Therapeutic combination of KRAS G12C inhibitor and TEAD inhibitor

Abstract

The present invention relates to a therapeutic combination comprising at least one KRAS G12C inhibitor and at least one specific TEAD inhibitor selected from the group consisting of molecules of formula (III), indole compounds of formula (IV), indane compounds of formula (V) and pharma- ceutical acceptable salts thereof; and its use in the treatment of KRAS G12C-mediated cancers, in particular lung cancer, pancreatic cancer or colon cancer. The present invention also relates to pharmaceutical compositions and kits comprising the therapeutic combination.

Description

[Technical field]

[0001] The present disclosure relates to therapeutic combinations of at least one KRAS G12C inhibitor and at least one specific TEAD inhibitor.

[0002] The therapeutic combinations disclosed herein are particularly advantageous in the treatment of KRAS G12C mediated cancers, more particularly in the treatment of lung, pancreatic or colon cancer. [Background technology]

[0003] RAS proteins, a family of small GTPases that integrate and transmit signals from upstream growth factor receptors, comprise the most frequently mutated protein family in human cancers, with frequent RAS mutations found in lung, colon, and pancreatic cancers, the top three causes of cancer death. RAS proteins function as molecular switches. Under normal signaling conditions, ligand stimulation leads to activation of the guanine nucleotide exchange factor Son of Sevenless (SOS), which facilitates the exchange of RAS from an inactive guanosine diphosphate (GDP)-bound state to an active guanosine triphosphate (GTP)-bound state. This switch between the inactive and active states allows RAS to adopt a conformation that interacts with the RAS-binding domain (RBD) of its downstream effectors, facilitating the recruitment of rapidly accelerated fibrosarcoma (RAF) family members (ARAF, BRAF, CRAF) from the cytoplasm to the cell membrane, which ultimately results in the activation of the MAPK signaling cascade. Active MAPK signaling further leads to the activation of gene transcription programs required for cell proliferation. Under normal conditions, activation of the RAS-RAF-MAPK signaling cascade is transient and is turned off through the action of RAS-GTPase-activating (GAP) proteins. These proteins activate GTPase enzymes found within RAS, which hydrolyze GTP to GDP, thus turning off RAS. Mutations in RAS proteins result in conformational changes whereby the RAS-GAP proteins can no longer activate the intrinsic GTPase enzyme. As a result, the GTP molecule is not hydrolyzed, but instead continually maintains RAS in its active state, thus causing a tumorigenic effect by amplifying signaling in the MAPK pathway (reviewed in Hymowitz and Malek, CHS Perspectives 2018:8(11)).

[0004] Recently, small molecules that specifically target the KRAS G12C oncogenic mutant protein have advanced in clinical trials (reviewed in Goebel et al, RSC Medicinal Chem:7, 2020). KRAS G12C refers to a mutant form of the mammalian KRAS protein that contains an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The amino acid codon and residue position assignments for human KRAS are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:variant p.Gly12Cys.

[0005] On the one hand, the transcription enhancer associated domain (TEAD) family of transcription factors TEAD1-TEAD4 are the most downstream effectors of the HIPPO-YAP1 signaling cascade, an evolutionarily conserved signaling pathway whose deregulation has been described for various cancer types (reviewed in Nguyen and Yi, Trends Cancer. 2019, 5:283-296). The core of the HIPPO pathway in mammals consists of a cascade of kinases including MST1 / 2 and LATS1 / 2, their associated adaptor proteins SAV1 and MOB1, and upstream regulators such as NF2, SCRIBBLE, CRUMBS, and multiple G protein-coupled receptors. In the healthy adult human organism, the HIPPO pathway kinases are found primarily in their "on" state, actively phosphorylating YAP1 and TAZ (WWTR1 gene) proteins. Phosphorylated YAP1 and TAZ then remain inactive by sequestration in the cytoplasm and / or degradation by the proteasome machinery. In many tumors, HIPPO signaling is found in an "off" state, where the cytoplasmic YAP1 and TAZ proteins are no longer phosphorylated and are therefore free to translocate to the cell nucleus, where they associate with TEAD transcription factors. The YAP1-TEAD or TAZ-TEAD couple then binds to DNA and induces the expression of genes that promote cell proliferation and cell survival (reviewed in Totaro et al., Nature Cell Bio. 2018, 20:888-899).

[0006] Small molecule allosteric ligands that bind to the central lipid pocket of TEAD proteins can inhibit aberrant YAP1-TEAD or TAZ-TEAD activation, and several such allosteric TEAD inhibitors have been described in the literature, with K-975 being one of the known examples (Kaneda et al., Am J Cancer Res. 2020, 10:4399-4415). Allosteric TEAD inhibitors inhibit tumor cell proliferation in vitro and in vivo and are active in tumor types that depend on TEAD activity, where activation of TEAD (YAP1-TEAD or TAZ-TEAD) is a major driver of tumor growth. This is the case, for example, in tumor indications with dysfunctional HIPPO signaling, which is the case, for example, in malignant mesothelioma tumors with HIPPO kinase or NF2 inactivation (Kaneda et al.). In tumors where TEAD is not a driver of tumor cell proliferation, TEAD inhibitors can be added to in vitro and in vivo models without effect, affecting tumor cell proliferation and survival.

[0007] Like all signaling pathways, the HIPPO-YAP1 / TAZ-TEAD signaling cascade does not exist in isolation, but crosstalks with other signaling pathways. For example, crosstalk between this pathway and the MAPK pathway has been recently reported (Pham et al., Cancer Discovery 2020, 11:778-793). The MAPK pathway is tightly regulated by RAS proteins. Summary of the Invention [Means for solving the problem]

[0008] The present disclosure provides the unexpected finding that combinations of certain TEAD inhibitors with KRAS G12C inhibitors are particularly effective in treating tumors harboring KRAS G12C mutations, and thus are particularly effective for use in treating KRAS G12C-associated cancers, including lung adenocarcinoma, pancreatic ductal adenocarcinoma, rectal adenocarcinoma, colon adenocarcinoma, cholangiocarcinoma, chronic myelomonocytic leukemia (CMML), rhabdomyosarcoma, endometrial cancer, bladder cancer, and ovarian cancer (Li et al., Nat Rev Cancer, 2018 Dec;18(12):767:777).

[0009] Thus, according to one of its aspects, the present disclosure provides a therapeutic combination comprising at least one KRAS G12C inhibitor and at least one specific TEAD inhibitor selected from the group consisting of molecules of formula (III), indole compounds of formula (IV), indane compounds of formula (V) and pharma- ceutical acceptable salts thereof, as detailed below.

[0010] Surprisingly, in different KRAS tumor models carrying a KRAS G12C mutation, as shown in the studies of the examples presented below, the inventors have discovered that the addition of said TEAD inhibitor in combination with a KRAS G12C inhibitor makes it possible to significantly improve the inhibition of the proliferation of KRAS G12C mutant cell lines compared to the effect achieved with the KRAS G12C inhibitor alone.

[0011] Thus, the presence of said TEAD inhibitor makes it possible to stimulate / potentiate the inhibitory effect of the KRAS G12C inhibitor.

[0012] As shown in the examples, the combination of the TEAD inhibitor with the KRAS G12C inhibitor unexpectedly enhances the effect of the KRAS G12C inhibitor by an order of magnitude, in some cases up to 100-fold. This significant synergistic effect on the inhibition of KRAS G12C is particularly even more surprising given that these particular TEAD inhibitors alone are completely inactive in tumor models harboring KRAS G12C mutations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In one embodiment, the therapeutic combination combines one or more of the KRAS G12C inhibitors disclosed below with one or more of the TEAD inhibitors disclosed below.

[0014] As used herein, certain terms have the following definitions: - Halogen atom: a fluorine, chlorine, bromine or iodine atom; - Alkyl group: a straight-chain or branched-chain saturated aliphatic group. More specifically, a (Cx-Cy) alkyl group (where x and y are integers and x < y) is a straight-chain or branched-chain saturated aliphatic group containing x to y carbon atoms, for example 1 to 4 carbon atoms. By way of example, and without limitation, methyl, ethyl, propyl, isopropyl groups and the like may be mentioned; - Cycloalkyl group: a cyclic alkyl group containing a spiro group. More specifically, a (C3-Cz) cycloalkyl group (where z is an integer of 4 or more) is a cyclic alkyl group containing 3 to z carbon atoms, unsubstituted or substituted, unless otherwise stated. By way of example, and without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexanyl and the like may be mentioned; - Alkenyl group: for example, a straight-chain or branched-chain monovalent or polyvalent unsaturated aliphatic group containing one or two ethylenic unsaturations. More specifically, a (C2-Cy) alkenyl group (where y is an integer of 3 or more) contains 2 to y carbon atoms, for example 2 to 4 carbon atoms, and is a straight-chain or branched-chain monovalent or polyvalent unsaturated aliphatic group containing, for example, one or two ethylenic unsaturations. By way of example, and without limitation, ethenyl, propenyl, n-propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, tert-butenyl groups and the like may be mentioned; - Alkoxy group: A group -O-alkyl where the alkyl group is as defined above. More specifically, a (Cx~Cy) alkoxy group (where x and y are integers and x < y) is a -O-(Cx~Cy) alkyl group where the (Cx~Cy) alkyl group is as already defined. For example, the alkoxy group is a (C1~C4) alkoxy group. By way of example, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy groups and the like may be mentioned; - Aryl group: A monocyclic or bicyclic aromatic group containing 6 to 10 carbon atoms. Examples of aryl groups may include phenyl or naphthyl groups; - Heteroaryl group: A monocyclic or bicyclic aromatic group containing 4 to 9 carbon atoms and oxygen atoms and 1 or 2 heteroatoms selected from nitrogen atoms and sulfur atoms, more specifically oxygen atoms and nitrogen atoms, and even more specifically nitrogen. By way of example, but not limited to, pyridinyl groups and the like may be mentioned; - Heterocyclyl or heterocyclic group: A ring structure having 3 to 12 atoms, particularly 4 to 8 atoms, where one or more atoms are selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms and the remainder of the ring atoms are carbon. More specifically, the heterocyclyl or heterocyclic group may, unless otherwise stated, have 4 to 9, particularly 4 to 8 carbon atoms and contain 1 or 2 heteroatoms selected from oxygen atoms, nitrogen atoms and sulfur atoms, particularly oxygen atoms and nitrogen atoms. The heterocyclic group may be monocyclic, bicyclic, spirocyclic or a bridged ring system. The heterocyclic group is optionally substituted at one or more positions at carbon or nitrogen. By way of example, but not limited to, pyrrolidine, piperazine, piperidine, tetrahydropyran, morpholine, diazepan groups and the like may be mentioned; - Alkylene group: A linear or branched saturated divalent alkyl group. More specifically, a (Cx-Cy) alkylene group (where x and y are integers and x < y) is a linear or branched saturated divalent alkyl group containing x to y carbon atoms. For example, a (C1-C3) alkylene group represents a linear or branched divalent carbon-based chain of 1 to 3 carbon atoms. By way of example, and not limitation, a methylene group, an ethylene group, a 1-methylethylene group, a propylene group, etc. may be mentioned; - Alkylthio group: A group -S-alkyl where the alkyl group is as defined above. More specifically, a (Cx-Cy) alkylthio group (where x and y are integers and x < y) is a group -S-(Cx-Cy) alkyl where (Cx-Cy) alkyl is as defined above, for example a (C1-C4) alkylthio group. By way of example, and not limitation, a methylthio group, an ethylthio group, a propylthio group, a butylthio group, etc. may be mentioned; - Benzyl group: The group -CH2-phenyl group; - Dialkylamino group: An amino group substituted with two alkyl groups where the alkyl group is as defined above; - Sulfonyl group: The SO2 group; - Alkylsulfonyl group: A group -SO2-alkyl where the alkyl group is as defined above. More specifically, a (Cx-Cy) alkylsulfonyl group (where x and y are integers and x < y) is a group -SO2-(Cx-Cy) alkyl where (Cx-Cy) alkyl is as defined above, for example a (C1-C4) alkylsulfonyl group. By way of example, and not limitation, a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, etc. may be mentioned; - Silyl group: A group containing a silicon atom. An example of a silyl group is a trimethylsilyl group.

[0015] All patents, patent applications, and publications referred to herein are incorporated by reference.

[0016] KRAS G12C inhibitor KRAS G12C inhibitors are compounds that inhibit the KRAS G12C mutant protein. In particular, the KRAS G12C inhibitors used in combination are compounds that negatively regulate or inhibit all or part of the enzymatic activity of KRAS G12C.

[0017] The KRAS G12C inhibitor can be any KRAS G12C inhibitor known in the art. In particular, it is one of the KRAS G12C inhibitors described in more detail in the following paragraphs.

[0018] The therapeutic combinations described below include one or more KRAS G12C inhibitors.

[0019] The KRAS G12C inhibitor, in one particular embodiment, may be selected from the compounds disclosed as KRAS G12C inhibitors in patent applications WO 2018 / 217651, WO 2019 / 213516, WO 2018 / 119183; and patent applications WO 2019 / 99524, WO 2017 / 201161 and WO 2020 / 101736.

[0020] In exemplary embodiments, the KRAS G12C inhibitor may be selected from the group including, in particular consisting of, a compound of formula (I), in particular formula (I'), as detailed below; a compound of formula (II), in particular formula (II'); pharma- ceutically acceptable salts thereof; and mixtures thereof.

[0021] In an exemplary embodiment, the KRAS G12C inhibitor used in the therapeutic combination has the following formula (I): [ka] (In the formula, R A is hydrogen, a (C1-C4) alkyl group or a halogen atom, in particular R A is a fluorine atom; R Bare each independently a hydrogen atom or a (C1-C4) alkyl group, in particular both R B is a hydrogen atom; R1 is a (C1-C3) alkylene group, in particular a methylene group; R2 is a (C4-C8)heterocyclyl group containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur atoms, in particular oxygen and nitrogen atoms, more particularly 1 or 2 nitrogen atoms, such as a pyrrolidinyl group unsubstituted or substituted by one or more R6; L1 is a bond or a (C1-C3) alkylene group, in particular, L1 is a bond; R3 is a (C6-C10)aryl group or a heteroaryl group containing 4 to 9 carbon atoms and 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur atoms, which is unsubstituted or substituted with one or more R7 groups; in particular, R3 is a naphthyl group substituted with one or more R7 groups; n is 0, 1 or 2, and R4 is selected from (C1-C4) alkyl groups that are unsubstituted or substituted with one or more cyano groups or halogen atoms; m is 0, 1 or 2; and R5 is selected from (C1-C4) alkyl groups that are unsubstituted or substituted with one or more halogen atoms; R6 is a (C1-C4) alkyl group, more particularly a methyl group; R7 is selected from halogen atoms, in particular chlorine atoms, and (C1-C4) alkyl groups which are unsubstituted or substituted with one or more halogen atoms. or a pharma- ceutically acceptable salt thereof.

[0022] In an exemplary embodiment, the KRAS G12C inhibitor has formula (I'): [ka] (In the formula, R A is a halogen atom, in particular a fluorine atom; R Bare, independently of each other, hydrogen or (C1-C4) alkyl; in particular, both R B is a hydrogen atom; R6 is as defined above, more particularly a methyl group; and R7 is a halogen atom, in particular a chlorine atom. or a pharma- ceutically acceptable salt thereof.

[0023] In an exemplary embodiment, the KRAS G12C inhibitor used in the therapeutic combination is 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile, in other words, a compound of the formula: [ka] which corresponds to Adagrasib provided by Mirati Therapeutics, Inc., also known as MRTX849.

[0024] In another exemplary embodiment, the KRAS G12C inhibitor used in the therapeutic combination has the following formula (II): [ka] (In the formula, R8 is a hydrogen atom, a halogen atom, such as a fluorine atom or a (C1-C3) alkyl group that is unsubstituted or substituted with one or more halogen atoms, in particular with one or more fluorine atoms; in particular, R8 is a hydrogen atom; R9 is a halogen atom, in particular a fluorine atom, or a (C1-C3) alkyl group that is unsubstituted or substituted with one or more halogen atoms, in particular one or more fluorine atoms; in particular, R9 is a fluorine atom; L2 is a single bond or a methylene group, in particular a single bond; R10 is a (C6-C10)aryl group or a heteroaryl group containing 4 to 9 carbon atoms and 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur atoms, in particular a phenyl group, which is unsubstituted or substituted with one or more R13 groups; R11 is a (C6-C10)aryl group or a heteroaryl group containing 4 to 9 carbon atoms and 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur atoms, which is unsubstituted or substituted, preferably at the ortho position, with one or more R14 groups; R C is a hydrogen atom or a (C1-C3) alkyl group; R D is a hydrogen atom, a (C1-C3) alkyl group or a halogen atom, particularly a fluorine atom; p is 0, 1 or 2; and R12 is a (C1-C3) alkyl group, in particular a methyl group; R13 is selected from halogen atoms, in particular fluorine atoms, hydroxyl groups (OH) and (C1-C3) alkoxy groups; R14 is selected from a hydrogen atom, a (C1-C4) alkyl group, and a (C3-C6) cycloalkyl group. or a pharma- ceutically acceptable salt thereof.

[0025] Among the KRAS G12C inhibitors of formula (II), mention may in particular be made of compounds in which R10 is [ka] , especially the base [ka]

[0026] Among the KRAS G12C inhibitors of formula (II), mention may in particular be made of compounds in which R11 is [ka] , especially the base [ka]

[0027] In an exemplary embodiment, the KRAS G12C inhibitor has the following formula (II'): [ka] (In the formula, R C and R D is as defined above, in particular R C and R D are hydrogen atoms, R8 is as defined above, in particular R8 is a hydrogen atom, R9 is as defined above, in particular a halogen atom, more particularly a fluorine atom; R12 is as defined above, in particular a methyl group; R13 is as defined above, in particular one is a hydroxyl group and the other is a fluorine atom, R14 is as defined above, in particular a (C1-C3) alkyl group, more particularly one is a methyl group and the other is an isopropyl group. or a pharma- ceutically acceptable salt thereof.

[0028] In an exemplary embodiment, the KRAS G12C inhibitor used in the therapeutic combination is 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one, in other words, a compound of the formula: [ka] which corresponds to Sotorasib provided by Amgen, also known as AMG 510.

[0029] In an exemplary embodiment, the KRAS G12C inhibitor used in the therapeutic combination is 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (also known as Adagrasib, MRTX849); 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (also known as Sotorasib, AMG-510); or A pharma- ceutically acceptable salt thereof It is.

[0030] In an exemplary embodiment, Adagrasib (MRTX849) is the KRAS G12C used in the therapeutic combination.

[0031] In another exemplary embodiment, Sotorasib (AMG-510) is the KRAS G12C used in the therapeutic combination.

[0032] TEAD inhibitors TEAD inhibitors are compounds that have inhibitory activity of YAP1 / TAZ-TEAD or TEAD-dependent gene transcription.

[0033] The therapeutic combinations described below include one or more of the specific TEAD inhibitors disclosed below.

[0034] The TEAD inhibitors used in the therapeutic combinations of the present disclosure are selected from the group including, and in particular consisting of, molecules of formula (III), indole compounds of formula (IV), indane compounds of formula (V), pharma- ceutically acceptable salts thereof, and mixtures thereof, as detailed below.

[0035] In an exemplary embodiment, the TEAD inhibitor used in the therapeutic combination has the following formula (III): [ka] (In the formula, X1 is a halogen atom, in particular a chlorine atom; X2 is a (C1-C4) alkyl group, particularly a methyl group. or a pharma- ceutically acceptable salt thereof.

[0036] Mention may be made, for example, of N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide, also known as K-975.

[0037] In another exemplary embodiment, the TEAD inhibitor used in the therapeutic combination is selected from the indole compounds disclosed in patent application WO 2021 / 204823.

[0038] Thus, in an exemplary embodiment, the TEAD inhibitor has the following formula (IV): [ka] (In the formula, q is an integer selected from 0 to 1; G1 is - a single bond, and - (C1-C4) alkylene group, especially methylene group is selected from G2 is - (C1-C4) alkyl groups which are unsubstituted or substituted with one or more fluorine atoms, - a (C1-C3)alkoxy group substituted with one or more fluorine atoms, a phenyl group which is unsubstituted or substituted by one or more G3 groups, - a (C4-C8)cycloalkyl group which is unsubstituted or substituted by one or more G5 groups, - (C4-C8)heterocyclyl groups containing 1 or 2 heteroatoms selected from oxygen and nitrogen atoms, which are unsubstituted or substituted by one or more G6 groups, and - NG9G10 units is selected from G3 is - (C1-C4) alkyl groups which are unsubstituted or substituted by one or more fluorine atoms, in particular methyl groups, - a cyclopropyl group, - halogen atoms, - a (C1-C3)alkoxy group which is unsubstituted or substituted by one or more fluorine atoms, - pentafluorosulfanyl group, - nitrile groups, - (C1-C3) trialkylsilyl group, - (C1-C3) alkylsulfonyl groups, and a phenyl group which is unsubstituted or substituted by a trifluoromethyl group; is selected from G4 is selected from a hydrogen atom and a (C1-C4) alkyl group; G5 is selected from a fluorine atom and a trifluoromethyl group; The G6 a phenyl group which is unsubstituted or substituted by one or more fluorine atoms or one or more CF3 groups, - (C1-C4) alkyl groups substituted with one or more fluorine atoms, and - Fluorine atom is selected from The G7 - hydrogen atom, - nitrile groups, - (C1-C4) alkyl groups, in particular methyl groups, which are unsubstituted or substituted by (C1-C3) alkoxy groups, in particular methoxy groups or hydroxy groups, - COO(C1-C4) alkyl group, and - 2 CONHs is selected from G8 is selected from a hydrogen atom and a (C1-C4) alkyl group that is unsubstituted or substituted with a di(C1-C4) alkylamino group; G9 and G10 are the same or different and are selected from (C1-C3) alkyl groups that are unsubstituted or substituted with one or more fluorine atoms; G11 is selected from a hydrogen atom, a fluorine atom and a chlorine atom. or a pharma- ceutically acceptable salt thereof.

[0039] In one embodiment, the TEAD inhibitor has the following formula (IV'): [ka] wherein G1, G2, G4, G7, G8 and G11 are as defined above.

[0040] Among the TEAD inhibitors of formula (IV) or (IV'), mention may be made of compounds in which G4 is a hydrogen atom.

[0041] Among the TEAD inhibitors of formula (IV) or (IV'), mention may be made of compounds in which G7 is a hydrogen atom or a (C1-C4) alkyl group, in particular a methyl group, which is unsubstituted or substituted with a (C1-C3) alkoxy group, in particular a methoxy group.

[0042] Among the TEAD inhibitors of formula (IV) or (IV'), mention may be made of compounds in which G8 is a hydrogen atom.

[0043] Among the TEAD inhibitors of formula (IV) or (IV'), mention may be made of compounds in which G11 is a hydrogen atom.

[0044] Among the TEAD inhibitors of formula (IV) are compounds q is 0, G1 is a single bond or a methylene group; G2 is a phenyl group which is unsubstituted or substituted by one or more G3 groups, - a (C4-C8)cycloalkyl group which is unsubstituted or substituted with one or more G5 groups, and - a (C4-C8)heterocyclyl group containing 1 or 2 heteroatoms selected from oxygen and nitrogen atoms, which is unsubstituted or substituted with one or more G6 groups; or a pharma- ceutically acceptable salt thereof.

[0045] In one embodiment, G2 is a phenyl group substituted with one or more G3 groups, and G3 is in particular a (C1-C4) alkyl group substituted with one or more fluorine atoms, in particular a trifluoromethyl group.

[0046] In certain embodiments, the TEAD inhibitor is represented by formula (IV): q is 0, G1 is a single bond or a methylene group; G2 is selected from a phenyl group which is unsubstituted or substituted with one or more G3 groups; G3 is a (C1-C4) alkyl group substituted with one or more fluorine atoms, in particular a trifluoromethyl group; G4 is a hydrogen atom; G7 is a hydrogen atom or a (C1-C4) alkyl group, in particular a methyl group, which is unsubstituted or substituted with a (C1-C3) alkoxy group, in particular a methoxy group; G8 is a hydrogen atom; G11 is a hydrogen atom. or a pharma- ceutically acceptable salt thereof.

[0047] For example, among the TEAD inhibitors of formula (IV), in particular the following compounds: N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide, N-(3-(methoxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide, N-(3-methyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide, and Pharmaceutically acceptable salts thereof may be mentioned.

[0048] The TEAD inhibitors of formula (IV) may be prepared according to the methods disclosed in the above-referenced patent application WO 2021 / 204823.

[0049] In another exemplary embodiment, the TEAD inhibitor used in the therapeutic combination is selected from the indane compounds disclosed in patent application WO 2022 / 023460 filed by SANOFI.

[0050] Thus, in an exemplary embodiment, the TEAD inhibitor has formula (V): [ka] (In the formula, F1 is - oxygen atoms, and - group -N(H)- or group -N(F8)- (wherein F8 is a (C1-C4) alkyl group, particularly a methyl group). Selected from; F2 is - a phenyl group which is unsubstituted or substituted by one or more F4 groups; a benzyl group which is unsubstituted or substituted by one or more F5 groups; - (C4-C8)cycloalkyl groups which are unsubstituted or substituted by one or more F5 groups, in particular cyclohexyl or cyclopentyl groups, more particularly cyclohexyl groups; heteroaryl groups containing 4 to 9 carbon atoms and 1 or 2 heteroatoms selected from oxygen and nitrogen atoms, which are unsubstituted or substituted by one or more F5 groups, in particular pyridinyl groups; - (C1-C6) alkyl groups, in particular (C1-C4) alkyl groups, substituted with one or more fluorine atoms. Selected from; F3 is, - hydrogen atoms, and - (C1-C4) alkyl groups, especially methyl groups Selected from; F4 is - halogen atoms, in particular fluorine or chlorine atoms; - (C1-C4)alkyl groups which are unsubstituted or substituted by one or more fluorine atoms, in particular methyl or trifluoromethyl groups; - (C1-C4)alkoxy groups which are unsubstituted or substituted by one or more fluorine atoms, in particular methoxy or trifluoromethoxy groups; - C(O)-O-(C1-C4) alkyl groups, in particular C(O)-O-methyl groups; - (C3-C6) cycloalkyl groups, in particular cyclopropyl groups; - (C1-C4) alkylthio groups, in particular methylthio groups; and - Pentafluorosulfanyl group Selected from; F5 is halogen atoms, in particular fluorine atoms; and - (C1-C4) alkyl groups which are unsubstituted or substituted by one or more fluorine atoms, in particular trifluoromethyl groups Selected from; F6 is selected from hydrogen atoms and halogen atoms, in particular fluorine atoms; F7 is - halogen atoms, in particular fluorine atoms; - (C1-C4) alkyl groups, in particular methyl groups; - hydroxyl group; - (C1-C4) alkoxy groups, especially methoxy groups are independently selected from; s is 0, 1 or 2) or a pharma- ceutically acceptable salt thereof.

[0051] In certain embodiments, the TEAD inhibitor has the formula (V'): [ka] (In the formula, F1 is - oxygen atoms, and - Group -N(H)- Selected from; F2 is - a phenyl group which is unsubstituted or substituted by one or more F4 groups; a benzyl group which is unsubstituted or substituted by one or more F5 groups; - (C4-C8)cycloalkyl groups, in particular cyclohexyl groups, which are unsubstituted or substituted by one or more F5 groups; heteroaryl groups containing 4 to 9 carbon atoms and 1 or 2 heteroatoms selected from oxygen and nitrogen atoms, which are unsubstituted or substituted by one or more F5 groups, in particular pyridinyl groups; - (C1-C4) alkyl groups substituted with one or more fluorine atoms, in particular (C2-C4) alkyl groups substituted with one or more fluorine atoms, more particularly (C2-C3) alkyl groups substituted with trifluoromethyl groups. Selected from; F3 is, - hydrogen atoms, and - (C1-C4) alkyl groups, especially methyl groups Selected from; F4 is - halogen atoms, in particular fluorine atoms; - (C1-C4)alkyl groups which are unsubstituted or substituted by one or more fluorine atoms, in particular methyl or trifluoromethyl groups; - (C1-C4)alkoxy groups which are unsubstituted or substituted by one or more fluorine atoms, in particular methoxy or trifluoromethoxy groups; and - -C(O)-O-(C1-C3) alkyl group, especially -C(O)-O-methyl group Selected from; F5 is halogen atoms, in particular fluorine atoms; and - (C1-C4) alkyl groups which are unsubstituted or substituted by one or more fluorine atoms, in particular trifluoromethyl groups (selected from or a pharma- ceutically acceptable salt thereof.

[0052] In one embodiment, the TEAD inhibitor is of formula (V) where the indane is substituted at the 1-position with a group -F1-F2 according to the IUPAC numbering, in other words the following formula (Va): [ka] or a pharma- ceutically acceptable salt thereof, wherein F1, F2, F3, F6, F7, and s are as defined herein.

[0053] In particular, the TEAD inhibitor is of formula (V') in which the indane is substituted at the 1-position with a group -F1-F2 according to the IUPAC numbering, in other words the following formula (V'a): [ka] or a pharma- ceutically acceptable salt thereof, wherein F1, F2, and F3 are as defined herein.

[0054] In another embodiment, the TEAD inhibitor is of formula (V) in which the indane is substituted at the 3-position with a group -F1-F2 according to the IUPAC numbering, in other words, of the following formula (Vb): [ka] or a pharma- ceutically acceptable salt thereof, wherein F1, F2, F3, F6, F7, and s are as defined herein.

[0055] In particular, the TEAD inhibitor is of formula (V') in which the indane is substituted at the 3-position with a group -F1-F2 according to the IUPAC numbering, in other words the following formula (V'b): [ka] or a pharma- ceutically acceptable salt thereof, wherein F1, F2, and F3 are as defined herein.

[0056] In certain embodiments, the TEAD inhibitor is of formula (V), particularly formula (V'), or any subformula (Va), (Vb), (V'a) or (V'b) thereof, wherein F3 is a hydrogen atom.

[0057] In certain embodiments, the TEAD is of formula (V), in particular of formula (V') or any subformula (Va), (Vb), (V'a) or (V'b) thereof, wherein: F1 is an oxygen atom and F2 is - a phenyl group which is unsubstituted or substituted by one or more F4 groups; - (C4-C8)cycloalkyl groups which are unsubstituted or substituted by one or more F5 groups, in particular cyclohexyl or cyclopentyl groups; - (C1-C5) alkyl groups substituted with one or more fluorine atoms, in particular (C1-C4) alkyl groups, in particular (C1-C4) alkyl groups substituted with trifluoromethyl groups, in particular (C2-C3) alkyl groups. or F1 is -N(H)- and F2 is - a phenyl group which is unsubstituted or substituted by one or more F4 groups; and heteroaryl groups containing 4 to 9 carbon atoms and 1 or 2 heteroatoms selected from oxygen and nitrogen, which are unsubstituted or substituted by one or more F5 groups, in particular pyridinyl groups is selected from.

[0058] In certain embodiments, the TEAD inhibitor is of formula (V), in particular of formula (V') or any subformula (Va), (Vb), (V'a) or (V'b) thereof, wherein F2 is - a phenyl group which is unsubstituted or substituted by one or more F4 groups; and - (C4-C8)cycloalkyl groups, in particular cyclohexyl groups, which are unsubstituted or substituted by one or more F5 groups, with the proviso that F1 is an oxygen atom; is selected from.

[0059] Among the TEAD inhibitors of formula (V), in particular of formula (V') or any sub-formula (Va), (Vb), (V'a) or (V'b) thereof, are in particular compounds, F1 is an oxygen atom, Mention may be made of compounds in which F2 is a (C4-C8)cycloalkyl group, in particular a cyclohexyl group, substituted by one or more F5 groups, said F5 groups being chosen from (C1-C4)alkyl groups, in particular a trifluoromethyl group, substituted by one or more fluorine atoms.

[0060] Among the TEAD inhibitors of formula (V), in particular of formula (V') or any sub-formula (Va), (Vb), (V'a) or (V'b) thereof, are in particular compounds, F1 is a -N(H)- group, Mention may in particular be made of compounds in which F2 is a phenyl group substituted by one or more F4 groups, said F4 groups being selected from (C1-C4)alkyl groups substituted by one or more fluorine atoms, in particular trifluoromethyl groups, or halogen atoms, in particular fluorine atoms.

[0061] In particular, in compounds of formula (V), especially formula (V') or any sub-formula (Va), (Vb), (V'a) or (V'b) thereof, the F4 group is in the meta and / or para position to the F2 phenyl group.

[0062] In particular, in compounds of formula (V), especially formula (V') or any sub-formulas (Va), (Vb), (V'a) or (V'b) thereof, the F5 group is in the para and / or meta position, especially the para position, to the F2 group.

[0063] In certain embodiments, the TEAD inhibitor is represented by formula (V'), particularly formulas (V'a) and (V'b), F1 is selected from an oxygen atom and a group -N(H)-; F2 is - a phenyl group which is unsubstituted or substituted by one or more F4 groups; a benzyl group which is unsubstituted or substituted by one or more trifluoromethyl groups, with the proviso that F1 is -N(H)-; - a cyclohexyl group substituted by one or more F5 groups; - a pyridinyl group substituted by one or more F5 groups; and - (C2-C4) alkyl groups substituted with one or more fluorine atoms, in particular (C2-C3) alkyl groups substituted with trifluoromethyl groups Selected from; F3 is selected from a hydrogen atom and a methyl group; F4 is selected from a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group and a -C(O)-O-methyl group; and F5 is selected from a fluorine atom and a trifluoromethyl group. or a pharma- ceutically acceptable salt thereof.

[0064] In certain embodiments, the TEAD inhibitor has formula (V), in particular formula (Va) or (Vb), F1 is an oxygen atom or a group -N(H)-; F2 is - a phenyl group which is unsubstituted or substituted by one or more F4 groups; - (C4-C8) cycloalkyl groups, in particular cyclohexyl groups, which are unsubstituted or substituted by one or more F5 groups. Selected from; F3 is a hydrogen atom or a methyl group; in particular, F3 is a hydrogen atom; F4 is a (C1-C4) alkyl group substituted with one or more fluorine atoms, particularly a trifluoromethyl group, or a halogen atom, particularly a fluorine atom; F5 is a (C1-C4) alkyl group substituted with one or more fluorine atoms, in particular a trifluoromethyl group; F6 is a hydrogen atom; s is 0) or a pharma- ceutically acceptable salt thereof.

[0065] For example, among the TEAD inhibitors of formula (V), in particular the following compounds: N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; and Pharmaceutically acceptable salts thereof may be mentioned.

[0066] The TEAD inhibitors of formula (V) may be prepared according to the methods disclosed in the above-referenced patent application WO 2022 / 023460.

[0067] In an exemplary embodiment, the therapeutic combination comprises, as the TEAD inhibitor: N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide (also known as K-975); N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; N-(3-(methoxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; N-(3-methyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide; N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; or A pharma- ceutically acceptable salt thereof Use.

[0068] The compounds of formula (I), (II), (III), (IV) and (V) above or any subformula thereof may contain one or more asymmetric carbon atoms and therefore may exist in the form of enantiomers or diastereoisomers and also mixtures thereof.

[0069] Compounds of formula (I), (II), (III), (IV) and (V) or any subformula thereof may also exist in tautomeric form.

[0070] The compounds of formula (I), (II), (III), (IV) and (V) or any subformula thereof may exist in the form of bases or addition salts with acids or bases, particularly pharma- ceutically acceptable salts.

[0071] All combinations of one or more of the specific KRAS G12C inhibitors detailed above and one or more of the specific TEAD inhibitors detailed above are part of the present specification.

[0072] Thus, the combination may comprise one or more KRAS G12C inhibitors, particularly selected from the group consisting of compounds of formula (I), compounds of formula (II), any subformulae thereof, and pharmaceutically acceptable salts thereof, as defined above; and one or more specific TEAD inhibitors, particularly selected from the group consisting of compounds of formula (III), compounds of formula (IV), compounds of formula (V), any subformulae thereof, and pharmaceutically acceptable salts thereof, as defined above.

[0073] In an exemplary embodiment, the combination is: - below: 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (also known as Adagrasib, MRTX849); 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (also known as Sotorasib, AMG-510) or a pharma- ceutically acceptable salt thereof; and - below: N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide (also known as K-975); N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; N-(3-(methoxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; N-(3-methyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide; N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide or a pharma- ceutically acceptable salt thereof. may include.

[0074] Purpose As described above, the inventors have shown that the presence of certain TEAD inhibitors, as described above, in combination with a KRAS G12C inhibitor makes it possible to dramatically improve the efficacy of the KRAS G12C inhibitor.

[0075] Therefore, the combination of the above disclosed TEAD inhibitor and KRAS G12C inhibitor provides a synergistic effect for inhibiting KRAS G12C protein.

[0076] The synergistic effect of the addition of said TEAD inhibitor in combination with a KRAS G12C inhibitor advantageously makes it possible to consider using it to implement a dose reduction or even an improvement in efficacy of the KRAS G12C inhibitor.

[0077] Therefore, the KRAS G12C inhibitor and the TEAD inhibitor are used in combination therapy.

[0078] The therapeutic combination of said KRAS G12C inhibitor and said TEAD inhibitor is more particularly for use in the treatment of a pathology involving KRAS G12C, in particular in the treatment of a KRAS G12C-associated disease or disorder, in particular a KRAS G12C-mediated cancer.

[0079] KRAS G12C-mediated cancers include lung adenocarcinoma, pancreatic ductal adenocarcinoma, rectal adenocarcinoma, colon adenocarcinoma, cholangiocarcinoma, chronic myelomonocytic leukemia (CMML), rhabdomyosarcoma, endometrial cancer, bladder cancer and ovarian cancer.

[0080] The combination of said KRAS G12C inhibitor and said TEAD inhibitor may be advantageously used in the treatment of non-small cell lung cancer, small cell lung cancer, pancreatic cancer or colon cancer.

[0081] Thus, according to another aspect, therapeutic combinations of KRAS G12C inhibitors and specific TEAD inhibitors as disclosed above for use in the treatment of KRAS G12C mediated cancers, in particular lung adenocarcinoma, pancreatic ductal adenocarcinoma, rectal adenocarcinoma, colon adenocarcinoma, cholangiocarcinoma, chronic myelomonocytic leukemia (CMML), rhabdomyosarcoma, endometrial cancer, bladder cancer and ovarian cancer; more particularly in the treatment of non-small cell lung cancer, small cell lung cancer, pancreatic cancer or colorectal cancer are described below.

[0082] The therapeutic combination may be used to treat patients who have demonstrated resistance to previous anti-cancer therapies.

[0083] The KRAS G12C inhibitor and the TEAD inhibitor used in combination can be administered simultaneously or separately.

[0084] Thus, administration of a therapeutic combination can include simultaneous administration of the two inhibitors in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.

[0085] The KRAS G12C inhibitor is more particularly administered in a therapeutically effective amount. A "therapeutically effective amount or dose" is an amount sufficient to negatively regulate or inhibit the activity of KRAS G12C and thus ameliorate or in any way alleviate the symptoms of, or stop or halt the progression of, a pathology involving KRAS G12C.

[0086] The therapeutically effective amount may vary depending on the subject (eg, the subject's weight, age, and sex), the condition being treated, the severity of the condition, and the method of administration.

[0087] TEAD inhibitor is co-administered in combination with KRAS G12C inhibitor in an amount sufficient to achieve the effect of enhancing the activity of said KRAS G12C inhibitor.In particular, the TEAD inhibitor in combination therapy is not administered in a therapeutically effective amount.This means that TEAD inhibitor alone is ineffective in therapeutic treatment, particularly in the treatment of targeted cancer.

[0088] The term "co-administration" or "administered in combination with" as used herein encompasses administering both a KRAS G12C inhibitor and a TEAD inhibitor to a subject such that both inhibitors and / or their metabolites are present in the subject at the same time. Co-administration includes combinations and pharmaceutical compositions that are not limited to those obtained by physical association of the components in a single unit dosage form, including those that allow for separate administration, which may be simultaneous or sequential (also referred to as "spaced" or "distributed") over a period of time. Co-administration in separate compositions and administration in a single unit dosage form are preferred.

[0089] The KRAS G12C inhibitor and the TEAD inhibitor of the therapeutic combination can be administered by any method known in the art. They can be administered by any route, including, but not limited to, parenteral, oral, transdermal, and other dosage forms.

[0090] The therapeutic combination may also be administered in combination with at least one third active agent, especially selected from active agents known in anti-cancer therapy.

[0091] The therapeutic combination or pharmaceutical composition may also be used in combination with other treatments, such as radiation therapy or chemotherapy.

[0092] In one embodiment, both a KRAS G12C inhibitor, particularly as described above, and a TEAD inhibitor may be formulated together in the same dosage form and administered simultaneously.

[0093] The combination of a KRAS G12C inhibitor and a TEAD inhibitor may be used as a drug, particularly as a drug for the treatment of KRAS-G12C mediated cancers.

[0094] Thus, medicaments comprising at least one KRAS G12C inhibitor and at least one specific TEAD inhibitor as disclosed above are also described.

[0095] According to another of its aspects, the present disclosure relates to a pharmaceutical composition comprising the aforementioned therapeutic combination, in other words a pharmaceutical composition comprising in particular at least one KRAS G12C inhibitor as described above and at least one TEAD inhibitor as disclosed above.

[0096] In particular, the pharmaceutical composition contains therapeutically effective doses of said KRAS G12C inhibitor and said TEAD inhibitor in effective amounts to reach a synergistic effect for inhibiting KRAS G12C protein.

[0097] In one embodiment, said pharmaceutical composition is for use in the treatment of a KRAS G12C mediated cancer as described above.

[0098] The pharmaceutical composition may also contain at least one pharma- ceutically acceptable excipient, diluent and / or carrier, which are selected according to the pharmaceutical form and the desired method of administration from the usual excipients, diluents and carriers known to those skilled in the art.

[0099] In another embodiment, a KRAS G12C inhibitor and a TEAD inhibitor as described above can be administered simultaneously, with both inhibitors being present in separate formulations.

[0100] In yet another embodiment, the KRAS G12C inhibitor and the TEAD inhibitor can be administered separately, for example, the KRAS G12C inhibitor can be administered immediately followed by the TEAD inhibitor, or vice versa. In some embodiments of the separate administration protocol, the KRAS G12C inhibitor and the TEAD inhibitor are administered minutes apart, or hours apart, or days apart.

[0101] The KRAS G12C inhibitor and the TEAD inhibitor may be administered simultaneously or separately in separate dosage forms and may be included in separate pharmaceutical compositions, which may contain at least one pharma- ceutically acceptable excipient, diluent and / or carrier as described above.

[0102] According to another of its aspects, the present disclosure relates to a kit comprising, in one or more separate packages, the aforementioned therapeutic combination or pharmaceutical composition comprising both a KRAS G12C inhibitor and a TEAD inhibitor as disclosed above, optionally together with instructions for its administration and / or a medical device for its administration.

[0103] The kit is for use in co-administration of said KRAS G12C inhibitor and said TEAD inhibitor, either simultaneously or separately, particularly for the treatment of KRAS G12C mediated cancer, particularly lung cancer, colon cancer or pancreatic cancer.

[0104] The KRAS G12C inhibitor and the TEAD inhibitor may be comprised in a single pharmaceutical composition or in two separate pharmaceutical compositions within the kit.

[0105] According to another aspect, there is also described a method for treating KRAS G12C associated cancer, comprising administering to a patient in need thereof the aforementioned therapeutic combination or pharmaceutical composition.

[0106] Also described is a method for treating a KRAS G12C-associated cancer, comprising co-administering therapeutically effective amounts of a KRAS G12C inhibitor and a TEAD inhibitor to a patient in need thereof.

[0107] Also provided herein is the use of a therapeutic combination disclosed herein in the manufacture of a medicament for the treatment of a KRAS G12C-mediated cancer.

[0108] The following examples are non-limiting and are intended merely to illustrate the present disclosure. EXAMPLES

[0109] The TEAD inhibitors and KRAS G12C inhibitors used in the examples described below are as follows:

[0110] TEAD inhibitors TEAD inhibitor N°1: commercially available TEAD K-975; TEAD inhibitor N°2: N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; TEAD inhibitor N°3: N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; TEAD inhibitor N°4: N-(3-(methoxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide; TEAD inhibitor N°5: N-(3-methyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide; TEAD inhibitor N°6: N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; TEAD inhibitor N°7: N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; TEAD inhibitor N°8: N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide.

[0111] TEAD inhibitors N°3, N°4 and N°5 were prepared according to the detailed synthesis described in PCT Patent Application WO 2021 / 204823.

[0112] TEAD inhibitors N°2, N°6, N°7 and N°8 were prepared according to the detailed synthesis described in PCT Patent Application WO 2022 / 023460.

[0113] KRAS G12C inhibitors KRAS G12C inhibitor N°1: Adagrasib MRTX849 from Mirati Therapeutics, Inc.; KRAS G12C inhibitor N°2: Sotorasib AMG 510 from Amgen.

[0114] Example 1: Ray design combination experiment in KRAS mutant HOP-62 cell line with KRAS G12C inhibitor N°1 and TEAD inhibitors N°1 and N°2 The NSCLC cell line HOP62, which harbors the KRASG12C mutation, was used for this study. HO-P62 cells were seeded in 384-well plates at 300 cells per well and incubated for 24 hours at 37°C and 5% CO2. KRAS G12C inhibitor N°1, used at 14 concentrations ranging from 10,000 nM to 0.006 nM, in combination with TEAD inhibitor, used at 18 concentrations ranging from 10,000 nM to 0.0001 nM, was added to HOP-62 cells and incubated for 96 hours at 37°C and 5% CO2. Compound dilution and distribution to cells was performed on a TECAN MCA384 robotics platform. Cell proliferation was measured using Cell Titer Glo (luminescence) from PROMEGA.

[0115] Three independent experiments with triplicates per experiment were performed and analyzed using the combinatorial analysis software Combo2Screen. TEAD inhibitors were defined as inactive in this cell line, and their effects against KRAS G12C inhibitors were determined as synergistic and quantified using a synergy index based on the following formula:

number

[0116] In this study, various TEAD inhibitors enhanced the effect of KRAS G12C inhibitor N°1 in HOP-62 KRAS G12C mutant NSCLC cells with a maximal effect of approximately 8-fold, as described below.

[0117] [Table 1]

[0118] Example 2: Ray design combination experiment in KRAS mutant H-2030 cell line with KRAS G12C inhibitor N°1 and TEAD inhibitors N°1 and N°2 The NSCLC cell line H-2030, which harbors the KRASG12C mutation, was used for this study. H-2030 cells were seeded in 384-well plates at 250 cells per well and incubated for 24 hours at 37°C and 5% CO2. KRAS G12C inhibitor N°1, used at 14 concentrations ranging from 10,000 nM to 0.006 nM, in combination with TEAD inhibitor, used at 18 concentrations ranging from 10,000 nM to 0.0001 nM, was added to H-2030 cells and incubated for 144 hours at 37°C and 5% CO2. Compound dilution and distribution to cells was performed on a TECAN MCA384 robotics platform. Cell proliferation was measured using Cell Titer Glo (luminescence) from PROMEGA.

[0119] Three independent experiments in triplicate / experiment were performed and analyzed using the combinatorial analysis software Combo2Screen. TEAD inhibitors were defined as inactive in this cell line, and their effects against KRAS G12C inhibitors were determined as synergistic and quantified using a synergy index based on the following formula:

number

[0120] In this study, various TEAD inhibitors enhanced the effect of KRASG12C inhibitor N°1 in H-2030 KRAS G12C mutant NSCLC cells with a maximal effect of approximately 18- to 33-fold, as described below.

[0121] [Table 2]

[0122] Example 3: IC50 shift experiments in the KRAS G12C mutant NSCLC cell line HOP-62 with KRAS G12C inhibitors N°1 and N°2 and a series of structurally distinct TEAD inhibitors. The KRAS G12C mutant NSCLC cell line HOP-62 was used for this study. Cells were seeded in 96-well plates at 1250 cells per well and incubated for 24 hours at 37°C and 5% CO2. KRAS G12C inhibitors N°1 and N°2 were used at 10 concentrations and combined with TEAD inhibitors used at two concentrations. Compound dilution and distribution to cells was performed on a TECAN MCA384 robotics platform. Cells were incubated with inhibitors for 144 hours at 37°C and 5% CO2. Cell proliferation was measured using Cell Titer Glo (luminescence) from PROMEGA. For each KRAS G12C inhibitor, IC50 values ​​in these cell lines were determined in the absence or presence of TEAD inhibitors.

[0123] In this study, various TEAD inhibitors potentiate the IC50 effect of KRAS G12C inhibitors N°1 or N°2 by up to 21-fold in HOP-62 KRAS G12C mutant NSCLC cells.

[0124] [Table 3]

[0125] [Table 4]

[0126] These studies in tumor models harboring KRAS G12C mutations show that combinations of certain TEAD inhibitors of the present disclosure with KRAS G12C inhibitors enhance the efficacy of the KRAS G12C inhibitor by orders of magnitude, between 4-33 fold in the examples above, depending on the inhibitor and cell line combination used.

[0127] Synergistic effects are observed in multiple different KRAS G12C models and assay settings.

Claims

1. A therapeutic combination comprising at least one KRAS G12C inhibitor and at least one TEAD inhibitor, wherein the at least one TEAD inhibitor is - Formula (III) 【Chemistry 1】 (In the formula, X1 is a halogen atom, in particular a chlorine atom; X2 is an alkyl group (C1-C4), particularly a methyl group. Compounds of or pharmaceutically acceptable salts thereof; - Formula (IV) 【Chemistry 2】 (In the formula, q is an integer selected from 0 to 1; G1 is, - Single bond, and - (C1-C4) alkylene groups, especially methylene groups Selected from, G2 is, - Unsubstituted (C1-C4) alkyl groups or (C1-C3) groups substituted with one or more fluorine atoms, - (C1-C3) alkoxy groups substituted with one or more fluorine atoms, - Phenyl groups that are unsubstituted or substituted with one or more G3 groups, - Unsubstituted or substituted with one or more G5 groups (C4-C8) cycloalkyl groups, - A (C4-C8) heterocyclyl group containing one or two heteroatoms selected from oxygen and nitrogen atoms, which is either unsubstituted or substituted with one or more G6 groups, and - 10 NG9G units Selected from, G3 is, - Unsubstituted or substituted with one or more fluorine atoms (C1-C4) alkyl groups, especially methyl groups, - Cyclopropyl group, - Halogen atom, - Unsubstituted or substituted with one or more fluorine atoms (C1-C3) alkoxy groups, - Pentafluorosulfanyl group, - Nitrile group, - (C1-C3) trialkylsilyl group, - (C1-C3) alkylsulfonyl groups, and - Unsubstituted or trifluoromethyl phenyl group Selected from, G4 is selected from a hydrogen atom and (C1-C4) alkyl groups. G5 is selected from a fluorine atom and a trifluoromethyl group. G6 is, - Phenyl groups that are unsubstituted or substituted with one or more fluorine atoms or one or more CF3 groups, - (C1-C4) alkyl groups substituted with one or more fluorine atoms, and - Fluorine atom Selected from, The G7 - Hydrogen atom, - Nitrile group, - Unsubstituted or (C1-C3) alkoxy groups, especially methoxy or hydroxyl groups, (C1-C4) alkyl groups, especially methyl groups, - COO (C1-C4) alkyl groups, and - CONH2 groups Selected from, G8 is selected from a hydrogen atom and an unsubstituted (C1-C4) alkyl group which is substituted with a di(C1-C4) alkylamino group. G9 and G10 are selected from (C1-C3) alkyl groups that are either the same or different and are either unsubstituted or substituted with one or more fluorine atoms. G11 is selected from hydrogen atoms, fluorine atoms, and chlorine atoms. Compounds of or pharmaceutically acceptable salts thereof; - Formula (V) 【Transformation 3】 (In the formula, F1 is, - Oxygen atom, and - Base-N(H)- or Base-N(F8)- (Here, F8 is a (C1-C4) alkyl group, particularly a methyl group.) Selected from; F2 is, - Phenyl groups that are unsubstituted or substituted with one or more F4 groups; - Unsubstituted or substituted benzyl groups with one or more F5 groups; - Unsubstituted or substituted with one or more F5 groups (C4-C8) cycloalkyl groups, particularly cyclohexyl or cyclopentyl groups, more specifically cyclohexyl groups; - Heteroaryl groups, particularly pyridinyl groups, that are unsubstituted or substituted with one or more F5 groups, containing four to nine carbon atoms and one or two heteroatoms selected from oxygen and nitrogen atoms; - (C1-C6) alkyl groups, particularly (C1-C4) alkyl groups, that are substituted with one or more fluorine atoms. Selected from; F3 is, - Hydrogen atom, and - (C1-C4) alkyl groups, especially methyl groups Selected from; F4 is, - Halogen atoms, especially fluorine atoms or chlorine atoms; - Unsubstituted or substituted with one or more fluorine atoms (C1-C4) alkyl groups, particularly methyl or trifluoromethyl groups; - Unsubstituted or substituted with one or more fluorine atoms (C1-C4) alkoxy groups, particularly methoxy or trifluoromethoxy groups; - C(O)-O(C1-C4) alkyl groups, especially C(O)-O-methyl groups; - (C3-C6) cycloalkyl groups, especially cyclopropyl groups; - (C1-C4) alkylthio groups, especially methylthio groups; and - Pentafluorosulfanyl group Selected from; F5 is, - Halogen atoms, especially fluorine atoms; and - Unsubstituted or substituted with one or more fluorine atoms (C1-C4) alkyl groups, especially trifluoromethyl groups Selected from; F6 is selected from hydrogen atoms and halogen atoms, especially fluorine atoms; F7 is, - Halogen atoms, especially fluorine atoms; - (C1-C4) alkyl groups, especially methyl groups; - Hydroxyl group; - (C1-C4) alkoxy groups, especially methoxy groups Selected independently of; (s is 0, 1, or 2) Compounds of or pharmaceutically acceptable salts thereof; and those mixtures A therapeutic combination selected from a group consisting of the following.

2. The at least one KRAS G12C inhibitor is - Equation (I) 【Chemistry 4】 (In the formula, R Ａ is hydrogen, (C1-C4) alkyl group or halogen atom, and in particular, R Ａ is a fluorine atom; R Ｂ These are, independently of each other, a hydrogen atom or a (C1-C4) alkyl group, and in particular, both R Ｂ is a hydrogen atom; R1 is a (C1-C3) alkylene group, especially a methylene group; R2 is an unsubstituted or substituted (C4-C8) heterocyclyl group containing a nitrogen atom, an oxygen atom, and a sulfur atom, particularly one or two heteroatoms selected from an oxygen atom and a nitrogen atom, more specifically one or two nitrogen atoms, such as a pyrrolidinyl group; L1 is a bond or a (C1-C3) alkylene group, and in particular L1 is a bond; R3 is an unsubstituted (C6-C10) aryl group or a heteroaryl group containing 4-9 carbon atoms and 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, either unsubstituted or substituted with one or more R7 groups; in particular, R3 is a naphthyl group substituted with one or more R7 groups; n is 0, 1, or 2, and R4 is selected from (C1-C4) alkyl groups that are unsubstituted or substituted with one or more cyano groups or halogen atoms; m is 0, 1, or 2; and R5 is selected from (C1-C4) alkyl groups that are unsubstituted or substituted with one or more halogen atoms; R6 is a (C1-C4) alkyl group, more specifically a methyl group; R7 is selected from halogen atoms, particularly chlorine atoms, and (C1-C4) alkyl groups that are unsubstituted or substituted with one or more halogen atoms. Compounds of or pharmaceutically acceptable salts thereof; - Formula (II) 【Transformation 5】 (In the formula, R8 is a hydrogen atom, a halogen atom, such as a fluorine atom, or an unsubstituted (C1-C3) alkyl group, or one or more halogen atoms, particularly one or more fluorine atoms; in particular, R8 is a hydrogen atom; R9 is a halogen atom, particularly a fluorine atom, or an unsubstituted (C1-C3) alkyl group, or one or more halogen atoms, particularly one or more fluorine atoms; in particular, R9 is a fluorine atom; L2 is a single bond or a methylene group, especially a single bond; R10 is an unsubstituted (C6-C10) aryl group or a heteroaryl group, particularly a phenyl group, containing 4-9 carbon atoms and 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur atoms; R11 is an unsubstituted (C6-C10) aryl group or a heteroaryl group containing 4-9 carbon atoms and 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, preferably substituted with one or more R14 groups at the ortho position. R Ｃ is a hydrogen atom or a (C1-C3) alkyl group, R Ｄ These are hydrogen atoms, (C1-C3) alkyl groups, or halogen atoms, especially fluorine atoms; p is 0, 1, or 2; and R12 is a (C1-C3) alkyl group, particularly a methyl group; R13 is selected from halogen atoms, particularly fluorine atoms, hydroxyl groups (OH), and (C1-C3) alkoxy groups; R14 is selected from a hydrogen atom, (C1-C4) alkyl groups, and (C3-C6) cycloalkyl groups. Compounds of or pharmaceutically acceptable salts thereof; and those mixtures A therapeutic combination according to claim 1, selected from the group consisting of the following.

3. The aforementioned at least one KRAS G12C inhibitor is given by formula (I'): 【Transformation 6】 (In the formula, R Ａ These are halogen atoms, especially fluorine atoms; R Ｂ is, independently of one another, hydrogen or (C1-C4) alkyl; in particular, both R Ｂ are hydrogen atoms; R6 is as defined in claim 2, more specifically a methyl group; and R7 is a halogen atom, specifically a chlorine atom. The therapeutic combination according to claim 2, wherein the compound is or a pharmaceutically acceptable salt thereof.

4. The aforementioned at least one KRAS G12C inhibitor is given by formula (II'): 【Transformation 7】 (In the formula, R Ｃ and R Ｄ This is as defined in claim 2, and in particular, R Ｃ and R Ｄ Both are hydrogen atoms; R8 is as defined in claim 2, and in particular R8 is a hydrogen atom. R9 is as defined in claim 2, and is in particular a halogen atom, more specifically a fluorine atom, R12 is as defined in claim 2, and is in particular a methyl group, R13 is as defined in claim 2, and in particular, one is a hydroxyl group and the other is a fluorine atom. R14 is as defined in claim 2, and in particular is a (C1-C3) alkyl group; more specifically, one is a methyl group and the other is an isopropyl group. The therapeutic combination according to claim 2, wherein the compound is or a pharmaceutically acceptable salt thereof.

5. The at least one KRAS G12C inhibitor is 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-yl)-1-(2-fluoroacryloyl)piperazine-2-yl)acetonitrile; 4-((S)-4-acryloyl-2-methylpiperazine-1-yl)-6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2(1H)-one; or The pharmaceutically acceptable salt The therapeutic combination according to claim 1.

6. The aforementioned at least one TEAD inhibitor is defined by formula (IV) (wherein, q is 0, G1 is a single bond or a methylene group. G2 is selected from phenyl groups that are either unsubstituted or substituted with one or more G3 groups. G3 is a (C1-C4) alkyl group substituted with one or more fluorine atoms, particularly a trifluoromethyl group; G4 is a hydrogen atom; G7 is a hydrogen atom or an unsubstituted (C1-C3) alkoxy group, in particular a methoxy group, or a (C1-C4) alkyl group, in particular a methyl group; G8 is a hydrogen atom; G11 is a hydrogen atom. The therapeutic combination according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

7. The aforementioned at least one TEAD inhibitor is given by formula (V') 【Transformation 8】 (In the formula, F1 is selected from oxygen atoms and the group -N(H)-; F2 is, - Phenyl groups that are unsubstituted or substituted with one or more F4 groups; - A benzyl group that is unsubstituted or substituted with one or more trifluoromethyl groups, wherein F1 is NH; - Cyclohexyl groups substituted with one or more F5 groups; - A pyridinyl group substituted with one or more F5 groups; and - Alkyl (C2-C4) groups substituted with one or more fluorine atoms, particularly (C2-C3) alkyl groups substituted with a trifluoromethyl group. Selected from; F3 is selected from a hydrogen atom and a methyl group; F4 is selected from a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group and a -C(O)-O-methyl group; and F5 is selected from a fluorine atom and a trifluoromethyl group. The therapeutic combination according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

8. The at least one TEAD inhibitor is N-(3-(4-chlorophenoxy)-4-methylphenyl)acrylamide; N-(1-(4-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide; N-(3-(methoxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide; N-(3-methyl-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-yl)acrylamide; N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; or The pharmaceutically acceptable salt The therapeutic combination according to claim 1.

9. A pharmaceutical composition comprising a therapeutic combination according to any one of claims 1 to 8 and at least one pharmaceutically acceptable excipient, diluent and / or carrier.

10. A therapeutic combination according to any one of claims 1 to 8 for use in the treatment of KRAS G12C-mediated cancer.

11. A therapeutic combination for use of the same according to claim 10, in the treatment of lung adenocarcinoma, pancreatic ductal adenocarcinoma, rectal adenocarcinoma, colon adenocarcinoma, bile duct cancer, chronic myelomonocytic leukemia, rhabdomyosarcoma, endometrial cancer, bladder cancer, and ovarian cancer; more specifically, in the treatment of non-small cell lung cancer, small cell lung cancer, pancreatic cancer, or colorectal cancer.

12. The therapeutic combination for use of the KRAS G12C inhibitor and the TEAD inhibitor according to claim 10, wherein they are administered simultaneously in the same dosage form, simultaneously in different dosage forms, or separately.

13. A kit comprising, in one or more separate packages, an optional therapeutic combination according to any one of claims 1 to 8, together with instructions for administration and / or a medical device for administration.

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