Combination therapy

Abstract

The present invention relates to combination therapies for treating KRas G12C cancer. In particular, the present invention relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a Raf family kinase inhibitor and a KRAS G12C inhibitor of Formula (I), Formula (IA), or Formula (IB), a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor, a kit comprising the composition, and methods of use thereof.

Description

[Technical Field]

[0001] This invention relates to combination therapies useful for treating cancer. In particular, the invention relates to therapeutically effective combinations of Raf family kinase inhibitors and KRas G12C inhibitors, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions, and methods of using the same. [Background technology]

[0002] The Kirsten rat sarcoma 2 virus oncogene homolog ("KRas") is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch that cycles between an inactive (GDP-bound) state and an active (GTP-bound) state to transmit upstream cellular signals received from multiple tyrosine kinases to downstream effectors, thereby regulating a wide variety of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of active KRas in malignancy was observed more than 30 years ago (see, e.g., Santos et al., (1984) Science 223:661-664). Abnormal KRas expression accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single nucleotide substitutions resulting in missense mutations at codons 12 and 13 of the primary amino acid sequence of KRas account for approximately 40% of these KRas driver mutations in lung adenocarcinoma, with the G12C transversion being the most common activating mutation (see, for example, Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, doi:10.1158 / 1078-0432.CCR-11-3265, published online on 26 September 2012).

[0004] The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas across various tumor types have made KRas a highly attractive target for the pharmaceutical industry in cancer treatment. Despite 30 years of extensive discovery efforts to develop KRas inhibitors to treat cancer, no KRas inhibitor has demonstrated sufficient safety and / or efficacy to obtain regulatory approval (see, for example, McCormick (2015) Clin Cancer Res. 21(8):1797-1801).

[0005] Compounds that inhibit KRas activity, including those that interfere with effectors such as guanine nucleotide exchange factors (see, e.g., Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie201201358), and those that target KRas G12C (see, e.g., Ostrem et al., (2013) Nature 503:548-551), remain highly desirable and are being investigated. Clearly, there is still ongoing interest in and attempts to develop KRas inhibitors, particularly inhibitors of activated KRas mutants, including KRas G12C.

[0006] The KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzyme activity and exhibit monotherapy activity that inhibits in vitro proliferation of cell lines carrying KRas G12C mutations. However, the relative potency and / or observed maximum effect of any given KRas G12C inhibitor may differ among KRAS mutant cell lines. The reasons for the range of potency and / or observed maximum effect are not fully understood, but certain cell lines appear to possess different inherent resistances. Therefore, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index, and / or clinical benefit of KRas G12C inhibitors in vitro and in vivo.

[0007] In one embodiment, the combination therapy of the present invention synergistically increases the potency of KRas G12C inhibitors, resulting in improved efficacy of the KRas G12C inhibitors disclosed herein. In another embodiment, the combination therapy of the present invention provides improved clinical benefits to patients compared to treatment with KRas G12C inhibitors disclosed herein as monotherapy. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Alamgeer et al.,(2013)Current Opin Pharmcol.13:394-401 [Non-Patent Document 2] Santos et al.,(1984)Science 223:661-664 [Non-Patent Document 3] Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428 [Non-Patent Document 4] Dogan et al.,(2012)Clin Cancer Res.18(22):6169-6177, doi:10.1158 / 1078-0432.CCR-11-3265 [Non-Patent Document 5] McCormick(2015)Clin Cancer Res.21(8):1797-1801 [Non-Patent Document 6] Sun et al.,(2012)Agnew Chem Int Ed Engl.51(25):6140-6143 doi:10.1002 / anie201201358 [Non-Patent Document 7] Ostrem et al.,(2013)Nature 503:548-551 [Overview of the project]

[0009] In one aspect of the present invention, a method for treating cancer in a subject requiring cancer treatment, comprising: a therapeutically effective dose of a Raf family kinase inhibitor and a KRAS G12C inhibitor of formula (I) to the subject. [ka] or a pharmaceutically acceptable salt thereof (in the formula, X is a 4- to 12-membered saturated or partially saturated monocyclic ring, bridging ring, or spiro ring, and the saturated or partially saturated monocyclic ring is one or more R 8 It is arbitrarily replaced with, Y is a bond, O, S, or NR5 and R 1 is [Chem.] or [Chem.] and R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z-NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, and each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R 9 , Z is C1-C4 alkylene, each R 3 is independently C1-C3 alkyl, oxo, or haloalkyl, L is a bond, -C(O)-, or C1-C3 alkylene, R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, and each of cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R 6 or R 7 , <00002​​​​​​​​​​​​However, independently, they are halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, where Q is O or S. R 8 However, oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 ,-C(O)N(R 5 )2, -N(R 5 )2, and C1-C3 alkyl is cyano, halogen, -OR 5 , -N(R 5 )2, or optionally substituted with a heteroaryl, Each R 9 However, independently, these are hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, and the C1-C6 alkyl may be optionally substituted with a cycloalkyl. Each R 10 However, independently, they are hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl. R 11 However, it is a haloalkyl, R A However, absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5 )2, or hydroxyalkyl, Each R B However, independently, hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 ,-C(O)N(R 5)2, -NHC(O)C1-C3 alkyl, -CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, wherein the heterocyclyl moiety is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl moiety of the heteroaryl or heteroarylalkyl is substituted with one or more R 7 It is arbitrarily replaced with, m is either zero or an integer between 1 and 2. p is 1 or 2, [ka] If R is a triple bond, A It does not exist, R B If such a thing exists, and p is 1, or [ka] If R is a double bond, A There exists, R B There exists such that p is 2 or R A , R B , and the carbon atoms to which they are bonded, one or more R 7 A method is provided herein that comprises administering a combination of (which optionally forms a 5- to 8-membered partially saturated cycloalkyl group) and

[0010] For use in the methods provided herein, a KRas G12C inhibitor compound of formula I having formula IA [ka] and its pharmaceutically acceptable salt (wherein R 1 , R 3 , R 4 , R 5 , R 10 , R 11 , L, and m are as defined in formula I, and the piperazinyl ring is R 8It is arbitrarily replaced in R 8 (As defined in Equation I) is also included.

[0011] For use in the methods provided herein, a KRas G12C inhibitor compound of formula I having formula IB. [ka] and its pharmaceutically acceptable salt (wherein R 1 , R 3 , R 4 , L, and m are as defined in Equation I, and R 2 However, one or more R 9 It is a heterocyclylalkyl which is arbitrarily substituted with R 9 However, as defined by formula I, the piperazinyl ring is R 8 It is arbitrarily replaced in R 8 (As defined in Equation I) is also included.

[0012] In another aspect of the present invention, a pharmaceutical composition is provided for use in the present method, comprising a therapeutically effective amount of a combination of a Raf family kinase inhibitor and a KRas G12C inhibitor compound of formula I, formula IA, or formula 1-B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0013] In one aspect of the present invention, a method for treating cancer in a subject requiring treatment for cancer is provided herein, comprising administering to the subject a therapeutically effective amount of a combination of a Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutically acceptable salt thereof, and a KRAS G12C inhibitor of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutically acceptable salt thereof. In one embodiment, the cancer is a KRas G12C-related cancer. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0014] In some aspects of the present invention, KRas G12C inhibitor compounds and Raf family kinase inhibitors are the sole activators in the provided combinations and methods.

[0015] Examples of Raf family kinase inhibitors suitable for the provided compositions and methods include: encorafenib (LGX818): methyl(S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamide)phenyl)-1-isopropyl-1H-pyrazole-4-yl)pyrimidine-2-yl)amino)propan-2-yl)carbamate; PLX-8394: N-(3-(5-(2-cyclopropylpyrimidine-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl )-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide; Raf-709: N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridine]-5-yl)-3-(trifluoromethyl)benzamide; LXH254: N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridine-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide; Sorafenib: 4-(4-(3-(4-chloro -3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide;LY3009120:1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-6-yl)phenyl)urea;rifilafenib (BGB-283);5-(((1R,1aS,6bS)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzo Lan-5-yl)methyl)-3,4-dihydro-1,8-naphthyridine-2(1H)-one; Tak-632:N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamide)phenoxy)benzo[d]thiazole-2-yl)cyclopropanecarboxamide; CEP-32496:1-(3-((6,7-dimethoxyquinazoline-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3-yl)urea;CCT196969:1-(3-(tert-butyl)-1-phenyl-1H-pyrazole-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-8-yl)oxy)phenyl)urea; and RO5126766:N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide; are included but not limited to these.

[0016] In yet another embodiment, the present invention provides a method for increasing the sensitivity of cancer cells to a KRas G12C inhibitor, comprising contacting cancer cells with a therapeutically effective amount of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in combination with a Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor. In one embodiment, the contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0017] Also provided herein is a method for treating cancer in a person requiring cancer treatment, comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., is a KRas G12C-associated cancer) (e.g., by using a regulatory-approved assay or kit, e.g., FDA-approved), and (b) administering to the patient a therapeutically effective dose of a combination of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of KRAS G12C-associated cancer to the KRAS G12C inhibitor.

[0018] Kits comprising a Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are also provided herein. Kits comprising a Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are also provided for use in the treatment of KRas G12C cancer.

[0019] In related embodiments, the present invention provides a kit comprising a certain dose of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, in an amount effective to inhibit the proliferation of cancer cells in a subject. The kit may optionally include an insert containing instructions for administering the Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. The insert may provide the user with a set of instructions for using the Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof in combination with the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0020] In some embodiments of the methods described herein, prior to treatment with the compositions or methods of the present invention, the patient has been treated with one or more of the following: chemotherapy, targeted anticancer agents, radiotherapy, and surgery, and optionally, prior treatment has failed, and / or the patient has undergone surgery, and optionally, the surgery has failed, and / or the patient has been treated with a platinum-based chemotherapeutic agent, and optionally, the patient has been previously determined not to respond to treatment with a platinum-based chemotherapeutic agent, and / or the patient has been treated with a kinase inhibitor, and optionally, prior treatment with a kinase inhibitor has failed, and / or the patient has been treated with one or more other therapeutic agents. [Modes for carrying out the invention]

[0021] The present invention relates to combination therapies for treating KRas G12C cancer. More particularly, the present invention relates to a method for treating cancer in a subject requiring cancer treatment, comprising administering to the subject a combination of a therapeutically effective amount of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof; a pharmaceutical composition each separately comprising a therapeutically effective amount of the inhibitor; a kit comprising the composition; and a method for using the same.

[0022] The combination of a Raf family kinase inhibitor with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt thereof, increases the potency of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt thereof, against cancer cells expressing KRas G12C, thereby increasing the efficacy of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt thereof.

[0023] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains. All patents, patent applications, and publications referenced herein are incorporated herein by reference.

[0024] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein containing an amino acid substitution from glycine to cysteine ​​at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by Uniplot KB / Swissplot P01116: variant p.Gly12Cys.

[0025] As used herein, “KRas G12C inhibitor” refers to the compounds of the present invention represented by formulas (I), IA, and IB as described herein, and their pharmaceutically acceptable salts. These compounds can negatively modulate or inhibit all or part of the enzymatic activity of KRas G12C. The KRas G12C inhibitors of the present invention interact with KRas G12C and irreversibly bind to it by forming a covalent adduct with the sulfhydryl side chain of the cysteine ​​residue at position 12, thereby inhibiting the enzymatic activity of KRas G12C. In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1 to 678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., examples 234, 359, 478, or 507, or their pharmaceutically acceptable salts).

[0026] As used herein, “KRas G12C-related disease or disorder” means a disease or disorder that is associated with, mediated by, or has a KRas G12C mutation. A non-exclusive example of a KRas G12C-related disease or disorder is KRas G12C-related cancer.

[0027] As used herein, “Raf family kinases” refers to members of mammalian serine / threonine kinases, comprising three isoforms (C-Raf, B-Raf, and A-Raf), including homodimers of each isoform and heterodimers between isoforms, such as the C-Raf / B-Raf heterodimer.

[0028] As used herein, “Raf family kinase inhibitor” refers to a compound that can negatively modulate or inhibit all or part of the enzymatic activity of one or more members of the Raf family kinases, or that can disrupt the formation of Raf homodimers or heterodimers for inhibiting activity.

[0029] As used herein, the terms “subject,” “individual,” or “patient” are interchangeable and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the disease or disorder being treated and / or prevented. In some embodiments, the subject is identified or diagnosed with having the KRas G12C mutation (e.g., determined using a regulatory-approved assay or kit, e.g., FDA-approved). In some embodiments, the subject has a tumor that is positive for the KRas G12C mutation (e.g., determined using a regulatory-approved assay or kit). The subject may have one tumor(s) that are positive for the KRas G12C mutation (e.g., identified as positive using a regulatory-approved assay or kit, e.g., FDA-approved). The subjects may be subjects whose tumors have the KRas G12C mutation (for example, the tumors are identified as such using regulatory-approved kits or assays, e.g., FDA-approved kits). In some embodiments, the subjects are suspected to have cancer associated with the KRas G12C gene. In some embodiments, the subjects have a clinical record indicating that they have a tumor with the KRas G12C mutation (and, where applicable, the clinical record indicates that the subjects should be treated with one of the compositions provided herein).

[0030] As used herein, the term “pediatric patient” refers to a patient under 16 years of age at the time of diagnosis or treatment. The term “pediatric” can be further divided into various subgroups, including neonates (from birth to 1 month of age), infants (1 month to 2 years of age), children (2 years to 12 years of age), and adolescents (12 years to 21 years of age (up to their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WBSaunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.

[0031] In some embodiments of the methods or uses described herein, assays used to determine whether a patient has a KRas G12C mutation using a sample (e.g., a biological sample, or a biopsy sample such as a paraffin-embedded biopsy sample) derived from a patient (e.g., a patient suspected of having KRas G12C-related cancer, a patient having one or more symptoms of KRas G12C-related cancer, and / or a patient at high risk of developing KRas G12C-related cancer) may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping, or ddPCR). As is well known in the art, these assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment.

[0032] The term "regulatory authority" refers to a national agency that authorizes the use of pharmaceuticals in medical treatment. A non-specific example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0033] The term "amino" refers to -NH2.

[0034] The term "acyl" refers to -C(O)CH3.

[0035] As used herein, the term "alkyl" refers to linear and branched aliphatic groups having 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms, which are optionally substituted with 1, 2, or 3 substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0036] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms are substituted by halogens. Examples of haloalkyls include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0037] The term "haloalkyloxy" refers to -O-haloalkyl groups.

[0038] An alkylene group is an alkyl group as defined above, which is located between two other chemical groups and functions to link them together. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0039] The term "alkoxy" refers to -OC1-C6 alkyl groups.

[0040] As used herein, the term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbon atoms, for example, 3 to 8 carbon atoms, and, as a further example, 3 to 6 carbon atoms, and cycloalkyl groups are further optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0041] The term "heteroalkyl" as defined herein refers to an alkyl group in which one or more carbon atoms in the chain are substituted by heteroatoms selected from the group consisting of O, S, and N.

[0042] As used herein, the term "hydroxyalkyl" refers to an alkyl-OH group.

[0043] The term "dihydroxyalkyl" refers to an alkyl group as defined herein, in which two carbon atoms are each substituted with a hydroxyl group.

[0044] The term "alkylaminyl" is -NR x - refers to alkyl, R x is hydrogen. In one embodiment, R x It is hydrogen.

[0045] The term "dialkylaminyl" is -N(R y ) refers to 2, and each R y It is a C1-C3 alkyl group.

[0046] The term "alkylaminylalkyl" is -alkyl-NR x - refers to alkyl, R x is hydrogen. In one embodiment, R x It is hydrogen.

[0047] The term "dialkylaminylalkyl" is defined as -alkyl-N(R y) refers to 2, and each R y It is a C1-C4 alkyl, and -alkyl-N(R y The alkyl group in )2 may be optionally substituted with a hydroxyl group or a hydroxyalkyl group.

[0048] The "aryl" group is a C6-C group containing 1 to 3 aromatic rings which are optionally substituted. 14 This is the aromatic moiety. In one embodiment, the aryl group is C6-C 10 These are aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl.

[0049] The "aralkyl" or "arylalkyl" group includes an aryl group covalently bonded to an alkyl group, and each of these may independently be optionally substituted or unsubstituted. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, and naphthylmethyl, as well as (C1-C6)alkyl(C6-C 10 ) It is an aryl group. An example of a substituted aralkyl group is one in which the alkyl group is substituted with a hydroxyalkyl group.

[0050] A "heterocyclyl" or "heterocyclic" group is a ring structure having approximately 3 to 12 atoms, for example, 4 to 8 atoms, where one or more atoms are selected from the group consisting of N, O, and S, and the remaining ring atoms are carbon. Heterocyclyls may be monocyclic, bicyclic, spirocyclic, or bridging ring systems. The heterocyclic group has R at one or more positions on the carbon or nitrogen. 7 It is arbitrarily replaced in R 7The heterocyclic group is defined by formula I. The heterocyclic group is also independently optionally substituted on nitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl, arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl, or optionally substituted on sulfur with oxo or lower alkyl. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, azilidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, thiomorpholinyl, thiomorpholinyl, 1,1-dioxide, morpholinyl, oxazepanyl, azabicyclohexane, azabicycloheptane, and oxazabicycloheptane. Compounds having adjacent cyclic O and / or S atoms are particularly excluded from the scope of this term.

[0051] The term "heterocyclylalkyl" refers to a heterocyclyl group as defined herein, linked to the rest of the molecule via an alkyl linker, the alkyl linker of the heterocyclylalkyl may optionally be substituted with hydroxy or hydroxyalkyl.

[0052] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 π electrons shared in the cyclic array, and having 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S, in addition to carbon atoms.Examples of heteroaryl groups include acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzoisoxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carborinyl, chromanil, clomenyl, sinnolinyl, furanil, flazanil, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, and indolinyl. Lu, indolidinyl, indolyl, 3H-indolyl, isobenzofuranil, isochromanil, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthilidinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, Phenanthrolinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, prinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrrolyl, quinazolinyl, quinolinyl, 4H-quinolidinyl, quinoxalinyl, quinuclidinyl, tetrahydro Examples include isoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0053] A "heteroarylalkyl" group includes a heteroaryl group covalently bonded to an alkyl group, where the radical is on the alkyl group, and both are independently optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include heteroaryl groups having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaryl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoinodylmethyl, synnolinylmethyl, and benzothiophenylethyl. Compounds having adjacent cyclic O and / or S atoms are specifically excluded from the scope of this term.

[0054] As used herein, an "effective dose" of a compound is an amount sufficient to negatively modulate or inhibit the activity of the desired target, namely, Raf family kinase or KRas G12C. Such a dose may be administered as a single dose or according to a dosage schedule, thereby ensuring that the dose is effective.

[0055] As used herein, a “therapeutic effective dose” of a compound is an amount sufficient to alleviate or reduce symptoms in any way, halt or stop the progression of a disease, or negatively modulate or inhibit the activity of Raf family kinases or KRas G12C. Such a dose may be administered as a single dose or according to a dosage regimen, thereby making the dose effective.

[0056] As used herein, the “therapeutic effective dose” of two compounds is the amount that synergistically increases the activity of the combination, i.e., not merely an additive, compared to the therapeutic effective dose of each compound in the combination. Alternatively, in vivo, a combination of a therapeutic effective dose of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition, results in increased overall survival ("OS") in subjects compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutic effective dose of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition, results in increased progression-free survival ("PFS") in subjects compared to treatment with the KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective dose of a Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor regression in the subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective dose of a Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in increased inhibition of tumor growth in the subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective dose of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in an improvement in the stable duration of the disease in the subject compared to treatment with the KRas G12C inhibitor alone.The amount of each compound in a combination may be the same as or different from the therapeutically effective dose of each compound when administered alone as monotherapy, as long as the combination achieves the desired antitumor effect. Such amounts may be administered as a single dose or according to a treatment plan, thereby ensuring effectiveness.

[0057] As used herein, treatment refers to any form of treatment that alleviates or favorably alters the symptoms or conditions of a disease, disorder, or illness. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0058] As used herein, relief of symptoms of a particular disorder by administration of a particular pharmaceutical composition means any relief, whether permanent or temporary, sustained or transient, that may be caused by or associated with the administration of the composition.

[0059] When used herein, the term “about” used to modify numerically defined parameters (e.g., doses of KRAS inhibitors or Raf family kinase inhibitors or their pharmaceutically acceptable salts, or the duration of treatment with combination therapies as described herein) means that the parameter may vary by up to 10% above or below the numerical value stated for that parameter. For example, a dose of about 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg. When “about” is used at the beginning of a list of parameters, it means that each parameter is modified. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, or about 25% or more.

[0060] Inhibitor compounds In one aspect of the present invention, a method for treating cancer in a subject requiring cancer treatment is provided herein, comprising administering to the subject a therapeutically effective amount of a combination of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0061] 1. Raf family kinase inhibitors The Raf family kinases are serine / threonine kinases composed of three isoforms (C-Raf, B-Raf, and A-Raf). Raf family members share three conserved regions (CRs) with distinct functions. CR1 contains a Ras-binding domain (RBD) necessary for interaction with Ras and membrane recruitment, and a cysteine-rich domain (CRD), a secondary Ras-binding site also necessary for the interaction between CR1 and the kinase domain for Raf autoinhibition. CR2 contains an inhibitory phosphorylation site involved in the negative regulation of Ras binding and Raf activation. CR3 features a kinase domain containing an activation segment whose phosphorylation is essential for kinase activation (see, e.g., Matallanas et al., (2011) Genes Cancer 2(3):232-260).

[0062] The binding of Ras to the CR1 RBD disrupts the binding of CR3 to the CRD, freeing the kinase domain from its autoinhibitory state, promoting alterations in Raf phosphorylation, and inducing the formation of a Raf dimer, which is now recognized as a necessary step in the Raf activation process. Raf kinases can dimerize with any of the other Raf family members, and although the factors determining dimerization preference are not well understood, B-Raf / C-Raf heterodimers are dominant in Ras-dependent signaling. Raf kinase domains come into contact with each other via left-right dimer interfaces, and as a result of protomeral transactivation, a catalytically active kinase conformation is assumed, leading to the phosphorylation and activation of MEK. Similarly, MEK phosphorylates and activates ERK, which plays a crucial role in forward signaling and contributes to an inhibitory feedback loop that controls the duration and amplitude of pathway signaling (see, e.g., Durrant & Morrison (2018) British J Cancer 118:3-8).

[0063] Upregulation of receptor tyrosine kinases, such as EGFR, and / or upregulation of N-Ras expression and / or activity, has been shown to overcome KRas inhibition by restoring downstream Raf / MEK / ERK signaling, resulting in resistance to KRas inhibition. The combination of the KRasG12C inhibitor and the Raf family kinase inhibitor of the present invention effectively blocks upstream signaling from KRas G12C, wild-type KRas, and / or N-Ras, as shown in Example B herein, for example, and shuts down further MEK and ERK signaling via RAF, thereby blocking this potential resistance mechanism and enhancing the overall tumor response. In certain embodiments, Raf family kinase inhibitors are active against wild-type A-Raf / A-Raf, C-Raf / C-Raf, and B-Raf / B-Raf homodimers, as well as Raf heterodimers, such as the C-Raf / B-Raf heterodimer (see, e.g., Lito et al., (2016) Science 351(6273):604-8. doi:10.1126 / science.aad6204. Epub 2016 Jan 14).

[0064] Examples of Raf family kinase inhibitors useful in the methods and compositions disclosed herein include: encorafenib (LGX818): methyl(S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamide)phenyl)-1-isopropyl-1H-pyrazole-4-yl)pyrimidine-2-yl)amino)propan-2-yl)carbamate; PLX-8394: N-(3-(5-(2-cyclopropylpyrimidine-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3- Carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide; Raf-709: N-(2-methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridine]-5-yl)-3-(trifluoromethyl)benzamide; LXH254: N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridine-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide; Sorafenib: 4-(4-(3-(4- Chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide;LY3009120:1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-6-yl)phenyl)urea;rifilafenib (BGB-283);5-(((1R,1aS,6bS)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzo furan-5-yl)methyl)-3,4-dihydro-1,8-naphthyridine-2(1H)-one; Tak-632:N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamide)phenoxy)benzo[d]thiazole-2-yl)cyclopropanecarboxamide; CEP-32496:1-(3-((6,7-dimethoxyquinazoline-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3-yl)urea;CCT196969:1-(3-(tert-butyl)-1-phenyl-1H-pyrazole-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-8-yl)oxy)phenyl)urea; and RO5126766:N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide are included, but are not limited to these. In one embodiment, the Raf family kinase inhibitor is encolatinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is rifilafenib (BGB-283).

[0065] Methods for producing Raf family kinase inhibitors are well known to those skilled in the art, and Raf family kinase inhibitors are available from a wide variety of commercial suppliers in forms suitable for both research and human use. In addition, Raf family kinase inhibitors suitable for use in the compositions and methods disclosed herein, as well as methods for preparing such inhibitors, are published in U.S. Patent Applications US2017 / 0233391, US2016 / 0368914, US2016 / 0199375, US2015 / 0119392, US2015 / 0105367, US2015 / 0080568, US2015 / 0045355, US2014 / 0329866, US2014 / 0221374, and This information is disclosed in US2014 / 0045868, US2013 / 0224195, US2013 / 0040983, US2012 / 0288501, US2012 / 0214811, US2012 / 0178780, US2011 / 0257207, US2011 / 0118245, US2010 / 0324047, US2010 / 0196368, US2009 / 0163596, US2009 / 0035309, and US2008 / 0108672.

[0066] 2. KRas G12C inhibitors In one embodiment, the KRas G12C inhibitor used in this method is a compound of formula (I). [ka] or a pharmaceutically acceptable salt thereof (in the formula, X is a 4- to 12-membered saturated or partially saturated monocyclic ring, bridging ring, or spiro ring, and the saturated or partially saturated monocyclic ring is one or more R 8 It is arbitrarily replaced with, Y is a bond, O, S, or NR 5 And, R 1 but, [ka] or [ka] And, R 2 However, hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, -Z- monomer 5 R 10 Z is a heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, and each of Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl is one or more R 9 It may be arbitrarily replaced with, Z is a C1-C4 alkylene, Each R 3 However, they are independently C1-C3 alkyl, oxo, or haloalkyl, L is a bond, -C(O)-, or C1-C3 alkylene. R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl, or heteroaryl, and each of cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl contains one or more R6 or R 7 may be optionally substituted with, each R 5 is, independently, hydrogen or C1-C3 alkyl, R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, and each of cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R 7 ; each R 7 is, independently, halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, where Q is O or S, R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, -C(O)OR 5 , -C(O)N(R 5 )2, -N(R 5 )2, and C1-C3 alkyl may be optionally substituted with cyano, halogen, -OR 5 , -N(R 5 )2, or heteroaryl; each R 9 is, independently, hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, and C1-C6 alkyl may be optionally substituted with cycloalkyl, each R 10 is, independently, hydrogen, acyl, C1-C3 alkyl, heteroalkyl, or hydroxyalkyl, R 11 is haloalkyl, R A is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, -C(O)N(R 5)2. or is hydroxyalkyl, each R B is independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, -ZNR 5 R 11 , -C(O)N(R 5 )2, -NHC(O)C1-C3 alkyl, -CH2NHC(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl, where the heterocyclyl moiety is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy, and C1-C3 alkyl, and the heteroaryl moiety of the heteroaryl or heteroarylalkyl is optionally substituted with one or more R 7 and m is zero or an integer from 1 to 2, p is 1 or 2,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0067] In one embodiment, the KRas G12C inhibitor used in the methods herein is a compound having formula I-A

Chemical formula

[0068] In one embodiment, the KRas G12C inhibitor used in the method herein is a compound having formula IB. [ka] and its pharmaceutically acceptable salt (wherein R 1 , R 3 , R 4 , R 9 , R 11 L and m are as defined in formula I.

[0069] Non-limiting examples of KRas G12C inhibitor compounds of formula (I), formula IA, and formula IB that are useful in the methods disclosed herein are examples 1 to 678 disclosed in WO2019 / 099524. [ka] [ka] [ka] [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0070] In one embodiment, the KRas G12C inhibitor is [ka] Selected from these as well as their pharmaceutically acceptable salts.

[0071] In one embodiment, the KRas G12C inhibitor is [ka] (referred to as Example 234) or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment, the KRas G12C inhibitor is [ka] (referred to as Example 359) or a pharmaceutically acceptable salt thereof.

[0073] In one embodiment, the KRas G12C inhibitor is [ka] (referred to as Example 478) or a pharmaceutically acceptable salt thereof.

[0074] In one embodiment, the KRas G12C inhibitor is [ka] (referred to as Example 507) or a pharmaceutically acceptable salt thereof.

[0075] The KRas G12C inhibitors used in the methods of the present invention may have one or more chiral centers and may be synthesized as stereoisomer mixtures, isomers with the same composition but different spatial arrangements of their atoms. The compounds may be used as mixtures, or individual components / isomers may be separated using commercially available reagents and conventional isolation methods for stereoisomers and enantiomers known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC columns, according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates for preparing individual isomers or enantiomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic mixtures are within the scope of the present invention. Unless otherwise specified, whenever this specification, including the claims, refers to the compounds of the present invention, the term “compound” should be understood to encompass all chiral (enantiomers and diastereomers) and racemic mixtures.

[0076] In one embodiment, the KRas G12C inhibitor compound of formula I, formula IA, or formula IB used in this method includes the trifluoroacetate of the above compound.

[0077] Methods for producing the KRas G12C inhibitors disclosed herein are known. For example, the co-owned and published international PCT applications WO2017 / 201161 and WO2019 / 099524 describe general reaction schemes for preparing compounds of formula I, formula IA, or formula IB, and also provide detailed synthetic routes for the preparation of each KRas G12C inhibitor disclosed herein.

[0078] Raf family kinase inhibitors and KRas G12C compounds of formula (I), formula IA, or formula IB, or pharmaceutically acceptable salts thereof, can be formulated into pharmaceutical compositions.

[0079] Pharmaceutical composition In another embodiment, the present invention provides a pharmaceutical composition comprising a Raf family kinase inhibitor and a KRas G12C inhibitor according to the present invention, and a pharmaceutically acceptable carrier, excipient, or diluent that can be used in the manner disclosed herein. The Raf family kinase inhibitor and the KRas G12C inhibitor may be independently formulated by any method well known in the art and may be prepared for administration by any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or rectal. In certain embodiments, the Raf family kinase inhibitor and / or the KRas G12C inhibitor are administered intravenously in a hospital setting. In one embodiment, administration may be by oral route.

[0080] The characteristics of the carrier will depend on the route of administration. As used herein, the term “pharmaceutically acceptable” refers to non-toxic materials that are compatible with biological systems such as cells, cell cultures, tissues, or organisms and do not interfere with the efficacy of the biological activity of the active ingredient(s). Thus, a composition may include, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0081] As used herein, a pharmaceutically acceptable salt of a term means a salt that retains the desired biological activity of the compound identified above and exhibits minimal or no undesirable toxic effects. Examples of such salts include, but are not limited to, acid addition salts formed by inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as acids formed by organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, which in particular include quaternary ammonium salts of the formula -NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion, which includes chlorides, bromides, iodides, -O-alkyls, toluenesulfonates, methylsulfonates, sulfonates, phosphates, or carboxylates (e.g., benzoates, succinates, acetates, glycoates, maleates, citrates, tartrates, ascorbates, benzoates, cinnamoates, mandeloates, benzyloates, and diphenylacetates).

[0082] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient without causing serious toxicity to the patient being treated. In one embodiment, for all of the above conditions, the dose of the active compound is in the range of about 0.01 to 300 mg / kg per day, for example, 0.1 to 100 mg / kg per day, and in further examples, in the range of 0.5 to about 25 mg per kilogram of body weight of the recipient per day. A typical topical dose is in the range of 0.01 to 3 wt / wt% in a suitable carrier. The effective dose range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound being delivered. If the derivative is active on its own, the effective dose can be estimated as described above using the weight of the derivative, or by other means known to those skilled in the art.

[0083] Pharmaceutical compositions comprising Raf family kinase inhibitors and KRas G12C inhibitors may be used in the manner of use described herein.

[0084] Simultaneous administration Raf family kinase inhibitors and KRasG12C inhibitors can be formulated into separate or individual dosage forms and administered sequentially and concurrently. Another option is that, if the route of administration is the same (e.g., orally), the two active compounds can be formulated into a single form for concurrent administration, provided that both concurrent administration methods are part of the same therapeutic treatment or regimen.

[0085] The pharmaceutical compositions for use in this method, comprising Raf family kinase inhibitors and / or KRas G12C inhibitors, may be for simultaneous, individual, or sequential use. In one embodiment, the Raf family kinase inhibitor is administered before administration of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB. In another embodiment, the Raf family kinase inhibitor is administered after administration of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB. In yet another embodiment, the Raf family kinase inhibitor is administered approximately simultaneously with the administration of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB.

[0086] Separate administration of each inhibitor at different times and via different routes may be advantageous in some cases. Therefore, the combination, i.e., the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB or its pharmaceutically acceptable salt or pharmaceutical composition, and the components of the Raf family kinase inhibitor or its pharmaceutically acceptable salt or pharmaceutical composition, do not necessarily have to be administered at essentially the same time or in any order.

[0087] Oncology drugs are typically administered at their maximum tolerated dose ("MTD"), which is the highest dose of the drug that does not cause unacceptable side effects. In one embodiment, a KRas G12C inhibitor and a Raf family kinase inhibitor are each administered at their respective MTDs. In another embodiment, a KRas G12C inhibitor is administered at its MTD, and a Raf family kinase inhibitor is administered at a lower dose than its MTD. In yet another embodiment, a KRas G12C inhibitor is administered at a lower dose than its MTD, and a Raf family kinase inhibitor is administered at its MTD. In yet another embodiment, a KRas G12C inhibitor and a Raf family kinase inhibitor are each administered at a lower dose than their respective MTDs. The administration can also be timed so that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.

[0088] In one embodiment, a single dose of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered daily (i.e., at approximately 24-hour intervals) (i.e., once daily). In another embodiment, two doses of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are administered daily (i.e., twice daily). In yet another embodiment, three doses of the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are administered daily (i.e., three times daily).

[0089] In one embodiment, the Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered once daily. In another embodiment, the Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered twice daily. In yet another embodiment, the Raf family kinase inhibitor of the present invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, is administered three times daily.

[0090] In one embodiment, a single dose of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, are each administered once daily.

[0091] Examples of Raf family kinase inhibitors useful in the methods disclosed herein include: encorafenib (LGX818): methyl(S)-(1-((4-(3-(5-chloro-2-fluoro-3-(methylsulfonamide)phenyl)-1-isopropyl-1H-pyrazole-4-yl)pyrimidine-2-yl)amino)propan-2-yl)carbamate; PLX-8394: N-(3-(5-(2-cyclopropylpyrimidine-5-yl)-3a,7a-dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbon LXH254: N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridine-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide; Sorafenib: 4-(4-(3-(4-chloro) -3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide;LY3009120:1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidine-6-yl)phenyl)urea;rifilafenib (BGB-283);5-(((1R,1aS,6bS)-1-(6-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzo Lan-5-yl)methyl)-3,4-dihydro-1,8-naphthyridine-2(1H)-one; Tak-632:N-(7-cyano-6-(4-fluoro-3-(2-(3-(trifluoromethyl)phenyl)acetamide)phenoxy)benzo[d]thiazole-2-yl)cyclopropanecarboxamide; CEP-32496:1-(3-((6,7-dimethoxyquinazoline-4-yl)oxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3-yl)urea;CCT196969:1-(3-(tert-butyl)-1-phenyl-1H-pyrazole-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-8-yl)oxy)phenyl)urea; and RO5126766:N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)-2H-1-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl-sulfamide; are included but not limited to these.

[0092] In one embodiment, the Raf family kinase inhibitor is encoratinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is rifilafenib (BGB-283).

[0093] Combination therapy In one aspect of the present invention, a method for treating cancer in a subject requiring treatment for cancer is provided herein, comprising administering to the subject a therapeutically effective amount of a combination of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In one embodiment, the cancer is a KRas G12C-related cancer. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0094] In yet another embodiment, the present invention provides a method for increasing the sensitivity of cancer cells to a KRas G12C inhibitor, comprising contacting cancer cells with an effective amount of a combination of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, and a Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor. In one embodiment, the contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0095] In one embodiment, the combination therapy involves a compound having the formula [ka] The present invention includes a combination of a pharmaceutically acceptable salt thereof or a Raf family kinase inhibitor. In one embodiment, the Raf family kinase inhibitor is encolatinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is rifirafenib (BGB-283).

[0096] In one embodiment, the combination therapy involves a compound having the formula [ka] The present invention includes a combination of a pharmaceutically acceptable salt thereof or a Raf family kinase inhibitor. In one embodiment, the Raf family kinase inhibitor is encolatinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is rifirafenib (BGB-283).

[0097] In one embodiment, the combination therapy involves a compound having the formula [ka] The present invention includes a combination of a pharmaceutically acceptable salt thereof or a Raf family kinase inhibitor. In one embodiment, the Raf family kinase inhibitor is encolatinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is rifirafenib (BGB-283).

[0098] In one embodiment, the combination therapy involves a compound having the formula [ka] The present invention includes a combination of a pharmaceutically acceptable salt thereof or a Raf family kinase inhibitor. In one embodiment, the Raf family kinase inhibitor is encolatinib (LGX818). In one embodiment, the Raf family kinase inhibitor is sorafenib. In one embodiment, the Raf family kinase inhibitor is rifirafenib (BGB-283).

[0099] As used herein, the term “contact” refers to bringing together the indicated parts in an in vitro or in vivo system. For example, “contact” cancer cells includes administering the combination provided herein to an individual or subject, such as a human, having KRas G12C, as well as introducing the combination provided herein into a sample, for example, a cell preparation or purified preparation containing KRas G12C.

[0100] The methods described herein are designed to inhibit undesirable cell proliferation caused by enhanced intracellular KRas G12C activity by negatively regulating KRas G12C activity. The degree of covalent modification of KRas G12C can be monitored in vitro using well-known methods, including those described in published international PCT applications WO2017 / 201161 and WO2019 / 099524. In addition, the inhibitory activity of the combination in cells can be monitored, for example, by measuring the inhibition of KRas G12C activity by the amount of phosphorylated ERK and evaluating the efficacy of the treatment, and therefore the dosage can be adjusted by the attending physician.

[0101] The compositions and methods provided herein may be used to treat KRas G12C-related cancers in subjects requiring treatment of KRas G12C-related cancers, comprising administering to the subject a therapeutically effective dose of a combination of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of KRas G12C-related cancers to the KRas G12C inhibitor. In one embodiment, the KRas G12C-related cancer is lung cancer.

[0102] In one embodiment, a combination of a therapeutically effective dose of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increased overall survival ("OS") in subjects compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective dose of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in an increased progression-free survival ("PFS") in subjects compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective dose of a Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in increased tumor regression in the subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective dose of a Raf family kinase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, results in increased inhibition of tumor growth in the subject compared to treatment with a KRas G12C inhibitor alone. In one embodiment, a combination of a therapeutically effective dose of a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof with a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharmaceutically acceptable salt or pharmaceutical composition thereof results in an improvement in the stable duration of the disease in the subject compared to treatment with the KRas G12C inhibitor alone.In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1 to 678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., example numbers 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof). In one embodiment, the Raf family kinase inhibitor is selected from encoratinib, sorafenib, or rifirafenib. In one embodiment, the treatment combination includes a therapeutically effective amount of example number 234 and encoratinib. In one embodiment, the treatment combination includes a therapeutically effective amount of example number 234 and sorafenib. In one embodiment, the treatment combination includes a therapeutically effective amount of example number 234 and rifirafenib. In one embodiment, the treatment combination includes a therapeutically effective amount of example number 359 and encoratinib. In one embodiment, the treatment combination includes a therapeutically effective amount of example number 359 and sorafenib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 359 and rifirafenib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 478 and encoratinib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 478 and sorafenib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 478 and rifirafenib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 507 and encoratinib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 507 and sorafenib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 507 and rifirafenib. In any one embodiment of the combination therapy, the combination is useful for treating cancer associated with KRas G12C. In one embodiment, the cancer associated with KRas G12C is lung cancer.

[0103] In another embodiment, a Raf family kinase inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in combination with a KRas G12C inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof when disease progression is observed with KRas G12C monotherapy, and the combination therapy results in enhanced clinical benefits or survival time in the patient by increasing OS, PFS, tumor regression, tumor growth inhibition, or duration of stable disease in the patient.

[0104] In one embodiment, the KRas G12C inhibitor is a compound selected from compound numbers 1 to 678 (as numbered in WO2019 / 099524), or a pharmaceutically acceptable salt thereof (e.g., example numbers 234, 359, 478, or 507, or a pharmaceutically acceptable salt thereof). In one embodiment, the Raf family kinase inhibitor is selected from encoratinib, sorafenib, or rifirafenib. In one embodiment, the treatment combination includes a therapeutically effective amount of example number 234 and encoratinib. In one embodiment, the treatment combination includes a therapeutically effective amount of example number 234 and sorafenib. In one embodiment, the treatment combination includes a therapeutically effective amount of example number 234 and rifirafenib. In one embodiment, the treatment combination includes a therapeutically effective amount of example number 359 and encoratinib. In one embodiment, the treatment combination includes a therapeutically effective amount of example number 359 and sorafenib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 359 and rifirafenib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 478 and encoratinib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 478 and sorafenib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 478 and rifirafenib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 507 and encoratinib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 507 and sorafenib. In one embodiment, the combination of treatments includes a therapeutically effective dose of Example No. 507 and rifirafenib. In any one embodiment of the combination therapy, the combination is useful for treating cancer associated with KRas G12C. In one embodiment, the cancer associated with KRas G12C is lung cancer.

[0105] The compositions and methods provided herein can be used to treat a wide variety of cancers, including, for example, tumors such as lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, brain tumors, skin cancer, cervical cancer, and testicular cancer. More specifically, cancers that can be treated with the compositions and methods of the present invention include, but are not limited to, astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, and thyroid cancer, as well as sarcomas. More specifically, these compounds are found in: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lungs: bronchogenic carcinomas (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrotoxic hamartoma, mesothelioma; digestive tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), Pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); urogenital tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), Prostate (adenocarcinoma, sarcoma), testes (seminocarcinoma, teratoma, fetal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: gallbladder cancer, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor Chordoma, osteochondroma (osteochondrogenic exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meninges (meningioma, meningiosarcoma, gliomas), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa follicular cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); Hematology: Blood (myeloid leukemia (acute oocyte) It can be used to treat: acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative disorders (multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.

[0106] Also provided herein is a method for treating cancer in a person requiring cancer treatment, comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., is a KRas G12C-associated cancer) (e.g., by using a regulatory-approved assay or kit, e.g., FDA-approved), and (b) administering to the patient a therapeutically effective dose of a combination of a Raf family inhibitor or a pharmaceutically acceptable salt or pharmaceutical composition thereof and a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of KRas G12C-associated cancer to the KRas G12C inhibitor.

[0107] In one embodiment, the compound of formula I is administered as a capsule over a period of time. In one embodiment, the tablet or capsule formulation of the compound of formula I is approximately 10 mg to approximately 100 mg (for example, approximately 10 mg to approximately 95 mg, approximately 10 mg to approximately 90 mg, approximately 10 mg to approximately 85 mg, approximately 10 mg to approximately 80 mg, approximately 10 mg to approximately 75 mg, approximately 10 mg to approximately 70 mg, approximately 10 mg to approximately 65 mg, approximately 10 mg to approximately 60 mg, approximately 10 mg to approximately 55 mg, approximately 10 mg to approximately 50 mg, approximately 10 mg to approximately 45 mg, approximately 10 mg to approximately 40 mg, approximately 10 mg to approximately 35 mg, approximately 10 mg to approximately 30 mg, approximately 10 mg to approximately 25 mg, approximately 10 mg to approximately 20 mg, approximately 10 mg ~ about 15mg, about 15mg - about 100mg, about 15mg - about 95mg, about 15mg - about 90mg, about 15mg - about 85mg, about 15mg - about 80mg, about 15mg - about 75mg, about 15mg - about 70mg, about 15mg - about 65mg, about 15mg - about 60mg, about 1 5mg to about 55mg, about 15mg to about 50mg, about 15mg to about 45mg, about 15mg to about 40mg, about 15mg to about 35mg, about 15mg to about 30mg, about 15mg to about 25mg, about 15mg to about 20mg, about 20mg to about 100mg, about 20mg to about 95mg, about 20mg to approx. 90mg, approx. 20mg to approx. 85mg, approx. 20mg to approx. 80mg, approx. 20mg to approx. 75mg, approx. 20mg to approx. 70mg, approx. 20mg to approx. 65mg, approx. 20mg to about 40mg, about 20mg to about 35mg, about 20mg to about 30mg, about 20mg to about 25mg, about 25mg to about 100mg, about 25mg to about 95mg, about 25mg to about 90mg, about 25mg to about 85mg, about 25mg to about 80mg, about 25mg to about 75mg, Approximately 25mg to approximately 70mg, approximately 25mg to approximately 65mg, approximately 25mg to approximately 60mg, approximately 25mg to approximately 55mg, approximately 25mg to approximately 50mg, approximately 25mg to approximately 45mg, approximately 25mg to approximately 40mg, approximately 25mg to approximately 35mg, approximately 25mg to approximately 30mg, approximately 30mg to approximately 100mg , about 30 mg to about 95 mg, about 30 mg to about 90 mg, about 30 mg to about 85 mg, about 30 mg to about 80 mg, about 30 mg to about 75 mg, about 30 mg to about 70 mg, about 30 mg to about 65 mg, about 30 mg to about 60 mg, about 30 mg to about 55 mg, about 30 mg to about 50 mg,Approximately 30mg~45mg, approximately 30mg~40mg, approximately 30mg~35mg, approximately 35mg~100mg, approximately 35mg~95mg, approximately 35mg~90mg, approximately 35mg~85mg, approximately 35mg~80mg, approximately 35mg~75mg, approximately 35mg~70mg, approximately 35mg~65mg, approximately 35mg~60mg, approximately 35mg~55mg, approximately 35mg~50mg, approximately 35mg~45mg, approximately 35mg~40mg, approximately 40mg~100mg, approximately 40mg~95mg, approximately 40mg~90mg, approximately 40mg~85mg, approximately 40mg~ Approximately 80mg, approximately 40mg~75mg, approximately 40mg~70mg, approximately 40mg~65mg, approximately 40mg~60mg, approximately 40mg~55mg, approximately 40mg~50mg, approximately 40mg~45mg, approximately 45mg~100mg, approximately 45mg~95mg, approximately 45mg~90mg, approximately 45mg~85mg, approximately 45mg~80mg, approximately 45mg~75mg, approximately 45mg~70mg, approximately 45mg~65mg, approximately 45mg~60mg, approximately 45mg~55mg, approximately 45mg~50mg, approximately 50mg~100mg, approximately 50mg~95mg Approximately 50mg~90mg, approximately 50mg~85mg, approximately 50mg~80mg, approximately 50mg~75mg, approximately 50mg~70mg, approximately 50mg~65mg, approximately 50mg~60mg, approximately 50mg~55mg, approximately 55mg~100mg, approximately 55mg~95mg, approximately 55mg~90mg, approximately 55mg~85mg, approximately 55mg~80mg, approximately 55mg~75mg, approximately 55mg~70mg, approximately 55mg~65mg, approximately 55mg~60mg, approximately 60mg~100mg, approximately 60mg~95mg, approximately 60mg~90mg, approximately 60mg~ Approximately 85mg, approximately 60mg~approximately 80mg, approximately 60mg~approximately 75mg, approximately 60mg~approximately 70mg, approximately 60mg~approximately 65mg, approximately 65mg~approximately 100mg, approximately 65mg~approximately 95mg, approximately 65mg~approximately 90mg, approximately 65mg~approximately 85mg, approximately 65mg~approximately 80mg, approximately 65mg~approximately 75mg, approximately 65mg~approximately 70mg, approximately 70mg~approximately 100mg, approximately 70mg~approximately 95mg, approximately 70mg~approximately 85mg, approximately 70mg~approximately 80mg, approximately 70mg~approximately 75mg, approximately 75mg~approximately 100mg, approximately 75mg~approximately 95mg, approximately 75mg~approximately 90mgApproximately 75mg to approximately 85mg, approximately 75mg to approximately 80mg, approximately 80mg to approximately 100mg, approximately 80mg to approximately 95mg, approximately 80mg to approximately 90mg, approximately 80mg to approximately 85mg, approximately 85mg to approximately 10 0mg, about 85mg to about 95mg, about 85mg to about 90mg, about 90mg to about 100mg, about 90mg to about 95mg, about 95mg to about 100mg, about 10mg, about 15mg, about 20mg The solution contains a compound of formula I (for example, a compound selected from compound numbers 1 to 553, e.g., compound numbers 234, 359, 478, or 507) in amounts of approximately 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg). In one embodiment, the compound of formula I is administered orally once daily (QD) for a period of time. In one embodiment, the compound of formula I is administered orally twice daily (BID) for a period of time. In one embodiment, the compound of formula I is administered in doses of approximately 20 mg to approximately 500 mg over a certain period (for example, approximately 20 mg to approximately 480 mg, approximately 20 mg to approximately 460 mg, approximately 20 mg to approximately 440 mg, approximately 20 mg to approximately 420 mg, approximately 20 mg to approximately 400 mg, approximately 20 mg to approximately 380 mg, approximately 20 mg to approximately 360 mg, approximately 20 mg to approximately 340 mg, approximately 20 mg to approximately 320 mg, approximately 20 mg to approximately 300 mg, approximately 20 mg to approximately 280 mg, approximately 20 mg to approximately 260 mg, approximately 20 mg to approximately 240 mg, approximately 20 mg to approximately 220 mg, approximately 20 mg to approximately 200 mg, approximately 20 mg to approximately 180 mg, approximately 20 mg to approximately 160 mg, approximately 20 mg to approximately 140 mg, approximately 20 mg to approximately 120 mg, approximately 20 mg ~100mg, approx. 20mg~approx. 80mg, approx. 20mg~approx. 60mg, approx. 20mg~approx. 40mg, approx. 40mg~approx. 500mg, approx. 40mg~approx. 480mg, approx. 40mg~approx. 460mg, approx. 40mg~approx. 440mg, approx. 40mg~approx. 420mg, approx. 40mg~approx. 400mg, approx. 40mg~approx. 380mg, approx. 40mg~approx. 360mg mg, about 40mg to about 340mg, about 40mg to about 320mg, about 40mg to about 300mg, about 40mg to about 280mg, about 40mg to about 260mg, about 40mg ~240mg, 40mg~220mg, 40mg~200mg, 40mg~180mg, 40mg~160mg, 40mg~140mg,Approximately 40mg~120mg, approximately 40mg~100mg, approximately 40mg~80mg, approximately 40mg~60mg, approximately 60mg~500mg, approximately 60mg~480mg, approximately 60mg~460mg, approximately 60mg~440mg, approximately 60mg~420mg, approximately 60mg~400mg, approximately 60mg~380mg, approximately 60mg~360mg, approximately 60mg~340mg, approximately 60mg~320mg, approximately 60mg~300mg, approximately 60mg~280mg, approximately 60mg~260mg, approximately 60mg~240mg, approximately 60mg~220mg, approximately 60mg~200mg, approximately 6 0mg~approx. 180mg, approx. 60mg~approx. 160mg, approx. 60mg~approx. 140mg, approx. 60mg~approx. 120mg, approx. 60mg~approx. 100mg, approx. 60mg~approx. 80mg, approx. 80mg~approx. 500mg, approx. 80mg~approx. 480mg, approx. 80mg~approx. 460mg, approx. 80mg~approx. 440mg, approx. 80mg~approx. 420mg, approx. 80mg~approx. 400mg, approx. 80mg~approx. 380mg, approx. 80mg~approx. 360mg, approx. 80mg~approx. 340mg, approx. 80mg~approx. 320mg, approx. 80mg~approx. 300mg, approx. 80mg~approx. 280mg, approx. 80mg~approx. 80mg~approx. 300mg, approx. 80mg~approx. 280mg, approx. 80mg~approx. 180mg, approx. 6 ... g ~ approx. 260mg, approx. 80mg ~ approx. 240mg, approx. 80mg ~ approx. 220mg, approx. 80mg ~ approx. 200mg, approx. 80mg ~ approx. 180mg, approx. 80mg ~ approx. 160mg, approx. 80mg ~ approx. 140mg, approx. 80mg ~ approx. 120mg, approx. 80mg ~ approx. 100mg, approx. 100mg ~ approx. 500mg, approx. 100mg ~ approx. 480mg, approx. 100mg ~ approx. 460mg, approx. 100mg ~ approx. 440mg, approx. 100mg ~ approx. 420mg, approx. 100mg ~ approx. 400mg, approx. 100mg ~ approx. 380mg, approx. 100mg ~ approx. 360mg, approx. 100mg ~ approx. 340mg, approx. 100mg g ~ approx. 320mg, approx. 100mg ~ approx. 300mg, approx. 100mg ~ approx. 280mg, approx. 100mg ~ approx. 260mg, approx. 100mg ~ approx. 240mg, approx. 100mg ~ approx. 220mg, approx. 100mg ~ approx. 200mg, approx. 100mg ~ approx. 180mg, approx. 100mg ~ approx. 160mg, approx. 100mg ~ approx. 140mg, approx. 100mg ~ approx. 120mg, approx. 120mg ~ approx. 500mg, approx. 120mg ~ approx. 480mg, approx. 120mg ~ approx. 460mg, approx. 120mg ~ approx. 440mg, approx. 120mg ~ approx. 420mg, approx. 120mg ~ approx. 400mg, approx. 120mg ~ approx. 380mg, approx. 120mg ~ approx. 360mgApproximately 120mg to approximately 340mg, approximately 120mg to approximately 320mg, approximately 120mg to approximately 300mg, approximately 120mg to approximately 280mg, approximately 120mg to approximately 260mg, approximately 120mg to approximately 240mg, approximately 120mg to approximately 220mg, approximately 120mg to approximately 200mg, approximately 120mg to approximately 180mg, approximately 120mg to approximately 160mg, approximately 120mg to approximately 140mg, approximately 140mg to approximately 500mg, approximately 140mg to approximately 480mg, approximately 140mg to approximately 460mg, approximately 140mg to approximately 440mg, approximately 140mg to approximately 420mg, approximately 140mg to approximately 400mg, approximately 140mg to approximately 380mg. 0mg, approximately 140mg to approximately 360mg, approximately 140mg to approximately 340mg, approximately 140mg to approximately 320mg, approximately 140mg to approximately 300mg, approximately 140mg to approximately 280mg, approximately 140mg to approximately 260mg, approximately 140mg to approximately 240mg, approximately 140mg to approximately 220mg, approximately 140mg to approximately 200mg, approximately 140mg to approximately 180mg, approximately 140mg to approximately 160mg, approximately 160mg to approximately 500mg, approximately 160mg to approximately 480mg, approximately 160mg to approximately 460mg, approximately 160mg to approximately 440mg, approximately 160mg to approximately 420mg, approximately 160mg to approximately 400mg, approximately 160mg~ Approximately 380mg, approximately 160mg~approximately 360mg, approximately 160mg~approximately 340mg, approximately 160mg~approximately 320mg, approximately 160mg~approximately 300mg, approximately 160mg~approximately 280mg, approximately 160mg~approximately 260mg, approximately 160mg~approximately 240mg, approximately 160mg~approximately 220mg, approximately 160mg~approximately 200mg, approximately 160mg~approximately 180mg, approximately 180mg~approximately 500mg, approximately 180mg~approximately 480mg, approximately 180mg~approximately 460mg, approximately 180mg~approximately 440mg, approximately 180mg~approximately 420mg, approximately 180mg~approximately 400mg, approximately 180mg~approximately 380mg, approximately 18 0mg~approx. 360mg, approx. 180mg~approx. 340mg, approx. 180mg~approx. 320mg, approx. 180mg~approx. 300mg, approx. 180mg~approx. 280mg, approx. 180mg~approx. 260mg, approx. 180mg~approx. 240mg, approx. 180mg~approx. 220mg, approx. 180mg~approx. 200mg, approx. 200mg~approx. 500mg, approx. 200mg~approx. 480mg, approx. 200mg~approx. 460mg, approx. 200mg~approx. 440mg, approx. 200mg~approx. 420mg, approx. 200mg~approx. 400mg, approx. 200mg~approx. 380mg, approx. 200mg~approx. 360mg, approx. 200mg~approx. 340mgApproximately 200mg to 320mg, approximately 200mg to 300mg, approximately 200mg to 280mg, approximately 200mg to 260mg, approximately 200mg to 240mg, approximately 200mg to 220mg, approximately 220mg to 500mg, approximately 220mg to 480mg, approximately 220mg to 460mg, approximately 220mg to 440mg, approximately 22... 0mg~approx. 420mg, approx. 220mg~approx. 400mg, approx. 220mg~approx. 380mg, approx. 220mg~approx. 360mg, approx. 220mg~approx. 340mg, approx. 220mg~approx. 320mg, approx. 220mg~approx. 300mg, approx. 220mg~approx. 280mg, approx. 220mg~approx. 260mg, approx. 220mg~approx. 240mg, approx. 240mg~approx. 500mg, approx. 240mg~approx. 480mg, approx. 240mg~approx. 460mg, approx. 240mg~approx. 440mg, approx. 240mg~approx. 420mg, approx. 240mg~approx. 400mg, approx. 240mg~approx. 380mg, approx. 240mg~approx. 360mg g, approximately 240mg to approximately 340mg, approximately 240mg to approximately 320mg, approximately 240mg to approximately 300mg, approximately 240mg to approximately 280mg, approximately 240mg to approximately 260mg, approximately 260mg to approximately 500mg, approximately 260mg to approximately 480mg, approximately 260mg to approximately 460mg, approximately 260mg to approximately 440mg, approximately 260mg to approximately 420mg, approximately 260mg to approximately 400mg, approximately 260mg to approximately 380mg, approximately 260mg to approximately 360mg, approximately 260mg to approximately 340mg, approximately 260mg to approximately 320mg, approximately 260mg to approximately 300mg, approximately 260mg to approximately 280mg, approximately 280mg to approximately 500mg, approximately 280mg~approx. 480mg, approximately 280mg~approx. 460mg, approximately 280mg~approx. 440mg, approximately 280mg~approx. 420mg, approximately 280mg~approx. 400mg, approximately 280mg~approx. 380mg, approximately 280mg~approx. 360mg, approximately 280mg~approx. 340mg, approximately 280mg~approx. 320mg, approximately 280mg~approx. 300mg, approximately 300mg~approx. 500mg, approximately 300mg~approx. 480mg, approximately 300mg~approx. 460mg, approximately 300mg~approx. 440mg, approximately 300mg~approx. 420mg, approximately 300mg~approx. 400mg, approximately 300mg~approx. 380mg, approximately 300mg~approx. 400mg, approximately 300mg~approx. 400mg, approximately 300mg~approx. 500mg, approximately 300mg~approx. 480mg, approximately 300mg~approx. 460mg, approximately 300mg~approx. 440mg, approximately 300mg~approx. 420mg, approximately 300mg~approx. 400mg, approximately 300mg~approx. ... mg~approx. 360mg, approx. 300mg~approx. 340mg, approx. 300mg~approx. 320mg, approx. 320mg~approx. 500mg, approx. 320mg~approx. 480mg, approx. 320mg~approx. 460mg, approx. 320mg~approx. 440mg, approx. 320mg~approx. 420mg, approx. 320mg~approx. 400mg, approx. 320mg~approx. 380mg, approx. 320mg~approx. 360mg, approx. 320mg~approx. 340mg, approx. 340mg~approx. 500mg, approx. 340mg~approx. 480mg, approx. 340mg~approx. 460mg, approx. 340mg~approx. 440mg, approx. 340mg~approx. 420mg, approx. 340mg~approx. 400mgApproximately 340mg to approximately 380mg, approximately 340mg to approximately 360mg, approximately 360mg to approximately 500mg, approximately 360mg to approximately 480mg, approximately 360mg to approximately 460mg, approximately 360mg to approximately 440mg, approximately 360mg to approximately 420mg, approximately 360mg to approximately 400mg, approximately 360mg to approximately 380 mg, approx. 380 mg ~ approx. 500 mg, approx. 380 mg ~ approx. 480 mg, approx. 380 mg ~ approx. 460 mg, approx. 380 mg ~ approx. 440 mg, approx. 380 mg ~ approx. It is administered orally in amounts of 460 mg, approximately 400 mg to 440 mg, approximately 400 mg to 420 mg, approximately 420 mg to 500 mg, approximately 420 mg to 480 mg, approximately 420 mg to 460 mg, approximately 420 mg to 440 mg, approximately 440 mg to 500 mg, approximately 440 mg to 480 mg, approximately 440 mg to 460 mg, approximately 460 mg to 500 mg, approximately 460 mg to 480 mg, approximately 480 mg to 500 mg, approximately 25, approximately 50, approximately 75, approximately 100, approximately 150, approximately 200, approximately 250, approximately 300, approximately 350, approximately 400, approximately 450, or approximately 500 mg.

[0108] In one embodiment, combination therapy involves taking a dose once or twice daily (for a certain period) in amounts ranging from approximately 10 mg to approximately 400 mg (for example, approximately 10 mg to approximately 380 mg, approximately 10 mg to approximately 360 mg, approximately 10 mg to approximately 340 mg, approximately 10 mg to approximately 320 mg, approximately 10 mg to approximately 300 mg, approximately 10 mg to approximately 280 mg, approximately 10 mg to approximately 260 mg, approximately 10 mg to approximately 240 mg, approximately 10 mg to approximately 220 mg, approximately 10 mg to approximately 200 mg, approximately 10 mg to approximately 180 mg, approximately 10 mg to approximately 160 mg, approximately 10 mg to approximately 140 mg, approximately 10 mg to approximately 120 mg, approximately 10 mg to approximately 100 mg) mg, approx. 10 mg to approx. 80 mg, approx. 10 mg to approx. 60 mg, approx. 10 mg to approx. 40 mg, approx. 10 mg to approx. 20 mg, approx. 20 mg to approx. 400 mg, approx. 20 mg to approx. 380 mg, approx. 00mg, about 20mg to about 280mg, about 20mg to about 260mg, about 20mg to about 240mg, about 20mg to about 220mg, about 20mg to about 200mg, about 20mg to about 180mg, about 20mg to about 160mg, about 20mg to about 140mg, about 20mg to about 120mg, about 20 mg ~ about 100mg, about 20mg - about 80mg, about 20mg - about 60mg, about 20mg - about 40mg, about 40mg - about 400mg, about 40mg - about 380mg, about 40mg - about 360mg, about 40mg - about 340mg, about 40mg - about 320mg, about 40mg - about 300mg, About 40mg to about 280mg, about 40mg to about 260mg, about 40mg to about 240mg, about 40mg to about 220mg, about 40mg to about 200mg, about 40mg to about 180mg, about 40mg to about 160mg, about 40mg to about 140mg, about 40mg to about 120mg, about 40mg to about 1 00mg, about 40mg to about 80mg, about 40mg to about 60mg, about 60mg to about 400mg, about 60mg to about 380mg, about 60mg to about 360mg, about 60mg to about 340mg, about 60mg to about 320mg, about 60mg to about 300mg, about 60mg to about 280mg, about 60m g ~ about 260mg, about 60mg - about 240mg, about 60mg - about 220mg, about 60mg - about 200mg, about 60mg - about 180mg, about 60mg - about 160mg, about 60mg - about 140mg, about 60mg - about 120mg, about 60mg - about 100mg, about 60mg - about 80mg,Approximately 80mg~400mg, approximately 80mg~380mg, approximately 80mg~360mg, approximately 80mg~340mg, approximately 80mg~320mg, approximately 80mg~300mg, approximately 80mg~280mg, approximately 80mg~260mg, approximately 80mg~240mg, approximately 80mg~220mg, approximately 80mg~200mg, approximately 80mg~180mg, approximately 80mg~160mg, approximately 80mg~140mg, approximately 80mg~120mg, approximately 80mg~100mg, approximately 100mg~400mg, approximately 10 0mg~approx. 380mg, approx. 100mg~approx. 360mg, approx. 100mg~approx. 340mg, approx. 100mg~approx. 320mg, approx. 100mg~approx. 300mg, approx. 100mg~approx. 280mg, approx. 100mg~approx. 260mg, approx. 100mg~approx. 240mg, approx. 100mg~approx. 220mg, approx. 100mg~approx. 200mg, approx. 100mg~approx. 180mg, approx. 100mg~approx. 160mg, approx. 100mg~approx. 140mg, approx. 100mg~approx. 120mg, approx. 120mg~approx. 400mg, approx. 120mg~approx. 380mg, approx. 120mg~approx. 360mg, approx. 120mg~approx. 340mg, approx. 120mg~ Approximately 320mg, approximately 120mg to approximately 300mg, approximately 120mg to approximately 280mg, approximately 120mg to approximately 260mg, approximately 120mg to approximately 240mg, approximately 120mg to approximately 220mg, approximately 120mg to approximately 200mg, approximately 120mg to approximately 180mg, approximately 120mg to approximately 160mg, approximately 120mg to approximately 140mg, approximately 140mg to approximately 400mg, approximately 140mg to approximately 380mg, approximately 140mg to approximately 360mg, approximately 140mg to approximately 340mg, approximately 140mg to approximately 320mg, approximately 140mg to approximately 300mg, approximately 140mg to approximately 280mg, approximately 140mg to approximately 260mg, approximately 140mg to approximately 240mg 0mg, approximately 140mg to approximately 220mg, approximately 140mg to approximately 200mg, approximately 140mg to approximately 180mg, approximately 140mg to approximately 160mg, approximately 160mg to approximately 400mg, approximately 160mg to approximately 380mg, approximately 160mg to approximately 360mg, approximately 160mg to approximately 360mg, approximately 160mg to approximately 340mg, approximately 160mg to approximately 320mg, approximately 160mg to approximately 300mg, approximately 160mg to approximately 280mg, approximately 160mg to approximately 260mg, approximately 160mg to approximately 240mg, approximately 160mg to approximately 220mg, approximately 160mg to approximately 200mg, approximately 160mg to approximately 180mg, approximately 180mg to approximately 400mg,Approx. 180mg to approx. 380mg, approx. 180mg to approx. 360mg, approx. 180mg to approx. 340mg, approx. 180mg to approx. 320mg, approx. 180mg to approx. 300mg, approx. 220mg, about 180mg to about 200mg, about 200mg to about 400mg, about 200mg to about 380mg, about 200mg to about 360mg, about 200mg to about 340mg, about 200mg to about 320mg, about 200mg to about 300mg, about 200mg to about 280mg, about 20 0mg to about 260mg, about 200mg to about 240mg, about 200mg to about 220mg, about 220mg to about 400mg, about 220mg to about 380mg, about 220mg to about 360mg, about 220mg to about 340mg, about 220mg to about 320mg, about 220mg to about 300 mg, approx. 220 mg ~ approx. 280 mg, approx. 220 mg ~ approx. 260 mg, approx. 220 mg ~ approx. 240 mg, approx. 240 mg ~ approx. 400 mg, approx. 240 mg ~ approx. 380 mg, approx. ~ about 300mg, about 240mg to about 280mg, about 240mg to about 260mg, about 260mg to about 400mg, about 260mg to about 380mg, about 260mg to about 360mg, about 260mg to about 340mg, about 260mg to about 320mg, about 260mg to about 300mg, Approximately 260mg to approximately 280mg, approximately 280mg to approximately 400mg, approximately 280mg to approximately 380mg, approximately 280mg to approximately 360mg, approximately 280mg to approximately 340mg, approximately 280mg to approximately 320mg, approximately 280mg to approximately 300mg, approximately 300mg to approximately 400mg, approximately 300mg to approximately 3 Oral administration of the compound of formula I in amounts of 80 mg, approximately 300 mg to approximately 360 mg, approximately 300 mg to approximately 340 mg, approximately 300 mg to approximately 320 mg, approximately 320 mg to approximately 400 mg, approximately 320 mg to approximately 380 mg, approximately 320 mg to approximately 360 mg, approximately 340 mg to approximately 360 mg, approximately 340 mg to approximately 400 mg, approximately 340 mg to approximately 380 mg, approximately 340 mg to approximately 360 mg, approximately 360 mg to approximately 400 mg, approximately 360 mg to approximately 380 mg, approximately 380 mg to approximately 400 mg, approximately 100 mg, approximately 200 mg, approximately 300 mg, or approximately 400 mg), and for example,This includes oral administration of a Raf family kinase inhibitor once daily (for a certain period). In one embodiment, the KRAS inhibitor is administered orally once daily. In another embodiment, the KRAS inhibitor is administered orally twice daily.

[0109] Those skilled in the art will understand that both in vivo and in vitro studies using suitable, known, and generally acceptable cell and / or animal models can predict the ability of a combination of test compounds or combinations to treat or prevent a given disorder.

[0110] Those skilled in the art will further understand that human clinical trials, including first-in-human studies, dose-ranging studies, and efficacy studies in healthy patients and / or patients with a given disorder, can be completed in accordance with methods well known in the clinical and medical fields.

[0111] Synergistic effect In one embodiment, the addition of a Raf family kinase inhibitor synergistically increases the activity of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB against cancer or cancer cell lines expressing KRas G12C. Any method for determining whether two compounds exhibit a synergistic effect can be used to determine the synergistic effect of the combination.

[0112] Several mathematical models have been developed to determine whether two compounds act synergistically, that is, to act beyond mere additive effects. For example, Loewe additiveity (Loewe (1928) Physiol. 27:47-187), Bliss independence (Bliss (1939) Ann. Appl. Biol. 26:585-615), best monotherapy, ZIP (Yadav et al (2015) Comput Struct Biotech J 13:504-513), as well as other models (Chou & Talalay (1984) Adv Enzyme Regul 22:27-55.#6382953, and Greco et al. (1995) Pharmacol Rev 47(2):331-85.#7568331) are well-known models in the pharmaceutical industry and can be used to determine whether a synergistic effect has been detected and to calculate a "synergy score" indicating the magnitude of such a synergistic effect. Combining these synergy scores generates a composite synergy score, which can be used to evaluate and characterize KRas G12C inhibitor compounds of formula (I), formula IA, or formula IB in combination with Raf family kinase inhibitors.

[0113] Generally, mathematical models use data obtained from individual agent values ​​to determine the predicted additive effect of a combination and compare it to the observed effect of the combination. If the observed effect is greater than the predicted effect, the combination is considered synergistic. For example, the Bliss independence model uses the observed combination response (Y O ) is the predicted combined response (Y) obtained based on the assumption that there is no influence from drug-drug interactions. P Compare with Y. O Y P When the values ​​are greater, the combination effect typically exhibits a synergistic effect.

[0114] In some embodiments, the term “synergistic effect” as used herein refers to a combination of a KRAS inhibitor or a pharmaceutically acceptable salt of a Raf family kinase

[0115] In some embodiments, the methods provided herein extend from 1 day to 2 years (for example, 1 day to 22 months, 1 day to 20 months, 1 day to 18 months, 1 day to 16 months, 1 day to 14 months, 1 day to 12 months, 1 day to 10 months, 1 day to 9 months, 1 day to 8 months, 1 day to 7 months, 1 day to 6 months, 1 day to 5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 9 months, 1 week to 8 months) 1 week to 7 months, 1 week to 6 months, 1 week to 5 months, 1 week to 4 months, 1 week to 3 months, 1 week to 2 months, 1 week to 1 month, 2 weeks to 2 years, 2 weeks to 22 months, 2 weeks to 20 months, 2 weeks to 18 months, 2 weeks to 16 months, 2 weeks to 14 months, 2 weeks to 12 months, 2 weeks to 10 months, 2 weeks to 9 months, 2 weeks to 8 months, 2 weeks to 7 months, 2 weeks to 6 months, 2 weeks to 5 months, 2 weeks to 4 months, 2 weeks to 3 months, 2 weeks to 2 months, 2 weeks to 1 month, 1 month to 2 years, 1 month to 22 months, 1 month to 20 months, 1 month to 18 months, 1 month to 16 months Months, 1-14 months, 1-12 months, 1-10 months, 1-9 months, 1-8 months, 1-7 months, 1-6 months, 1-6 months, 1-5 months, 1-4 months, 1-3 months, 1-2 months, 2 months-2 years, 2 months-22 months, 2 months-20 months, 2 months-18 months, 2 months-16 months, 2 months-14 months, 2 months-12 months, 2 months-10 months, 2 months-9 months, 2 months-8 months, 2 months-7 months, 2 months-6 months, or 2-5 months, 2-4 months, 3 months-2 years, 3 months-22 months, 3 months During the period of 1 month to 20 months, 3 months to 18 months, 3 months to 16 months, 3 months to 14 months, 3 months to 12 months, 3 months to 10 months, 3 months to 8 months, 3 months to 6 months, 4 months to 2 years, 4 months to 22 months, 4 months to 20 months, 4 months to 18 months, 4 months to 16 months, 4 months to 14 months, 4 months to 12 months, 4 months to 10 months, 4 months to 8 months, 4 months to 6 months, 6 months to 2 years, 6 months to 22 months, 6 months to 20 months, 6 months to 18 months, 6 months to 16 months, 6 months to 14 months, 6 months to 12 months, 6 months to 10 months, or 6 months to 8 months,1% to 99% of the volume of one or more solid tumors in patients after treatment with combination therapy (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%) , 2%~45%, 2%~40%, 2%~35%, 2%~30%, 2%~25%, 2%~20%, 2%~15%, 2%~10%, 2%~5%, 4%~99%, 4%~95%, 4%~90%, 4%~85%, 4%~80%, 4%~75%, 4%~70%, 4%~65%, 4%~60% , 4%~55%, 4%~50%, 4%~45%, 4%~40%, 4%~35%, 4%~30%, 4%~25%, 4%~20%, 4%~15%, 4%~10%, 6%~99%, 6%~95%, 6%~90%, 6%~85%, 6%~80%, 6%~75%, 6%~70%, 6%~65 %, 6%~60%, 6%~55%, 6%~50%, 6%~45%, 6%~40%, 6%~35%, 6%~30%, 6%~25%, 6%~20%, 6%~15%, 6%~10%, 8%~99%, 8%~95%, 8%~90%, 8%~85%, 8%~80%, 8%~75%, 8%~7 0%, 8%~65%, 8%~60%, 8%~55%, 8%~50%, 8%~45%, 8%~40%, 8%~35%, 8%~30%, 8%~25%, 8%~20%, 8%~15%, 10%~99%, 10%~95%, 10%~90%, 10%~85%, 10%~80%, 10%~7 5%, 10%~70%, 10%~65%, 10%~60%, 10%~55%, 10%~50%, 10%~45%, 10%~40%, 10%~35%, 10%~30%, 10%~25%, 10%~20%, 10%~15%, 15%~99%, 15%~95%, 15%~90%, 15 %~85%, 15%~80%, 15%~75%, 15%~70%, 15%~65%, 15%~60%, 15%~55%, 15%~50%, 15%~55%, 15%~50%, 15%~45%, 15%~40%, 15%~35%, 15%~30%, 15%~25%, 15%~20%,20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、55%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、65%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、70%~99%、70%~95%、70%~90%、70%~85%、70%~80%、70%~75%、This can result in a reduction of 75%-99%, 75%-95%, 75%-90%, 75%-85%, 75%-80%, 80%-99%, 80%-95%, 80%-90%, 80%-85%, 85%-99%, 85%-95%, 85%-90%, 90%-99%, 90%-95%, or 95%-100% (for example, compared to the size of one or more solid tumors in the patient before treatment).

[0116] The term "survival time" refers to the length of time from the identification or diagnosis of a mammalian cancer (e.g., any of the cancers described herein) by a medical professional to the time of death of the mammal (caused by the cancer). Methods for increasing the survival time of mammals with cancer are described herein.

[0117] In some embodiments, any of the methods described herein may be used during the patient's survival time, (e.g., 1%~400%, 1%~380%, 1%~360%, 1%~340%, 1%~320%, 1%~300%, 1%~280%, 1%~260%, 1%~240%, 1%~220%, 1%~200%, 1%~180%, 1%~160%, 1%~140%, 1%~120%, 1%~100%, 1%~95%, 1%~90%, 1%~85%, 1%~80%, 1%~75%, 1%~70%, 1%~65%, 1%~60%, 1%~55%, 1%~50%, 1%~4 5%, 1%~40%, 1%~35%, 1%~30%, 1%~25%, 1%~20%, 1%~15%, 1%~10%, 1%~5%, 5%~400%, 5%~380%, 5%~360%, 5%~340%, 5%~320%, 5%~300%, 5%~280%, 5%~260%, 5% ~240%, 5%~220%, 5%~200%, 5%~180%, 5%~160%, 5%~140%, 5%~120%, 5%~100%, 5%~90%, 5%~80%, 5%~70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~10%, 10%~400%, 10%~380%, 10%~360%, 10%~340%, 10%~320%, 10%~300%, 10%~280%, 10%~260%, 10%~240%, 10%~220%, 10%~200%, 10%~180%, 10%~160%, 10%~140 %, 10%~120%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10%~20%, 20%~400%, 20%~380%, 20%~360%, 20%~340%, 20%~3 20%, 20%~300%, 20%~280%, 20%~260%, 20%~240%, 20%~220%, 20%~200%, 20%~180%, 20%~160%, 20%~140%, 20%~120%, 20%~100%, 20%~90%, 20%~80%, 20%~7 0%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~400%, 30%~380%, 30%~360%, 30%~340%, 30%~320%, 30%~300%, 30%~280%, 30%~260%, 30%~240%, 30%~220%,30%~200%、30%~180%、30%~160%、30%~140%、30%~120%、30%~100%、30%~90%、30%~80%、30%~70%、30%~60%、30%~50%、30%~40%、40%~400%、40%~380%、40%~360%、40%~340%、40%~320%、40%~300%、40%~280%、40%~260%、40%~240%、40%~220%、40%~200%、40%~180%、40%~160%、40%~140%、40%~120%、40%~100%、40%~90%、40%~80%、40%~70%、40%~60%、40%~50%、50%~400%、50%~380%、50%~360%、50%~340%、50%~320%、50%~300%、50%~280%、50%~260%、50%~240%、50%~220%、50%~200%、50%~180%、50%~160%、50%~140%、50%~140%、50%~120%、50%~100%、50%~90%、50%~80%、50%~70%、50%~60%、60%~400%、60%~380%、60%~360%、60%~340%、60%~320%、60%~300%、60%~280%、60%~260%、60%~240%、60%~220%、60%~200%、60%~180%、60%~160%、60%~140%、60%~120%、60%~100%、60%~90%、60%~80%、60%~70%、70%~400%、70%~380%、70%~360%、70%~340%、70%~320%、70%~300%、70%~280%、70%~260%、70%~240%、70%~220%、70%~200%、70%~180%、70%~160%、70%~140%、70%~120%、70%~100%、70%~90%、70%~80%、80%~400%、80%~380%、80%~360%、80%~340%、80%~320%、80%~300%、80%~280%、80%~260%、80%~240%、80%~220%、80%~200%、80%~180%、80%~160%、80%~140%、80%~120%、80%~100%、80%~90%、90%~400%、90%~380%、90%~360%、90%~340%、90%~320%、90%~300%、90%~280%、90%~260%、90%~240%、90%~220%、90%~200%、90%~180%、90%~160%、90%~140%、90%~120%、90%~100%、100%~400%、100%~380%、100%~360%、100%~340%、100%~320%、100%~300%、100%~280%、100%~260%、100%~240%、100%~220%、100%~200%、100%~180%、100%~160%、100%~140%、100%~120%、120%~400%、120%~380%、120%~360%、120%~340%、120%~320%、120%~300%、120%~280%、120%~260%、120%~240%、120%~220%、120%~200%、120%~180%、120%~160%、120%~140%、140%~400%、140%~380%、140%~360%、140%~340%、140%~320%、140%~300%、140%~280%、140%~260%、140%~240%、140%~220%、140%~200%、140%~180%、140%~160%、160%~400%、160%~380%、160%~360%、160%~340%、160%~320%、160%~300%、160%~280%、160%~260%、160%~240%、160%~220%、160%~200%、160%~180%、180%~400%、180%~380%、180%~360%、180%~340%、180%~320%、180%~300%、180%~280%、180%~260%、180%~240%、180%~220%、180%~200%、200%~400%、200%~380%、200%~360%、200%~340%、200%~320%、200%~300%、200%~280%、200%~260%、200%~240%、200%~220%、220%~400%、220%~380%、220%~360%、220%~340%、220%~320%、220%~300%、220%~280%、220%~260%、220%~240%、240%~400%、240%~380%、240%~360%、240%~340%、240%~320%、240%~300%、This can result in increases of 240%-280%, 240%-260%, 260%-400%, 260%-380%, 260%-360%, 260%-340%, 260%-320%, 260%-300%, 260%-280%, 280%-400%, 280%-380%, 280%-360%, 280%-340%, 280%-320%, 280%-300%, 300%-400%, 300%-380%, 300%-360%, 300%-340%, or 300%-320% (for example, compared to patients with similar cancer who received different treatments or no treatment at all).

[0118] In some embodiments of the methods described herein, prior to treatment with the compositions or methods of the present invention, the patient has been treated with one or more of the following: chemotherapy, targeted anticancer agents, radiotherapy, and surgery, and optionally, prior treatment has failed, and / or the patient has undergone surgery, and optionally, the surgery has failed, and / or the patient has been treated with a platinum-based chemotherapeutic agent, and optionally, the patient has been previously determined not to respond to treatment with a platinum-based chemotherapeutic agent, and / or the patient has been treated with a kinase inhibitor, and optionally, prior treatment with a kinase inhibitor has failed, and / or the patient has been treated with one or more other therapeutic agents.

[0119] kit The present invention also relates to a kit comprising a Raf family kinase inhibitor and a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB. A kit comprising a Raf family kinase inhibitor or a pharmaceutically acceptable salt thereof and a KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharmaceutically acceptable salt thereof is also provided for use in the treatment of hematological malignancies.

[0120] In related embodiments, the present invention provides a kit comprising a certain dose of a Raf family kinase inhibitor or a pharmaceutically acceptable salt thereof and a certain dose of a KRas G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the proliferation of cancer cells, particularly KRas G12C-expressing cancer cells, in a subject. The kit may optionally include an insert containing instructions for administering the Raf family kinase inhibitor or a pharmaceutically acceptable salt thereof and a KRAS G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharmaceutically acceptable salt thereof. The insert may provide the user with a set of instructions for using the Raf family kinase inhibitor or a pharmaceutically acceptable salt thereof in combination with the KRas G12C inhibitor compound of formula (I), formula IA, or formula IB or a pharmaceutically acceptable salt thereof.

[0121] Example A Raf family kinase inhibitors synergistically increase the activity of KRas G12C inhibitors in cell lines expressing KRas G12C. This example can be used to demonstrate that a combination of exemplary KRas G12C inhibitor compounds of formulas I, IA, and 1-B or pharmaceutically acceptable salts thereof (e.g., compounds selected from compound example numbers 1 to 678, or pharmaceutically acceptable salts thereof, e.g., example numbers 234, 359, 478, or 507, or pharmaceutically acceptable salts thereof) and a Raf family kinase inhibitor or a pharmaceutically acceptable salt thereof synergistically inhibits the growth of tumor cell lines expressing KRas G12C.

[0122] To determine whether combining Raf family kinase inhibitors with exemplary KRas G12C inhibitors disclosed herein results in synergistic activity, a panel of eight lung cancer and one colorectal cell line carrying KRas G12C mutations is assembled. The collection may include NCI-H1373 (ATCC CRL-5866), NCI-H1792 (ATCC CRL-5895), NCI-H2030 (ATCC CRL-5985), NCI-H2122 (ATCC CRL-5985), HCC1171 (KCLB 71171), HCC44 (DSMZ ACC-534), LU99 (RCB1900), SW1573 (ATCC CRL-2170), and SW837 (ATCC CCL-235).

[0123] The assay to determine the synergistic score of each pair of cell lines is performed three times. A specific cell line, at 2000 cells / well, is seeded in a growth medium suitable for that cell line, e.g., RPMI 1640 medium supplemented with 10% FBS, and a total of 90 μl of any cell line-specific reagents required for growth, into three 96-well plates for determining baseline luminescence and four additional wells on a separate 96-well control plate. The plates are incubated overnight at 37°C in a 5% CO2 atmosphere.

[0124] Add 30 μl of Cell-Titer Glo reagent (CTG; Promega Corporation) to each of the designated baseline wells, and incubate the plate at room temperature for 20 minutes with shaking. Baseline luminescence is quantified using a BMG ClarioStar multimode plate reader according to the manufacturer's instructions.

[0125] A series of working stock 1000X drug dilutions in 100% DMSO were prepared, including eight monotherapy dilutions of exemplary KRas G12C inhibitors and five monotherapy dilutions of Raf family kinase inhibitors of formula (I). The dilutions used for KRas G12C inhibitors and Raf family kinase inhibitors varied for each individual compound, but were typically in the range of 3-6 serial dilutions.

[0126] Exemplary KRasG12C inhibitors to be tested in this example include the following: [Table 1]

[0127] 10X intermediate dose plates are prepared in serum-free RPMI medium containing monotherapy dilutions of exemplary KRas G12C inhibitors or Raf family kinase inhibitors of formula (I). In addition, combinations of 40 matrix dilutions of exemplary KRas G12C inhibitors of formula (I), formula IA, or formula IB with Raf family kinase inhibitors are prepared as test samples.

[0128] Add 10 μl of each 10X monotherapy compound and dose matrix 40 combination to each corresponding well of three 96-well plates seeded with the appropriate cell lines described above, and incubate the plates at 37C in a 5% CO2 atmosphere for 72 hours. Add 30 μl aliquot of Cell-Titer Glo reagent (CTG) to each test well, and incubate the plates at room temperature with shaking for 20 minutes. Luminescence is quantified using a BMG ClarioStar multimode plate reader according to the manufacturer's instructions.

[0129] Raw data and metadata files can be used as input files to calculate the efficacy rate for each treatment condition and analyze it using four independent mathematical reference models (Loewe additiveity, Bliss independence, best monotherapy, and ZIP) designed to determine whether two test compounds exhibit a synergistic effect. The output of the data from each mathematical model is the assignment of relative synergy scores ("composite synergy scores") such as Loewe additivity, Bliss independence, best single agent, and the sum of ZIP scores.

[0130] Example B In vivo model to investigate combinations of KRas G12C inhibitors and Raf family kinase inhibitors Cells with the KRas G12C mutation or patient-derived tumor samples were inoculated into the right hindlimb side of immunodeficient nude / nude mice. When the tumor volume reached a size of 200 - 400 mm 3 ³, the mice were divided into four groups of 5 - 12 mice each. The first group was administered only the vehicle. The second group was administered a single-agent dose of a KRas G12C inhibitor at a concentration that resulted in the maximum biological effect or a sub-maximum biological effect depending on the cell line and single-agent activity, which did not result in complete tumor regression. The third group was administered a single-agent dose of a Raf family kinase inhibitor at a concentration that resulted in the maximum biological effect or a sub-maximum biological effect depending on the cell line and single-agent activity, which did not result in complete tumor regression. The fourth group was administered a single-agent dose of a KRas G12C inhibitor in combination with a single-agent dose of a Raf family kinase inhibitor. The treatment period varied for each cell line but was usually 21 - 35 days. The tumor volume was measured using calipers every 2 - 3 days, and the tumor volume was calculated using the formula: 0.5 × (length × width) 2 The high degree of tumor growth inhibition of the combination in this model indicated that combination therapy was likely to provide clinically significant benefits to the treatment subjects compared to treatment with only a KRas G12C inhibitor or only a Raf family kinase inhibitor.

[0131] For example, on day 1, 20 nude / nude mice were inoculated with 5 × 10 6 ⁶ NCI-H2122 cells in the right hindlimb. When the tumor volume reached approximately 300 mm 3When reaching (day 0 of the study), each of the five mice in each of the four groups was orally administered vehicle only (10% captisol), 100 mg / kg of the KRAS G12C inhibitor compound 478 (10% captisol in 50 mM citrate buffer (pH 5.0) once a day), 10 mg / kg of the Raf family kinase inhibitor BGB-283 (0.5% methylcellulose / 0.4% Tween-80) twice a day, or 100 mg / kg of the KRas G12C inhibitor compound 478 once a day and 10 mg / kg of BGB-283 twice a day, daily for 21 days. In addition, five mice were administered 100 mg / kg of the KRas G12C inhibitor compound 478 once a day for 15 days. On day 16 of the study, these mice were further administered 100 mg / kg of the KRas G12C inhibitor compound 478 once a day in combination with 10 mg / kg of BGB-283 twice a day for an additional 9 days. Tumor volumes were measured on the pre-specified days shown below. The tumor volumes of five mice per group were averaged and reported in Table 1. N.D. = not measured.

Table 2

[0132] As shown in Table 1, administration of compound 478 or BGB-283 as monotherapies showed 82.8% and 48.9% tumor growth inhibition, respectively, on day 9 of the study. The combination of the Raf family kinase inhibitor BGB-283 and compound 478 resulted in 34.6% tumor regression after 9 days of concurrent combination therapy. In addition, after administering compound 478 for 15 days, combination therapy with BGB-283 for 9 days resulted in 73.8% regression of tumor growth after only 9 days of combination therapy. These results indicate that, in contrast to monotherapy with any of the drugs that produced tumor growth inhibition, combination therapy resulted in potent tumor regression regardless of whether it was administered as a combination of 25 days or only 9 days of treatment. These results demonstrate the enhanced in vivo antitumor effect of the combination against cancers expressing KRas G12C.

[0133] While the present invention has been described in relation to its specific embodiments, those embodiments are further modifiable, and this application is generally intended to encompass any variations, uses, or alterations of the present invention in accordance with the principles of the invention, and will be understood to include deviations from the present disclosure that may fall within the scope of known or routine practices within the art to which the invention belongs and which may fall within the scope of essential features set forth above and in the appendix claims below.

Claims

1. A pharmaceutical composition for use in a method of treating cancer in a person requiring cancer treatment, The method involves administering to the subject a therapeutically effective dose of rifilafenib (BGB-283), a Raf family kinase inhibitor, and a KRAS G12C inhibitor of the following formula. 【Chemistry 1】 or administering a combination of a pharmaceutically acceptable salt thereof, The pharmaceutical composition comprises the Raf family kinase inhibitor and / or the KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof. A pharmaceutical composition wherein the cancer is lung cancer or colorectal cancer associated with the KRas G12C mutation.

2. The pharmaceutical composition according to claim 1, wherein the Raf family kinase inhibitor and the KRAS G12C inhibitor are administered on the same day.

3. The pharmaceutical composition according to claim 1, wherein the Raf family kinase inhibitor and the KRAS G12C inhibitor are administered on different days.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the KRas G12C inhibitor is administered at the maximum tolerated dose.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the Raf family kinase inhibitor and the KRAS G12C inhibitor are each administered at the maximum tolerated dose.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the combination of the Raf family kinase inhibitor and the KRAS G12C inhibitor in a therapeutically effective amount results in increased overall survival, increased progression-free survival, increased tumor growth regression, increased tumor growth inhibition, or increased duration of stable disease in the subject, compared to treatment with the KRAS G12C inhibitor alone.

7. A pharmaceutical composition for treating cancer in a subject, A therapeutically effective dose of rifilafenib (BGB-283), a Raf family kinase inhibitor, and the KRas G12C inhibitor shown below. 【Chemistry 2】 or a combination thereof with a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient, A pharmaceutical composition wherein the cancer is lung cancer or colorectal cancer associated with the KRas G12C mutation.

8. A pharmaceutical composition for use in a method for inhibiting KRas G12C activity in cancer cells, The above method involves inhibiting KRas G12C activity in the cancer cells, and then using an effective amount of rifilafenib (BGB-283), a Raf family kinase inhibitor, and a KRas G12C inhibitor compound of the following formula to control the cancer cells. 【Transformation 3】 or including contact with a pharmaceutically acceptable salt thereof, The pharmaceutical composition comprises the Raf family kinase inhibitor and / or the KRas G12C inhibitor compound or a pharmaceutically acceptable salt. The Raf family kinase inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor. A pharmaceutical composition wherein the cancer is lung cancer or colorectal cancer associated with the KRas G12C mutation.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the Raf family kinase inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor.

10. KRas G12C inhibitor compounds of the following formula 【Chemistry 4】 or a pharmaceutical composition for use in a method for increasing the sensitivity of cancer cells to a pharmaceutically acceptable salt thereof, The above method, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, produces a compound of the following formula. 【Transformation 5】 This includes administering a therapeutically effective dose of rifirafenib (BGB-283), a Raf family kinase inhibitor, to subjects receiving KRas G12C treatment with a pharmaceutically acceptable salt thereof. The pharmaceutical composition comprises the Raf family kinase inhibitor, The Raf family kinase inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor. A pharmaceutical composition wherein the cancer is lung cancer or colorectal cancer associated with the KRas G12C mutation.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the therapeutically effective dose of the KRas G12C inhibitor in the combination is about 0.01 to 100 mg / kg / day.

12. The pharmaceutical composition according to claim 11, wherein the therapeutically effective dose of the KRas G12C inhibitor in the above combination is about 0.1 to 50 mg / kg / day.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the therapeutically effective dose of the Raf family kinase inhibitor in the combination is about 0.01 to 100 mg / kg / day.

14. The pharmaceutical composition according to claim 13, wherein the therapeutically effective dose of the Raf family kinase inhibitor in the combination is about 0.1 to 50 mg / kg / day.

15. A kit for treating KRas G12C cancer in a subject, comprising the pharmaceutical composition according to claim 1, wherein the KRas G12C cancer is lung cancer or colorectal cancer associated with the KRas G12C mutation.

16. a) A pharmaceutical composition comprising rifilafenib (BGB-283), a Raf family kinase inhibitor, b) KRas G12C inhibitors of the following formula 【Transformation 6】 A pharmaceutical composition comprising or a pharmaceutically acceptable salt thereof, A kit for treating KRas G12C cancer in the target group, The kit wherein the KRas G12C cancer is lung cancer or colorectal cancer associated with the KRas G12C mutation.

17. The kit according to claim 15 or 16, further comprising an insert containing instructions for administering the pharmaceutical composition.

Images