Combination therapy for treating abnormal cell growth

Abstract

The present invention relates, in part, to methods, compounds, and compositions of KRAS G12D inhibitors in combination with dual RAF / MEK inhibitors for the treatment of abnormal cell growth (e.g., cancer).

Description

[0001] Cross - reference to related applications

[0002] This application claims priority and the benefit of U.S. Provisional Patent Application No. 63 / 348,703, filed on June 3, 2022, the entire content of which is incorporated herein by reference. Background of the Invention

[0003] Components of the RAS / RAF / MEK / ERK (MAPK) signal transduction pathway represent opportunities for treating abnormal cell growth such as cancer. RAS / RAF / MEK / ERK mutations are common in human cancers. These mutants lead to constitutively active MAPK kinase cascades, resulting in tumor cell proliferation, differentiation, survival, and migration. Selective inhibitors of certain components of the RAS / RAF / MEK / ERK signal transduction pathway (such as RAS, RAF, MEK, and ERK) can be used to treat abnormal cell growth (especially cancer) in mammals.

[0004] Due to the severity and breadth of diseases and disorders associated with abnormal cell growth (such as cancer), there is a need for effective therapeutic means and methods for treatment. The compounds, compositions, and methods described herein are all directed to this purpose. Summary of the Invention

[0005] The present disclosure in part provides combinations (e.g., combinations of the compounds described herein, such as dual RAF / MEK inhibitors and KRAS G12D inhibitors), which can be used, for example, in methods for treating abnormal cell growth (e.g., cancer) in a subject in need thereof. In some embodiments, the cancer is identified as having a KRAS G12D mutation.

[0006] In one aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor and an effective amount of a KRAS G12D inhibitor.

[0007] In some embodiments, the dual RAF / MEK inhibitor is a compound of formula (I):

[0008] or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the dual RAF / MEK inhibitor is a compound of formula (II):

[0010]

[0011] including its pharmaceutically acceptable salts, wherein the variables are as defined herein.

[0012] In some embodiments, the dual RAF / MEK inhibitor is IMM-1-104, or a pharmaceutically acceptable salt thereof.

[0013] Other objects and advantages will be apparent to those skilled in the art upon consideration of the following detailed description of the invention, examples, and claims. Brief Description of the Drawings

[0015] Figure 1 Shows the prevalence of KRAS G12D mutations in exemplary cancers (e.g., pancreatic cancer, colorectal cancer, endometrial cancer, and NSCLC) and the synergy scores of exemplary combinations of dual RAF / MEK inhibitors and KRAS G12D inhibitors (e.g., VS-6766 and MRTX-1133, respectively).

[0016] Figure 2 Shows the effects of an exemplary combination of a dual RAF / MEK inhibitor and a KRAS G12D inhibitor (VS-6766 and MRTX-1133) in cell lines.

[0017] Figure 3 Illustrates the exemplary cytotoxicity scores of an exemplary combination (VS-6766 and MRTX-1133) in 3D Matrigel proliferation assays in various cell lines. Detailed Description of the Invention

[0019] As generally described herein, the present disclosure provides, in part, methods for treating abnormal cell growth (e.g., cancer) in a subject in need thereof, comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor and an effective amount of a KRAS G12D inhibitor.

[0020] Definition

[0021] Chemical Definitions

[0022] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements (CAS version), inside cover of the 75th edition of the Handbook of Chemistry and Physics, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5 thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0023] The compounds described herein may contain one or more asymmetric centers and can thus exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of a single enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention also includes the compounds described herein as a single isomer substantially free of other isomers or as a mixture of various isomers.

[0024] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of that compound (i.e., enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess over the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains greater than 75 wt%, greater than 80 wt%, greater than 85 wt%, greater than 90 wt%, greater than 91 wt%, greater than 92 wt%, greater than 93 wt%, greater than 94 wt%, greater than 95 wt%, greater than 96 wt%, greater than 97 wt%, greater than 98 wt%, greater than 98.5 wt%, greater than 99 wt%, greater than 99.2 wt%, greater than 99.5 wt%, greater than 99.6 wt%, greater than 99.7 wt%, greater than 99.8 wt% or greater than 99.9 wt% of the enantiomer. In some embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0025] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound can contain, for example, about 90% excipient and about 10% enantiomerically pure R compound. In some embodiments, the enantiomerically pure R compound in such a composition can contain, for example, at least about 95 wt% R compound and at most about 5 wt% S compound (based on the total weight of the compound). For example, a pharmaceutical composition containing an enantiomerically pure S compound can contain, for example, about 90% excipient and about 10% enantiomerically pure S compound. In some embodiments, the enantiomerically pure S compound in such a composition can contain, for example, at least about 95 wt% S compound and at most about 5 wt% R compound (based on the total weight of the compound). In some embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0026] The compounds described herein can also contain one or more isotope substitutions. For example, H can be any isotopic form, including 1 H, 2 H (D or deuterium) and 3 H (T or tritium); C can be any isotopic form, including 12 C, 13 C and 14 C; O can be any isotopic form, including 16 O and 18 O; F can be any isotopic form, including 18 F and 19 F; and so on.

[0027] The following terms are intended to have the meanings presented below and to facilitate understanding of the description and the intended scope of the present invention. In describing the present invention, the present invention may include compounds and their pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions. Unless otherwise indicated, the following terms (if present) shall have the following meanings. It should also be understood that any part defined below may be substituted by various substituents when described herein, and the respective definitions are intended to include such substituted parts within the scope described below.

[0028] As used herein, the term "halogen atom" refers to any radioactively stable atom in column 7 of the periodic table, such as fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0029] As used herein, the term "ester" refers to a chemical moiety having the formula -(R) n -COOR', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloaliphatic (bonded through a ring carbon), and where n is 0 or 1.

[0030] As used herein, the term "amide" refers to a chemical moiety having the formula -(R) n -C(O)NHR' or -(R) n -NHC(O)R', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloaliphatic (bonded through a ring carbon), and where n is 0 or 1. The amide may be an amino acid or peptide molecule linked to a molecule of the present invention to form a prodrug.

[0031] Any amine, hydroxyl, or carboxyl side chain on the compounds disclosed herein may be esterified or amidated. The procedures and specific groups for achieving this are known to those skilled in the art and can be readily found in references such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, the entire contents of which are incorporated herein by reference.

[0032] As used herein, the term "aromatic" refers to an aromatic group having at least one ring with a conjugated π - electron system, and includes carbocyclic aryl (e.g., phenyl) and heteroaryl groups (e.g., pyridine). The term includes monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups. The term "carbocyclic" refers to a compound containing one or more covalently closed ring structures and having all atoms forming the ring skeleton being carbon atoms. Thus, the term distinguishes carbocycles from heterocycles in which the ring skeleton contains at least one atom other than carbon. The term "heteroaromatic" refers to an aromatic group containing at least one heterocycle.

[0033] As used herein, "Ca to Cb", where "a" and "b" are integers, refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or in the ring of a cycloalkyl, aryl, heteroaryl, or heterocyclic group. That is, the ring of an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group can contain "a" to "b" (including the end values) carbon atoms. Thus, for example, a "C1 to C4 alkyl" group or a "C1 - C4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH 3 -、CH 3 CH 2 -、CH 3 CH 2 CH 2 -、(CH 3 ) 2 CH-、CH 3 CH 2 CH 2 CH 2 -、CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3C-. Similarly, for example, a cycloalkyl group may contain "a" to "b" (including the end values) total atoms, such as a C3-C8 cycloalkyl group, containing 3 to 8 carbon atoms in the ring. If "a" and "b" are not specified for an alkyl, cycloalkyl, or cycloalkenyl group, the broadest ranges described in these definitions are assumed. Similarly, a "4- to 7-membered heterocyclic group" refers to all heterocyclic groups having 4 to 7 total ring atoms, such as azetidine, oxetane, oxazoline, pyrrolidine, piperidine, piperazine, morpholine, etc. As used herein, the term "C1-C6" includes C1, C2, C3, C4, C5, and C6, as well as the ranges defined by any two of the foregoing numbers. For example, C1-C6 alkyl includes C1, C2, C3, C4, C5, and C6 alkyl, C2-C6 alkyl, C1-C3 alkyl, etc. Similarly, C3-C8 carbocyclic or cycloalkyl groups each include those containing 3, 4, 5, 6, 7, and 8 carbon atoms, or the ranges defined by any two of the numbers, such as C3-C7 cycloalkyl or C5-C6 cycloalkyl. As another example, a 3- to 10-membered heterocyclic group includes 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, or the ranges defined by any two of the foregoing numbers, such as a 4- to 6-membered or 5- to 7-membered heterocyclic group.

[0034] As used herein, "alkyl" refers to a hydrocarbon group that is completely saturated (no double or triple bonds) in a straight-chain or branched-chain hydrocarbon chain. An alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer within the given range; for example, "1 to 20 carbon atoms" means an alkyl group that may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although this definition also encompasses the occurrence of the term "alkyl" without a specified numerical range). An alkyl group may also be a medium-sized alkyl group having 1 to 10 carbon atoms. An alkyl group may also be a lower alkyl group having 1 to 5 carbon atoms. The alkyl group of a compound may be designated as "C1-C4 alkyl" or a similar nomenclature. By way of example only, "C1-C4 alkyl" means that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Exemplary alkyl groups include, but are not limited in any way to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, etc.

[0035] The alkyl group can be substituted or unsubstituted. When substituted, one or more substituent groups are one or more groups independently selected from the following: alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycloalkyl, aralkyl, heteroaralkyl, (heterocycloalkyl)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and amino, including mono- and di-substituted amino groups and their protected derivatives. Whenever a substituent is described as "optionally substituted", the substituent can be substituted by one of the above substituents.

[0036] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. The alkenyl group can be unsubstituted or substituted. When substituted, one or more substituents can be selected from the same groups as disclosed above for alkyl group substitution. The alkenyl group can have 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" without a specified numerical range. The alkenyl group can also be a medium-sized alkenyl having 2 to 9 carbon atoms. The alkenyl group can also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group of a compound can be designated as "C2-C4 alkenyl" or a similar nomenclature. By way of example only, "C2-C4 alkenyl" means that there are 2 to 4 carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from vinyl, prop-1-enyl, prop-2-enyl, prop-3-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-4-enyl, 1-methyl-prop-1-enyl, 2-methyl-prop-1-enyl, 1-ethyl-vinyl-1-enyl, 2-methyl-prop-3-enyl, buta-1,3-dienyl, buta-1,2-dienyl, and buta-1,2-dien-4-yl. Exemplary alkenyl groups include, but are not limited in any way to, vinyl, propenyl, butenyl, pentenyl, and hexenyl, etc.

[0037] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. The alkynyl group may be unsubstituted or substituted. When substituted, one or more substituents may be selected from the same groups as disclosed above for alkyl group substitution. The alkynyl group may have 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" without a specified numerical range. The alkynyl group may also be a medium-sized alkynyl having 2 to 9 carbon atoms. The alkynyl group may also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group of a compound may be designated as "C2-C4 alkynyl" or a similar nomenclature. By way of example only, "C2-C4 alkynyl" means that there are 2 to 4 carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-3-ynyl, but-4-ynyl, and 2-butynyl. Exemplary alkynyl groups include, but are not limited in any way to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, etc.

[0038] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur) in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term "heteroalkyl" without a specified numerical range. The heteroalkyl group may also be a medium-sized heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group may also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group of a compound may be designated as "C1-C4 heteroalkyl" or a similar nomenclature. The heteroalkyl group may contain one or more heteroatoms. By way of example only, "C1-C4 heteroalkyl" means that there are 1 to 4 carbon atoms in the heteroalkyl chain and one or more additional heteroatoms in the backbone of the chain.

[0039] As used herein, "aryl" refers to a carbocyclic (all-carbon) or two or more fused rings (rings sharing two adjacent carbon atoms) having a completely delocalized π-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group can be substituted or unsubstituted. When substituted, a hydrogen atom is replaced by a substituent group that is independently one or more groups selected from the following: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycloalkyl, aralkyl, heteroaralkyl, (heterocycloalkyl)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfoxido, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups and their protected derivatives. When substituted, the substituents on the aryl group can form non-aromatic rings fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclic groups.

[0040] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system with a fully delocalized π - electron system) containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur), which is one or two or more fused rings. Examples of heteroaryl rings include but are not limited to furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. The heteroaryl group can be substituted or unsubstituted. When substituted, a hydrogen atom is replaced by a substituent group, which is one or more groups independently selected from the following: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycloalkyl, aralkyl, heteroaralkyl, (heterocycloalkyl)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O - carbamoyl, N - carbamoyl, O - thiocarbamoyl, N - thiocarbamoyl, C - amido, N - amido, S - sulfonamido, N - sulfonamido, C - carboxy, protected C - carboxy, O - carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfoxido, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono - and di - substituted amino groups and their protected derivatives. When substituted, the substituents on the heteroaryl group can form a non - aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclic groups.

[0041] As used herein, "aralkyl" or "arylalkyl" refers to an aryl group attached as a substituent via an alkylene group. The alkylene and aryl groups of the aralkyl can be substituted or unsubstituted. Examples include but are not limited to benzyl, substituted benzyl, 2 - phenylethyl, 3 - phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group.

[0042] As used herein, "heteroaralkyl" or "heteroarylalkyl" refers to a heteroaryl group attached as a substituent via an alkylene group. The alkylene and heteroaryl groups of the heteroaralkyl can be substituted or unsubstituted. Examples include but are not limited to 2 - thiophenemethyl, 3 - thiophenemethyl, furanylmethyl, thiophenylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their substituted and benzo - fused analogs. In some cases, the alkylene group is a lower alkylene group.

[0043] As used herein, "alkylene" refers to a branched or straight-chain, fully saturated, divalent chemical group containing only carbon and hydrogen that is attached to the remainder of the molecule via two attachment points (i.e., alkanediyl). The alkylene group can have from 1 to 20 carbon atoms, although this definition also encompasses the term alkylene without a specified numerical range. The alkylene group can also be a medium-sized alkylene having 1 to 9 carbon atoms. The alkylene group can also be a lower alkylene having 1 to 4 carbon atoms. The alkylene group can be designated as "C1-C4 alkylene" or a similar nomenclature. By way of example only, "C1-C4 alkylene" means that there are one to four carbon atoms present in the alkylene chain, i.e., the alkylene chain is selected from methylene, ethylene, ethane-1,1-diyl, propylene, propane-1,1-diyl, propane-2,2-diyl, 1-methyl-ethylene, butylene, butane-1,1-diyl, butane-2,2-diyl, 2-methyl-propane-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

[0044] As used herein, "alkenylene" refers to a straight-chain or branched-chain divalent chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond that is attached to the remainder of the molecule via two attachment points. The alkenylene group can have from 2 to 20 carbon atoms, although this definition also encompasses the term alkenylene without a specified numerical range. The alkenylene group can also be a medium-sized alkenylene having 2 to 9 carbon atoms. The alkenylene group can also be a lower alkenylene having 2 to 4 carbon atoms. The alkenylene group can be designated as "C2-C4 alkenylene" or a similar nomenclature. By way of example only, "C2 alkenylene" means that there are 2 to 4 carbon atoms present in the alkenylene chain, i.e., the alkenylene chain is selected from vinylidene, vinyl-1,1-diyl, propenylene, propene-1,1-diyl, prop-2-ene-1,1-diyl, 1-methyl-vinylidene, but-1-enyl, but-2-enyl, but-1,3-dienyl, butene-1,1-diyl, but-1,3-diene-1,1-diyl, but-2-ene-1,1-diyl, but-3-ene-1,1-diyl, 1-methyl-prop-2-ene-1,1-diyl, 2-methyl-prop-2-ene-1,1-diyl, 1-ethyl-vinylidene, 1,2-dimethyl-vinylidene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propene-1,1-diyl, and 2,2-dimethyl-ethylene-1,1-diyl.

[0045] As used herein, "alkylidene" refers to a divalent group such as =CR’R”, which is attached to a carbon of another group to form a double bond. Alkylidene groups include, but are not limited to, methylidene (=CH 2 ) and ethylidene (=CHCH 3) As used herein, "arylalkylene" refers to an alkylene group in which R' and R" are aryl groups. The alkylene group can be substituted or unsubstituted.

[0046] As used herein, "alkoxy" refers to the formula -OR, where R is an alkyl group as defined above, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, and the like. The alkoxy group can be substituted or unsubstituted.

[0047] As used herein, "alkylthio" refers to the formula -SR, where R is an alkyl group as defined above, such as methylthio, ethylthio, n-propylthio, 1-methylethylthio (isopropylthio), n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like. The alkylthio group can be substituted or unsubstituted.

[0048] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, respectively, where R is an aryl group, such as, but not limited to, phenyl. Both aryloxy and arylthio can be substituted or unsubstituted.

[0049] As used herein, "acyl" refers to -C(=O)R, where R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 carbocyclic group, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic group, all as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl, and acryloyl.

[0050] As used herein, "cycloalkyl" refers to a fully saturated (no double bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings can be joined together in a fused, bridged, or spiro-linked manner. The cycloalkyl group can range from C3 to C10, and in other embodiments, it can range from C3 to C6. The cycloalkyl group can be unsubstituted or substituted. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, unless otherwise specified, the substituent can be an alkyl group or selected from those noted above for the substitution of alkyl groups. When substituted, the substituent on the cycloalkyl group can form an aromatic ring fused to the cycloalkyl group, including aryl and heteroaryl.

[0051] As used herein, "cycloalkenyl" means a cycloalkyl group containing one or more double bonds in the ring, provided that if there are multiple double bonds, they do not form a completely delocalized π - electron system in the ring (otherwise the group would be an "aryl" as defined herein). When composed of two or more rings, the rings can be connected together in a fused, bridged, or spiro - linked manner. The cycloalkenyl group can be unsubstituted or substituted. When substituted, unless otherwise specified, the substituent can be an alkyl group or a group selected from those disclosed above for alkyl group substitution. When substituted, the substituent on the cycloalkenyl group can form an aromatic ring fused to the cycloalkenyl group, including aryl and heteroaryl.

[0052] As used herein, "cycloalkynyl" means a cycloalkyl group containing one or more triple bonds in the ring. When composed of two or more rings, the rings can be connected together in a fused, bridged, or spiro - linked manner. The cycloalkynyl group can be unsubstituted or substituted. When substituted, unless otherwise specified, the substituent can be an alkyl group or a group selected from those disclosed above for alkyl group substitution. When substituted, the substituent on the cycloalkynyl group can form an aromatic ring fused to the cycloalkynyl group, including aryl and heteroaryl.

[0053] As used herein, "heteroalicyclic" or "heteroalicyclic group" refers to a stable 3- to 18-membered ring composed of carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. "Heteroalicyclic" or "heteroalicyclic group" can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can be connected together in a fused, bridged, or spiro-linked manner; and the nitrogen, carbon, and sulfur atoms in the "heteroalicyclic" or "heteroalicyclic group" can be optionally oxidized; nitrogen can be optionally quaternized; and the ring can also contain one or more double bonds, provided that they do not form a completely delocalized π-electron system in all rings. The heteroalicyclic group can be unsubstituted or substituted. When substituted, the substituents can be one or more groups independently selected from the following: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic)alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and their protected derivatives. Examples of such "heteroalicyclic" or "heteroalicyclic group" include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl A-oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidinone, pyrazolidinyl, 2-oxopyrrolidinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, and thiomorpholinyl sulfone. When substituted, the substituents on the heteroalicyclic group can form an aromatic ring fused to the heteroalicyclic group, including aryl and heteroaryl.

[0054] As used herein, the term "(cycloalkenyl)alkyl" refers to a cycloalkenyl group attached as a substituent via an alkylene group. The alkylene and cycloalkenyl of (cycloalkenyl)alkyl can be substituted or unsubstituted. In some cases, the alkylene group is a lower alkylene group.

[0055] As used herein, the term "(cycloalkynyl)alkyl" refers to a cycloalkynyl group attached as a substituent via an alkylene group. The alkylene and cycloalkynyl of (cycloalkynyl)alkyl can be substituted or unsubstituted. In some cases, the alkylene group is a lower alkylene group.

[0056] As used herein, the term "O-carboxy" refers to an "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycloalkyl, aralkyl, or (heterocycloalkyl)alkyl, as each is defined herein. The O-carboxy can be substituted or unsubstituted.

[0057] As used herein, the term "C-carboxy" refers to a "-C(=O)R" group, where R can be the same as that defined for O-carboxy. The C-carboxy can be substituted or unsubstituted.

[0058] As used herein, the term "trihalomethanesulfonyl" refers to an "X 3 CSO 2 -" group, where X is a halogen.

[0059] As used herein, the term "cyano" refers to a "-CN" group.

[0060] As used herein, the term "cyanate" refers to an "-OCN" group.

[0061] As used herein, the term "isocyanate" refers to an "-NCO" group.

[0062] As used herein, the term "thiocyanate" refers to an "-SCN" group.

[0063] As used herein, the term "isothiocyanate" refers to an "-NCS" group.

[0064] As used herein, the term "sulfinyl" refers to a "-S(=O)-R" group, where R can be the same as that defined for O-carboxy. The sulfinyl can be substituted or unsubstituted.

[0065] As used herein, the term "sulfonyl" refers to a "-SO 2 R" group, where R can be the same as that defined for O-carboxy. The sulfonyl can be substituted or unsubstituted.

[0066] As used herein, the term "S-sulfonamido" refers to a "-SO 2 NRARB" group, where RA and RB can be the same as that defined for O-carboxy. The S-sulfonamido can be substituted or unsubstituted.

[0067] As used herein, the term "N-sulfonamido" refers to a "-SO 2 N(RA)(RB)" group, where RA and RB can be the same as that defined for O-carboxy. The sulfonyl can be substituted or unsubstituted.

[0068] As used herein, the term "trihalomethanesulfonamido" refers to the group "X 3 CSO 2 N(R)-", where X is a halogen and R can be the same as defined for O-carboxy. The trihalomethanesulfonamido group can be substituted or unsubstituted.

[0069] As used herein, the term "O-carbamoyl" refers to the group "-OC(=O)NRARB", where RA and RB can be the same as defined for O-carboxy. The O-carbamoyl group can be substituted or unsubstituted.

[0070] As used herein, the term "N-carbamoyl" refers to the group "ROC(=O)NRA group, where R and RA can be the same as defined for O-carboxy. The N-carbamoyl group can be substituted or unsubstituted.

[0071] As used herein, the term "O-thiocarbamoyl" refers to the group "-OC(=S)-NRARB", where RA and RB can be the same as defined for O-carboxy. The O-thiocarbamoyl group can be substituted or unsubstituted.

[0072] As used herein, the term "N-thiocarbamoyl" refers to the group "ROC(=S)NRA-", where R and RA can be the same as defined for O-carboxy. The N-thiocarbamoyl group can be substituted or unsubstituted.

[0073] As used herein, the term "C-amido" refers to the group "-C(=O)NRARB", where RA and RB can be the same as defined for O-carboxy. The C-amido group can be substituted or unsubstituted.

[0074] As used herein, the term "N-amido" refers to the group "RC(=O)NRA-", where R and RA can be the same as defined for O-carboxy. The N-amido group can be substituted or unsubstituted.

[0075] As used herein, the term "amino" refers to the group "-NRARB", where RA and RB are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 carbocyclic group, C6-C10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclic group, all as defined herein.

[0076] As used herein, the term "aminoalkyl" refers to an amino group linked via an alkylene group.

[0077] As used herein, the term "ester" refers to the group "-C(=O)OR", where R can be the same as defined for O-carboxy. The ester can be substituted or unsubstituted.

[0078] As used herein, the term "lower aminoalkyl" refers to an amino group linked via a lower alkylene group. The lower aminoalkyl may be substituted or unsubstituted.

[0079] As used herein, the term "lower alkoxyalkyl" refers to an alkoxy group linked via a lower alkylene group. The lower alkoxyalkyl may be substituted or unsubstituted.

[0080] As used herein, the term "acetyl" refers to -C(=O)CH 3 group.

[0081] As used herein, the term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0082] As used herein, the term "carbocyclic group" refers to a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclic group is a ring system, two or more rings may be connected together in a fused, bridged or spiro-linked manner. The carbocyclic group may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Thus, the carbocyclic group includes cycloalkyl, cycloalkenyl and cycloalkynyl. The carbocyclic group may have 3 to 20 carbon atoms, although this definition also covers occurrences of the term "carbocyclic group" without a specified numerical range. The carbocyclic group may also be a medium-sized carbocyclic group having 3 to 10 carbon atoms. The carbocyclic group may also be a carbocyclic group having 3 to 6 carbon atoms. The carbocyclic group may be designated as "C3-C6 carbocyclic group" or a similar nomenclature. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octyl, adamantyl and spiro[4.4]nonyl.

[0083] As used herein, the term "(cycloalkyl)alkyl" refers to a cycloalkyl group linked as a substituent via an alkylene group. The alkylene and cycloalkyl of the (cycloalkyl)alkyl may be substituted or unsubstituted. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc. In some cases, the alkylene group is a lower alkylene group.

[0084] As used herein, the term "cycloalkyl" refers to a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0085] As used herein, the term "cycloalkenyl" refers to a carbocyclic ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0086] As used herein, the term "heterocyclic group" refers to a three-, four-, five-, six-, seven-, eight- or more-membered ring in which carbon atoms together with one to three heteroatoms form the ring. The heterocyclic group may optionally contain one or more unsaturated bonds, provided that their positions do not give rise to an aromatic π-electron system. The heteroatoms are independently selected from oxygen, sulfur and nitrogen. The heterocyclic group may further contain one or more carbonyl or thiocarbonyl functional groups so as to include oxo and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, etc. "Heterocyclic group" may refer to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring skeleton. Heterocyclic groups may be joined together in a fused, bridged or spiro-linked fashion. The heterocyclic group may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. One or more heteroatoms may be present in non-aromatic or aromatic rings in the ring system. The heterocyclic group may have from 3 to 20 ring members (i.e., the number of atoms making up the ring skeleton, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heterocyclic group" for which no numerical range is specified. The heterocyclic group may also be a medium-sized heterocyclic group having from 3 to 10 ring members. The heterocyclic group may also be a heterocyclic group having from 3 to 6 ring members. The heterocyclic group may be designated as a "3-6 membered heterocyclic group" or a similar designation.In a preferred six-membered monocyclic heterocyclic group, one or more heteroatoms are selected from one to three of O, N, or S, and in a preferred five-membered monocyclic heterocyclic group, one or more heteroatoms are selected from one or two heteroatoms of O, N, or S. Examples of the heterocyclic group ring include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidone, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxolanyl, 1,4-dioxinyl, 1,4-dioxolanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxolanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinone, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuryl, benzimidazolidinyl, and tetrahydroquinoline.

[0087] As used herein, the term “(heterocyclic group)alkyl” refers to a heterocyclic group attached as a substituent via an alkylene group. Examples include, but are not limited to, imidolinylmethyl and indolinylethyl.

[0088] A substituted group is based on or derived from an unsubstituted parent group in which one or more hydrogen atoms are exchanged with another atom or group. Unless otherwise specified, when a group is considered to be "substituted", the group is substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclic group (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10-membered heterocyclic group (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10-membered heterocyclic-C1-C6-alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10-membered heteroaryl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10-membered heteroaryl(C1-C6)alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, mercapto (thiol group), halo(C1-C6)alkyl (e.g., -CF 3 )), halo(C1-C6)alkoxy (e.g., -OCF 3 ), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl and oxo(=O). When a group is described as "optionally substituted", the group may be substituted by the above substituents.

[0089] In some embodiments, the substituted group is substituted by one or more substituents independently selected from the following: C1-C4 alkyl, amino, hydroxy and halogen.

[0090] It should be understood that certain radical naming conventions may include monoradicals or diradicals, depending on the context. For example, when a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a diradical. For example, substituents of an alkyl group that are recognized as requiring two points of attachment include diradicals such as -CH 2 -、-CH 2 CH 2 -、-CH 2 CH(CH 3 )CH 2 - etc. Other radical naming conventions clearly indicate that the radical is a diradical, such as "alkylene" or "alkenylene".

[0091] Unless otherwise specified, when a substituent is considered to be "optionally substituted", it means that the substituent is a group that can be substituted by one or more groups independently selected from the following: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloaliphatic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl and amino, including mono- and disubstituted amino groups, and their protected derivatives. Protecting groups that can form protected derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts mentioned above.

[0092] Other definitions

[0093] "About" and "approximately" generally should refer to the acceptable degree of error in the quantity measured for a given property or accuracy of measurement. Exemplary degrees of error are within 20% (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0094] As used herein, "pharmaceutically acceptable salts" refers to those salts that are suitable, within the scope of sound medical judgment, for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc. and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed by the reaction of an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecyl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, tosylates, undecanoates, valerates, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1–4 alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. When appropriate, further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates).

[0095] As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polypropylene-block polymers, polyethylene glycol, and lanolin.

[0096] As used herein, and unless otherwise specified, the term "subject" in consideration of administration includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient", and "subject" are used interchangeably herein.

[0097] Disease, disorder, and condition are used interchangeably herein.

[0098] As used herein, and unless otherwise indicated, the terms "treat", "treating", and "treatment" encompass actions that occur when a subject has a particular disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (also referred to as "therapeutic treatment").

[0099] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those skilled in the art, the effective amount of the compounds of the present disclosure can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount of the compound sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves the overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves the overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0100] As used herein, "prophylactic treatment" encompasses actions that occur before a subject begins to suffer from a particular disease, disorder, or condition.

[0101] As used herein, the term "oral dosage form" refers to a composition or vehicle for administering an agent to a subject. Generally, an oral dosage form is administered via the oral cavity; however, "oral dosage form" is intended to cover any substance that is administered to a subject and absorbed through the membranes (such as mucosal membranes) of the gastrointestinal tract (including, for example, the oral cavity, esophagus, stomach, small intestine, large intestine, and colon). For example, "oral dosage form" covers a solution administered to the stomach via a feeding tube.

[0102] As used herein, in the context of a dosing cycle of a drug, a "cycle" refers to the time period during which the drug is administered and can further include a rest period during which the drug is not administered to the subject. In some embodiments, a cycle is four weeks.

[0103] "KRAS mutation" refers to a mutation of the KRAS gene (i.e., nucleic acid mutation) or the Kras protein (i.e., amino acid mutation), which results in abnormal Kras protein function associated with increased and / or constitutive activity by favoring the active GTP-bound state of the KRAS protein. The mutation may occur at a conserved site that favors GTP binding and constitutively active Kras protein. In some cases, the mutation is at codon 12 of the KRAS gene. For example, a KRAS mutation can be at codon 12 of the KRAS gene, such as, for example, a single point substitution mutation at codon 12 (i.e., the KRAS G12D mutation).

[0104] Therapeutic method

[0105] In one aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor and an effective amount of a KRAS G12D inhibitor.

[0106] In some embodiments, the cancer is identified as having a KRAS G12D mutation.

[0107] In some embodiments, the dual RAF / MEK inhibitor is a compound of formula (I):

[0108] or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the dual RAF / MEK inhibitor is a compound of formula (I):

[0110]

[0111] In some embodiments, the dual RAF / MEK inhibitor is a potassium salt of a compound of formula (I).

[0112] In some embodiments, the dual RAF / MEK inhibitor is IMM-1-104, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the dual RAF / MEK inhibitor is a compound of formula (II):

[0114]

[0115] including its pharmaceutically acceptable salts, wherein the variables are as defined herein.

[0116] In some embodiments, the dual RAF / MEK inhibitor is a compound selected from the compounds of Table I, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the KRAS G12D inhibitors are selected from: KRAS G12D inhibitor (GenFleet), KRAS G12D degrader (Progenra), KRAS G12D inhibitor (Shenzhen Forward), KRAS G12D inhibitor (Abbisko), KRAS G12D inhibitor (Allist), KRAS G12D inhibitor (Anhorn), KRAS G12D inhibitor (Impact), TSL1502 (Tasly), KT-NIH anti-KRAS G12D mTCR PBL (Gilead), siG12D-LODER (Silenseed), siG12D inhibitor (Silenseed), Anocca-KRAS-G12D inhibitor (Anocca), KRASONCOlogue (Oncogenuity), Curve-KRAS G12D inhibitor (Curve Therapeutics), AST-KRASG12D inhibitor (Allist Pharmaceuticals), VRTX144 (VRise Therapeutics), KRAS G12D inhibitor (Affini-T Therapeutics Inc), BPI-001 (BeyondSpring Inc), anti-KRAS G12D monoclonal antibody (LA Cell Inc), MRTX-1133 (Mirati Therapeutics Inc), NT-0300D (NeuBaseTherapeutics Inc), PP-008 (Primary Peptides Inc), RMC-6236 (Revolution MedicinesInc), RMC-9805 (Revolution Medicines Inc), KRAS-G12D inhibitor (Arvinas Inc), anti-KRASG12D synthetic peptide (Indi Molecular Inc), BBP-KRAS G12D inhibitor (BridgeBio Pharma Inc), ERAS-4 (Erasca Inc), JAB-22000 (Jacobio Pharmaceuticals Group Co Ltd), KRpep-2d (peptide) (Takeda Pharmaceutical Co Ltd), anti-KRAS G12D monoclonal antibody (Oblique TherapeuticsAB), small molecule KRAS G12D inhibitor (Shenzhen Forward PharmaceuticalCo Ltd), Proteovant KRAS G12D inhibitor (Proteovant Therapeutics Inc), BIGPRO (bifunctional ligand-induced proteolysis) proteolysis agent (Anhorn Medicines Co Ltd), STX-XX KRAS G12D inhibitor (Seed Therapeutics Inc) and TPX-KRAS G12D inhibitor (Turning Point Therapeutics Inc), and pharmaceutically acceptable salts thereof.

[0118] In some embodiments, the KRAS G12D inhibitor is orally administered to the subject. In some embodiments, the KRAS G12D inhibitor is parenterally administered to the subject. In some embodiments, the KRAS G12D inhibitor is intravenously administered to the subject. In some embodiments, the KRAS G12D inhibitor is subcutaneously administered to the subject. In some embodiments, the KRAS G12D inhibitor is administered once a day. In some embodiments, the KRAS G12D inhibitor is administered twice a day. In some embodiments, the KRAS G12D inhibitor is administered at a dose of 10 mg to 2000 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at a dose of 100 mg to 1000 mg per administration.

[0119] In some embodiments, the dual RAF / MEK inhibitor and the KRAS G12D inhibitor are administered cyclically independently.

[0120] In some embodiments, the dual RAF / MEK inhibitor and the KRAS G12D inhibitor are administered cyclically simultaneously.

[0121] In some embodiments, the methods described herein further comprise administering to the subject an effective amount of a FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof). In some embodiments, the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) is administered at about 100 mg to about 1000 mg. In some embodiments, the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) is administered at about 100 mg to about 400 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) is administered at 200 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) is administered at 400 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) is administered twice daily. In some embodiments, the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) is administered in cycles, comprising administering the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) for 3 weeks, then withholding the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) for 1 week. In some embodiments, the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) is administered orally to the subject.

[0122] In some embodiments, the dual RAF / MEK inhibitor and the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) are administered independently in cycles.

[0123] In some embodiments, the dual RAF / MEK inhibitor and the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) are administered simultaneously in cycles.

[0124] In some embodiments, the KRAS G12D inhibitor and the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) are administered independently in cycles.

[0125] In some embodiments, the KRAS G12D inhibitor and the FAK inhibitor (e.g., defactinib, or a pharmaceutically acceptable salt thereof) are administered simultaneously in cycles.

[0126] In other embodiments, the methods described herein further comprise administering to the subject an effective amount of an EGFR inhibitor.

[0127] In some embodiments, the EGFR inhibitor is doxorubicin + erlotinib, voltiximab + zatuximab, abivertinib (e.g., abivertinib maleate), ABP-1119, ABP-1130, afatinib (e.g., afatinib bismaleate), AG-101, AL-6802, almonertinib (e.g., almonertinib mesylate), AM-105, amelimumab, amivantamab, AMX-3009, APL-1898, ASK-120067, AST-2818, BBT-176, BDTX-189, BEBT-108, BEBT-109, BH-2922, BLU-4810, BMX-002, BO-1978, BPI-15086, BPI-7711, brigatinib, C-005, cetuximab, CK-101, CLM-29, CLM-3, CMAB-017, CR-13626, CSHEGF-29, D-0316, D2C7-IT + PVSRIPO, dabrafenib mesylate + panitumumab + trametinib dimethyl sulfoxide, dacomitinib, DBPR-112, ditumumab, DGD-1202, dositinib (e.g., dositinib mesylate), DZD-9008, EO-1001, aplidinib, erlotinib (e.g., erlotinib hydrochloride), ES-072, FCN-411, FHND-9041, FLAG-001, FLAG-003, FmAb-2, GB-263, GC-1118A, gefitinib, GS-03 + osimertinib, HA-12128, HMPL-309, HMPL-813, HS-627, icotinib (e.g., icotinib hydrochloride), JMT-101, JRF-103, JZB-29, KBP-5209, KNP-501, KU-004, lapatinib (e.g., lapatinib ditosylate), lorlatinib, lazertinib, lifirafenib (e.g., lifirafenib maleate), MCLA-129, MCLA-158, MDC-22, mobocertinib, mRX-7, MTX-211, MVC-101, naquotinib (e.g., naquotinib mesylate), nazartinib (e.g., nazartinib mesylate), necitumumab, neratinib, nimotuzumab, NRC-2694, NT-004, NT-113, OBX-1012, omotinib (e.g., omotinib hydrochloride), osimertinib (e.g., osimertinib mesylate), panitumumab, PB-357, poziotinib, pyrrotinib, QL-1105, QL-1203, RXDX-105, SAH-EJ1, sapitinib, SCT-200,selatinib (such as selatinib ditosylate), ceritinib, SKLB-1028, SKLB-1206, SPH-118811, SYN-004, TAS-6417, tesevatinib (such as tesevatinib tosylate), TGRX-360, tomitumomab, TQB-3804, UBP-1215, vandetanib, varlitinib, VRN-071918, VRN-6, WBP-297, WJ-13404, WSD-0922, XZP-5809, yinglitinib, YZJ-0318, ZNE-4, zolotinib, ZR-2002, ZSP-0391, ORIC-114, DS-2087b, JS-111, LL-191, BI-4020 or BAY-2476568, or a pharmaceutically acceptable salt thereof.

[0128] In other embodiments, the methods described herein further comprise administering to the subject an effective amount of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0129] In some embodiments, the anti-PD-1 antibody is selected from batrilizumab, camrelizumab, cemiplimab, dostarlimab, gerplimab, nivolumab, pembrolizumab, pamiprilimab, pidilizumab, palorolizumab, rivulizumab, sasanlimab, surulizumab, sintilimab, spartalizumab, sulituzumab, teprotumumab, toripalimab, tislelizumab, toripalimab, toripalimab, sepacilimab, AMP-224, AMP-514, AT-16201, AVI-102, BAT-1308, BH-2950, BSI-050K01, CB-201, CYTO-101, DB-004, EX-105, EX-108, GNR-051, HAB-21, IBI-319, IBI-321, IKT-202, IMU-201, JS-201, LBL-006, LBL-024, LD-01, LQ-005, LQ-008, MD-402, OT-2, PE-0105, PF-07209960, PH-762, REGN-PD-1 / XX, RO7121661, SAUG-1, SCT-I10A, SG-001, SG001, SI-B003, SL-279137, SSI-361, STI-A1110, STM-418, Sym-021, TSR-075, TY101, Twist-PD-1, XmAb-TGFβR2, XmAb-YYCD28, XmAb20717, XmAb23104, YBL-006, YBL-019, and mDX-400.

[0130] In some embodiments, the anti-PD-L1 antibody is selected from atezolizumab, avelumab, durvalumab, enfortumab vedotin, socazolimab, sugemalimab, ABM-101, AP-505, APL-801, ATG-101, AVA-027, AUNP12, B-1961, BH-3120, BMS-986189, BPI-9220, BPI-9320, CA-170, CCX-559, CK-301, CS-17938, CTX-8371, CYTCDR-2, DB-003, DPDL-1E, DR-30207, DSP-105, DSP-502, EI-011, EI-014, EMB-08, ENN-101, ENN-102, GB-7003, Gensci-047, HB-0025, HB-0028, HB-0036, HBM-7015, IBI-327, IGM-7354, IKT-201, IMC-2101, IMC-2102, IMGS-002, IMM-2510, INBRX-105, JBI-426, JNB-809, JNB-809, JNB-813, JNB-813, KN-052, KN035, KY-1043, LP-008, LQ-002, LQ-004, LVGN-1673, LY-3434172, LYN-102, MCLA-145, MEDI-7526, PH-790, PM-1003, PRS-344, Q-1802, QL-301, QLS31901, RC98, SHR-1316, SHR-1701, SIM-236, SL-279252, SL-279258, SLSP-03, SNA-02, STT-01, TI-1007, TJ-L1C4, TJ-L1D5, TJ-L1H3, TJ-L1I7, TJL-14B, TS1905, TST-005, TTXsiPDL-1, TXB-4BC3, VXM-10, YBL-007, YBL-008, YBL-009, YBL-013, YBL-016, and YBL-020.

[0131] In some embodiments, the cancer is pancreatic cancer, pancreatic ductal adenocarcinoma, gynecological cancer (such as cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, endometrial cancer, or vulvar cancer), liver cancer, prostate cancer, mesothelioma, breast cancer, bladder cancer, melanoma, lung cancer, colorectal cancer, thyroid cancer, glioblastoma, or kidney cancer. In some embodiments, the cancer is melanoma, lung cancer, colorectal cancer, thyroid cancer, glioblastoma, or kidney cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the cancer is colorectal cancer, pancreatic cancer, or non-small cell lung cancer. In some embodiments, the lung cancer is metastatic non-small cell lung cancer. In some embodiments, the melanoma is unresectable melanoma. In some embodiments, the melanoma is metastatic melanoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the thyroid cancer is papillary thyroid cancer. In some embodiments, the thyroid cancer is follicular thyroid cancer. In some embodiments, the thyroid cancer is anaplastic thyroid cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is pancreatic ductal adenocarcinoma.

[0132] Dual RAF / MEK inhibitor

[0133] An exemplary dual RAF / MEK inhibitor described herein is VS-6766 (also known as CKI27, CH5126766, or RO5126766).

[0134] In some embodiments, the dual RAF / MEK inhibitor is a compound of formula (I):

[0135]

[0136] or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the compound of formula (I) is:

[0138]

[0139] which is also referred to herein as Compound 1 or the free form of VS-6766.

[0140] In some embodiments, the dual RAF / MEK inhibitor is a pharmaceutically acceptable salt of the compound of formula (I). In some embodiments, the dual RAF / MEK inhibitor is the potassium salt of the compound of formula (I), which is also known as VS-6766. Other pharmaceutically acceptable salts of the compound of formula (I) are encompassed herein.

[0141] In some embodiments, the dual RAF / MEK inhibitor is a compound having the structure of formula (II):

[0142]

[0143] including its pharmaceutically acceptable salts, wherein:

[0144] Ring A is

[0145] R 1 、R 2 、R 3 and R 4 are each independently selected from H, deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamide, optionally substituted N-sulfonamide, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C8 heterocyclic group, optionally substituted C3-C10 heteroaryl, and L; R 6 is selected from H, deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, and optionally substituted C2-C6 alkynyl;

[0146] X is C(R 5 ) 2 、CH(R 5 )、CH 2 、-O-、

[0147] L is -Z 1 -Z 2 or -Z 1 -Z 2 -Z 3 ;

[0148] Z 1 、Z 2 and Z 3 are independently selected from -CH 2 -、-O-、-S-、S=O、-SO2 -, C=O, -CO 2 -, -NO 2 , -NH-, -CH 2 CCH, -CH 2 CN, -NR 5 R 5 ’, -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5 ’-, -NH-SO 2 -, -SO 2 -NH-, -R 5 CH 2 -, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO 2 -, R 5 -C=O, -R 5 CO 2 -, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO 2 -, -R 5 SO 2 -NH-, -NHCH 2 CO-, -CH 2 R 5 -, -OR 5 -, -SR 5 -, S=O-R 5 , -SO 2 R 5 -, C=O-R 5 , -CO 2 R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO 2 R 5 -, -SO 2 -NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C8 heterocyclic group, optionally substituted C3-C10 heteroaryl, -CH 2 -(optionally substituted aryl), -CH 2 -(optionally substituted C3-C8 cycloalkyl) and -CH 2-(optionally substituted C3-C10 heteroaryl); each R 5 and R 5 are independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 carbocyclic group, optionally substituted C6-C10 aryl, optionally substituted C3-C8 heterocyclic group, and optionally substituted C3-C10 heteroaryl; and

[0149] Y is CH 2 、NH or O, provided that R 1 is not -O-pyrimidinyl.

[0150] In some embodiments, the dual RAF / MEK inhibitor is a compound selected from the compounds in Table I:

[0151] Table I.

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177] and its pharmaceutically acceptable salts.

[0178] In some embodiments, the dual RAF / MEK inhibitor is IMM-1-104 (Immuneering) or its pharmaceutically acceptable salts.

[0179] In some embodiments, the dual RAF / MEK inhibitor is administered at least once a week (e.g., once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). In some embodiments, the dual RAF / MEK inhibitor is administered once a week. In some embodiments, the dual RAF / MEK inhibitor is administered twice a week. In some embodiments, the dual RAF / MEK inhibitor is administered three times a week.

[0180] In some embodiments, the dual RAF / MEK inhibitor is administered at about 0.1 mg to about 100 mg, such as about 0.1 mg to about 50 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg, about 0.1 mg to about 4 mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 20 mg, about 1 mg to about 40 mg, about 1 mg to about 60 mg, about 1 mg to about 80 mg, about 1 mg to about 100 mg, about 10 mg to about 100 mg, about 20 mg to about 100 mg, about 40 mg to about 100 mg, about 60 mg to about 100 mg, or about 80 mg to about 100 mg. In some embodiments, the dual RAF / MEK inhibitor is administered at about 0.5 mg to about 10 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at about 0.8 mg to about 10 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at about 1 mg to about 5 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at about 2 mg to about 4 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at about 0.1 mg, 0.2 mg, 0.5 mg, 1 mg, 1.5 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at about 4 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at about 3.2 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered orally.

[0181] In some embodiments, the dual RAF / MEK inhibitor is administered in cycles. In some embodiments, a cycle comprises administering the dual RAF / MEK inhibitor for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered once a week. In some embodiments, the dual RAF / MEK inhibitor is administered twice a week. In some embodiments, the dual RAF / MEK inhibitor is administered three times a week. In some embodiments, the dual RAF / MEK inhibitor is administered at a dose of about 0.8 mg to about 10 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at a dose of about 1 mg to about 5 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at a dose of about 2 mg to about 4 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at a dose of about 4 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at a dose of about 3.2 mg per administration.

[0182] In some embodiments, the dual RAF / MEK inhibitor is administered in cycles, twice a week, wherein a cycle comprises administering the dual RAF / MEK inhibitor at a dose of about 0.8 mg to about 10 mg per administration for three weeks, followed by no administration of the dual RAF / MEK inhibitor for one week. In some embodiments, the dual RAF / MEK inhibitor is administered in cycles, twice a week, wherein a cycle comprises administering the dual RAF / MEK inhibitor at a dose of about 1 mg to about 5 mg per administration for three weeks, followed by no administration of the dual RAF / MEK inhibitor for one week. In some embodiments, the dual RAF / MEK inhibitor is administered in cycles, twice a week, wherein a cycle comprises administering the dual RAF / MEK inhibitor at a dose of about 2 mg to about 4 mg per administration for three weeks, followed by no administration of the dual RAF / MEK inhibitor for one week. In some embodiments, the dual RAF / MEK inhibitor is administered in cycles, twice a week, wherein a cycle comprises administering the dual RAF / MEK inhibitor at a dose of 3.2 mg per administration for three weeks, followed by no administration of the dual RAF / MEK inhibitor for one week. In some embodiments, the dual RAF / MEK inhibitor is administered in cycles, twice a week, wherein a cycle comprises administering the dual RAF / MEK inhibitor at a dose of 4 mg per administration for three weeks, followed by no administration of the dual RAF / MEK inhibitor for one week. In some embodiments, the cycle is repeated at least once.

[0183] In some embodiments, the dual RAF / MEK inhibitor is administered in cycles, three times per week, where the cycle comprises administering the dual RAF / MEK inhibitor at a dose of from about 0.8 mg to about 10 mg per administration for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered in cycles, three times per week, where the cycle comprises administering the dual RAF / MEK inhibitor at a dose of from about 1 mg to about 5 mg per administration for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered in cycles, three times per week, where the cycle comprises administering the dual RAF / MEK inhibitor at a dose of from about 2 mg to about 4 mg per administration for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered in cycles, three times per week, where the cycle comprises administering the dual RAF / MEK inhibitor at a dose of 3.2 mg per administration for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered in cycles, three times per week, where the cycle comprises administering the dual RAF / MEK inhibitor at a dose of 4 mg per administration for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the cycle is repeated at least once.

[0184] In alternative embodiments, the dual RAF / MEK inhibitor is administered continuously (i.e., there is no period of time (such as one week) where the dual RAF / MEK inhibitor is not administered). In some embodiments, the dual RAF / MEK inhibitor is administered once per week. In some embodiments, the dual RAF / MEK inhibitor is administered twice per week. In some embodiments, the dual RAF / MEK inhibitor is administered three times per week.

[0185] KRAS G12D inhibitor

[0186] In some embodiments, the KRAS G12D inhibitor is selected from the compounds in Table II:

[0187] Table II.

[0188]

[0189]

[0190]

[0191] and pharmaceutically acceptable salts thereof.

[0192] In some embodiments, the KRAS G12D inhibitors are selected from: KRAS G12D inhibitor (GenFleet), KRAS G12D degrader (Progenra), KRAS G12D inhibitor (Shenzhen Forward), KRAS G12D inhibitor (Abbisko), KRAS G12D inhibitor (Allist), KRAS G12D inhibitor (Anhorn), KRAS G12D inhibitor (Impact), TSL1502 (Tasly), KT-NIH anti-KRAS G12D mTCR PBL (Gilead), siG12D-LODER (Silenseed), siG12D inhibitor (Silenseed), Anocca-KRAS-G12D inhibitor (Anocca), KRASONCOlogue (Oncogenuity), Curve-KRAS G12D inhibitor (Curve Therapeutics), AST-KRASG12D inhibitor (Allist Pharmaceuticals), VRTX144 (VRise Therapeutics), KRAS G12D inhibitor (Affini-T Therapeutics Inc), BPI-001 (BeyondSpring Inc), anti-KRAS G12D monoclonal antibody (LA Cell Inc), MRTX-1133 (Mirati Therapeutics Inc), NT-0300D (NeuBaseTherapeutics Inc), PP-008 (Primary Peptides Inc), RMC-6236 (Revolution MedicinesInc), RMC-9805 (Revolution Medicines Inc), KRAS-G12D inhibitor (Arvinas Inc), anti-KRASG12D synthetic peptide (Indi Molecular Inc), BBP-KRAS G12D inhibitor (BridgeBio Pharma Inc), ERAS-4 (Erasca Inc), JAB-22000 (Jacobio Pharmaceuticals Group Co Ltd), KRpep-2d (peptide) (Takeda Pharmaceutical Co Ltd), anti-KRAS G12D monoclonal antibody (Oblique TherapeuticsAB), small molecule KRAS G12D inhibitor (Shenzhen Forward PharmaceuticalCo Ltd), Proteovant KRAS G12D inhibitor (Proteovant Therapeutics Inc), BIGPRO (bifunctional ligand-induced proteolysis) proteolysis agent (Anhorn Medicines Co Ltd), STX-XX KRAS G12D inhibitor (Seed Therapeutics Inc), and TPX-KRAS G12D inhibitor (Turning Point Therapeutics Inc), and pharmaceutically acceptable salts thereof.

[0193] In some embodiments, the KRAS G12D inhibitor is MRTX-1133, which has the following structure:

[0194]

[0195] or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the KRAS G12D inhibitor is administered at about 0.1 mg to about 5000 mg per dose, for example, about 1 mg to about 3000 mg, about 10 mg to about 2000 mg, for example, about 100 mg to about 2000 mg, about 100 mg to about 1500 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 100 mg to about 200 mg, about 200 mg to about 2000 mg, about 200 mg to about 1500 mg, about 200 mg to about 1000 mg, about 200 mg to about 800 mg, about 200 mg to about 600 mg, about 200 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1500 mg, about 400 mg to about 1000 mg, about 400 mg to about 800 mg, about 400 mg to about 600 mg, about 600 mg to about 2000 mg, about 600 mg to about 1500 mg, about 600 mg to about 1000 mg, about 600 mg to about 800 mg, about 800 mg to about 2000 mg, 800 mg to about 1500 mg, about 800 mg to about 1000 mg, about 600 mg to about 2000 mg, about 600 mg to about 1500 mg, about 600 mg to about 1000 mg, about 600 mg to about 800 mg. In some embodiments, the KRAS G12D inhibitor is administered at 10 mg to 2000 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at 100 mg to 1000 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at 100 mg to 200 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at 300 mg to 500 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at 200 mg to 600 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at 800 mg to 1000 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 1 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 5 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 10 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 50 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 100 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 150 mg per dose.In some embodiments, the KRAS G12D inhibitor is administered at about 200 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 250 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 300 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 350 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 400 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 450 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 500 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 550 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 600 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 650 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 700 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 750 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 800 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 850 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 900 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 950 mg per administration. In some embodiments, the KRAS G12D inhibitor is administered at about 1000 mg per administration.

[0197] In some embodiments, the KRAS G12D inhibitor is administered at least once a week. In some embodiments, the KRAS G12D inhibitor is administered once a week. In some embodiments, the KRAS G12D inhibitor is administered twice a week. In some embodiments, the KRAS G12D inhibitor is administered three times a week. In some embodiments, the KRAS G12D inhibitor is administered four times a week. In some embodiments, the KRAS G12D inhibitor is administered five times a week. In some embodiments, the KRAS G12D inhibitor is administered six times a week. In some embodiments, the KRAS G12D inhibitor is administered at least once a day. In some embodiments, the KRAS G12D inhibitor is administered once a day. In some embodiments, the KRAS G12D inhibitor is administered twice a day. In some embodiments, the KRAS G12D inhibitor is administered orally. In some embodiments, the KRAS G12D inhibitor is administered parenterally. In some embodiments, the KRAS G12D inhibitor is administered intravenously. In some embodiments, the KRAS G12D inhibitor is administered subcutaneously.

[0198] In some embodiments, the dual RAF / MEK inhibitor is administered before the KRAS G12D inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered after the KRAS G12D inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered concurrently with the KRAS G12D inhibitor.

[0199] FAK inhibitor

[0200] An effective inhibitor of FAK protein tyrosine kinase may be suitable for therapeutic use as an anti-proliferative agent (e.g., anti-cancer), anti-tumor (e.g., effective against solid tumors), anti-angiogenic (e.g., stopping or preventing blood vessel proliferation) in mammals, particularly in humans. In some embodiments, the methods described herein further comprise administering to the subject a FAK inhibitor described herein. FAK inhibitors can be used for the prevention and treatment of non-blood malignancies, a variety of human hyperproliferative disorders, such as liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreas, lung, vulva, thyroid, liver cancer, sarcoma, glioblastoma, malignant and benign tumors of the head and neck, and other proliferative conditions (e.g., benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH), as well as the prevention and treatment of disorders (e.g., mesothelioma)). In some embodiments, the compounds described herein, such as FAK inhibitors, inhibit protein tyrosine kinase 2 (PYK2).

[0201] In some embodiments, the methods described herein further comprise administering to the subject an effective amount of a FAK inhibitor.

[0202] Exemplary FAK inhibitors include, but are not limited to, defactinib having the following structure:

[0203] or a pharmaceutically acceptable salt thereof. Defactinib is also known as VS-6063 (e.g., VS-6063 free base) or PF-04554878. VS-6063 and related compounds are also disclosed, for example, in U.S. Patent No. 7,928,109, the content of which is incorporated herein by reference. In some embodiments, VS-6063 can form a pharmaceutically acceptable salt (e.g., VS-6063 hydrochloride).

[0204] In some embodiments, the FAK inhibitor is VS-4718, which has the following structure:

[0205] or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the FAK inhibitor is TAE226, which has the following structure:

[0207] or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the FAK inhibitor is GSK2256098, which has the following structure:

[0209] or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the FAK inhibitor is PF-03814735, which has the following structure:

[0211] or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the FAK inhibitor is BI-4464, which has the following structure:

[0213] or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the FAK inhibitor is BI-853520 (IN10018; Boehringer Ingelheim). In some other embodiments, the FAK inhibitor is APG-2449 (Ascentage Pharma Group).

[0215] In some embodiments, the FAK inhibitor is selected from defactinib, TAE226, BI-853520, GSK2256098, PF-03814735, BI-4464, VS-4718, and APG-2449, or a pharmaceutically acceptable salt thereof. For example, the FAK inhibitor is defactinib or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at least once a day. For example, in some embodiments, the FAK inhibitor (e.g., defactinib) is administered once a day. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered twice a day.

[0217] In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at a dose of about 100 mg to about 1000 mg per administration, such as about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 100 mg to about 200 mg, about 200 mg to about 1000 mg, about 400 mg to about 1000 mg, about 600 mg to about 1000 mg, about 800 mg to about 1000 mg, about 200 mg to about 800 mg, about 200 mg to about 600 mg, about 200 mg to about 400 mg, about 400 mg to about 800 mg, or about 400 mg to about 600 mg. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at a dose of about 200 mg to about 400 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at a dose of about 100 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at a dose of about 200 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at a dose of about 300 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at a dose of about 400 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at a dose of about 500 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at a dose of about 600 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered orally.

[0218] In some embodiments, the FAK inhibitor is administered in cycles, where each cycle comprises administering the FAK inhibitor for three weeks, followed by one week without administering the FAK inhibitor. In some examples, the cycle is repeated at least once.

[0219] EGFR inhibitor

[0220] In some embodiments, the methods described herein further contemplate administering to a subject an effective amount of an EGFR inhibitor.

[0221] Exemplary EGFR inhibitors include, but are not limited to:

[0222] ASK-120067 (Jiangsu Aosaikang Pharmaceutical Co Ltd) having the following structure:

[0223]

[0224] AST-2818 (Allist Shanghai Pharmaceutical Technology Co Ltd) having the following structure:

[0225]

[0226] BI-4020 having the following structure:

[0227]

[0228] BDTX-189 (Black Diamond Therapeutics Inc) having the following structure:

[0229]

[0230] BPI-7711 (Beta Pharma Inc) having the following structure:

[0231]

[0232] NRC-2694 (Natco Pharma Ltd) having the following structure:

[0233]

[0234] SKLB-1028 (CSPC Pharmaceutical Group Ltd) having the following structure:

[0235] TAS-6417 (Cullinan Oncology LLC) having the following structure:

[0236]

[0237] BAY-2476568 (Bayer) having the following structure:

[0238]

[0239] Doxorubicin + Erlotinib, Fotusab + Zalutumumab, Ivaciclib maleate, ABP-1119 (ABPharma Ltd), ABP-1130 (AB Pharma Ltd), Afatinib, Afatinib dimaleate, AG-101 (Arrogene Inc), AL-6802 (Jiangsu Simcere Pharmaceutical Co Ltd), Amelitinib mesylate, AM-105 (AbClon Inc), Amelimumab, Amivantamab, AMX-3009 (Arromax Pharmatech Co Ltd), APL-1898 (Wigen Biomedicine Technology (Shanghai) Co Ltd), BBT-176 (Bridge Biotherapeutics Inc), BEBT-108 (Guangzhou BeBetter Medicine Technology Co Ltd), BEBT-109 (Guangzhou BeBetter Medicine Technology Co Ltd), BH-2922 (Beijing Hanmi Pharmaceutical Co Ltd), BLU-4810 (Blueprint Medicines Corp), BMX-002 (Biomunex Pharmaceuticals), BO-1978 (National Yang Ming University), BPI-15086 (Betta Pharmaceuticals Co Ltd), Brigatinib, C-005 (Wuxi Shuangliang Biotechnology Co Ltd), Cetuximab, CK-101 (Checkpoint Therapeutics Inc), CLM-29 (University of Pisa), CLM-3 (University of Pisa), CMAB-017 (Mabpharm Ltd), CR-13626 (Rottapharm Biotech Srl), CSHEGF-29 (Guangzhou Institute of Biomedicine and Health), D-0316 (InventisBio Inc), D2C7-IT + PVSRIPO (Istari OncologyInc), Dabrafenib Mesylate + Panitumumab + Trametinib Dimethyl Sulfoxide, Dacomitinib, DBPR-112 (National Health Research Institutes), Depatuxizumab, DGD-1202 (MAIA Biotechnology Inc), Doritinib Mesylate, DZD-9008 (Dizal (Jiangsu) Pharmaceutical Co Ltd), EO-1001 (Senz Oncology Pty Ltd), Apatinib, Erlotinib (such as Erlotinib Hydrochloride), ES-072 (Apollomics Inc), FCN-411 (Fochon Pharma Inc), FHND-9041 (Jiangsu Zhengda Fenghai Pharmaceutical Co Ltd), FLAG-001 (Flag Therapeutics Inc), FLAG-003 (Flag Therapeutics Inc), FmAb-2 (Biocon Ltd), GB-263 (GenorBioPharma Co Ltd), GC-1118A (GC Pharma), Gefitinib, GS-03 + Osimertinib, HA-12128 (CSPC Pharmaceutical Group Ltd), HMPL-309 (Hutchison MediPharma Ltd), HMPL-813 (Hutchison MediPharma Ltd), HS-627 (Zhejiang Hisun Pharmaceutical Co Ltd), Icotinib Hydrochloride, JMT-101 (CSPC Pharmaceutical Group Ltd), JRF-103 (Chengdu Jinrui Foundation Biotechnology Co Ltd), JZB-29 (Shanghai Jing Ze Biotechnology Co Ltd), KBP-5209 (XuanZhu Pharma Co Ltd), KNP-501 (Kanaph Therapeutics Inc), KU-004 (Jiangsu Kanion Pharmaceutical Co Ltd), Lapatinib (such as Lapatinib Ditosylate), Larotinib, Lazertinib, Lifirafenib Maleate, MCLA-129 (MerusNV), MCLA-158 (Merus NV), MDC-22 (Medicon Pharmaceuticals Inc), mobocertinib, mRX-7 (MiReven Pty Ltd), MTX-211 (Mekanistic Therapeutics LLC), MVC-101 (Maverick Therapeutics Inc), naquotinib mesylate, nazartinib mesylate, necitumumab, neratinib, nimotuzumab, NT-004 (NewGen Therapeutics Inc), NT-113 (NewGen Therapeutics Inc), OBX-1012 (Oncobix Co Ltd), omotinib hydrochloride, osimertinib (e.g., osimertinib mesylate), panitumumab, PB-357 (Puma Biotechnology Inc), poziotinib, pyrotinib, QL-1105 (Qilu Pharmaceutical Co Ltd), QL-1203 (Qilu Pharmaceutical Co Ltd), RXDX-105 (agerafenib, Teva Pharmaceutical Industries Ltd), SAH-EJ1 (Arizona Cancer Therapeutics LLC), sapitinib, SCT-200 (Beijing Shenzhou Cell Biotechnology Group Co Ltd), selatinib ditosylate, ceritinib (sirotinib), SKLB-1206 (Sichuan University), SPH-118811 (Shanghai Pharmaceutical Group Co Ltd), SYN-004 (Synermore Biologics Co Ltd), tevatrunib tosylate, TGRX-360 (Shenzhen Targetrx Inc), tomuzotuximab, TQB-3804 (Chia Tai Tianqing Pharmaceutical Group Co Ltd), UBP-1215 (Chi Cheung (Shanghai) Biomedical Co Ltd), vandetanib, varlitinib, VRN-071918 (Voronoi Group), VRN-6 (Voronoi Group), WBP-297 (Hualan BiologicalEngineering Inc), WJ-13404 (WigenBiomedicine Technology (Shanghai) Co Ltd), WSD-0922 (Wayshine Biopharma Inc), XZP-5809 (Sihuan Pharmaceutical Holdings Group Ltd), Yinglitinib, YZJ-0318 (YangtzeRiver Pharmaceutical Group), ZNE-4 (Zentalis Pharmaceuticals Inc), Zolitinib, ZR-2002 (McGill University) or ZSP-0391 (Guangdong Zhongsheng Pharmaceutical Co Ltd), JS-111 (Shanghai Junshi Biosciennce), LL-191 (Capella Therapeutics), ORIC-114 (Oric Pharmaceuticals), DS-2087b (Daiichi Sankyo), and their hydrates, solvates and pharmaceutically acceptable salts.

[0240] In some embodiments, the EGFR inhibitor is doxorubicin + erlotinib, vorsetuzumab + zatuximab, avitinib maleate, ABP-1119, ABP-1130, afatinib dimaleate, AG-101, AL-6802, amitinib mesylate, AM-105, amelimumab, amivantamab, AMX-3009, APL-1898, ASK-120067, AST-2818, BBT-176, BDTX-189, BEBT-108, BEBT-109, BH-2922, BLU-4810, BMX-002, BO-1978, BPI-15086, BPI-7711, brigatinib, C-005, cetuximab, CK-101, CLM-29, CLM-3, CMAB-017, CR-13626, CSHEGF-29, D-0316, D2C7-IT + PVSRIPO, dabrafenib mesylate + panitumumab + trametinib dimethyl sulfoxide, dacomitinib, DBPR-112, ditumumab, DGD-1202, doxonib mesylate, DZD-9008, EO-1001, aplidinib, erlotinib (e.g., erlotinib hydrochloride), ES-072, FCN-411, FHND-9041, FLAG-001, FLAG-003, FmAb-2, GB-263, GC-1118A, gefitinib, GS-03 + osimertinib, HA-12128, HMPL-309, HMPL-813, HS-627, icotinib hydrochloride, JMT-101, JRF-103, JZB-29, KBP-5209, KNP-501, KU-004, lapatinib (e.g., lapatinib ditosylate), lorlatinib, lazertinib, lifirafenib maleate, MCLA-129, MCLA-158, MDC-22, mobocertinib, mRX-7, MTX-211, MVC-101, naquotinib mesylate, nazartinib mesylate, necitumumab, neratinib, nimotuzumab, NRC-2694, NT-004, NT-113, OBX-1012, omotinib hydrochloride, osimertinib (e.g., osimertinib mesylate), panitumumab, PB-357, poziotinib, pyrotinib, QL-1105, QL-1203, RXDX-105, SAH-EJ1, sapitinib, SCT-200, selatinib ditosylate, ceritinib, SKLB-1028, SKLB-1206, SPH-118811, SYN-004, TAS-6417, tevatinib tosylate, TGRX-360, tomutuximab, TQB-3804, UBP-1215, vandetanib,varlitinib, VRN-071918, VRN-6, WBP-297, WJ-13404, WSD-0922, XZP-5809, yinlitinib, YZJ-0318, ZNE-4, zorifertinib, ZR-2002, ZSP-0391, ORIC-114, DS-2087b, JS-111, LL-191, BI-4020 or BAY-2476568, or a hydrate, solvate, or pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is afatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is osimertinib or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is cetuximab, or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the EGFR inhibitor is administered at least once a week. In some embodiments, the EGFR inhibitor is administered at least once a day. In some embodiments, the EGFR inhibitor is administered once a day. In some embodiments, the EGFR inhibitor is administered twice a day. In some embodiments, the EGFR inhibitor is administered orally. In some embodiments, the EGFR inhibitor is administered parenterally. In some embodiments, the EGFR inhibitor is administered intravenously.

[0242] In some embodiments, the EGFR inhibitor is administered at about 0.1 mg to about 5000 mg per administration, for example, about 1 mg to about 3000 mg, about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 10 mg to about 2000 mg, for example, about 100 mg to about 2000 mg, about 100 mg to about 1500 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 100 mg to about 200 mg, about 200 mg to about 2000 mg, about 200 mg to about 1500 mg, about 200 mg to about 1000 mg, about 200 mg to about 800 mg, about 200 mg to about 600 mg, about 200 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1500 mg, about 400 mg to about 1000 mg, about 400 mg to about 800 mg, about 400 mg to about 600 mg, about 600 mg to about 2000 mg, about 600 mg to about 1500 mg, about 600 mg to about 1000 mg, about 600 mg to about 800 mg, about 800 mg to about 2000 mg, 800 mg to about 1500 mg, about 800 mg to about 1000 mg, about 600 mg to about 2000 mg, about 600 mg to about 1500 mg, about 600 mg to about 1000 mg, about 600 mg to about 800 mg. In some embodiments, the EGFR inhibitor is administered at about 1 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 5 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 10 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 50 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 100 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 200 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 300 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 400 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 500 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 600 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 700 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 800 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 900 mg per administration. In some embodiments, the EGFR inhibitor is administered at about 1000 mg per administration.

[0243] Anti-PD-1 antibody / anti-PD-L1 antibody

[0244] In some embodiments, the methods described herein further involve administering to a subject an effective amount of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0245] Antibody therapy is an antibody protein produced by the immune system and that binds to a target antigen on the cell surface. Antibodies are typically encoded by immunoglobulin gene(s) or fragments thereof. In normal physiology, antibodies are used by the immune system to combat pathogens. Each antibody is specific for one or several proteins, and those antibodies that bind to cancer antigens are used, for example, to treat cancer. Antibodies are capable of specifically binding to an antigen or epitope. (Fundamental Immunology, 3 rd Edition, W.e., Paul, ed., Raven Press, N.Y. (1993)). Specific binding to the corresponding antigen or epitope occurs even in the presence of a heterogeneous population of proteins and other organisms. Specific binding of an antibody indicates that the binding of the antibody to its target antigen or epitope has an affinity that is significantly greater than the binding to an unrelated antigen. The relative difference in affinity is typically at least 25%, more typically at least 50%, and most typically at least 100%. The relative difference can be, for example, at least 2-fold, at least 5-fold, at least 10-fold, at least 25-fold, at least 50-fold, at least 100-fold, or at least 1000-fold.

[0246] Exemplary types of antibodies include, but are not limited to, human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, polyclonal antibodies, single-chain antibodies, antibody-binding fragments, and diabodies. Once bound to a cancer antigen, an antibody can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent a receptor from interacting with its ligand, or deliver a payload of chemotherapy or radiotherapy, all of which may result in cell death.

[0247] In some embodiments, the anti-PD-1 antibody is selected from batrilizumab, camrelizumab, cemiplimab, dostarlimab, gerplimab, nivolumab, pembrolizumab, pamiprilimab, pidilizumab, palorolizumab, rivulizumab, sasanlimab, suruilizumab, sintilimab, spartalizumab, sulituzumab, teprotumumab, toripalimab, tislelizumab, toripalimab, toripalimab, sepacalimab, AMP-224 (MedImmune), AMP-514 (MedImmune), AT-16201 (AIMM Therapeutics BV), AVI-102 (AbVision Inc), BAT-1308 (Bio-Thera Solutions Ltd), BH-2950 (Beijing Hanmi Pharmaceutical Co Ltd), BSI-050K01 (Biosion Inc), CB-201 (Crescendo Biologics Ltd), CYTO-101 (Cytocom Inc), DB-004 (DotBio Pte Ltd), EX-105 (Excelmab Inc), EX-108 (Excelmab Inc), GNR-051 (Generium), HAB-21 (Suzhou Stainwei Biotech Inc), IBI-319 (Innovent Biologics Inc), IBI-321 (Innovent Biologics Inc), IKT-202 (Icell Kealex Therapeutics LLC), IMU-201 (Imugene Ltd), JS-201 (Shanghai Junshi Bioscience Co Ltd), LBL-006 (Leads Biolabs Inc), LBL-024 (Leads Biolabs Inc), LD-01 (Leidos Health Holdings LLC), LQ-005 (Shanghai Novamab Biopharmaceuticals Co Ltd), LQ-008 (Shanghai Novamab Biopharmaceuticals Co Ltd), MD-402 (MD Biosciences GmbH), OT-2 (OncoTrap Inc), PE-0105 (Shanghai Yunyi Health Technology Development CoLtd), PF-07209960 (Pfizer Inc), PH-762 (Phio Pharmaceuticals Corp), REGN-PD-1 / XX (Regeneron), RO7121661 (Genentech), SAUG-1 (Juvenescence UK Ltd), SCT-I10A (Sinocelltech), SG-001 (CSPC Pharmaceutical Group Ltd), SI-B003 (SystImmune), SL-279137 (Shattuck Labs), SSI-361 (Lyvgen Biopharma Ltd), STI-A1110 (Servier), STM-418 (Stcube Inc), Sym-021 (Symphogen A / S), TSR-075 (GlaxoSmithKline Plc), TY101 (Tayu Huaxia Biotech), Twist-PD-1 (Twist Bioscience), XmAb-TGFβR2 (Xencor), XmAb-YYCD28 (Xencor), XmAb20717 (Xencor), XmAb23104 (Xencor), YBL-006 (Y Biologics), YBL-019 (Y Biologics), and mDX-400 (Merck & Co Inc). In some embodiments, the anti-PD-1 antibody is selected from cemiplimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, AMP-224, and AMP-514. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0248] In some embodiments, the anti-PD-1 antibody is administered at least once a week. In some embodiments, the anti-PD-1 antibody is administered once a week. In some embodiments, the anti-PD-1 antibody is administered twice a week. In other embodiments, the anti-PD-1 antibody is administered once every two weeks. In other embodiments, the anti-PD-1 antibody is administered once every three weeks. In other embodiments, the anti-PD-1 antibody is administered once every four weeks. In other embodiments, the anti-PD-1 antibody is administered once every five weeks. In other embodiments, the anti-PD-1 antibody is administered once every six weeks.

[0249] In some embodiments, the anti-PD-1 antibody is administered at about 100 mg to about 2000 mg, about 100 mg to about 1500 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, (e.g., about 200 mg, 240 mg, or about 480 mg) per administration.

[0250] In some embodiments, the anti-PD-1 antibody is administered parenterally (e.g., by intravenous infusion).

[0251] In some embodiments, the anti-PD-L1 antibody is selected from atezolizumab, avelumab, durvalumab, enfortumab vedotin, sokazolimab, sugemalimab, ABM-101 (Abeome Corp), AP-505 (AP Biosciences Inc), APL-801 (Apollomics Inc), ATG-101 (Antengene Corp Ltd), AVA-027 (Avacta Life Sciences Ltd), AUNP12 (Aurigene), B-1961 (AP Biosciences Inc), BH-3120 (Hanmi Pharmaceuticals Co Ltd), BMS-986189 (Bristol Myers Squibb), BPI-9220 (Β Pharma Inc), BPI-9320 (Β Pharma Inc), CA-170 (Curis Inc), CCX-559 (ChemoCentryx Inc), CK-301 (cosibelimab), CS-17938 (Shenzhen Chipscreen Biosciences Co Ltd), CTX-8371 (Compass Therapeutics Inc), CYTCDR-2 (CytImmune Sciences Inc), DB-003 (DotBio Pte Ltd), DF-002 (Suzhou Dingfu Target Biotechnology Co Ltd), DPDL-1E (Shanghai Hycharm Inc), DR-30207 (Zhejiang Doer Biologics Corp), DSP-105 (KAHR medical Ltd), DSP-502 (KAHR medical Ltd), EI-011 (Elixiron Immunotherapeutics Inc), EI-014 (Elixiron Immunotherapeutics Inc), EMB-08 (EpimAb Biotherapeutics Inc), ENN-101 (Ennovabio), ENN-102 (Ennovabio), GB-7003 (Shanghai GeneChem Co Ltd), Gensci-047 (GeneScience Pharmaceuticals Co Ltd), HB-0025 (Huabo Biopharm(Shanghai)Co Ltd), HB-0028 (HuaboBiopharm(Shanghai)Co Ltd), HB-0036(Huabo Biopharm(Shanghai)Co Ltd), HBM-7015(Harbour BioMed(Guangzhou)Co Ltd), IBI-327(Innovent Biologics Inc), IGM-7354(IGM Biosciences Inc), IKT-201(Icell Kealex Therapeutics LLC), IMC-2101(ImmuneOncia Therapeutics LLC), IMC-2102(ImmuneOncia Therapeutics LLC), IMGS-002(Immunogenesis Inc), IMM-2510(ImmuneOncoBiopharmaceuticals(Shanghai)Co Ltd), INBRX-105(Elpiscience Biopharmaceutical Ltd), JBI-426(Jubilant Therapeutics Inc), JNB-809(JN Biosciences LLC), JNB-813(JN Biosciences LLC), KN-052(Αmab Oncology), KY-1043(Kymab Ltd), LP-008(Lepu Biopharma Co Ltd), LQ-002(Shanghai Novamab Biopharmaceuticals Co Ltd), LQ-004(Shanghai Novamab Biopharmaceuticals Co Ltd), LVGN-1673(Lyvgen Biopharma Ltd), LY-3434172(Eli Lilly and Co), LYN-102(LynkCell Inc), MCLA-145(Merus NV), MEDI-7526(AstraZeneca Plc), PH-790(Phio Pharmaceuticals Corp), PM-1003(Biotheus Inc), PRS-344(Pieris Pharmaceuticals Inc), Q-1802(QureBio), QL-301(QLSF Biotherapeutics Inc), QLS31901(Qilu Pharmaceutical), RC98(RemeGen), SHR-1316(JiangsuHengrui Medicine Co Ltd), SHR-1701 (Jiangsu Hengrui Medicine Co Ltd), SIM-236 (Jiangsu Simcere Pharmaceutical Co Ltd), SL-279252 (Shattuck Labs Inc), SL-279258 (Shattuck Labs Inc), SLSP-03 (Salspera LLC), SNA-02 (Oneness Biotech Co Ltd), STT-01 (Stcube Inc), TI-1007 (Timmune Biotech), TJ-L1C4 (I-Mab Biopharma), TJ-L1D5 (I-Mab Biopharma), TJ-L1H3 (I-Mab Biopharma), TJ-L1I7 (I-Mab Biopharma), TJL-14B (I-Mab Biopharma), TS1905 (Luye Pharma Group), TST-005 (Transcenta Holding Ltd), TTXsiPDL-1 (Transcode Therapeutics Inc), TXB-4BC3 (Ossianix Inc), VXM-10 (Vaximm AG), YBL-007 (Y-Biologics Inc), YBL-008 (Y-Biologics Inc), YBL-009 (Y-Biologics Inc), YBL-013 (Y-Biologics Inc), YBL-016 (Y-Biologics Inc), and YBL-020 (Y-Biologics Inc). In some embodiments, the anti-PD-L1 antibody is selected from avelumab, durvalumab, atezolizumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0252] In some embodiments, the anti-PD-L1 antibody is administered at least once a week. In some embodiments, the anti-PD-L1 antibody is administered once a week. In some embodiments, the anti-PD-L1 antibody is administered twice a week. In other embodiments, the anti-PD-L1 antibody is administered once every two weeks. In other embodiments, the anti-PD-L1 antibody is administered once every three weeks. In other embodiments, the anti-PD-L1 antibody is administered once every four weeks. In other embodiments, the anti-PD-L1 antibody is administered once every five weeks. In other embodiments, the anti-PD-L1 antibody is administered once every six weeks.

[0253] In some embodiments, the anti-PD-L1 antibody is administered at about 100 mg to about 2000 mg per administration, about 100 mg to about 1500 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 500 mg to about 1500 mg, about 500 mg to about 1200 mg, about 800 mg to about 1200 mg, about 800 mg to about 1500 mg. For example, the anti-PD-L1 antibody can be administered at about 400 mg, about 800 mg, or about 1200 mg per administration.

[0254] In some embodiments, the anti-PD-L1 antibody is administered parenterally (e.g., by intravenous infusion).

[0255] Diseases and disorders

[0256] Abnormal cell growth

[0257] As used herein and unless otherwise indicated, abnormal cell growth refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the following abnormal growths: (1) tumor cells (tumors) that proliferate, for example, by overexpression of mutant tyrosine kinases or receptor tyrosine kinases; (2) benign and malignant cells of other proliferative diseases, such as those in which abnormal tyrosine kinase activation occurs; (3) any tumors that proliferate, for example, by receptor tyrosine kinases; (4) any tumor pads that proliferate, for example, by abnormal serine / threonine kinase activation; (5) benign and malignant cells of other proliferative diseases, such as those in which abnormal serine / threonine kinase activation occurs. Abnormal cell growth can refer to cell growth of epithelial cells (e.g., carcinoma, adenocarcinoma); mesenchymal cells (e.g., sarcoma (e.g., leiomyosarcoma, Ewing's sarcoma)); hematopoietic (e.g., lymphoma, leukemia, myelodysplasia (e.g., pre-malignant)); or other (e.g., melanoma, mesothelioma, and tumors of unknown origin) cells.

[0258] Neoplastic disorder

[0259] Abnormal cell growth can refer to neoplastic disorders. A "neoplastic disorder" is a disease or disorder characterized by cells having the ability to grow or replicate autonomously, such as an abnormal condition or disease characterized by proliferative cell growth. An abnormal mass of tissue or "tumor" resulting from abnormal cell growth or division can be benign, pre-malignant (carcinoma in situ), or malignant (cancer).

[0260] Exemplary neoplastic disorders include: cancer, sarcoma, metastatic disorders (e.g., tumors arising from prostate, colon, lung, breast, and liver origin), hematopoietic neoplastic disorders such as leukemia, metastatic tumors. Treatment with a compound can be at an effective amount to improve at least one symptom of a neoplastic disorder, such as reduced cell proliferation, reduced tumor mass, etc.

[0261] Cancer

[0262] The methods of the present disclosure can be used for the prevention and treatment of cancer, including, for example, solid tumors, soft tissue tumors, and their metastases. The disclosed methods can also be used for the treatment of non-solid cancers. Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of various organ systems (e.g., lung, breast, lymph, gastrointestinal tract (e.g., colon), and urogenital tract (e.g., renal, urothelial, or testicular tumors), pharynx, prostate, and ovary). Exemplary adenocarcinomas include colorectal cancer, renal cell carcinoma, liver cancer (e.g., hepatocellular carcinoma), non-small cell lung cancer, pancreatic cancer (e.g., metastatic pancreatic adenocarcinoma), and small intestine cancer.

[0263] In some embodiments, the cancer is a cancer characterized by having a KRAS G12D mutation.

[0264] The cancer can include mesothelioma; neurofibromatosis, e.g., neurofibromatosis type 2, neurofibromatosis type 1; renal cancer; lung cancer, e.g., non-small cell lung cancer, e.g., metastatic NSCLC; lung adenocarcinoma, e.g., NSCLC adenocarcinoma; liver cancer; thyroid cancer; ovarian cancer, e.g., low-grade serous ovarian cancer; breast cancer; pancreatic cancer, e.g., pancreatic adenocarcinoma; colorectal cancer, e.g., colorectal adenocarcinoma; endometrioid carcinoma; gynecological cancers, e.g., cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, endometrial cancer, or vulvar cancer; liver cancer; prostate cancer; mesothelioma; bladder cancer; melanoma, e.g., unresectable melanoma, metastatic melanoma; thyroid cancer, e.g., papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer; glioblastoma; renal cancer; nervous system tumors; schwannoma; meningioma; schwannomatosis; acoustic neuroma; adenoid cystic carcinoma; ependymoma; and ependymal tumors.

[0265] Cancer can include cancers characterized by containing cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells. Cancer can include cancers characterized by being rich in cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells (e.g., tumors or metastatic tumors rich in cells that have undergone epithelial-to-mesenchymal transition).

[0266] Cancer can be a primary tumor, i.e., located at the anatomical site where tumor growth originates. Cancer can also be metastatic, i.e., present in at least a second anatomical site in addition to the anatomical site where tumor growth originates. Cancer can be recurrent cancer, i.e., cancer that reappears after treatment and after a period of undetectable cancer. Recurrent cancer can be anatomically local to the original tumor, e.g., anatomically close to the original tumor; regional to the original tumor, e.g., in lymph nodes near the original tumor; or distant from the original tumor, e.g., in regions anatomically distant from the original tumor.

[0267] Cancer can also include, for example but not limited to, epithelial cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, prostate cancer, head and neck cancer, melanoma, acute myeloid leukemia, and glioblastoma. Exemplary breast cancers include triple-negative breast cancer, basal-like breast cancer, claudin-low breast cancer, invasive, inflammatory, metaplastic, and advanced HER-2 positive or ER positive cancers resistant to therapy.

[0268] Cancer can also include lung adenocarcinoma, colorectal cancer (CRC), uveal melanoma, ovarian cancer, endometrioid cancer, bladder urothelial cancer, invasive lobular carcinoma of the breast, cervical squamous cell carcinoma, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic pleural mesothelioma, clear cell renal cell carcinoma, clear cell renal cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, carcinosarcoma of the uterus, or malignant mixed Müllerian tumor of the uterus.

[0269] In some embodiments, the cancer is unresectable or metastatic melanoma, melanoma with lymph node involvement or metastatic disease that has undergone complete resection, metastatic non-small cell lung cancer that develops during or after platinum-based chemotherapy, metastatic small cell lung cancer that develops after platinum-based chemotherapy and at least one other line of therapy, advanced renal cell carcinoma that has previously received anti-angiogenic therapy, advanced renal cell carcinoma, classical Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck in which disease progresses during or after platinum-based therapy, locally advanced or metastatic urothelial cancer, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer, or hepatocellular carcinoma.

[0270] In some embodiments, the cancer is melanoma, non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial cancer, microsatellite instability-high cancer, gastric cancer, esophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, or endometrial cancer.

[0271] Other cancers include, but are not limited to, uveal melanoma, brain cancer, abdominal cancer, esophageal cancer, gastrointestinal cancer, glioma, liver cancer, tongue cancer, neuroblastoma, osteosarcoma, ovarian cancer, retinoblastoma, Wilm's tumor, multiple myeloma, skin cancer, lymphoma, blood cancer, and bone marrow cancer (e.g., advanced hematological malignancies, leukemia, e.g., acute myeloid leukemia (e.g., primary or secondary), acute lymphoblastic leukemia, acute lymphocytic leukemia, T-cell leukemia, hematological malignancies, advanced myeloproliferative disorders, myelodysplastic syndromes, relapsed or refractory multiple myeloma, advanced myeloproliferative disorders), retinocarcinoma, bladder cancer, cervical cancer, kidney cancer, endometrial cancer, meningioma, lymphoma, skin cancer, uterine cancer, lung cancer, non-small cell lung cancer, nasopharyngeal cancer, neuroblastoma, solid tumors, hematological malignancies, squamous cell carcinoma, testicular cancer, thyroid cancer, mesothelioma, brain cancer, vulvar cancer, sarcoma, bowel cancer, oral cancer, endocrine cancer, salivary gland cancer, spermatocytic seminoma, sporadic medullary thyroid cancer, non-proliferative testicular cell cancer, cancers associated with malignant mast cells, non-Hodgkin lymphoma, and diffuse large B-cell lymphoma.

[0272] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is locally advanced or metastatic. In some embodiments, the solid tumor is refractory (e.g., resistant) to standard therapies.

[0273] The methods described herein can reduce, ameliorate, or completely eliminate the disorder and / or its associated symptoms to prevent them from getting worse, slow the rate of progression, or minimize the recurrence rate of the disorder once the disorder has been initially eliminated (i.e., avoid recurrence). Appropriate dosages and treatment regimens can vary depending on the specific compounds, combinations, and / or pharmaceutical compositions used and the mode of delivery of the compounds, combinations, and / or pharmaceutical compositions. In some embodiments, the method increases the average survival length of subjects treated with the combinations described herein, increases the average length of progression-free survival, and / or decreases the recurrence rate in a statistically significant manner.

[0274] In some embodiments, the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, melanoma of the skin or eye, uterine cancer, ovarian cancer (e.g., unresectable low-grade ovarian cancer, advanced or metastatic ovarian cancer), rectal cancer, cancer of the anal area, stomach cancer, colon cancer, breast cancer (e.g., triple-negative breast cancer (e.g., breast cancer that does not express the genes for estrogen receptor, progesterone receptor, and Her2 / neu)), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid adenocarcinoma, parathyroid adenocarcinoma, adrenal adenocarcinoma, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney cancer or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma) or a combination of one or more of the foregoing cancers. In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth is locally recurrent (e.g., the subject has locally recurrent disease, e.g., cancer).

[0275] Additional therapy

[0276] In some embodiments, the methods and compositions described herein are administered in combination with additional therapies or additional agents. In one embodiment, a mixture of one or more compounds or pharmaceutical compositions can be administered to a subject in need thereof in combination with the combinations described herein. In yet another embodiment, one or more compounds or compositions (e.g., pharmaceutical compositions) can be administered in combination with the combinations described herein for treating or preventing various diseases, including, for example, cancer, diabetes, neurodegenerative diseases, cardiovascular diseases, blood coagulation, inflammation, flushing, obesity, aging, stress, and the like. In various embodiments, combination therapies comprising the compounds or pharmaceutical compositions described herein can refer to (1) a pharmaceutical composition comprising one or more compounds in combination with the combinations described herein; and (2) co-administration of one or more compounds or pharmaceutical compositions described herein with the combinations described herein, wherein the compounds or pharmaceutical compositions described herein are not formulated in the same composition. In some embodiments, the combinations described herein are administered in combination with additional treatments (e.g., additional cancer treatments). In some embodiments, the additional treatment (e.g., additional cancer treatment) can be administered simultaneously (e.g., at the same time) or sequentially in the same or separate compositions. Sequential administration refers to administering one treatment (e.g., a compound or therapy) before (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 or more hours; 4, 5, 6, 7, 8, 9 or more days; 1, 2, 3, 4, 5, 6, 7, 8 or more weeks before) administering an additional (e.g., second) treatment (e.g., a compound or therapy). The order of administration of the first and second compounds or therapies can also be reversed.

[0277] Exemplary cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapies, immunotherapies, and hormone therapies. Examples of each of these treatments are provided below.

[0278] Chemotherapy

[0279] In some embodiments, the combinations described herein are administered in combination with chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy" generally refers to cytotoxic drugs that affect rapidly dividing cells, as opposed to targeted therapies. Chemotherapy drugs interfere with cell division in various possible ways, such as interfering with DNA replication or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, although some degree of specificity may result from the inability of many cancer cells to repair DNA damage, while normal cells generally can.

[0280] In some embodiments, the combinations described herein are administered with one or more chemotherapeutic agents. Examples of chemotherapeutic agents for cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle toxins, cytotoxic agents, topoisomerase inhibitors, etc.).Exemplary agents include aclarubicin, actinomycin, alitretinon, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquone, carmofur, carmustine, celecoxib, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, colchicine amide, docetaxel, doxorubicin, epirubicin, elsamitrucin, epristeride, enocitabine, epirubicin, estramustine, etoglucid, etoposide, floxuridine, fludarabine, fluorouracil (5FU), Folfirinox, fotemustine, gemcitabine, Gliadel implant, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, ilofibrate, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, mitoxantrone, mannomustine, masoprocol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, dibromomannitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semustine, sitimagene ceradenovec, strataplatin, streptozocin, talaporfin, tegafururacil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, thiazofurin, thioguanine, tipifarnib, topotecan, trabectedin, triaziquone, triethylenemelamine, triplatin, tretinoin, trimetrexate, trimetrexate glucuronate, uracil mustard, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, zorubicin, and other cell growth inhibitors or cytotoxic agents described herein.

[0281] Since certain drugs work better when used together than when used alone, two or more drugs are usually administered at the same time or sequentially. Typically, two or more chemotherapeutic agents are used as combination chemotherapy. In some embodiments, chemotherapeutic agents (including combination chemotherapy) can be used in combination with the combinations described herein.

[0282] Targeted therapy

[0283] In some embodiments, the combinations described herein are administered in combination with targeted therapy. Targeted therapy involves the use of specific agents directed against dysregulated proteins in cancer cells. Small molecule targeted therapy drugs are typically inhibitors of mutated, overexpressed, or other key protein enzyme domains within cancer cells. Prominent examples are tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, dasatinib, erlotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, and cyclin-dependent kinase inhibitors such as alvocidib and seliciclib. Monoclonal antibody therapy is another strategy where the therapeutic agent is an antibody that specifically binds to a protein on the surface of cancer cells. Examples include the anti-HER2 / neu antibody trastuzumab commonly used in breast cancer and the anti-CD20 antibodies rituximab and tositumomab commonly used in various B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, elotuzumab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin. In some embodiments, targeted therapy can be used in combination with the combinations described herein.

[0284] Targeted therapy can also involve small peptides as "homing devices" that can bind to cell surface receptors or the extracellular matrix surrounding the affected tumor. If the radionuclide decays near the cell, the radionuclide attached to these peptides (such as RGD) will ultimately kill the cancer cells. An example of such a therapy includes

[0285] Immunotherapy

[0286] In some embodiments, the combinations described herein are administered in combination with immunotherapy. Cancer immunotherapy refers to a variety of treatment strategies aimed at inducing a subject's own immune system to fight tumors.

[0287] Modern methods of generating an immune response against tumors include intravesical BCG immunotherapy for superficial bladder cancer and the use of interferons and other cytokines to induce an immune response in subjects with renal cell carcinoma and melanoma. Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy since the donor's immune cells typically attack the tumor with a graft-versus-tumor effect. In some embodiments, immunotherapy agents can be used in combination with the combinations described herein.

[0288] Hormone therapy

[0289] In some embodiments, the combinations described are administered in combination with hormone therapy. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancer. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administering a hormone agonist (e.g., progesterone) can be therapeutically beneficial. In some embodiments, hormone therapy agents can be used in combination with the combinations described herein.

[0290] In some embodiments, the additional agent is an agent that modifies ER, PR, and / or AR. For example, the additional agent is an AR antagonist, including but not limited to flutamide, bicalutamide, and nilutamide. In some embodiments, the additional agent is an agent that blocks estrogen or progesterone, including aromatase inhibitors, including but not limited to anastrozole, letrozole, and exemestane. In some embodiments, the additional agent is an estrogen receptor modulator, including but not limited to fulvestrant, tamoxifen, and raloxifene.

[0291] Radiation therapy

[0292] The combinations described herein can be used in combination with directed energy or particles, or radioisotope therapy (e.g., radiotherapy, e.g., radiation oncology) for treating proliferative diseases such as cancer, e.g., cancer associated with cancer stem cells. The combinations described herein can be administered to a subject simultaneously or sequentially with directed energy or particles, or radioisotope therapy. For example, the combinations described herein can be administered before, during, or after directed energy or particles, or radioisotope therapy, or combinations thereof. Directed energy or particle therapy can include total body irradiation, partial body irradiation, or spot irradiation. Directed energy or particles can be derived from an accelerator, synchrotron, nuclear reaction, vacuum tube, laser, or from a radioisotope. Therapy can include external beam radiotherapy, teletherapy, brachytherapy, sealed source radiotherapy, systemic radioisotope therapy, or unsealed source radiotherapy. Therapy can include ingestion of a radioisotope (e.g., radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, carbon) or placement near a radioisotope (e.g., radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, carbon). External beam radiation can include exposure to directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radio waves, millimeter waves, microwaves, infrared light, visible light, ultraviolet light, X-ray, or gamma ray photons). Radiation can be directed at any part of the subject in need of treatment.

[0293] Surgery

[0294] The combinations described herein can be used in combination with surgery (e.g., surgical exploration, intervention, biopsy) for treating proliferative diseases such as cancer, e.g., cancer associated with cancer stem cells. The combinations described herein can be administered to a subject simultaneously or sequentially with surgery. For example, the combinations described herein can be administered before (pre-surgery), during, or after (post-surgery) surgery, or combinations thereof. Surgery can be a biopsy, during which one or more cells are collected for further analysis. A biopsy can be done, for example, with a scalpel, needle, catheter, endoscope, spatula, or scissors. A biopsy can be an excisional biopsy, incisional biopsy, core biopsy, or needle biopsy, e.g., fine needle aspiration biopsy. Surgery may involve removal of local tissue suspected or determined to be cancerous. For example, the surgery may involve removal of a cancerous lesion, mass, polyp, or mole. The surgery may involve removal of a large amount of tissue, such as breast, bone, skin, fat, or muscle. The surgery may involve removal of part or all of an organ or node, such as the lung, throat, tongue, bladder, cervix, ovary, testicle, lymph node, liver, pancreas, brain, eye, kidney, gallbladder, stomach, colon, rectum, or intestine. In one embodiment, the cancer is breast cancer, e.g., triple negative breast cancer, and the surgery is a mastectomy or lumpectomy.

[0295] Anti-inflammatory agent

[0296] The combinations described herein can be administered together with an anti-inflammatory agent. The anti-inflammatory agent can include, but is not limited to, non-steroidal anti-inflammatory agents (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), fenamic acid derivatives (Fenamates) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxibs) (celecoxib), sulfonanilides (nimesulide), steroidal agents (e.g., hydrocortisone (cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, desoxycorticosterone acetate, aldosterone).

[0297] Analgesic

[0298] Analgesics can include, but are not limited to, opioid drugs (e.g., morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine, tramadol, venlafaxine), paracetamol, and non-steroidal anti-inflammatory agents (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), fenamic acid derivatives (Fenamates) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxibs) (celecoxib), sulfonanilides (nimesulide).

[0299] Antiemetic

[0300] The combinations described herein can be administered together with an antiemetic. The antiemetic can include, but is not limited to, 5-HT3 receptor antagonists (dolasetron (Anzemet), granisetron (Kytril, Sancuso), ondansetron (Zofran), tropisetron (Navoban), palonosetron (Aloxi), mirtazapine (Remeron)), dopamine antagonists (domperidone, olanzapine, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide (Reglan), alizapride, prochlorperazine (methotrimeprazine, Stemzine, Buccastem, Stemetil, Phenotil)), NK1 receptor antagonists (aprepitant (Emend), antihistamines (cyclizine, diphenhydramine (Benadryl), dimenhydrinate (Gravol, Dramamine), meclizine (Bonine, Antivert), promethazine (Phenergan, Promacot), hydroxyzine), benzodiazepines (lorazepam, midazolam), anticholinergic drugs (scopolamine), steroids (dexamethasone).

[0301] Combination

[0302] The phrases "in combination with" and the terms "co-administration", "co-administering", or "co-providing", as used herein in the context of administering the compounds or therapies described herein, mean the delivery of two or more different compounds or therapies to a subject during the course of the subject being afflicted with a disease or disorder (e.g., a disease or disorder described herein, such as cancer), e.g., the delivery of two or more different compounds or therapies to a subject after the subject has been diagnosed with a disease or disorder (e.g., a disease or disorder described herein, such as cancer) and before the disease or disorder has been cured or eliminated or treatment has been discontinued for other reasons.

[0303] In some embodiments, when the delivery of a second compound or therapy is initiated, the delivery of a first compound or therapy continues such that there is an overlap in administration. This is sometimes referred to herein as "simultaneous" or "parallel delivery". In other embodiments, the delivery of a first compound or therapy ends before the delivery of a second compound or therapy is initiated. In some embodiments of either case, the treatment (e.g., administration of a compound, composition, or therapy) is more effective due to the combination administration. For example, the second compound or therapy is more effective, e.g., comparable effects can be seen with less of the second compound or therapy, or the second compound or therapy results in a greater degree of symptom alleviation than when the second compound or therapy is administered without the first compound or therapy, or a similar situation is observed with the first compound or therapy. In some embodiments, the delivery results in a greater reduction in symptoms or other parameters associated with the disorder than is observed with the delivery of a single compound or therapy in the absence of the other. The effects of the two compounds or therapies can be partially cumulative, fully cumulative, or greater than cumulative (e.g., synergistic). The delivery can be such that the first compound or therapy being delivered is still detectable when the second compound or therapy is delivered.

[0304] In some embodiments, the first compound or therapy and the second compound or therapy can be administered simultaneously (e.g., at the same time), in the same or separate compositions, or sequentially. Sequential administration means that a first compound or therapy is administered before (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 or more hours; 4, 5, 6, 7, 8, 9 or more days; 1, 2, 3, 4, 5, 6, 7, 8 or more weeks before) the administration of another (e.g., the second compound or therapy). The order of administration of the first and second compounds or therapies can also be reversed.

[0305] The combinations described herein can be for first-line treatment of abnormal cell growth such as cancer, i.e., for patients who have not previously been administered another drug intended to treat cancer; for second-line treatment of cancer, i.e., for subjects in need who have previously been administered another drug intended to treat cancer; for third or fourth treatment of cancer, i.e., for subjects who have previously been administered two or three other drugs intended to treat cancer.

[0306] Administration and Dosage

[0307] The combinations of the present disclosure can be administered orally, parenterally, topically, rectally, or via an implanted reservoir, preferably orally or by injection. In some cases, the pH of the composition (e.g., pharmaceutical composition) can be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability or efficacy of the composition.

[0308] In some embodiments, the composition (e.g., pharmaceutical composition) is administered orally to a subject. In some embodiments, the composition (e.g., pharmaceutical composition) is orally administered in any orally acceptable dosage form, including but not limited to liquid gels, tablets or capsules, syrups, emulsions, and aqueous suspensions. The liquid gel may contain gelatin, plasticizer, and / or opacifier as needed to achieve a suitable viscosity and may be coated with an approved enteric coating, such as shellac. When used as an oral dose, additional thickeners, such as gums (e.g., xanthan gum), starches (e.g., corn starch), or gluten, may be added to achieve the desired viscosity of the composition (e.g., pharmaceutical composition). If desired, certain sweeteners and / or flavoring agents and / or coloring agents may be added.

[0309] In some embodiments, the composition (e.g., pharmaceutical composition) is administered to a subject in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions. The composition (e.g., pharmaceutical composition) can be a unit dosage form suitable for a single administration of a precise dose. In addition to the compounds described herein, the pharmaceutical composition may also contain a pharmaceutically acceptable carrier and may optionally further contain one or more pharmaceutically acceptable excipients, such as stabilizers, diluents, binders, and lubricants. Additionally, the tablets may contain other drugs or pharmaceutical agents, carriers, and / or adjuvants. Exemplary pharmaceutical compositions include compressed tablets (e.g., direct compression tablets).

[0310] Tablets containing an active or therapeutic ingredient (e.g., a compound described herein) are also provided. In addition to the active or therapeutic ingredient, the tablets may also contain a number of inert materials, such as carriers. Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, sesame oil, etc. Aqueous solutions of saline and aqueous dextrose can also be used as liquid carriers. Thus, the oral dosage forms used according to the present disclosure can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and auxiliaries that facilitate the processing of the active ingredient into a pharmaceutically acceptable preparation.

[0311] Excipients can impart good powder flow and compression properties to the material being compressed. Examples of excipients are described, for example, in Handbook of Pharmaceutical Excipients (5th edition), edited by Raymond C Rowe, Paul J. Sheskey and Sian C. Owen; Publisher: Pharmaceutical Press.

[0312] For oral administration, an active ingredient (such as a compound described herein) can be readily formulated by combining it with pharmaceutically acceptable carriers well known in the art. Such carriers enable the active ingredients of the present disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, powders or granules, suspensions or solutions in aqueous or non-aqueous media, etc., for oral ingestion by a subject. Pharmacological preparations for oral use can be prepared using solid excipients, optionally grinding the resulting mixture, and processing the granule mixture after adding suitable auxiliaries (if necessary) to obtain, for example, tablets. Suitable excipients such as diluents, binders or disintegrants may be desirable.

[0313] The dosage can vary depending on the dosage form employed and the route of administration used. The exact formulation, route of administration and dosage can be selected by each physician in view of the patient's condition. (See, for example, "Pharmacological Basis of Therapeutics" by Fingl et al. in 1975). Doses lower or higher than those recited above may be required. The specific dose and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, excretion rate, drug combination, disease, disorder or symptom severity and course, subject's susceptibility to the disease, disorder or symptom, and the judgment of the attending physician. The course of therapy can include one or more individual administrations of the compounds described herein. The course of therapy can include one or more cycles of the compounds described herein.

[0314] In some embodiments, a cycle as used herein in the context of a drug administration cycle is the time period during which a drug is administered to a patient. For example, if the drug administration cycle is 21 days, regular administration (such as once or twice a day) continues for 21 days. A drug can be administered for more than one cycle. A rest period can be inserted between cycles. The length of the rest cycle can be 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 1, 2, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 or more weeks.

[0315] If desired, the oral dosage form may be present in a package or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The package may include, for example, a metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for administration. The package or dispenser may also be accompanied by a notice associated with the container, the form of which is prescribed by a governmental agency that regulates the manufacture, use, or sale of the medicament, and which notice is a reflection of the agency's approval of the form of the composition or of human or veterinary administration. For example, such notice may be a prescription drug label approved by the U.S. Food and Drug Administration or an approved product insert. Examples

[0316] To more fully understand the invention described herein, the following examples are set forth. The examples described in this application are used to illustrate the pharmaceutical compositions and methods provided herein and should not be construed in any way as limiting their scope.

[0317] Example 1. Synergistic effect of VS-6766 and KRAS G12D inhibitor in preclinical solid tumor models

[0318] This study investigated the vertical pharmacological blockade of RAS, RAF, and MEK by a G12D inhibitor in combination with a dual RAF / MEK inhibitor (such as VS-6766) + / - a FAK inhibitor, + / - an EGFR inhibitor, + / - a PD-1 / PD-L1 antibody, or + / - chemotherapy, which the inventors believed would result in superior pathway blockade and anti-tumor efficacy.

[0319] Materials and Methods

[0320] In vitro 3D proliferation assay

[0321] A KRAS G12D mutant human cancer cell line was used. Briefly, 96-well plates were coated with 50 μL of Matrigel (100%) and incubated at 37 °C and 5% CO2 for 30 minutes to allow the Matrigel to solidify. Cells were seeded in 100 μL of medium containing 2% Matrigel. After incubation overnight (17 - 22 hours), the cells were treated with VS-6766 + / - the G12D inhibitor for 7 days. Cell viability was measured using the CellTiter-Glo 3D assay for cell viability. Bliss, Loewe, HSA, and ZIP synergy analyses were performed to generate a combined synergy score.

[0322] Results

[0323] VS-6766 has a synergistic effect with a KRAS G12D inhibitor (such as MRTX-1133), and this combination promotes tumor cell death, including, for example, KRAS G12D colorectal and pancreatic cancer cell lines. Figure 1Shows the prevalence of the KRAS G12D mutation in exemplary cancers (pancreatic cancer, colorectal cancer, endometrial cancer, and NSCLC) and the synergy scores of exemplary combinations (VS-6766 and MRTX-1133). Figure 2 Shows the effect of the combination in exemplary cell lines. Figure 3 Illustrates exemplary cytotoxicity scores in 3D Matrigel proliferation assays in various cell lines.

[0324] Equivalent forms and ranges

[0325] In the claims, unless the contrary is indicated or is obvious from the context, articles such as "a" and "the" may refer to one or more than one. Unless the contrary is indicated or is obvious from the context, a claim or specification that includes "or" among one or more members of a group is considered satisfied if one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to a given product or process.

[0326] In addition, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are incorporated into another claim. For example, any claim that depends on another claim may be modified to include one or more limitations that exist in any other claim that depends on the same base claim. When elements are presented in a list form (e.g., in Markush group format), each subgroup of the elements is also disclosed, and any element may be removed from the group. It should be understood that, in general, when the present invention or aspects of the present invention are referred to as including specific elements and / or features, certain embodiments of the present invention or aspects of the present invention consist of or consist essentially of these elements and / or features. For simplicity purposes, those embodiments are not explicitly set forth in these terms herein. Also note that the terms "comprising" and "containing" are intended to be open and allow the inclusion of additional elements or steps. When ranges are given, the endpoints are included. In addition, unless otherwise stated or otherwise obvious from the context and understood by one of ordinary skill in the art, values expressed as ranges in different embodiments of the present invention may take any specific value or subrange within the range, to one-tenth of the unit of the lower limit of the range, unless the context clearly states otherwise.

[0327] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If any conflict exists between any of the incorporated references and this specification, then this specification shall govern. Additionally, any particular embodiment of the invention that falls within the scope of the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if not explicitly set forth as such herein. Any particular embodiment of the invention may be excluded from any claim for any reason, regardless of whether related to the existence of the prior art.

[0328] Those skilled in the art will recognize or be able to ascertain, using only routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the foregoing specification, but rather is as set forth in the appended claims. Those of ordinary skill in the art will understand that various changes and modifications may be made to this specification without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor and an effective amount of a KRAS G12D inhibitor.

2. The method of claim 1, wherein the cancer is identified as having a KRAS G12D mutation.

3. The method of claim 1 or 2, wherein the dual RAF / MEK inhibitor is a compound of formula (I): or a pharmaceutically acceptable salt thereof.

4. The method of claim 3, wherein the dual RAF / MEK inhibitor is a compound of formula (I):

5. The method of claim 3, wherein the dual RAF / MEK inhibitor is a potassium salt of the compound of formula (I).

6. The method of claim 1 or 2, wherein the dual RAF / MEK inhibitor is IMM-1-104, or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 or 2, wherein the dual RAF / MEK inhibitor is a compound of formula (II): including its pharmaceutically acceptable salts, wherein: Ring A is R 1 、R 2 、R 3 and R 4 are each independently selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamide, optionally substituted N-sulfonamide, optionally substituted sulfonate, optionally substituted O-thiocarbamoyl, optionally substituted N-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C8 heterocyclic group, optionally substituted C3-C10 heteroaryl and L; R 6 is selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl and optionally substituted C2-C6 alkynyl; X is C(R 5 ) 2 , CH(R 5 ), CH 2 , -O-, L is -Z 1 -Z 2 or -Z 1 -Z 2 -Z 3 ; Z 1 、Z 2 和Z 3 独立地选自-CH 2 -、-O-、-S-、S=O、-SO 2 -、C=O、-CO 2 -、-NO 2 、-NH-、-CH 2 CCH、-CH 2 CN、-NR 5 R 5’ 、-NH(CO)-、-(CO)NH-、-(CO)NR 5 R 5’ -、-NH-SO 2 -、-SO 2 -NH-、-R 5 CH 2 -、-R 5 O-、-R 5 S-、R 5 -S=O、-R 5 SO 2- 、R 5 -C=O、-R 5 CO 2 -、-R 5 NH-、-R 5 NH(CO)-、-R 5 (CO)NH-、-R 5 NH-SO 2 -、-R 5 SO 2 -NH-、-NHCH 2 CO-、-CH 2 R 5 -、-OR 5 -、-SR 5 -、S=OR 5 、-SO 2 R 5 -、C=OR 5 、-CO 2 R 5 -、-NHR 5 -、-NH(CO)R 5 -、-(CO)NHR 5 -、-NH-SO 2 R 5 -、-SO 2 -NHR 5 - An optionally substituted C1-C6 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C10 aryl group, an optionally substituted C3-C8 heterocyclic group, an optionally substituted C3-C10 heteroaryl group, -CH 2 -(Optionally substituted aryl), -CH 2 -(Optionally substituted C3-C8 cycloalkyl) and -CH 2 -(Optionally substituted C3-C10 heteroaryl); each R 5 and R 5’ is independently selected from H, deuterium, an optionally substituted C1-C6 alkyl group, an optionally substituted C2-C6 alkenyl group, an optionally substituted C2-C6 alkynyl group, an optionally substituted C3-C8 carbocyclic group, an optionally substituted C6-C10 aryl group, an optionally substituted C3-C8 heterocyclic group, and an optionally substituted C3-C10 heteroaryl group; and Y is CH 2 , NH, or O, provided that R 1 is not -O-pyrimidinyl.

8. The method of any one of claims 1, 2, and 7, wherein the dual RAF / MEK inhibitor is a compound selected from the compounds of Table I, or a pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1-8, wherein the dual RAF / MEK inhibitor is orally administered to the subject.

10. The method of any one of claims 1-9, wherein the dual RAF / MEK inhibitor is administered at least once a week.

11. The method of any one of claims 1-10, wherein the dual RAF / MEK inhibitor is administered twice a week.

12. The method of any one of claims 1-11, wherein the dual RAF / MEK inhibitor is administered at a dose of 0.5 mg to about 10 mg per administration.

13. The method of claim 12, wherein the dual RAF / MEK inhibitor is administered at a dose of 3.2 mg per administration.

14. The method of claim 12, wherein the dual RAF / MEK inhibitor is administered at a dose of 4 mg per administration.

15. The method of any one of claims 1-14, wherein the dual RAF / MEK inhibitor is administered in a cycle, which comprises administering the dual RAF / MEK inhibitor for 3 weeks and then not administering the dual RAF / MEK inhibitor for 1 week.

16. The method according to any one of claims 1-15, wherein the KRAS G12D inhibitor is selected from KRAS G12D inhibitor (GenFleet), KRAS G12D degrader (Progenra), KRAS G12D inhibitor (Shenzhen Forward), KRAS G12D inhibitor (Abbisko), KRAS G12D inhibitor (Allist), KRAS G12D inhibitor (Anhorn), KRAS G12D inhibitor (Impact), TSL1502 (Tasly), KT-NIH anti-KRAS G12D mTCR PBL (Gilead), siG12D-LODER (Silenseed), siG12D inhibitor (Silenseed), Anocca-KRAS-G12D inhibitor (Anocca), KRASONCOlogue (Oncogenuity), Curve-KRAS G12D inhibitor (Curve Therapeutics), AST-KRAS G12D inhibitor (Allist Pharmaceuticals), VRTX144 (VRise Therapeutics), KRAS G12D inhibitor (Affini-T Therapeutics Inc), BPI-001 (BeyondSpring Inc), anti-KRAS G12D monoclonal antibody (LA Cell Inc), MRTX-1133 (Mirati Therapeutics Inc), NT-0300D (NeuBase Therapeutics Inc), PP-008 (Primary Peptides Inc), RMC-6236 (Revolution Medicines Inc), RMC-9805 (Revolution Medicines Inc), KRAS-G12D inhibitor (Arvinas Inc), anti-KRAS G12D synthetic peptide (Indi Molecular Inc), BBP-KRAS G12D inhibitor (BridgeBio Pharma Inc), ERAS-4 (Erasca Inc), JAB-22000 (Jacobio Pharmaceuticals Group Co Ltd), KRpep-2d (peptide) (Takeda Pharmaceutical Co Ltd), anti-KRAS G12D monoclonal antibody (Oblique Therapeutics AB), small molecule KRAS G12D inhibitor (Shenzhen ForwardPharmaceutical Co Ltd), Proteovant KRAS G12D inhibitor (Proteovant Therapeutics Inc), BIGPRO (bifunctional ligand-induced proteolysis) proteolysis agent (Anhorn Medicines Co Ltd), STX-XX KRAS G12D inhibitor (Seed Therapeutics Inc) and TPX-KRAS G12D inhibitor (Turning Point Therapeutics Inc), and pharmaceutically acceptable salts thereof.

17. The method of any one of claims 1-16, wherein the KRAS G12D inhibitor is MRTX-1133, or a pharmaceutically acceptable salt thereof.

18. The method of any one of claims 1-17, wherein the KRAS G12D inhibitor is orally administered to the subject.

19. The method of any one of claims 1-17, wherein the KRAS G12D inhibitor is intravenously administered to the subject.

20. The method of any one of claims 1-17, wherein the KRAS G12D inhibitor is subcutaneously administered to the subject.

21. The method of any one of claims 1-20, wherein the KRAS G12D inhibitor is administered once a day.

22. The method according to any one of claims 1-20, wherein the KRAS G12D inhibitor is administered twice a day.

23. The method according to any one of claims 1-22, wherein the KRAS G12D inhibitor is administered at a dose of 1 mg to 2000 mg per administration.

24. The method according to any one of claims 1-23, wherein the KRAS G12D inhibitor is administered at a dose of 10 mg to 1000 mg per administration.

25. The method according to any one of claims 1-24, wherein the KRAS G12D inhibitor is administered at a dose of 100 mg to 1000 mg per administration.

26. The method according to any one of claims 1-25, wherein the cancer is pancreatic cancer, pancreatic ductal adenocarcinoma, gynecological cancer (e.g., cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, endometrial cancer, or vulvar cancer), liver cancer, prostate cancer, mesothelioma, breast cancer, bladder cancer, melanoma, lung cancer, colorectal cancer, thyroid cancer, glioblastoma, or kidney cancer.

27. The method according to any one of claims 1-26, wherein the cancer is lung cancer, colorectal cancer, or pancreatic cancer.

28. The method according to claim 26 or 27, wherein the lung cancer is non-small cell lung cancer.

29. The method according to any one of claims 26-28, wherein the lung cancer is metastatic non-small cell lung cancer.

30. The method according to claim 26 or 27, wherein the cancer is colorectal cancer.

31. The method according to claim 26 or 27, wherein the cancer is pancreatic cancer.

32. The method according to any one of claims 1-31, further comprising administering to the subject an effective amount of a FAK inhibitor.

33. The method according to claim 32, wherein the FAK inhibitor is defactinib, or a pharmaceutically acceptable salt thereof.

34. The method according to claim 32 or 33, wherein the FAK inhibitor is administered at about 100 mg to about 1000 mg.

35. The method according to claim 34, wherein the FAK inhibitor is administered at about 100 mg to about 400 mg per administration.

36. The method according to claim 35, wherein the FAK inhibitor is administered at 200 mg per administration.

37. The method according to claim 35, wherein the FAK inhibitor is administered at 400 mg per administration.

38. The method according to any one of claims 32-37, wherein the FAK inhibitor is administered once a day.

39. The method according to any one of claims 32-37, wherein the FAK inhibitor is administered twice a day.

40. The method according to any one of claims 32-39, wherein the FAK inhibitor is administered in cycles, comprising administering the FAK inhibitor for 3 weeks and then not administering the FAK inhibitor for 1 week.

41. The method according to any one of claims 32-40, wherein the FAK inhibitor is orally administered to the subject.

42. The method according to any one of claims 1-31, further comprising administering to the subject an effective amount of an EGFR inhibitor.

43. The method according to claim 42, wherein the EGFR inhibitor is doxorubicin + erlotinib, voltiximab + zatuximab, ivitinib (such as ivitinib maleate), ABP-1119, ABP-1130, afatinib (such as afatinib dimaleate), AG-101, AL-6802, amitinib (such as amitinib mesylate), AM-105, amelimumab, amivantamab, AMX-3009, APL-1898, ASK-120067, AST-2818, BBT-176, BDTX-189, BEBT-108, BEBT-109, BH-2922, BLU-4810, BMX-002, BO-1978, BPI-15086, BPI-7711, brigatinib, C-005, cetuximab, CK-101, CLM-29, CLM-3, CMAB-017, CR-13626, CSHEGF-29, D-0316, D2C7-IT + PVSRIPO, dabrafenib mesylate + panitumumab + trametinib dimethyl sulfoxide, dacomitinib, DBPR-112, ditumumab, DGD-1202, dositinib (such as dositinib mesylate), DZD-9008, EO-1001, epitinib, erlotinib (such as erlotinib hydrochloride), ES-072, FCN-411, FHND-9041, FLAG-001, FLAG-003, FmAb-2, GB-263, GC-1118A, gefitinib, GS-03 + osimertinib, HA-12128, HMPL-309, HMPL-813, HS-627, icotinib (such as icotinib hydrochloride), JMT-101, JRF-103, JZB-29, KBP-5209, KNP-501, KU-004, lapatinib (such as lapatinib ditosylate), lorlatinib, lazertinib, lifirafenib (such as lifirafenib maleate), MCLA-129, MCLA-158, MDC-22, mobocertinib, mRX-7, MTX-211, MVC-101, naquotinib (such as naquotinib mesylate), nazartinib (such as nazartinib mesylate), necitumumab, neratinib, nimotuzumab, NRC-2694, NT-004, NT-113, OBX-1012, omotinib (such as omotinib hydrochloride), osimertinib (such as osimertinib mesylate), panitumumab, PB-357, poziotinib, pyrrotinib, QL-1105, QL-1203, RXDX-105, SAH-EJ1, sapitinib, SCT-200, selatinib (such as selatinib ditosylate), ceritinib,SKLB-1028, SKLB-1206, SPH-118811, SYN-004, TAS-6417, tevatide (such as tevatide tosylate), TGRX-360, tometuximab, TQB-3804, UBP-1215, vandetanib, varlitinib, VRN-071918, VRN-6, WBP-297, WJ-13404, WSD-0922, XZP-5809, yinglitinib, YZJ-0318, ZNE-4, zolotinib, ZR-2002, ZSP-0391, ORIC-114, DS-2087b, JS-111, LL-191, BI-4020 or BAY-2476568, or a pharmaceutically acceptable salt thereof.

44. The method according to claim 42 or 43, wherein the EGFR inhibitor is cetuximab or a pharmaceutically acceptable salt thereof.

45. The method according to any one of claims 1-31, further comprising administering to the subject an effective amount of an anti-PD-1 antibody.

46. The method according to claim 45, wherein the anti-PD-1 antibody is selected from batrilizumab, camrelizumab, cemiplimab, dostarlimab, genolimzumab, nivolumab, pembrolizumab, penpulimab, pidilizumab, palorolizumab, reflimzumab, sasanlimab, suruilizumab, sintilimab, spartalizumab, sulituzumab, teprotumumab, toripalimab, tislelizumab, toripalimab, toripalimab, sepantronium bromide, AMP-224, AMP-514, AT-16201, AVI-102, BAT-1308, BH-2950, BSI-050K01, CB-201, CYTO-101, DB-004, EX-105, EX-108, GNR-051, HAB-21, IBI-319, IBI-321, IKT-202, IMU-201, JS-201, LBL-006, LBL-024, LD-01, LQ-005, LQ-008, MD-402, OT-2, PE-0105, PF-07209960, PH-762, REGN-PD-1 / XX, RO7121661, SAUG-1, SCT-I10A, SG-001, SG001, SI-B003, SL-279137, SSI-361, STI-A1110, STM-418, Sym-021, TSR-075, TY101, Twist-PD-1, XmAb-TGFβR2, XmAb-YYCD28, XmAb20717, XmAb23104, YBL-006, YBL-019 and mDX-40.

47. The method according to any one of claims 1-31, further comprising administering to the subject an effective amount of an anti-PD-L1 antibody.

48. The method according to claim 47, wherein the anti-PD-L1 antibody is selected from atezolizumab, avelumab, durvalumab, enfortumab vedotin, sokazolimab, sugemalimab, ABM-101, AP-505, APL-801, ATG-101, AVA-027, AUNP12, B-1961, BH-3120, BMS-986189, BPI-9220, BPI-9320, CA-170, CCX-559, CK-301, CS-17938, CTX-8371, CYTCDR-2, DB-003, DPDL-1E, DR-30207, DSP-105, DSP-502, EI-011, EI-014, EMB-08, ENN-101, ENN-102, GB-7003, Gensci-047, HB-0025, HB-0028, HB-0036, HBM-7015, IBI-327, IGM-7354, IKT-201, IMC-2101, IMC-2102, IMGS-002, IMM-2510, INBRX-105, JBI-426, JNB-809, JNB-809, JNB-813, JNB-813, KN-052, KN035, KY-1043, LP-008, LQ-002, LQ-004, LVGN-1673, LY-3434172, LYN-102, MCLA-145, MEDI-7526, PH-790, PM-1003, PRS-344, Q-1802, QL-301, QLS31901, RC98, SHR-1316, SHR-1701, SIM-236, SL-279252, SL-279258, SLSP-03, SNA-02, STT-01, TI-1007, TJ-L1C4, TJ-L1D5, TJ-L1H3, TJ-L1I7, TJL-14B, TS1905, TST-005, TTXsiPDL-1, TXB-4BC3, VXM-10, YBL-007, YBL-008, YBL-009, YBL-013, YBL-016, and YBL-020.

49. The method according to any one of claims 1-31, further comprising administering to the subject an effective amount of one or more chemotherapeutic agents.

50. The method according to claim 49, wherein the one or more chemotherapeutic agents are selected from folfirinox, gemcitabine, and paclitaxel.

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