Cyclin-dependent kinase (CDK) 12 and / or CDK13 inhibitor combinations and uses thereof

Abstract

Described herein are methods of treating cancer using a small molecule CDK12 and / or CDK13 inhibitor and an additional agent. In some embodiments, the small molecule CDK12 and / or CDK13 inhibitor is a compound of Formula (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the small molecule CDK12 and / or CDK13 inhibitor is a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an anti-cancer agent.

Description

CYCLIN-DEPENDENT KINASE (CDK) 12 AND / OR CDK13 INHIBITOR COMBINATIONS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of International Application No. PCT / CN2024 / 076680, filed February 7, 2024, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] Cyclin-dependent kinases (CDKs) are a family of multifunctional enzymes that play important regulatory roles in proliferation, such as modifying various protein substrates involved in cell cycle progression. The discovery of selective inhibitors of CDK12 and / or CDK13 has been limited due to the high sequence and structural similarities of the kinase domain of CDK family members. Therefore, it is imperative to discover and develop selective CDK12 and / or CDK13 inhibitors.

[0003] Accordingly, there is a need for agents that inhibit the enzymatic activities of CDK12 and / or CDK13 to treat diseases, disorders, and conditions associated with CDK12 and / or CDK13 activity, such as cancer.SUMMARY

[0004] Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) a compound of Formula (III), or a pharmaceutically acceptable salt thereof:Formula (III)；and(b) an additional agent, wherein the combined amount of the compound of Formula (III), or a pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer. In some embodiments, the additional agent is an anti-cancer agent.

[0005] In some embodiments, the cancer is primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, lung cancer, bladder cancer, prostate cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, liver cancer or mesothelioma.

[0006] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), small cell lung cancer, colon cancer, pancreatic cancer, prostate cancer, triple-negative breast cancer (TNBC), gastrointestinal stromal tumor, biliary tract cancer, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) B-lineage, lymphoma, or T cell leukemia.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The features of the invention are set forth with particularity in the appended claims. A better understanding of the features 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:

[0008] FIG. 1 Illustrates the anti-tumour activity of Compound 123 in combination with Olaparib in SUM149PT human TNBC xenograft model.

[0009] FIG. 2 Illustrates the anti-tumour activity of Compound 123 in combination with Cisplatin in NCI-H1417 human SCLC xenograft model.DETAILED DESCRIPTION Definitions

[0010] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0011] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0012] Use of absolute or sequential terms, for example, “will,” “will not,” “shall,” “shall not,” “must,” “must not,” “first,” “initially,” “next,” “subsequently,” “before,” “after,” “lastly,” and “finally,” are not meant to limit scope of the present embodiments disclosed herein but as exemplary.

[0013] As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms “including”, “includes”, “having”, “has”, “with”, or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising.”

[0014] As used herein, the phrases “at least one”, “one or more”, and “and / or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions “at least one of A, B and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and / or C” means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together.

[0015] As used herein, “or” may refer to “and”, “or,” or “and / or” and may be used both exclusively and inclusively. For example, the term “A or B” may refer to “A or B”, “A but not B”, “B but not A”, and “A and B”. In some cases, context may dictate a particular meaning.

[0016] Any systems, methods, software, and platforms described herein are modular. Accordingly, terms such as “first” and “second” do not necessarily imply priority, order of importance, or order of acts.

[0017] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and the number or numerical range may vary from, for example, from 1% to 15% of the stated number or numerical range. In some embodiments, the term “about” refers to ±10% of a stated number or value.

[0018] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the disclosure be limited by the specific examples provided within the specification. While the disclosure has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. Furthermore, it shall be understood that all aspects of the disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is therefore contemplated that the disclosure shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0019] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0020] “oxo” refers to =O.

[0021] “Carboxyl” refers to -COOH.

[0022] “Cyano” refers to -CN.

[0023] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl” or “C1-6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-10alkyl. In some embodiments, the alkyl is a C1-6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0024] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0025] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0026] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0027] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0028] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0029] “Cycloalkyl” refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0030] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0031] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0032] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0033] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0034] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0035] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0036] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0037] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and / or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0038] As used herein, the term “variant” refers to a protein having characteristics that deviate from what occurs in nature that retains at least one functional i.e. binding, interaction, or enzymatic activity and / or therapeutic property thereof. A “variant” is at least about 70% identical, at least about 80% identical, at least about 90% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, at least about 99% identical, at least about 99.5% identical, or at least about 99.9% identical to the wild type protein. The changes include chemical modifications, substitutions of different amino acid residues truncations, covalent additions (e.g. of a tag), and any other changes. This term also embraces fragments of a wild type protein.

[0039] “Biosimilar” is a biotherapeutic product that is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product, for example, defined in WHO guidelines (Guidelines on evaluation of similar Biotherapeutic Products (SBPs), Annex 2, Technical Report Series No. 977, 2009) or a biosimilar of a reference product as set forth under Biologies Price Competition and Innovation Act of 2009 and section 351 (k) of the Public Health Service Act. A biosimilar has the same polypeptide sequence as the reference product.

[0040] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0041] “Treatment” of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition, subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition. As used herein, a “disease or disorder associated with CDK12 and / or CDK13” or, alternatively, “a CDK12 and / or CDK13-mediated disease or disorder” means any disease or other deleterious condition in which CDK12 and / or CDK13, or a mutant thereof, is known or suspected to play a role. CDK12 and / or CDK13 inhibitorInhibitors

[0042] In some embodiments disclosed herein is a CDK12 and / or CDK13 inhibitor of Formula (III), or a pharmaceutically acceptable salt thereof:,Formula (III), wherein:X1 is N or CR1; X2 is N or CR2; X3 is N or CR3; X4 is N or CR4; R1 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SF5, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R1a; R2 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R2a;R3 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R3a; orR2 and R3 are taken together with the intervening groups to form a 5 or 6 membered ring, which is optionally substituted with one or more RCC;R4 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R4a; R8 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R5 and R6 are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; or R5 and R6 are taken together with the carbon to which they are attached to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R6a;n is 1 or 2;W is a bond or -C(=O)-;Ring E is heteroaryl; Ring F is phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl; provided that when Ring F is a phenyl, then R5 and R6 are taken together with the carbon to which they are attached to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R6a; each R71 and R72 is independently halogen, -CN, -NO2, -OH, oxo, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R7a;m1 is 0, 1, 2, or 3;m2 is 0, 1, 2, 3, or 4;R10 is CN, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;p is 1 or 2;q is 0, 1, or 2;R10a, R10b, R10c, and R10d are each independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; independently optionally substituted with one or more R10e;each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;each RCC is independently halogen, -CN, -NO2, -OH, oxo, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more RCa;RCa, R1a, R2a, R3a, R4a, R6a, R7a, and R10e are each independently halogen, -CN, -OH, oxo, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; andeach R is independently halogen, -CN, -OH, oxo, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl.

[0043] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt or stereoisomer thereof, the compound is of Formula (III-A), Formula (III-A-1), Formula (III-B), Formula (III-B-1), Formula (III-C), Formula (III-C-1), Formula (III-D), Formula (III-D-1), Formula (III-E), Formula (III-E-1), Formula (III-F), or Formula (III-F-1) :; ; ;Formula (III-A); Formula (III-A-1); Formula (III-B);; ; ;Formula (III-B-1); Formula (III-C); Formula (III-C-1);; ; ;Formula (III-D); Formula (III-D-1); Formula (III-E);; ; ;Formula (III-E-1); Formula (III-F); Formula (III-F-1)；Wherein: X1 is N or CR1; X2 is N or CR2; X3 is N or CR3; X4 is N or CR4; R1 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SF5, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R1a; R2 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R2a;R3 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R3a; orR2 and R3 are taken together with the intervening groups to form a 5 or 6 membered ring, which is optionally substituted with one or more RCC;R4 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R4a.

[0044] In some embodiments of a compound of Formula (III), (III-A), (III-A-1), (III-B), (III-B-1), (III-C), (III-C-1), (III-D), (III-D-1), (III-E), (III-E-1), (III-F), or (III-F-1), or a pharmaceutically acceptable salt or stereoisomer thereof, Ring F is cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl. In some embodiments, Ring F is 5-6 membered heterocycloalkyl. In some embodiments, Ring F is 6 membered heterocycloalkyl. In some embodiments, Ring F is 6 membered heterocycloalkyl containing 1 or 2 ring nitrogen atoms. In some embodiments, Ring F is piperidine. In some embodiments, is .In some embodiments of a compound of Formula (III), (III-A), (III-A-1), (III-B), (III-B-1), (III-C), (III-C-1), (III-D), (III-D-1), (III-E), (III-E-1), (III-F), or (III-F-1), or a pharmaceutically acceptable salt or stereoisomer thereof, each R72 is independently halogen, -CN, -NO2, -OH, oxo, -ORa, -OC(=O)Ra, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each of the alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R7a.

[0045] In some embodiments of a compound of Formula (III), (III-A), (III-A-1), (III-B), (III-B-1), (III-C), (III-C-1), (III-D), (III-D-1), (III-E), (III-E-1), (III-F), or (III-F-1), or a pharmaceutically acceptable salt or stereoisomer thereof, is .

[0046] In some embodiments of a compound of Formula (III), (III-A), (III-A-1), (III-B), (III-B-1), (III-C), (III-C-1), (III-D), (III-D-1), (III-E), (III-E-1), (III-F), or (III-F-1), or a pharmaceutically acceptable salt or stereoisomer thereof, is , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0047] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt or stereoisomer thereof, is , , ,, , or .

[0048] In some embodiments of a compound of Formula (III), or a pharmaceutically acceptable salt or stereoisomer thereof, is , , , , , , , , , , , , , , , , , , , or .

[0049] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0050] In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is one of the compounds in Table 1.TABLE 1NoStructureNoStructureNoStructure1951372961383971394981405991416100142710114381021449103145101211461112214712123148131241491412515015126151161271521712815318129154881301558913115690132157911331589213415993135  94136   

[0051] Small molecule inhibitors of CDK12 and / or CDK13 are known in the art and suitable for use in the methods disclosed herein. The CDK12 and / or CDK13 inhibitor selected from a compound disclosed in PCT / CN2023 / 111521, WO2023091726, WO2023102184, WO2021011796, WO2020006497, WO2023250430, WO2024009232, the entire contents of which are hereby incorporated by reference in their entirety.Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0052] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Isotopically enriched compounds

[0053] Unless otherwise stated, 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, denoted 1H (protium), 2H (deuterium), and 3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford some 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.

[0054] For example, the compounds described herein may be artificially enriched in one or more particular isotopes. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes that are not predominantly found in nature. In some embodiments, the compounds described herein may be artificially enriched in one or more isotopes selected from deuterium (2H), tritium (3H), iodine-125 (125I) or carbon14 (14C). In some embodiments, the compounds described herein are artificially enriched in one or more isotopes selected from 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, 131I, and 125I. In some embodiments, the abundance of the enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

[0055] In some embodiments, the compound is deuterated in at least one position. In some embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms.

[0056] The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997, and the following synthetic methods. For example, deuterium substituted compounds may be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. Pharmaceutically acceptable salts

[0057] 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.

[0058] 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, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0059] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0060] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1 -carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0061] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like.

[0062] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Tautomers

[0063] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Compound 123

[0064] Compound 123 is (R)-1-(4-(3-((4-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)prop-2-en-1-one: . Compound 123 is a CDK12 and / or CDK13 inhibitor. In some embodiments, Compound 123 is in the form of a freebase. In some embodiments Compound 123 is in the form of a pharmaceutically acceptable salt thereof.Methods / Combinations

[0065] Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) a CDK12 and / or CDK13 inhibitor or a pharmaceutically acceptable salt thereof; and(b) an additional agent, wherein the combined amount of the CDK12 and / or CDK13 inhibitor, or a pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer.

[0066] In some embodiments, the CDK12 and / or CDK13 inhibitor is a compound selected from Table 1. In some embodiments, the CDK12 and / or CDK13 inhibitor is a compound having the structure of Formula (III). In some embodiments, the CDK12 and / or CDK13 inhibitor is a compound having the structure of Formula (III-A), (III-A-1), (III-B), (III-B-1), (III-C), (III-C-1), (III-D), (III-D-1), (III-E), (III-E-1), (III-F), or (III-F-1).

[0067] In some embodiments, the additional agent is an anti-cancer agent.

[0068] Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) or a pharmaceutically acceptable salt thereof; and (b) an additional agent.

[0069] Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) (Compound 123) or a pharmaceutically acceptable salt thereof; and(b) an additional agent.In some embodiments, Compound 123 or the pharmaceutically acceptable salt thereof and the additional agent are administered in a therapeutically effective amount for treating the cancer. In some embodiments, the combined amount of Compound 123 or the pharmaceutically acceptable salt thereof and the additional agent is therapeutically effective for treating the cancer.

[0070] In some embodiments, the cancer is primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, lung cancer, bladder cancer, prostate cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, liver cancer or mesothelioma.

[0071] In some embodiments, the cancer is, non-small cell lung cancer (NSCLC), small cell lung cancer, colon cancer, pancreatic cancer, prostate cancer, triple-negative breast cancer (TNBC), gastrointestinal stromal tumor, biliary tract cancer, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) B-lineage, lymphoma, or T cell leukemia.

[0072] In some embodiments of a method of treating cancer, the additional agent is a PARP inhibitor, an alkylating agent, an immune checkpoint inhibitor, a KRAS inhibitor, an EGFR inhibitor, a VEGFR inhibitor, an aromatase inhibitor, a mitotic inhibitor, a CDK4 / 6 inhibitor, a JAK inhibitor, a Bcr-Abl inhibitor, a Flt-3 inhibitor, or a RAF inhibitor, or any combination thereof.

[0073] In some embodiments of a method of treating cancer, the additional agent is a PARP inhibitor.

[0074] In some embodiments of a method of treating cancer, the PARP inhibitor is olaparib (AZD2281), veliparib (ABT-888), rucaparib, talazoparib (BMN 673), AZD5305, AG- 14361, INO-1001 (3-aminobenzamide), A-966492, PJ34 HC1, niraparib, UPF 1069, ME0328, RK-287107, pamiparib (BGB-290), NMS-P118, E7449, picolinamide, benzamide, NU1025, iniparib (B SI-201), AZD2461, BGP-15 2HC1, XAV-939, 4-hydroxyquinazoline, NVP-TNKS656, MN 64, or G007-LK, or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments of a method of treating cancer, the PARP inhibitor is olaparib (AZD2281) , veliparib (ABT-888), rucaparib, or talazoparib (BMN 673), or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments of a method of treating cancer, the PARP inhibitor is olaparib (AZD2281) or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments of a method of treating cancer, the PARP inhibitor is talazoparib (BMN 673) or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments of a method of treating cancer, the additional agent is an alkylating agent.

[0079] In some embodiments of a method of treating cancer, the alkylating agent is altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, temozolomide, thiotepa, trabectedin, platinum coordination complexes, or a pharmaceutically acceptable salt thereof. In some embodiments, the alkylating agent is cisplatin, or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments of a method of treating cancer, the additional agent is an immune checkpoint inhibitor.

[0081] In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is an antagonist of PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A and CCR2, or a pharmaceutically acceptable salt thereof, or avariant thereof or biosimilar thereof.

[0082] In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is anti-PD-L1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-LAG-3 antibody, anti-TIGIT antibody, anti-TIM-3 antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-B7-H4 antibody, CD73 antagonist, anti-CCR2 antibody, or a variant thereof or biosimilar thereof.

[0083] In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is an anti-PD-L1 antibody, an anti-PD-1 antibody or an anti-CTLA-4 antibody. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is an anti-PD-L1 antibody, an anti-PD-1 antibody or an anti-CTLA-4 antibody, or a variant thereof or biosimilar thereof.

[0084] In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is an anti-PD-L1 antibody or an anti-PD-1 antibody, or a variant thereof or biosimilar thereof.

[0085] In some embodiments of a method of treating cancer, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, sugemalimab, envafolimab, cosibelimab, or adebrelimab, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is atezolizumab, avelumab, durvalumab, sugemalimab, envafolimab, cosibelimab, adebrelimab, or a variant thereof or biosimilar thereof. In some embodiments, the anti-PD-L1 antibody is atezolizumab or a variant or biosimilar thereof. In some embodiments, the anti-PD-L1 antibody is avelumab, or a variant or biosimilar thereof. In some embodiments, the anti-PD-L1 antibody is durvalumab, or a variant or biosimilar thereof. In some embodiments, the anti-PD-L1 antibody is sugemalimab, or a variant or biosimilar thereof. In some embodiments, the anti-PD-L1 antibody is envafolimab, or a variant or biosimilar thereof. In some embodiments, the anti-PD-L1 antibody is cosibelimab, or a variant or biosimilar thereof. In some embodiments, the anti-PD-L1 antibody is adebrelimab, or a variant or biosimilar thereof.

[0086] In some embodiments of a method of treating cancer, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, toripalimab, camrelizumab, tislelizumab, penpulimab, or sintilimab, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is nivolumab, pembrolizumab, cemiplimab, toripalimab, camrelizumab, tislelizumab, penpulimab, or sintilimab, or a variant thereof or biosimilar thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is nivolumab, or a variant or biosimilar thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is pembrolizumab, or a variant or biosimilar thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is cemiplimab, or a variant or biosimilar thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is toripalimab, or a variant or biosimilar thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is camrelizumab, or a variant or biosimilar thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is tislelizumab, or a variant or biosimilar thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is penpulimab, or a variant or biosimilar thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is sintilimab, or a variant or biosimilar thereof.

[0087] In some embodiments of a method of treating cancer, the anti-CTLA-4 antibody is ipilimumab, or tremelimumab, or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is ipilimumab, or tremelimumab, or a variant thereof or biosimilar thereof.

[0088] In some embodiments of a method of treating cancer, the anti-LAG-3 antibody is relatlimab, fianlimab, miptenalimab, favezelimab, ieramilimab, Sym022, GSK2831781, INCAGN02385, TSR-033, or a variant thereof or biosimilar thereof.

[0089] In some embodiments of a method of treating cancer, the anti-TIGIT antibody is tiragolumab, domvanalimab, vibostolimab, etigilimab, tamgiblimab, M6223, ociperlimab, or EOS884448, or a variant thereof or biosimilar thereof.

[0090] In some embodiments of a method of treating cancer, the anti-TIM-3 antibody is sabatolimab, surzebiclimab, cobolimab, Sym023, R07121661, LY3321367, ICAGN02390, or BMS-986258, or a variant thereof or biosimilar thereof.

[0091] In some embodiments of a method of treating cancer, the anti-B7-H3 antibody is enoblituzumab, omburtamab, vobramitamab, mirzotamab, B7-H3 TriKE, 131I-omburtamab, DS-7300a, or 177Lu-DTPA-omburtamab, or a variant thereof or biosimilar thereof.

[0092] In some embodiments of a method of treating cancer, the anti-B7-H4 antibody is alsevalimab, FPA150, or a variant thereof or biosimilar thereof.

[0093] In some embodiments of a method of treating cancer, the A2aR antagonist is ciforadenant, imaradenant, etrumadenant, NIR178, inupadenant, CS3005, PBF-999, or INCB106385, or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments of a method of treating cancer, the CD73 antagonist is quemliclustat, AB680, methADP, OP-5244, MRS4620, PSB-12379, or BK50164, or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments of a method of treating cancer, the anti-CCR2 antibody is plozalizumab, or a variant thereof or biosimilar thereof.

[0096] In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is nivolumab, pembrolizumab, cemiplimab, toripalimab, camrelizumab, tislelizumab, penpulimab, sintilimab, atezolizumab, avelumab, durvalumab, sugemalimab, envafolimab, cosibelimab, adebrelimab, AMP -224, PF- 06801591, MEDI0680, PDR001, REGN2810, SHR-1210, TSR-042, CA-170, KN035, and BMS-936559, abatacept, belatacept, ipilimumab, tremelimumab, AGEN1884, AGEN2041, BMS-986016, GSK2831781, IMP321, LAG525, MGD013, or TSR- 022, or a pharmaceutically acceptable salt thereof, or a variant thereof or biosimilar thereof.

[0097] In some embodiments of a method of treating cancer, the additional agent is an immune checkpoint inhibitor.

[0098] In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is nivolumab, pembrolizumab, cemiplimab, toripalimab, camrelizumab, tislelizumab, penpulimab, sintilimab or a variant thereof or biosimilar thereof.

[0099] In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is atezolizumab, avelumab, durvalumab, sugemalimab, envafolimab, cosibelimab, adebrelimab or a pharmaceutically acceptable salt thereof. In some embodiments of a method of treating cancer, the immune checkpoint inhibitor is atezolizumab, avelumab, durvalumab, sugemalimab, envafolimab, cosibelimab, adebrelimab, or a variant thereof or biosimilar thereof.

[00100] In some embodiments of a method of treating cancer, the additional agent is a KRAS inhibitor.

[00101] In some embodiments of a method of treating cancer, the KRAS inhibitor is a KRAS G12C inhibitor.

[00102] In some embodiments of a method of treating cancer, the KRAS inhibitor is a KRAS G12D inhibitor.

[00103] In some embodiments of a method of treating cancer, the KRAS inhibitor is a KRAS G12S inhibitor.

[00104] In some embodiments of a method of treating cancer, the KRAS inhibitor is a KRAS G12Vinhibitor.

[00105] In some embodiments of a method of treating cancer, the KRAS inhibitor is a pan-KRAS inhibitor.

[00106] In some embodiments of a method of treating cancer, the KRAS inhibitor is 6H05, adagrasib, ARS-1323, ARS-1323-alkyne, ARS-1620, ARS-1630, ARS-853, ASP2453 , AZD4625, BAY-293, BI-0474, BI-2852, BI-3406, divarasib, G12Si-1, G12Si-5 formic, G12Si-5, garsorasib, K20, KRAS G12C inhibitor 1, KRAS G12C inhibitor 2, KRAS G12C inhibitor 3, KRAS G12C inhibitor 4, KRAS G12C inhibitor 5, KRAS G12C inhibitor 13, KRAS G12C inhibitor 14, KRAS G12C inhibitor 15, KRAS G12C inhibitor 16, KRAS G12C inhibitor 17, KRAS G12C inhibitor 18, KRAS G12C inhibitor 23, KRAS G12C inhibitor 24, KRAS G12C inhibitor 25, KRAS G12C inhibitor 26, KRAS G12C inhibitor 27, KRAS G12C inhibitor 28, KRAS G12C inhibitor 32, KRAS G12C inhibitor 43, KRAS G12C inhibitor 44, KRAS G12C inhibitor 45, KRAS G12C inhibitor 46, KRAS G12C inhibitor 47, KRAS G12C inhibitor 48, KRAS G12C inhibitor 49, KRAS G12C inhibitor 50, KRAS G12C inhibitor 51, KRAS G12C inhibitor 52, KRAS G12C inhibitor 53, KRAS G12C inhibitor 54, KRAS G12C inhibitor 55, KRAS G12C inhibitor 57, K-Ras G12C-IN-2, KRAS G12D inhibitor 3, KRAS G12D inhibitor 7, KRAS G12D inhibitor 14, KRAS G12D inhibitor 16, KRAS G12D inhibitor 17, KRAS inhibitor-3, KRAS inhibitor-6, KRAS inhibitor-7, KRAS inhibitor-8, KRAS inhibitor-10, KRAS inhibitor-11, KRAS inhibitor-12, KRAS inhibitor-13, KRAS inhibitor-14, KRAS inhibitor-15, KRAS inhibitor-16, KRAS inhibitor-17, KRAS inhibitor-18, KRAS inhibitor-20, K-Ras(G12C) inhibitor 6, KRpep-2d , LC-2, MRTX1133, MRTX-1257, MRTX849 acid, MRTX-EX185 formic, opnurasib, Pan KRas-IN-1, PROTAC K-Ras Degrader-1, RM-018, SAH-SOS1A, SOS1-IN-4, SOS1-IN-9, sotorasib, or ZG1077, or a pharmaceutically acceptable salt thereof.

[00107] In some embodiments of a method of treating cancer, the KRAS inhibitor is ARS-3248 (JNJ-74699157), AMG510, MRTX849, MRTX1133, ASP245, 3GDC6036, BI-2852, BI 1701963, mRNA-5671, JDQ443, RAS(ON) inhibitors, BBP-454, RM-018, RMC-6291, or RMC-6236, or a pharmaceutically acceptable salt thereof.

[00108] In some embodiments of a method of treating cancer, the KRAS inhibitor is adagrasib, divarasib, garsorasib, opnurasib, or sotorasib, or a pharmaceutically acceptable salt thereof.

[00109] In some embodiments of a method of treating cancer, the KRAS inhibitor is sotorasib or a pharmaceutically acceptable salt thereof.

[00110] In some embodiments of a method of treating cancer, the KRAS inhibitor is adagrasib or a pharmaceutically acceptable salt thereof.

[00111] In some embodiments of a method of treating cancer, the KRAS inhibitor is selected from a compound disclosed in WO2018119183, WO2018217651, WO2019051291, WO2019213526, WO2019213516, WO2019217691, WO2019232419, WO2019241157, WO2020106640, WO2021081212, WO2022083569, WO2022093856, WO2022232332, WO2022232331, WO2020146613, WO2020097537, WO2015054572, WO2020177629, WO2019141250, WO2020081282, WO2020085493, WO2018143315, WO2018206539, WO2019110751, WO2019195609, WO2021207172, WO2021041671, WO2021150613, WO2021142252, WO2021152149, WO2021248090, WO2021216770, WO2022002102, WO2022031678, WO2023099623, WO2023099608, WO2023099592, WO2024012519, WO2024015262, WO2024015731, WO2024012456, US10662204B2, US10689377B2, US10689377B2, US10689377B2, US10689377B2, or US10519146B2, the entire contents of which are hereby incorporated by reference in their entirety.

[00112] In some embodiments of a method of treating cancer, the additional agent is an EGFR inhibitor.

[00113] In some embodiments of a method of treating cancer, the EGFR inhibitor is Erlotinib (OSI-774) HCl, Gefitinib (ZD1839), Lapatinib (GW-572016) Ditosylate, Afatinib (BIBW2992), Saracatinib (AZD0530), Vandetanib (ZD6474), Neratinib (HKI-272), Canertinib (CI-1033), Lapatinib (GW-572016), AG-490 (Tyrphostin B42), CP-724714, Orsimertinib, Dacomitinib (PF-00299804), WZ4002, Sapitinib (AZD8931), CUDC-101, AG-1478 (Tyrphostin AG-1478), PD153035 HCl, Pelitinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), AP26113-analog (ALK-IN-1), OSI-420, WZ3146, Allitinib tosylate, Rociletinib (CO-1686), Varlitinib, Icotinib (BPI-2009H), TAK-285, WHI-P154, Daphnetin, PD168393, CNX-2006, Tyrphostin 9, AG-18, O-Demethyl-Gefitinib, AST-1306, BDTX-189, Epertinib hydrochloride, JND3229, BI-4020, Tyrphostin AG-528, AG 556, Canertinib dihydrochloride, EGFR Inhibitor, Gefitinib-based PROTAC 3, SU5214, RG 13022, TQB3804 (EGFR-IN-7), zipalertinib, Pyrotinib (SHR-1258) dimaleate, PD153035, AG 494, AG 555, Theliatinib (HMPL-309), Avitinib (AC0010), Lazertinib, Gefitinib hydrochloride, Cetuximab (anti-EGFR), Lifirafenib (BGB-283), Nazartinib (EGF816), Brigatinib (AP26113), Tucatinib, Zorifertinib (AZD3759), Afatinib (BIBW2992) Dimaleate, Erlotinib (OSI-774), CL-387785 (EKI-785), Poziotinib (HM781-36B), Osimertinib (AZD9291), AZ5104, AV-412 free base, WZ8040, Genistein (NPI 031L), Falnidamol, BLU-945, Sunvozertinib, CH7233163, Licochalcone D, Alflutinib (AST2818) mesylate, (Rac)-JBJ-04-125-02, Mobocertinib (TAK788), Tyrphostin AG30 (AG30), AG-1557, AG99, MTX-211, RG14620, Almonertinib (HS-10296), Cyasterone, Osimertinib mesylate, Norcantharidin, Naquotinib(ASP8273), EAI045, Lidocaine hydrochloride, Olmutinib (BI 1482694), Butein, Chrysophanic Acid, or (-)-Epigallocatechin Gallate, or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is cetuximab, necitumumab, or panitumumab, or a variant thereof or biosimilar thereof.

[00114] In some embodiments of a method of treating cancer, the additional agent is a VEGFR inhibitor.

[00115] In some embodiments of a method of treating cancer, the VEGFR inhibitor is Sorafenib (BAY 43-9006) tosylate, Sunitinib (SU11248) malate, Cabozantinib (BMS-907351), Ponatinib (AP24534), Axitinib (AG 013736), Foretinib (GSK1363089), Vandetanib (ZD6474), Nintedanib (BIBF 1120), Regorafenib (BAY 73-4506), Pazopanib HCl (GW786034 HCl), Cediranib (AZD2171), PD173074, Dovitinib (TKI-258), Linifanib (ABT-869), Vatalanib (PTK787) 2HCl, RAF265 (CHIR-265), Tivozanib (AV-951), Motesanib Diphosphate (AMG-706), Lenvatinib (E7080), Brivanib (BMS-540215), MGCD-265 analog, AEE788 (NVP-AEE788), ENMD-2076, OSI-930, CYC116, Ki8751, Telatinib, PP121, Pazopanib, KRN 633, SAR131675, Apatinib (YN968D1) mesylate, BMS-794833, Sorafenib (BAY 43-9006), Cabozantinib malate, Brivanib Alaninate (BMS-582664), Golvatinib (E7050), Semaxanib (SU5416), ZM 323881 HCl, ZM 306416, ENMD-2076 L-(+)-Tartaric acid, R1530, Chiauranib, Emvododstat (PTC299), XL092, Regorafenib Hydrochloride, Lucitanib (E3810) hydrochloride, Ningetinib, Donafenib (Sorafenib D3), Ki20227, Tyrphostin AG1433, SU14813, Sulfatinib, CS-2660 (JNJ-38158471), SU5204, SU5214, SU5205, SU5408, Pamufetinib (TAS-115), ODM-203, WHI-P180, Altiratinib, Motesanib (AMG-706), Fruquintinib (HMPL-013), Lenvatinib (E7080) Mesylate, Nintedanib Ethanesulfonate Salt, Apatinib, Cediranib Maleate, Toceranib phosphate, Anlotinib (AL3818) dihydrochloride, Regorafenib (BAY-734506) Monohydrate, Sitravatinib (MGCD516), Ramucirumab, BFH772, BAW2881 (NVP-BAW2881), SU5402, Sunitinib (SU11248), Dovitinib (TKI258) Lactate monohydrate, LY2874455, SKLB1002, AZD2932, Lenalidomide (CC-5013), WAY-340935, Oglufanide, hVEGF-IN-1, 4SC-203, Chebulinic acid, Nastorazepide, X-82 (Vorolanib), MAZ51, TMTD (Tetramethylthiuram disulfide), SU5208, SU5614, AG-13958, SKLB 610, SU1498, ZD-4190, PDGFR inhibitor 1, Bevacizumab, Erdafitinib (JNJ-42756493), Vitamin E, or Taxifolin (Dihydroquercetin), or a pharmaceutically acceptable salt thereof.

[00116] In some embodiments of a method of treating cancer, the additional agent is an aromatase inhibitor.

[00117] In some embodiments of a method of treating cancer, the aromatase inhibitor is Letrozole (CGS 20267), Anastrozole (ZD-1033), Exemestane (FCE 24304), Formestane, Fadrozole (CGS16949A), alpha-Naphthoflavone, or Obacunone (AI3-37934), or a pharmaceutically acceptable salt thereof.

[00118] In some embodiments of a method of treating cancer, the additional agent is a mitotic inhibitor.

[00119] In some embodiments of a method of treating cancer, the mitotic inhibitor is a taxane (e.g., Paclitaxel and Docetaxel), a vinca alkaloid (e.g., Vinblastine, Vincristine, Vindesine, and Vinorelbine), Colchicine, Podophyllotoxin, Griseofulvin, or Glaziovianin A, or a pharmaceutically acceptable salt thereof.

[00120] In some embodiments of a method of treating cancer, the additional agent is a CDK4 / 6 inhibitor.

[00121] In some embodiments of a method of treating cancer, the CDK4 / 6 inhibitor is palbociclib, ribociclib, trilaciclib, lerociclib, or abemaciclib, or a pharmaceutically acceptable salts.

[00122] In some embodiments of a method of treating cancer, the additional agent is a JAK inhibitor.

[00123] In some embodiments of a method of treating cancer, the JAK inhibitor is ruxolitinib, baricitinib, itacitinib (INCB39110), INCB052793, or INCB054707, or a pharmaceutically acceptable salts.

[00124] In some embodiments of a method of treating cancer, the additional agent is a Bcr-Abl inhibitor.

[00125] In some embodiments of a method of treating cancer, the Bcr-Abl inhibitor is imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, or ponatinib, or a pharmaceutically acceptable salts.

[00126] In some embodiments of a method of treating cancer, the additional agent is a Flt-3 inhibitor.

[00127] In some embodiments of a method of treating cancer, the Flt-3 inhibitor is midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397,or ASP2215, or a pharmaceutically acceptable salts.

[00128] In some embodiments of a method of treating cancer, the additional agent is a RAF inhibitor.

[00129] In some embodiments of a method of treating cancer, the RAF inhibitor is dabrafenib, sorafenib, or vemurafenib, or a pharmaceutically acceptable salts.

[00130] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need:(a) (Compound 123) or a pharmaceutically acceptable salt thereof; and(b) a PARP inhibitor.

[00131] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need:(a) (Compound 123) or a pharmaceutically acceptable salt thereof; and(b) an alkylating agent.

[00132] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need:(a) (Compound 123) or a pharmaceutically acceptable salt thereof; and(b) an immune checkpoint inhibitor.  Administration

[00133] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.  Pharmaceutical Compositions / Formulations

[00134] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[00135] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. EXAMPLES

[00136] Example1: Preparation of Compound 123 To a solution of 123-1 (460 mg, 2.12 mmol) and DIEA (820 mg, 6.36 mmol) in THF (10 mL) at 0 ℃ was added tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (395 mg, 2.12 mmol). After the addition, the reaction mixture was stirred at 25℃ for 2 h. Then the mixture was poured into ice water (50 mL). After extraction with EtOAc (30 mL x 3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate (from 0% to 20%) in petroleum ether to give compound 123-2 (600 mg, 77.2% yield). LC-MS (ESI+): m / z 367.3 [M+H]+.

[00137] To a solution of 123-2 (500 mg, 1.36 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (426 mg, 2.05 mmol) and K2CO3 (565 mg, 4.08 mmol) in 1,4-dioxane-H2O (6 mL, 5:1 ) was added Pd(dppf)Cl2 (200 mg, 0.27 mmol) at 25 ℃. The mixture was stirred at 100 ℃ under N2 for 12 h. After cooling to 25 ℃, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 123-3 (507 mg, 90.2% yield). LC-MS (ESI+): m / z 413.3 (M+H)+.

[00138] To a solution of 123-3 (507 mg, 1.22 mmol) in DCM (6 mL) were added HCl (3 mL, 4M in dioxane). The mixture was stirred at 25 ℃ for 1 h, then concentrated and dried under vacuum to afford 123-4 (383 mg, 99.8% yield), which was directly used in the next step without further purification. LC-MS (ESI+): m / z 313.3(M+H)+.

[00139] To a solution of 123-4 (757 mg, 2.42 mmol)) in ACN (7 mL) were added tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (719 mg, 2.67 mmol) and DIEA (1.20 mL, 7.27 mmol). The reaction mixture was stirred at 25 ℃ for 18 h, then added ice-water (100 mL) and extracted with EtOAc (50 mL x 3). The organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 123-5 (842 mg, 63.7% yield). LC-MS (ESI+): m / z 546.3 (M+H)+.

[00140] To a solution of 123-5 (842 mg, 1.54 mmol) in DCM (7 mL) were added HCl (3 mL, 4 M in dioxane). The reaction mixture was stirred at 25 ℃ for 1 h, then concentrated and dried under vacuum to afford 123-6 (687 mg, 99.9% yield), which was directly used in the next step without further purification. LC-MS (ESI+): m / z 446.3 (M+H)+.To a solution of 123-6 (587 mg, 1.32 mmol) and DIEA (0.87 mL, 5.27 mmol) in DCM (7 mL) was dropwise added acrylic anhydride (166 mg, 1.30 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 0.5 h, then concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford compound 123 (263 mg, 40% yield). LC-MS (ESI+): m / z 500.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) δ 8.58 (s, 1H), 8.27 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H), 6.93 - 6.69 (m, 2H), 6.26 (dd, J = 16.7, 1.9 Hz, 1H), 5.80 (d, J = 10.4 Hz, 1H), 4.75 - 4.57 (m, 3H), 4.16 - 3.65 (m, 9H), 3.09 - 2.91 (m, 2H), 2.36 - 2.23 (m, 1H), 2.18 - 2.04 (m, 1H).Examples A: biological CDK12 / CyclinK and CDK13 / CyclinK kinase inhibition assaysThe objective of this experiment was to assess the potential inhibitory effect of compounds on CDK12 / CyclinK and CDK13 / CyclinK kinase.Echo655 was used to transfer the compound dilution (50 nL for CDK12 / CyclinK and CDK13 / CyclinK) to each well of the assay plate (784075, Greiner). The final concentration of DMSO was 1%. The assay plate was sealed, and the compound plates were centrifuged at 1000g for 1 min. 1 × kinase buffer was prepared by mixing 1 volume of 5x kinase buffer with 4 volumes of distilled water, 1.5 mM DTT. 2 × kinase solution was prepared in 1× kinase buffer. 2.5 μL 2× kinase solution was added into the assay plate, and the plates were centrifuged at 1000 g for 1 min and incubated at room temperature for 10 min. 2× Substrates and ATP mixture (160 uM pS7-CTD peptide for CDK12 / CyclinK and CDK13 / CyclinK) and ATP (40 μM for CDK12 / CyclinK, 60 μM for CDK13 / CyclinK) mixture in 1× kinase buffer. The assay reaction was started by adding 2.5 μL 2× Substrates and ATP mixture. The plates were centrifuged at 1000 g for 1 min. The assay plates were sealed and incubated at room temperature for 120 min. 4 μL ADP-Glo reagents were added. The plate was centrifuged at 1000 g for 1 min and incubated at room temperature for 40 min. 8 μL kinase detection reagents were added. The plate was centrifuged at 1000 g for 1 min and incubated at room temperature for 40 min. The plate was centrifuged at 1000 g for 1 min. The luminescence signal was read on Envision 2104 plate reader. Calculate IC50 by fitting % Inhibition values and log of compound concentrations to nonlinear regression (dose response – variable slope) with Graphpad:Y=Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))X: log of Inhibitor concentration; Y: % Inhibition.The results for exemplary compounds of the present application are illustrated in Table 2.Table 2. IC50 values of exemplary compoundsCompoundCDK12 / CyclinK IC50 (nM)CompoundCDK12 / CyclinK IC50 (nM)CompoundCDK12 / CyclinK IC50 (nM)1C95C137A2C96–138A3C97B139B4B98C140B5C99A141B6B100B142A7C101B143B8D102A144B9C103B145A10C121A146B11C122B147A12C123B148A13B124B149A14B125C150B15A126B151B16A127B152B17A128B153A18D129C154A88B130A155B89C131B156B90C132B157A91C133A158A92C134A159A93C135B  94C136A  CDK12 IC50 (nM): 0 nM <A≤ 25 nM; 25 nM <B≤ 100 nM; 100 nM <C≤ 1000 nM; 1000 nM <D≤ 10,000 nM; and E >10,000 nM.

[00141] Example B:Pharmacokinetic profileevaluation

[00142] Species and strain: CD-1 mice of SPF. Source: Sino-British SIPPR / BK Lab Animal Ltd, Shanghai. Three mice were intravenously administrated with given compounds (Formulation: 5% DMSO + 10% Solutol + 85% Saline) or orally gavage administrated with given compounds (Formulation: 5% DMSO + 10% Solutol + 85% Saline). The blood samples were taken via cephalic vein at timepoints 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after intravenous (iv) administration or at timepoints 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6h, 8 h, and 24 h after oral gavage administration, 30 μL / time point. Blood samples were placed in tubes containing K2-EDTA and stored on ice until centrifuged. The blood samples were centrifuged at 6800 g for 6 minutes at 2-8 ℃ within 1 h after collected and stored frozen at approximately -80 ℃. An aliquot of 20 µL plasma samples were protein precipitated with 400 µL MeOH in which contains 100 ng / mL Verapamil (IS). The mixture was vortexed for 1 min and centrifuged at 18000 g for 10 min. Transfer 400 µL supernatant to 96 well plates. An aliquot of 5 µL supernatant was injected for LC-MS / MS analysis by LC-MS / MS-27 (TQ6500+) instrument. The analytical results were confirmed using quality control samples for intra-assay variation. The accuracy of >66.7% of the quality control samples should be between 80 - 120% of the known value(s). Standard set of parameters including Area Under the Curve (AUC(0-t) and AUC(0-∞)), elimination half-life (T1 / 2), maximum plasma concentration (Cmax), oral bioavailability (F) will be calculated using noncompartmental analysis modules in FDA certified pharmacokinetic program Phoenix WinNonlin 7.0 (Pharsight, USA).

[00143] The data for Example B is shown in Table 3 and Table 4.Table 3. Mouse PK profile after iv administration at 1 mg / kgCompoundT1 / 2 (h)Cmax (ng / mL)AUC0~t (ng*h / mL)AUC0~∞ (ng*h / mL)CL (ml / min / kg)10.2865719319486.420.3797043044038.040.7290740440941.070.25137947347435.2430.28106237637744.4880.3662023724070.41230.183339697174.61450.27123335836046.6Reference 1NA*10634NA*NA*Reference 20.052046565258NA*: Not available, failed to calculate the parameter since the plasma concentrations for timepoints from 0.5 h to 24 h were below the lower limit of quantitation.Table 4. Mouse PK profile after oral administration at 5 mg / kgCompoundT1 / 2 (h)Cmax (ng / mL)AUC0~t (ng*h / mL)AUC0~∞ (ng*h / mL)F (%)10.40111551652053.620.5818811601161474.640.6718581443145671.470.5119281248125952.8431.27117395696851.4880.66116962963153.21230.7787943343590.11451.02127194394752.8Reference 2NA#4918NA#5.6NA#: Not available, failed to calculate the parameter since the plasma concentrations for timepoints from 2 h to 24 h were below the lower limit of quantitation.

[00144] The mouse PK data of compounds disclosed herein demonstrated good PK properties, especially for plasma exposure (AUC) and oral bioavailability (F) compared with the existing compounds (Reference 1, Compound 4 in WO2021011796) and (Reference 2, Synthetic Chemistry Example 47 in WO2020006497).

[00145] Examples C: Combination with Olaparib efficacy study of SUM149PT human breast cancer xenograft model in Balb / c nude mice

[00146] The objective of this study is to evaluate the efficacy of selected compounds in combination with Olaparib in SUM149PT human breast cancer xenograft model in female BALB / c nude mice.

[00147] Each mouse was inoculated subcutaneously on the central right flank with SUM149PT tumor cells (1 x 107) in 0.1 mL of Ham F12 Matrigel mixture (1:1 ratio) for the tumor development. Mice were randomly assigned to respective groups post tumor implantation with an average tumor volume of 155 mm3. For routine monitoring, all study animals were monitored not only tumor growth but also behavior such as mobility, food and water consumption (by cage side checking only), body weight (BW), eye / hair matting, and any other abnormal effect. Any mortality and / or abnormal clinical signs were recorded. The measurement of tumor size was conducted twice a week with a caliper and the tumor volume (mm3) was estimated using the formula: TV = a × b2 / 2 throughout the study, where a and b are the long and short diameters of a tumor, respectively. The TVs were used for calculation of the tumor growth inhibition (TGI, an indicator of antitumor effectiveness) value using the formula: TGI = (1-T / C) × 100%, where T and C are the mean relative volumes (% tumor growth) of the tumors in the treated and the control groups, respectively. Relative tumor growth inhibition was calculated using the equation: TGI = [1-(Tn-T0) / (Cn-C0)] × 100, only over the dosing period (dosing days 0 to days n). Where: Tn - is the average tumor volume at the respective day “n” after dosing throughout treatment period; T0 - is the average tumor volume in the treatment group at day 0 before treatment (immediately before); Cn - average tumor volume in the control group at the respective day “n” after dosing throughout treatment period; and C0 - average tumor volume in the control group at day 0 before treatment (immediately before).

[00148] All statistical tests were conducted, and the level of significance were set at 5% or P < 0.05. The group means and standard deviation were calculated for all measurement parameters as study designed. For comparison among three or more groups, a one-way ANOVA was performed followed by multiple comparison procedures. When a significant statistic was obtained, comparisons between groups were carried out with Games-Howell test. When a non-significant statistic was obtained, comparisons between groups were carried out with Tukey test. All data was analyzed using SPSS 24 software, p < 0.05 is considered to be statistically significant.

[00149] The coefficient of drug interaction (CDI) was used to analyze the synergistic potential of the two drugs. CDI value was calculated using the formula CDI = AB / (A×B), AB is the ratio of the combination group to the control group in mean TV; A or B is the ratio of the corresponding single drug group to the control group in mean TV. CDI < 1 indicates synergism, CDI < 0.7 indicates a significantly synergistic effect, CDI =1 indicates additive, and CDI > 1 indicates antagonism.

[00150] Overall, Compound 123 at 25 mg / kg and 50 mg / kg as single agent produced significant anti-tumor activities with 87% and 112% of TGIs compared with vehicle control group (P values < 0.001), respectively.

[00151] Regarding the safety profile, Compound 123 at 15, 25 mg / kg and 50 mg / kg were tolerated well by SUM149PT tumor bearing BABL / c nude mice during the treatment period.

[00152] In FIG. 1, Compound 123 demonstrated excellent dose-dependent anti-tumor efficacy as mono-therapy and combined with Olaparib in one Olaparib resistant TNBC CDX model, suggesting that Compound 123 has the potential for the treatment of tumor patients resistant to PARP inhibitors and for producing a synergistic effect when used in combination with a PARP inhibitor.

[00153] Examples D: Combination with Cisplatin efficacy study of NCI-H1417 human small cell lung cancer xenograft model in CB17 SCID mice.

[00154] The objective of this study is to evaluate the efficacy of selected compounds in combination with Cisplatin in NCI-H1417 human small cell lung cancer xenograft model in CB17 SCID mice.

[00155] Each mouse will be inoculated subcutaneously at the right flank with NCI-H1417 tumor cells (10*106+50% Martrigel) for tumor development. The animals will be randomized and treatment will be started when the average tumor volume reaches ~150 mm3. At the time of routine monitoring, the animals will be checked for any effects of tumor growth and treatments on normal behavior such as mobility, food and water consumption, body weight gain / loss, eye / hair matting and any other abnormal effect. Death and observed clinical signs will be recorded on the basis of the numbers of animals within each subset. The major endpoint is to see if the tumor growth can be delayed or mice can be cured. Tumor sizes will be measured twice weekly in two dimensions using a caliper, and the volume will be expressed in mm3 using the formula: V = 0.5 a x b2 where a and b are the long and short diameters of the tumor, respectively. The TVs were used for calculation of the tumor growth inhibition (TGI, an indicator of antitumor effectiveness) value using the formula: TGI = (1-T / C) × 100%, where T and C are the mean relative volumes (% tumor growth) of the tumors in the treated and the control groups, respectively. Relative tumor growth inhibition was calculated using the equation: TGI = [1-(Tn-T0) / (Cn-C0)] × 100, only over the dosing period (dosing days 0 to days n). Where: Tn - is the average tumor volume at the respective day “n” after dosing throughout treatment period; T0 - is the average tumor volume in the treatment group at day 0 before treatment (immediately before); Cn - average tumor volume in the control group at the respective day “n” after dosing throughout treatment period; and C0 - average tumor volume in the control group at day 0 before treatment (immediately before).

[00156] All statistical tests were conducted, and the level of significance were set at 5% or P < 0.05. The group means and standard deviation were calculated for all measurement parameters as study designed. For comparison among three or more groups, a one-way ANOVA was performed followed by multiple comparison procedures. When a significant statistic was obtained, comparisons between groups were carried out with Games-Howell test. When a non-significant statistic was obtained, comparisons between groups were carried out with Tukey test. All data was analyzed using SPSS 24 software, p < 0.05 is considered to be statistically significant.

[00157] The coefficient of drug interaction (CDI) was used to analyze the synergistic potential of the two drugs. CDI value was calculated using the formula CDI = AB / (A×B), AB is the ratio of the combination group to the control group in mean TV; A or B is the ratio of the corresponding single drug group to the control group in mean TV. CDI < 1 indicates synergism, CDI < 0.7 indicates a significantly synergistic effect, CDI =1 indicates additive, and CDI > 1 indicates antagonism.

[00158] Overall, Compound 123 at 20 mg / kg and 30 mg / kg as single agent produced significant anti-tumor activities with 80% and 115% of TGIs compared with vehicle control group (P values < 0.001), respectively.

[00159] In FIG. 2, compound 123 demonstrated excellent dose-dependent anti-tumor efficacy as mono-therapy and in combination with cisplatin in SCLC CDX model, suggesting that combination with cisplatin could achieve synergistic effect in the treatment of solid tumors..

Claims

WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) a compound of Formula (III), or a pharmaceutically acceptable salt thereof: Formula (III), wherein:X1 is N or CR1; X2 is N or CR2; X3 is N or CR3; X4 is N or CR4; R1 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SF5, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R1a; R2 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R2a;R3 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R3a; orR2 and R3 are taken together with the intervening groups to form a 5 or 6 membered ring, which is optionally substituted with one or more RCC;R4 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R4a; R8 is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;R5 and R6 are each independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; or R5 and R6 are taken together with the carbon to which they are attached to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R6a;n is 1 or 2;W is a bond or -C(=O)-;Ring E is heteroaryl; Ring F is phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl; provided that when Ring F is a phenyl, then R5 and R6 are taken together with the carbon to which they are attached to form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R6a; each R71 and R72 is independently halogen, -CN, -NO2, -OH, oxo, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R7a;m1 is 0, 1, 2, or 3;m2 is 0, 1, 2, 3, or 4;R10 is CN, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;p is 1 or 2;q is 0, 1, or 2;R10a, R10b, R10c, and R10d are each independently selected from hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl; independently optionally substituted with one or more R10e;each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl), wherein each of the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;each RCC is independently halogen, -CN, -NO2, -OH, oxo, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -S(=O)(=NRb)Rb, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)(Rb)2, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -P(=O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more RCa;RCa, R1a, R2a, R3a, R4a, R6a, R7a, and R10e are each independently halogen, -CN, -OH, oxo, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; andeach R is independently halogen, -CN, -OH, oxo, -SF5, -SH, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -S(=O)(=NC1-C3alkyl)(C1-C3alkyl), -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -N=S(=O)(C1-C3alkyl)2, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(C1-C3alkyl)2, -P(=O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl; and(b) an additional agent;wherein the combined amount of the CDK12 and / or CDK13 inhibitor and the additional agent is therapeutically effective for treating the cancer.

2. The method of claim 1, wherein the compound of Formula (III) is selected from Table 1 or Table 2.

3. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject:(a) (R)-1-(4-(3-((4-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrrolidin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)prop-2-en-1-one: (Compound 123) or a pharmaceutically acceptable salt thereof; and(b) an additional agent.

4. The method of claim 3, wherein the combined amount of Compound 123 or the pharmaceutically acceptable salt thereof and the additional agent are therapeutically effective.

5. The method of any one of claims 1-4, wherein the cancer is primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, lung cancer, bladder cancer, prostate cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, liver cancer or mesothelioma.

6. The method of any one of claims 1-5, wherein the cancer is non-small cell lung cancer (NSCLC), small cell lung cancer, colon cancer, pancreatic cancer, prostate cancer, triple-negative breast cancer (TNBC), gastrointestinal stromal tumor, biliary tract cancer, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) B-lineage, lymphoma, or T cell leukemia.

7. The method of any one of claims 1-6, wherein the additional agent is a PARP inhibitor, an alkylating agent, an immune checkpoint inhibitor, a KRAS inhibitor, an EGFR inhibitor, a VEGFR inhibitor, an aromatase inhibitor, a mitotic inhibitor, a CDK4 / 6 inhibitor, a JAK inhibitor, a Bcr-Abl inhibitor, a Flt-3 inhibitor, or a RAF inhibitor, or any combination thereof.

8. The method of any one of claims 1-7, wherein the additional agent is a PARP inhibitor.

9. The method of claim 8, wherein the PARP inhibitor is olaparib (AZD2281), veliparib (ABT-888), rucaparib, talazoparib (BMN 673), AG- 14361, INO-1001 (3-aminobenzamide), A-966492, PJ34 HC1, niraparib, UPF 1069, ME0328, RK-287107, pamiparib (BGB-290), NMS-P118, E7449, picolinamide, benzamide, NU1025, iniparib (B SI-201), AZD2461, BGP-15 2HC1, XAV-939, 4-hydroxyquinazoline, NVP-TNKS656, MN 64, or G007-LK, or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein the PARP inhibitor is olaparib (AZD2281), veliparib (ABT-888), rucaparib, or talazoparib (BMN 673), or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 1-7, wherein the additional agent is an alkylating agent.

12. The method of claim 11, wherein the alkylating agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, altretamine, bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, temozolomide, thiotepa, trabectedin, platinum coordination complexes, or a pharmaceutically acceptable salt thereof.

13. The method of any one of claims 1-7, wherein the additional agent is an immune checkpoint inhibitor.

14. The method of claim 13, wherein the immune checkpoint inhibitor is an antagonist of PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM-3, B7-H3, B7-H4, A2aR, CD73, NKG2A and CCR2, or a pharmaceutically acceptable salt thereof, or a variant thereof or biosimilar thereof.

15. The method of claim 14, wherein the immune checkpoint inhibitor is anti-PD-L1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-LAG-3 antibody, anti-TIGIT antibody, anti-TIM-3 antibody, anti-B7-H3 antibody, anti-B7-H4 antibody, anti-B7-H4 antibody, CD73 antagonist, anti-CCR2 antibody, or a pharmaceutically acceptable salt thereof, or a variant thereof or biosimilar thereof.

16. The method of claim 15, wherein the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, sugemalimab, envafolimab, cosibelimab, or adebrelimab, or a variant thereof or biosimilar thereof.

17. The method of claim 15, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, toripalimab, camrelizumab, tislelizumab, penpulimab, or sintilimab, or a variant thereof or biosimilar thereof.

18. The method of claim 15, wherein the anti-CTLA-4 antibody is ipilimumab, or tremelimumab, or a variant thereof or biosimilar thereof.

19. The method of claim 15, wherein the anti-LAG-3 antibody is relatlimab, fianlimab, miptenalimab, favezelimab, ieramilimab, Sym022, GSK2831781, INCAGN02385, TSR-033, or a variant thereof or biosimilar thereof.

20. The method of claim 15, wherein the anti-TIGIT antibody is tiragolumab, domvanalimab, vibostolimab, etigilimab, tamgiblimab, M6223, ociperlimab, or EOS884448, or a variant thereof or biosimilar thereof.

21. The method of claim 15, wherein the anti-TIM-3 antibody is sabatolimab, surzebiclimab, cobolimab, Sym023, R07121661, LY3321367, ICAGN02390, or BMS-986258, or a variant thereof or biosimilar thereof.

22. The method of claim 15, wherein the anti-B7-H3 antibody is enoblituzumab, omburtamab, vobramitamab, mirzotamab, B7-H3 TriKE, 131I-omburtamab, DS-7300a, or 177Lu-DTPA-omburtamab, or a variant thereof or biosimilar thereof.

23. The method of claim 15, wherein the anti-B7-H4 antibody is alsevalimab, FPA150, or a variant thereof or biosimilar thereof.

24. The method of claim 15, wherein the A2aR antagonist is ciforadenant, imaradenant, etrumadenant, NIR178, inupadenant, CS3005, PBF-999, or INCB106385, or a pharmaceutically acceptable salt thereof.

25. The method of claim 15, wherein the CD73 antagonist is quemliclustat, AB680, methADP, OP-5244, MRS4620, PSB-12379, or BK50164, or a pharmaceutically acceptable salt thereof.

26. The method of claim 14, wherein the anti-NKG2A antibody is monalizumab, or a variant thereof or biosimilar thereof.

27. The method of claim 15, wherein the anti-CCR2 antibody is plozalizumab, or a variant thereof or biosimilar thereof.

28. The method of claim 13, wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, AMP -224, PF- 06801591, MEDI0680, PDR001, REGN2810, SHR-1210, TSR-042, CA-170, atezolizumab, durvalumab, KN035, and BMS-936559, ipilimumab, tremelimumab, AGEN1884, AGEN2041, BMS-986016, GSK2831781, IMP321, LAG525, MGD013, or TSR-022, or a pharmaceutically acceptable salt thereof or a variant thereof or biosimilar thereof.

29. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need:(a) (Compound 123) or a pharmaceutically acceptable salt thereof; and(b) a PARP inhibitor, an alkylating agent, an immune checkpoint inhibitor, a KRAS inhibitor, an EGFR inhibitor, a VEGFR inhibitor, an aromatase inhibitor, a mitotic inhibitor, or any combination thereof. 

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