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 treating abnormal cell growth (e.g., cancer). The present disclosure relates, in part, to combinations (e.g., compounds described herein, e.g., combinations of dual RAF / MEK inhibitors and KRAS G12D inhibitors) that can be used in methods of treating abnormal cell growth (e.g., cancer) in a subject in need thereof, e.g., treating abnormal cell growth (e.g., cancer).

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority and the benefit thereof to 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 Art

[0002] Background Components of the RAS / RAF / MEK / ERK (MAPK) signaling pathway present opportunities to treat abnormal cell growth, such as cancer. Mutations in RAS / RAF / MEK / ERK are frequently found in human cancers. These mutants result in constitutively active MAP kinase cascades, leading to tumor cell proliferation, differentiation, survival, and migration. Selective inhibitors of certain components of the RAS / RAF / MEK / ERK signaling pathway, such as RAS, RAF, MEK, and ERK, are useful in treating abnormal cell growth in mammals, particularly cancer.

[0003] Due to the severity and breadth of diseases and disorders associated with abnormal cell growth (such as cancer), effective treatment means and methods are needed. The compounds, compositions, combinations, and methods described herein are directed to this purpose.

Summary of the Invention

Means for Solving the Problems

[0004] Summary The present disclosure provides, in part, combinations (such as combinations of compounds described herein, such as dual RAF / MEK inhibitors and KRAS G12D inhibitors) that can be used in methods of treating abnormal cell growth (such as cancer) in a subject in need thereof, for example, treating abnormal cell growth (such as cancer). In some embodiments, the cancer has been identified as having a KRAS G12D mutation.

[0005] In one aspect, provided herein is 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.

[0006] In some embodiments, the dual RAF / MEK inhibitor is of formula (I):

Chemical formula

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

Chemical formula

[0008] In some embodiments, the dual RAF / MEK inhibitor is IMM-1-104 or a pharmaceutically acceptable salt thereof.

[0009] Other objects and advantages will become apparent to those skilled in the art from the following detailed description, examples, and claims.

Brief Description of the Drawings

[0010]

Figure 1

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Figure 2

[0012]

Figure 3

[0013] Detailed Description As generally described herein, the present disclosure provides, in part, methods useful for treating abnormal cell growth (e.g., cancer) in a subject in need thereof, the methods comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor and an effective amount of a KRAS G12D inhibitor. Definitions Chemical Definitions

[0014] 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 on the inside front cover of the CAS version, Handbook of Chemistry and Physics, 75 th Ed., and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as the moieties and reactivity of specific functional groups, 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 are described therein.

[0015] The compounds described herein can contain one or more chiral centers and thus can exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of a mixture of stereoisomers including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers can be isolated from the mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), as well as 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 further encompasses the compounds described herein as individual isomers substantially free of other isomers and, alternatively, as mixtures of various isomers.

[0016] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and thus is the enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.2%, greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 99.9% enantiomer. In some embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0017] 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% additive and about 10% enantiomerically pure R-compound. In some embodiments, the enantiomerically pure R-compound in such a composition can contain, for the total weight of the compound, at least about 95% R-compound and at most about 5% S-compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound can contain, for example, about 90% additive and about 10% enantiomerically pure S-compound. In some embodiments, the enantiomerically pure S-compound in such a composition can contain, for the total weight of the compound, at least about 95% S-compound and at most about 5% R-compound. In some embodiments, the active ingredient can be formulated with minor additives or carriers or without additives or carriers.

[0018] The compounds described herein may also contain one or more isotope substitutions. For example, H is 1 H,2 H (D or deuterium), and 3 H (T or tritium) in any isotopic form that may be present; C can be 12 C, 13 C, and 14 C in any isotopic form that may be present; O can be 16 O and 18 O in any isotopic form that may be present; F can be 18 F and 19 F in any isotopic form that may be present, and so on.

[0019] The following terms are intended to have the meanings presented with them below and are useful for understanding the description and intended scope of the present invention. When describing the present invention, which may include compounds and their pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present and unless otherwise indicated, have the following meanings. It should also be understood that as described herein, any of the moieties defined below may be substituted with a variety of substituents and that the individual definitions are intended to include such substituted moieties within their indicated ranges below.

[0020] The term "halogen atom", as used herein, means any one of the radioactively stable atoms in column 7 of the periodic table of the elements, for example, any one of fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

[0021] The term "ester", as used herein, refers to a chemical moiety having the formula -(R) n -COOR' (wherein R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloaliphatic (bonded through a ring carbon), and n is 0 or 1).

[0022] The term "amide", as used herein, has the formula -(R) n -C(O)NHR' or -(R)n -NHC(O)R' (wherein R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon), and n is 0 or 1). The amide can be an amino acid or peptide molecule bonded to the molecule of the present invention, thereby forming a prodrug.

[0023] Any amine, hydroxyl, or carboxyl side chain on the compounds disclosed herein can be esterified or amidated. The techniques and specific groups used to achieve this are known to those skilled in the art and are incorporated herein by reference in their entirety, such as in Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999 and other reference sources can be readily found.

[0024] The term "aromatic" as used herein refers to an aromatic group having at least one ring with a conjugated pi electron system, including both carbocyclic aryl groups (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine). The term includes monocyclic groups or fused ring 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, where all the atoms forming the ring backbone are carbon atoms. Thus, this term distinguishes carbocyclic rings from heterocyclic rings that contain at least one atom different from carbon in the ring backbone. The term "heteroaromatic" refers to an aromatic group containing at least one heterocyclic ring.

[0025] As used herein, "Ca~Cb" (where "a" and "b" are integers) refers to the number of carbon atoms in an alkyl group, alkenyl group, or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl group, aryl group, heteroaryl group, or heterocyclyl group. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can inclusively contain "a" to "b" carbon atoms. Thus, for example, a "C1~C4 alkyl" group or a "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. Similarly, for example, a cycloalkyl group can contain "a" to "b" (including both ends) total atoms in the ring(s), e.g., a C3~C8 cycloalkyl group can contain 3 to 8 carbon atoms. When "a" and "b" are not specified with respect to alkyl, cycloalkyl, or cycloalkenyl, the maximum ranges described in these definitions are assumed. Similarly, a "4~7-membered heterocyclyl" group refers to all heterocyclyl 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 preceding 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 includes hydrocarbon rings containing 3, 4, 5, 6, 7, and 8 carbon atoms, or the ranges defined by any two of the numbers, e.g., C3~C7 cycloalkyl or C5~C6 cycloalkyl, respectively.As another example, a 3- to 10-membered heterocycle includes 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, or a range defined by any two of the preceding numbers, e.g., a 4- to 6-membered or 5- to 7-membered heterocycle.

[0026] As used herein, "alkyl" refers to a fully saturated (no double or triple bonds) hydrocarbon group of a straight-chain or branched hydrocarbon chain. An alkyl group can have from 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, e.g., "from 1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms, but this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified). An alkyl group can also be a medium-sized alkyl having from 1 to 10 carbon atoms. An alkyl group can also be a lower alkyl having from 1 to 5 carbon atoms. The alkyl group of a compound can be designated as "C1-C4 alkyl" or a similar name. Merely by way of example, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Exemplary alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.

[0027] The alkyl group can be substituted or unsubstituted. When substituted, the substituent(s), individually and independently, are alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, 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 disubstituted amino groups, and one or more groups selected from their protected derivatives. Whenever a substituent is described as being "optionally substituted", that substituent may be substituted with one of the above substituents.

[0028] 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, the substituent(s) can be selected from the same groups as those disclosed above for substitution of alkyl groups. The alkenyl group can have 2 to 20 carbon atoms, but this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. 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 name. By way of example only, "C2-C4 alkenyl" indicates the presence of 2 to 4 carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2-dienyl, and buta-1,2-dien-4-yl. Exemplary alkenyl groups include, but are by no means limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0029] 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 can be unsubstituted or substituted. When substituted, the substituent(s) can be selected from the same groups as those disclosed above with respect to substitution of the alkyl group. The alkynyl group can have 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" for which no numerical range is specified. The alkynyl group can also be a medium-sized alkynyl having 2 to 9 carbon atoms. The alkynyl group can also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group of a compound can be designated as "C2-C4 alkynyl" or a similar name. By way of example only, "C2-C4 alkynyl" indicates that there are 2 to 4 carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propin-1-yl, propin-2-yl, butin-1-yl, butin-3-yl, butin-4-yl, and 2-butynyl. Exemplary alkynyl groups include, but are by no means limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0030] 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 can have 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term "heteroalkyl" for which no numerical range is specified. The heteroalkyl group can also be a medium-sized heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group can also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group of a compound can be designated as "C1-C4 heteroalkyl" or a similar name. The heteroalkyl group can contain one or more heteroatoms. By way of example only, "C1-C4 heteroalkyl" indicates that there are 1 to 4 carbon atoms in the heteroalkyl chain and further that there is one or more heteroatoms in the backbone of the chain.

[0031] As used herein, "aryl" refers to a carbocyclic (all-carbon) ring, or two or more fused rings (rings sharing two adjacent carbon atoms), having a fully delocalized pi electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. An aryl group may be substituted or unsubstituted. When substituted, the hydrogen atoms may independently be replaced by one or more substituents (plural possible) selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, 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 disubstituted amino groups, and their protected derivatives. When substituted, the substituents on the aryl group may form a non-aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0032] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized pi electron system), one or more heteroatoms, i.e., one or two or more fused rings containing elements other than carbon including, but not limited to, nitrogen, oxygen, and sulfur. 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, the hydrogen atoms are independently replaced by one or more substituents (s) selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, 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 disubstituted amino groups, and their protected derivatives. When substituted, the substituents on the heteroaryl(heteroayl) group may form a non-aromatic ring fused to an aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclic.

[0033] As used herein, "aralkyl" or "arylalkyl" refers to an aryl group connected via an alkylene group as a substituent. The alkylene group and aryl group 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.

[0034] As used herein, "heteroaralkyl" or "heteroarylalkyl" refers to a heteroaryl group connected via an alkylene group as a substituent. The alkylene group and heteroaryl group of the heteroaralkyl can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and not only their substituted ones, but also benzo-fused analogs. In some cases, the alkylene group is a lower alkylene group.

[0035] As used herein, "alkylene" refers to a branched or straight-chain, fully saturated diradical chemical group (i.e., alkanediyl) containing only carbon and hydrogen atoms that are bonded to the remainder of the molecule through two attachment points. An alkylene group may have from 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkylene" where a numerical range is not specified. The alkylene group may also be a medium-sized alkylene having from 1 to 9 carbon atoms. The alkylene group may also be a lower alkylene having from 1 to 4 carbon atoms. The alkylene group may be designated as "C1-C4 alkylene" or a similar name. Merely by way of example, "C1-C4 alkylene" indicates that there are from 1 to 4 carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of 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.

[0036] As used herein, "alkenylene" refers to a straight-chain or branched-chain diradical chemical group that contains only carbon and hydrogen bonded to the remainder of the molecule through two attachment points and contains at least one carbon-carbon double bond. The alkenylene group can have from 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term alkenylene where no numerical range is specified. The alkenylene group can also be a medium-sized alkenylene having from 2 to 9 carbon atoms. The alkenylene group can also be a lower alkenylene having from 2 to 4 carbon atoms. The alkenylene group can be designated as "C2-C4 alkenylene" or a similar name. Merely by way of example, "C2 alkenylene" indicates that there are 2 to 4 carbon atoms present in the alkenylene chain, i.e., the alkenylene chain can be selected from the group consisting of ethenylene, ethene-1,1-diyl, propenylene, propene-1,1-diyl, propa-2-ene-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, butene-1,1-diyl, buta-1,3-diene-1,1-diyl, but-2-ene-1,1-diyl, but-3-ene-1,1-diyl, 1-methyl-propa-2-ene-1,1-diyl, 2-methyl-propa-2-ene-1,1-diyl, 1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propene-1,1-diyl, and 2,2-dimethyl-ethene-1,1-diyl.

[0037] As used herein, "alkylidene" refers to a divalent group such as =CR’R” that is bonded to one carbon of another group and forms a double bond, and the alkylidene group includes, but is not limited to, methylidene (=CH2) and ethylidene (=CHCH3). As used herein, "arylalkylidene" refers to an alkylidene group where either R’ or R’’ is an aryl group. The alkylidene group can be substituted or unsubstituted.

[0038] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl as defined above, for example, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy, etc. Alkoxy can be substituted or unsubstituted.

[0039] As used herein, "alkylthio" refers to the formula -SR, where R is alkyl as defined above, for example, methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, isobutylmercapto, sec-butylmercapto, tert-butylmercapto, etc. Alkylthio can be substituted or unsubstituted.

[0040] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, respectively, where R is aryl such as, but not limited to, phenyl. Both aryloxy and arylthio can be substituted or unsubstituted.

[0041] 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, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acrylyl.

[0042] As used herein, "cycloalkyl" refers to a fully saturated (no double bonds) monocyclic or polycyclic cyclic hydrocarbon ring system. When composed of two or more rings, the rings can be joined together in a fused, bridged, or spiro-connected fashion. The cycloalkyl group can range from C3 to C10 and, in other embodiments, 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, etc. When substituted, the substituent(s) can be alkyl or can be selected from those indicated above with respect to substitution of alkyl groups, unless otherwise indicated. When substituted, the substituent on the cycloalkyl group can form an aromatic ring fused to the cycloalkyl group, including aryl and heteroaryl.

[0043] As used herein, "cycloalkenyl" refers to a cycloalkyl group containing one or more double bonds in the ring, provided that when more than one is present, a fully delocalized pi electron system cannot be formed in the ring (otherwise, the group would be "aryl" as defined herein). When composed of two or more rings, the rings can be connected together in a fused, bridged, or spiro-connected fashion. The cycloalkenyl group can be unsubstituted or substituted. When substituted, the substituent(s) can be alkyl or can be selected from the groups disclosed above with respect to substitution of alkyl groups, unless otherwise indicated. When substituted, the substituent on the cycloalkenyl group can form an aromatic ring fused to the cycloalkenyl group, including aryl and heteroaryl.

[0044] As used herein, "cycloalkynyl" refers to a cycloalkyl group containing one or more triple bonds in the ring. When composed of two or more rings, the rings can be joined together in a fused, bridged or spiro-connected fashion. The cycloalkynyl group can be unsubstituted or substituted. When substituted, the substituent(s) can be alkyl or, unless otherwise indicated, can be selected from the groups disclosed above with respect to substitution of alkyl groups. When substituted, the substituents on the cycloalkynyl group can form an aromatic ring fused to the cycloalkynyl group, including aryl and heteroaryl.

[0045] As used herein, "heteroalicyclic" or "heteroaricyclic" refers to a stable 3- to 18-membered ring consisting of carbon atoms and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. "Heteroalicyclic" or "heteroaricyclic" can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can be joined together in a fused, bridged, or spiro-connected manner. The nitrogen, carbon, and sulfur atoms in "heteroalicyclic" or "heteroaricyclic" can be oxidized as necessary, the nitrogen can be quaternized as necessary, and the ring can also contain one or more double bonds provided that they do not form a completely delocalized pi-electron system throughout the entire ring. The heteroaricyclic group can be unsubstituted or substituted. When substituted, the substituent(s) can independently be selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroaricyclic, aralkyl, heteroaralkyl, (heteroaricyclic)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and amino including mono- and disubstituted amino groups, and their protected derivatives, and can be one or more groups selected from the group. Examples of such "heteroalicyclic" or "heteroaricyclic" include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxolanyl, piperidinyl A-oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, and thiomorpholinyl sulfone.When substituted, the substituent on the heteroaricyclic group may form an aromatic ring fused to the heteroaricyclic group, including aryl and heteroaryl.

[0046] As used herein, the term “(cycloalkenyl)alkyl” refers to a cycloalkenyl group connected via an alkylene group as a substituent. The alkylene and cycloalkenyl of (cycloalkenyl)alkyl may be substituted or unsubstituted. In some cases, the alkylene group is a lower alkylene group.

[0047] As used herein, the term “(cycloalkynyl)alkyl” refers to a cycloalkynyl group connected via an alkylene group as a substituent. The alkylene and cycloalkynyl of (cycloalkynyl)alkyl may be substituted or unsubstituted. In some cases, the alkylene group is a lower alkylene group.

[0048] 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, heteroaricyclic, aralkyl, or (heteroaricyclic)alkyl as defined herein. O-carboxy may be substituted or unsubstituted.

[0049] 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. C-carboxy may be substituted or unsubstituted.

[0050] As used herein, the term “trihalomethanesulfonyl” refers to an “X3CSO2-” group (wherein X is halogen).

[0051] As used herein, the term “cyano” refers to a “-CN” group.

[0052] As used herein, the term "cyanato" refers to the "-OCN" group.

[0053] As used herein, the term "isocyanato" refers to the "-NCO" group.

[0054] As used herein, the term "thiocyanato" refers to the "-SCN" group.

[0055] As used herein, the term "isothiocyanato" refers to the "-NCS" group.

[0056] As used herein, the term "sulfinyl" refers to the "-S(=O)-R" group, where R can be the same as that defined for O-carboxy. Sulfinyl can be substituted or unsubstituted.

[0057] As used herein, the term "sulfonyl" refers to the "-SO2R" group, where R can be the same as that defined for O-carboxy. Sulfonyl can be substituted or unsubstituted.

[0058] As used herein, the term "S-sulfonamide" refers to the "-SO2NRARB" group, where RA and RB can be the same as that defined for O-carboxy. S-sulfonamide can be substituted or unsubstituted.

[0059] As used herein, the term "N-sulfonamide" refers to the "-SO2N(RA)(RB)" group, where RA and RB can be the same as that defined for O-carboxy. Sulfonyl can be substituted or unsubstituted.

[0060] As used herein, the term "trihalomethanesulfonamide" refers to the group "X3CSO2N(R)-", where X as halogen and R can be the same as those defined with respect to O-carboxy. Trihalomethanesulfonamide can be substituted or unsubstituted.

[0061] As used herein, the term "O-carbamyl" refers to the group "-OC(=O)NRARB", where RA and RB can be the same as those defined with respect to O-carboxy. O-carbamyl can be substituted or unsubstituted.

[0062] As used herein, the term "N-carbamyl" refers to the group "ROC(=O)NRA", where R and RA can be the same as those defined with respect to O-carboxy. N-carbamyl can be substituted or unsubstituted.

[0063] As used herein, the term "O-thiocarbamyl" refers to the group "-OC(=S)-NRARB", where RA and RB can be the same as those defined with respect to O-carboxy. O-thiocarbamyl can be substituted or unsubstituted.

[0064] As used herein, the term "N-thiocarbamyl" refers to the group "ROC(=S)NRA-", where R and RA can be the same as those defined with respect to O-carboxy. N-thiocarbamyl can be substituted or unsubstituted.

[0065] As used herein, the term "C-amide" refers to the group "-C(=O)NRARB", where RA and RB can be the same as those defined with respect to O-carboxy. C-amide can be substituted or unsubstituted.

[0066] As used herein, the term "N-amide" refers to an "RC(=O)NRA-" group, where R and RA can be the same as those defined with respect to O-carboxy. The N-amide can be substituted or unsubstituted.

[0067] As used herein, the term "amino" refers to a "-NRARB" group, where RA and RB are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 carbocyclic, C6-C10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclic as defined herein.

[0068] As used herein, the term "aminoalkyl" refers to an amino group connected via an alkylene group.

[0069] As used herein, the term "ester" refers to a "-C(=O)OR" group, where R can be the same as that defined with respect to O-carboxy. The ester can be substituted or unsubstituted.

[0070] As used herein, the term "lower aminoalkyl" refers to an amino group connected via a lower alkylene group. The lower aminoalkyl can be substituted or unsubstituted.

[0071] As used herein, the term "lower alkoxyalkyl" refers to an alkoxy group connected via a lower alkylene group. The lower alkoxyalkyl can be substituted or unsubstituted.

[0072] As used herein, the term "acetyl" refers to a -C(=O)CH3 group.

[0073] As used herein, the term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0074] As used herein, the term "carbocyclic" refers to a non-aromatic cyclic ring or ring system that contains only carbon atoms in the backbone of the ring system. When the carbocyclic is a ring system, two or more rings can be joined together in a fused, bridged, or spiro-connected manner. The carbocyclic can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, carbocyclics include cycloalkyl, cycloalkenyl, and cycloalkynyl. A carbocyclic group can have 3 to 20 carbon atoms, although this definition also encompasses occurrences of the term "carbocyclic" where no numerical range is specified. A carbocyclic group can also be a medium-sized carbocyclic having 3 to 10 carbon atoms. A carbocyclic group can also be a carbocyclic having 3 to 6 carbon atoms. A carbocyclic group can be designated as "C3-C6 carbocyclic" or a similar name. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydroindene, bicyclo[2.2.2]octanyl, adam antyl, and spiro[4.4]nonanyl.

[0075] As used herein, the term "(cycloalkyl)alkyl" refers to a cycloalkyl group connected via an alkylene group as a substituent. The alkylene and cycloalkyl of (cycloalkyl)alkyl can 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.

[0076] As used herein, the term "cycloalkyl" refers to a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0077] As used herein, the term "cycloalkenyl" means a carbocyclic ring or ring system having at least one double bond, where the rings in the ring system are not aromatic. An example is cyclohexenyl.

[0078] As used herein, the term "heterocyclyl" refers to 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered or higher-membered rings in which carbon atoms together with 1 to 3 heteroatoms form said ring. Heterocyclyl may optionally contain one or more unsaturated bonds in a manner suitable therefor, but without generating an aromatic pi-electron system. The heteroatoms are independently selected from oxygen, sulfur, and nitrogen. Heterocyclyl may further contain one or more carbonyl or thiocarbonyl functional groups such that the definition includes oxo- and thio-based systems, such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, etc. "Heterocyclyl" may refer to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring skeleton. Heterocyclyls may be joined together in a fused, bridged or spiro-connected manner. Heterocyclyl may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatoms may be present in either non-aromatic or aromatic rings in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring skeleton, including carbon atoms and heteroatoms), but this definition also encompasses occurrences of the term "heterocyclyl" for which no numerical range is specified. The heterocyclyl group may also be a medium-sized heterocyclyl having 3 to 10 ring members. The heterocyclyl group may also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as "3- to 6-membered heterocyclyl" or a similar name. In a preferred 6-membered monocyclic heterocyclyl, the heteroatom(s) are selected from 1 to 3 O, N, or S, and in a preferred 5-membered monocyclic heterocyclyl, the heteroatom(s) are selected from 1 or 2 heteroatoms selected from O, N, or S.Examples of heterocyclic rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0079] As used herein, the term "(heterocyclyl)alkyl" refers to a heterocyclic group connected via an alkylene group as a substituent. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0080] The replaced group is based on, or derived from, an unsubstituted parent group in which one or more hydrogen atoms are replaced by another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", the group is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclic (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl,It is substituted with one or more substituents independently selected from O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo(=O). Whenever a group is described as being "optionally substituted", the group can be substituted with the above substituents.

[0081] In some embodiments, the substituted group is substituted with one or more substituents individually and independently selected from C1-C4 alkyl, amino, hydroxy, and halogen.

[0082] It should be understood that certain radical naming rules can include either a monoradical or a diradical depending on the context. For example, when a substituent requires two points of attachment to the remainder of the molecule, it is understood that the substituent is a diradical. For example, a substituent identified as an alkyl that requires two points of attachment includes diradicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical naming rules explicitly indicate that the radical is a diradical such as "alkylene" or "alkenylene".

[0083] Unless otherwise indicated, when a substituent is considered to be "optionally substituted", the substituent is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino including mono- and di-substituted amino groups, and means a group that can be substituted with one or more groups individually and independently selected from the protected derivatives thereof. Protecting groups that can form the 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.

[0084] Other definitions "About" and "approximately" are generally meant to refer to the degree of error tolerated for a measured quantity, taking into account the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10%, more typically within 5%.

[0085] As used herein, "pharmaceutically acceptable salts" refer to salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1~4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. 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, where appropriate.

[0086] 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 being formulated. 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, buffers such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures 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-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0087] As used herein, "subject" to which administration is contemplated 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 including, but not limited to, primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, 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.

[0088] The terms disease, disorder, and condition are used interchangeably herein.

[0089] As used herein, unless otherwise specified, the terms "treat", "treating" and "treatment" are intended to mean an act that is performed while a patient is suffering from a particular disease, disorder or condition and that reduces the severity of the disease, disorder or condition, or delays or slows the progression of the disease, disorder or condition (also referred to as "therapeutic treatment").

[0090] Generally, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be recognized by those of skill in the art, the effective amount of the compounds of the present invention can vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, weight, health, and condition of the subject. As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount 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 means the amount of a therapeutic agent that provides a therapeutic benefit in the treatment of a disease, disorder or condition, either alone or in combination with other treatments. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent. As used herein, 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 means the amount of a therapeutic agent that provides a prophylactic benefit in the prevention of a disease, disorder or condition, either alone or in combination with other agents. The term "prophylactically effective amount" can include an amount that improves the overall prophylaxis, or enhances the prophylactic effectiveness of another prophylactic agent.

[0091] As used herein, "prophylactic treatment" contemplates an action that is taken before a subject begins to suffer from a particular disease, disorder or condition.

[0092] The term "oral dosage form," as used herein, refers to a composition or vehicle used to administer a drug to a subject. Typically, an oral dosage form is administered via the mouth, but the term "oral dosage form" is intended to encompass any substance that is administered to a subject and absorbed across the membranes of the gastrointestinal tract, including, for example, the mouth, esophagus, stomach, small intestine, large intestine, and colon, such as the mucosa. For example, the term "oral dosage form" encompasses solutions administered via a feeding tube to the stomach.

[0093] As used herein in the context of a cycle of drug administration, the term "cycle" refers to a period that may further include a period during which the drug is administered and a period of rest during which the drug is not administered to the subject. In some embodiments, one cycle is four weeks.

[0094] A "KRAS mutation" is a mutation in the KRAS gene (i.e., a nucleic acid mutation) or a mutation in the Kras protein (i.e., an amino acid mutation) that results in abnormal Kras protein function associated with increased and / or constitutive activity by favorably acting on the active GTP-bound state of the Kras protein. The mutation can be at a conserved site that favorably acts on the GTP-bound and constitutively active Kras protein. In some examples, the mutation is at codon 12 of the KRAS gene. For example, a KRAS mutation can be at codon 12 of the KRAS gene as, for example, a single point substitution mutation at codon 12 (i.e., the KRAS G12D mutation).

[0095] Method of treatment In one aspect, provided herein is 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.

[0096] In some embodiments, the cancer has been identified as having a KRAS G12D mutation.

[0097] In some embodiments, the dual RAF / MEK inhibitor has the formula (I):

Chemical formula

[0098] In some embodiments, the dual RAF / MEK inhibitor is of formula (I):

Chemical formula

[0099] In some embodiments, the dual RAF / MEK inhibitor is a potassium salt of a compound of formula (I).

[0100] In some embodiments, the dual RAF / MEK inhibitor is IMM-1-104 or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the dual RAF / MEK inhibitor is a compound of formula (II) including its pharmaceutically acceptable salt:

Chemical formula

[0102] In some embodiments, the dual RAF / MEK inhibitor is a compound selected from the compounds of Table I or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the KRAS G12D inhibitor is 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), KRAS ONCOlogue (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 (ShenzhenSelected from the group consisting of Forward Pharmaceutical Co Ltd), Proteovant KRAS G12D inhibitor (Proteovant Therapeutics Inc), BIGPRO (bifunctional ligand-induced proteolysis) protease (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.

[0104] In some embodiments, the KRAS G12D inhibitor is administered orally to the subject. In some embodiments, the KRAS G12D inhibitor is administered parenterally to the subject. In some embodiments, the KRAS G12D inhibitor is administered intravenously to the subject. In some embodiments, the KRAS G12D inhibitor is administered subcutaneously to the subject. In some embodiments, the KRAS G12D inhibitor is administered once daily. In some embodiments, the KRAS G12D inhibitor is administered twice daily. 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.

[0105] In some embodiments, the dual RAF / MEK inhibitor and the KRAS G12D inhibitor are administered periodically and independently.

[0106] In some embodiments, the dual RAF / MEK inhibitor and the KRAS G12D inhibitor are administered periodically and simultaneously.

[0107] In some embodiments, the methods described herein further comprise administering to a 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 as a cycle that includes administering the FAK inhibitor (e.g., defactinib or a pharmaceutically acceptable salt thereof) for 3 weeks and then not administering 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.

[0108] In some embodiments, the dual RAF / MEK inhibitor and the FAK inhibitor (e.g., defactinib or a pharmaceutically acceptable salt thereof) are administered periodically and independently.

[0109] In some embodiments, the dual RAF / MEK inhibitor and the FAK inhibitor (e.g., defactinib or a pharmaceutically acceptable salt thereof) are administered periodically and simultaneously.

[0110] In some embodiments, the KRAS G12D inhibitor and the FAK inhibitor (e.g., defactinib or a pharmaceutically acceptable salt thereof) are administered periodically and independently.

[0111] In some embodiments, a KRAS G12D inhibitor and a FAK inhibitor (e.g., defactinib or a pharmaceutically acceptable salt thereof) are administered periodically and simultaneously.

[0112] In other embodiments, the methods described herein further comprise administering to the subject an effective amount of an EGFR inhibitor.

[0113] In some embodiments, the EGFR inhibitor is doxorubicin + erlotinib, futuximab + motuximab, avibertinib (e.g., avibertinib maleate), ABP-1119, ABP-1130, afatinib (e.g., afatinib dimaleate), 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, depatuxizumab, DGD-1202, doxitinib (e.g., doxitinib mesylate), DZD-9008, EO-1001, epertinib, 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), larotinib, 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, olmutinib (e.g., olmutinib hydrochloride), osimertinib (e.g., osimertinib mesylate), panitumumab, PB-357, poziotinib, pyrotinib, QL-1105, QL-1203, RXDX-105, SAH-EJ1, sapitinib, SCT-200, selatinib (e.g., selatinib ditosylate), sirotinib, SKLB-1028, SKLB-1206, SPH-118811, SYN-004, TAS-6417, tesevatinib (e.g., tesevatinib tosylate), TGRX-360, tomuzotuximab, 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 pharmaceutically acceptable salt thereof.

[0114] 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.

[0115] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of balstilimab, camrelizumab, semiprilimab, dostarlimab, geptanolimab, nivolumab, pembrolizumab, pemprimumab, pidilizumab, prolego limab, retifanlimab, sasanlimab, serplulimab, sintilimab, spartalizumab, sulituzumab, tebotelimab, teripalimab, tislelizumab, tripalimab, tripalimab, zinberelimab, 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.

[0116] In some embodiments, the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, avelumab, durvalumab, enobafolimab, 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.

[0117] In some embodiments, 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. 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.

[0118] Dual RAF / MEK inhibitor Exemplary dual RAF / MEK inhibitors described herein are VS-6766 (also referred to as CKI27, CH5126766, or RO5126766).

[0119] In some embodiments, the dual RAF / MEK inhibitor is a compound of formula (I):

Chemical formula

[0120] In some embodiments, the compound of formula (I) is

Chemical formula

[0121] 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 referred to as VS-6766. Other pharmaceutically acceptable salts of the compound of formula (I) are contemplated herein.

[0122] In some embodiments, the dual RAF / MEK inhibitor has the structure of formula (II) including its pharmaceutically acceptable salt:

Chemical formula

Chemical formula

Chemical formula

[0123] In some embodiments, the dual RAF / MEK inhibitor is a compound selected from the compounds in Table I and pharmaceutically acceptable salts thereof.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

[0124] In some embodiments, the dual RAF / MEK inhibitor is IMM-1-104 (Immuneering) or a pharmaceutically acceptable salt thereof.

[0125] 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.

[0126] 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.

[0127] In some embodiments, the dual RAF / MEK inhibitor is administered in cycles. In some embodiments, a cycle includes administering the dual RAF / MEK inhibitor for 3 weeks, followed by not administering the dual RAF / MEK inhibitor for 1 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. 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 4 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at about 3.2 mg per administration.

[0128] In some embodiments, the dual RAF / MEK inhibitor is administered twice a week as a cycle, and the cycle involves administering the dual RAF / MEK inhibitor at a dose of about 0.8 mg to about 10 mg per administration for 3 weeks, and then not administering the dual RAF / MEK inhibitor for 1 week. In some embodiments, the dual RAF / MEK inhibitor is administered twice a week as a cycle, and the cycle involves administering the dual RAF / MEK inhibitor at a dose of about 1 mg to about 5 mg per administration for 3 weeks, and then not administering the dual RAF / MEK inhibitor for 1 week. In some embodiments, the dual RAF / MEK inhibitor is administered twice a week as a cycle, and the cycle involves administering the dual RAF / MEK inhibitor at a dose of about 2 mg to about 4 mg per administration for 3 weeks, and then not administering the dual RAF / MEK inhibitor for 1 week. In some embodiments, the dual RAF / MEK inhibitor is administered twice a week as a cycle, and the cycle involves administering the dual RAF / MEK inhibitor at a dose of 3.2 mg per administration for 3 weeks, and then not administering the dual RAF / MEK inhibitor for 1 week. In some embodiments, the dual RAF / MEK inhibitor is administered twice a week as a cycle, and the cycle involves administering the dual RAF / MEK inhibitor at a dose of 4 mg per administration for 3 weeks, and then not administering the dual RAF / MEK inhibitor for 1 week. In some embodiments, the cycle is repeated at least once.

[0129] In some embodiments, the dual RAF / MEK inhibitor is administered three times a week as a cycle, where the cycle involves administering the dual RAF / MEK inhibitor at a dose of about 0.8 mg to about 10 mg per administration for 3 weeks, and then not administering the dual RAF / MEK inhibitor for 1 week. In some embodiments, the dual RAF / MEK inhibitor is administered three times a week as a cycle, where the cycle involves administering the dual RAF / MEK inhibitor at a dose of about 1 mg to about 5 mg per administration for 3 weeks, and then not administering the dual RAF / MEK inhibitor for 1 week. In some embodiments, the dual RAF / MEK inhibitor is administered three times a week as a cycle, where the cycle involves administering the dual RAF / MEK inhibitor at a dose of about 2 mg to about 4 mg per administration for 3 weeks, and then not administering the dual RAF / MEK inhibitor for 1 week. In some embodiments, the dual RAF / MEK inhibitor is administered three times a week as a cycle, where the cycle involves administering the dual RAF / MEK inhibitor at a dose of 3.2 mg per administration for 3 weeks, and then not administering the dual RAF / MEK inhibitor for 1 week. In some embodiments, the dual RAF / MEK inhibitor is administered three times a week as a cycle, where the cycle involves administering the dual RAF / MEK inhibitor at a dose of 4 mg per administration for 3 weeks, and then not administering the dual RAF / MEK inhibitor for 1 week. In some embodiments, the cycle is repeated at least once.

[0130] In alternative embodiments, the dual RAF / MEK inhibitor is administered continuously (i.e., without a period during which the dual RAF / MEK inhibitor is not administered, e.g., for 1 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.

[0131] KRAS G12D inhibitor In some embodiments, the KRAS G12D inhibitor is a compound in Table II: [Table 2] and is selected from the group consisting of said compound and its pharmaceutically acceptable salts.

[0132] In some embodiments, the KRAS G12D inhibitor is a KRAS G12D inhibitor (GenFleet), a KRAS G12D degrader (Progenra), a KRAS G12D inhibitor (Shenzhen Forward), a KRAS G12D inhibitor (Abbisko), a KRAS G12D inhibitor (Allist), a KRAS G12D inhibitor (Anhorn), a KRAS G12D inhibitor (Impact), TSL1502 (Tasly), KT-NIH anti-KRAS G12D mTCR PBL (Gilead), siG12D-LODER (Silenseed), an siG12D inhibitor (Silenseed), an Anocca-KRAS-G12D inhibitor (Anocca), KRAS ONCOlogue (Oncogenuity), a Curve-KRAS G12D inhibitor (Curve Therapeutics), an AST-KRAS G12D inhibitor (Allist Pharmaceuticals), VRTX144 (VRise Therapeutics), a KRAS G12D inhibitor (Affini-T Therapeutics Inc), BPI-001 (BeyondSpring Inc), an 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), a KRAS-G12D inhibitor (Arvinas Inc), an anti-KRAS G12D synthetic peptide (Indi Molecular Inc), a 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), an anti-KRAS G12D monoclonal antibody (Oblique Therapeutics AB), a small molecule KRAS G12D inhibitor (ShenzhenSelected from the group consisting of Forward Pharmaceutical Co Ltd), Proteovant KRAS G12D inhibitor (Proteovant Therapeutics Inc), BIGPRO (bifunctional ligand-induced proteolysis) protease (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.

[0133] In some embodiments, the KRAS G12D inhibitor has the following structure:

Chemical formula

[0134] In some embodiments, the KRAS G12D inhibitor is administered at about 0.1 mg to about 5000 mg per dose, such as about 1 mg to about 3000 mg, about 10 mg to about 2000 mg, such as 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 dose. In some embodiments, the KRAS G12D inhibitor is administered at about 250 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 300 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 350 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 400 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 450 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 500 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 550 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 600 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 650 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 700 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 750 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 800 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 850 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 900 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 950 mg per dose. In some embodiments, the KRAS G12D inhibitor is administered at about 1000 mg per dose.

[0135] 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 daily. In some embodiments, the KRAS G12D inhibitor is administered once daily. In some embodiments, the KRAS G12D inhibitor is administered twice daily. 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.

[0136] In some embodiments, the dual RAF / MEK inhibitor is administered before the KRAS G12D inhibitor is administered. In some embodiments, the dual RAF / MEK inhibitor is administered after the KRAS G12D inhibitor is administered. In some embodiments, the dual RAF / MEK inhibitor is administered in combination with the KRAS G12D inhibitor.

[0137] FAK inhibitor Potent inhibitors of FAK protein tyrosine kinase are suitable for therapeutic use as anti-proliferative agents (e.g., anti-cancer agents), anti-tumor agents (e.g., effective against solid tumors), and anti-angiogenic agents (e.g., stopping or preventing blood vessel growth) in mammals, particularly humans. In some embodiments, the methods described herein further contemplate administering a FAK inhibitor described herein to a subject. FAK inhibitors are useful in the prevention and treatment of non-hematological malignancies, various human hyperproliferative disorders, such as liver, kidney, bladder, breast, stomach, ovarian, colorectal, prostate, pancreatic, lung, vulvar, thyroid, liver cancer, sarcoma, glioblastoma, head and neck malignant and benign tumors, and other hyperplastic conditions, such as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH), and in the prevention and treatment of disorders such as mesothelioma. In some embodiments, the compounds described herein, e.g., FAK inhibitors, inhibit protein tyrosine kinase 2 (PYK2).

[0138] In some embodiments, the methods described herein further contemplate administering an effective amount of a FAK inhibitor to a subject.

[0139] Exemplary FAK inhibitors include, but are not limited to, the following structures:

Chemical formula

[0140] In some embodiments, the FAK inhibitor has the following structure:

Chemical formula

[0141] In some embodiments, the FAK inhibitor has the following structure:

Chemical Structure

[0142] In some embodiments, the FAK inhibitor has the following structure:

Chemical Structure

[0143] In some embodiments, the FAK inhibitor has the following structure:

Chemical Structure

[0144] In some embodiments, the FAK inhibitor has the following structure:

Chemical Structure

[0145] 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).

[0146] In some embodiments, the FAK inhibitor is selected from the group consisting of 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.

[0147] In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at least once daily. For example, in some embodiments, the FAK inhibitor (e.g., defactinib) is administered once daily. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered twice daily.

[0148] In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at 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 about 200 mg to about 400 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 100 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 200 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 300 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 400 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 500 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 600 mg per administration. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered orally.

[0149] In some embodiments, the FAK inhibitor is administered in cycles, where a cycle includes administering the FAK inhibitor for 3 weeks and then not administering the FAK inhibitor for 1 week. In some embodiments, the cycle is repeated at least once.

[0150] EGFR inhibitor In some embodiments, the methods described herein further contemplate administering an effective amount of an EGFR inhibitor to a subject.

[0151] Exemplary EGFR inhibitors include, but are not limited to, the following structures: [Chemical formula] having ASK-120067 (Jiangsu Aosaikang Pharmaceutical Co Ltd); the following structure: [Chemical formula] having AST-2818 (Allist Shanghai Pharmaceutical Technology Co Ltd); the following structure: [Chemical formula] having BI-4020; the following structure: [Chemical formula] having BDTX-189 (Black Diamond Therapeutics Inc); the following structure: [Chemical formula] having BPI-7711 (Beta Pharma Inc); the following structure: [Chemical formula] having NRC-2694 (Natco Pharma Ltd); the following structure: [Chemical formula] having SKLB-1028 (CSPC Pharmaceutical Group Ltd); the following structure: [Chemical formula] having TAS-6417 (Cullinan Oncology LLC); the following structure: [Chem.] BAY-2476568 (Bayer) having; Doxorubicin + Erlotinib, Futsukiximab + Modotsukiximab, Avibertinib Maleate, ABP-1119 (AB Pharma Ltd), ABP-1130 (AB Pharma Ltd), Afatinib, Afatinib Dimaleate, AG-101 (Arrogene Inc), AL-6802 (Jiangsu Simcere Pharmaceutical Co Ltd), Almonertinib Mesylate, AM-105 (AbClon Inc), Amerimab, 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), Doxitinib Mesylate, DZD-9008 (Dizal (Jiangsu) Pharmaceutical Co Ltd), EO-1001 (Senz Oncology Pty Ltd), Epertinib, Erlotinib (e.g., 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 (Genor BioPharma Co Ltd), GC-1118A (GC Pharma), Gefitinib, GS-03 + Osimertinib (National Taiwan University), 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 CoLtd), lapatinib (e.g., lapatinib ditosylate), larotrectinib, lazertinib, refilrafenib maleate, MCLA-129 (Merus NV), 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), nakotineb mesylate, nazartinib mesylate, necitumumab, neratinib, nimotuzumab, NT-004 (NewGen Therapeutics Inc), NT-113 (NewGen Therapeutics Inc), OBX-1012 (Oncobix Co Ltd), olmutinib 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), seratinib ditosylate, sirotinib, SKLB-1206 (Sichuan University), SPH-118811 (Shanghai Pharmaceutical Group Co Ltd), SYN-004 (Synermore Biologics Co Ltd), tesevatinib tosylate, TGRX-360 (Shenzhen Targetrx Inc), tomozotuximab, TQB-3804 (Chia Tai Tianqing Pharmaceutical Group Co Ltd), UBP-1215 (Chi Cheung(Shanghai) Biomedical CoLtd), vandetanib, baricitinib, VRN-071918 (Voronoi Group), VRN-6 (Voronoi Group), WBP-297 (Hualan Biological Engineering Inc), WJ-13404 (Wigen Biomedicine Technology (Shanghai) Co Ltd), WSD-0922 (Wayshine Biopharma Inc), XZP-5809 (Sihuan Pharmaceutical Holdings Group Ltd), inlitinib, YZJ-0318 (Yangtze River Pharmaceutical Group), ZNE-4 (Zentalis Pharmaceuticals Inc), zolifertinib, 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 hydrates, solvates, and pharmaceutically acceptable salts thereof.

[0152] In some embodiments, the EGFR inhibitor is doxorubicin + erlotinib, futuximab + motuximab, abivertinib maleate, ABP-1119, ABP-1130, afatinib dimaleate, AG-101, AL-6802, almonertinib mesylate, AM-105, amerimumab, 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, depatuxizumab, DGD-1202, docitinib mesylate, DZD-9008, EO-1001, epertinib, 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), larotrectinib, lazertinib, refilrafenib maleate, MCLA-129, MCLA-158, MDC-22, mobocertinib, mRX-7, MTX-211, MVC-101, nacotinib mesylate, nazartinib mesylate, necitumumab, neratinib, nimotuzumab, NRC-2694, NT-004, NT-113, OBX-1012, olmutinib hydrochloride, osimertinib (e.g., osimertinib mesylate), panitumumab, PB-357, pozotinib, pyrotinib, QL-1105, QL-1203, RXDX-105, SAH-EJ1, sapitinib, SCT-200, seratinib ditosylate, sirotinib, SKLB-1028, SKLB-1206,SPH-118811, SYN-004, TAS-6417, tesevatinib tosylate, TGRX-360, tozotuximab, TQB-3804, UBP-1215, vandetanib, baricitinib, VRN-071918, VRN-6, WBP-297, WJ-13404, WSD-0922, XZP-5809, inlitinib, YZJ-0318, ZNE-4, zolifertinib, 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.,

[0153] In some embodiments, the EGFR inhibitor is administered at least once a week. In some embodiments, the EGFR inhibitor is administered at least once daily. In some embodiments, the EGFR inhibitor is administered once daily. In some embodiments, the EGFR inhibitor is administered twice daily. 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.

[0154] 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 dose. In some embodiments, the EGFR inhibitor is administered at about 1000 mg per dose.

[0155] Anti-PD-1 antibody / anti-PD-L1 antibody In some embodiments, the methods described herein further contemplate administering to a subject an effective amount of an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0156] Antibody therapy is an antibody protein produced by the immune system that binds to a target antigen on the surface of cells. Antibodies are typically encoded by one or more immunoglobulin genes, or fragments thereof. In normal physiological function, antibodies are used by the immune system to fight pathogens. Each antibody is specific for one or a few proteins, and those that bind to cancer antigens are used, for example, for the treatment of cancer. Antibodies can specifically bind to an antigen or epitope (Fundamental Immunology, 3 rd Edition, W.e., Paul, ed., Raven Press, N.Y. (1993)). Specific binding occurs to the corresponding antigen or epitope even in the presence of proteins and other biological heterogeneous populations. Specific binding of an antibody indicates that it binds to its target antigen or epitope with a substantially higher affinity than binding to an irrelevant antigen. The relative difference in affinity is often greater than at least 25%, more often greater than at least 50%, and most often greater than at least 100%. For example, the relative difference can be 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.

[0157] Exemplary types of antibodies include, but are not limited to, human, humanized, chimeric, monoclonal, polyclonal, single-chain, antibody-binding fragments, and diabodies. When binding to a cancer antigen, the antibody can induce antibody-dependent cell-mediated cytotoxicity, activate the complement system, prevent receptors from interacting with their ligands, or deliver a chemotherapy or radiation payload, all of which can lead to cell death.

[0158] In some embodiments, the anti-PD-1 antibody is balstilimab, camrelizumab, semaprilimab, dostarlimab, gepotidacin, nivolumab, pembrolizumab, pemprimumab, pidilizumab, proleukinumab, retifanlimab, sasamlimab, serplulimab, serplulimab, sintilimab, spartalizumab, surlituzumab, tebotelimab, telisotuzumab, tislelizumab, tripalizumab, tripalizumab, zimberelimab, 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 Healthselected from the group consisting of Technology Development Co Ltd, 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 the group consisting of semiprimab, nivolumab, pembrolizumab, pidilizumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, AMP-224 (NCI), and AMP-514. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0159] 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 every two weeks. In other embodiments, the anti-PD-1 antibody is administered every three weeks. In other embodiments, the anti-PD-1 antibody is administered every four weeks. In other embodiments, the anti-PD-1 antibody is administered every five weeks. In other embodiments, the anti-PD-1 antibody is administered every six weeks.

[0160] 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.

[0161] In some embodiments, the anti-PD-1 antibody is administered parenterally (e.g., by intravenous infusion).

[0162] In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, enobafolimab, socazolimab, 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 (Beta Pharma Inc), BPI-9320 (Beta 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 (HuaboBiopharm(Shanghai) Co Ltd), HB-0028 (Huabo Biopharm(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 (ImmuneOnco Biopharmaceuticals(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 (Alphamab 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および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 Biotherapeuticsselected from the group consisting of Inc), QLS31901 (Qilu Pharmaceutical), RC98 (RemeGen), SHR-1316 (Jiangsu Hengrui 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 the group consisting of avelumab, durvalumab, atezolizumab, KN035, CK-301, AUNP12, CA-170, and BMS-986189.

[0163] 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 every two weeks. In other embodiments, the anti-PD-L1 antibody is administered every three weeks. In other embodiments, the anti-PD-L1 antibody is administered every four weeks. In other embodiments, the anti-PD-L1 antibody is administered every five weeks. In other embodiments, the anti-PD-L1 antibody is administered every six weeks.

[0164] In some embodiments, the anti-PD-L1 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, 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 per administration. For example, the anti-PD-L1 antibody can be administered at about 400 mg, about 800 mg, or about 1200 mg per administration.

[0165] In some embodiments, the anti-PD-L1 antibody is administered parenterally (e.g., by intravenous infusion).

[0166] Diseases and Disorders Abnormal Cell Growth Abnormal cell growth, as used herein, unless otherwise indicated, refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes (1) tumor cells (neoplasms) that grow, for example, by expressing a mutant tyrosine kinase or by overexpressing a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which, for example, abnormal tyrosine kinase activation occurs; (3) any tumor that grows by a receptor tyrosine kinase; (4) any tumor that may grow by abnormal serine / threonine kinase activation; and (5) abnormal growth of benign and malignant cells of other proliferative diseases in which, for example, abnormal serine / threonine kinase activation occurs. Abnormal cell growth can refer to cell growth in epithelial (e.g., carcinoma, adenocarcinoma); mesenchymal (e.g., sarcoma (e.g., leiomyosarcoma, Ewing's sarcoma)); hematopoietic; or other (e.g., melanoma, mesothelioma, and other tumors of unknown origin) cells.

[0167] Neoplastic disorder Abnormal cell growth can refer to a neoplastic disorder. A "neoplastic disorder" is a disease or disorder characterized by cells having the ability to grow or replicate autonomously, e.g., an abnormal condition or state characterized by proliferative cell growth. An abnormal mass of tissue, or "neoplasm," resulting from abnormal cell growth or division can be benign, premalignant (intraepithelial carcinoma), or malignant (cancer).

[0168] Exemplary neoplastic disorders include carcinomas, sarcomas, metastatic disorders (e.g., tumors arising from prostate, colon, lung, breast, and liver origin), hematopoietic neoplastic disorders, e.g., leukemias, metastatic tumors. Treatment with a compound can be effective in an amount that ameliorates at least one symptom of the neoplastic disorder, e.g., reduces cell proliferation, reduces tumor mass, etc.

[0169] Cancer The inventive method of the present invention can be useful, for example, in the prevention and treatment of cancer, including solid tumors, soft tissue tumors, and their metastases. The disclosed method is also useful in the treatment of non-solid cancers. Exemplary solid tumors include malignant diseases of various organ systems (e.g., sarcomas, adenocarcinomas, and carcinomas), such as those of the lung, breast, lymphatic system, gastrointestinal tract (e.g., colon), and urogenital tract (e.g., kidney, 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, pancreas (e.g., metastatic pancreatic adenocarcinoma), and small intestine cancer.

[0170] In some embodiments, the cancer is a cancer characterized as having a KRAS G12D mutation.

[0171] Cancers can include mesothelioma; neurofibromatosis, such as neurofibromatosis type 2, neurofibromatosis type 1; kidney cancer; lung cancer, such as non-small cell lung cancer, such as metastatic NSCLC; lung adenocarcinoma, such as NSCLC adenocarcinoma; liver cancer; thyroid cancer; ovarian cancer, such as low-grade serous ovarian cancer; breast cancer; pancreatic cancer, such as pancreatic adenocarcinoma; colorectal cancer, such as colorectal adenocarcinoma; endometrial cancer; gynecological cancers, such as cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, endometrial cancer, or vulvar cancer; liver cancer; prostate cancer; mesothelioma; bladder cancer; melanoma, such as unresectable melanoma, metastatic melanoma; thyroid cancer, such as papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer; glioblastoma; kidney cancer; nervous system tumors; schwannoma; meningioma; neurofibromatosis; acoustic neuroma; adenoid cystic carcinoma; epithelioma; and epithelioma tumors.

[0172] Cancers can include cancers characterized as including cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells. Cancers can include cancers characterized as being enriched in cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells (e.g., tumors or metastatic tumors enriched in cells that have undergone epithelial-mesenchymal transition).

[0173] Cancer can be a primary tumor, i.e., it can be located at the anatomical site where tumor growth begins. Cancer can also be metastatic, i.e., it can appear at at least a second anatomical site outside the anatomical site where tumor growth begins. Cancer can be recurrent cancer, i.e., cancer that recurs after treatment and after a period during which the cancer was undetectable. Recurrent cancer can be anatomically local to the original tumor, e.g., anatomically near the original tumor; local to the original tumor, e.g., in lymph nodes located near the original tumor; or distal to the original tumor, e.g., in regions anatomically distant from the original tumor.

[0174] 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, low-claudin breast cancer, invasive, inflammatory, dysplastic, and treatment-resistant advanced HER-2 positive or ER positive cancers.

[0175] Cancer can also include lung adenocarcinoma, colorectal cancer (CRC), choroidal melanoma, ovarian cancer, endometrial cancer, bladder urothelial cancer, invasive lobular carcinoma of the breast, squamous cell carcinoma of the cervix, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic type pleural mesothelioma, renal clear cell carcinoma, renal clear cell carcinoma, gastric adenocarcinoma, gastric tubular adenocarcinoma, carcinosarcoma of the uterus, or uterine malignant mixed Mullerian tumor.

[0176] In some embodiments, the cancer is unresectable melanoma or metastatic melanoma, melanoma with lymph node metastasis or metastatic disease that has undergone complete resection, metastatic non-small cell lung cancer and progression during or after platinum-based chemotherapy, metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy, progressive renal cell carcinoma that has previously received anti-angiogenic therapy, progressive renal cell carcinoma, classical Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression during or after platinum-based therapy, locally advanced or metastatic urothelial carcinoma, high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) metastatic colorectal cancer, or hepatocellular carcinoma.

[0177] 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 carcinoma, high-frequency microsatellite instability cancer, gastric cancer, esophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, or endometrial cancer.

[0178] 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, Wilms tumor, multiple myeloma, skin cancer, lymphoma, blood cancer and bone marrow cancer (e.g., advanced hematological malignancies, leukemia, e.g., acute myeloid leukemia (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), retinal cancer, bladder cancer, cervical cancer, kidney cancer, endometrial cancer, meningioma, lymphoma, skin cancer, uterine cancer, lung cancer, non-small cell lung cancer, nasopharyngeal carcinoma, neuroblastoma, solid tumors, hematological malignancies, squamous cell carcinoma, testicular cancer, thyroid cancer, mesothelioma, brain cancer, vulvar cancer, sarcoma, intestinal cancer, oral cancer, endocrine cancer, salivary gland cancer, spermatocytic seminoma, sporadic medulalry thyroid carcinoma, non-proliferating testicular cells, cancers associated with malignant mast cells, non-Hodgkin lymphoma, and diffuse large B-cell lymphoma.

[0179] 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) after standard treatment.

[0180] The methods described herein can reduce, ameliorate, or completely eliminate a disorder and / or its associated symptoms, prevent it from worsening, slow its progression, or minimize its recurrence rate (i.e., avoid relapse) if the disorder has been initially eliminated. Suitable dosages and treatment regimens can vary depending on the specific compounds, combinations, and / or pharmaceutical compositions used, as well as the mode of delivery of the compounds, combinations, and / or pharmaceutical compositions. In some embodiments, the methods significantly increase, statistically, the mean length of survival, the mean length of progression-free survival, and / or decrease the recurrence rate of subjects treated with the combinations described herein.

[0181] In some embodiments, the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer (e.g., unresectable low-grade ovarian cancer, advanced or metastatic ovarian cancer), rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer (e.g., triple-negative breast cancer (e.g., breast cancer that does not express the estrogen receptor, progesterone receptor, and Her2 / neu genes)), uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma) or one or more combinations 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 a locally recurrent disease, such as cancer).

[0182] Additional treatment In some embodiments, the methods and compositions described herein are administered in combination with additional therapies. 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 the treatment or avoidance of various diseases, including, for example, cancer, diabetes, neurodegenerative diseases, cardiovascular diseases, blood clotting, inflammation, flushing, obesity, aging, stress, and the like. In various embodiments, a combination therapy comprising a compound or pharmaceutical composition 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 that are not formulated in the same composition with the combinations described herein. 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 a separate composition. Sequential administration refers to the administration of a treatment prior to an additional, e.g., secondary, treatment (e.g., a compound or treatment), e.g., immediately prior, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, less than 60 minutes prior; 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 48 hours, 72 hours, 96 hours or longer prior; 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or longer prior; 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or longer prior. The order of administration of the first and second compounds or treatments can also be reversed.

[0183] In some embodiments, the additional treatment is a cancer treatment. Exemplary cancer treatments include, for example, chemotherapy, targeted chemotherapy, such as antibody therapy, immunotherapy, and hormone therapy. Examples of each of these treatments are provided below.

[0184] Chemotherapy In some embodiments, the combinations described herein are administered with chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy" typically refers to cytotoxic drugs that affect cells that are generally rapidly dividing, as opposed to targeted chemotherapy. Chemotherapy drugs interfere with cell division in various possible ways, such as the replication of DNA or the separation of newly formed chromosomes. Almost all forms of chemotherapy target rapidly dividing cells and are not specific to cancer cells, although some degree of specificity can arise from the fact that many cancer cells cannot repair DNA damage, while normal cells generally can.

[0185] In some embodiments, the combinations described herein are administered with one or more chemotherapeutic agents. Examples of chemotherapeutic agents used in cancer treatment include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustard, nitrosourea, platinum, alkyl sulfonate, hydrazine, triazene, aziridine, spindle poison, cytotoxic agent, topoisomerase inhibitor, 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, chloromethine, cisplatin, cladribine, clofarabine, chrysantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, dexamethasone, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine, epirubicin, estramustine, etoglucid, etoposide, floxuridine, fludarabine, fluorouracil (5FU), folfirinox, fotemustine, gemcitabine, gliadel implant, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lukantan, mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegasparaginase,Pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, rubitecan, sapacitabine, semustine, sitimagene ceradenovec, strataplatin, streptozocin, talaporfm, tegafur-uracil, temoporfin, temozolomide, teniposide, tesetaxel, testolactone, tetranitrate, thiotepa, thiazofurin, thioguanine, tipifarnib, topotecan, trabectedin, triaziquone, triethylenemelamine, triplatin, tretinoin, treosulfan, trophosphamide, uramustine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorinostat, zolbetuximab, and other cytostatic or cytotoxic agents described herein are included.,

[0186] Some drugs work better together than alone, so often two or more drugs are given at the same time or sequentially. Often, 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.

[0187] Targeted chemotherapy In some embodiments, the combinations described herein are administered with a targeted therapy. Targeted therapy consists of the use of agents specific to deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of the enzymatic domains of proteins that are mutated, overexpressed, or otherwise critically important within cancer cells. Prominent examples are tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, dasatinib, erolotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, as well as cyclin-dependent kinase inhibitors such as albosidib 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 (HERCEPTIN®), which is typically used in breast cancer, and the anti-CD20 antibodies rituximab and tositumomab, which are typically used in various B cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin diftitox. In some embodiments, the targeted therapy can be used in combination with the combinations described herein.

[0188] Targeted therapy can also involve small molecule peptides as "homing devices" that can bind to cell surface receptors or the extracellular matrix surrounding the tumor of diseased cells. Radioactive nuclides (e.g., RGD) attached to these peptides, if decayed in the vicinity of the cells, will ultimately kill cancer cells. An example of such a therapy is BEXXAR®.

[0189] Immunotherapy In some embodiments, the combinations described herein are administered together with immunotherapy. Cancer immunotherapy refers to a diverse set of treatment strategies designed to induce the subject's own immune system to fight the tumor.

[0190] Modern methods for generating an immune response against tumors include intravesical BCG immunotherapy for superficial bladder cancer, as well as the use of interferon 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 donor immune cells often attack tumors with a graft-versus-tumor effect. In some embodiments, immunotherapy agents can be used in combination with the combinations described herein.

[0191] Hormone therapy In some embodiments, the described combinations are administered together 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 cancer and prostate cancer. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of a hormone agonist such as a progestogen can be therapeutically beneficial. In some embodiments, hormone therapy agents can be used in combination with the combinations described herein.

[0192] 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 but not limited to aromatase inhibitors such as anastrozole, letrozole, and exemestane. In some embodiments, the additional agent is an estrogen receptor modulator, including but not limited to fulvestrant, tamoxifen, and raloxifene.

[0193] Radiation therapy The combinations described herein can be used in combination with directed energy or particles, or radioisotope treatment, such as radiation therapy, such as radiation oncology, to treat proliferative diseases, such as cancer, such as 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 treatment. For example, the combinations described herein can be administered before, during, or after directed energy or particles, or radioisotope treatment, or a combination thereof. Directed energy or particle therapy can include whole body irradiation, local irradiation, or point irradiation. Directed energy or particles can be derived from an accelerator, synchrotron, nuclear reaction, vacuum tube, laser, or radioisotope. This therapy can include external beam radiation therapy, teletherapy, brachytherapy, sealed source radiation therapy, systemic radioisotope therapy, or unsealed source radiotherapy. This therapy can include the uptake of radioisotopes, such as radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, carbon, or placement in proximity thereto. External irradiation 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-rays, or gamma ray photons). Radiation can be directed to any part of the subject in need of treatment.

[0194] Surgery The combinations described herein can be used in combination with surgery, such as a surgical examination, intervention, biopsy, to treat proliferative diseases, such as cancer, such as cancer associated with cancer stem cells. The combinations described herein can be administered to a subject simultaneously with or sequentially to surgery. For example, the combinations described herein can be administered before (pre-operative), during, or after (post-operative) surgery, or a combination thereof. The surgery can be a biopsy in which one or more cells are collected for further analysis. The biopsy can be achieved, for example, by a scalpel, needle, catheter, endoscope, spatula, or forceps. The biopsy can be an excisional biopsy, incisional biopsy, core biopsy, or needle biopsy, such as a needle aspiration biopsy. The surgery can involve the removal of local tissue suspected or identified as being cancerous. For example, the procedure can involve the removal of a cancerous lesion, mass, polyp, or mole. The procedure can involve the removal of large amounts of tissue, such as breast, bone, skin, fat, or muscle. The procedure can involve the removal of an organ or node, such as a lung, throat, tongue, bladder, cervix, ovary, testis, lymph node, liver, pancreas, brain, eye, kidney, gallbladder, stomach, colon, rectum, or part or all of the intestine. In one embodiment, the cancer is breast cancer, such as triple negative breast cancer, and the surgery is a mastectomy or lumpectomy.

[0195] Anti-inflammatory agent The combinations described herein can be administered together with an anti-inflammatory agent. Anti-inflammatory agents include, but are 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, lomoxicam, isoxicam), fenamic acid derivatives (fenamates) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxibs) (celecoxib), sulfonanilide (nimesulide), steroids (e.g., hydrocortisone (cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone).

[0196] Analgesic Analgesics may include, but are not limited to, opioids (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).

[0197] Antiemetics The combinations described herein may be administered together with an antiemetic. Antiemetics include, but are 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 (Compazine, Stemzine, Buccastem, Stemetil, Phenotil)), NK1 receptor antagonists (aprepitant (Emend), antihistamines (cyclizine, diphenhydramine (Benadryl), dimenhydrinate (Gravol, Dramamine), meclizine (Bonine, Antivert), promethazine (Pentazine, Phenergan, Promacot), hydroxyzine), benzodiazapines (lorazepam, midazolam), anticholinergics (hyoscyamine), steroids (dexamethasone).

[0198] Combination The phrase "in combination with" and the terms "co-administer", "co-administering" or "co-providing" as used herein in the context of the administration of the compounds described herein or the treatments described herein mean that two (or more) different compounds or treatments are delivered to a subject during the course of the subject's affliction with a disease or disorder (e.g., a disease or disorder described herein, such as cancer), e.g., two (or more) different compounds or treatments are delivered to the 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 is cured or eliminated or the treatment is discontinued for some other reason.

[0199] In some embodiments, the delivery of a compound or treatment continues when the delivery of a second compound or treatment begins such that there is an overlap with respect to administration. This is sometimes referred to herein as "simultaneous" or "co - delivery". In other embodiments, the delivery of a compound or treatment ends before the delivery of another compound or treatment begins. In some embodiments in either case, the treatment (e.g., administration of a compound, composition, or treatment) is more effective for combination administration. For example, the second compound or treatment is more effective than would be seen if the second compound or treatment were administered in the absence of the first compound or treatment, e.g., seen with a second compound or treatment with less equivalent effect, or the second compound or treatment reduces symptoms to a greater extent, or a similar situation is seen with the first compound or treatment. In some embodiments, the delivery is such that the reduction of symptoms, or other parameters related to the disorder, is greater than that observed with one compound or treatment delivered in the absence of the other. The effects of the two compounds or treatments can be partially additive, fully additive, or more than additive (e.g., synergistic). The delivery can be such that the first compound or treatment delivered is still detectable when the second compound or treatment is delivered.

[0200] In some embodiments, the first compound or treatment and the second compound or treatment can be administered simultaneously (e.g., at the same time) or sequentially in the same or separate compositions. Sequential administration refers to the administration of a compound or treatment prior to the administration of an additional, e.g., secondary, compound or treatment (e.g., immediately before, 5 minutes, 10 minutes, 15 minutes, less than 30 minutes, 45 minutes, 60 minutes before; 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 48 hours, 72 hours, 96 hours or longer before; 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or longer before; 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or longer before). The order of administration of the first and second compounds or treatments can also be reversed.

[0201] The combinations described herein can be a first-line treatment for abnormal cell growth, such as cancer (i.e., used in subjects not previously administered another drug intended to treat cancer); can be a second-line treatment for cancer (i.e., used in subjects in need thereof who have previously been administered another drug intended to treat cancer); can be a third or fourth treatment for cancer (i.e., used in subjects who have previously been administered two or three other drugs intended to treat cancer).

[0202] Administration and Dosage The combinations of the present invention can be administered via oral, parenteral, topical, rectal, or implant reservoir, preferably by oral administration or 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 effectiveness of the composition.

[0203] In some embodiments, the subject is administered the composition (e.g., pharmaceutical composition) orally. In some embodiments, the composition (e.g., pharmaceutical composition) is orally administered in any orally acceptable dosage form including, but not limited to, liquid gel tablets or capsules, syrups, emulsions, and aqueous suspensions. The liquid gel may contain gelatin, plasticizer, and / or opacifier, if necessary to achieve a suitable consistency, and may be coated with an enteric coating approved for use, such as shellac. When used as an oral dosage form, additional thickening agents, such as gums, such as xanthan gum, starches, such as corn starch, or gluten, may be added to achieve the desired consistency of the composition (e.g., pharmaceutical composition). If desired, certain sweetening agents and / or flavoring agents and / or coloring agents may be added.

[0204] In some embodiments, a composition (e.g., a pharmaceutical composition) in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions, is administered to a subject. The composition (e.g., a pharmaceutical composition) can be in a unit dosage form suitable for a single administration of an accurate dosage. The pharmaceutical composition may include, in addition to the compounds described herein, a pharmaceutically acceptable carrier, and optionally one or more pharmaceutically acceptable additives such as stabilizers, diluents, binders, and lubricants. Further, the tablets can contain other medicinal or pharmaceutical agents, carriers, and / or adjuvants. Exemplary pharmaceutical compositions include compressed tablets (e.g., direct compression tablets).

[0205] Tablets containing an active ingredient or therapeutic ingredient (e.g., a compound described herein) are also provided. In addition to the active ingredient or therapeutic ingredient, the tablets can contain some inert substances such as carriers. The pharmaceutically acceptable carrier can be a sterile liquid such as water and oils of animal, vegetable, or synthetic origin, for example, oils including peanut oil, sesame oil, etc. Saline solutions and aqueous dextrose can also be employed as liquid carriers. Thus, the oral dosage forms for use according to the present invention can be formulated by conventional methods using one or more pharmaceutically acceptable carriers including additives and adjuvants that facilitate the processing of the active ingredient into a pharmaceutically usable preparation.

[0206] Additives can impart excellent powder flow and compression properties to the substances to be compressed. Examples of additives are described, for example, in Handbook of Pharmaceutical Excipients (5 th edition), Edited by Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen; Publisher: Pharmaceutical Press.

[0207] For oral administration, the active ingredient, e.g., the compounds described herein, can be readily formulated by combining the active ingredient with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the active ingredient of the present invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, powders or granules, suspensions or solutions in water or non-aqueous media, etc. for oral ingestion by a subject. Pharmacological preparations for oral use can be manufactured by using solid additives, grinding the resulting mixture as necessary, and treating the mixture of granules after adding auxiliaries suitable for obtaining, for example, tablets, if desired. Suitable additives such as diluents, binders or disintegrants would be desirable.

[0208] The dosage can vary depending on the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the subject's condition. (See, for example, Fingl, et al., 1975, in 'he Pharmacological Basis of Therapeutics"). Lower or higher dosages than those listed above may be required. The specific dosage and treatment regimen for a particular subject will depend on a variety of factors including the activity of the specific compound employed, age, weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, disease, state or severity and course of symptoms, predisposition of the subject to the disease, state or symptom, as well as the judgment of the physician treating the subject. The course of treatment can include one or more separate administrations of the compounds described herein. The course of treatment can include one or more cycles of the compounds described herein.

[0209] In some embodiments, when a cycle is used herein in the context of a cycle of drug administration, it refers to the period during which the drug is administered to a subject. For example, if a drug is administered over a 21-day cycle, dosing is given periodically, such as daily or twice daily, for 21 days. The drug can be administered over more than one cycle. A rest period can be inserted between cycles. The rest period can be 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or 1 week, 2 weeks, 3 weeks, 4 weeks or longer weeks.

[0210] Oral dosage forms can be presented in a pack or dispenser device, such as an FDA-approved kit, which can contain one or more unit dosage forms containing the active ingredient, if desired. A pack, such as a blister pack, can include, for example, a metal or plastic foil. The pack or dispenser device can be accompanied by instructions for administration. The pack or dispenser can also be accompanied by a notice associated with a container in a form defined by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, reflecting the form of the composition or approval by a human or veterinary administration authority. Such notice can be, for example, that of a label approved by the US Food and Drug Administration for a prescription drug or an approved product insert.

Examples

[0211] The following examples are provided to enable a more complete understanding of the invention described herein. The examples described in this application are provided to illustrate the pharmaceutical compositions and methods provided herein and should in no way be construed as limiting their scope.

[0212] (Example 1) Synergistic effect of VS-6766 and KRAS G12D inhibitor in preclinical solid tumor models The study investigated that the vertical pharmacological blockade of RAS, RAF, and MEK using a G12D inhibitor in combination with a dual RAF / MEK inhibitor (e.g., VS-6766) + / - a FAK inhibitor, + / - an EGFR inhibitor, + / - a PD-1 / PD-L1 antibody, or + / - chemotherapy, as contemplated by the inventors, confers excellent pathway blockade and antitumor efficacy.

[0213] Materials and Methods in vitro 3D Proliferation Assay KRAS G12D mutant human cancer cell lines were 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 solidify the Matrigel. Cells were seeded in 100 μL of medium containing 2% Matrigel. After overnight (17 - 22 hours) incubation, cells were treated with VS-6766 + / - a 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 composite synergy score.

[0214] Results VS-6766 was synergistic with a KRAS G12D inhibitor (e.g., MRTX-1133), and this combination promoted tumor cell death, including in, for example, KRAS G12D colorectal and pancreatic cancer cell lines. Figure 1 shows the prevalence of KRAS G12D mutations in exemplary cancers (pancreatic, colorectal, endometrial, 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 across various cell lines.

[0215] Equivalents and Ranges In the claims, articles such as "a", "an", and "the" may mean one or more than one unless the contrary is indicated or is not apparent from the context. A claim or description that includes "or" between one or more members of a group is considered satisfied where, unless the contrary is indicated or is not apparent from the context, one, more than one, or all of the members of the group are present in, employed in, or relevant to a given product or process. The invention includes embodiments where exactly one member of the group is present in, employed in, or relevant to a given product or process. The invention includes embodiments where more than one or all of the members of the group are present in, employed in, or relevant to a given product or process.

[0216] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms derived from one or more of the recited claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in other claims that depend on the same basic claim. When elements are presented as a list, for example in Markush group form, each subgroup of the elements is also disclosed and any element can be removed from the group. Generally, when the invention, or an aspect of the invention, is referred to as including a particular element and / or feature, it should be understood that some embodiments of the invention or aspect of the invention consist of, or consist essentially of, such element and / or feature. For brevity, these embodiments are not specifically set forth in these words herein. Note also that the terms "comprising" and "including" are intended to be open and allow the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Further, unless otherwise indicated or not apparent from the context and the understanding of one of ordinary skill in the art, values expressed as ranges are assumed to be any specific value or subrange within the stated range to one tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0217] This application references various registered patents, published patent applications, journal articles, and other publications, all of which are hereby incorporated by reference into this specification. In the event of any conflict between any of the incorporated references and this specification, this specification shall prevail. Further, any particular embodiment of the invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Such embodiments are considered to be known to those skilled in the art and may be excluded even if not explicitly shown as such in this specification. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not in relation to the existence of the prior art.

[0218] Those skilled in the art will recognize, or be able to ascertain using no more than 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 above description but rather is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications can be made to this specification without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. The use of an effective amount of a dual RAF / MEK inhibitor and an effective amount of a KRAS G12D inhibitor in the manufacture of a pharmaceutical for the treatment of cancer in subjects requiring cancer treatment, wherein the dual RAF / MEK inhibitor is a compound of formula (I): 【Chemistry 27】 or a pharmaceutically acceptable salt thereof, for use.

2. The use according to claim 1, wherein the cancer has been identified as having a KRAS G12D mutation.

3. The aforementioned bilayer RAF / MEK inhibitor is a compound of formula (I): 【Chemistry 28】 The use described in claim 1.

4. The use according to claim 1, wherein the dual RAF / MEK inhibitor is the potassium salt of the compound of formula (I).

5. The use according to claim 1, wherein the dual RAF / MEK inhibitor is administered orally to the subject.

6. The use according to claim 1, wherein the dual RAF / MEK inhibitor is administered at least once a week.

7. The use according to claim 6, wherein the dual RAF / MEK inhibitor is administered twice a week.

8. The use according to claim 5, wherein the dual RAF / MEK inhibitor is administered in a dose of 0.5 mg to about 10 mg per dose.

9. The use according to claim 8, wherein the dual RAF / MEK inhibitor is administered at a dose of 3.2 mg per administration.

10. The use according to claim 8, wherein the dual RAF / MEK inhibitor is administered at a dose of 4 mg per administration.

11. The use according to any one of claims 1 to 10, wherein the dual RAF / MEK inhibitor is administered as a cycle comprising administering the dual RAF / MEK inhibitor for three weeks, followed by a one-week period without administering the dual RAF / MEK inhibitor.

12. The aforementioned KRAS G12D inhibitors include KRAS G12D degrading agent (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), and KRAS ONCOlogue (Oncogeneity), 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) 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. Takeda Pharmaceutical Co Ltd., Ltd., KRpep-2d (peptide), anti-KRAS G12D monoclonal antibody (Oblique Therapeutics AB), small molecule KRAS G12D inhibitor (Shenzhen Forward Pharmaceutical Co.The use according to claim 1, selected from the group consisting of Proteovant Therapeutics Inc., BIGPRO (Bifunctional Ligand-Induced Proteolytic 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.

13. The use according to claim 12, wherein the KRAS G12D inhibitor is MRTX-1133 or a pharmaceutically acceptable salt thereof.

14. The use according to claim 12 or 13, wherein the KRAS G12D inhibitor is administered orally to the subject.

15. The use according to claim 12 or 13, wherein the KRAS G12D inhibitor is administered intravenously to the subject.

16. The use according to claim 12 or 13, wherein the KRAS G12D inhibitor is administered subcutaneously to the subject.

17. The use according to claim 12 or 13, wherein the KRAS G12D inhibitor is administered once daily.

18. The use according to claim 12 or 13, wherein the KRAS G12D inhibitor is administered twice daily.

19. The use according to claim 12 or 13, wherein the KRAS G12D inhibitor is administered in an amount of 1 mg to 2000 mg per dose.

20. The use according to claim 19, wherein the KRAS G12D inhibitor is administered in an amount of 10 mg to 1000 mg per dose.

21. The use according to claim 20, wherein the KRAS G12D inhibitor is administered in an amount of 100 mg to 1000 mg per dose.

22. The use according to claim 1, 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.

23. The use according to claim 22, wherein the cancer is lung cancer, colorectal cancer, or pancreatic cancer.

24. The use according to claim 23, wherein the lung cancer is non-small cell lung cancer or metastatic non-small cell lung cancer.

25. The use according to claim 23, wherein the cancer is colorectal cancer.

26. The use according to claim 23, wherein the cancer is pancreatic cancer.

27. The use according to claim 1, further comprising administering an effective amount of a FAK inhibitor to the subject, wherein the FAK inhibitor is defactinib or a pharmaceutically acceptable salt thereof.

28. The use according to claim 27, wherein the FAK inhibitor is administered in an amount of approximately 100 mg to approximately 400 mg per dose.

29. The use according to claim 28, wherein the FAK inhibitor is administered at a dose of 200 mg per administration.

30. The use according to claim 28, wherein the FAK inhibitor is administered at a dose of 400 mg per administration.

31. The use according to any one of claims 27 to 30, wherein the FAK inhibitor is administered once daily.

32. The use according to any one of claims 27 to 30, wherein the FAK inhibitor is administered twice daily.

33. The use according to claim 27, wherein the FAK inhibitor is administered in a cycle comprising administering the FAK inhibitor for three weeks, followed by not administering the FAK inhibitor for one week.

34. The use according to claim 27, wherein the FAK inhibitor is administered orally to the subject.

35. A combination for the treatment of cancer in a subject requiring treatment for cancer, wherein the combination comprises a dual RAF / MEK inhibitor and a KRAS G12D inhibitor, wherein the dual RAF / MEK inhibitor is a compound of formula (I): 【Chemistry 51】 A combination of either or a pharmaceutically acceptable salt thereof.

36. A composition for the treatment of cancer in a subject requiring cancer treatment, wherein the composition comprises a dual RAF / MEK inhibitor, and the composition is administered in combination with a KRAS G12D inhibitor, wherein the dual RAF / MEK inhibitor is a compound of formula (I): 【Chemistry 52】 A composition that is either a pharmaceutically acceptable salt thereof or the same.

37. A composition for the treatment of cancer in a subject requiring treatment for cancer, wherein the composition comprises a KRAS G12D inhibitor, and the composition is administered in combination with a dual RAF / MEK inhibitor, wherein the dual RAF / MEK inhibitor is a compound of formula (I): 【Chemistry 53】 A composition that is either a pharmaceutically acceptable salt thereof or the same.

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