1 inhibitor (e.g., entrectinib), (32) an inhibitor of Src, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT, (33) an inhibitor of KRAS G12C mutant (e.g., including but not limited to AMG510, MRTX849, and any covalent inhibitors binding to the cysteine residue 12 of KRAS, the structures of which are publicly known) (e.g., an inhibitor of Ras G12C as described in US20180334454, US20190144444, US20150239900, US10246424, US20180086753, WO2018143315, WO2018206539, WO20191107519, WO2019141250, WO2019150305, US9862701, US20170197945, US20180086753, US10144724, US20190055211, US20190092767, US20180127396, US20180273523, US10280172, US20180319775, US20180273515, US20180282307, US20180282308, WO2019051291, WO2019213526, WO2019213516, WO2019217691, WO2019241157, WO2019217307, WO2020047192, WO2017087528, WO2018218070, WO2018218069, WO2018218071, WO2020027083, WO2020027084, WO2019215203, WO2019155399, WO2020035031, WO2014160200, WO2018195349, WO2018112240, WO2019204442, WO2019204449, WO2019104505, WO2016179558, WO2016176338, or related patents and applications, each of which is incorporated by reference in its entirety), (34) an SHC inhibitor (e.g., PP2, AID371185), (35) a GAB inhibitor (e.g., GAB-0001), (36) a GRB inhibitor, (37) a PI-3 kinase inhibitor (e.g., idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, NVP-BEZ235-AN), (38) a MARPK inhibitor, (39) a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, abemaciclib), (40) a MAPK inhibitor (e.g., VX-745, VX-702, RO-4402257, SCIO-469, BIRB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB- 681323, GW-856553, RWJ67657, BCT-197), or (41) a SHP pathway inhibitor, such as a SHP2 inhibitor (e.g., RMC-4630, ERAS-601, some embodiments, a Ras inhibitor described herein, such as a compound, salt, or solvate of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), is administered in combination or in conjunction with one or more checkpoint immune blockade agents (e.g., anti-PD-1 and / or anti-PD-L1 antibody, anti-CLTA-4 antibody). In some embodiments, a Ras inhibitor described herein, such as a compound, salt, or solvate of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), is administered in combination or in conjunction with one or more pharmacologically active agents comprising an inhibitor against one or more targets selected from: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, mitotic kinase, topoisomerase, ALK, ALK5, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1 / 2, IGF1-R, CDK9, SHIP1, SHIP2, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, KRAS G12C mutant, and ROS1. In some embodiments, a Ras inhibitor described herein, such as a compound, salt, or solvate of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), is administered in combination or in conjunction with one or more additional pharmacologically active agents comprising an inhibitor of SOS (e.g., SOS1, SOS2) or of mutants thereof, such as 5845, or BI-1701963. In some embodiments, a Ras inhibitor described herein, such as a compound, salt, or solvate of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), is administered in combination or in conjunction with an inhibitor of SOS described in WO2021092115, WO2018172250, WO2019201848, WO2019122129, WO2018115380, WO2021127429, WO2020180768, or WO2020180770, each of which is herein incorporated by reference in its entirety for all purposes.

[0287] In some embodiments, a Ras inhibitor described herein, such as a compound, salt, or solvate of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), is administered in combination or in conjunction with one or more checkpoint immune blockade agents (e.g., anti-PD-1 and / or anti-PD-L1 antibody, anti-CLTA-4 antibody).

[0288] In some embodiments, a compound described herein, such as a compound, salt, or solvate of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), and one or more pharmacologically active agents are administered either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two or more compounds in the body of the patient.

[0289] In some embodiments, a compound described herein, such as a compound, salt, or solvate of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), and one or more pharmacologically active agents are administered sequentially in any order by a suitable route, such as infusion or orally. The dosing regimen may vary depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria known to the attending physician and medical practitioner(s) administering the combination. The compound of the present disclosure and other pharmacologically active agent(s) may be administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment. In addition, the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug.

[0290] In some cases, a treatment regime may be dosed according to a body weight of a subject. In subjects who are determined obese (BMI > 35) a practical weight may need to be utilized. BMI is calculated by: BMI = weight (kg) / [height (m)]2. Body weight may be calculated for men as 50 kg + 2.3*(number of inches over 60 inches) or for women 45.5 kg + 2.3*(number of inches over 60 inches). An adjusted body weight may be calculated for subjects who are more than 20% of their ideal body weight. An adjusted body weight may be the sum of an ideal body weight + (0.4*(Actual body weight – ideal body weight)). In some cases, a body surface area may be utilized to calculate a dosage. A body surface area (BSA) may be calculated by: BSA (m2) = √Height (cm) ∗Weight (kg) / 3600.

[0291] In certain aspects, the present disclosure provides a method of modulating activity of a Ras (e.g., K-Ras) protein, comprising contacting a Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the Ras (e.g., K-Ras) protein. In some embodiments, the subject method comprises administering an additional agent or therapy.

[0292] In certain aspects, the present disclosure provides a method of modulating activity of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound described, or a pharmaceutically acceptable salt or solvate thereof, wherein said modulating comprises inhibiting the Ras (e.g., K-Ras) protein activity. In certain aspects, the present disclosure provides a method of modulating activity of a Ras protein, such as Ras mutant (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D) proteins of K-Ras, H-Ras, and N-Ras, comprising contacting the Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0293] In certain aspects, the present disclosure provides a method of reducing Ras signaling output in a cell by contacting the cell with a compound described herein. A reduction in Ras signaling can be evidenced by one or more of the following: (i) an increase in steady state level of GDP-bound modified protein; (ii) a reduction in steady state level of GTP-bound Ras protein; (iii) a reduction of phosphorylated AKTs473, (iv) a reduction of phosphorylated ERKT202 / y204, (v) a reduction of phosphorylated S6S235 / 236, (vi) a reduction of cell growth of a tumor cell expressing a Ras mutant (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D) protein, and (vii) a reduction in Ras interaction with a Ras-pathway signaling protein. Non-limiting examples of Ras-pathway signaling proteins include SOS (including SOS1 and SOS2), RAF, SHC, SHP (including SHP1 and SHP2), MEK, MAPK, ERK, GRB, RASA1, and GNAQ. In some embodiments, the reduction in Ras signaling output can be evidenced by two, three, four, five, six, or all of (i)-(vii) above. In some embodiments, the reduction of any one or more of (i)-(vii) can be 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5- fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100- fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more as compared to a control not treated with a subject compound. A reduction in cell growth can be demonstrated with the use of tumor cells or cell lines. A tumor cell line can be derived from a tumor in one or more tissues, e.g., pancreas, lung, ovary, biliary tract, intestine (e.g., small intestine, large intestine, colon), endometrium, stomach, hematopoietic tissue (e.g., lymphoid tissue), etc. Examples of tumor cell lines comprising a K-Ras mutation include, but are not limited to, A549 (e.g., K-Ras G12S), AGS (e.g., K-Ras G12D), ASPC1 (e.g., K-Ras G12D), Calu-6 (e.g., K-Ras Q61K), CFPAC-1 (e.g., K-Ras G12V), CL40 (e.g., K-Ras G12D), COLO678 (e.g., K-Ras G12D), COR-L23 (e.g., K-Ras G12V), DAN-G (e.g., K-Ras G12V), GP2D (e.g., K-Ras G12D), GSU (e.g., K-Ras G12F), HCT116 (e.g., K-Ras G13D), HEC1A (e.g., K-Ras G12D), HEC1B (e.g., K-Ras G12F), HEC50B (e.g., K-Ras G12F), HEYA8 (e.g., K-Ras G12D or G13D), HPAC (e.g., K-Ras G12D), HPAFII (e.g., K- Ras G12D), HUCCT1 (e.g., K-Ras G12D), KARPAS620 (e.g., K-Ras G13D), KOPN8 (e.g., K-Ras G13D), KP-3 (e.g., K-Ras G12V), KP-4 (e.g., K-Ras G12D), L3.3 (e.g., K-Ras G12D), LoVo (e.g., K-Ras G13D), LS180 (e.g., K- Ras G12D), LS513 (e.g., K-Ras G12D), MCAS (e.g., K-Ras G12D), NB4 (e.g., K-Ras A18D), NCI-H1355 (e.g., K- Ras G13C), NCI-H1573 (e.g., K-Ras G12A), NCI-H1944 (e.g., K-Ras G13D), NCI-H2009 (e.g., K-Ras G12A), NCI-H441 (e.g., K-Ras G12V), NCI-H747 (e.g., K-Ras G13D), NOMO-1 (e.g., K-Ras G12D), OV7 (e.g., K-Ras G12D), PANC0203 (e.g., K-Ras G12D), PANC0403 (e.g., K-Ras G12D), PANC0504 (e.g., K-Ras G12D), PANC0813 (e.g., K-Ras G12D), PANC1 (e.g., K-Ras G12D), Panc-10.05 (e.g., K-Ras G12D), PaTu-8902 (e.g., K- Ras G12V), PK1 (e.g., K-Ras G12D), PK45H (e.g., K-Ras G12D), PK59 (e.g., K-Ras G12D), SK-CO-1 (e.g., K- Ras G12V), SKLU1 (e.g., K-Ras G12D), SKM-1 (e.g., K-Ras K117N), SNU1 (e.g., K-Ras G12D), SNU1033 (e.g., K-Ras G12D), SNU1197 (e.g., K-Ras G12D), SNU407 (e.g., K-Ras G12D), SNU410 (e.g., K-Ras G12D), SNU601 (e.g., K-Ras G12D), SNU61 (e.g., K-Ras G12D), SNU8 (e.g., K-Ras G12D), SNU869 (e.g., K-Ras G12D), SNU- C2A (e.g., K-Ras G12D), SU.86.86 (e.g., K-Ras G12D), SUIT2 (e.g., K-Ras G12D), SW1990 (e.g., K-Ras G12D), SW403 (e.g., K-Ras G12V), SW480 (e.g., K-Ras G12V), SW620 (e.g., K-Ras G12V), SW948 (e.g., K-Ras Q61L), T3M10 (e.g., K-Ras G12D), TCC-PAN2 (e.g., K-Ras G12R), TGBC11TKB (e.g., K-Ras G12D), and MIA Pa-Ca (e.g., MIA Pa-Ca 2 (e.g., K-Ras G12C)).

[0294] In an aspect is provided a modified Ras mutant protein comprising a compound described herein (or a remnant of a compound described herein wherein the remnant of said compound is...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein: L is -L1-L2-L3-, wherein L2or L3is bound to -C(O)R19via a nitrogen atom, thereby forming a urea; L1is selected from a bond, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C(O)-, -S(O)-, -S(O)2-, -P(O)R12-, -P(O)R12O-, - C(O)N(R12)-, -S(O)N(R12)-, -S(O)2N(R12)-, and -P(O)R12N(R12)-, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; L3is selected from a bond, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, nitrene, -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R19is selected from imidazol-1-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol- 4-yl, each of which is optionally substituted; A and B are independently selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; C is selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted; and R13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle.

2. The compound, salt, or solvate of claim 1, wherein C is selected from hydrogen, halogen, -CN, C1-3alkyl, C3-5cycloalkyl, C1-3 haloalkyl, -CH2CN, -CH(CN)CH3, -CH2OH, and -CH(OH)CH3.

3. The compound, salt, or solvate of claim 1 or 2, wherein A and B are independently selected from optionally substituted indazolyl.

4. The compound of claim 1, having the structure of Formula (II):or a pharmaceutically acceptable salt or solvate thereof.

5. The compound, salt, or solvate of any one of the preceding claims, wherein: L1is selected from a bond, C1-6 alkyl, 2- to 6-membered heteroalkyl, -C(O)-, and -C(O)N(R12)-, wherein C1- 6 alkyl and 2- to 6-membered heteroalkyl are optionally substituted; L2is selected from a bond, C3-12carbocycle and 3- to 12-membered heterocycle, wherein C3-12carbocycle and 3- to 12-membered heterocycle are optionally substituted; and L3is selected from a bond, 2- to 6-membered heteroalkyl, and nitrene, wherein 2- to 6-membered heteroalkyl and nitrene are optionally substituted.

6. The compound, salt, or solvate of any one of the preceding claims, wherein L1is selected from a bond and C1-3alkyl.

7. The compound, salt, or solvate of any one of claims 1 to 6, wherein: L2is optionally substituted 3- to 12-membered heterocycle; and L3is a bond.

8. The compound, salt, or solvate of any one of claims 1 to 6, wherein: L2is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted; and L3is optionally substituted nitrene.

9. The compound, salt, or solvate of any one of the preceding claims, wherein L2is optionally substituted 6- to 12-membered spirocyclic heterocycle.

10. The compound, salt, or solvate of any one of claims 1 to 6, wherein -L2-L3-C(O)R19is selected from:, wherein: a1, b1, b3, and b4 are independently 1, 2, 3, 4, or 5; a2, a3, and b2 are independently 0, 1, 2, 3, 4, or 5; c1, c2, c3, c4, d1, d2, e1, and e2 are independently 0, 1, 2, 3, or 4; wherein the sum of a1, a2, and a3 is less than 9; the sum of b1, b2, b3, and b4 is less than 9; the sum of c1, c2, c3, and c4 is less than 8; the sum of d1 and d2 is less than 6; and the sum of e1 and e2 is less than 6; T is independently selected at each occurrence from N(R35), C(R36)2, C(O), O, S(O), and S(O)2; T2and T3are independently selected at each occurrence from N and C(R36); R31, R32, R33, and R36are independently selected at each occurrence from hydrogen and R40; R34and R35are independently selected at each occurrence from hydrogen and R41; R40is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(=O)(=NR12)N(R12)(R13), and -OCH2C(O)OR12; wherein two R40attached to the same carbon atom optionally join to form =NR12, =C(R14)2, or =O; wherein two R40and the atom(s) to which they are attached optionally form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein R40and R41and the atoms to which they are attached optionally form 3- to 12-membered heterocycle; and wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; R41is independently selected at each occurrence from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6- membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted; and R14is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted.

11. The compound, salt, or solvate of claim 10, wherein R40is independently selected at each occurrence fromhalogen, -CN, C1-6 alkyl, and C3-6 cycloalkyl, or two R40attached to the same carbon atom form C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -O(C1-6alkyl), and -O(C1-6haloalkyl).

12. The compound, salt, or solvate of claim 10 or 11, wherein R41is independently selected at each occurrence from C1-6 alkyl and C3-6 cycloalkyl, each of which is optionally substituted with one, two, or three substituents selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), and -O(C1-6 haloalkyl).

13. The compound of claim 1, having the structure:, or a pharmaceutically acceptable salt or solvate thereof.

14. The compound, salt, or solvate of any one of claims 1 to 13, wherein R19is selected from 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-1-yl, and 1,2,4-triazol-4-yl, each of which is optionally substituted.

15. The compound, salt, or solvate of any one of claims 1 to 13, wherein R19is optionally substituted imidazol- 1-yl.

16. The compound, salt, or solvate of any one of the preceding claims, wherein R19is optionally substituted with one or two substituents independently selected from halogen, -CN, C1-6 alkyl, and C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, -CN, C1-6alkyl, -O(C1-6alkyl), and -O(C1-6haloalkyl).

17. A pharmaceutical composition comprising a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

18. A method of modifying a Ras mutant protein, comprising contacting the Ras mutant protein with an effective amount of the compound, salt, or solvate of any one of claims 1 to 16.

19. The method of claim 18, wherein the modified Ras mutant protein exhibits a reduced Ras signaling output.

20. The method of claim 19, wherein the reduced Ras signaling output is evidenced by one or more output selected from (i) an increase in steady state level of GDP-bound modified protein; (ii) a reduction in steady state level of GTP-bound modified protein; (iii) a reduction of phosphorylated AKTs473; (iv) a reduction of phosphorylated ERK T202 / Y204; (v) a reduction of phosphorylated S6 S235 / 236; (vi) a reduction of cell growth of a tumor cell expressing a Ras G12S mutant protein; and (vii) a reduction in Ras interaction with a Ras-pathway signaling protein.

21. The method of any one of claims 18 to 20, wherein the Ras mutant protein comprises an amino acidsequence in SEQ ID No. 4 having a serine residue corresponding to position 12 of SEQ ID No. 1.

22. The method of any one of claims 18 to 20, wherein the Ras mutant protein comprises an amino acid sequence of SEQ ID No. 4.

23. The method of any one of claims 18 to 20, wherein the modified Ras mutant protein comprises an amino acid sequence of SEQ ID No. 1, or a fragment thereof that comprises the serine residue corresponding to position 12 of SEQ ID No. 1, and wherein the compound selectively labels the serine residue as compared to (i) an aspartate residue of a K-Ras G12D mutant protein, said aspartate corresponding to position 12 of SEQ ID No. 2: (ii) a valine residue of a K-Ras G12V mutant protein, said valine corresponding to position 12 of SEQ ID No. 3; and / or (iii) a glycine residue of a K-Ras wildtype protein, said glycine corresponding to position 12 of SEQ ID No. 1.

24. The method of claim 23, wherein the compound selectively labels the serine residue by at least 2-fold when assayed under comparable conditions.

25. The method of claim 23, wherein the compound selectively labels the serine residue by at least 5-fold when assayed under comparable conditions.

26. The method of any one of claims 18 to 25, wherein the contacting occurs in vivo.

27. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof.

28. A method of treating cancer in a subject comprising a Ras mutant protein, the method comprising: inhibiting the Ras mutant protein of said subject by administering to said subject a compound of any one of claims 1 to 16, wherein the compound is characterized in that upon contacting the Ras mutant protein, said Ras mutant protein exhibits reduced Ras signaling output.

29. The method of claim 27 or 28, wherein the cancer is a solid tumor or a hematological cancer.

30. The method of any one of claims 27 to 29, wherein the cancer comprises a K-Ras G12S mutant protein.

31. A method of modulating signaling output of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the signaling output of the Ras protein.

32. A method of inhibiting cell growth, comprising administering an effective amount of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.

33. The method of any one of claims 18 to 32, comprising administering an additional agent.

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