Piperidine derivatives as mettl3 inhibitors for the treatment of carcinomas

Abstract

The present invention relates to the use of METTL3 inhibitors piperidine derivatives of formula (I), for the treatment of carcinomas.

Description

PIPERIDINE DERIVATIVES AS METTL3 INHIBITORS FOR THETREAMENT OF CARCINOMASFIELD OF INVENTION

[0001] The present invention relates to the use of METTL3 inhibitors piperidine derivatives for the treatment of carcinomas.BACKGROUND OF INVENTION

[0002] Cancer is the second leading cause of death in the United States where 1 in 3 people will be diagnosed with cancer during their lifetime. In 2024, over 611,000 deaths from cancer are projected for the US. That is more than 1,600 deaths from cancer each day (American Cancer Society). This shows that the threat of cancer to human health has reached a level that cannot be ignored.

[0003] Cancers can be classified by the type of tissue or cells they start in. The mains groups of cancers are: carcinomas: cancers that start in epithelial tissues; sarcomas: cancers that start in connective and supportive tissue, such as for example in muscles, bones or cartilages; leukemias: this is cancers of the white blood cells. It starts in the tissues that make blood cells such as the bone marrow; lymphomas: cancers that start in the lymphatic system, such as for example in lymph nodes or spleen; myelomas: cancers that start in plasma cells. Plasma cells are a type of white blood cell made in the bone marrow; and brain and spinal cord cancers: these are known as central nervous system cancers. These cancers can start in the cells of the brain or spinal cord. The most common type of brain tumors develops from glial cells and are called glioma.

[0004] A distinguishing feature of carcinoma is an abnormal mass of epithelial tissue caused by cell hyperplasia. The proliferation of cancer cells is not limited as for normal cells. Thus, the cancer cells would invade other tissues abnormally. Basically, any organ with epithelial tissue in the body may suffer from carcinoma. The most common carcinomas include lung carcinoma, breast carcinoma, oral carcinoma, esophageal carcinoma, hypopharyngeal carcinoma, stomach carcinoma, small intestine carcinoma, large intestine carcinoma, colon carcinoma, colorectal carcinoma, hepatoma (also called hepatocellular carcinoma (HCC)), thymoma, cervical carcinoma, endometrial carcinoma, bladder carcinoma, pancreatic carcinoma, prostate carcinoma, renal carcinoma, thyroid carcinoma and cutaneous carcinoma.

[0005] In carcinoma, therapeutic management is usually achieved through the use of multidisciplinary approaches that may include surgery, chemotherapy, radiotherapy and more recently immunotherapy. Relapse rates are high in this type of cancer. Further treatments after the relapse are more intense, increasing the toxicity, resistance to chemotherapy drugs, and financial burden to patients with poor quality-of-life.

[0006] Therefore, there is an urgent need to provide new therapeutic approaches which can improve the treatment efficacy in carcinoma.

[0007] The present invention provides METTL3 inhibitor piperidine derivatives of formula (I) as defined hereafter, for the treatment of carcinomas. The piperidine derivatives of formula (I) of the present invention were selected among METTL3 inhibitors described in PCT / EP2024 / 051219, as providing a promising therapy specifically against carcinomas.SUMMARY

[0008] This invention thus relates to a compound for use in the treatment of carcinoma, wherein the compound is of formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, wherein m, n, R1, R2, R3, R4, R5, L, Ar1and Ar2are as defined in the claims and hereafter.

[0009] In one embodiment, the compound of formula (I) is selected from the compounds of Table 1 as recited hereafter, stereoisomers, and pharmaceutically acceptable salts and / or solvates thereof.

[0010] In one embodiment, the carcinoma is selected from adenocarcinomas, basal cell carcinomas (BCC), squamous cell carcinomas (SCC), ductal carcinomas in situ (DCIS), invasive (infiltrating) ductal carcinomas (IDC), and transitional cell carcinoma (TCC).

[0011] In one embodiment, the carcinoma is selected from lung carcinoma, non- small cell lung carcinoma, breast carcinoma, triple negative breast carcinoma, oral carcinoma, esophageal carcinoma, hypopharyngeal carcinoma, head and neck carcinoma, stomach carcinoma, small intestine carcinoma, large intestine carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, cholangiocarcinoma, hepatoma, thymoma, cervical carcinoma, endometrial carcinoma, bladder carcinoma, pancreatic carcinoma, prostate carcinoma, renal carcinoma, testicular carcinoma, thyroid carcinoma and cutaneous carcinoma. In one embodiment, the carcinoma is selected from lung carcinoma, breast carcinoma, oral carcinoma, esophageal carcinoma, hypopharyngeal carcinoma, stomach carcinoma, small intestine carcinoma, large intestine carcinoma, colon carcinoma, colorectal carcinoma, hepatoma, thymoma, cervical carcinoma, endometrial carcinoma, bladder carcinoma, pancreatic carcinoma, prostate carcinoma, renal carcinoma, thyroid carcinoma and cutaneous carcinoma.

[0012] In one embodiment, the compound is to be administered orally or parenterally.DEFINITIONS

[0013] The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims. When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless indicated otherwise.

[0014] Where chemical substituents are combinations of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group recited. For example, an arylalkyl substituent is linked to the rest of the molecule through the alkyl moiety and it may by represented as follows: “-alkyl-aryl”.

[0015] In the present invention, the following terms have the following meanings:

[0016] “About” preceding a figure encompasses plus or minus 10%, or less, of the value of said figure. It is to be understood that the value to which the term “about” refers is itself also specifically, and preferably, disclosed.

[0017] “Alkyl”, by itself or as part of another substituent, refers to a hydrocarbyl radical of formula CnEhn+i wherein n is a number greater than or equal to 1. Generally, alkyl groups of this invention comprise from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Suitable alkyl groups include methyl, ethyl, zz-propyl, z-propyl, / 7-butyl, z-butyl, .s-butyl, / -butyl, pentyl and its isomers (e.g. n-pentyl, z^o- pentyl), and hexyl and its isomers (e.g. zz-hexyl, z.so-hcxyl). Preferred alkyl groups include methyl, ethyl, / z-propyl, z-propyl, / z-butyl, z-butyl, .s-butyl, and / -butyl.

[0018] “Alkylamino” as used herein means an amino group (z.e. -NH2) substituted with one alkyl group as herein defined. “Dialkylamino” as used herein means an amino group substituted with two alkyl groups as herein defined.

[0019] “Alkylaminocarbonyl” and “dialkylaminocarbonyl”, refer to any group -(C=O)-alkylamino and -(C=O)-dialkylamino respectively, wherein alkylamino and dialkylamino are as defined above.

[0020] “Alkoxy” as used herein refers to any group -O-alkyl, wherein alkyl is as defined above. Suitable alkoxy groups include for example methoxy, ethoxy, n-propoxy, isopropoxy, / -butoxy, / -butoxy, .s-butoxy, and n-pcntoxy.

[0021] “Alkynyl” as used herein refers to a monovalent unsaturated hydrocarbyl group, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Generally, alkynyl groups comprise from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms. Suitable alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, and the like.

[0022] “Aryl”, by itself or as part of another substituent, refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or 2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl.

[0023] “Cycloalkyl”, by itself or as part of another substituent, refers to a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0024] “Cycloalkyl-alkyl”, refers to any group -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[0025] “Cycloalkyloxy ”, refers to any group -O-cycloalkyl, wherein cycloalkyl is as defined above.

[0026] “Haloalkyl”, by itself or as part of another substituent, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl,1.1.1 -trifluoroethyl and the like.

[0027] “Haloalkoxy”, by itself or as part of another substituent, refers to an alkoxy radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Suitable haloalkoxy groups include for example trifluoromethoxy .

[0028] “Heteroaryl”, by itself or as part of another substituent, refers to 5 to 12 carbon- atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and / or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,l-b][l,3]thiazolyl, thieno [3, 2-b] furanyl, thieno[3,2-b] thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl,2.1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl, 6-oxo-pyridazin-l(677)-yl, 2-oxopyridin- l(277)-yl, 6-oxo-pyridazin- l(677)-yl,2-oxopyridin- l (2 / 7)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.

[0029] “Heterocyclyl", by itself or as part of another substituent, refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3- to 7-member monocyclic, 7- to 11-member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quatemized. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone). The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and / or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 377-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tctrahydro-2 / 7-pyranyl, 277-pyranyl, 477-pyranyl, 3,4-dihydro-277-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin- 1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-ylsulf oxide, thiomorpholin-4-ylsulfone, 1, 3-dioxolanyl, 1,4-oxathianyl, 177-pyrrolizinyl, tetrahydro- 1,1 -dioxothiophenyl, A-formylpiperazinyl, and morpholin-4-yl.

[0030] “Heterocyclyl-alkyl”, refers to any group -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are as defined above.

[0031] “Oxo”, refers to the substituent =0. “Thioxo”, refers to the substituent =S.

[0032] “Pharmaceutically acceptable” means that the component not deleterious to the subject to which it is administered and is compatible with each other component administered together.

[0033] “Pharmaceutically acceptable carrier” refers to an excipient that does not produce an adverse, allergic, or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices, such as, e.g., FDA Office or EMA.

[0034] “Prodrug” as used herein means the pharmacologically acceptable derivatives of the compounds of the invention, whose in vivo biotransformation product is the active drug. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active compounds in vivo. Suitable prodrugs for the purpose of the invention include carboxylic esters, in particular alkyl esters, aryl esters, acyloxyalkyl esters, and dioxolene carboxylic esters; ascorbic acid esters.

[0035] “Solvate” is used herein to describe a molecular complex comprising a compound of the invention and contains stoichiometric or sub- stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol. The term “hydrate” refers to when said solvent is water.

[0036] “Administration”, or a variant thereof (e.g. , “administering"), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the subject in need thereof.

[0037] “Subject” refers to a mammal, preferably a human. According to the present invention, a subject is a mammal, preferably a human, suffering from the targeted disease and / or prone to develop the targeted disease. In one embodiment, the subject is a “patient”, i.e., a mammal, preferably a human, who / which is awaiting the receipt of, or is receiving medical care or was / is / will be the object of a medical procedure or is monitored for the development of the targeted disease.

[0038] “Therapeutically effective amount’’ (or more simply an “effective amount ”) as used herein refers to the amount of active agent or active ingredient that is aimed at, without causing significant negative or adverse side effects to the subject in need of treatment, preventing, reducing, alleviating, or slowing down (lessening) one or more of the symptoms of the targeted disease

[0039] “Treating” or “treatment” refers to a therapeutic treatment, to a prophylactic (or preventative) treatment, or to both a therapeutic treatment and a prophylactic (or preventative) treatment, wherein the object is to prevent, reduce, alleviate, and / or slow down (lessen) one or more of the symptoms the targeted disease, in a subject in need thereof. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.DETAILED DESCRIPTION

[0040] This invention thus relates to the use of METTL3 inhibitors piperidine derivatives for the treatment of carcinomas.

[0041] The invention is based on the recognition that the selected piperidine derivatives of formula (I) as defined hereafter are particularly effective for the treatment of carcinomas. Especially, the compounds of formula (I) were evidenced to significantly decrease the viability of several carcinoma cell lines, including cells of lung carcinoma, squamous cell carcinoma, hepatocellular carcinoma, breast carcinoma, colorectal carcinoma, pancreas carcinoma, urinary bladder carcinoma, and prostate carcinoma.Compounds

[0042] Among the METTL3 inhibitors piperidine derivatives disclosed in PCT / EP2024 / 051219, it was evidenced, as reported in the experimental part below, that the compounds as defined below are particularly useful for the treatment of carcinomas.

[0043] The compounds of the present invention are those of formula (I):or pharmaceutically acceptable salts and / or solvates thereof, whereinAr1is a 6-membered aryl or 6-membered heteroaryl group selected from:wherein * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety;R1is C2-i2-alkyl, C2-i2-haloalkyl, C3-8-cycloalkyl-Ci-3-alkyl, heterocyclyl-C 1-3 -alkyl, C3-8-cycloalkyl, or heterocyclyl; in which the cycloalkyl and heterocyclyl moieties are optionally substituted by one of more substituents selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl and heterocyclyl moieties are optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl and heterocyclyl moieties are optionally bridged ring systems;R2is H, a Ci-4-alkyl optionally substituted by one or more substituent selected from halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; or a C3-6-cycloalkyl; or R1and R2form together with the nitrogen atom to which they are attached a heterocyclic ring,wherein the heterocyclic ring is optionally substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the heterocyclic ring is optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the heterocyclyl ring is optionally a bridged ring system; each R3is independently Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, Ci-4-haloalkoxy, oxo, or thioxo; or two R3groups present on the same carbon atom form together with the carbon atom to which they are attached a spiro-fused C3-6-cycloalkyl; or two R3groups present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a fused C3-6-cycloalkyl; or two R3groups present on two non-adjacent carbon atoms are linked and form a Ci-4-alkyl bridge; m is 0, 1, 2, 3 or 4; n is 1 or 2;R4and R5are each independently H, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, halo, cyano or hydroxy; orR4and R5form together with the carbon atom to which they are attached a heterocyclyl ring or a C3-4-cycloalkyl ring, in which the heterocyclyl and cycloalkyl moieties are optionally substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, or cyano; orR4and R5form together with the carbon atom to which they are attached an ethylenyl;L is selected from (L1), (L2) and 5-membered heteroaryl (L3):..wherein:X1is O or S; preferably X1is O; each Z is independently selected from N, NR11, S, O, C, CR12, C(O), and C(S), wherein at least one of Z is N, NR11, S, or O;R11is H, Ci-4-alkyl, C3-6-cycloalkyl, or Ci-4-haloalkyl;R12is H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; represents a single or double bond, depending on Z;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2;Ar2is a 5- to 10- membered, mono- or bicyclo-, aryl or heteroaryl group, optionally substituted by one or more substituent selected preferably from halo, cyano, oxo, hydroxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino, N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino, Ci-4-alkoxy, Ci-4-haloalkoxy, C3-6-cycloalkyloxy, (Ci-4-alkyl)aminocarbonyl,(Ci-4-haloalkyl)aminocarbonyl, di(Ci-4-alkyl)aminocarbonyl, di(Ci-4-haloalkyl)aminocarbonyl, N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)aminocarbonyl, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, Ce-io-aryl, heteroaryl, and heterocyclyl; wherein the substituents are optionally substituted by one or more group selected preferably from halo, cyano, oxo, hydroxy, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, Ci-4-alkoxy, Ci-4-haloalkoxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino, N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group optionally substituted by one or more halo.n, m, R3

[0044] According to one embodiment, the compounds of formula (I) comprise a piperidine group, i.e. n is 1. According to another embodiment, the compounds of formula (I) comprise an azepane group, i.e. n is 2. According to a preferred embodiment, n is 1.

[0045] According to one embodiment, m is preferably 0, 1 or 2. According to a preferred embodiment, m is 0.

[0046] According to one embodiment, when present, R3is selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and oxo; preferably R3is Ci-2-alkyl or halo; more preferably R3is methyl or F.

[0047] According to another embodiment, m is at least equal to 2 and two R3groups are linked together. When the two R3groups are present on the same carbon atom, they can form a spiro-fused cycloalkyl with the carbon atom to which they are attached. When the two R3groups are present on two adjacent carbon atoms, they can form a fused cycloalkyl with the carbon atoms to which they are attached. When the two R3groups are present on two non-adjacent carbon atoms, they can form an alkyl bridge on the piperidine or azepane group to which they are attached.NR'R2

[0048] According to one embodiment, R1is C2-i2-alkyl, C2-i2-haloalkyl, C3-8-cycloalkyl-Ci-3-alkyl, heterocyclyl-Ci-3-alkyl, C3-8-cycloalkyl, or heterocyclyl; in which the cycloalkyl and heterocyclyl moieties are optionally substituted by one of more substituents selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl and heterocyclyl moieties are optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy;and / or the cycloalkyl and heterocyclyl moieties are optionally bridged ring systems.

[0049] In above definition of R1, the expressions “zzz which the cycloalkyl and heterocyclyl moieties are optionally..." refer both to the groups as such, i.e. C3-8-cycloalkyl and heterocyclyl, and also to the moieties being part of a composed group, i.e. the cycloalkyl or heterocyclyl groups in the C3-8-cycloalkyl-Ci-3-alkyl or heterocyclyl-C i-3 -alkyl groups.

[0050] In a preferred embodiment, R1is a C3-8-cycloalkyl-C 1-3 -alkyl (preferably a C3-4-cycloalkyl-Ci -alkyl); in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Cn 4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl moiety is optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl moiety is optionally a bridged ring system.

[0051] In a more preferred embodiment, R1is a C3-8-cycloalkyl-C 1-3 -alkyl (preferably a C3-4-cycloalkyl-Ci -alkyl); in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from Ci-4-alkyl, and halo; and / or the cycloalkyl moiety is optionally a bridged ring system.

[0052] According to one embodiment, R2is H, or a Ci-4-alkyl, optionally substituted by one or more substituent selected from halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy, or a C3-6-cycloalkyl.

[0053] In a preferred embodiment, R2is H or methyl.

[0054] In a more preferred embodiment, R2is H.

[0055] In a preferred embodiment, R2is H or methyl (preferably H), and R1is a C3-8- cycloalkyl-C 1-3 -alkyl (preferably a C3-4-cycloalkyl-Ci -alkyl); in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Cn 4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl moiety is optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl moiety is optionally a bridged ring system.

[0056] In a more preferred embodiment, R2is H, and R1is a C3-8-cycloalkyl-C 1-3 -alkyl (preferably a C3-4-cycloalkyl-Ci-alkyl), in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from Ci-4-alkyl, and halo; and / or the cycloalkyl moiety is optionally a bridged ring system.

[0057] According to another embodiment, R1and R2form together with the nitrogen atom to which they are attached a heterocyclic ring, wherein the heterocyclic ring is optionally substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the heterocyclic ring is optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the heterocyclyl ring is optionally a bridged ring system.

[0058] When R1and R2form together with the nitrogen atom to which they are attached a heterocyclic ring, this heterocyclic ring may comprise one or more supplementary heteroatom selected from nitrogen, oxygen and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.

[0059] According to one embodiment, NR'R2is selected from:wherein < represents the point of attachment to the rest of the compound.5

[0060] According to one embodiment, NR'R2is preferably selected from:wherein < represents the point of attachment to the rest of the compound.

[0061] According to one embodiment, NR'R2is more preferable selected from:wherein < represents the point of attachment to the rest of the compound.R4, R5

[0062] According to one embodiment, R4and R5are each independently H, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, halo, cyano or hydroxy; preferably R4and R5are each independently H, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl; more preferably R4and R5are each independently H, methyl, ethyl, CF3, cyclopropyl. In a preferred embodiment, R4and R5are each independently H or Ci-4-alkyl; more preferably R4and R5are each independently H or methyl. In a more preferred embodiment, R4and R5are both H, or one is H and the other is methyl.

[0063] According to another embodiment, R4and R5form together with the carbon atom to which they are attached: a heterocyclyl ring or a C3-4-cycloalkyl ring, in which the heterocyclyl and cycloalkyl moieties are optionally substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, or cyano; or an ethylenyl group.

[0064] In a preferred embodiment, R4and R5form together with the carbon atom to which they are attached a group selected from oxetane, cyclopropyl, cyclobutyl optionally substituted by one or two halo substituents (preferably fluoro), azetidine optionally substituted by Ci-4-alkyl (preferably methyl), and ethylenyl. In a more preferred embodiment, R4and R5form together with the carbon atom to which they are attached a group selected from oxetane, cyclopropyl, and ethylenyl. In an even more preferred embodiment, R4and R5form together with the carbon atom to which they are attached an oxetane group.

[0065] In a preferred embodiment, R4and R5are each independently H or Ci-4-alkyl; or R4and R5form together with the carbon atom to which they are attached a heterocyclyl ring. In a more preferred embodiment, R4and R5are both H; or one is H and the other is methyl; or R4and R5form together with the carbon atom to which they are attached an oxetane group.Linker L

[0066] According to one embodiment, L is selected from amide or thioamide (L1), retro- amide or retro-thioamide (L2) and 5-membered heteroaryl (L3) as defined hereinabove.

[0067] According to one embodiment, L is an amide link (Lla), corresponding to L1wherein X1is O:wherein:• represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2.

[0068] According to one embodiment, L is a retro-amide link (L2a), corresponding to L2wherein X1is O:wherein:• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.

[0069] According to one embodiment, L is a 5-membered heteroaryl link (L3):wherein: each Z is independently selected from N, NR11, S, O, C, CR12, C(O), and C(S), wherein at least one of Z is N, NR11, S, or O;R11is H, Ci-4-alkyl, C3-6-cycloalkyl, or Ci-4-haloalkyl;R12is H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; represents a single or double bond, depending on Z;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.

[0070] In a preferred embodiment, L is a 5-membered heteroaryl link (L3):wherein:each Z is independently selected from N, NR11, S, C, and CR12, wherein at least one of Z is N, NR11, or S;R11is H, Ci-4-alkyl, C3-6-cycloalkyl, or Ci-4-haloalkyl; preferably R11is H or methyl; more preferably R11is H; R12is H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy,Ci-4-alkoxy, or Ci-4-haloalkoxy; preferably R12is H, methyl, halo, cyano or methoxy; more preferably R12is H; represents a single or double bond, depending on Z;• represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2.

[0071] According to one embodiment, L3is selected from:wherein: each R11is independently H, Ci-4-alkyl, C3-6-cycloalkyl, or Ci-4-haloalkyl; preferably R11is H or methyl; more preferably R11is H;each R12is independently H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; preferably R12is H, methyl, halo, cyano or methoxy; more preferably R12is H;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.

[0072] According to one embodiment, L3is preferably selected from:wherein: each R12 is independently H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; preferably R12is H, methyl, halo, cyano or methoxy; more preferably R12is H;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.

[0073] According to one preferred embodiment, L3is selected from:wherein:• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.

[0074] According to one more preferred embodiment, L3is selected from:wherein:• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.

[0075] According to one embodiment, L is selected from:wherein: each R11is independently H, Ci-4-alkyl, C3-6-cycloalkyl, or Ci-4-haloalkyl; preferably R11is H or methyl; more preferably R11is H; each R12is independently H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; preferably R12is H, methyl, halo, cyano or methoxy; more preferably R12is H;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.

[0076] According to one embodiment, L is preferably selected from:wherein: each R11is independently H, Ci-4-alkyl, C3-6-cycloalkyl, or Ci-4-haloalkyl; preferably R11is H or methyl; more preferably R11is H; each R12is independently H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; preferably R12is H, methyl, halo, cyano or methoxy; more preferably R12is H;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.

[0077] According to one embodiment, L is more preferably selected from:wherein: each R12is independently H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; preferably R12is H, methyl, halo, cyano or methoxy; more preferably R12is H;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.

[0078] According to one embodiment, L is even more preferably selected from:wherein:• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.Ar2

[0079] In the compounds of the invention, Ar2is a 5- to 10- membered, mono- or bicyclo-, aryl or heteroaryl group, optionally substituted by one or more substituent selected preferably from halo, cyano, oxo, hydroxy, amino, Ci-4-alkylamino, C i -4-haloalkylamino , di(C i -4-alkyl) amino , di(C i -4-haloalkyl)amino ,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino, Ci-4-alkoxy, Ci-4-haloalkoxy,C3-6-cycloalkyloxy, (Ci-4-alkyl)aminocarbonyl, (Ci-4-haloalkyl)aminocarbonyl, di(Ci-4-alkyl)aminocarbonyl, di(Ci-4-haloalkyl)aminocarbonyl,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)aminocarbonyl, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, Ce-io-aryl, heteroaryl, and heterocyclyl; wherein the substituents are optionally substituted by one or more group selected preferably from halo, cyano, oxo, hydroxy, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, Ci-4-alkoxy, Ci-4-haloalkoxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino, N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group optionally substituted by one or more halo.

[0080] According to one embodiment, Ar2is selected from:wherein R13, R14, R15, R16, R17, R18, R19, R20, and R21, are each independently selected from H, halo, cyano, oxo, hydroxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino, Ci-4-alkoxy, Ci-4-haloalkoxy, C3-6-cycloalkyloxy, (Ci-4-alkyl)aminocarbonyl, (Ci-4-haloalkyl)aminocarbonyl, di(Ci-4-alkyl)aminocarbonyl, di(Ci-4-haloalkyl)aminocarbonyl,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)aminocarbonyl, Ci-4-alkyl, Ci-4-haloalkyl,C3-6-cycloalkyl, Ci-4-alkynyl, Ce-io-aryl, heteroaryl, andheterocyclyl; wherein these substituents are optionally substituted by one or more group selected preferablyfrom halo, cyano, oxo, hydroxy, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, Ci-4-alkoxy, C 1-4 -haloalkoxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group optionally substituted by one or more halo; and represents the point of attachment to the rest of the compound.

[0081] In one embodiment, R13, R14, R15, R16, R17, R18, R19, R20, and R21, are preferably each independently selected from H, F, Cl, Br, cyano, hydroxy, methylamino, isopropylamino, 2-hydroxy ethylamino, dimethylamino, N-methyl-N-ethylamino, N- methyl-N-(2,2,2-trifluoroethyl)amino, N-methyl-N-(trifhioromethyl)amino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclobutoxy, methyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, 1-propynyl, pyrazolyl, imidazolyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 3-methyl-2-oxoimidazolidin-l-yl, 2-oxopyrrolidin-l-yl, 4- methylpiperazin-l-yl, 2-methylpyrrolidin-l-yl, 3-methylazetidin-l-yl, 3,3- difluoroazetidin-l-yl, 3 -methoxy azetidin-l-yl, 3-(difluoromethyl)azetidin-l-yl, 3,3- dimethylpyrrolidin-l-yl, 3,3-difhroropyrrolidin-l-yl, 3-methylpyrrolidin-l-yl, 3- fluoropyrrolidin-l-yl, azabicyclo[3.1.0]hexan-3-yl, 2-oxa-6-azaspiro[3.3]heptan-2-yl, 2- azaspiro[3.3]heptan-2-yl, 5-azaspiro[2.3]hexan-5-yl, l,l-difluoro-5-azaspiro[2.3]hexan- 5-yl, and 5-azaspiro[2.4]heptan-5-yl.

[0082] According to one embodiment, Ar2is preferably selected from:wherein R13, R14, R15, R17, R18, R19, R20, and R21, are each independently selected from H, halo, cyano, oxo, hydroxy, amino, Ci-4-alkylamino, C 1 -4-haloalkylamino , di(C 1 -4-alkyl) amino , di(C 1 -4-haloalkyl)amino ,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino, Ci-4-alkoxy, Ci-4-haloalkoxy, C3-6-cycloalkyloxy, (Ci-4-alkyl)aminocarbonyl, (Ci-4-haloalkyl)aminocarbonyl, di(Ci-4-alkyl)aminocarbonyl, di(Ci-4-haloalkyl)aminocarbonyl,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)aminocarbonyl, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, Ce-io-aryl, heteroaryl, andheterocyclyl; wherein these substituents are optionally substituted by one or more group selected preferably from halo, cyano, oxo, hydroxy, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, Ci-4-alkoxy, C 1-4 -haloalkoxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group optionally substituted by one or more halo; preferably R13, R14, R15, R17, R18, R19, R20, and R21, are each independently selected from H, di(Ci-4-alkyl)amino, C3-6-cycloalkyl, and heterocyclyl; wherein these substituents are optionally substituted by one or more group selected from halo, Ci-4-alkyl, Ci-4-alkoxy; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl group optionally substituted by one or more halo; and represents the point of attachment to the rest of the compound.

[0083] In one embodiment, R13, R14, R15, R17, R18, R19, R20, and R21, are more preferably each independently selected from H, dimethylamino, N-methyl-N-ethylamino, cyclopropyl, pyrrolidinyl, 3-methylazetidin-l-yl, 3 -methoxy azetidin-l-yl,3,3-difluoropyrrolidin- 1 -yl, 3-methylpyrrolidin- 1 -yl, 3-fluoropyrrolidin- 1 -yl, azabicyclo[3.1.0]hexan-3-yl, 5-azaspiro[2.3]hexan-5-yl, 5-azaspiro[2.4]heptan-5-yl, and 1 , 1 -difluoro- 5 - azaspiro [2.3 ]hexan- 5 -yl .

[0084] According to one embodiment, Ar2is selected from:wherein < represents the point of attachment to the rest of the compound.

[0085] According to one embodiment, Ar2is preferably selected from:wherein < represents the point of attachment to the rest of the compound.Subformulae

[0086] In one embodiment, the compounds of the invention are of formula (la) or (la’):or pharmaceutically acceptable salts and / or solvates thereof, wherein m, R1, R2, R3, R4, R5, L, Ar1and Ar2are as defined herein.

[0087] In one preferred embodiment, the compounds of the invention are of formula (lb) or (lb’):or pharmaceutically acceptable salts and / or solvates thereof, wherein R1, R2, R4, R5, L, Ar1and Ar2are as defined herein.

[0088] In a preferred embodiment, the compounds of the invention are of formula (la), (la’), (lb) or (lb’), or a pharmaceutically acceptable salt and / or solvate thereof, wherein:Ar1, and when m and R3are present, are as defined above with regard for formula (I),R1is a C3-8-cycloalkyl-Ci-3-alkyl, preferably a C3-4-cycloalkyl-Ci-alkyl; in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl moiety is optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one ormore substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl moiety is optionally a bridged ring systemR2is H or methyl, preferably H;R4and R5are each independently H or Ci-4-alkyl; or R4and R5form together with the carbon atom to which they are attached a heterocyclyl ring;L is selected from (L2) and 5-membered heteroaryl (L3):(L2) (L3) wherein:X1is O or S; preferably X1is O; each Z is independently selected from N, NR11, S, C, and CR12, wherein at least one of Z is N, NR11, or S;R11is H, Ci-4-alkyl, C3-6-cycloalkyl, or Ci-4-haloalkyl; preferably R11is H or methyl; more preferably R11is H;R12is H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; preferably R12is H, methyl, halo, cyano or methoxy; more preferably R12is H; represents a single or double bond, depending on Z;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2;Ar2is a 5- to 10- membered, mono- or bicyclo-, aryl or heteroaryl group, optionally substituted by one or more substituent selected preferably from halo, cyano, oxo, hydroxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino, N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino, Ci-4-alkoxy, Ci-4-haloalkoxy, C3-6-cycloalkyloxy, (Ci-4-alkyl)aminocarbonyl,(Ci-4-haloalkyl)aminocarbonyl, di(Ci-4-alkyl)aminocarbonyl,di(Ci-4-haloalkyl)aminocarbonyl, N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)aminocarbonyl, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, Ce-io-aryl, heteroaryl, and heterocyclyl; wherein the substituents are optionally substituted by one or more group selected preferably from halo, cyano, oxo, hydroxy, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, Ci-4-alkoxy, Ci-4-haloalkoxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino, N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group optionally substituted by one or more halo.

[0089] In a more preferred embodiment, the compounds of the invention are of formula (la), (la’), (lb) or (lb’), or a pharmaceutically acceptable salt and / or solvate thereof, wherein:Ar1, and when m and R3are present, are as defined above with regard for formula (I),R1is a C3-8-cycloalkyl-Ci-3-alkyl, preferably a C3-4-cycloalkyl-Ci-alkyl; in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl moiety is optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl moiety is optionally a bridged ring systemR2is H or methyl, preferably H;R4and R5are each independently H or Ci-4-alkyl; or R4and R5form together with the carbon atom to which they are attached a heterocyclyl ring;L is selected from (L2) and 5-membered heteroaryl (L3):(L2) (L3) wherein:X1is O or S; preferably X1is O; each Z is independently selected from N, NR11, S, C, and CR12, wherein at least one of Z is N, NR11, or S;R11is H, Ci-4-alkyl, C3-6-cycloalkyl, or Ci-4-haloalkyl; preferably R11is H or methyl; more preferably R11is H;R12is H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; preferably R12is H, methyl, halo, cyano or methoxy; more preferably R12is H; represents a single or double bond, depending on Z;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2;Ar2is selected from:wherein R13, R14, R15, R17, R18, R19, R20, and R21, are each independently selected from H, halo, cyano, oxo, hydroxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino, N-(C 1 -4-alkyl) -N- (C 1 -4-haloalkyl) amino , Ci-4-alkoxy, C 1-4 -haloalkoxy, C3-6-cycloalkyloxy, (Ci-4-alkyl)aminocarbonyl, (Ci-4-haloalkyl)aminocarbonyl, di(Ci-4-alkyl)aminocarbonyl, di(Ci-4-haloalkyl)aminocarbonyl, N-(Ci-4-alkyl)-N-(Ci-4- haloalkyl)aminocarbonyl, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, Ce-io-aryl, heteroaryl, and heterocyclyl; wherein these substituents are optionally substituted by one or more group selected preferablyfrom halo, cyano, oxo, hydroxy, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, Ci-4-alkoxy, Ci-4-haloalkoxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino, N-(Ci-4-alkyl)-N-(Ci-4- haloalkyl)amino; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group optionally substituted by one or more halo; preferably R13, R14, R15, R17, R18, R19, R20, and R21, are each independently selected from H, di(Ci-4-alkyl)amino, C3-6-cycloalkyl, and heterocyclyl; wherein these substituents are optionally substituted by one or more group selected from halo, Ci-4-alkyl, Ci-4-alkoxy; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl group optionally substituted by one or more halo; andrepresents the point of attachment to the rest of the compound.

[0090] In an even more preferred embodiment, the compounds of the invention are of formula (la), (la’), (lb) or (lb’), or a pharmaceutically acceptable salt and / or solvate thereof, wherein:Ar1is a 6-membered aryl or 6-membered heteroaryl group selected from:wherein * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety;NR'R2is selected from:R4and R5are both H; or one is H and the other is methyl; or R4and R5form together with the carbon atom to which they are attached an oxetane group;L is selected from:wherein:• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2; andwherein < represents the point of attachment to the rest of the compound.

[0091] In one embodiment, the compounds of the invention are of formula (Ic): or (Ic’):or pharmaceutically acceptable salts and / or solvates thereof, wherein R1, R2, R4, R5, Ar1and Ar2are as defined herein.

[0092] In one embodiment, the compounds of the invention are of formula (Id): or (Id’):or pharmaceutically acceptable salts and / or solvates thereof, wherein R1, R2, R4, R5, L3, Ar1and Ar2are as defined herein.

[0093] In one embodiment, in formula (Id) or (Id’), L3is preferably selected from:wherein • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2.

[0094] In one embodiment, in formula (Id) or (Id’), L3is more preferably selected from:wherein • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2.

[0095] Unless otherwise specified, when it is referred to formula (I), it also encompasses any of above subformulae thereof.

[0096] According to one embodiment, the compound according to the invention is selected from those listed in Table 1: Table 1and stereoisomers thereof, and pharmaceutically acceptable salts and / or solvates thereof.

[0097] The compounds of Table 1 were named using ChemDraw 21® purchased from CambridgeSoft (Cambridge, MA, USA).

[0098] In one particular embodiment, the compound of formula (I) is selected from compounds 142, 148, 207, 223, 239, 256, 301, 309, 340, and 352, as defined in Table 1, and stereoisomers thereof, and pharmaceutically acceptable salts and / or solvates thereof.

[0099] All references to compounds of formula (I) include references to salts, solvates, multi-component complexes and / or liquid crystals thereof. All references to compounds of formula (I) include references to polymorphs and / or crystal habits thereof. All references to compounds of formula (I) include references to pharmaceutically acceptable prodrugs thereof.

[0100] The compounds of formula (I), subformulae thereof, and compounds of Table 1, contain at least one asymmetric centre(s) and thus may exist as different stereoisomeric forms. Accordingly, all references to compounds of formula (I), sub formulae thereof, and compounds of Table 1, include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art.

[0101] Bonds from an asymmetric carbon in compounds are generally depicted using a solid line ( ), a solid wedge (— -^«), or a dotted wedge ( m).The use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included. The use of a solid line to depict bonds from an asymmetric carbon atom is meant to indicate that all possible stereoisomers are meant to be included, unless it is clear from the context that a specific stereoisomer is intended.

[0102] All references to compounds of formula (I) include references to isotopically-labelled compounds of formula (I), including deuterated compounds of formula (I).

[0103] The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

[0104] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, ammonium, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, bitartrate / tartrate, borate, bromide, calcium edetate, camsylate, chloride, citrate, clavulanate, cyclamate, dihydrochloride, edetate, edisylate, estolate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hibenzate, hydrochloride / chloride, hydrabamine, hydrobromide / bromide, hydroiodide / iodide, hydroxynaphthoate, isethionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, methylbromide, N-methylglucamine, methylnitrate, methylsulphate, mucate, naphthylate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate, pantothenate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, pyroglutamate, saccharate, salicylate, stearate, succinate, sulfate, subacetate, tannate, teoclate, tosylate, triethiodide, trifluoroacetate, valerate, and xinofoate salts.

[0105] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, ammonia, arginine, benzathine, N-benzylphenethylamine, calcium, choline, chloroprocaine, N,N -dibenzylethylenediamine, diethanolamine, diethylamine, 2-(diethylamino)ethanol, diolamine, ethylenediamine, ethanolamine, glycine, 4-(2-hydroxyethyl)morpholine, lithium, lysine, magnesium, meglumine, N- methyl-glutamine, morpholine, olamine, ornithine, potassium, piperazine, procaine, sodium, tetramethylammonium hydroxide, tris(hydroxymethyl)aminomethane, tromethamine and zinc salts.

[0106] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

[0107] When the compounds of formula (I) contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compoundsare within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g., NH), the invention also covers salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.

[0108] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of these methods:(i) by reacting the compound of formula (I) with the desired acid;(ii) by reacting the compound of formula (I) with the desired base;(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and / or(iv) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

[0109] All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0110] Although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and / or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of formula (I) above.

[0111] The compound of formula (I) can be synthesized by methods known in the art. Especially, the compound of invention can be synthesized by the methods detailed in PCT / EP2024 / 051219.Carcinomas

[0112] Compounds of formula (I) and pharmaceutical compositions containing the same described herein are useful in the treatment of carcinomas in a subject in need thereof.

[0113] In one embodiment, the present invention thus provides a compound of formula (I) as herein defined or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of a carcinoma in a subject in need thereof.

[0114] Also provided is a method for treating a carcinoma in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) as herein defined or a pharmaceutically acceptable salt and / or solvate thereof. Further provided is the use of a compound of formula (I) as herein defined or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment of a carcinoma in a subject in need thereof or for use in a method of treating a carcinoma in a subject in need thereof. Further provided is a pharmaceutical composition for use in the treatment of a carcinoma in a subject in need thereof, said pharmaceutical composition comprising a compound of formula (I) as herein defined or a pharmaceutically acceptable salt and / or solvate thereof and optionally at least one pharmaceutically acceptable carrier.

[0115] The embodiments detailed hereafter with regard to carcinomas are to be read in combination with any of the embodiments detailed above with regards to compounds of formula (I).

[0116] “Carcinoma” refers to a cancer that starts in epithelial tissues. Methods for identifying, detecting, or characterizing a carcinoma are well known in the art.

[0117] Carcinomas include, without being limited to, several subtypes: adenocarcinoma, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), ductal carcinoma in situ (DCIS), invasive (infiltrating) ductal carcinoma (IDC), and transitional cell carcinoma (TCC).

[0118] Adenocarcinoma starts in the glands that line the organs (glandular epithelial cells). Glandular epithelial cells secrete fluids, like mucus and digestive juices. Examples of adenocarcinomas include prostate adenocarcinoma, breast adenocarcinoma, colorectal adenocarcinoma, pancreatic adenocarcinoma, non-small cell lung adenocarcinoma, renal cell carcinoma (RCC) (also referred to as hypernephroma or renal cell carcinoma), hepatocellular carcinoma (HCC).

[0119] Basal cell carcinoma (BCC) starts in the basal cell layer of the epidermis. The cells of the epidermis constantly divide to form new cells to replace the squamous cells that wear off the skin’s surface. Examples of basal cell carcinoma include skin basal cell carcinoma.

[0120] Squamous cell carcinoma (SCC) usually refers to cutaneous squamous cell carcinoma (cSCC). These carcinomas develop from cells of the middle and outer layer of epidermis, particularly exposed to solar radiation. Squamous cells carcinoma can also form in mucosa in the head and neck region or in the lung. Head and neck squamous cells carcinoma (HNSCC) can form in the pharyngeal, laryngeal and esophageal mucosa. Examples of squamous cell carcinoma include cutaneous squamous cell carcinoma (cSCC), head and neck squamous cell carcinoma (HNSCC), and non-small cell lung squamous cell carcinoma.

[0121] Ductal carcinoma in situ (DOS) starts in the breast milk ducts. Being "in situ" means that the carcinoma hasn't spread to cells outside the milk ducts. DOS is considered noninvasive or pre-invasive breast cancer.

[0122] Invasive (infiltrating) ductal carcinoma (IDC) starts in the breast milk ducts, like DCIS. Unlike DCIS, invasive ductal carcinoma has spread to nearby tissue. Untreated, it has the potential of spreading to other parts of the body via the lymphatic system and bloodstream.

[0123] Transitional cell carcinoma (TCC) starts in transitional cells. Transitional cells are a type of cell that lines the inside of the renal pelvis, ureters, and other organs. TCC develop in different sites of the upper urinary tract (renal pelvis, bladder, ureter).

[0124] In one embodiment, the carcinoma is thus selected from adenocarcinomas, basal cell carcinomas (BCC), squamous cell carcinomas (SCC), ductal carcinomas in situ (DCIS), invasive (infiltrating) ductal carcinomas, (IDC) and transitional cell carcinoma (TCC).

[0125] In one specific embodiment, the carcinoma is selected from adenocarcinomas, and squamous cell carcinomas (SCC).

[0126] In one embodiment, the carcinoma is thus selected from adenocarcinomas such as prostate adenocarcinoma, breast adenocarcinoma, colorectal adenocarcinoma, pancreatic adenocarcinoma, non-small cell lung adenocarcinoma, renal cell carcinoma (RCC), and hepatocellular carcinoma (HCC); basal cell carcinomas (BCC) such as skin basal cell carcinoma; squamous cell carcinomas (SCC) such as cutaneous squamous cell carcinoma (cSCC), head and neck squamous cell carcinoma (HNSCC), and non-small cell lung squamous cell carcinoma; ductal carcinomas in situ (DCIS); invasive (infiltrating) ductal carcinomas (IDC); and transitional cell carcinoma (TCC).

[0127] The carcinomas can in addition be defined by the organ where they appear: lung carcinoma, non-small cell lung carcinoma, breast carcinoma, triple negative breast carcinoma, oral carcinoma, esophageal carcinoma, hypopharyngeal carcinoma, head and neck carcinoma, stomach carcinoma, small intestine carcinoma, large intestine carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, cholangiocarcinoma, hepatoma (also called hepatocellular carcinoma (HCC)), thymoma, cervical carcinoma, endometrial carcinoma, bladder carcinoma, pancreatic carcinoma, prostate carcinoma, renal carcinoma, testicular carcinoma, thyroid carcinoma and cutaneous carcinoma.

[0128] Thus, in one embodiment, the carcinoma is selected from lung carcinoma, non- small cell lung carcinoma, breast carcinoma, triple negative breast carcinoma, oral carcinoma, esophageal carcinoma, hypopharyngeal carcinoma, head and neck carcinoma, stomach carcinoma, small intestine carcinoma, large intestine carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, cholangiocarcinoma, hepatoma (also called hepatocellular carcinoma (HCC)), thymoma, cervical carcinoma, endometrialcarcinoma, bladder carcinoma, pancreatic carcinoma, prostate carcinoma, renal carcinoma, testicular carcinoma, thyroid carcinoma and cutaneous carcinoma. In one embodiment, the carcinoma is selected from lung carcinoma, breast carcinoma, oral carcinoma, esophageal carcinoma, hypopharyngeal carcinoma, stomach carcinoma, small intestine carcinoma, large intestine carcinoma, colon carcinoma, colorectal carcinoma, hepatoma (also called hepatocellular carcinoma (HCC)), thymoma, cervical carcinoma, endometrial carcinoma, bladder carcinoma, pancreatic carcinoma, prostate carcinoma, renal carcinoma, thyroid carcinoma and cutaneous carcinoma.

[0129] In a preferred embodiment, the carcinoma is selected from lung carcinoma, breast carcinoma, hypopharyngeal carcinoma, colorectal carcinoma, hepatoma (also called hepatocellular carcinoma (HCC)), bladder carcinoma, pancreatic carcinoma, and prostate carcinoma.

[0130] In a more preferred embodiment, the carcinoma is selected from lung carcinoma, breast carcinoma, hypopharyngeal carcinoma, colorectal carcinoma, hepatoma (also called hepatocellular carcinoma (HCC)), and pancreatic carcinoma.

[0131] In a particular embodiment, the carcinoma is not an ovarian carcinoma. In a particular embodiment, the carcinoma is not an ovarian adenocarcinoma.

[0132] Subjects to be treated according to the methods described herein include mammals and preferably humans. In one embodiment, the subject is a human. In a preferred embodiment, the subject is a human patient. In one embodiment, the subject is diagnosed with a carcinoma.

[0133] According to one embodiment, the compound of the invention is to be administrated to the subject as sole therapeutic agent.

[0134] According to another embodiment, the compound of the invention is to be administrated to the subject in combination with at least another therapeutic agent. In one embodiment, the other therapeutic agent may be selected from a second anti-cancer therapy, such as chemotherapy, immunotherapy, cell therapy and / or any anti-cancer agent currently in clinical use or in clinical trials.

[0135] According to one embodiment, the compound according to the invention may be administered in combination with conventional surgery, radiotherapy, or transplantation, and / or with at least another therapeutic agent as mentioned above.

[0136] Such conjoint treatments may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment. Such combination products employ the compounds of the invention within the dosage range described herein and the other therapeutic agent within its approved dosage range.

[0137] In the context of the present invention the term “combination” preferably means a combined occurrence of the compound according to the invention and an additional therapeutic agent. Therefore, the combination may occur either as one composition, comprising all the components in one and the same mixture (e.g. a pharmaceutical composition), or may occur as a kit of parts, wherein the different components form different parts of such a kit of parts. The administration of the compound according to the invention and of the additional therapeutic agent may occur either simultaneously or timely staggered, with similar or different timing of administration (i.e. similar or different numbers of administration of each component), either at the same site of administration or at different sites of administration, under similar of different dosage forms.Pharmaceutical compositions and dosage forms

[0138] In all the uses according to the invention detailed herein, the compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracerebroventricular, intracistemal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

[0139] In one embodiment, the compound is preferably administered within a pharmaceutical composition. The pharmaceutical composition comprises a compound offormula (I) as herein defined or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be any such excipient known in the art, including those described in, for example, Remington’s Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).

[0140] The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active ingredient is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0141] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents,for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0142] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0143] The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0144] For topical use, creams, ointments, jellies, solutions, or suspensions, etc., containing the compounds of the present invention are employed.

[0145] In the treatment or prevention of carcinomas, an appropriate dosage level will generally be about 0.01 to 250 mg per kg patient body weight per day (mg / kg per day) which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 100 mg / kg per day, such as between 0.1 and 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered as a single daily dose, divided over one or more daily doses, for example on a regimen of 1 to 4 times per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0146] According to one embodiment, the pharmaceutical composition or dosage form comprises the compound according to the invention as sole therapeutic agent. According to another embodiment, the pharmaceutical composition or dosage form further comprises at least another therapeutic agent, preferably a therapeutic agent usually applied in the treatment of the targeted pathological condition.BRIEF DESCRIPTION OF THE DRAWINGS

[0147] Figures 1A and IB are graphs showing the efficacy evaluation of Compound 142* against established subcutaneous FaDu human hypopharyngeal squamous cell carcinoma in female NSG mice. Daily, intra-peritoneal dosing beginning on day 5 post-implant until day 24 in surviving mice; Compound 142* (30 mg / kg) versus vehicle-treated control. Figure 1A: Tumor growth evaluated by caliper measurement over time. Figure IB: Survival Plot over time.

[0148] Figure 2 is a graph showing the efficacy evaluation of Compound 142* against established orthotopic A549-Luc-C8 human non-small cell lung adenocarcinoma infemale C.B-17 SCID mice. Daily, intra-peritoneal dosing beginning on day 16 postimplant until day 66 in surviving mice; Compound 142* (30 mg / kg) versus vehicle-treated control. Survival plot over time.EXAMPLES

[0149] The present invention is further illustrated by the following examples.

[0150] The compounds of formula (I) used in the examples were synthesized as described in PCT / EP2024 / 051219.Example 1: Cell viability assayPurpose

[0151] The sensitivity of various carcinoma cells lines to compounds of formula (I) according to the present invention was evaluated.

[0152] The tested cell lines are:Calu-6 cell line: lung adenocarcinoma;A549 cell line: lung adenocarcinoma;Fadu cell line: squamous cell carcinoma;HCT-116 cell line: colorectal carcinoma;HepG2 cell line: hepatocellular carcinoma;MDA-MB-231 cell line: breast adenocarcinoma;PANC-1 cell line: pancreatic carcinoma;5637 cell line: urinary bladder carcinoma;DU 145 cell line: prostate carcinoma;PC-3 cell line: prostatic adenocarcinoma;MCF7 cell line: breast adenocarcinoma;HT-29 cell line: colorectal adenocarcinoma;LS174T cell line: colorectal adenocarcinoma.MethodsCalu-6 cell line

[0153] Calu-6 cell line was purchased from ATCC (ATCC® HTB-56™). Calu-6 cell line has been established from the pleural effusion of a 61 -year-old woman with pulmonary anaplastic adenocarcinoma. Calu-6 is a cell line exhibiting epithelial morphology.

[0154] Calu-6 cells are cultured in EMEM (ATCC 30-2003) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106). The cells are seeded at 5E+4cell / cm2within the recommended subcultivation ratio of 1:3 to 1:6, as stated on the certificate of analysis issued by the provider of the cells.

[0155] Cellular viability assay: Calu-6 cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 7500 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (EMEM, 10% FBS). Then 50 pl of test compound were added to Calu-6 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe- Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentration-response profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.A549 cell line

[0156] A549 cell line was purchased from ATCC (ATCC® CCL-185™). Cells were isolated from the lung tissue of a White, 58-year-old male with lung adenocarcinoma.

[0157] A549 cells are cultured in F-12K (Gibco 21127-022) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106). The cells are seeded at 6E+3 cell / cm2. The culture is maintained at a cell concentration between 6E+3 and 6E+4 cell / cm2 as recommended by the provider.

[0158] Cellular viability assay: A549 cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 7500 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (EMEM, 10% FBS). Then 50 pl of test compound were added to Calu-6 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe- Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentration-response profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellularFadu cell line

[0159] Fadu cell line was purchased from DSMZ, cat nb ACC 784. Cell line was established in 1968 from a punch biopsy of a hypopharyngeal tumor removed from a 56- year-old, White, male patient with squamous cell carcinoma.

[0160] Fadu cells are cultured in EMEM (ATCC 30-2003) containing 10% heat- inactivated and 0.22 p m filtered FBS (Gibco 10270-106). The cells are seeded at 8.6E+3cell / cm2 within the recommended subcultivation ratio of 1:10 to 1:20, as stated on the certificate of analysis issued by the provider of the cells.

[0161] Cellular viability assay: Fadu cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 10000 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (EMEM, 10% FBS). Then 50 pl of test compound were added to Calu-6 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe- Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentration-response profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.HCT-116 cell line

[0162] HCT-116 cell line was purchased from ATCC (ATCC® CCL-247™). HCT 116 cell line was isolated from the colon of an adult male with colorectal carcinoma. It has a mutation in codon 13 of the ras proto-oncogene. HCT-116 is a cell line exhibiting epithelial morphology.

[0163] HCT-116 cells are cultured in Me Coys (Gibco 26600-23) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106). The cells are seeded at 1.2E+4 viable cells / cm2within the recommended subcultivation ratio of 1:3 to 1:8 as stated bythe provider.

[0164] Cellular viability assay: HCT-116 cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 500 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (Me Coys, 10% FBS). Then 50 pl of test compound were added to HCT-116 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe-Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentration-response profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.HepG2 cell culture

[0165] HepG2 cell line was purchased from ATCC (ATCC® HB-80657™). HepG2 cell line was isolated from a hepatocellular carcinoma of a 15-year-old, White, male youth with liver cancer. HepG2 is a cell line exhibiting epithelial-like morphology.

[0166] HepG2 cells are cultured in DMEM (Gibco 41966-029) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106) and 1% L-Glutamine (2 mM). The cells are seeded at 6E+4 viable cells / cm2for 2 days or at 3E+4 for 3 days.

[0167] Cellular viability assay: HepG2 cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 5000 cells / well. The compounds of the invention were dissolved in DMSO, and a titrationcurve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (DMEM, 10% FBS 1% L-Glutamine). Then 50 pl of test compound were added to HepG2 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe-Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentrationresponse profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.MDA-MB-231 cell culture

[0168] MDA-MB-231 cell line was purchased from ATCC (ATCC® HTB-26™). MDA-MB-231 cell line was isolated from the mammary gland of a 40-year-old White female with adenocarcinoma. MDA-MB-231 is a cell line exhibiting epithelial-like morphology.

[0169] MDA-MB-231 cells are cultured in DMEM (ATCC 30-2002) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106). The cells are seeded at 1.3E+4 viable cells / cm2within the recommended subcultivation ratio of 1:2 to 1:4 as stated by the provider.

[0170] Cellular viability assay: MDA-MB-231 cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 7500 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (DMEM 10% FBS). Then 50 pl of test compound were added to MDA-MB-231 cells in a final DMSO concentration of 0.1%, final volume100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe-Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentrationresponse profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.PANC-1 cell culture

[0171] PANC-1 cell line was purchased from ATCC (ATCC® CRL-1469™). PANC-1 cell line was isolated from the pancreatic duct of a 56-year-old, White, male with epithelioid carcinoma. PANC-1 is a cell line exhibiting epithelial morphology.

[0172] PANC-1 cells are cultured in DMEM (ATCC 30-2002) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106). The cells are seeded at 1E+4 viable cells / cm2within the recommended subcultivation ratio of 1:2 to 1:4 as stated by the provider.

[0173] Cellular viability assay: PANC-1 cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 7500 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (DMEM 10% FBS). Then 50 pl of test compound were added to PANC-1 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe- Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-LiteOne Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentration-response profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability5637 cell culture

[0174] 5637 cell line was purchased from ATCC (ATCC® HTB-9™). 5637 is a cell line isolated from the urinary bladder of a 68-year-old, White male patient with grade II carcinoma. 5637 is a cell line exhibiting epithelial morphology.

[0175] 5637 cells are cultured in RPMI-1640 (ATCC 30-2001) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106). The cells are seeded at 1E+4 viable cells / cm2within the recommended subcultivation ratio of 1:4 to 1:8 as stated by the provider.

[0176] Cellular viability assay: 5637 cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 2500 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (RPMI-1640 10% FBS). Then 50 pl of test compound were added to 5637 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe- Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Eite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control andan IC50 was calculated based on the concentration-response profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.DU 145 cell culture

[0177] DU 145 cell line was purchased from ATCC (ATCC® HTB-81™). DU 145 cell line was isolated from the metastatic central nervous system lesion of a 69-year-old, White, male with prostate carcinoma. DU 145 is a cell line exhibiting epithelial morphology.

[0178] DU 145 cells are cultured in EMEM (ATCC 30-2003) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106). The cells are seeded at 1E+4 viable cells / cm2within the recommended subcultivation ratio of 1:4 to 1:6 as stated by the provider.

[0179] Cellular viability assay: DU 145 cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 1000 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (EMEM 10% FBS). Then 50 pl of test compound were added to DU 145 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe- Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentration-response profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.PC-3 cell culture

[0180] PC-3 cell line was purchased from ATCC (ATCC® CRL-1435™). PC-3 is a cell line initiated from a bone metastasis of a grade IV prostatic adenocarcinoma from a 62- year-old, White, male. PC-3 is a cell line exhibiting epithelial morphology.

[0181] PC3 cells are cultured in F12K (Gibco 21127-022) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106). The cells are seeded at 2E+4 viable cells / cm2within the recommended subcultivation ratio of 1:3 to 1:6 as stated by the provider.

[0182] Cellular viability assay: PC-3 cells were plated (50 pL) in 96- well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 1000 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (F12K 10% FBS). Then 50 pl of test compound were added to PC-3 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe-Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentration-response profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.MCF7 cell culture

[0183] MCF7 cell line was purchased from ATCC (ATCC® HTB-™). MCF7 is a cell line established from the pleural effusion from a 69-year-old female Caucasian sufferingfrom a breast adenocarcinoma. MCF7 is a cell line exhibiting epithelial morphology.

[0184] MCF7 cells are cultured in EMEM (ATCC 30-2003) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106) and O.Olmg / mL of human insulin (Sigma 19278). The cells are seeded at 5.7E+4 viable cells / cm2within the recommended subcultivation ratio of 1:3 to 1:6 as stated by the provider.

[0185] Cellular viability assay: MCF7 cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 5000 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (EMEM 10% FBS and O.Olmg / mL of human insulin). Then 50 pl of test compound were added to MCF7 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe-Easy sealing membrane, Sigma Z380059- 1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentrationresponse profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.HT-29 cell culture

[0186] HT-29 cell line was purchased from ATCC (ATCC® HTB-38™). HT-29 is a cell line isolated in 1964 from a primary tumor obtained from a 44-year-old, White, female patient with colorectal adenocarcinoma. HT-29 is a cell line exhibiting epithelial morphology.

[0187] HT-29 cells are cultured in Me Coys (Gibco 26600-23) containing 10% heat-inactivated and 0.22 m filtered FBS (Gibco 10270-106). The cells are seeded at 2.4E+4 viable cells / cm2within the recommended subcultivation ratio of 1:3 to 1:8 as stated by the provider.

[0188] Cellular viability assay: HT-29 cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 2500 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (Me Coys 10% FBS). Then 50 pl of test compound were added to HT-29 cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe- Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentration-response profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.LS174T cell culture

[0189] LS174T cell line was purchased from ATCC (ATCC® CL-188™). LS174T is a cell line isolated from the colon of a White, 58-year-old, female adenocarcinoma patient with colorectal cancer. LS174T is a cell line exhibiting epithelial morphology.

[0190] LS174T cells are cultured in EMEM (ATCC 30-2003) containing 10% heat- inactivated and 0.22 pm filtered FBS (Gibco 10270-106). The cells are seeded at 8E+4 viable cells / cm2within the recommended subcultivation ratio of 1:4 to 1:6 as stated by the provider.

[0191] Cellular viability assay: LS174T cells were plated (50 pL) in 96-well cell culture microplates (PS, F-Bottom white, Cellstar, Greiner 655083) at final concentration of 2500 cells / well. The compounds of the invention were dissolved in DMSO, and a titration curve was generated at 1000X final concentration. Compounds were then diluted 500X in tissue culture medium (EMEM 10% FBS). Then 50 pl of test compound were added to LS174T cells in a final DMSO concentration of 0.1%, final volume 100 pl. A gas permeable sealing membrane was applied to the plate to prevent evaporation (Breathe- Easy sealing membrane, Sigma Z380059-1PK) and cells were incubated for 72 h at 37°C, 5% CO2, 80%RH. After 72 h of treatment, the plates were taken out of the incubator and left for a few minutes at room temperature. 100 pl of the reconstituted reagent ATP-Lite One Step (Perkin Elmer, 6016739) were added to each well. The plates were shaken for 2 min at 700 rpm and placed in the dark for 10 minutes at room temperature before measurement of luminescence intensity with Envision instrument. The raw data were expressed in RLU. Results were expressed in % of viability relative to DMSO control and an IC50 was calculated based on the concentration-response profile of individual compounds. IC50 is the concentration of compound of the invention that induces 50% inhibition of cellular viability.Results

[0192] The IC50 of the compounds for the tested carcinoma cell lines are reported inTables 2, 3, 4a and 4b, with +++: IC50 < 200 nM, ++: 200 nM < IC50 < 500 nM, +:500 nM < IC50.Table 2wherein * denotes that the compound exists as two diastereomeric forms which were separated after non-chiral synthesis (as reported in the experimental section of PCT / EP2024 / 051219), that both forms were tested in METTL3 / 14 Scintillation Proximity Assay (SPA) as reported in PCT / EP2024 / 051219, and that the diastereomeric form tested in the present assay corresponds to the form that gave the best result in the SPA assay.Table 3wherein * has the same meaning as detailed above for Table 2.Table 4awherein * has the same meaning as detailed above for Table 2.Table 4bwherein * has the same meaning as detailed above for Table 2.Conclusion

[0193] Collectively, the above data from the cellular viability assays demonstrate that the compounds of the invention inhibit cellular viability of various carcinoma cells.Example 2: In vivo assay - FaDu modelMethods

[0194] FaDu human hypopharyngeal squamous cell carcinoma is a representative type of head and neck cancer. FaDu cells were used to induce tumor growth. Female NSG (NOD. Cg-PrkdcscldU2rg"nlWjl / SzJ , immunodeficient) mice (6-7 weeks old; N=5 / group) were subjected to subcutaneous (thigh; right axilla, high) implantation of lelO6cells (day 0) and overall tumor burden was assessed on day 5 by caliper measurement and mice were sorted into study groups accordingly. Drug treatment started on day 5 and continued to day 24 in surviving mice (Compound 142*, wherein * has the same meaning as detailed in Example 1, 30 mg / kg versus vehicle-treated control; daily dosing by intra-peritoneal dose route). Mice were monitored for tumor growth by caliper measurement once every 2-3 days and also monitored for disease survival.Results

[0195] The efficacy of Compound 142* against established subcutaneous FaDu human hypopharyngeal squamous cell carcinoma in female NSG mice is reported in Figures 1A and IB. It was evidenced that treatment with Compound 142* is effective in inhibiting tumor growth and prolonging survival in a mouse model of hypopharyngeal squamous cell carcinoma, a representative type of head and neck carcinoma.3: In vivo assay - A549 orthotopic non-small cell lung adenocarcinoma modelMethods

[0196] A549-Luc-C8 human non-small cell lung adenocarcinoma is a representative type of non-small cell lung cancer. A549-Luc-C8 cells were used to induce tumor growth. Female C.B-17 SCID D (C.B-17 / IcrHsd-Prk<7Ccld, immunodeficient) mice (6-7 weeks old; N=8 / group) were subjected to orthotopic (lung) implantation of 5el06cells (day 0) and overall tumor burden was assessed on day 16 by bioluminescence imaging (BLI) mice were sorted into study groups accordingly. Drug treatment started on day 16 and continued to day 66 in surviving mice (Compound 142*, wherein * has the same meaning as detailed in Example 1, 30 mg / kg versus vehicle-treated control; daily dosing by intraperitoneal dose route). Mice were monitored for disease survival.Results

[0197] The efficacy of Compound 142* against established orthotopic A549-Luc-C8 human non-small cell lung adenocarcinoma in female C.B-17 SCID mice is reported in Figure 2. It was evidenced that treatment with Compound 142* is effective in prolonging survival in a mouse model of non-small cell lung adenocarcinoma.

Claims

CLAIMS1. A compound for use in the treatment of carcinoma, wherein the compound is of formula (I):or a pharmaceutically acceptable salt and / or solvate thereof, whereinAr1is a 6-membered aryl or 6-membered heteroaryl group selected from:wherein * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety;R1is C2-i2-alkyl, C2-i2-haloalkyl, C3-8-cycloalkyl-Ci-3-alkyl, heterocyclyl-C 1-3 -alkyl, C3-8-cycloalkyl, or heterocyclyl; in which the cycloalkyl and heterocyclyl moieties are optionally substituted by one of more substituents selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl and heterocyclyl moieties are optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl and heterocyclyl moieties are optionally bridged ring systems;R2is H, a Ci-4-alkyl optionally substituted by one or more substituent selected from halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; or a C3-6-cycloalkyl;or R1and R2form together with the nitrogen atom to which they are attached a heterocyclic ring, wherein the heterocyclic ring is optionally substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl,Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the heterocyclic ring is optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the heterocyclyl ring is optionally a bridged ring system; each R3is independently Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, Ci-4-haloalkoxy, oxo, or thioxo; or two R3groups present on the same carbon atom form together with the carbon atom to which they are attached a spiro-fused C3-6-cycloalkyl; or two R3groups present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a fused C3-6-cycloalkyl; or two R3groups present on two non-adjacent carbon atoms are linked and form a Ci-4-alkyl bridge; m is 0, 1, 2, 3 or 4; n is 1 or 2;R4and R5are each independently H, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, halo, cyano or hydroxy; orR4and R5form together with the carbon atom to which they are attached a heterocyclyl ring or a C3-4-cycloalkyl ring, in which the heterocyclyl and cycloalkyl moieties are optionally substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, or cyano; orR4and R5form together with the carbon atom to which they are attached an ethylenyl;L is selected from (L1), (L2) and 5-membered heteroaryl (L3):(L1) (L2) (L3) wherein:X1is O or S; preferably X1is O; each Z is independently selected from N, NR11, S, O, C, CR12, C(O), and C(S), wherein at least one of Z is N, NR11, S, or O;R11is H, Ci-4-alkyl, C3-6-cycloalkyl, or Ci-4-haloalkyl;R12is H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; represents a single or double bond, depending on Z;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2;Ar2is a 5- to 10- membered, mono- or bicyclo-, aryl or heteroaryl group, optionally substituted by one or more substituent selected preferably from halo, cyano, oxo, hydroxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino, N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino, Ci-4-alkoxy, Ci-4-haloalkoxy, C3-6-cycloalkyloxy, (Ci-4-alkyl)aminocarbonyl,(Ci-4-haloalkyl)aminocarbonyl, di(Ci-4-alkyl)aminocarbonyl, di(Ci-4-haloalkyl)aminocarbonyl, N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)aminocarbonyl, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, Ce-io-aryl, heteroaryl, and heterocyclyl; wherein the substituents are optionally substituted by one or more group selected preferably from halo, cyano, oxo, hydroxy, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, Ci-4-alkoxy, Ci-4-haloalkoxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino, N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group optionally substituted by one or more halo.

2. The compound for use according to claim 1, whereinR1is a C3-8-cycloalkyl-Ci-3-alkyl; preferably a C3-4-cycloalkyl-Ci-alkyl; in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl moiety is optionally spiro-fused to a C3-6-cycloalkyl or heterocyclyl ring, which spiro-ring can optionally be substituted by one or more substituent selected from Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, and Ci-4-haloalkoxy; and / or the cycloalkyl moiety is optionally a bridged ring system; andR2is H or methyl, preferably H.

3. The compound for use according to claim 1 or claim 2, wherein R2is H, and R1is a C3-4-cycloalkyl-Ci -alkyl, in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from Ci-4-alkyl, and halo; and / or the cycloalkyl moiety is optionally a bridged ring system.

4. The compound for use according to any one of claims 1 to 3, wherein R4and R5are each independently H or Ci-4-alkyl; or R4and R5form together with the carbon atom to which they are attached a heterocyclyl ring.

5. The compound for use according to any one of claims 1 to 4, wherein L is selected from:wherein: each R11is independently H, Ci-4-alkyl, C3-6-cycloalkyl, or Ci-4-haloalkyl; preferably R11is H or methyl; more preferably R11is H; each R12 is independently H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; preferably R12is H, methyl, halo, cyano or methoxy; more preferably R12is H;• represents the point of attachment to the -CR4R5- moiety; and•• represents the point of attachment to Ar2.

6. The compound for use according to any one of claims 1 to 5, wherein L is selected from:wherein:each R12is independently H, Ci-4-alkyl, C3-6-cycloalkyl, Ci-4-haloalkyl, halo, cyano, hydroxy, Ci-4-alkoxy, or Ci-4-haloalkoxy; preferably R12is H, methyl, halo, cyano or methoxy; more preferably R12is H;• represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2.

7. The compound for use to any one of claims 1 to 6, wherein Ar2is selected from:whereinR13, R14, R15, R16, R17, R18, R19, R20, and R21, are each independently selected fromH, halo, cyano, oxo, hydroxy, amino, Ci-4-alkylamino,C i -4-haloalkylamino , di(C i -4-alkyl) amino , di(C i -4-haloalkyl)amino ,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino, Ci-4-alkoxy, Ci-4-haloalkoxy, C3-6-cycloalkyloxy, (Ci-4-alkyl)aminocarbonyl, (Ci-4-haloalkyl)aminocarbonyl, di(Ci-4-alkyl)aminocarbonyl, di(Ci-4-haloalkyl)aminocarbonyl,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)aminocarbonyl, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, Ce-io-aryl, heteroaryl, andheterocyclyl; wherein these substituents are optionally substituted by one or more group selected preferably from halo, cyano, oxo, hydroxy, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, Ci-4-alkoxy, C 1-4 -haloalkoxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group optionally substituted by one or more halo; and represents the point of attachment to the rest of the compound.

8. The compound for use to any one of claims 1 to 7, wherein Ar2is selected from:wherein R13, R14, R15, R17, R18, R19, R20, and R21, are each independently selected from H, halo, cyano, oxo, hydroxy, amino, Ci-4-alkylamino, C i -4-haloalkylamino , di(C i -4-alkyl) amino , di(C i -4-haloalkyl)amino ,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino, Ci-4-alkoxy, Ci-4-haloalkoxy, C3-6-cycloalkyloxy, (Ci-4-alkyl)aminocarbonyl, (Ci-4-haloalkyl)aminocarbonyl, di(Ci-4-alkyl)aminocarbonyl, di(Ci-4-haloalkyl)aminocarbonyl,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)aminocarbonyl, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, Ce-io-aryl, heteroaryl, andheterocyclyl; wherein these substituents are optionally substituted by one or more group selected preferably from halo, cyano, oxo, hydroxy, Ci-4-alkyl, Ci-4-haloalkyl, C3-6-cycloalkyl,Ci-4-alkoxy, C 1-4 -haloalkoxy, amino, Ci-4-alkylamino, Ci-4-haloalkylamino, di(Ci-4-alkyl)amino, di(Ci-4-haloalkyl)amino,N-(Ci-4-alkyl)-N-(Ci-4-haloalkyl)amino; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl or heterocyclyl group optionally substituted by one or more halo; preferably R13, R14, R15, R17, R18, R19, R20, and R21, are each independently selected from H, di(Ci-4-alkyl)amino, C3-6-cycloalkyl, and heterocyclyl; wherein these substituents are optionally substituted by one or more group selected from halo, Ci-4-alkyl, Ci-4-alkoxy; or fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl group; or spiro-fused to the heterocyclyl substituent may be one or more C3-6-cycloalkyl group optionally substituted by one or more halo; and represents the point of attachment to the rest of the compound.

9. The compound for use according to any one of claims 1 to 8, wherein the compound is of formula (la) or (la’):or a pharmaceutically acceptable salt and / or solvate thereof, wherein m, R1, R2, R3, R4, R5, L, Ar1and Ar2are as defined in any one of the preceding claims.

10. The compound for use according to any one of claims 1 to 9, wherein the compound is of formula (lb) or (lb’):or a pharmaceutically acceptable salt and / or solvate thereof, wherein R1, R2, R4, R5, L, Ar1and Ar2are as defined in any one of the preceding claims.

11. The compound for use according to any one of claims 1 to 10, wherein the compound is selected from:and stereoisomers, and pharmaceutically acceptable salts and / or solvates thereof.

12. The compound for use according to any one of claims 1 to 11, wherein the carcinoma is selected from adenocarcinomas, basal cell carcinomas (BCC), squamous cell carcinomas (SCC), ductal carcinomas in situ (DCIS), invasive (infiltrating) ductal carcinomas (IDC), and transitional cell carcinoma (TCC).

13. The compound for use according to any one of claims 1 to 12, wherein the carcinoma is selected from lung carcinoma, non-small cell lung carcinoma, breast carcinoma, triple negative breast carcinoma, oral carcinoma, esophageal carcinoma, hypopharyngeal carcinoma, head and neck carcinoma, stomach carcinoma, small intestine carcinoma, large intestine carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, cholangiocarcinoma, hepatoma, thymoma, cervical carcinoma, endometrial carcinoma, bladder carcinoma, pancreatic carcinoma, prostate carcinoma, renal carcinoma, testicular carcinoma, thyroid carcinoma and cutaneous carcinoma.

14. The compound for use according to any one of claims 1 to 13, wherein the carcinoma is selected from lung carcinoma, breast carcinoma, hypopharyngeal carcinoma, colorectal carcinoma, hepatoma, bladder carcinoma, pancreatic carcinoma, and prostate carcinoma.

15. The compound for use according to any one of claims 1 to 14, wherein the compound is to be administered orally or parenterally.

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