Combination of substituted 2,4 diamino-quinoline compounds and MEK inhibitors for use in the treatment of liver cancer

Abstract

The present invention relates to a combination of a substituted 2,4-diaminoquinoline compound and a MEK inhibitor, a pharmaceutical composition containing the same, and its use as a medicine. The present invention further relates to a combination of a substituted 2,4-diaminoquinoline compound and a MEK inhibitor for use in the prevention and / or inhibition of progression and / or treatment of liver cancer. The substituted 2,4-diaminoquinoline compound and the MEK inhibitor constituting the combination can be used simultaneously, separately, or sequentially.

Description

[Technical Field]

[0001] The present invention relates to a combination of a substituted 2,4 diamino-quinoline compound and a MEK inhibitor, a pharmaceutical composition containing the same, and its use as a medicament. The present invention further relates to a combination of a substituted 2,4 diamino-quinoline compound and a MEK inhibitor for use in the prevention and / or inhibition of progression and / or treatment of liver cancer.

[0002] The substituted 2,4 diamino-quinoline compound and mitogen-activated protein kinase kinase inhibitor (MEK inhibitor) that make up the combination can be used simultaneously, separately or sequentially. [Background technology]

[0003] KRAS mutations are a driving factor in pancreatic ductal adenocarcinoma (PDAC). Targeting non-wild-type KRAS in cancer therapy has proven challenging. However, targeting oncogenic signaling pathways is a clinically validated approach in several cancer types (e.g., chronic myeloid leukemia, melanoma). A subpopulation of dormant tumor cells that survive after KRAS suppression and contribute to tumor recurrence has been described as dependent on mitochondrial function, lysosomal activity, and autophagy activation for survival. Furthermore, inhibition of the MEK-ERK signaling pathway induces PDAC cells to become highly dependent on autophagy for survival. Mitogen-activated protein kinase kinase inhibitors (MEK inhibitors) induce cancer cells to become highly dependent on cellular autophagy for survival. This potentially induces cancer cells to become dependent on autophagy for survival, which provides a facile pathway for cancer cells to acquire drug resistance to MEK inhibitors in the clinical oncology setting.

[0004] Several studies have highlighted a link between the use of MEK inhibitors and their effects on the autophagy pathway. PDAC is resistant to monotherapy with trametinib (a MEK inhibitor) or chloroquine / hydroxychloroquine (autophagy inhibitors), but has been found to be highly sensitive to dual therapy with trametinib and chloroquine preclinically and to dual therapy with trametinib and hydroxychloroquine clinically. Inhibition of the KRAS→RAF→MEK→ERK signaling pathway induces cellular autophagy, which is involved in cell recycling and protects PDAC from the cytotoxic effects of KRAS pathway inhibition (e.g., with MEK inhibitors). Inhibition of mitogen-activated protein kinase kinase 1 / 2 (MEK1 / 2 kinases) activates the LKB1→AMPK→ULK1 signaling pathway, a key regulator of cellular autophagy.

[0005] Induction of cellular autophagy in response to the KRAS inhibitory pathway was similarly observed upon inhibition of ERK effectors downstream of KRAS. Along the same lines, inhibition of cellular autophagy with autophagy inhibitors such as chloroquine, or by genetic or pharmacological means, was found to enhance the ability of ERK inhibitors to mediate antitumor responses in KRAS-driven pancreatic cells. Collectively, these data suggest that inhibition of the ERK signaling pathway renders cancer cells acutely dependent on the cellular autophagy process and confer ERK drug resistance.

[0006] These studies are consistent with previous observations that autophagy functions as an adaptive and protective response to inhibition of KRAS→RAF→MEK→ERK signaling in cancer. Autophagy is also involved in resistance to many other standard anticancer chemotherapies. For example, induction of autophagy has been found to be responsible for ovarian cancer resistance to the highly cytotoxic drug paclitaxel. The same pathway of autophagy induction allows ovarian and esophageal cancers to evade cisplatin therapy. Cisplatin-induced lung cancer drug resistance can also be achieved through hypoxia-induced autophagy. In other cancers, induction of endoplasmic reticulum stress response-associated autophagy confers drug resistance to cyclin-dependent kinase inhibitors in cells derived from primary chronic lymphocytic leukemia patients and to HDAC inhibitors (e.g., tavastatin A) in glioblastoma cell lines. Autophagy is particularly activated during metabolic stresses that occur in the tumor microenvironment and is a critical survival pathway for cancer cells under other stress conditions, making autophagy a cellular partner in tumor growth.

[0007] Hepatocellular carcinoma (HCC) is an aggressive malignant tumor and the most common primary liver cancer. It is characterized by highly aggressive biology and limited effective treatment options. A key signaling pathway in hepatocarcinogenesis is the MEK cascade, which is involved in various cellular responses, including adaptation and survival. MEK plays a key role in this cascade, and MEK1 / 2, among them, are prototypic and attractive therapeutic targets for novel oncological drugs. MEK1 / 2 inhibitors represent a novel targeted therapy for the management of patients with advanced hepatocellular carcinoma (HCC). However, inhibition of the KRAS→RAF→MEK→ERK signaling pathway induces autophagy in some cancer models, which is associated with tumor survival and drug resistance. Therefore, incorporating MEK inhibitors into HCC anticancer therapy may rapidly lose robust anticancer responses in clinical settings due to the acquisition of MEK inhibitor-induced drug resistance. In the field of hepato-oncology, intrahepatic cholangiocarcinoma (iCCA) is the most common malignant tumor of the biliary system. Surgical resection or liver transplantation are potentially curative treatment options for patients with early-stage disease. However, most patients present with advanced-stage disease, limiting treatment options. Acquired KRAS mutations occur in approximately 20% of iCCA cases. Activated KRAS mutations overactivate the KRAS→RAF→MEK→ERK pathway, resulting in enhanced cell proliferation and survival. MEK inhibition has demonstrated efficacy in both wild-type and mutant KRAS (e.g., KRAS V12D).

[0008] Therefore, there is a need to treat liver cancer, including hepatocellular carcinoma, hepatoblastoma, intrahepatic cholangiocarcinoma, or extrahepatic cholangiocarcinoma, while maintaining a robust and durable response to anti-cancer therapy by avoiding the acquisition of drug resistance during MEK inhibitor therapy, particularly in a clinical setting. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2016 / 067112 [Patent Document 2] WO2020 / 048694 [Non-patent literature]

[0010] [Non-Patent Document 1] FJ Leinweber, Drug Metab.Res.1987, (Vol. 18) pp.379 [Non-patent document 2] "Prodrugs: Challenges and Rewards (Part 1 and 2)"; editors: V. Stella, R. Borchardt et al., Springer, 2007 [Non-patent document 3] "Prodrugs and Targeted Delivery: Towards Better ADME Properties", Editor: J. Rautio, Series Editors: R. Mannhold, H. Kubinyl, G. Folkers. Wiley-VCH 2011 [Non-patent document 4] "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems" (10th Edition) 2014, Editors: Loyd Allen, Howard C. Ansel, Publisher: Wolters Kluwer Health [Non-Patent Document 5] “Remington: The Science and Practice of Pharmacy” (22nd edition), 2012, edited by Loyd V. Allen, Publisher: Pharmaceutical Press Summary of the Invention [Problem to be solved by the invention]

[0011] We now demonstrate that the combination of a substituted 2,4-diaminoquinoline compound and a MEK inhibitor not only exhibits an overall additive effect but also significantly synergistic effects in inhibiting the growth of liver cancer cells, potentially having important implications in vivo and in clinical settings. These results suggest a new avenue for overcoming the challenge of drug resistance to potential MEK inhibitors in liver anticancer therapy. [Means for solving the problem]

[0012] The present invention provides ◆ Compound of formula (I)

[0013] [ka]

[0014] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, polymorphs, tautomers, isotopic variants, isomers, stereoisomers or mixtures of stereoisomers thereof, and ♦ Combinations comprising a mitogen-activated protein kinase kinase inhibitor (MEK inhibitor) and a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0015] The present invention also relates to a pharmaceutical composition containing the combination, wherein each component of the combination may be contained in a separate pharmaceutical composition.

[0016] Another object of the present invention is the combination of a compound of formula (I) and a MEK inhibitor for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0017] The compound of formula (I) and the MEK inhibitor, or the pharmaceutical composition containing them, may be administered simultaneously, separately or sequentially.

[0018] The present invention further relates to a kit comprising a combination of a compound of formula (I) and a MEK inhibitor, wherein either or both of the components are in the form of pharmaceutical compositions which may be administered simultaneously, separately or sequentially. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention provides ◆ Compound of formula (I)

[0020] [ka]

[0021] [In the formula, L1 is a single bond; optionally substituted (-CH2-) p groups; optionally substituted alkylene; carbonyl; R1, alone or, if m>1, simultaneously or independently, is selected from: a hydrogen atom; a halogen atom; optionally substituted alkyl; haloalkyl; fluoroalkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted alkoxy; -O-R7; -O-(CO)-R7; -O-(CO)-NR5R6; -NR5-(CO)-R7; -O-(CO)-O-R7; -NR5-(CO)-O-R7; azido; hydroxyl; cyano; nitro; -NR5R6; R2 and R3 are simultaneously or independently selected from a hydrogen atom; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted heterocyclyl group; optionally substituted aryl; optionally substituted benzyl; optionally substituted heteroaryl; or R2 and R3 can be joined together with the nitrogen atom to which they are linked via a covalent bond to form an optionally substituted heterocyclyl group; R4, alone or when n>1, simultaneously or independently, is selected from: a hydrogen atom; a halogen atom; optionally substituted alkyl; haloalkyl; fluoroalkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted alkoxy; -O-R7; -O-(CO)-R7; -O-(CO)-NR5R6; -NR5-(CO)-R7; -O-(CO)-O-R7; -NR5-(CO)-O-R7; azido; hydroxyl; cyano; nitro; -NR5R6; R5 and R6 are simultaneously or independently selected from a hydrogen atom; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted heterocyclyl group; optionally substituted aryl; optionally substituted heteroaryl; or R5 and R6 can be joined together with the nitrogen atom to which they are linked via a covalent bond to form an optionally substituted heterocyclyl group; R7 may be selected from optionally substituted alkyl; haloalkyl; fluoroalkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted heterocyclyl group; optionally substituted aryl; optionally substituted heteroaryl; n is an integer and can take the value 0, 1, 2, 3 or 4; m is an integer and can take the value 0, 1, 2, 3, 4 or 5; · p is an integer that can take on the value of either 0 or 1]; and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, polymorphs, tautomers, isotopic variants, isomers, stereoisomers or mixtures of stereoisomers thereof, and * Combinations comprising mitogen-activated protein kinase kinase inhibitors (MEK inhibitors) and pharmaceutically acceptable salts, hydrates or solvates thereof.

[0022] ◆ The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms joined by the chemical bond are considered to be part of a larger substructure.

[0023] The phrase "simultaneously or independently" is used herein to indicate that a variable applies in any one instance, regardless of the presence or absence of variables having the same or different definitions within the same compound. Thus, for example, in a compound in which a substituent Xi appears twice and is defined as "simultaneously or independently a group G1 or a group G2," both Xi may (simultaneously) be G1, both Xi may (simultaneously) be G2, or (independently) one Xi may be G1 and the other Xi may be G2.

[0024] ◆ The expressions "halogen", "halogen atom", "halogens" or "halogen atoms", wherever they appear, mean one or more atoms selected from fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0025] ◆ The term "alkyl" means, alone or in combination with other groups, an alkyl group containing 1 to 20 carbon atoms (C1 to C 20 It refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 16 carbon atoms (C1 to C 16 carbon atoms), more preferably 1 to 10 carbon atoms (C 10and lower alkyl (of 10 carbon atoms). Alkyl groups can be optionally substituted as defined herein.

[0026] ◆ The term "alkylene" refers to the alkyl groups described above, where alkyl is a diradical also defined as alkanediyl. Typically, an alkylene group has two points of attachment to the rest of the molecule (e.g., -L1- in a molecule represented by formula (I) of the present invention). The two points of attachment of an alkylene group may be located on one specific carbon atom thereof or on two different carbon atoms.

[0027] ◆ The term "lower alkyl", alone or in combination, refers to a straight or branched chain alkyl group having 1 to 10 carbon atoms ("C1-C 10 -alkyl"), preferably a straight-chain or branched alkyl group having 1 to 5 carbon atoms ("C1-C5-alkyl"), particularly preferably a straight-chain or branched alkyl group having 1 to 3 carbon atoms ("C1-C3-alkyl"). Lower alkyl groups can be optionally substituted as defined herein. Non-limiting examples of straight-chain and branched lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, the isomeric pentyls, isomeric hexyls, isomeric heptyls, isomeric octyls, isomeric nonyls, isomeric decanyls, preferably methyl and ethyl and n-propyl and isopropyl and tert-butyl and isobutyl and sec-butyl and the isomeric pentyls, most preferably methyl and ethyl and n-propyl and isopropyl, and n-butyl and tert-butyl.

[0028] ◆ The term "alkenyl" refers to an olefinic bond.

[0029] [ka]

[0030] [Wherein R', R'', R''', and R IVrepresents a straight or branched chain hydrocarbon residue containing the R', R'', R''', and R of the alkenyl moiety. IV The moiety may be branched, straight chain, or cyclic. An alkenyl group is an alkyl group having 2 to 10 carbon atoms ("C2-C 10 C2-C5-alkenyl"), preferably having 2 to 5 carbon atoms ("C2-C5-alkenyl"), particularly preferably having 2 to 4 carbon atoms ("C2-C4-alkenyl"). The alkenyl moiety may be branched, straight-chain, or cyclic (in which case it is also known as a "cycloalkenyl" group). The alkenyl group may also be a "lower alkenyl" having 2 to 6 carbon atoms, including all isomeric forms (cis, trans, Z, E). The alkenyl group may be optionally substituted as defined herein. Non-limiting examples of lower alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 3-penten-2-yl, 3-penten-4-yl, isopentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, isohexenyl. Preferred examples are ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-buten-2-yl and isopentenyl.

[0031] ◆ The term "alkynyl" refers to a straight or branched chain hydrocarbon residue containing an alkyne bond in which two carbon atoms form a triple bond R'-C≡C-R'', where R' and R'' refer to the remainder of the alkynyl group and may be the same or different. The R' and R'' portions of the alkynyl moiety may be branched, straight chain, or cyclic. An alkynyl group is a group having 2 to 10 carbon atoms ("C2-C 10Alkynyl groups can have from 2 to 5 carbon atoms ("C2-C5-alkynyl"), and particularly preferably from 2 to 4 carbon atoms ("C2-C4-alkynyl"). Alkynyl groups can be optionally substituted as defined herein. Non-limiting examples of alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl, 4-butynyl, but-2-yn-1-yl, 1-pentynyl, pent-2-yn-1-yl, pent-3-yn-1-yl, pent-4-yn-1-yl, and pent-2-yn-3-yl. Preferred examples are propyn-1-yl, propyn-3-yl, butyn-1-yl, butyn-3yl, butyn-4-yl, and but-2-yn-1-yl. An alkynyl group can also be a "lower alkynyl" having two to six carbon atoms (a "C2-C6 alkynyl").

[0032] ◆ The term "cycloalkyl" refers to a monocyclic or polycyclic group "C3-C" that contains only carbon and hydrogen, is a saturated ring, and contains 3 to 12 carbon atoms. 12 -cycloalkyl" refers to a group having 3 to 12 ring atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecane. A cycloalkyl group includes a group having 3 to 12 ring atoms, such as "C3-C 12 Preferably, the group is "C-C-cycloalkyl" having 3 to 8 ring atoms, more preferably "C-C-cycloalkyl" having 3 to 7 ring atoms, and even more preferably "C-C-cycloalkyl" having 3 to 6 ring atoms. Depending on the structure, cycloalkyl groups can include adjacent substituted cycloalkenyl and / or alkenyl groups. Cycloalkyl groups can be optionally substituted as defined herein.

[0033] ◆ The term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond, C=C, and having about 3 to about 12 carbon atoms, preferably about 5 to about 10 carbon atoms, more preferably about 5 to about 7 carbon atoms, and even more preferably about 5 to about 6 carbon atoms. A cycloalkenyl can be optionally substituted with one or more "ring system substituents," which may be the same or different and are as defined above. Non-limiting examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. Non-limiting examples of suitable polycyclic cycloalkenyls include norbornylenyl, and the like. Cycloalkenyl groups can be optionally substituted as defined herein.

[0034] ◆ The term "cycloalkynyl" means a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon triple bond (C≡C) and containing about 8 to about 12 carbon atoms, preferably about 8 to about 10 carbon atoms. A cycloalkynyl can be optionally substituted with one or more "ring system substituents," which may be the same or different, and are as defined above. Non-limiting examples of monocyclic cycloalkynyls include cyclooctynyl, cyclononynyl, cyclodecynyl, and the like. A cycloalkynyl group can be optionally substituted as defined herein.

[0035] ◆ The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures, as defined herein, in which at least one hydrogen is replaced with a halogen atom, as defined herein. In some embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another. In other embodiments in which two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are all the same as one another, or are not all the same as one another.

[0036] ◆ As used herein, the term "fluoroalkyl" refers to a straight or branched chain alkyl group, as defined herein, in which at least one hydrogen is replaced with a fluorine atom. Examples of fluoroalkyl groups include, but are not limited to, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, -CF2CH3, -CH2CH2CF3, -CH(CF3)2, -CF2CH(CH3)2, and the like. A "fluoroalkyl" can be optionally substituted as defined herein.

[0037] ◆ The "alkoxy" group is -O(C1-C 10 -O (alkyl), -O (cycloalkyl), and -O (heterocyclyl) groups, and "C1-C 10 Alkyl, C1-C 10 "Cycloalkyl" and "heterocyclyl" are as defined herein. The term "lower alkoxy" refers to the group R'-O-, where R' is lower alkyl, and the term "lower alkyl" has the meaning given above. The alkoxy group can be optionally substituted as defined herein. Non-limiting examples of lower alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, n-pentoxy, n-hexyloxy, preferably methoxy, ethoxy, isopropoxy and tert-butoxy, and most preferably methoxy and ethoxy. Non-limiting examples of "alkoxy" having an -O(cycloalkyl) group are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0038] The terms "heterocyclic group," "non-aromatic heterocycle," "heterocycloalkyl," "heterocyclyl," or "heteroalicyclic" refer to a 3-9-membered monocyclic group, preferably a 3-7-membered monocyclic group, more preferably a 3-6-membered monocyclic group, or a fused heterocyclic ring system containing 5-16 atoms, preferably 5-14 atoms, more preferably 5-10 atoms, and even more preferably 5-9 atoms, and having at least one heteroatom, which may be fully saturated or unsaturated but not completely unsaturated, and which may be two or more heteroatoms, simultaneously or independently selected from oxygen, nitrogen, or sulfur atoms. Each ring of the heterocyclic group may have at least one heteroatom, which may be two or more heteroatoms, simultaneously or independently selected from nitrogen, oxygen, and / or sulfur atoms. A "heterocycloalkyl" can be optionally substituted as defined herein. A "heterocycloalkyl" may be covalently bonded at a heteroatom or through a carbon atom. In some embodiments, non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups, such as, for example, oxo and thio-containing groups. Heterocycle groups can be optionally substituted as defined herein.Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, cyclic ureas, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxins, 1,3-dioxanes, 1,4-dioxanes, 1,4-dioxanes, piperazines, 1,3-oxathianes, 1,4-oxathiines, 1,4-oxathianes, tetrahydro-1,4-thiazines, 2H-1,2-oxazines, maleimides, succinimides, barbiturates, thiobarbiturates, dioxopiperazines, hydantoins, and the like. Examples of such heterocyclic compounds include 1,3-dimethyl-1,3-dioxane, 1,3-dimethyl-2 ...

[0039] ◆ The term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. An aryl ring can contain 5, 6, 7, 8, 9, or more than 9 carbon atoms, preferably 5 to 16 carbon atoms, more preferably 5 to 12 carbon atoms, and even more preferably 5 to 10 carbon atoms, and refers to any stable monocyclic, bicyclic, or tricyclic ring system in which at least one ring is aromatic. Aryl groups can be optionally substituted as defined herein. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, biphenyl, and indenyl. Depending on the structure, aryl groups can be monoradicals or diradicals, in which case they are known as arylene groups. Examples of arylene groups include, but are not limited to, benzene-1,2-diyl, benzene-1,3-diyl, benzene-1,4-diyl, naphthalene-2,7-diyl, naphthalene-2,6-diyl, naphthalene-1,4-diyl, naphthalene-1,5-diyl, acenaphthene-diyl, phenanthrene-3,8-diyl, fluoranthene-diyl, and 3-methylbenzene-1,4-diyl.

[0040] ◆ The term "heteroaryl" generally refers to an aromatic 5- or 11-membered ring containing at least one heteroatom and may further contain 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and / or sulfur, such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 2-oxo-1,2-dihydropyridinyl, oxadiazolyl, isoxazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiophenyl, furanyl, oxazolyl, isothiazolyl, and thiazolyl. The term "heteroaryl" also refers to bicyclic aromatic or partially unsaturated groups containing two 5- or 6-membered rings, in which one or both rings can contain 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, or sulfur, such as quinolinyl, isoquinolinyl, cinnolinyl, pyrazolyl, imidazolyl, thiazolyl, thiophenyl, furanyl, oxazolyl, isothiazolyl, pyrazolo[1,5-a]pyridinyl, and the like. benzo[d]imidazole, benzo[d]isoxazolyl, benzo[d]isothiazolyl, benzo[c]isoxazolyl, benzo[c]isothiazolyl, indolyl, isoindolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 2,3-dihydro-1H-pyrrolo[3,4- ... benzo[d]imidazole, benzo[d]isoxazolyl, benzo[d]isothiazolyl, benzo[c]isoxazolyl, benzo[c]isothiazolyl, indolyl, isoindolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, 2,3-dihydro-1H-pyrrolo[3,4-c]isothiazolyl, indolyl, isoindolinyl, ]pyridinyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, purinyl, indazolyl, indolizinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazo[1,5-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[4,5-b]pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyri Razinyl, pyrrolo[1,2-c]pyrimidinyl, oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-c]pyridinyl, oxazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, thiazolo[4,5-c]pyridinyl, thiazolo[5,4-c]pyridinyl, thiazolo[5,4-b]pyridinyl, oxazolo[5,4-d]pyrimidinyl, oxazolo[4,5-d]pyrimidinyl, thiazolo[5,4-d]pyrimidinyl, thiazolo[4,5-d]pyrimidinyl, oxazolo[4,5-b]pyrazinyl, thiazolo[4,5-b]pyrazinyl, isoxazolo[4,5-b]pyrazinyl, isothiazolo[4,5-b]pyrazinyl, isoxazolo[4,5-d]pyrimidinyl, isothiazolo[4,5-d]pyrimidinyl, isoxazolo[5,4-d]pyrimidinyl, isothiazolo[5,4-b]pyridinyl, isothiazolo[5,4-c]pyrimidinyl, isoxazolo[5,4-c]pyridinyl, isothiazolo[4,5-c]pyridinyl, isoxazolo[4,5 [1,2,3]triazolo[4,5-b]pyridinyl, [1,2,3]triazolo[4,5-c]pyridinyl, isoxazolo[4,3-d]pyrimidinyl, isothiazolo[4,3-d]pyrimidinyl, isoxazolo[3,4-d]pyrimidinyl, isothiazolo[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, [1,2,3]triazolo[4,5-b]pyridinyl, [1,2,3]triazolo[4,5-c]pyridinyl, 3H-[1,2,3]triazolo[4,5-d]pyrimidinyl. Preferred heteroaryl groups are pyridyl, pyrazinyl, pyrimidinyl, thiozolyl, isothiazolyl, oxazolyl, isoxazolyl, quinozolinyl, and pyrazinyl.

[0041] ◆ The terms "heteroaryl" or "heteroaromatic" refer to an aryl group containing one or more rings and one or more heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S). An N-containing "heteroaryl" or "heteroaromatic" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom (N). Heteroaryl groups can be optionally substituted as defined herein.

[0042] ◆ The terms "heteroaryl" or "heteroaromatic" also refer to fused heteroaryl systems, in which two or more rings share one or more bonds, contain 7 to 16 ring atoms, preferably 8 to 13 ring atoms, and more preferably 8 to 10 ring atoms, with 1, 2, 3, 4, or 5 heteroatoms simultaneously or independently selected from nitrogen (N), oxygen (O), and sulfur (S), and contain at least one carbon atom (C), provided that the fused rings do not contain adjacent oxygen (O) and / or sulfur (S) atoms. The "heteroaryl" can be optionally substituted as defined herein. A heteroaryl can be covalently bonded at a heteroatom or through a carbon atom. N-oxides of ring nitrogens are also included, as are heteroaryls in which a ring nitrogen is substituted with an optionally substituted alkyl group to form a quaternary amine. Preferred heteroaryl groups include pyridyl, pyrimidyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinazolinyl, pyrazinyl, and their N-oxides. All positional isomers are contemplated (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, pyridin-6-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-6-yl). Heteroaryl groups can be optionally substituted as defined herein.

[0043] ◆ The phrase "optionally substituted" means unsubstituted or substituted with one or more substituents selected, simultaneously or independently, from a halogen atom as defined herein; hydroxyl; cyano; azido; -nitro; carboxyl; -CF3; alkyl as defined herein; haloalkyl as defined herein; fluoroalkyl as defined herein; alkenyl as defined herein; alkynyl as defined herein; cycloalkyl as defined herein; cycloalkenyl as defined herein; cycloalkynyl as defined herein; heterocyclyl as defined herein; and alkoxy as defined herein.

[0044] ◆ The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid and is not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, preferably hydrochloric acid, and with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, glutaric acid, cinnamic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, N-acetylcysteine, N-acetyllysine, lysine, N-acetylarginine, and arginine. Furthermore, these salts can be prepared from the addition of inorganic or organic bases to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins, etc. The compounds of Formula (I), (II), (III), or (IV) may also exist in zwitterionic form.

[0045] A particularly preferred pharmaceutically acceptable salt of a compound of formula (I), (II), (III) or (IV) is the hydrochloride salt.

[0046] ◆ The compounds of formula (I), (II), (III) or (IV) may also be solvated, e.g., hydrated. Solvation may occur during the manufacturing process or may occur, for example, as a result of the hygroscopic nature of an initially anhydrous compound of formula (I) (hydration). The term "pharmaceutically acceptable salts" also includes physiologically acceptable solvates that contain water.

[0047] ◆ The mitogen-activated protein kinase kinase inhibitors (MEK inhibitors) described herein can also be solvated, e.g., hydrated. Solvation can occur during the manufacturing process (e.g., in the form of a dimethyl sulfoxide solvate) or can occur as a result of the hygroscopic nature of an initially anhydrous MEK inhibitor (e.g., hydration to a hydrated form). The term "pharmaceutically acceptable salt" also includes physiologically acceptable solvates that include water.

[0048] ◆ "Isomers" are compounds that have identical molecular formulae but that differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers.

[0049] ◆ "Prodrug" refers to a compound that converts to a compound of the present invention in a biological system. A prodrug is a chemical derivative that is inactive or less active than the drug itself. After administration and diffusion into the body, the prodrug derivative undergoes one or more metabolic processes that release the active drug. The conversion of a prodrug to a drug generally occurs under the control of an enzymatic process (usually by metabolic means, e.g., hydrolysis, reduction, or oxidation) and less frequently occurs by classical chemical reactions during diffusion in the body. The linkage between the carrier and the drug can be, but is not limited to, an ester, an amide, a carbonate, a carbamate, an imine, an acetal, an ether (e.g., glucuronidation), an oxidizable function and molecular system, a reducible function and molecular system, or a photoactivatable function and molecular system. For example, an ester prodrug of a compound containing a hydroxyl group can be converted to the parent molecule by hydrolysis in vivo. Suitable esters of the compounds of the present invention containing a hydroxyl group include, for example, acetate, citrate, lactate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoate, gestidate, isethionate, di-p-toluoyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate. As another example, ester prodrugs of the compounds of the present invention containing a carboxy group can be converted to the parent molecule by in vivo hydrolysis (examples of ester prodrugs are described by FJ Leinweber, Drug Metab. Res. 1987, (18) pp. 379, which is incorporated herein by reference).Similarly, acyl prodrugs of compounds containing an amino group can be converted to the parent molecule by hydrolysis in vivo (examples of prodrugs for these and other functional groups, including amines and alcohols, are described in "Prodrugs: Challenges and Rewards (Part 1 and 2)"; Editors: V. Stella, R. Borchardt et al., Springer, 2007, and "Prodrugs and Targeted Delivery: Towards Better ADME Properties," Editor: J. Rautio, Series Editors: R. Mannhold, H. Kubinyl, G. Folkers, Wiley-VCH 2011, each of which is incorporated herein by reference).

[0050] ◆ Prodrug carrier systems generally have the following properties: they increase water or lipid solubility, reduce toxicity, increase the chemical and biological stability of sensitive compounds, and shorten circulation time (T 1 / 2 ), increasing total drug exposure (AUC) and organ distribution (PK-PD profiling), and site-specific targeting.

[0051] ◆ The term "pharmaceutically acceptable carrier" is intended to include any and all materials compatible with pharmaceutical administration, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the compositions of the present invention is contemplated. Additional active compounds can also be incorporated into the compositions. These compositions can be prepared by applying techniques known in the art, such as those described in "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems" (10th Edition) 2014, edited by Loyd Allen and Howard C. Ansel, published by Wolters Kluwer Health, and Remington: The Science and Practice of Pharmacy (22nd Edition) 2012, edited by Loyd V. Allen, published by Pharmaceutical Press.

[0052] ◆ As used herein, the terms "subject" or "patient" are used interchangeably. As used herein, the term "subject" refers to animals (e.g., birds, reptiles, and mammals), preferably mammals, including non-primates (e.g., camels, donkeys, zebras, cows, pigs, horses, goats, sheep, cats, dogs, rats, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and most preferably humans.

[0053] ◆ As used herein, the term "therapy" can refer to any protocol, method, composition, combination, and / or agent that can be used in the prevention, treatment, management, or amelioration of a disease. In some embodiments, the term "therapy" refers to biologic therapy, supportive therapy, and / or other therapies known to those of skill in the art that are useful in the treatment, management, prevention, or amelioration of different diseases.

[0054] ◆ The term "cholangiocarcinoma" refers to cancer that forms in the bile duct, a series of small tubes that lead from the liver to the small intestine. The bile duct carries a fluid called bile from the liver and gallbladder to the small intestine and helps digest fats in food. Cholangiocarcinoma is also known as bile duct cancer.

[0055] ◆ The term "intrahepatic cholangiocarcinoma" refers to cholangiocarcinoma that occurs in the bile ducts within the liver.

[0056] ◆ The term "extrahepatic cholangiocarcinoma" refers to cholangiocarcinoma that occurs in the part of the bile duct closest to the small intestine.

[0057] ◆ The term "therapeutically effective amount" of a compound means an amount of compound effective to prevent, alleviate or ameliorate symptoms of a disease, or an amount of compound effective to prolong the survival of a treated subject. Determining a therapeutically effective amount is within the skill of the art. The therapeutically effective amount or dose of a compound according to the present invention can vary within a wide range and can be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements of each particular case, including the particular compound administered, the route of administration, the condition being treated, and the patient receiving treatment. Generally, when administered orally or parenterally to an adult human weighing approximately 70 kg, - 50 mg to 500 mg, preferably 50 mg to 200 mg, more preferably 50 mg to 100 mg of a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof; and With respect to the MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof, a daily dosage of 0.5 mg to 150 mg, preferably 1 mg to 100 mg, more preferably 1.5 mg to 90 mg is appropriate, However, if instructed, the upper limit may be exceeded. Alternatively, for the MEK inhibitor trametinib or a pharmaceutically acceptable salt or solvate thereof, a dose of 0.5 mg to 5 mg, preferably 0.5 mg to 2 mg, more preferably 1 mg to 2 mg, and even more preferably 1.5 mg to 2 mg is appropriate, although the upper limit can be exceeded if indicated.

[0058] Alternatively, for the MEK inhibitor cobimetinib or a pharmaceutically acceptable salt (e.g., fumarate) or solvate thereof, a dose of 10 mg to 80 mg, preferably 10 mg to 60 mg, more preferably 20 mg to 60 mg, and even more preferably 40 mg to 60 mg is appropriate, although the upper limit can be exceeded if indicated.

[0059] The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it can be given as continuous infusion.

[0060] Preferred embodiments of the present invention are set forth below, however, any combination of two or more of these embodiments is considered to be within the scope of the present invention.

[0061] That is, it is within the scope of the present invention to combine the preferred definitions of each substituent or moiety in formula (I) as defined below with each other.

[0062] According to a preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which L1 is selected from a single bond or alkylene.

[0063] In a preferred embodiment, the combination defined above comprises a compound of formula (I) wherein L1 is a single bond.

[0064] In a preferred embodiment, the combination defined above comprises a compound of formula (I) in which L1 is alkylene.

[0065] In another preferred embodiment, the combination as defined above comprises a compound of formula (I) wherein L1 is carbonyl.

[0066] In another preferred embodiment, the combination as defined above comprises compounds of formula (I) wherein L1 is selected from -CH2-, -CHF-, -CF2-, -CH2-CH2.

[0067] In another more preferred embodiment, the combination as defined above comprises a compound of formula (I) wherein L1 is -CH2-.

[0068] According to a preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R1, alone or, if m>1, simultaneously or independently, is selected from: a hydrogen atom, a halogen atom, optionally substituted alkyl, haloalkyl; fluoroalkyl; optionally substituted alkoxy; azido; hydroxyl; cyano; nitro; -NR5R6.

[0069] In particular, the combination according to the invention comprises compounds of formula (I) in which R1, alone or jointly or independently when m>1, is selected from: a hydrogen atom, a halogen atom, optionally substituted alkyl, haloalkyl; fluoroalkyl; optionally substituted alkoxy; hydroxyl; -NR5R6.

[0070] Furthermore, another preferred embodiment provides a combination comprising a compound of formula (I) wherein R1, alone or, when m>1, simultaneously or independently, is selected from: a hydrogen atom, a halogen atom, optionally substituted alkyl, haloalkyl; fluoroalkyl; optionally substituted alkoxy; hydroxyl.

[0071] In another embodiment, the combination defined above comprises compounds of formula (I) wherein R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom, a halogen atom, optionally substituted alkyl, optionally substituted alkoxy; hydroxyl.

[0072] In another embodiment, the combination according to the present invention comprises a compound of formula (I) in which R1, alone or, when m>1, simultaneously or independently, is selected from a hydrogen atom, a halogen atom, -NR5R6 [wherein R5 and R6 can be selected from a hydrogen atom; an optionally substituted alkyl; an optionally substituted cycloalkyl; an optionally substituted heterocyclyl group, or R5 and R6 can be linked together with the nitrogen atom to which they are linked via a covalent bond to form an optionally substituted heterocyclyl group].

[0073] In another preferred embodiment, the combination according to the present invention comprises a compound of formula (I) in which R1, alone or, when m>1, simultaneously or independently, is selected from a hydrogen atom, a halogen atom, -NR5R6 [wherein R5 and R6 can be selected from a hydrogen atom; an optionally substituted alkyl; or R5 and R6 can be linked together with the nitrogen atom to which they are linked via a covalent bond to form an optionally substituted heterocyclyl group].

[0074] In another embodiment, the combination according to the invention comprises a compound of formula (I) wherein R1, alone or, if m>1, simultaneously or independently, is selected from: a hydrogen atom, a halogen atom, -NR5R6 (wherein R5 and R6 may be selected from: a hydrogen atom; an optionally substituted alkyl).

[0075] In particular, the combination according to the invention comprises compounds of formula (I) in which R1, alone or, if m>1, simultaneously or independently, is selected from: a hydrogen atom, a halogen atom, -NR5R6, wherein R5 and R6 may be selected from: a hydrogen atom; methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0076] In particular, the combination according to the invention includes compounds of formula (I) in which R1, alone or, if m>1, simultaneously or independently, is selected from a hydrogen atom, -NR5R6 (wherein R5 and R6 may be selected from a hydrogen atom; methyl, an optionally substituted heterocyclyl group).

[0077] In particular, the combination according to the invention includes compounds of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom, -NR5R6 (wherein R2 and R3 can be linked together with the nitrogen atom to which they are linked via a covalent bond to form an optionally substituted heterocyclyl group).

[0078] According to a preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom or a halogen atom.

[0079] According to a more preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom, fluorine, chlorine, bromine, more preferably a hydrogen atom or chlorine.

[0080] According to a further more preferred embodiment, the combination according to the invention comprises compounds of formula (I) wherein R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom, fluorine, chlorine, bromine, most preferably a hydrogen atom or fluorine.

[0081] According to a further more preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from: a hydrogen atom, a fluorine atom.

[0082] According to a further more preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from: a hydrogen atom, chlorine.

[0083] According to a preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom, optionally substituted alkyl, haloalkyl; fluoroalkyl.

[0084] In a preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from: a hydrogen atom, alkyl.

[0085] In a more preferred embodiment, the combination according to the invention comprises a compound of formula (I) wherein R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl.

[0086] In an even more preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom or methyl.

[0087] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) wherein R1, alone or simultaneously or independently when m>1, is selected from: a hydrogen atom, cycloalkyl.

[0088] In a further more preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R1, alone or simultaneously if m>1, or independently, is selected from a hydrogen atom, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0089] Furthermore, another preferred embodiment provides a combination comprising a compound of formula (I) wherein R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom, hydroxyl, optionally substituted alkoxy.

[0090] In a more preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from: hydrogen atom, hydroxyl, methoxy; ethoxy; isopropoxy; sec-butoxy, tert-butoxy.

[0091] In a further preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from: a hydrogen atom, hydroxyl, cyclopropoxy; cyclobutoxy; cyclopentoxy; cyclohexyloxy.

[0092] In a further more preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R1, alone or simultaneously if m>1 or independently, is selected from a hydrogen atom, chlorine, hydroxyl, methoxy.

[0093] In yet another more preferred embodiment, the combination according to the invention comprises a compound of formula (I) wherein R1, alone or simultaneously or independently when m>1, is selected from: a hydrogen atom, chlorine, hydroxyl.

[0094] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom, fluorine, chlorine, bromine, -CF3.

[0095] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from a hydrogen atom, fluorine, chlorine, bromine.

[0096] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R1, alone or simultaneously or independently when m>1, is selected from: a hydrogen atom, chlorine.

[0097] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) wherein R1, alone or simultaneously or independently when m>1, is selected from: a hydrogen atom, cyano.

[0098] According to a preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R2 and R3, simultaneously or independently, can be selected from a hydrogen atom; an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted cycloalkynyl, an optionally substituted heterocyclyl group.

[0099] In another preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R2 and R3 may be simultaneously or independently selected from a hydrogen atom; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl.

[0100] In another preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R2 and R3 may be simultaneously or independently selected from a hydrogen atom; optionally substituted alkyl, optionally substituted heterocyclyl.

[0101] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R2 and R3 may be simultaneously or independently selected from: a hydrogen atom; alkyl, cycloalkyl.

[0102] In yet another preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R2 and R3 may, simultaneously or independently, be selected from a hydrogen atom or a heterocyclyl.

[0103] In a further preferred embodiment, the combination according to the invention comprises compounds of formula (I), wherein R2 and R3 may simultaneously or independently be selected from: a hydrogen atom; alkyl.

[0104] In another preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R2 and R3 may be simultaneously or independently selected from a hydrogen atom; methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl.

[0105] In an even more preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R2 and R3 may be simultaneously or independently selected from: a hydrogen atom; tert-butyl.

[0106] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R2 and R3 may be selected, simultaneously or independently, from a hydrogen atom; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0107] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I), wherein R2 and R3 may simultaneously or independently be selected from: a hydrogen atom; heterocyclyl.

[0108] In another preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R2 and R3, together with the nitrogen atom to which they are linked via a covalent bond, can form an optionally substituted heterocyclyl group.

[0109] According to a preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R4, alone or, if m>1, simultaneously or independently, is selected from: a hydrogen atom, a halogen atom, optionally substituted alkyl, haloalkyl; fluoroalkyl; optionally substituted alkoxy; azide; hydroxyl; cyano; nitro; -NR5R6.

[0110] In another preferred embodiment, the combination according to the present invention comprises a compound of formula (I) in which R4, alone or, when n>1, simultaneously or independently, is selected from a hydrogen atom, a halogen atom, -NR5R6 [wherein R5 and R6 can be selected from a hydrogen atom; an optionally substituted alkyl; an optionally substituted cycloalkyl; an optionally substituted heterocyclyl group, or R5 and R6 can be linked together with the nitrogen atom to which they are linked via a covalent bond to form an optionally substituted heterocyclyl group].

[0111] In another preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R4, alone or, if n>1, simultaneously or independently, is selected from a hydrogen atom, -NR5R6 (wherein R5 and R6 may be selected from a hydrogen atom; optionally substituted alkyl).

[0112] In another preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R4, alone or, if n>1, simultaneously or independently, is selected from: a hydrogen atom; -NR5R6 (wherein R5 and R6 may be selected from: a hydrogen atom; an optionally substituted cycloalkyl).

[0113] In a preferred embodiment, the combination according to the present invention comprises a compound of formula (I) in which R4, alone or simultaneously or independently when n>1, is selected from a hydrogen atom, -NR5R6 [wherein R5 and R6 can be selected from a hydrogen atom; a heterocyclyl group; or R5 and R6 can be linked together with the nitrogen atom to which they are linked via a covalent bond to form a heterocyclyl group].

[0114] In another preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R4, alone or simultaneously or independently when n>1, is selected from a hydrogen atom, -NR5R6 [wherein R5 and R6 can be linked together with the nitrogen atom to which they are linked via a covalent bond to form a heterocyclyl group].

[0115] In a further preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R4, alone or simultaneously or independently when n>1, is selected from a hydrogen atom, -NR5R6, wherein R5 and R6 can be selected from a hydrogen atom or a heterocyclyl group.

[0116] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R4, alone or, if n>1, simultaneously or independently, is selected from: a hydrogen atom, -NR5R6 (wherein R5 and R6 can be selected from: a hydrogen atom; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl).

[0117] In another preferred embodiment, the combination according to the invention comprises a compound of formula (I) in which R4, alone or, if n>1, simultaneously or independently, is selected from: a hydrogen atom, -NR5R6 (wherein R5 and R6 may be selected from: a hydrogen atom; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl).

[0118] In another preferred embodiment, the combination according to the invention comprises a compound of formula (I) wherein R4, alone or simultaneously or independently when n>1, is selected from: a hydrogen atom, a halogen atom, optionally substituted alkyl.

[0119] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) wherein R4, alone or simultaneously or independently when n>1, is selected from a hydrogen atom or cycloalkyl.

[0120] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) wherein R4, alone or simultaneously or independently when n>1, is selected from: a hydrogen atom, alkyl.

[0121] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) wherein R4, alone or simultaneously or independently when n>1, is selected from: a hydrogen atom, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl.

[0122] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R4, alone or simultaneously or independently when n>1, is selected from: a hydrogen atom, a halogen atom, alkyl, haloalkyl; fluoroalkyl; alkoxy, hydroxyl.

[0123] In another more preferred embodiment, the combination according to the invention comprises a compound of formula (I) wherein R4, alone or simultaneously or independently when n>1, is selected from: a hydrogen atom, alkoxy.

[0124] In another preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R4, alone or simultaneously or independently when n>1, is selected from: hydrogen atom, hydroxyl, methoxy; ethoxy; isopropoxy; sec-butoxy, tert-butoxy.

[0125] In a further preferred embodiment, the combination according to the invention comprises compounds of formula (I) in which R4, alone or simultaneously or independently when m>1, is selected from: a hydrogen atom, hydroxyl, cyclopropoxy; cyclobutoxy; cyclopentoxy; cyclohexyloxy.

[0126] In a further preferred embodiment, the combination according to the invention comprises compounds of formula (I) wherein R4, alone or simultaneously or independently when m>1, is selected from: a hydrogen atom, methoxy.

[0127] In another erred embodiment, the combination according to the invention comprises compounds of formula (I) in which R4, alone or simultaneously or independently when n>1, is selected from: a hydrogen atom, hydroxyl, methoxy.

[0128] In another embodiment, the combination according to the invention comprises a compound of formula (I) wherein R4, alone or simultaneously or independently when n>1, is selected from: a hydrogen atom, hydroxyl, methyl, methoxy.

[0129] In another more preferred embodiment, the combination according to the invention comprises a compound of formula (I) wherein R4, alone or simultaneously or independently when n>1, is selected from a hydrogen atom, fluorine, chlorine, bromine, -CF3.

[0130] In a further preferred embodiment, the combination according to the invention comprises compounds of formula (I) wherein R4, alone or simultaneously or independently when n>1, is selected from a hydrogen atom or a halogen.

[0131] In another more preferred embodiment, the combination according to the invention comprises a compound of formula (I) wherein R4, alone or simultaneously or independently when n>1, is selected from a hydrogen atom, fluorine, chlorine.

[0132] In another even more preferred embodiment, the combination according to the invention comprises a compound of formula (I) wherein R4, alone or simultaneously or independently when n>1, is selected from a hydrogen atom or cyano.

[0133] In another more preferred embodiment, the combination according to the invention comprises a compound of formula (I) wherein R4, alone or simultaneously or independently when n>1, is a hydrogen atom.

[0134] In another embodiment, the combination according to the present invention comprises: ◆ Formulas (II), (III), and (IV) shown below:

[0135] [ka]

[0136] [In the formula, R1, alone or, when m>1, simultaneously or independently, is selected from: a hydrogen atom; a halogen atom; optionally substituted alkyl; haloalkyl; fluoroalkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted alkoxy; -O-R7; azido; hydroxyl; cyano; nitro; -NR5R6; R2 and R3 are simultaneously or independently selected from a hydrogen atom; an optionally substituted alkyl; an optionally substituted alkenyl; an optionally substituted alkynyl; an optionally substituted cycloalkyl; an optionally substituted cycloalkenyl; an optionally substituted cycloalkynyl; an optionally substituted heterocyclyl group; or R2 and R3 can be joined together with the nitrogen atom to which they are linked via a covalent bond to form an optionally substituted heterocyclyl group; R4, alone or when n>1, simultaneously or independently, is selected from: a hydrogen atom; a halogen atom; optionally substituted alkyl; haloalkyl; fluoroalkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted alkoxy; -O-R7; azido; hydroxyl; cyano; nitro; -NR5R6; R5 and R6 are simultaneously or independently selected from a hydrogen atom; an optionally substituted alkyl; an optionally substituted alkenyl; an optionally substituted alkynyl; an optionally substituted cycloalkyl; an optionally substituted cycloalkenyl; an optionally substituted cycloalkynyl; an optionally substituted heterocyclyl group; or R5 and R6 can be joined together with the nitrogen atom to which they are linked via a covalent bond to form an optionally substituted heterocyclyl group; R7 may be selected from optionally substituted alkyl; haloalkyl; fluoroalkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted heterocyclyl groups; n is an integer and can take the value 0, 1, 2, 3 or 4; m is an integer that can take the value of 0, 1, 2, 3, 4 or 5 for formula (II); m is an integer that can take the value of 0, 1, 2, 3, or 4 for formulas (III) and (IV). a compound selected from the compounds of and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, polymorphs, tautomers, isotopic variants, isomers, stereoisomers or mixtures of stereoisomers thereof, and ◆ Includes mitogen-activated protein kinase kinase inhibitors (MEK inhibitors) and pharmaceutically acceptable salts, hydrates or solvates thereof.

[0137] Compounds of formula (II), (III) and (IV) are preferred embodiments of compounds of formula (I).

[0138] All definitions and alternative preferred embodiments relating to formula (I) set forth above also apply to formulas (II), (III) and (IV).

[0139] In particular, the combination according to the invention L1 is a single bond and (-CH2-) p selected from the group R1 is a halogen atom, in particular chlorine; R2 and R3 are simultaneously or independently selected from hydrogen atoms and optionally substituted alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, m=1, n=0, a compound of formula (I) in which p=1 and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, polymorphs, tautomers, isotopic variants, isomers, stereoisomers or mixtures of stereoisomers thereof.

[0140] In a preferred embodiment, the combination according to the invention comprises the following compound: 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (1-5) of formula (Ia)

[0141] [ka]

[0142] or a pharmaceutically acceptable salt, solvate or prodrug thereof, and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib)

[0143] [ka]

[0144] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0145] In particular, the combination according to the present invention comprises a compound selected from 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline hydrochloride (1-6) and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline hydrochloride (2-3).

[0146] The preparation of compounds of formula (I), (II), (III) and (IV) is described in WO2016 / 067112 and WO2020 / 048694. In particular, compounds 1-5, 1-6, 2-2 and 2-3 are described in Examples 1 and 2 of WO2016 / 067112 and WO2020 / 048694.

[0147] In certain embodiments of the invention, the MEK inhibitor is abtometinib (RO-5126766) [946128-88-7], BI-847325 [1207293-36-4], binimetinib [606143-89-9], cobimetinib [934660-93-2], selumetinib [606143-52-6], trametinib [871700-17-3], AZD8330 [869357-68-6], BI-847325 [1207293-36-4], GD C-0623 [1168091-68-6], Mirdametinib (PD0325901) [391210-10-9], PD184352 (CI-1040) [212631-79-3], Pimasertib (AS-703026) [1236699-92-5], Lefametinib [923032-37-5], TAK-733 [1035555-63-5], Tunlametinib (HL-085) [1801756-06-8], BIX 02188 [1094614-84-2], BIX 02189 [1265916-41-3], E6201 [603987-35-5], FCN-159, GDC-0623 [1168091-68-6], honokiol [35354-74-6], myricetin [529-44-2], PD98059 [167869-21-8], PD184352 (CI-1040) [212631-79-3], PD318088 [391210-00-7], SL-327 [305350-87-2], SHR7390, TAK-733 [1035555-63-5], U0126 [109511-58-2].

[0148] In a further embodiment of the invention, the MEK inhibitor is binimetinib [606143-89-9], cobimetinib [934660-93-2], selumetinib [606143-52-6], trametinib [871700-17-3], AZD8330 [869357-68-6], BI-847325 [1207293-36-4], GDC-0623 [1168091-68-6], Mirdametinib (PD0325901) [391210-10-9], PD184352 (CI-1040) [212631-79-3], Pimasertib (AS-703026) [1236699-92-5], Lefametinib [923032-37-5], TAK-733 [1035555-63-5], BIX 02188 [1094614-84-2], BIX 02189 [1265916-41-3], honokiol [35354-74-6], myricetin [529-44-2], PD98059 [167869-21-8], PD318088 [391210-00-7], SL-327 [305350-87-2], U0126 [109511-58-2] and pharmaceutically acceptable salts, hydrates or solvates thereof.

[0149] In a preferred embodiment, the MEK inhibitor is selected from the group consisting of binimetinib [606143-89-9], cobimetinib [934660-93-2], selumetinib [606143-52-6], trametinib [871700-17-3], AZD8330 [869357-68-6], BI-847325 [1207293-36-4], GDC-0623 [1168091- 68-6], mirdametinib (PD0325901) [391210-10-9], PD184352 (CI-1040) [212631-79-3], pimasertib (AS-703026) [1236699-92-5], refametinib [923032-37-5], TAK-733 [1035555-63-5].

[0150] In another preferred embodiment, the MEK inhibitor can be selected from the group consisting of binimetinib [606143-89-9], cobimetinib [934660-93-2], selumetinib [606143-52-6], trametinib [871700-17-3].

[0151] In another preferred embodiment, the MEK inhibitor can be selected from the group consisting of binimetinib [606143-89-9], cobimetinib [934660-93-2], selumetinib [606143-52-6], trametinib [871700-17-3], and pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0152] In a further preferred embodiment, the MEK inhibitor is trametinib [871700-17-3] or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0153] In a further preferred embodiment, the MEK inhibitor is cobimetinib [934660-93-2] or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0154] In a further embodiment, the MEK inhibitor is trametinib [871700-17-3].

[0155] In a preferred embodiment, the MEK inhibitor is the dimethyl sulfoxide solvate form of trametinib [1187431-43-1].

[0156] In a further embodiment, the MEK inhibitor is cobimetinib [934660-93-2].

[0157] In a preferred embodiment, the MEK inhibitor is cobimetinib hemifumarate [1369665-02-0].

[0158] In particular, the combination according to the invention comprises 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib), or a salt, solvate or prodrug thereof, and trametinib [871700-17-3], or a pharmaceutically acceptable salt or solvate thereof.

[0159] In a further embodiment, the combination according to the invention comprises 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib), or a salt, solvate or prodrug thereof, and the dimethyl sulfoxide solvate form of trametinib [1187431-43-1].

[0160] In a further embodiment, the combination according to the invention comprises 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib), or a salt, solvate or prodrug thereof, and cobimetinib [934660-93-2], or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0161] In another embodiment, a combination according to the present invention comprises 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a salt, solvate or prodrug thereof and cobimetinib hemifumarate [1369665-02-0] or a hydrate or solvate thereof.

[0162] According to one embodiment, the present invention provides a method for producing a medicament for the treatment of ... ◆ Compounds of formula (I), (II), (III) or (IV), and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, polymorphs, tautomers, isotopic variants, isomers, stereoisomers or mixtures of stereoisomers; * The present invention relates to a combination comprising a mitogen-activated protein kinase kinase inhibitor (MEK inhibitor) and a pharmaceutically acceptable salt or solvate thereof.

[0163] The present invention further relates to pharmaceutical compositions comprising a therapeutically effective amount of the combinations defined above comprising compounds of Formula (I), (II), (III) or (IV) and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, polymorphs, tautomers, isotopic variants, isomers, stereoisomers or mixtures of stereoisomers, and MEK inhibitors and their pharmaceutically acceptable salts and solvates, and at least one pharmaceutically acceptable carrier, wherein each component of the combination may be contained in a separate pharmaceutical composition.

[0164] The present invention further relates to pharmaceutical compositions comprising a therapeutically effective amount of the combinations defined above comprising compounds of Formula (I), (II), (III) or (IV) and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, polymorphs, tautomers, isotopic variants, isomers, stereoisomers or mixtures of stereoisomers, and MEK inhibitors and their pharmaceutically acceptable salts and solvates, and at least one pharmaceutically acceptable carrier, wherein each component of the combination can be contained in the same pharmaceutical composition.

[0165] That is, the active ingredients of the combination (a compound of Formula (I), (II), (III) or (IV) and a MEK inhibitor as defined above) may be administered simultaneously (i.e., concurrently) in either the same or different pharmaceutical compositions, separately in different pharmaceutical compositions, or sequentially in any order in different pharmaceutical compositions.

[0166] Each pharmaceutical composition comprising a component of the combination can be administered once or several times, in one or different dosages, by the same or different administration routes.

[0167] The amounts of the active ingredients, the relative timing and routes of administration are selected in order to achieve a desired combined therapeutic effect.

[0168] According to a preferred embodiment, each component of the combination may be contained in a separate pharmaceutical composition.

[0169] According to a further preferred embodiment, each component of the combination may be contained in the same pharmaceutical composition.

[0170] All general and preferred embodiments described above in relation to the combination of a compound of Formula (I), (II), (III) or (IV) with a MEK inhibitor, and each component of the combination, also apply to the pharmaceutical composition.

[0171] Pharmaceutical compositions of the invention may be suitable for oral, parenteral, ocular, transdermal or intranasal administration, or for inhalation.

[0172] The present invention further relates to a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof, as defined above, for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0173] The present invention further relates to a combination comprising a compound of formula (II), (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0174] The present invention also relates to a combination comprising a compound of formula (II), (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof and a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof, as defined above, for use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases, in particular intrahepatic cholangiocarcinoma and / or extrahepatic cholangiocarcinoma.

[0175] The present invention further relates to a combination comprising a compound of formula (II), (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof and a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof, as defined above, for use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases, in particular intrahepatic cholangiocarcinoma.

[0176] The present invention further relates to a combination comprising a compound of formula (I) selected from 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (1-5) and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) and a MEK inhibitor, as defined above, for use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0177] The present invention further relates to a combination comprising a compound of formula (I) selected from 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline hydrochloride (1-6) and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline hydrochloride (2-3) and a MEK inhibitor, as defined above, for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0178] The present invention also relates to a combination comprising a compound of formula (I) selected from 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (1-5) and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) and a MEK inhibitor as defined above for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular intrahepatic cholangiocarcinoma and / or extrahepatic cholangiocarcinoma.

[0179] The present invention also relates to a combination comprising a compound of formula (I) selected from 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline hydrochloride (1-6) and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline hydrochloride (2-3) and a MEK inhibitor, as defined above, for use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases, in particular intrahepatic cholangiocarcinoma and / or extrahepatic cholangiocarcinoma.

[0180] In another aspect, the present invention relates to a combination comprising a compound of formula (I) selected from 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (1-5) and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) and a MEK inhibitor as defined above for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular hepatocellular carcinoma.

[0181] In a further aspect, the present invention relates to a combination comprising a compound of formula (I) selected from 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline hydrochloride (1-6) and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline hydrochloride (2-3) and a MEK inhibitor as defined above for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular hepatocellular carcinoma.

[0182] In another aspect, the present invention also relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) and a MEK inhibitor as defined above for use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0183] The present invention also relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) and a MEK inhibitor, as defined above, for use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases, in particular intrahepatic cholangiocarcinoma and / or extrahepatic cholangiocarcinoma.

[0184] In a further aspect, the present invention also relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) and a MEK inhibitor as defined above for use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases, in particular intrahepatic cholangiocarcinoma.

[0185] In a further aspect, the present invention also relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) and a MEK inhibitor as defined above for use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases, in particular extrahepatic cholangiocarcinoma.

[0186] In another aspect, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) and a MEK inhibitor, as defined above, for use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases, in particular hepatocellular carcinoma.

[0187] In a further aspect, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and trametinib [871700-17-3] or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0188] In a further preferred aspect, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and trametinib [871700-17-3] or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and / or prevention and / or suppression of progression of hepatocellular carcinoma.

[0189] In a further preferred aspect, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline of formula (Ib) (2-2) or a pharmaceutically acceptable salt or solvate thereof and trametinib [871700-17-3] or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and / or prevention and / or suppression of progression of cholangiocarcinoma, wherein the cholangiocarcinoma is intrahepatic cholangiocarcinoma and / or extrahepatic cholangiocarcinoma.

[0190] In a further aspect, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and a dimethyl sulfoxide (DMSO) solvate of trametinib [1187431-43-1] in a 1:1 form for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0191] In a further preferred embodiment, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and a dimethyl sulfoxide (DMSO) solvate of trametinib [1187431-43-1] in a 1:1 form for use in the treatment and / or prevention and / or suppression of progression of hepatocellular carcinoma.

[0192] In a further preferred embodiment, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and a dimethyl sulfoxide (DMSO) solvate of trametinib [1187431-43-1] in 1:1 form for use in the treatment and / or prevention and / or suppression of progression of cholangiocarcinoma, wherein the cholangiocarcinoma is intrahepatic cholangiocarcinoma and / or extrahepatic cholangiocarcinoma.

[0193] More preferably, the combination comprises 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, and trametinib [871700-17-3], or a pharmaceutically acceptable salt or solvate thereof.

[0194] In a further embodiment, the combination comprises 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a 1:1 form of a dimethyl sulfoxide (DMSO) solvate of trametinib [1187431-43-1].

[0195] In another aspect, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and cobimetinib [934660-93-2] or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0196] In a further preferred aspect, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt, solvate or prodrug thereof and cobimetinib [934660-93-2] or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and / or prevention and / or suppression of progression of hepatocellular carcinoma.

[0197] In a further preferred aspect, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and cobimetinib [934660-93-2] or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and / or prevention and / or suppression of progression of cholangiocarcinoma, wherein the cholangiocarcinoma is intrahepatic cholangiocarcinoma and / or extrahepatic cholangiocarcinoma.

[0198] In another aspect, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline of formula (Ib) (2-2) or a pharmaceutically acceptable salt or solvate thereof and cobimetinib hemifumarate [1369665-02-0] for use in the treatment and / or prevention and / or suppression of progression of liver cancer related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0199] In a further preferred aspect, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline of formula (Ib) (2-2) or a pharmaceutically acceptable salt or solvate thereof and cobimetinib hemifumarate [1369665-02-0] for use in the treatment and / or prevention and / or suppression of progression of hepatocellular carcinoma.

[0200] In a further preferred embodiment, the present invention relates to a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and cobimetinib hemifumarate [1369665-02-0] for use in the treatment and / or prevention and / or suppression of progression of cholangiocarcinoma, wherein the cholangiocarcinoma is intrahepatic cholangiocarcinoma and / or extrahepatic cholangiocarcinoma.

[0201] More preferably, the combination comprises 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, and cobimetinib [934660-93-2] or a pharmaceutically acceptable salt or solvate thereof.

[0202] In a further embodiment, the combination comprises 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of Formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and cobimetinib hemifumarate [1369665-02-0].

[0203] In a preferred embodiment, the liver cancer-related disease is cholangiocarcinoma.

[0204] In a more preferred embodiment, the liver cancer-related disease is selected from intrahepatic cholangiocarcinoma and / or extrahepatic cholangiocarcinoma.

[0205] In a more preferred embodiment, the liver cancer-related disease is intrahepatic cholangiocarcinoma.

[0206] In a more preferred embodiment, the liver cancer-related disease is extrahepatic cholangiocarcinoma.

[0207] In a more preferred embodiment, the liver cancer-related disease is hepatocellular carcinoma.

[0208] In a more preferred embodiment, the liver cancer-related disease is hepatoblastoma.

[0209] According to the present invention, each component of the combination may be for simultaneous, separate or sequential use in liver cancer therapy.

[0210] According to the present invention, the compounds of formula (I), (II), (III) or (IV) defined above and the MEK inhibitors defined above, as well as pharmaceutical compositions containing them (each component of the composition may be contained in a separate pharmaceutical composition), may be administered to a human or animal in need thereof as a combination therapy in the treatment and / or suppression of progression and / or prevention of liver cancer, and said administration may be simultaneous, separate or sequential.

[0211] All general and preferred embodiments described above in relation to the combination of a compound of formula (I), (II), (III) or (IV) with a MEK inhibitor, and each component of the combination, also apply to their use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0212] In another aspect, the present invention also relates to a method for treating and / or inhibiting the progression and / or preventing liver cancer-related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma, comprising the step of administering to a patient in need thereof a combination comprising a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof and a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof, as described above.

[0213] In another aspect, the present invention also relates to a method for treating and / or inhibiting the progression and / or preventing liver cancer-related diseases, particularly cholangiocarcinoma, wherein the cholangiocarcinoma is intrahepatic cholangiocarcinoma and / or extrahepatic cholangiocarcinoma.

[0214] All general and preferred embodiments described above in relation to the combination of a compound of formula (I), (II), (III) or (IV) with a MEK inhibitor, and each component of the combination, also apply to methods for treating and / or inhibiting the progression of and / or preventing liver cancer-related diseases, in particular hepatocellular carcinoma, hepatoblastoma or cholangiocarcinoma.

[0215] The present invention further relates to a kit comprising a combination of a compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof and a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof, as defined above, wherein both or either of the components are in the form of pharmaceutical compositions which can be administered simultaneously, separately or sequentially.

[0216] The present invention is illustrated in a non-limiting manner by the following examples. [Example]

[0217] Example 1 In vitro evaluation of the cytotoxic activity of compound 2-2, hydroxychloroquine (HCQ), trametinib, and cobimetinib in the intrahepatic cholangiocarcinoma cell line HuCCT1 (KRAS G12D state) Cell Culture: HuCCT1 cell line (JCRB Cell Bank No. JCRB0425) harboring the KRAS G12D mutation was maintained in RPMI medium (Dutscher Product No. L0498-500) containing 1% penicillin-streptomycin (Dutscher Product No. P06-07100) and 10% fetal bovine serum (Dutscher Product No. SV30160.03C) and cultured at 37°C in a humidified cell incubator with 5% CO2.

[0218] HuCCT1 cells were plated at 4.10 µL per well in 80 µL of medium in a Greiner Bio-one µClear® P96-well plate (Dutscher product no. 655098). 3HuCCT1 cells were seeded with hydroxychloroquine sulfate (HCQ, [747-36-4]), trametinib (Selleckchem catalog number S2673, [871700-17-3]), or cobimetinib (Selleckchem catalog number S8041, [934660-93-2]) after 24 hours. Cell viability was assessed 72 hours after molecule treatment using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega product catalog number G7573) according to the manufacturer's protocol using an Infinity F200 Pro luminometer (Tecan). DMSO was used as a negative control for compound 2-2, trametinib, and cobimetinib, and water was used as a negative control for HCQ. IC 50 The luminescence intensity was determined as the dose of compound required to reduce the luminescence intensity to 50% of the reference signal obtained for untreated cell cultures. Raw data were analyzed using GraphPad Prism software v9.4 (GraphPad Software, Inc. La Jolla, CA). For all experiments, the analyzed data are presented as the mean value of three replicates and four independent experiments. Four compounds, 2-2, HCQ, trametinib, and cobimetinib, demonstrated dose-responsive cytotoxic activity against the intrahepatic cholangiocarcinoma cell line HuCCT1 (Table 1).

[0219] [Table 1]

[0220] Example 2 In vitro evaluation of the cytotoxic activity of the combination of compound 2-2 + trametinib and hydroxychloroquine (HCQ) + trametinib in the intrahepatic cholangiocarcinoma cell line HuCCT1 (KRAS G12D state) due to the interaction between the two drugs HuCCT1 cell viability assays for two-drug interactions were performed as described in Example 1. Two-drug interactions of compound 2-2 + trametinib and HCQ + trametinib were tested in a checkerboard format in Greiner Bio-one μClear® 96-well plates (Dutscher product number 655098). Concentration ranges were determined based on the IC4 of the individual compounds. 50 The concentrations were selected within a range of approximately 100 μM. Compound 2-2 was tested in combination with trametinib at 1.28 μM, 1.6 μM, 2.0 μM, 2.5 μM, and 3.125 μM. HCQ [747-36-4] was tested in combination with trametinib at 15 μM, 20 μM, 30 μM, 45 μM, and 60 μM. Trametinib (Selleckchem catalog number S2673, [871700-17-3]) was tested in combination with compound 2-2 or HCQ at 0.005 μM, 0.03 μM, 6.0 μM, 15 μM, 30 μM, 60 μM, and 90 μM. The combined effects of the two-drug interactions of Compound 2-2 + trametinib and HCQ + trametinib were analyzed using two software programs: MacSynergy™ II (1) and SynergyFinder. (2) MacSynergy™ II was used to analyze the combined effects according to the Bliss independence model, which assumes probabilistic statistical independence between the combined compounds. (3) The main assumption of the Bliss independence principle is that two or more combined drugs act independently of each other through different mechanisms of action. SynergyFinder was used to analyze the combined effects according to the Loewe additive model, which is based on the principle of pseudo-drug combinations, which assumes that there is no interaction when a compound is used with itself. (4)

[0221] Analysis of combined effects using the Loewe additive model (SynergyFinder): The combined drug-drug interaction effects of compound 2-2 + trametinib (Table 2) and HCQ + trametinib (Table 3) were evaluated according to the Loewe additive model using SynergyFinder for their respective abilities to inhibit the proliferation of the intrahepatic cholangiocarcinoma cell line HuCCT1.

[0222] [Table 2]

[0223] The drug-drug interaction of compound 2-2 + trametinib showed an overall additive combination effect according to the Loewe additivity model when analyzed by SynergyFinder (-10 < synergy score < +10) for its ability to inhibit the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1 by inducing cytotoxic effects as assessed by the CellTiter-Glo® luminescent cell viability assay (Table 2). The overall additive combination effect of the drug-drug interaction of compound 2-2 + trametinib according to the Loewe non-independent additivity model is not due to the substantial discrepancy in the mechanisms of action of the two compounds, namely, compound 2-2 as an autophagy inhibitor and trametinib as an MEK inhibitor.

[0224] [Table 3]

[0225] The drug-drug interaction of hydroxychloroquine and trametinib, when analyzed by SynergyFinder (-10 < synergy score < +10) for its ability to inhibit the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1 by inducing cytotoxic effects as assessed by the CellTiter-Glo® luminescent cell viability assay, showed an overall additive combination effect according to the Loewe non-independent model (Table 3). The overall additive combination effect of the drug-drug interaction of hydroxychloroquine and trametinib according to the Loewe non-independent additivity model is not due to the substantial discrepancy in the mechanisms of action of the two compounds, i.e., hydroxychloroquine as an autophagy inhibitor and trametinib as an MEK inhibitor.

[0226] Combination Effect Analysis by Bliss Independence Model (MacSynergy™ II): The combined drug-drug interaction effects of compound 2-2 + trametinib and hydroxychloroquine + trametinib were evaluated according to the Bliss independence model using MacSynergy™ II for their respective abilities to inhibit the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1 (Table 4).

[0227] [Table 4]

[0228] According to the Bliss independence model, the interaction between compound 2-2 and trametinib showed significant moderate synergy in inhibiting the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1 (synergy score = 62.8 ± 23.9 μM). 2 .%, Table 4), which may have important implications in vivo and in clinical settings. The combination of compound 2-2 + trametinib did not show any areas of antagonism (antagonism score = -7.2 ± 7.20 μM 2 .%, Table 4). In comparison, the two-drug interaction of hydroxychloroquine + trametinib was predicted using the Bliss independence model (synergy score = 18.3 ± 10.6 μM 2 .%, Table 4 (Table 4) showed a non-significant drug synergistic combination effect, with an overall additive effect in inhibiting the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1 (5, 6). Furthermore, the combination of hydroxychloroquine and trametinib showed a non-significant antagonism equivalent to its synergy score (synergy score = -18.3 ± 10.6 μM). 2 .%, antagonism score = -21.5 ± 2.9 μM 2 .%, see Table 4).

[0229] Both compound 2-2 and hydroxychloroquine are known in the art as autophagy inhibitors. (7, 8) However, when these two autophagy inhibitors were individually combined with the MEK inhibitor trametinib to inhibit the growth of the intrahepatic cholangiocarcinoma (HuCCT1) cell line, compound 2-2 showed a significant synergistic effect, whereas hydroxychloroquine showed only an additive effect.

[0230] Example 3 In vitro evaluation of the combined cytotoxic activity of compound 2-2 + cobimetinib and hydroxychloroquine (HCQ) + cobimetinib in the intrahepatic cholangiocarcinoma cell line HuCCT1 (KRAS G12D status) due to the interaction between the two drugs HuCCT1 cell viability assays for two-drug interactions were performed as described in Example 1. Two-drug interactions of Compound 2-2 + cobimetinib and HCQ + cobimetinib were tested in a checkerboard format in Greiner Bio-one μClear® 96-well plates (Dutscher product number 655098). Concentration ranges were determined based on the IC400 of the individual compounds. 50The values ​​were selected within a range of approximately 100 μM. Compound 2-2 was tested in combination with cobimetinib at 1.28 μM, 1.6 μM, 2.0 μM, 2.5 μM, and 3.125 μM. HCQ [747-36-4] was tested in combination with cobimetinib at 15 μM, 20 μM, 30 μM, 45 μM, and 60 μM. Cobimetinib (Selleckchem catalog number S8041, [934660-93-2]) was tested in combination with compound 2-2 or HCQ at 0.10 μM, 1.0 μM, 10 μM, 30 μM, 60 μM, 80 μM, and 100 μM. The combined effects of the two drugs, Compound 2-2 + cobimetinib and HCQ + cobimetinib, were analyzed using two software programs: MacSynergy™ II (1) and SynergyFinder (2). MacSynergy™ II was used to analyze the combined effects according to the Bliss independence model, which assumes probabilistic statistical independence between the combined compounds. (3) SynergyFinder was used to analyze the combined effects according to the Loewe additive model, which is based on the principle of pseudo-drug combinations, which assumes no interactions when a compound is used with itself. (4)

[0231] Analysis of combined effects according to the Loewe additive model (SynergyFinder): The combined effects of two-drug interactions, compound 2-2 + cobimetinib (Table 5) and HCQ + cobimetinib (Table 6), were evaluated according to the Loewe additive model using SynergyFinder for their respective abilities to inhibit the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1.

[0232] [Table 5]

[0233] According to the Loewe additivity model, the drug-drug interaction of compound 2-2 + cobimetinib showed an overall additive combination effect when analyzed by SynergyFinder (-10<synergy score<+10) for their combined properties to inhibit the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1 by inducing a cytotoxic effect as assessed by the CellTiter-Glo® luminescent cell viability assay (Table 5). Advantageously, the two ... the Bliss additivity model (50 μM 2 .%<synergy score<100 μM 2 The combination showed a significant synergistic effect when analyzed according to the RI and RI data (Table 7).

[0234] When analyzed using SynergyFinder with the Loewe non-independent additive model, the overall additive combination effect of the drug-drug interaction of compound 2-2 + cobimetinib (-10 < synergy score < +10) is not due to substantial discrepancies due to differences in the mechanisms of action of the two compounds, compound 2-2, a known autophagy inhibitor, and cobimetinib, a MEK inhibitor.

[0235] [Table 6]

[0236] According to the Loewe non-independent additivity model, the two-drug interaction of hydroxychloroquine and cobimetinib showed an overall additive combination effect when analyzed by SynergyFinder (synergy score < +10) for its ability to inhibit the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1 by inducing cytotoxic effects as assessed by the CellTiter-Glo® luminescent cell viability assay (Table 6). The overall additive combination effect of the two-drug interaction of hydroxychloroquine and trametinib according to the Loewe non-independent additivity model is not due to substantial discrepancies in the mechanisms of action of the two compounds, i.e., hydroxychloroquine as an autophagy inhibitor and cobimetinib as a MEK inhibitor.

[0237] Combination Effect Analysis by Bliss Independence Model (MacSynergy™ II): The combined effects of two-drug interactions of compound 2-2 + cobimetinib and hydroxychloroquine + cobimetinib were evaluated for their respective abilities to inhibit the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1 according to the Bliss independence model using MacSynergy™ II (Table 7).

[0238] [Table 7]

[0239] According to the Bliss independence model, the interaction between the two drugs, compound 2-2 and cobimetinib, showed an overall significant moderate synergy in inhibiting the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1, which may have important implications in vivo and in clinical settings (synergy score = 90.2 ± 8.40 μM). 2 .%, Table 7). Furthermore, the interaction between the two drugs, compound 2-2 and cobimetinib, showed no room for antagonism (antagonism score = -1.00 ± 1.62 μM 2.%, Table 7). In comparison, the two-drug interaction of hydroxychloroquine + cobimetinib was predicted using the Bliss independence model (synergy score = 39.8 ± 2.77 μM 2 .%, Table 7), indicating a mild synergistic drug combination effect in inhibiting the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1, with likely minimal or no in vivo effects (5, 6). The interaction between the two drugs, hydroxychloroquine and cobimetinib, showed no room for antagonism within the tested concentration range (antagonism score = -2.03 ± 0.78 μM). 2 .%, Table 7).

[0240] Both compound 2-2 and hydroxychloroquine are known in the art as autophagy inhibitors. (7, 8) However, when these two autophagy inhibitors were individually combined with the MEK inhibitor cobimetinib to inhibit the growth of the intrahepatic cholangiocarcinoma cell line HuCCT1, hydroxychloroquine showed only an overall additive effect in the Loewe model, slight synergism in the Bliss model, and no significant effect in vivo. Compound 2-2, on the other hand, showed an overall additive effect in the Loewe model and significant synergism in the Bliss model.

[0241] The present invention discloses that compound 2-2, when combined with MEK inhibitors (e.g., trametinib, cobimetinib), showed significant synergistic combination effects according to the Bliss independent model to inhibit the in vitro growth of cholangiocarcinoma, as evidenced in the cell line HuCCT1 (intrahepatic cholangiocarcinoma cell line, Cellosaurus ID: CVCL_0324). (References) TIFF2025534441000014.tif132156

Claims

1. ◆ Compound of formula (I) 【Chemical 1】 [In the formula, ・L 1 is a single bond; optionally substituted (CH 2 ) p an optionally substituted alkylene; a carbonyl; ・ R 1 represents, alone or when m>1, simultaneously or independently, a hydrogen atom; a halogen atom; an optionally substituted alkyl; a haloalkyl; a fluoroalkyl; an optionally substituted alkenyl; an optionally substituted alkynyl; an optionally substituted cycloalkyl; an optionally substituted cycloalkenyl; an optionally substituted cycloalkynyl; an optionally substituted alkoxy; -OR 7 ;-O-(CO)-R 7 ;-O-(CO)-NR 5 R 6 ;-NR 5 -(CO)-R 7 ;-O-(CO)-OR 7 ;-NR 5 -(CO)-OR 7 ;Azide;Hydroxyl;Cyano;Nitro;-NR 5 R 6 Selected from; ・ R 2 and R 3 are simultaneously or independently selected from a hydrogen atom; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted heterocyclyl group; optionally substituted aryl; optionally substituted benzyl; and optionally substituted heteroaryl; Or R 2 and R 3 can be joined together with the nitrogen atom to which it is linked via a covalent bond to form an optionally substituted heterocyclyl group; ・ R 4 represents, alone or when n>1, simultaneously or independently, a hydrogen atom; a halogen atom; an optionally substituted alkyl; a haloalkyl; a fluoroalkyl; an optionally substituted alkenyl; an optionally substituted alkynyl; an optionally substituted cycloalkyl; an optionally substituted cycloalkenyl; an optionally substituted cycloalkynyl; an optionally substituted alkoxy; -OR 7 ;-O-(CO)-R 7 ;-O-(CO)-NR 5 R 6 ;-NR 5 -(CO)-R 7 ;-O-(CO)-OR 7 ;-NR 5 -(CO)-OR 7 ;Azide;Hydroxyl;Cyano;Nitro;-NR 5 R 6 Selected from; ・ R 5 and R 6 are simultaneously or independently selected from a hydrogen atom; optionally substituted alkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted heterocyclyl group; optionally substituted aryl; optionally substituted heteroaryl; Or R 5 and R 6 can be joined together with the nitrogen atom to which it is linked via a covalent bond to form an optionally substituted heterocyclyl group; ・ R 7 may be selected from optionally substituted alkyl; haloalkyl; fluoroalkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted heterocyclyl group; optionally substituted aryl; optionally substituted heteroaryl; n is an integer and can take the values ​​0, 1, 2, 3, or 4; m is an integer and can take the values ​​0, 1, 2, 3, 4, or 5; p is an integer that can take on the value of either 0 or 1; and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers, isotopic variants, stereoisomers or mixtures of stereoisomers thereof, and ♦ A combination comprising a mitogen-activated protein kinase kinase inhibitor (MEK inhibitor) and a pharmaceutically acceptable salt or solvate thereof.

2. R 1 is selected from the group consisting of: hydrogen, halogen, optionally substituted alkyl, haloalkyl; fluoroalkyl; optionally substituted alkoxy; and hydroxyl.

3. R 1 3. The combination according to claim 1 or 2, comprising a compound of formula (I) wherein, alone or jointly or independently when m>1, is selected from a hydrogen atom and chlorine.

4. R 2 and R 3 is simultaneously or independently selected from a hydrogen atom; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl.

5. R 2 and R 3 is simultaneously or independently selected from a hydrogen atom; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

6. R 2 and R 3 5. The combination according to claim 1, comprising a compound of formula (I), wherein is simultaneously or independently selected from hydrogen and tert-butyl.

7. R 4 7. The combination according to any one of claims 1 to 6, comprising a compound of formula (I) wherein, alone or, if n>1, simultaneously or independently, is selected from: a hydrogen atom, a halogen atom, alkyl, haloalkyl; fluoroalkyl; alkoxy, hydroxyl.

8. R 4 8. A combination according to any one of claims 1 to 7, comprising a compound of formula (I) wherein, alone or together or independently when n>1, is selected from: a hydrogen atom, hydroxyl, methoxy.

9. The compound of formula (I) may be a compound of the following formulas (II), (III), and (IV): 【Chemistry 2】 [In the formula, ・ R 1 represents, alone or when m>1, simultaneously or independently, a hydrogen atom; a halogen atom; optionally substituted alkyl; haloalkyl; fluoroalkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; optionally substituted alkoxy; -OR 7 ;Azide;Hydroxyl;Cyano;Nitro;-NR 5 R 6 Selected from; ・ R 2 and R 3 are simultaneously or independently selected from a hydrogen atom; an optionally substituted alkyl; an optionally substituted alkenyl; an optionally substituted alkynyl; an optionally substituted cycloalkyl; an optionally substituted cycloalkenyl; an optionally substituted cycloalkynyl; an optionally substituted heterocyclyl group; or R 2 and R 3 can be joined together with the nitrogen atom to which it is linked via a covalent bond to form an optionally substituted heterocyclyl group; ・ R 4 represents, alone or when n>1, simultaneously or independently, a hydrogen atom; a halogen atom; an optionally substituted alkyl; a haloalkyl; a fluoroalkyl; an optionally substituted alkenyl; an optionally substituted alkynyl; an optionally substituted cycloalkyl; an optionally substituted cycloalkenyl; an optionally substituted cycloalkynyl; an optionally substituted alkoxy; -OR 7 ;Azide;Hydroxyl;Cyano;Nitro;-NR 5 R 6 is selected from ・ R 5 and R 6 are simultaneously or independently selected from a hydrogen atom; an optionally substituted alkyl; an optionally substituted alkenyl; an optionally substituted alkynyl; an optionally substituted cycloalkyl; an optionally substituted cycloalkenyl; an optionally substituted cycloalkynyl; an optionally substituted heterocyclyl group; or R 5 and R 6 can be joined together with the nitrogen atom to which it is linked via a covalent bond to form an optionally substituted heterocyclyl group; ・ R 7 may be selected from optionally substituted alkyl; haloalkyl; fluoroalkyl; optionally substituted alkenyl; optionally substituted alkynyl; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted cycloalkynyl; and optionally substituted heterocyclyl groups; n is an integer and can take the values ​​0, 1, 2, 3, or 4; m is an integer which can take on any of the values ​​0, 1, 2, 3, 4 or 5 for formula (II); m is an integer which can take on any of the values ​​0, 1, 2, 3 or 4 for formulas (III) and (IV); and a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, isotopic variant, stereoisomer or mixture of stereoisomers thereof.

10. R 1 , R 2 , R 3 and R 4 is as defined in any one of claims 2 to 8 for formula (II) or (III), and R 1 and R 4 is as defined in any one of claims 2, 3, 7 and 8 for formula (IV).

11. ・L 1 is a single bond and (-CH 2 -) p selected from the group ・ R 1 is a halogen atom, in particular chlorine; ・ R 2 and R 3 are simultaneously or independently selected from hydrogen atoms and optionally substituted alkyl, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; m=1, n=0, Compounds of formula (I) where p=1 and a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, isotopic variant, stereoisomer or mixture of stereoisomers thereof.

12. The compound of formula (I) may be the following compound: 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (1-5) of formula (Ia) 【Chemistry 3】 and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) 【Chemistry 4】 or a pharmaceutically acceptable salt or solvate thereof.

13. 2. The combination according to claim 1, wherein the compound of formula (I) is selected from 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline hydrochloride (1-6) and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline hydrochloride (2-3).

14. MEK inhibitors include binimetinib [606143-89-9], cobimetinib [934660-93-2], selumetinib [606143-52-6], trametinib [871700-17-3], AZD8330 [869357-68-6], BI-847325 [1207293-36-4], and GDC-0623 [116809 1-68-6], mirdametinib (PD0325901) [391210-10-9], PD184352 (CI-1040) [212631-79-3], pimasertib (AS-703026) [1236699-92-5], refametinib [923032-37-5], TAK-733 [1035555-63-5], BIX 02188 [1094614-84-2], BIX 02189 [1265916-41-3], honokiol [35354-74-6], myricetin [529-44-2], PD98059 [167869-21-8], PD318088 [391210-00-7], SL-327 [305350-87-2], U0126 [109511-58-2] or a pharmaceutically acceptable salt or solvate thereof.

15. 15. The combination of any one of claims 1 to 14, wherein the MEK inhibitor is selected from the group consisting of binimetinib [606143-89-9], cobimetinib [934660-93-2], selumetinib [606143-52-6], trametinib [871700-17-3] or a pharmaceutically acceptable salt or solvate thereof.

16. 16. The combination according to any one of claims 1 to 15, comprising 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a salt, solvate thereof, and trametinib [871700-17-3] or a pharmaceutically acceptable salt or solvate thereof.

17. 16. The combination according to any one of claims 1 to 15, comprising 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a salt or solvate thereof, and cobimetinib [934660-93-2] or a pharmaceutically acceptable salt or solvate thereof.

18. 18. A pharmaceutical composition comprising a therapeutically effective amount of the combination according to any one of claims 1 to 17, comprising a compound of Formula (I), (II), (III) or (IV) and a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer, isotopic variant, stereoisomer or mixture of stereoisomers thereof, and a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, wherein each component of the combination can be contained in a separate pharmaceutical composition or in the same pharmaceutical composition.

19. 20. A combination comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 18 for use in the treatment and / or prevention and / or suppression of progression of liver cancer-related diseases.

20. 20. A combination for use according to claim 19, comprising a compound of formula (II), (III) or (IV) as defined in claim 9 or 10, or a pharmaceutically acceptable salt or solvate thereof.

21. 20. A combination for use according to claim 19, comprising a compound of formula (I) selected from 2-(4-chlorophenylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (1-5) and 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2).

22. 20. The combination for use according to claim 19, which is a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and trametinib [871700-17-3] or a pharmaceutically acceptable salt or solvate thereof.

23. 20. The combination for use according to claim 19, which is a combination of 2-(4-chlorobenzylamino)-4-(4-tert-butylaminopiperidin-1-yl)-quinoline (2-2) of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof and cobimetinib [934660-93-2] or a pharmaceutically acceptable salt or solvate thereof.

24. 23. The combination for use according to any one of claims 19 to 22, wherein each component of the combination may be for simultaneous, separate or sequential use in liver cancer therapy.

25. 25. The combination for use according to any one of claims 19 to 24, wherein the liver cancer related disease is selected from hepatocellular carcinoma, hepatoblastoma and cholangiocarcinoma.

26. 26. The combination for use according to any one of claims 19 to 25, wherein the liver cancer related disease is selected from intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

27. 26. The combination for use according to any one of claims 19 to 25, wherein the liver cancer related disease is hepatocellular carcinoma.

28. 20. A kit comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a MEK inhibitor or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 18, wherein both or either of the components of the combination are in the form of pharmaceutical compositions which can be administered simultaneously, separately or sequentially.

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