Methods for Treating Abnormal Cell Growth - Patent application

Abstract

The disclosure provides, in part, methods of reducing or preventing the severity of toxicity or adverse events associated with administration of a dual RAF / MEK inhibitor in a subject, comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor, an effective amount of an antibiotic agent, and optionally an effective amount of a corticosteroid. The disclosure provides, in part, methods and combinations of compounds (e.g., compounds described herein, e.g., a combination of a dual RAF / MEK inhibitor and an antibiotic agent, and optionally a corticosteroid) useful for treating abnormal cell growth (e.g., cancer) in a subject in need of such treatment.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 274,745, filed November 2, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background Components of the RAS / RAF / MEK / ERK (MAPK) signaling pathway provide an opportunity to treat abnormal cell growth, e.g., cancer. Mutations in RAS / RAF / MEK / ERK are frequently found in human cancers. These mutants result in a constitutively active MAPK kinase cascade, 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, particularly cancer, in mammals.

[0003] Due to the severity and breadth of diseases and disorders associated with abnormal cell growth (e.g., cancer), effective therapeutic approaches and treatment methods are needed. The compounds, compositions, combinations, and methods described herein are directed to this end. Summary of the Invention [Means for solving the problem]

[0004] overview The disclosure provides, in part, methods and combinations of compounds (e.g., compounds described herein, e.g., a combination of a dual RAF / MEK inhibitor and an antibiotic agent, and optionally a corticosteroid) useful for treating abnormal cell growth (e.g., cancer) in a subject in need of such treatment.

[0005] In some embodiments, provided herein is a method of administering a dual RAF / MEK inhibitor to a subject in need thereof, the method comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor, an effective amount of an antibiotic agent, and an effective amount of a corticosteroid.

[0006] In some embodiments, provided herein is a method of reducing the severity of or preventing a toxicity or adverse event associated with administration of a dual RAF / MEK inhibitor in a subject, the method comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor, an effective amount of an antibiotic agent, and an effective amount of a corticosteroid.

[0007] In some embodiments, provided herein is a method of treating cancer in a subject in need of such treatment, comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor and an effective amount of an antibiotic agent.

[0008] In some embodiments, the methods further comprise administering to the subject an effective amount of a FAK inhibitor.

[0009] In some embodiments, provided herein is a method of treating cancer in a subject in need of such treatment, comprising administering to the subject an effective amount of a FAK inhibitor and an effective amount of an antibiotic agent.

[0010] In some embodiments, the dual RAF / MEK inhibitor has formula (I): [ka] or a pharma- ceutically acceptable salt thereof.

[0011] In some embodiments, the dual RAF / MEK inhibitor is IMM-1-104 or a pharma- ceutically acceptable salt thereof.

[0012] In some embodiments, the dual RAF / MEK inhibitor has formula (II), including pharma- ceutically acceptable salts thereof: [ka] where the variables are as defined herein.

[0013] In some embodiments, the dual RAF / MEK inhibitor is a compound selected from the compounds of Table I, or a pharma- ceutically acceptable salt thereof.

[0014] In some embodiments, the corticosteroid is hydrocortisone, prednisone, triamcinolone, cortisol, corticosterone, cortisone, aldosterone, dexamethasone, prednisolone, or methylprednisolone.

[0015] In some embodiments, the antibiotic agent is minocycline, doxycycline, tetracycline, clindamycin, sulfadiazine, diphenhydramine, polysporin, prednisone, neomycin, bacitracin, erythromycin, or azithromycin.

[0016] In some embodiments, the FAK inhibitor is defactinib, or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 illustrates an exemplary combination effect of VS-6766 or defactinib with and without minocycline or doxycycline.

[0018] [Figure 2-1] FIG. 2 illustrates a plot of an exemplary calculated synergy score for the combination of VS-6766 and doxycycline. [Figure 2-2] FIG. 2 illustrates a plot of an exemplary calculated synergy score for the combination of VS-6766 and doxycycline. [Figure 2-3] FIG. 2 illustrates a plot of an exemplary calculated synergy score for the combination of VS-6766 and doxycycline.

[0019] [Diagram 3] FIG. 3 illustrates a plot of exemplary calculated synergy scores for combinations of VS-6766 or defactinib with minocycline or doxycycline in the NCI-H358 cell line.

[0020] [Figure 4] FIG. 4 illustrates a plot of exemplary calculated synergy scores for combinations of VS-6766 and doxycycline across multiple cell lines. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Detailed Description As generally described herein, the disclosure provides methods and combinations of compounds (e.g., compounds described herein, e.g., a combination of a dual RAF / MEK inhibitor and an antibiotic agent, and optionally a corticosteroid) useful for treating abnormal cell growth (e.g., cancer) in a subject in need of such treatment. definition chemical definition

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

[0023] The compounds described herein may contain one or more asymmetric centers, and therefore may exist in various isomers, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers.Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, e.g., 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 (EL 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.

[0024] As used herein, a pure enantiomer 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 is thus an enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" refers to a compound that contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of an enantiomer. In certain embodiments, the weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0025] In the compositions provided herein, the enantiomerically pure compound can be present with other active or non-active ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound can comprise, for example, about 90% of excipients and about 10% of the enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition can comprise, for example, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound can comprise, for example, about 90% of excipients and about 10% of the enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition can comprise, for example, at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with little excipients or carriers or without excipients or carriers.

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

[0027] The following terms are intended to have the meanings presented below with them and are useful in understanding the description and intended scope of the present invention. In describing the present invention, which may include compounds and their pharma- ceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. As described herein, it should also be understood that any of the moieties defined below may be substituted with a wide variety of substituents, and that the individual definitions are intended to include such substituted moieties within their scope as set forth below.

[0028] The term "halogen atom" as used herein means any one of the radiostable atoms in column 7 of the periodic table of the elements, e.g., fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

[0029] The term "ester" as used herein refers to an ester of the formula -(R) n refers to a chemical moiety having the formula -COOR', where 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.

[0030] The term "amide" as used herein refers to a group of the formula -(R) n-C(O)NHR' or -(R) n It refers to a chemical moiety having the formula -NHC(O)R', where 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. An amide can be an amino acid or peptide molecule attached to a molecule of the invention, thereby forming a prodrug.

[0031] Any amine, hydroxyl, or carboxyl side chain on the compounds disclosed herein can be esterified or amidified. The procedures and specific groups used to achieve this end are known to those of skill in the art and are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, incorporated herein in its entirety. rd Ed., John Wiley & Sons, New York, NY, 1999.

[0032] 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 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, in which the atoms forming the backbone of the ring are all carbon atoms. Thus, this term distinguishes carbocyclic rings from heterocyclic rings in which the ring backbone contains at least one atom different from carbon. The term "heteroaromatic" refers to an aromatic group containing at least one heterocyclic ring.

[0033] As used herein, "Ca-Cb" (where "a" and "b" are integers) refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a cycloalkyl, aryl, heteroaryl, or heterocyclyl ring. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain "a" to "b" carbon atoms, inclusive. Thus, for example, a "C1 to C4 alkyl" group or a "C1-C4 alkyl" group refers to all alkyl groups having one to four carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. Similarly, for example, a cycloalkyl group may contain from "a" to "b" (inclusive) total atoms in the ring(s), e.g., a C3-C8 cycloalkyl group may contain from 3 to 8 carbon atoms. When "a" and "b" are not specified for alkyl, cycloalkyl, or cycloalkenyl, the maximum range described in these definitions is assumed. Similarly, a "4-7 membered heterocyclyl" group refers to all heterocyclyl groups having 4 to 7 total ring atoms, e.g., azetidine, oxetane, oxazoline, pyrrolidine, piperidine, piperazine, morpholine, and the like. As used herein, the term "C1-C6" includes C1, C2, C3, C4, C5, and C6, as well as the range defined by either of the two preceding numbers. For example, C1-C6 alkyl includes C1, C2, C3, C4, C5, and C6 alkyl, C2-C6 alkyl, C1-C3 alkyl, and the like. Similarly, C3-C8 carbocyclyl or cycloalkyl includes hydrocarbon rings containing 3, 4, 5, 6, 7, and 8 carbon atoms, or a range defined by either of the two numbers, e.g., C3-C7 cycloalkyl or C5-C6 cycloalkyl, respectively.As another example, a 3- to 10-membered heterocyclyl includes 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, or a range defined by either of the two preceding numbers, such as a 4- to 6-membered or 5- to 7-membered heterocyclyl.

[0034] As used herein, "alkyl" refers to a fully saturated (no double or triple bonds) hydrocarbon group of a straight or branched hydrocarbon chain. The alkyl group may have 1-20 carbon atoms (wherever it occurs herein, a numerical range such as "1-20" refers to each integer in the given range, e.g., "1-20 carbon atoms" means that the alkyl group may 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). The alkyl group may also be a medium-sized alkyl having 1-10 carbon atoms. The alkyl group may also be a lower alkyl having 1-5 carbon atoms. The alkyl group of the compound may be designated as "C1-C4 alkyl" or a similar designation. Merely by way of example, "C1-C4 alkyl" indicates that there are 1-4 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 in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.

[0035] An alkyl group can be substituted or unsubstituted. When substituted, the substituent(s) can be individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocayl, aryloxy ... The substituents are one or more groups selected from carbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as being "optionally substituted," that substituent may be substituted with one of the above substituents.

[0036] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in the straight or branched hydrocarbon chain. Alkenyl groups can be unsubstituted or substituted. If substituted, the substituent(s) can be selected from the same groups disclosed above for substitution on alkyl groups. Alkenyl groups can have from 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Alkenyl groups can also be medium size alkenyls having from 2 to 9 carbon atoms. Alkenyl groups can also be lower alkenyls having from 2 to 4 carbon atoms. The alkenyl groups of the compounds can be designated as "C2-C4 alkenyl" or similar designations. By way of example only, "C2-C4 alkenyl" indicates that there are 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 in no way limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

[0037] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in the straight or branched hydrocarbon chain. Alkynyl groups can be unsubstituted or substituted. If substituted, the substituent(s) can be selected from the same groups disclosed above for substitution on alkyl groups. Alkynyl groups can have from 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Alkynyl groups can also be medium size alkynyls having from 2 to 9 carbon atoms. Alkynyl groups can also be lower alkynyls having from 2 to 4 carbon atoms. The alkynyl groups of the compounds can be designated as "C2-C4 alkynyl" or similar designations. 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, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Exemplary alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0038] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur, in the backbone of the chain. A heteroalkyl group can have 1-20 carbon atoms, although this definition also encompasses occurrences of the term "heteroalkyl" where no numerical range is specified. A heteroalkyl group can also be a medium size heteroalkyl having 1-9 carbon atoms. A heteroalkyl group can also be a lower heteroalkyl having 1-4 carbon atoms. The heteroalkyl group of a compound can be designated as "C1-C4 heteroalkyl" or a similar designation. A heteroalkyl group can contain one or more heteroatoms. By way of example only, "C1-C4 heteroalkyl" indicates that there are 1-4 carbon atoms in the heteroalkyl chain, and further, one or more heteroatoms in the backbone of the chain.

[0039] As used herein, "aryl" refers to a carbocyclic (all carbon) ring or two or more fused rings (rings sharing two adjacent carbon atoms) with a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups can be substituted or unsubstituted. When substituted, hydrogen atoms are independently replaced by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N ... The aryl group is substituted with a substituent(s) that is one or more groups selected from aryl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. 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.

[0040] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a completely delocalized pi-electron system), one or two or more fused rings containing one or more heteroatoms, i.e., 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. Heteroaryl groups can be substituted or unsubstituted. When substituted, hydrogen atoms are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, The heteroaryl group is substituted with a substituent(s) that is one or more groups selected from aryl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. When substituted, the substituents on the heteroayl group may form a non-aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

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

[0042] As used herein, "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group connected as a substituent via an alkylene group. The alkylene and heteroaryl groups of the heteroaralkyl can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, as well as substituted versions thereof, as well as benzo-fused analogs thereof. In some cases, the alkylene group is a lower alkylene group.

[0043] As used herein, "alkylene" refers to a branched or straight chain, fully saturated diradical chemical group (i.e., alkanediyl) containing only carbon and hydrogen attached to the remainder of the molecule through two points of attachment. Alkylene groups can have from 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term alkylene where no numerical range is specified. Alkylene groups can also be medium size alkylenes having from 1 to 9 carbon atoms. Alkylene groups can also be lower alkylenes having from 1 to 4 carbon atoms. Alkylene groups can be designated as "C1-C4 alkylene" or similar designations. By way of example only, "C1-C4 alkylene" indicates that there are 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.

[0044] As used herein, "alkenylene" refers to a straight or branched chain diradical chemical group containing only carbon and hydrogen attached to the remainder of the molecule through two points of attachment and containing at least one carbon-carbon double bond. Alkenylene groups can have from 2 to 20 carbon atoms, although this definition also encompasses occurrences of the term alkenylene where no numerical range is specified. Alkenylene groups can also be medium size alkenylenes having from 2 to 9 carbon atoms. Alkenylene groups can also be lower alkenylenes having from 2 to 4 carbon atoms. Alkenylene groups can be designated as "C2-C4 alkenylene" or similar designations. By way of example only, "C2 alkenylene" indicates that there are 2 to 4 carbon atoms in the alkenylene chain, i.e., the alkenylene chain can be selected from the following: ethenylene, ethene-1,1-diyl, propenylene, propene-1,1-diyl, prop-2-ene-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, buta-1,3-dienylene, butene-1,1-diyl, buta-1,3-diene-1,1-diyl, 1,2-Dimethyl-2-propenylene, 3-methyl-2-propenylene, 2-methyl-propen-1,1-diyl, 2,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propen-1,1-diyl, and 2,2-dimethyl-ethen-1,1-diyl.

[0045] As used herein, "alkylidene" refers to a divalent group such as =CR'R" that is attached to a carbon of another group forming a double bond, and alkylidene groups include, but are 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. Alkylidene groups can be substituted or unsubstituted.

[0046] As used herein, "alkoxy" refers to a group of the formula -OR, where R is alkyl as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy, etc. Alkoxy can be substituted or unsubstituted.

[0047] As used herein, "alkylthio" refers to a group of the formula -SR, where R is alkyl as defined above, e.g., methyl mercapto, ethyl mercapto, n-propyl mercapto, 1-methylethyl mercapto (isopropyl mercapto), n-butyl mercapto, isobutyl mercapto, sec-butyl mercapto, tert-butyl mercapto, etc. Alkylthio can be substituted or unsubstituted.

[0048] 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.

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

[0050] 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 may be joined together in a fused, bridged or spiro-connected fashion. The cycloalkyl group may range from C3 to C10, and in other embodiments, from C3 to C6. The cycloalkyl group may be unsubstituted or substituted. Exemplary cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. When substituted, the substituent(s) may be alkyl or may be selected from those pointed out above with respect to substitution of alkyl groups, unless otherwise indicated. When substituted, the substituents on the cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including aryl and heteroaryl.

[0051] As used herein, "cycloalkenyl" refers to a cycloalkyl group that contains one or more double bonds in the ring, but if more than one is present, the ring cannot form a completely delocalized pi-electron system (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 manner. Cycloalkenyl groups can be unsubstituted or substituted. When substituted, the substituent(s) can be alkyl or selected from the groups disclosed above for substitution of alkyl groups, unless otherwise indicated. When substituted, the substituents on the cycloalkenyl group can form an aromatic ring fused to the cycloalkenyl group, including aryl and heteroaryl.

[0052] 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 manner. Cycloalkynyl groups can be unsubstituted or substituted. When substituted, the substituent(s) can be alkyl or can be selected from the groups disclosed above for substitution of alkyl groups, unless otherwise indicated. When substituted, the substituents on the cycloalkynyl group can form an aromatic ring fused to the cycloalkynyl group, including aryl and heteroaryl.

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

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

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

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

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

[0058] As used herein, the term "trihalomethanesulfonyl" refers to a "X3CSO2-" group where X is a halogen.

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

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

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

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

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

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

[0065] As used herein, the term "sulfonyl" refers to the group "-SO2R", where R can be the same as defined for O-carboxy. Sulfonyl can be substituted or unsubstituted.

[0066] As used herein, the term "S-sulfonamido" refers to the group "-SONRARB", where R and R can be the same as defined for O-carboxy. S-sulfonamido can be substituted or unsubstituted.

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

[0068] As used herein, the term "trihalomethanesulfonamide" refers to the group "X3CSON(R)-" where X and R as halogens can be the same as defined for O-carboxy. Trihalomethanesulfonamide can be substituted or unsubstituted.

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

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

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

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

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

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

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

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

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

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

[0079] 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.

[0080] As used herein, the term "acetyl" refers to a -C(=O)CH3 group.

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

[0082] As used herein, the term "carbocyclyl" refers to a non-aromatic cyclic ring or ring system that contains only carbon atoms in the backbone of the ring system. When a carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged, or spiro-connected fashion. A carbocyclyl may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl, and cycloalkynyl. A carbocyclyl group may have 3 to 20 carbon atoms, although this definition also encompasses occurrences of the term "carbocyclyl" where no numerical range is specified. A carbocyclyl group may also be a medium-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl group may also be a carbocyclyl having 3 to 6 carbon atoms. A carbocyclyl group may be designated as "C3-C6 carbocyclyl" or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydroindene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0083] As used herein, the term "(cycloalkyl)alkyl" refers to a cycloalkyl group connected, as a substituent, through an alkylene group. The alkylene and cycloalkyl of the (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, and the like. In some cases, the alkylene group is a lower alkylene group.

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

[0085] As used herein, the term "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, where none of the rings in the ring system are aromatic. An example is cyclohexenyl.

[0086] As used herein, the term "heterocyclyl" refers to 3-, 4-, 5-, 6-, 7-, and 8-membered or higher rings in which carbon atoms, together with one to three heteroatoms, constitute the ring. Heterocyclyls may optionally contain one or more unsaturated bonds suitable for such processes, however aromatic pi-electron systems do not result. Heteroatoms are independently selected from oxygen, sulfur, and nitrogen. Heterocyclyls may further contain one or more carbonyl or thiocarbonyl functional groups, such that the definition includes oxo and thio systems, e.g., lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like. "Heterocyclyl" may refer to non-aromatic cyclic rings or ring systems containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged, or spiro-connected fashion. Heterocyclyls may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Heteroatoms may be present in either non-aromatic or aromatic rings in the ring system. Heterocyclyl groups may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heterocyclyl" where no numerical range is specified. Heterocyclyl groups may also be medium-sized heterocyclyls having 3 to 10 ring members. Heterocyclyl groups may also be heterocyclyls having 3 to 6 ring members. Heterocyclyl groups may be designated as "3- to 6-membered heterocyclyl" or similar designations. In preferred 6-membered monocyclic heterocyclyls, the heteroatom(s) are selected from 1 to 3 O, N, or S; in preferred 5-membered monocyclic heterocyclyls, the heteroatom(s) are selected from 1 or 2 heteroatoms selected from O, N, or S.Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidionyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathiyl, 1,4-oxathiinyl, 1,4-oxathiyl, 2 / / -1,2-oxazinyl, trioxadiyl, 1,2-oxazin ... Examples of such radicals include tetrahydrofuranyl, 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.

[0087] As used herein, the term "(heterocyclyl)alkyl" refers to a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0088] A substituted group is based on or derived from an unsubstituted parent group in which there is the replacement of one or more hydrogen atoms with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", it is understood that the group can be any of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy). 1 to 6 haloalkoxy), 5 to 10-membered heterocyclyl (optionally substituted with halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, and C1 to C6 haloalkoxy), 5 to 10-membered heterocyclyl-C1 to C6-alkyl (optionally substituted with halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, and C1 to C6 haloalkoxy), aryl (optionally substituted with halo, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 halo ... 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); 1-C6 alkoxy, C1-C6 haloalkyl, and substituted with 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,Substituted with one or more substituents independently selected from O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as being "optionally substituted," that group can be substituted with the above-mentioned substituents.

[0089] In some embodiments, substituted groups are substituted with one or more substituents individually and independently selected from C1-C4 alkyl, amino, hydroxy, and halogen.

[0090] It should be understood that certain radical naming conventions may include either monoradicals or diradicals depending on the context. For example, if 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, which requires two points of attachment, includes diradicals, such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical naming conventions clearly indicate that the radical is a diradical, such as "alkylene" or "alkenylene."

[0091] Unless otherwise indicated, when a substituent is deemed to be "optionally substituted", it means that the substituent can be substituted with one or more groups individually and independently selected from 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-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and protective derivatives thereof. Protecting groups that can form protective derivatives of the above-mentioned substituents are known to those skilled in the art and can be found in references such as Greene and Wuts, above.

[0092] Other definitions "About" and "approximately" are intended to generally mean an acceptable degree of error for the quantity measured, given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0093] As used herein, "pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment, and are commensurate with 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 with 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 pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N-terminated salts, such as lactobionate, lactate, laurate, lauryl sulfate, 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, and the like. + (C 1~4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0094] As used herein, "pharmaceutical acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound that is formulated.The pharmaceutical acceptable carrier, adjuvant, or vehicle that can be used in the compositions described herein includes, but is not limited to, ion exchanger, alumina, aluminum stearate, lecithin, serum protein, such as human serum albumin, buffer substances, such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and wool fat.

[0095] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or a non-human animal, e.g., a mammal such as a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and / or dog. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0096] Disease, disorder, and condition are used interchangeably herein.

[0097] As used herein, unless otherwise specified, the terms "treat", "treating" and "treatment" contemplate actions taken while a patient is suffering from a particular disease, disorder or condition that reduce the severity of the disease, disorder or condition, or that delay or slow the progression of the disease, disorder or condition (also "therapeutic treatment").

[0098] In general, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be appreciated by those skilled in the art, an effective amount of a compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. As used herein, 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 a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other treatments, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves 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 or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0099] As used herein, "prophylactic treatment" contemplates actions taken before a subject begins to suffer from a particular disease, disorder, or condition.

[0100] The term "oral dosage form" as used herein refers to a composition or vehicle used to administer a drug to a subject. Typically, oral dosage forms are administered via the mouth, but "oral dosage form" is intended to cover any substance that is administered to a subject and absorbed across a membrane, e.g., a mucous membrane, of the digestive tract, including, for example, the mouth, esophagus, stomach, small intestine, large intestine, and colon. For example, "oral dosage form" covers a solution that is administered via a feeding tube to the stomach.

[0101] "Cycle" as used herein in the context of a cycle of administration of a drug refers to the period during which the drug is administered and may further include a rest period during which the drug is not administered to the subject. In some embodiments, a cycle is 4 weeks.

[0102] Kras protein (i.e., amino acid mutation) that favors the active GTP-bound state of Kras protein, resulting in abnormal Kras protein function associated with increased and / or constitutive activity. The mutation can be in a conserved site that favors GTP-bound and constitutively active Kras protein. In some cases, the mutation is in one or more of codons 12, 13, and 16 of the KRAS gene. For example, the KRAS mutation can be in codon 12 of the KRAS gene, for example, as a single point substitution mutation at codon 12 (i.e., KRAS G12X mutation) (e.g., KRAS G12V mutation results from a single nucleotide change (c.35G>T), resulting in an amino acid substitution of glycine (G) at position 12 with valine (V)). Exemplary KRAS G12X mutations include, but are not limited to, KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, and KRAS G12C.

[0103] A "RAF mutation" is a mutation in the RAF gene, such as a BRAF mutation. For example, a "BRAF mutation" is a mutation in the BRAF gene.

[0104] Treatment The methods described herein relate, in part, to a method of treating cancer in a subject in need of such treatment, comprising administering to the subject a dual RAF / MEK inhibitor in combination with an additional agent.

[0105] In some embodiments, provided herein is a method of administering a dual RAF / MEK inhibitor to 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 an antibiotic agent.

[0106] In some embodiments, provided herein is a method of administering a dual RAF / MEK inhibitor to 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 corticosteroid.

[0107] In some embodiments, provided herein is a method of administering a dual RAF / MEK inhibitor to a subject in need thereof, the method comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor, an effective amount of an antibiotic agent, and an effective amount of a corticosteroid.

[0108] In some embodiments, provided herein is a method for reducing the severity of or preventing a toxicity or adverse event associated with administration of a dual RAF / MEK inhibitor in a subject, the method comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor and an effective amount of an antibiotic agent.

[0109] In some embodiments, provided herein is a method for reducing the severity of or preventing a toxicity or adverse event associated with administration of a dual RAF / MEK inhibitor in a subject, the method comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor and an effective amount of a corticosteroid.

[0110] In some embodiments, provided herein is a method of reducing the severity of or preventing a toxicity or adverse event associated with administration of a dual RAF / MEK inhibitor in a subject, the method comprising administering to the subject an effective amount of a dual RAF / MEK inhibitor, an effective amount of an antibiotic agent, and an effective amount of a corticosteroid.

[0111] In some embodiments, the dual RAF / MEK inhibitor has formula (I): [ka] or a pharma- ceutically acceptable salt thereof.

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

[0113] In some embodiments, the dual RAF / MEK inhibitor has formula (II), including pharma- ceutically acceptable salts thereof: [ka] wherein the variables are as described herein.

[0114] In some embodiments, the corticosteroid is hydrocortisone, prednisone, triamcinolone, cortisol, corticosterone, cortisone, aldosterone, dexamethasone, prednisolone, or methylprednisolone. In some embodiments, the corticosteroid is administered topically. In some embodiments, the corticosteroid is administered at least once daily. In some embodiments, the corticosteroid is administered once daily or twice daily. In some embodiments, the corticosteroid is administered once daily. In some embodiments, the corticosteroid is administered twice daily. In some embodiments, the corticosteroid is administered for at least 4 weeks. In some embodiments, the corticosteroid is administered for at least 8 weeks. In some embodiments, the corticosteroid is administered for 8 weeks. For example, the corticosteroid may be administered for 8 consecutive weeks (e.g., the first two cycles of administration of the dual RAF / MEK inhibitor). In some embodiments, the corticosteroid is administered for at least 8 consecutive weeks (eg, the first 2 cycles and any additional subsequent cycles of administration of the dual RAF / MEK inhibitor).

[0115] In some embodiments, the antibiotic agent is administered twice daily. In some embodiments, the antibiotic agent is minocycline, doxycycline, tetracycline, clindamycin, sulfadiazine, diphenhydramine, polysporin, prednisone, neomycin, bacitracin, erythromycin, or azithromycin. In some embodiments, the antibiotic agent is administered at least once daily. In some embodiments, the antibiotic agent is administered once daily or twice daily. In some embodiments, the antibiotic agent is administered once daily. In some embodiments, the antibiotic agent is administered for at least 4 weeks. In some embodiments, the antibiotic agent is administered for at least 8 weeks. In some embodiments, the antibiotic agent is administered for 8 weeks. For example, the antibiotic agent may be administered for 8 consecutive weeks (e.g., the first two cycles of administration of the dual RAF / MEK inhibitor). In some embodiments, the antibiotic agent is administered for at least 8 consecutive weeks (e.g., the first two cycles of administration of the dual RAF / MEK inhibitor and additional subsequent cycles).

[0116] In some embodiments, administration of the dual RAF / MEK inhibitor and the antibiotic agent is synergistic (e.g., provides a synergistic effect in inhibiting tumor cell proliferation). In some embodiments, administration of the dual RAF / MEK inhibitor and the antibiotic agent is synergistic, as identified by a combined synergy score of ≧5. In some embodiments, administration of the dual RAF / MEK inhibitor and the antibiotic agent has a combined synergy score of ≧5. In some embodiments, administration of the dual RAF / MEK inhibitor and the antibiotic agent has a combined synergy score of ≧10. In some embodiments, administration of the dual RAF / MEK inhibitor and the antibiotic agent has a combined synergy score of ≧15.

[0117] In some embodiments, the method treats inflammation, hi some embodiments, the method reduces the severity of inflammation or prevents inflammation.

[0118] In some embodiments, the toxicity or adverse event is skin toxicity, macular edema, nausea, diarrhea, hyperbilirubinemia, elevated CPK, elevated AST, elevated ALT, fatigue, glossitis, oral mucositis, oral ulcers, visual disturbances, peripheral edema, pruritic lesions, fissuring lesions, desquamation, paronychia, or infectious lesions, or any combination thereof. In some embodiments, the toxicity or adverse event is skin toxicity, such as, but not limited to, a rash. In some embodiments, the toxicity or adverse event is macular edema. In some embodiments, the toxicity or adverse event is nausea. In some embodiments, the toxicity or adverse event is diarrhea. In some embodiments, the toxicity or adverse event is hyperbilirubinemia. In some embodiments, the toxicity or adverse event is elevated CPK. In some embodiments, the toxicity or adverse event is elevated AST. In some embodiments, the toxicity or adverse event is elevated ALT. In some embodiments, the toxicity or adverse event is fatigue. In some embodiments, the toxicity or adverse event is fissuring lesions. In some embodiments, the toxicity or adverse event is desquamation. In some embodiments, the toxicity or adverse event is paronychia. In some embodiments, the toxicity or adverse event is an infectious lesion.

[0119] In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is NSCLC. In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is gynecological cancer (e.g., cervical cancer, ovarian cancer (e.g., low-grade serous ovarian cancer), uterine cancer, vaginal cancer, or vulvar cancer).

[0120] In some embodiments, the cancer is characterized as having a RAS mutation. In some embodiments, the cancer is characterized as having a RAF mutation. In some embodiments, the cancer is characterized as having a KRAS, NRAS, HRAS, and / or BRAF mutation. In some embodiments, the cancer is characterized as having a KRAS mutation. In some embodiments, the cancer is characterized as having a NRAS mutation. In some embodiments, the cancer is characterized as having a HRAS mutation. In some embodiments, the cancer is characterized as having a BRAF mutation. Dual RAF / MEK inhibitor

[0121] An exemplary dual RAF / MEK inhibitor described herein is VS-6766 (also known as CKI27, CH5126766, or RO5126766).

[0122] In some embodiments, the dual RAF / MEK inhibitor is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments, the compound of formula (I) [ka] which is also referred to herein as Compound 1 or VS-6766 free form.

[0124] In some embodiments, the dual RAF / MEK inhibitor is a pharma- ceutically acceptable salt of the compound of formula (I). In some embodiments, the dual RAF / MEK inhibitor is a potassium salt of the compound of formula (I), also known as VS-6766. Other pharma-ceutically acceptable salts of the compound of formula (I) are contemplated herein.

[0125] In some embodiments, the dual RAF / MEK inhibitor has the structure of Formula (II), including pharma- ceutically acceptable salts thereof: [ka] [In the formula, Ring A is [ka] and R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C10 heteroaryl, and L; R 6 is selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, and optionally substituted C2-C6 alkynyl; X is C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] and; L is -Z1-Z2 or -Z1-Z2-Z3; Z1, Z2, and Z3 are independently -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5’ , -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -,-SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C10 heteroaryl); each R5 and R 5 is independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C10 aryl, optionally substituted C3-C8 heterocyclyl, and optionally substituted C3-C10 heteroaryl; Y is CH, NH, or O, with the proviso that R 1 is not -O-pyrimidyl.

[0126] In some embodiments, the dual RAF / MEK inhibitor is a compound selected from the compounds in Table I. [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]

[0127] In some embodiments, the dual RAF / MEK inhibitor is IMM-1-104 (Immuneering) or a pharma- ceutically acceptable salt thereof.

[0128] 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.

[0129] In some embodiments, the dual RAF / MEK inhibitor is administered at about 0.1 mg to about 100 mg, e.g., 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 50 mg per administration. In some embodiments, the dual RAF / MEK inhibitor is administered at about 0.1 mg to about 50 mg per administration. 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 dose. In some embodiments, the dual RAF / MEK inhibitor is administered at about 4 mg per dose. In some embodiments, the dual RAF / MEK inhibitor is administered at about 3.2 mg per dose. In some embodiments, the dual RAF / MEK inhibitor is administered orally.

[0130] In some embodiments, the dual RAF / MEK inhibitor is administered in a cycle. In some embodiments, the cycle comprises administering the dual RAF / MEK inhibitor for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered once per week. In some embodiments, the dual RAF / MEK inhibitor is administered twice per week. In some embodiments, the dual RAF / MEK inhibitor is administered three times per week. 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.

[0131] In some embodiments, the dual RAF / MEK inhibitor is administered twice per week in a cycle, the cycle comprising administering the dual RAF / MEK inhibitor at a dose of about 0.8 mg to about 10 mg per administration for three weeks, followed by one week without administration of the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered twice per week in a cycle, the cycle comprising administering the dual RAF / MEK inhibitor at a dose of about 1 mg to about 5 mg per administration for three weeks, followed by one week without administration of the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered twice per week in a cycle, the cycle comprising administering the dual RAF / MEK inhibitor at a dose of about 2 mg to about 4 mg per administration for three weeks, followed by one week without administration of the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered twice a week as a cycle, the cycle comprising administering the dual RAF / MEK inhibitor at a dose of 3.2 mg per administration for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered twice a week as a cycle, the cycle comprising administering the dual RAF / MEK inhibitor at a dose of 4 mg per administration for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the cycle is repeated at least once.

[0132] In some embodiments, the dual RAF / MEK inhibitor is administered three times per week in a cycle, the cycle comprising administering the dual RAF / MEK inhibitor at a dose of about 0.8 mg to about 10 mg per administration for three weeks, followed by one week without administration of the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered three times per week in a cycle, the cycle comprising administering the dual RAF / MEK inhibitor at a dose of about 1 mg to about 5 mg per administration for three weeks, followed by one week without administration of the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered three times per week in a cycle, the cycle comprising administering the dual RAF / MEK inhibitor at a dose of about 2 mg to about 4 mg per administration for three weeks, followed by one week without administration of the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered three times a week in a cycle, the cycle comprising administering the dual RAF / MEK inhibitor at a dose of 3.2 mg per administration for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the dual RAF / MEK inhibitor is administered three times a week in a cycle, the cycle comprising administering the dual RAF / MEK inhibitor at a dose of 4 mg per administration for three weeks, followed by one week without administering the dual RAF / MEK inhibitor. In some embodiments, the cycle is repeated at least once.

[0133] 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 a week). In some embodiments, the dual RAF / MEK inhibitor is administered once per week. In some embodiments, the dual RAF / MEK inhibitor is administered twice per week. In some embodiments, the dual RAF / MEK inhibitor is administered three times per week.

[0134] FAK inhibitors Potent inhibitors of FAK protein tyrosine kinase may be adapted for therapeutic use as antiproliferative agents (e.g., anticancer agents), antitumor agents (e.g., effective against solid tumors), antiangiogenic agents (e.g., stop or prevent blood vessel growth) in mammals, particularly humans. In some embodiments, the methods described herein further comprise administering to a subject a FAK inhibitor as described herein. FAK inhibitors may be useful in preventing and treating non-hematologic malignancies, various human hyperproliferative disorders, such as liver, kidney, bladder, breast, stomach, ovary, colorectal, prostate, pancreatic, lung, vulva, thyroid, liver cancer, sarcoma, glioblastoma, malignant and benign tumors of the head and neck, 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 preventing and treating disorders such as mesothelioma. In some embodiments, the compounds described herein, such as FAK inhibitors, inhibit protein tyrosine kinase 2 (PYK2).

[0135] In some embodiments, the methods described herein further comprise administering to the subject an effective amount of a FAK inhibitor.

[0136] Exemplary FAK inhibitors include, but are not limited to, those having the following structure: [ka] Defactinib includes defactinib having the formula: or a pharmaceutically acceptable salt thereof. Defactinib is also known as VS-6063 (e.g., VS-6063 free base) or PF-04554878. VS-6063 and related compounds are also disclosed in, for example, U.S. Patent No. 7,928,109, the contents of which are incorporated herein by reference. In some embodiments, VS-6063 can form a pharmaceutically acceptable salt (e.g., VS-6063 hydrochloride).

[0137] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0138] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0139] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0140] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0141] In some embodiments, the FAK inhibitor has the following structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0142] 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).

[0143] 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 its pharmaceutically acceptable salt.For example, the FAK inhibitor is defactinib or its pharmaceutically acceptable salt.

[0144] In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at least once every day. For example, in some embodiments, the FAK inhibitor (e.g., defactinib) is administered once every day. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered twice every day.

[0145] In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 100 mg to about 1000 mg per administration, e.g., 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 dose. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 200 mg per dose. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 300 mg per dose. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 400 mg per dose. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 500 mg per dose. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered at about 600 mg per dose. In some embodiments, the FAK inhibitor (e.g., defactinib) is administered orally.

[0146] In some embodiments, the FAK inhibitor is administered in a cycle, the cycle comprising administering the FAK inhibitor for three weeks, followed by not administering the FAK inhibitor for one week. In some embodiments, the cycle is repeated at least once.

[0147] Corticosteroids Exemplary corticosteroids include, but are not limited to, hydrocortisone, prednisone, triamcinolone, cortisol, corticosterone, cortisone, aldosterone, dexamethasone, prednisolone, and methylprednisolone.

[0148] In some embodiments, the corticosteroid is administered topically. In other embodiments, the corticosteroid is administered orally.

[0149] In some embodiments, the corticosteroid is administered at least once per week. In some embodiments, the corticosteroid is administered once per week. In some embodiments, the corticosteroid is administered twice per week. In some embodiments, the corticosteroid is administered three times per week. In some embodiments, the corticosteroid is administered four times per week. In some embodiments, the corticosteroid is administered five times per week. In some embodiments, the corticosteroid is administered six times per week. In some embodiments, the corticosteroid is administered at least once per day. In some embodiments, the corticosteroid is administered once per day. In some embodiments, the corticosteroid is administered twice per day. In some embodiments, the corticosteroid is administered three times per day. In some embodiments, the corticosteroid is administered twice per day. In some embodiments, the corticosteroid is administered four times per day. In some embodiments, the corticosteroid is administered twice per day. In some embodiments, the corticosteroid is administered five times per day. In some embodiments, the corticosteroid is administered twice per day. In some embodiments, the corticosteroid is administered six times daily.

[0150] In some embodiments, the corticosteroid is hydrocortisone. In some embodiments, hydrocortisone is included in a composition comprising about 0.01%-10% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition comprising about 0.01%-1% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition comprising about 0.01%-5% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition comprising about 0.1%-10% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition comprising about 0.1%-5% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition comprising about 0.1%-1% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition comprising about 0.1%-1% w / w hydrocortisone.

[0151] In some embodiments, hydrocortisone is present in a composition comprising about 0.1% w / w hydrocortisone. In some embodiments, hydrocortisone is present in a composition comprising about 0.2% w / w hydrocortisone. In some embodiments, hydrocortisone is present in a composition comprising about 0.3% w / w hydrocortisone. In some embodiments, hydrocortisone is present in a composition comprising about 0.4% w / w hydrocortisone. In some embodiments, hydrocortisone is present in a composition comprising about 0.5% w / w hydrocortisone. In some embodiments, hydrocortisone is present in a composition comprising about 0.6% w / w hydrocortisone. In some embodiments, hydrocortisone is present in a composition comprising about 0.7% w / w hydrocortisone. In some embodiments, hydrocortisone is present in a composition comprising about 0.8% w / w hydrocortisone. In some embodiments, hydrocortisone is present in a composition comprising about 0.9% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition comprising about 1% hydrocortisone w / w. In some embodiments, hydrocortisone is included in a composition comprising about 2% hydrocortisone w / w. In some embodiments, hydrocortisone is included in a composition comprising about 3% hydrocortisone w / w. In some embodiments, hydrocortisone is included in a composition comprising about 4% hydrocortisone w / w. In some embodiments, hydrocortisone is included in a composition comprising about 5% hydrocortisone w / w.

[0152] In some embodiments, hydrocortisone is included in a composition suitable for topical administration, the composition comprising from about 0.1% to about 5% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition suitable for topical administration, the composition comprising from about 0.1% to about 2% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition suitable for topical administration, the composition comprising from about 0.1% to about 1% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition suitable for topical administration, the composition comprising from about 0.5% to about 5% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition suitable for topical administration, the composition comprising from about 0.5% to about 2% w / w hydrocortisone. In some embodiments, hydrocortisone is included in a composition suitable for topical administration, the composition comprising from about 0.5% to about 1% w / w hydrocortisone. In some embodiments, the hydrocortisone is included in a composition suitable for topical administration, the composition comprising about 1% w / w hydrocortisone. In some embodiments, the hydrocortisone is included in a composition suitable for topical administration, the composition comprising about 0.5% w / w hydrocortisone. In some embodiments, the hydrocortisone is included in a composition suitable for topical administration, the composition comprising about 0.1% w / w hydrocortisone. In some embodiments, the hydrocortisone is included in a composition suitable for topical administration, the composition comprising about 2% w / w hydrocortisone. In some embodiments, the hydrocortisone is included in a composition suitable for topical administration, the composition comprising about 3% w / w hydrocortisone. In some embodiments, the hydrocortisone is included in a composition suitable for topical administration, the composition comprising about 5% w / w hydrocortisone. For example, the hydrocortisone can be in the form of a topical cream comprising about 0.1% to 10% w / w hydrocortisone. In some embodiments, the hydrocortisone cream is a 1% w / w hydrocortisone cream. In some embodiments, the hydrocortisone cream is a 2% w / w hydrocortisone cream. In some embodiments, the hydrocortisone cream is a 3% w / w hydrocortisone cream. In some embodiments, the hydrocortisone cream is a 0.1% w / w hydrocortisone cream.In some embodiments, the hydrocortisone cream is a 0.5% w / w hydrocortisone cream.

[0153] In some embodiments, the corticosteroid is administered for at least one week. In some embodiments, the corticosteroid is administered for two weeks. In some embodiments, the corticosteroid is administered for three weeks. In some embodiments, the corticosteroid is administered for four weeks. In some embodiments, the corticosteroid is administered for five weeks. In some embodiments, the corticosteroid is administered for six weeks. In some embodiments, the corticosteroid is administered for seven weeks. In some embodiments, the corticosteroid is administered for eight weeks. In some embodiments, the corticosteroid is administered for the first two cycles (e.g., the dual RAF / MEK inhibitor is administered for three weeks, then not administered for one week, then administered for three weeks, then not administered for one week). In other embodiments, the corticosteroid is administered at least once a week for as long as the dual RAF / MEK inhibitor is administered to the subject. In some embodiments, the corticosteroid is administered at least twice a week for as long as the dual RAF / MEK inhibitor is administered to the subject. In some embodiments, the corticosteroid is administered at least three times a week as long as the dual RAF / MEK inhibitor is administered to the subject. In some embodiments, the corticosteroid is administered at least four times a week as long as the dual RAF / MEK inhibitor is administered to the subject. In some embodiments, the corticosteroid is administered at least five times a week as long as the dual RAF / MEK inhibitor is administered to the subject. In some embodiments, the corticosteroid is administered at least once a day as long as the dual RAF / MEK inhibitor is administered to the subject. In some embodiments, the corticosteroid is administered at least twice a day as long as the dual RAF / MEK inhibitor is administered to the subject.

[0154] antibiotics Exemplary antibiotic agents include, but are not limited to, minocycline, doxycycline, tetracycline, clindamycin, sulfadiazine, polysporin, neomycin, bacitracin, erythromycin, and azithromycin. In some embodiments, the antibiotic agent is minocycline. In some embodiments, the antibiotic agent is doxycycline.

[0155] In some embodiments, the antibiotic agent reduces inflammation, hi some embodiments, the antibiotic agent is an anti-inflammatory agent.

[0156] In some embodiments, the antibiotic agent is administered topically, hi other embodiments, the antibiotic agent is administered orally.

[0157] In some embodiments, the antibiotic agent is administered at least once daily. In some embodiments, the antibiotic agent is administered once daily. In some embodiments, the antibiotic agent is administered twice daily. In some embodiments, the antibiotic agent is administered three times daily. In some embodiments, the antibiotic agent is administered at least once weekly. In some embodiments, the antibiotic agent is administered once weekly. In some embodiments, the antibiotic agent is administered twice weekly. In some embodiments, the antibiotic agent is administered three times weekly. In some embodiments, the antibiotic agent is administered four times weekly. In some embodiments, the antibiotic agent is administered five times weekly. In some embodiments, the antibiotic agent is administered six times weekly. In some embodiments, the antibiotic agent is administered seven times weekly.

[0158] In some embodiments, the antibiotic agent is administered at a dose of about 1 mg to 10,000 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 1 mg to 5,000 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 10 mg to 5,000 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 10 mg to 2,000 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 10 mg to 1,000 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 50 mg to 1,000 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 50 mg to 500 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 100 mg to 900 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 100 mg to 800 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 100 mg to 700 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 100 mg to 600 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 100 mg to 500 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 10 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 50 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 100 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 150 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 200 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 250 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 300 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 350 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 400 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 450 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 500 mg per dose.In some embodiments, the antibiotic agent is administered at a dose of about 550 mg per dose.In some embodiments, the antibiotic agent is administered at a dose of about 600 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 650 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 700 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 750 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 800 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 850 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 900 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 950 mg per dose. In some embodiments, the antibiotic agent is administered at a dose of about 1000 mg per dose.

[0159] In some embodiments, the antibiotic agent is administered in combination with the dual RAF / MEK inhibitor to produce synergistic effects.For example, the effective amount of the antibiotic agent to be administered to the subject is the amount that produces synergistic effects (i.e., more than additive effects) with the administration of the dual RAF / MEK inhibitor.In some embodiments, the administration of the dual RAF / MEK inhibitor and the antibiotic agent is synergistic, as identified by a combination synergy score of ≧5.In some embodiments, the combination synergy score is the sum of Bliss score, ZIP score, HSA score and Loewe score.

[0160] In some embodiments, the antibiotic agent is administered for at least one week. In some embodiments, the antibiotic agent is administered for two weeks. In some embodiments, the antibiotic agent is administered for three weeks. In some embodiments, the antibiotic agent is administered for four weeks. In some embodiments, the antibiotic agent is administered for five weeks. In some embodiments, the antibiotic agent is administered for six weeks. In some embodiments, the antibiotic agent is administered for seven weeks. In some embodiments, the antibiotic agent is administered for eight weeks. In some embodiments, the antibiotic agent is administered for the first two cycles in which the subject is administered the dual RAF / MEK inhibitor (e.g., the dual RAF / MEK inhibitor is administered for three weeks, then not administered for one week, then administered for three weeks, then not administered for one week). In other embodiments, the antibiotic agent is administered at least once daily for as long as the dual RAF / MEK inhibitor is administered to the subject. In some embodiments, the antibiotic agent is administered at least twice daily for as long as the dual RAF / MEK inhibitor is administered to the subject.

[0161] Additional drugs In some embodiments, the methods described herein further include administering one or more medications (e.g., preventative agents), including, but not limited to, cold compresses, oral antihistamines (e.g., diphenhydramine), Monsell's solution, silver nitrate or zinc oxide creams, emollients, mild soaps, antiseptic baths, fungal driven systemic or topical antibiotic agents, and sunscreen. Diseases and Disorders Abnormal cell growth

[0162] Abnormal cell growth, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition).This includes: (1) tumor cells (tumors), for example, that grow by expressing mutant tyrosine kinases or by overexpressing receptor tyrosine kinases; (2) benign and malignant cells, for example, of other proliferative diseases, where abnormal tyrosine kinase activation occurs; (3) any tumor, for example, that grows by receptor tyrosine kinases; (4) any tumor, for example, that can grow by abnormal serine / threonine kinase activation; and (5) the abnormal growth of benign and malignant cells, for example, of other proliferative diseases, where abnormal serine / threonine kinase activation occurs. Abnormal cell growth may refer to cell growth in epithelial (e.g., carcinoma, adenocarcinoma); mesenchymal (e.g., sarcoma (e.g., leiomyosarcoma, Ewing's sarcoma)); hematopoietic (e.g., lymphoma, leukemia, myelodysplasia (e.g., premalignant)); or other (e.g., melanoma, mesothelioma, and other tumors of unknown origin) cells. Neoplastic Disorders

[0163] Abnormal cell growth may refer to a neoplastic disorder. A "neoplastic disorder" is a disease or disorder characterized by cells capable of autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. An abnormal mass of tissue, or "neoplasm," resulting from abnormal cell growth or division, may be benign, premalignant (intracellular carcinoma) or malignant (cancer).

[0164] Exemplary neoplastic disorders include carcinomas, sarcomas, metastatic disorders (e.g., tumors arising from prostate, colon, lung, breast, and liver origins), hematopoietic neoplastic disorders, e.g., leukemias, metastatic tumors. Treatment with the compound can be in an amount effective to ameliorate at least one symptom of the neoplastic disorder, e.g., reduce cell proliferation, reduce tumor mass, etc. cancer

[0165] The inventive method of the present invention may be useful in the prevention and treatment of cancer, including, for example, solid tumors, soft tissue tumors, and metastases thereof. The disclosed method is also useful in the treatment of non-solid cancers. Exemplary solid tumors include malignancies of various organ systems (e.g., sarcomas, adenocarcinomas, and carcinomas), such as malignancies of the lung, breast, lymphatic system, gastrointestinal tract (e.g., colon), and genitourinary tract (e.g., renal, urothelial, or testicular tumors), pharynx, prostate, and ovary. Exemplary adenocarcinomas include colorectal cancer, renal cell carcinoma, liver cancer (e.g., hepatocellular carcinoma), non-small cell carcinoma of the lung, pancreas (e.g., metastatic pancreatic adenocarcinoma), and small intestine.

[0166] The cancer may include mesothelioma, neurofibromatosis, e.g., neurofibromatosis type 2, neurofibromatosis type 1, renal cancer, lung cancer, non-small cell lung cancer, liver cancer, thyroid cancer, ovarian cancer, breast cancer, nervous system tumors, schwannoma, meningioma, schwannomatosis, acoustic neuroma, adenoid cystic carcinoma, ependymoma, ependymal tumor, or any other tumor that exhibits reduced merlin expression and / or mutation, and / or deletion and / or promoter hypermethylation of NF-2 gene. In some embodiments, the cancer is renal cancer.

[0167] For example, cancer may include, but is not limited to, ovarian cancer, non-small cell lung cancer (e.g., NSCLC adenocarcinoma), endometrioid carcinoma, pancreatic adenocarcinoma, colorectal adenocarcinoma, colorectal cancer, pancreatic cancer, or lung adenocarcinoma.In some embodiments, NSCLC is characterized as having KRAS mutation.In some embodiments, ovarian cancer is low-grade serous ovarian cancer.

[0168] The cancer may include cancers characterized as containing cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells. The cancer may include cancers characterized as 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).

[0169] Cancer can be a primary tumor, i.e., located at the anatomical site of tumor growth initiation. Cancer can also be metastatic, i.e., appear at at least a second anatomical site other than the anatomical site of tumor growth initiation. Cancer can be a recurrent cancer, i.e., cancer that recurs after treatment and after a period of time during which the cancer was undetectable. Recurrent cancer can be anatomically local to the original tumor, e.g., anatomically near the original tumor; regionally to the original tumor, e.g., in a lymph node located near the original tumor; or distal to the original tumor, e.g., in an area anatomically distant from the original tumor.

[0170] Cancers may also include, for example, but are not limited to, epithelial cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer (e.g., metastatic colorectal cancer, e.g., metastatic KRAS mutation), prostate cancer, head and neck cancer, melanoma (e.g., NRAS mutation locally advanced or metastatic malignant cutaneous melanoma), acute myeloid leukemia, and glioblastoma. Exemplary breast cancers include triple-negative breast cancer, basal-like breast cancer, claudin-low breast cancer, invasive, inflammatory, dysplastic, and treatment-resistant advanced HER-2 positive or ER positive cancers.

[0171] In some embodiments, cancer is characterized as having RAS mutation.In some embodiments, cancer is characterized as having KRAS mutation.In some embodiments, KRAS mutation is KRAS G12V mutation, KRAS G12D mutation, KRAS G12A mutation, KRAS G12R mutation, KRAS G12S mutation or KRAS G12C mutation.In some embodiments, cancer is characterized as having NRAS mutation.In some embodiments, cancer is characterized as having HRAS mutation.

[0172] In some embodiments, the cancer is characterized as having a RAF mutation. In some embodiments, the cancer is characterized as having a BRAF mutation. In some embodiments, the BRAF mutation is a BRAF V600E / K mutation. In some embodiments, the cancer is characterized as having a CRAF mutation. In some embodiments, the cancer is characterized as having an atypical BRAF mutation.

[0173] The cancer may also include lung adenocarcinoma, colorectal cancer (CRC), uveal melanoma, ovarian cancer, uterine endometrioid carcinoma, bladder urothelial carcinoma, invasive lobular carcinoma of the breast, cervical squamous cell carcinoma, cutaneous melanoma, endocervical adenocarcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, biphasic type pleural mesothelioma, renal clear cell carcinoma, gastric adenocarcinoma, gastric tubular adenocarcinoma, uterine carcinosarcoma, or uterine malignant mixed Mullerian tumor.

[0174] In some embodiments, the cancer is unresectable or metastatic melanoma, melanoma with lymph node metastases 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, advanced renal cell carcinoma that has previously received antiangiogenic therapy, advanced 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, microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, or hepatocellular carcinoma.

[0175] 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, microsatellite instability high carcinoma, gastric cancer, esophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, or endometrial carcinoma.

[0176] 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 and bone marrow cancers (e.g., advanced hematologic malignancies, leukemias, e.g., acute myeloid leukemia (primary or secondary), acute lymphoblastic leukemia, acute lymphocytic leukemia, T-cell leukemia, hematologic malignancies, advanced myeloproliferative disorders, The following cancer types are considered to be present in the clinical trials: myelodysplastic syndromes, relapsed or refractory multiple myeloma, progressive 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-proliferative testicular cells, malignant mast cell associated cancer, non-Hodgkin's lymphoma, and diffuse large B-cell lymphoma.

[0177] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is locally advanced or metastatic. In some embodiments, the solid tumor is refractory (e.g., resistant) to standard treatments.

[0178] The methods described herein can reduce, improve or completely eliminate the disorder and / or its associated symptoms, prevent it from getting worse, slow down the rate of progression, or minimize the recurrence rate of the disorder once it is initially eliminated (i.e., avoid relapse). Suitable doses and treatment regimens can vary depending on the specific compounds, combinations, and / or pharmaceutical compositions used, and the mode of delivery of the compounds, combinations, and / or pharmaceutical compositions. In some embodiments, the methods statistically significantly increase the average length of survival, increase the average length of progression-free survival, and / or reduce the recurrence rate of subjects treated with the combinations described herein.

[0179] In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (CNSCLC), e.g., KRAS mutant NSCLC; metastatic cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer (e.g., unresectable low-grade ovarian cancer, advanced or metastatic ovarian cancer), rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer (e.g., triple-negative breast cancer (e.g., estrogen receptor, progesterone receptor, and Her2 / neu genes), In some embodiments, the cancer is a cancer of the breast (e.g., breast cancer not expressing the gene), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, mesothelioma (e.g., malignant pleural mesothelioma, e.g., surgically resectable malignant pleural mesothelioma), or a combination of one or more of the foregoing cancers. In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth is locally recurrent (eg, the subject has a locally recurrent disease, eg, cancer). Additional treatment

[0180] In some embodiments, the methods and compositions described herein are administered together with an additional treatment. In one embodiment, a mixture of one or more compounds or pharmaceutical compositions may be administered with the combination described herein to a subject in need thereof. In yet another embodiment, one or more compounds or compositions (e.g., pharmaceutical compositions) may be administered with the combination described herein for treating or avoiding various diseases, including, for example, cancer, diabetes, neurodegenerative diseases, cardiovascular diseases, blood clotting, inflammation, flushing, obesity, aging, stress, and the like. In various embodiments, combination therapy comprising a compound or pharmaceutical composition described herein may refer to (1) a pharmaceutical composition comprising one or more compounds in combination with a combination described herein and (2) the simultaneous administration of one or more compounds or pharmaceutical compositions described herein that are not formulated in the same composition with the combination described herein. In some embodiments, the combination described herein is administered with an additional treatment (e.g., an additional cancer treatment). In some embodiments, the additional treatment (e.g., an additional cancer treatment) may be administered simultaneously (e.g., at the same time) in the same or separate compositions, or sequentially. Sequential administration refers to administration of one treatment prior to (e.g., immediately before, 5 minutes, 10 minutes, 15 minutes, 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 more before; 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or more before; 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or more before) administration of an additional, e.g., second, treatment (e.g., compound or treatment). The order of administration of the first and second compounds or treatments can also be reversed.

[0181] In some embodiments, the additional therapy is a cancer treatment. Exemplary cancer treatments include, for example, chemotherapy, targeted therapy, such as antibody therapy, immunotherapy, and hormonal therapy. Examples of each of these treatments are provided below. chemotherapy

[0182] In some embodiments, the combination described herein is administered with chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "Chemotherapy" usually refers to cytotoxic drugs that generally affect rapidly dividing cells, in contrast to targeted therapy. Chemotherapy drugs interfere with cell division, for example, DNA replication or the separation of newly formed chromosomes, in various possible ways. Most forms of chemotherapy all target rapidly dividing cells and are not specific to cancer cells, but some degree of specificity may result from the fact that many cancer cells cannot repair DNA damage, whereas normal cells generally can.

[0183] 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 mustards, nitrosoureas, platinum, alkylsulfonates, hydrazines, triazenes, aziridines, spindle poisons, cytotoxic agents, topoisomerase inhibitors, etc.). Exemplary agents include aclarubicin, actinomycin, alitretin, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglucan cyclosporine, etoposide, floxuridine, fludarabine, fluorouracil (5FU), fotemustine, gemcitabine, gliadel implant, hydroxycarbamide, hydroxyurea, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, larotaxel, leucovorin, liposomal doxorubicin, liposomal daunorubicin, lonidamine, lomustine, lucantone, mannosulfan, masoprocol, melphalan, mercapto Purine, mesna, methotrexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, plicamycin, porfimer sodium, prednimustine, procarbazine,Raltitrexed, Ranimustine, Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin, Talaporfm, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurin, Thioguanine, Tipifarnib, Topotecan, Trabectedin, Triazicon, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein.

[0184] 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. targeted therapy

[0185] In some embodiments, the combination described herein is administered with targeted therapy. Targeted therapy constitutes the use of drugs specific to deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of the enzyme domain of proteins that are mutated, overexpressed, or otherwise critical in cancer cells. Notable examples are tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, dasatinib, erolotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, and also cyclin-dependent kinase inhibitors such as alvocidib and seliciclib. Monoclonal antibody therapy is another strategy in which 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®), typically used in breast cancer, and the anti-CD20 antibodies rituximab and tositumomab, typically used in various B-cell malignancies. Other exemplary antibodies include cetuximab (Ctuximab), panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin diftitox. In some embodiments, targeted therapy may be used in combination with the combinations described herein.

[0186] Targeted therapy may also involve small peptides as "homing devices" that can bind to cell surface receptors or the diseased extracellular matrix surrounding the tumor. Radionuclides (e.g., RGD) attached to these peptides ultimately kill the cancer cells if they decay in the vicinity of the cells. An example of such a therapy is BEXXAR®. immunotherapy

[0187] In some embodiments, the combinations described herein are administered with immunotherapy. Cancer immunotherapy refers to a diverse set of treatment strategies designed to induce a subject's own immune system to fight the tumor.

[0188] Modern methods for generating immune responses against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, and the use of interferon and other cytokines to induce immune responses 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 in a graft-versus-tumor effect.In some embodiments, immunotherapeutic agents can be used in combination with the combinations described herein. Hormone therapy

[0189] In some embodiments, the combination described is administered 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 hormone agonists such as progestogens can be therapeutically beneficial.In some embodiments, hormone therapy agents can be used in combination with the combination described herein.

[0190] 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 inhibitor, including but not limited to anastrozole, letrozole and exemestane.In some embodiments, the additional agent is an estrogen receptor modulator, including but not limited to fulvestrant, tamoxifen and raloxifene. Radiation therapy

[0191] The combinations described herein can be used in combination with directed energy or particle, or radioisotope treatment, e.g., radiation therapy, e.g., radiation oncology, to treat proliferative diseases, e.g., cancer, e.g., cancer associated with cancer stem cells. The combinations described herein can be administered to a subject simultaneously or sequentially with directed energy or particle, or radioisotope treatment. For example, the combinations described herein can be administered before, during, or after directed energy or particle, or radioisotope treatment, or combinations thereof. Directed energy or particle therapy can include total body irradiation, localized irradiation, or point irradiation. Directed energy or particle can be derived from an accelerator, synchrotron, nuclear reaction, vacuum tube, laser, or radioisotope. The therapy can include external beam radiation therapy, teletherapy, brachytherapy, sealed source radiation therapy, total body radioisotope therapy, or unsealed source radiotherapy. The therapy may involve the ingestion or placement in close proximity of a radioisotope, such as radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, or carbon. External radiation may involve exposure to directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radio waves, millimeter waves, microwaves, infrared, visible light, ultraviolet light, X-rays, or gamma ray photons). Radiation may be directed to any part of the subject requiring treatment. surgery

[0192] The combinations described herein can be used in combination with surgery, e.g., surgical exploration, intervention, biopsy, to treat proliferative diseases, e.g., cancer, e.g., cancer associated with cancer stem cells. The combinations described herein can be administered to a subject simultaneously or sequentially with surgery. For example, the combinations described herein can be administered before (pre-op), during, or after (post-op), 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 accomplished, for example, with a scalpel, needle, catheter, endoscope, spatula, or scissors. The biopsy can be an excision biopsy, an incision biopsy, a core biopsy, or a needle biopsy, e.g., a needle aspiration biopsy. The surgery can involve the removal of localized tissue suspected or identified as cancerous. For example, the procedure can involve the removal of a cancerous lesion, mass, polyp, or birthmark. The procedure can involve the removal of a large amount of tissue, e.g., breast, bone, skin, fat, or muscle. The procedure may involve removal of part or all of an organ or node, such as the lung, throat, tongue, bladder, cervix, ovaries, testes, lymph nodes, liver, pancreas, brain, eye, kidney, gallbladder, stomach, colon, rectum, or intestine. In one embodiment, the cancer is breast cancer, such as triple-negative breast cancer, and the surgery is a mastectomy or lumpectomy. Anti-inflammatory agents

[0193] The combinations described herein may be administered with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, nonsteroidal 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, inoxicam, nabumetone ... Soxicam), fenamic acid derivatives (fenamates) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxibs) (celecoxib), sulfonanilides (nimesulide), steroids (Steriods) (e.g., hydrocortisone (cortisol), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone). Painkillers

[0194] Analgesics include, but are not limited to, opiates (e.g., morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine, tramadol, venlafaxine), paracetomal, and nonsteroidal anti-inflammatory drugs (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, ophthalmic solution, etc.), and / or steroids (e.g., benzodiazepine, benzocaine ... xaprozin, 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). Antiemetics

[0195] The combinations described herein may be administered with antiemetic agents. Antiemetic agents 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, Stem These may include: acetaminophen (Aminox, Buccastem, Stemetil, Phenotil), NK1 receptor antagonists (Aprepitant (Emend), antihistamines (cyclizine, diphenhydramine (Benadryl), dimenhydrinate (Gravol, Dramamine), meclozine (Bonin, Antivert), promethazine (Pentazin, Phenergan, Promacot), hydroxyzine), benzodiazapines (lorazepam, midazolam), anticholinergics (hyoscine), steroids (dexamethasone). combination

[0196] The phrase "in combination with," as well as the terms "co-administration," "co-administering," or "co-providing," as used herein in the context of administration of a compound described herein or a treatment described herein, means that two (or more) different compounds or treatments are delivered to a subject during the course of the subject's illness with a disease or disorder (e.g., a disease or disorder described herein, e.g., cancer), e.g., two (or more) different compounds or treatments are delivered to a subject after the subject has been diagnosed with a disease or disorder (e.g., a disease or disorder described herein, e.g., cancer), but before the disease or disorder is cured or eliminated, or treatment is otherwise discontinued.

[0197] In some embodiments, the delivery of one compound or treatment is still occurring when the delivery of the second compound or treatment begins, such that there is an overlap in terms of administration. This is sometimes referred to herein as "simultaneous" or "concurrent delivery". In other embodiments, the delivery of one compound or treatment ends before the delivery of the other compound or treatment begins. In some embodiments in either case, the treatment (e.g., administration of a compound, composition, or treatment) is more effective due to the combined administration. For example, the second compound or treatment is more effective than would be seen when the second compound or treatment is administered in the absence of the first compound or treatment, e.g., a comparable effect is seen with the second compound or treatment to a lesser extent, 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 in symptoms, or other parameters associated with the disorder, is greater than that observed with one compound or treatment delivered in the absence of the other. The effect of the two compounds or treatments can be partially additive, fully additive, or greater than additive (e.g., synergistic). The delivery can be such that the first compound or therapy delivered is still detectable when the second compound or therapy is delivered.

[0198] 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 administration of a compound or treatment before administration of an additional, e.g., second, compound or treatment (e.g., immediately before, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, less than 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 more before; 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or more before; 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or more before). The order of administration of the first and second compound or treatment can also be reversed.

[0199] The combinations described herein may be first line treatments for abnormal cell growth, e.g., cancer (i.e., used in subjects who have not previously been administered another drug intended to treat cancer); second line treatments for cancer (i.e., used in subjects in need thereof who have previously been administered another drug intended to treat cancer); or third or fourth line treatments for cancer (i.e., used in subjects who have previously been administered two or three other drugs intended to treat cancer). Administration and Dosage

[0200] The combination of the present invention can be administered orally, parenterally, topically, rectally, or via an implanted reservoir, preferably by oral administration or injection. In some cases, the pH of a composition (e.g., pharmaceutical composition) can be adjusted with a pharma- ceutically acceptable acid, base, or buffer to enhance the stability or effectiveness of the composition.

[0201] In some embodiments, the subject is orally administered the composition (e.g., pharmaceutical composition). In some embodiments, the composition (e.g., pharmaceutical composition) is orally administered in any orally acceptable dosage form, including, but not limited to, liqui-gel tablets or capsules, syrups, emulsions, and aqueous suspensions. The liquid gel may contain gelatin, plasticizers, and / or opacifiers, 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 xanthum gum, starches, such as cornstarch, or gluten, may be added to achieve the desired consistency of the composition (e.g., pharmaceutical composition). If desired, certain sweeteners and / or flavorings and / or colorings may be added.

[0202] In some embodiments, the subject is administered a composition (e.g., a pharmaceutical composition) in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained release formulation, liquid, and suspension. The composition (e.g., a pharmaceutical composition) may be in a unit dosage form suitable for single administration of a precise dosage. In addition to the compounds described herein, the pharmaceutical composition may include a pharma- ceutically acceptable carrier, and may further include one or more pharma- ceutically acceptable excipients, such as, for example, stabilizers, diluents, binders, and lubricants, as necessary. In addition, the tablet may include other medicinal or pharmaceutical agents, carriers, and / or adjuvants. Exemplary pharmaceutical compositions include compressed tablets (e.g., direct compressed tablets).

[0203] Tablets containing active or therapeutic ingredients (e.g., compounds described herein) are also provided. In addition to active or therapeutic ingredients, tablets may contain some inert substances, such as carriers. Pharmaceutically acceptable carriers may be sterile liquids, such as water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, sesame oil, and the like. Saline solution and aqueous dextrose may also be employed as liquid earners. Thus, oral dosage forms for use according to the present invention may be formulated in a conventional manner using one or more pharma-ceutically acceptable carriers, including excipients and auxiliaries that facilitate the processing of the active ingredient into a medicament that can be used.

[0204] Excipients can impart good powder flow and compression properties to the material being compressed. Examples of excipients can be found, for example, in the Handbook of Pharmaceutical Excipients (5 th edition), Edited by Raymond C Rowe, Paul J. Sheskey, and Sian C. Owen; Publisher: Pharmaceutical Press.

[0205] For oral administration, the active ingredient, for example, the compounds described herein, can be easily formulated by combining the active ingredient with pharma- ceutically acceptable carriers well known in the art. Such carriers allow 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 subjects. Pharmacological preparations for oral use can be produced using solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, for example, to obtain tablets. Suitable excipients, such as diluents, binders or disintegrants, may be desirable.

[0206] Dosages may vary depending on the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage may be chosen by the individual physician in light of the subject's condition. (See, e.g., Fingl, et al., 1975, in 'the Pharmacological Basis of Therapeutics'). Lower or higher doses 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, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptom, the subject's predisposition to the disease, condition or symptom, and the judgment of the treating physician. A course of treatment may include one or more separate administrations of the compounds described herein. A course of treatment may include one or more cycles of the compounds described herein.

[0207] In some embodiments, when used herein in the context of the cycle of administration of a drug, cycle refers to the period during which the drug is administered to a subject.For example, when the drug is administered over a 21-day cycle, periodic administration, for example, every day or twice every day, is given for 21 days.The drug can be administered over more than one cycle.Residual periods can be inserted between cycles.Residual cycles 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 more weeks in length.

[0208] Oral dosage forms may be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing active ingredients if desired. Packs, such as blister packs, may comprise, for example, metal or plastic foil. Packs or dispenser devices may be accompanied by instructions for administration. Packs or dispensers may also be accompanied by a notice associated with the container, in a form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceuticals, reflecting the form of composition or the agency's approval for human or veterinary administration. Such notice may be, for example, that of the label approved by the US Food and Drug Administration for prescription drugs or the approved product insert. EXAMPLES

[0209] The following representative examples are intended to help illustrate the present invention, and they are not intended, nor should they be construed, as limiting the scope of the invention.

[0210] Example 1 Rash prophylaxis for the administration of VS-6766 alone or in combination with defactinib in subjects with cancer, such as recurrent low-grade serous ovarian cancer or non-small cell lung cancer One cohort of subjects with KRAS mutant tumors received 4.0 mg of VS-6766 orally twice weekly (Monday / Thursday or Tuesday / Friday) for 3 weeks, each in a 4-week (28 day) cycle, followed by a 1-week washout period (i.e., no VS-6766 administration).

[0211] A separate cohort of subjects with KRAS mutant tumors received 3.2 mg VS-6766 orally twice weekly (Monday / Thursday or Tuesday / Friday) and 200 mg defactinib orally twice daily, both for 3 weeks, each in a 4-week (28 day) cycle, followed by a 1-week washout period (i.e., no VS-6766 or defactinib administration).

[0212] Risks of VS-6766 treatment include skin toxicity. No overt toxicity specific to the combination of VS-6766 and defactinib was observed in the 52 subjects treated with the combination. The most common treatment-related AEs were rash (90%), CPK elevation (56%), hyperbilirubinemia (42%), AST elevation (38%), fatigue (31%), glossitis / oral mucositis / oral ulcer (31%), ALT elevation (29%), diarrhea (29%), visual disturbance (29%), nausea (25%) and peripheral edema (21%).

[0213] Prophylactic medications were used during the first two cycles of study therapy, and cycle 3 was initiated as needed to mitigate dermatological toxicity. Hydrocortisone 1% cream, moisturizer, and sunscreen were applied topically twice daily along with systemic antibiotics (minocycline 100 mg daily or doxycycline 100 mg twice daily). Topical medication applications included the most commonly affected skin areas, such as the face, scalp, neck, upper chest, and upper back. In addition, subjects were advised to avoid unnecessary exposure to sunlight.

[0214] Subjects who developed a rash / skin toxicity were advised to see a board-certified dermatologist and be evaluated for management of symptomatic / supportive care.

[0215] General recommendations for symptomatic care may include the following: Pruritic lesions: Cold compresses and oral antihistamine therapy Fissure lesions: Monsel's solution, silver nitrate or zinc oxide cream Desquamation: Thick emollients and mild soaps Paronychia: Antiseptic baths, antibiotics plus topical strong corticosteroids; if no improvement, consult a dermatologist or surgeon Infectious lesions: systemic or topical antibiotics driven by appropriate bacterial / fungal cultures

[0216] Table 2 provides dose modifications and clinical management guidance for specific toxicities. [Table 2-1] [Table 2-2] [Table 2-3]

[0217] Example 2 Combination of VS-6766 and / or defactinib with antibiotics The antiproliferative effects of antibiotic agents such as doxycycline (e.g., 5 or 10 μM) or minocycline (e.g., 1.25 μM) in combination with VS-6766 (e.g., 40 nM) or defactinib (e.g., 1 μM) were tested in three different human tumor cell lines in 2D culture.

[0218] In vitro 2D proliferation assay Human cancer cell lines were grown under 2D conditions. Briefly, cells were seeded in 100 μL of growth medium. After overnight (17-22 h) incubation, cells were treated with VS-6766 + / - minocycline or doxycycline for 7 days. Alternatively, cells were treated with defactinib + / - doxycycline for 7 days. Cell viability was measured using the CellTiter-Glo Cell Viability Assay.

[0219] Synergy Analysis Raw data and metadata files were processed with custom R-scripts for single agent and combination activity. Bliss, Loewe, Highest Single Agent (HSA) and ZIP synergy analyses were performed to generate composite synergy scores (see, e.g., Malyutina A et al, "Drug combination sensitivity scoring facilitates the discovery of synergistic and efficacious drug combinations in cancer," PLOS Computational Biology 15(5): e1006752). Summary images and reports were saved for visualization and further analysis.

[0220] For example, combining drug 1 at concentration x1 and drug 2 at concentration x2, c The inhibitory effect of each drug is considered to be y1(x1) and y2(x2), while the effects of each drug are considered to be y1(x1) and y2(x2). The synergy score is calculated by c Expected effect in the absence of synergy y e Each synergy score was calculated as the difference between y e We will adopt different models for 1. HSA:y e is the maximum single drug effect, S HSA =y c -max(y1(x1),y2(x2)) (1) Define it as: 2.Bliss:y e is the expected effect of the two drugs acting independently, S Bliss =y c -(y1(x1)+y2(x2)-y1(x1)y2(x2)) (2) Define it as: 3.Loewe:y e is the expected effect of the drug in combination with itself, S Loewe =y c -y1(x1+x2)=y c -y2(x1+x2) (3) Define it as: 4.ZIP:y e is the expected effect of the two drugs not reinforcing each other, S ZIP =y' c -y'1(x1+x2)=y' c -y'2(x1+x2) (4) (In the formula, y' c’ -y'1(x1) and y'2(x2) are the fitted values ​​based on the full-dose response matrix for the combination and monotherapy drugs, respectively.

[0221] A dose-response matrix was used to evaluate the anti-proliferative effects of VS-6766 + / - minocycline or doxycycline combinations and defactinib + / - doxycycline combinations. Figure 1 shows an exemplary combination effect of VS-6766 or defactinib with and without minocycline or doxycycline. H358 human non-small cell lung cancer (NSCLC) cells were grown under 2D conditions. Cells were treated with VS-6766 + / - minocycline or doxycycline for 7 days. Alternatively, cells were treated with defactinib + / - doxycycline for 7 days. Cell viability was measured using the Cell Viability CellTiter-Glo assay.

[0222] Figure 2 shows an exemplary plot of calculated synergy scores for the combination of VS-6766 and doxycycline. Synergy scores were calculated using a combination of four different methods (Bliss, Loewe, HSA, and ZIP). Human cancer cell lines were introduced into the CTG proliferation assay. Raw data and metadata files were processed with custom R-scripts for single agent and combination activity. Bliss, Loewe, Highest Single Agent (HSA), and ZIP synergy analyses were performed to generate a composite synergy score. The example used in this figure is VS-6766 + doxycycline in H358 cells.

[0223] FIG. 3 shows an exemplary plot of calculated synergy scores for the combination of minocycline or doxycycline with VS-6766 or defactinib in the NCI-H358 cell line. H358 human NSCLC cells were introduced into the CTG proliferation assay. Raw data and metadata files were processed with custom R-scripts for single agent and combination activity. Bliss, Loewe, Highest Single Agent (HSA), and ZIP synergy analyses were performed to generate a composite synergy score. As an example, the 3D plot shows the Bliss synergy analysis of the combinations VS-6766 + doxycycline, VS-6766 + minocycline + defactinib + doxycycline in H358 cells.

[0224] Figure 4 shows an exemplary plot of calculated synergy scores for the combination of VS-6766 and doxycycline across multiple cell lines. Human cancer cell lines (H358 NSCLC, H2122 NSCLC and TOV21G ovarian cancer) were introduced into the CTG proliferation assay. Raw data and metadata files were processed with custom R-scripts for single agent and combination activity. Bliss, Loewe, Highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. As an example, the 3D plot shows the Bliss synergy analysis of the combination of VS-6766 + doxycycline in H358, H2122 and TOV21.

[0225] It was surprising to find that doxycycline or minocycline increased the antitumor efficacy of VS-6766 and defactinib. As shown in Figure 3, VS-6766 and defactinib are synergistic with antibiotics in inhibiting tumor cell proliferation. Figure 4 shows that this synergistic effect spans multiple tumor cell lines.

[0226] Equivalents and Scope In the claims, articles such as "a," "an," and "the" may mean one or more than one, unless indicated to the contrary or obvious from the context. A claim or description containing "or" between one or more members of a group is considered to be satisfied when 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, unless indicated to the contrary or obvious from the context. The invention includes embodiments in which exactly one member of a group is present in, employed in, or relevant to a given product or process. The invention includes embodiments in which more than one, or all of the members of a group are present in, employed in, or relevant to a given product or process.

[0227] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim can be amended to include one or more limitations found in other claims that are dependent on the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element can be removed from the group. In general, where the invention, or aspects of the invention, are referred to as including certain elements and / or features, it should be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For the sake of brevity, these embodiments have not been specifically set forth in these exact terms herein. It is also noted that the terms "comprising" and "containing" are intended to be open-ended, permitting the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or obvious from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the range stated in different embodiments of the invention to one tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0228] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. Furthermore, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, since they are deemed to be known to those skilled in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0229] 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 the present specification without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

1. Use of an effective amount of a dual RAF / MEK inhibitor, an effective amount of an antibiotic, and an effective amount of a corticosteroid in the manufacture of a medicament for reducing the severity of or preventing toxicity or adverse events associated with the administration of a dual RAF / MEK inhibitor in a subject in need thereof.

2. The use described in claim 1, wherein the use further comprises an effective amount of a FAK inhibitor.

3. 3. The use according to claim 2, wherein the FAK inhibitor is defactinib or a pharmaceutically acceptable salt thereof.

4. The dual RAF / MEK inhibitor has formula (I): 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

5. 2. The use of claim 1, wherein the dual RAF / MEK inhibitor is for administration at a dose of 0.5 mg to 10 mg per administration.

6. 6. The use of claim 5, wherein the dual RAF / MEK inhibitor is for administration at a dose of 3.2 mg per administration or at a dose of 4 mg per administration.

7. 2. The use of claim 1, wherein the dual RAF / MEK inhibitor is for administration twice a week.

8. 2. The use of claim 1, wherein the dual RAF / MEK inhibitor is to be administered as a cycle comprising administering the dual RAF / MEK inhibitor for three weeks, followed by not administering the dual RAF / MEK inhibitor for one week.

9. 2. The use of claim 1, wherein the dual RAF / MEK inhibitor is for oral administration to the subject.

10. 2. The use of claim 1, wherein the corticosteroid is hydrocortisone, prednisone, triamcinolone, cortisol, corticosterone, cortisone, aldosterone, dexamethasone, prednisolone, or methylprednisolone.

11. 2. The use of claim 1, wherein the corticosteroid is for topical administration.

12. 2. The use of claim 1, wherein the corticosteroid is for twice-daily or once-daily administration.

13. 11. The use according to claim 10, wherein the corticosteroid is hydrocortisone.

14. 14. The use according to claim 13, wherein the hydrocortisone is contained in a composition comprising 0.1 to 10% hydrocortisone.

15. 15. The use of claim 14, wherein the composition is a topical cream containing 1% hydrocortisone.

16. 2. The use of claim 1, wherein the antibiotic agent is for once-daily or twice-daily administration.

17. 17. The use of claim 16, wherein the antibiotic agent is minocycline, doxycycline, tetracycline, clindamycin, sulfadiazine, diphenhydramine, polysporin, prednisone, neomycin, bacitracin, erythromycin, or azithromycin.

18. 2. The use of claim 1, wherein the antibiotic agent is for oral administration.

19. 2. The use of claim 1, wherein the antibiotic agent is for administration at a dose of 50 to 500 mg per administration.

20. 18. The use of claim 17, wherein the antibiotic agent is minocycline.

21. 21. The use of claim 20, wherein the minocycline is for once-daily administration.

22. 22. The use of claim 20 or 21, wherein the minocycline is for administration at a dose of 100 mg per administration.

23. The use of claim 1, wherein the medicament is for reducing inflammation.

24. 2. The use of claim 1, wherein the toxicity or adverse event is skin toxicity, macular edema, nausea, or diarrhea.

25. 25. The use of claim 24, wherein the skin toxicity is a rash.

26. 2. The use of claim 1, wherein the antibiotic or corticosteroid is for administration for at least 8 weeks.

27. 2. The use of claim 1, wherein the antibiotic or corticosteroid is for administration for 8 consecutive weeks.

28. 2. The use of claim 1, wherein the antibiotic or corticosteroid is for continuous administration for more than 8 weeks.

29. The use of claim 1, wherein the subject is identified as having cancer.

30. 30. The use of claim 29, wherein the cancer is a cancer characterized as having a RAS mutation or a RAF mutation.

31. 31. The use of claim 30, wherein the cancer is a cancer characterized as having a KRAS, NRAS, HRAS, and / or BRAF mutation.

32. 30. The use of claim 29, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, melanoma, or gynecological cancer, and the gynecological cancer is cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, or vulvar cancer.

33. A combination for reducing the severity of or preventing toxicity or adverse events associated with administration of a dual RAF / MEK inhibitor in a subject in need thereof, comprising a dual RAF / MEK inhibitor, an antibiotic, and a corticosteroid, the subject has been identified as having cancer; Combination.

34. A combination for reducing the severity of or preventing a toxicity or adverse event, comprising an antibiotic and a corticosteroid, wherein the composition is administered in combination with a dual RAF / MEK inhibitor; the toxicity or adverse event is associated with the administration of a dual RAF / MEK inhibitor in a subject in need thereof; the subject has been identified as having cancer; Combination.

35. A combination for reducing the severity of or preventing toxicity or adverse events associated with the administration of a dual RAF / MEK inhibitor in a subject in need thereof, comprising a dual RAF / MEK inhibitor, a FAK inhibitor, an antibiotic and a corticosteroid, the subject has been identified as having cancer; Combination.

36. A combination for reducing the severity of or preventing a toxicity or adverse event, comprising a FAK inhibitor, an antibiotic, and a corticosteroid, wherein the composition is administered in combination with a dual RAF / MEK inhibitor; the toxicity or adverse event is associated with the administration of a dual RAF / MEK inhibitor in a subject in need thereof; the subject has been identified as having cancer; Combination.

37. A combination for reducing the severity of or preventing a toxicity or adverse event, comprising a dual RAF / MEK inhibitor, an antibiotic, and a corticosteroid, wherein the composition is administered in combination with a FAK inhibitor; the toxicity or adverse event is associated with the administration of a dual RAF / MEK inhibitor in a subject in need thereof; the subject has been identified as having cancer; Combination.

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