COMBINATION THERAPIES COMPRISING A METTL3 INHIBITOR AND A BCL2 INHIBITOR FIELD OF INVENTION [0001] The present invention relates to combination therapies for the treatment of cancer comprising the administration of a METTL3 inhibitor of formula (I) as defined hereafter, in combination with a BCL2 inhibitor, or pharmaceutically acceptable salts thereof. BACKGROUND OF INVENTION [0002] Cancer is caused by uncontrolled and unregulated cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of a number of molecular targets and key metabolic pathways that are known to be associated with malignancy. [0003] Despite numerous advances in the treatment of cancer, there remains a need for new therapies that provide improved therapeutic outcomes. [0004] One particular target that is attracting interest is m6A methyltransferase METTL3. N6 -methyladenosine (m6A) is an abundant internal RNA modification that is catalyzed predominantly by the METTL3/METTL14 methyltransferase complex. METTL3 enzyme has been linked to all hallmarks of cancer and regulates major tumorigenic processes: cell cycle and proliferation, apoptosis, migration, stemness, metabolism and immune surveillance. An oncogenic activity has been attributed to this methyltransferase in most cancers (Barbieri and Kouzarides, Nature Reviews Cancer, 2020, 20, 303-322). METTL3 pro-tumoral activity primarily relies on its ability to regulate the stability and translation of key oncogene and tumor suppressor mRNA targets (MYC, SOX4, mTORC, PTEN, BCL2, SP1) in a m6A-dependent manner.
[0005] Several studies have shown that the m6A methyltransferase METTL3 as essential to the growth and maintenance of acute myeloid leukaemia (AML) (Barbieri et al., Nature, 2017, 552, 126-131; Vu et al., Nature Medicine, 2017, 23, 1369-1376). METTL3 has also been found to be upregulated in AML when compared to healthy human hematopoietic stem/progenitor cells and other types of tumor cells (ibid. Vu et al., 2017). METTL3 depletion promotes leukaemic cell differentiation and impairs tumor growth, while the overexpression of its wildtype, but not catalytically mutant form, sustains AML maintenance and proliferation. The same study reported that downregulation of METTL3 in in vivo models of leukaemia favors cell differentiation and apoptosis of AML. The pro- tumorigenic function of METTL3-mediated m6A modification in AML was attributed to the increased translation of key leukaemia mRNA targets c-MYC, BCL2 and PTEN and activation of AKT signaling pathway. Inhibition of METTL3 activity by small-molecule inhibitors has been proved to have a successful anti-cancer response in patient-derived leukaemia models (Yankova et al., Nature, 2021, 593, 597-601). [0006] Altogether, these findings identify METTL3 as a promising therapeutic target in AML whereupon small-molecule inhibitors of METTL3 represent a promising avenue for anticancer therapy more generally. In particular, international patent application PCT/EP2024/051219 describes METTL3 inhibitors that are suitable for the treatment of cancer. [0007] Impaired apoptosis plays a central role in the development of cancer and also reduces the efficacy of traditional cytotoxic therapies. Members of the B-cell lymphoma 2 (BCL-2) protein family have pro- or anti-apoptotic activities and have been studied intensively over the past decade for their importance in regulating apoptosis, tumorigenesis and cellular responses to anticancer therapy (D’Aguanno and Del Bufalo, Cells 2020, 9, 1287; DOI:10.3390/cells9051287). [0008] Bcl-2 is the most well-characterized anti-apoptotic protein in the BCL-2 protein family. It can inhibit apoptosis by forming a heterodimer with BAX and ensure cell survival by regulating the Ca2+ concentration and antioxidant effect. Additionally, it can also inhibit the activities of caspase, thereby inhibiting apoptosis, prolonging the survival
time of tumor cells and causing malignant transformation of cells (Qian et al., Frontiers in Oncology, 2022, DOI: 10.3389/fonc.2022.985363). [0009] The turning point in the research for BCL-2 inhibitors was reached with the development of venetoclax, a potent and selective BH3 mimetic for Bcl-2 protein, which was able to circumvent the thrombocytopenia observed with navitoclax, a non-selective Bcl-2 inhibitor. The first FDA approval for venetoclax in first-line treatment of patients with relapsed/refractory chronic lymphocytic leukaemia (R/R CLL) and carrying the 17p deletion came in 2016. Subsequently, in June 2018, the clinical practice of venetoclax was introduced by the FDA for patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL), regardless of the 17p deletion. After this initial approval for clinical use, venetoclax was further tested in combination and demonstrated clinical efficacy in various, additional hematological malignancies (ibid. D’Aguanno and Del Bufalo, 2020). [0010] However, treatment with venetoclax can lead to the development of resistance largely through the upregulation of alternative anti-apoptotic proteins. Upregulation of another BCL2 family anti-apoptotic protein, namely myeloid cell leukemia 1 (MCL1), is seen in AML and myelodysplastic syndromes (MDS) patients treated with venetoclax, and is a noted mechanism of venetoclax resistance. Follicular lymphoma cells treated with venetoclax developed resistance associated with the upregulation of MCL1 and, conversely, loss of MCL1 sensitized non-Hodgkin lymphoma to BCL2 inhibition with venetoclax. Venetoclax treatment failure most strongly correlated with elevated MCL1 protein in a clinical trial of relapsed and refractory AML (Fischer et al., Haematologica, 2023, 108, 522-531; Ramsey et al., Cancer Discovery, 2018, 8(12), 1566-1581). [0011] Agents which are able to overcome venetoclax resistance mediated by MCL1 upregulation may represent an interesting therapeutic strategy for use in combination therapy with venetoclax. [0012] The present invention relates to combination therapies, particularly combination therapies for the treatment of cancers, especially hematological malignancies. The combination therapies of the invention are also particularly useful to prevent the
development of venetoclax resistance in patient mediated by MCL1 upregulation. The combination therapies of the invention include a METTL3 inhibitor of formula (I) as defined hereafter and as described in PCT/EP2024/051219, and a BCL2 inhibitor, for example venetoclax, or a pharmaceutical acceptable salt thereof. SUMMARY [0013] This invention thus relates to a combination comprising: (i) a BCL2 inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) a compound of formula (I):
or a pharmaceutically acceptable salt and/or solvate thereof, wherein m, n, R1, R2, R3, R4, R5, L, Ar1 and Ar2 are as defined in the claims and hereafter. [0014] In one embodiment, the BCL2 inhibitor is selected from venetoclax, oblimersen, obatoclax, navitoclax, pelcitoclax, R-(-)-gossypol, and pharmaceutically acceptable salts thereof; preferably the BCL2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof. [0015] 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. [0016] The invention also relates to a kit of parts comprising: (a) a first part comprising a BCL2 inhibitor, or a pharmaceutically acceptable salt thereof, as herein defined; and (b) a second part comprising a compound of formula (I), as herein defined.
[0017] The invention further relates to a pharmaceutical composition comprising a combination according to the invention, and one or more pharmaceutically acceptable carrier. [0018] The invention further relates to a combination, a kit of part, or a pharmaceutical composition according to the invention, for use in the treatment of cancer in a patient in need thereof. [0019] The invention further relates to a compound of formula (I) as herein defined, for use in the treatment of cancer in a patient in need thereof, wherein the compound of formula (I) is for administration in combination with a BCL2 inhibitor as herein defined. [0020] The invention further relates to a BCL2 inhibitor as herein defined, for use in the treatment of cancer in a patient in need thereof, wherein the BCL2 inhibitor is for administration in combination with a compound of formula (I) as herein defined. [0021] In one embodiment, the cancer is selected from acute myeloid leukaemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukaemia, small lymphocytic lymphoma, myelodysplastic syndromes, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, myeloma, and multiple myeloma. [0022] In one embodiment, the patient is overexpressing MCL1. [0023] In one embodiment, the patient is resistant to a BCL2 inhibitor therapy, especially patient is resistant to a BCL2 inhibitor therapy by upregulation of MCL1. [0024] In one embodiment, the combination of the invention is for sensitizing a patient who is refractory to a BCL2 inhibitor therapy. DEFINITIONS [0025] 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. [0026] 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”. [0027] In the present invention, the following terms have the following meanings: [0028] “Alkyl”, by itself or as part of another substituent, refers to a hydrocarbyl radical of formula CnH2n+1 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, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl and its isomers (e.g. n-pentyl, iso- pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. [0029] “Alkylamino” as used herein means an amino group (i.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. [0030] “Alkylaminocarbonyl” and “dialkylaminocarbonyl”, refer to any group –(C=O)-alkylamino and –(C=O)-dialkylamino respectively, wherein alkylamino and dialkylamino are as defined above. [0031] “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, n-butoxy, t-butoxy, s-butoxy, and n-pentoxy. [0032] “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. [0033] “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. [0034] “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. [0035] “Cycloalkyl-alkyl”, refers to any group –alkyl-cycloalkyl, wherein alkyl and cycloalkyl are as defined above. [0036] “Cycloalkyloxy”, refers to any group –O-cycloalkyl, wherein cycloalkyl is as defined above. [0037] “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. [0038] “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. [0039] “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[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b] thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-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[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl. [0040] “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 quaternized. 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, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-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, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl. [0041] “Heterocyclyl-alkyl”, refers to any group –alkyl-heterocyclyl, wherein alkyl and heterocyclyl are as defined above. [0042] “Oxo”, refers to the substituent =O. “Thioxo”, refers to the substituent =S. [0043] “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. [0044] “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. [0045] “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. [0046] “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. [0047] “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. [0048] “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. [0049] “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 [0050] “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 [0051] The invention thus relates to combination therapies for the treatment of cancer, comprising the administration of a METTL3 inhibitor of formula (I) as defined hereafter, in combination with a BCL2 inhibitor, or pharmaceutically acceptable salts thereof. [0052] The invention is based on the recognition that a compound of formula (I) as defined hereafter, when administered in combination with a BCL2 inhibitor (e.g. venetoclax), produces a synergistic increase in potency (see example 1). In other words, the administration of a compound of formula (I) synergistically enhances the anticancer effect of BCL2 inhibitor therapy (e.g. venetoclax), and vice versa. Therefore, the combination of a compound of formula (I) with a BCL2 inhibitor (e.g. venetoclax) offers a promising therapy for diseases and conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancers, especially hematological cancers). [0053] Moreover, the compounds of formula (I) were evidenced to reduce the content in anti-apoptotic biomarker MCL1 in tested cell lines (see example 2). MCL1 is the most prominent anti-apoptotic alternative to BCL2 in hematologic cancers. Treatment of AML and other hematological malignancies with venetoclax is known to possibly lead to resistance through the upregulation of MCL1. Therefore, the combination of a compound of formula (I) with a BCL2 inhibitor (e.g. venetoclax) offers a promising therapy to overcome treatment resistance mediated by MCL1 upregulation. [0054] Overall, the combination therapies of the present invention have the potential to provide better therapeutic outcomes in cancer patients, especially in cancer patients that do not respond well to therapy with a BCL2 inhibitor alone.
METTL3 inhibitor [0055] The combination therapies of the invention comprise the administration of a METTL3 inhibitor of formula (I). [0056] In one embodiment, compounds of formula (I) those as defined in PCT/EP2024/051219. [0057] According to the invention, the METTL3 inhibitor is a compound of formula (I):
or a pharmaceutically acceptable salt and/or solvate thereof, wherein: R1 is C2-12-alkyl, C2-12-haloalkyl, C3-8-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, C3-8-cycloalkyl, or heterocyclyl; in which the cycloalkyl and heterocyclyl moieties are optionally substituted by one of more substituents selected from C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-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 C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-haloalkoxy; and/or the cycloalkyl and heterocyclyl moieties are optionally bridged ring systems; R2 is H, a C1-4-alkyl optionally substituted by one or more substituent selected from halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-haloalkoxy; or a C3-6-cycloalkyl; or R1 and R2 form 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 C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-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 C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-haloalkoxy; and/or the heterocyclyl ring is optionally a bridged ring system; each R3 is independently C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, C1-4-haloalkoxy, oxo, or thioxo; or two R3 groups 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 R3 groups present on two adjacent carbon atoms form together with the carbon atoms to which they are attached a fused C3-6-cycloalkyl; or two R3 groups present on two non-adjacent carbon atoms are linked and form a C1-4-alkyl bridge; m is 0, 1, 2, 3 or 4; n is 1 or 2; R4 and R5 are each independently H, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl, halo, cyano or hydroxy; or R4 and R5 form 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 C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, or cyano; or R4 and R5 form together with the carbon atom to which they are attached an ethylenyl; Ar1 is an aryl or heteroaryl group selected from (Ar1a), (Ar1b) and (Ar1c):
(Ar1a) (Ar1b) (Ar1c) wherein: p is 0, 1, 2, 3 or 4; R6 is C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, or cyano; each X is independently selected from N, NR7, C, CR8, C(O), and C(S), wherein at least one of X is N or NR7; R7 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; R8 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; each Y is independently selected from N, NR9, S, O, C, CR10, C(O), and C(S), wherein at least one of Y is N, NR9, S, or O; R9 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; R10 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; represents a single or double bond, depending on X or Y; * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety; L is selected from (L1), (L2) and 5-membered heteroaryl (L3):
wherein: X1 is O or S; preferably X1 is 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; R11 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; R12 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-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; Ar2 is 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, C1-4-alkylamino, C1-4-haloalkylamino, di(C1-4-alkyl)amino, di(C1-4-haloalkyl)amino, N-(C1-4-alkyl)-N-(C1-4-haloalkyl)amino, C1-4-alkoxy, C1-4-haloalkoxy, C3-6-cycloalkyloxy, (C1-4-alkyl)aminocarbonyl, (C1-4-haloalkyl)aminocarbonyl, di(C1-4-alkyl)aminocarbonyl, di(C1-4-haloalkyl)aminocarbonyl, N-(C1-4-alkyl)-N-(C1-4-haloalkyl)aminocarbonyl, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, C6-10-aryl, heteroaryl, and heterocyclyl; wherein the substituents are optionally substituted by one or more group selected preferably from halo, cyano, oxo, hydroxy, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl, C1-4-alkoxy, C1-4-haloalkoxy, amino, C1-4-alkylamino, C1-4-haloalkylamino, di(C1-4-alkyl)amino, di(C1-4-haloalkyl)amino, N-(C1-4-alkyl)-N-(C1-4-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 [0058] 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.
[0059] According to one embodiment, m is preferably 0, 1 or 2. In one preferred embodiment, m is 0. [0060] According to one embodiment, when present, R3 is selected from C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and oxo; preferably R3 is C1-2-alkyl or halo; more preferably R3 is methyl or F. [0061] According to another embodiment, m is at least equal to 2 and two R3 groups are linked together. When the two R3 groups 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 R3 groups 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 R3 groups 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. NR1R2 [0062] According to one embodiment, R1 is C2-12-alkyl, C2-12-haloalkyl, C3-8-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, C3-8-cycloalkyl, or heterocyclyl; in which the cycloalkyl and heterocyclyl moieties are optionally substituted by one of more substituents selected from C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-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 C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-haloalkoxy; and/or the cycloalkyl and heterocyclyl moieties are optionally bridged ring systems. [0063] In above definition of R1, the expressions “in 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-C1-3-alkyl or heterocyclyl-C1-3-alkyl groups. [0064] In a preferred embodiment, R1 is a C3-8-cycloalkyl-C1-3-alkyl (preferably C3-4-cycloalkyl-C1-alkyl); in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1- 4-alkoxy, and C1-4-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 C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-haloalkoxy; and/or the cycloalkyl moiety is optionally a bridged ring system. [0065] In a more preferred embodiment, R1 is a C3-8-cycloalkyl-C1-3-alkyl (preferably C3-4-cycloalkyl-C1-alkyl); in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from C1-4-alkyl, and halo; and/or the cycloalkyl moiety is optionally a bridged ring system. [0066] According to one embodiment, R2 is H, or a C1-4-alkyl, optionally substituted by one or more substituent selected from halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-haloalkoxy, or a C3-6-cycloalkyl. [0067] In a preferred embodiment, R2 is H or methyl. [0068] In a more preferred embodiment, R2 is H. [0069] In one embodiment, R2 is H or methyl (preferably H), and R1 is a C3-8-cycloalkyl- C1-3-alkyl (preferably C3-4-cycloalkyl-C1-alkyl); in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1- 4-alkoxy, and C1-4-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 C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-haloalkoxy; and/or the cycloalkyl moiety is optionally a bridged ring system. [0070] In a more preferred embodiment, R2 is H, and R1 is a C3-8-cycloalkyl-C1-3-alkyl (preferably C3-4-cycloalkyl-C1-alkyl), in which the cycloalkyl moiety is optionally substituted by one of more substituents selected from C1-4-alkyl, and halo; and/or the cycloalkyl moiety is optionally a bridged ring system. [0071] According to another embodiment, R1 and R2 form 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 C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-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 C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, and C1-4-haloalkoxy; and/or the heterocyclyl ring is optionally a bridged ring system. [0072] When R1 and R2 form 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. [0073] According to one embodiment, NR1R2 is selected from:
wherein represents the point of attachment to the rest of the compound. [0074] According to one embodiment, NR1R2 is preferably selected from:
wherein represents the point of attachment to the rest of the compound. [0075] According to one embodiment, NR1R2 is more preferably selected from:
wherein represents the point of attachment to the rest of the compound. Ar1 [0076] In the compounds of the invention, Ar1 is a 6-membered aryl or 5- or 6- membered heteroaryl group, selected from (Ar1a), (Ar1b) and (Ar1c) as defined hereinabove. In a specific embodiment, Ar1 is a 6-membered aryl or a 6-membered heteroaryl group, selected from (Ar1a) and (Ar1b) as herein defined. [0077] According to one embodiment, Ar1 is a 6-membered aryl group (Ar1a):
wherein: p is 0, 1, 2, 3 or 4; preferably p is 0 or 1; more preferably p is 0; R6 is C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, or cyano; preferably R6 is methyl, F, Cl, or cyano; * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety. [0078] According to one embodiment, Ar1 is a 6-membered heteroaryl group (Ar1b):
wherein: each X is independently selected from N, NR7, C, CR8, C(O), and C(S), wherein at least one of X is N or NR7; R7 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; preferably R7 is H; R8 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R8 is H, methyl, halo; more preferably R8 is H; represents a single or double bond, depending on X; * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety. [0079] In one embodiment, Ar1b is preferably selected from:
wherein: R7 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; preferably R7 is H; R8 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R8 is H, methyl, halo; more preferably R8 is H; * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety. [0080] In one preferred embodiment, Ar1b is preferably selected from:
wherein: R8 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R8 is H, methyl, halo; more preferably R8 is H; * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety. [0081] According to one embodiment, Ar1 is a 5-membered heteroaryl group (Ar1c):
wherein: each Y is independently selected from N, NR9, S, O, C, CR10, C(O), and C(S), wherein at least one of Y is N, NR9, S, or O; R9 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; preferably R9 is H; R10 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R10 is H; represents a single or double bond, depending on Y; * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety. [0082] According to another one embodiment, Ar1c is selected from:
wherein: R9 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; preferably R9 is H;
R10 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R10 is H; * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety. [0083] According to one embodiment, Ar1 is selected from:
wherein: R7 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; preferably R7 is H; R8 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R8 is H, methyl, halo; more preferably R8 is H;
R9 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; preferably R9 is H; R10 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R10 is H; * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety. [0084] According to one preferred embodiment, Ar1 is selected from:
wherein: R8 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R8 is H, methyl, halo; more preferably R8 is H; * represents the point of attachment to the piperidine ring; and ** represents the point of attachment to the -CR4R5- moiety. R4, R5 [0085] According to one embodiment, R4 and R5 are each independently H, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl, halo, cyano or hydroxy; preferably R4 and R5 are each independently H, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl; more preferably R4 and R5 are each independently H, methyl, ethyl, CF3, cyclopropyl. In a preferred embodiment, R4 and R5 are each independently H or C1-4-alkyl; even more preferably R4 and R5 are each independently H or methyl. In a more preferred embodiment, R4 and R5 are both H, or one is H and the other is methyl. [0086] According to another embodiment, R4 and R5 form 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 C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, or cyano; or
- an ethylenyl group. [0087] In a preferred embodiment, R4 and R5 form 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 C1-4-alkyl (preferably methyl), and ethylenyl. In a more preferred embodiment, R4 and R5 form together with the carbon atom to which they are attached a group selected from oxetane, cyclopropyl, and ethylenyl. In an even more preferred embodiment, R4 and R5 form together with the carbon atom to which they are attached an oxetane group. [0088] In a preferred embodiment, R4 and R5 are each independently H or C1-4-alkyl; or R4 and R5 form together with the carbon atom to which they are attached a heterocyclyl ring. [0089] In a more preferred embodiment, R4 and R5 are both H; or one is H and the other is methyl; or R4 and R5 form together with the carbon atom to which they are attached an oxetane group. Linker L [0090] 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. [0091] According to one embodiment, L is an amide link (L1a), corresponding to L1
wherein: • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2.
[0092] According to one embodiment, L is a retro-amide link (L2a), corresponding to L2 wherein X1 is O:
wherein: • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2. [0093] 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; R11 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; R12 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-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. [0094] 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; R11 is H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; preferably R11 is H or methyl; more preferably R11 is H;
R12 is H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R12 is H, methyl, halo, cyano or methoxy; more preferably R12 is 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. [0095] According to one embodiment, L3 is selected from:
wherein: each R11 is independently H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; preferably R11 is H or methyl; more preferably R11 is H; each R12 is independently H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R12 is H, methyl, halo, cyano or methoxy; more preferably R12 is H; • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2. [0096] According to one embodiment, L3 is preferably selected from:
wherein: each R12 is independently H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R12 is H, methyl, halo, cyano or methoxy; more preferably R12 is H; • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2. [0097] According to one preferred embodiment, L3 is selected from:
wherein: • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2. [0098] According to one more preferred embodiment, L3 is selected from:
wherein: • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2. [0099] According to one embodiment, L is selected from:
wherein: each R11 is independently H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; preferably R11 is H or methyl; more preferably R11 is H; each R12 is independently H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R12 is H, methyl, halo, cyano or methoxy; more preferably R12 is H; • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2. [0100] According to one embodiment, L is preferably selected from:
each R11 is independently H, C1-4-alkyl, C3-6-cycloalkyl, or C1-4-haloalkyl; preferably R11 is H or methyl; more preferably R11 is H; each R12 is independently H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R12 is H, methyl, halo, cyano or methoxy; more preferably R12 is H; • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2. [0101] According to one embodiment, L is more preferably selected from:
each R12 is independently H, C1-4-alkyl, C3-6-cycloalkyl, C1-4-haloalkyl, halo, cyano, hydroxy, C1-4-alkoxy, or C1-4-haloalkoxy; preferably R12 is H, methyl, halo, cyano or methoxy; more preferably R12 is H; • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2.
[0102] 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 [0103] In the compounds of the invention, Ar2 is 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, C1-4-alkylamino, C1-4-haloalkylamino, di(C1-4-alkyl)amino, di(C1-4-haloalkyl)amino, N-(C1-4-alkyl)-N-(C1-4-haloalkyl)amino, C1-4-alkoxy, C1-4-haloalkoxy, C3-6-cycloalkyloxy, (C1-4-alkyl)aminocarbonyl, (C1-4-haloalkyl)aminocarbonyl, di(C1-4-alkyl)aminocarbonyl, di(C1-4-haloalkyl)aminocarbonyl, N-(C1-4-alkyl)-N-(C1-4-haloalkyl)aminocarbonyl, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, C6-10-aryl, heteroaryl, and heterocyclyl; wherein the substituents are optionally substituted by one or more group selected preferably from halo, cyano, oxo, hydroxy, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl, C1-4-alkoxy, C1-4-haloalkoxy, amino, C1-4-alkylamino, C1-4-haloalkylamino, di(C1-4-alkyl)amino, di(C1-4-haloalkyl)amino, N-(C1-4-alkyl)-N-(C1-4-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. [0104] According to one embodiment, Ar2 is selected from:
wherein R13, R14, R15, R16, R17, R18, R19, R20, and R21, are each independently selected from H, halo, cyano, oxo, hydroxy, amino, C1-4-alkylamino, C1-4-haloalkylamino, di(C1-4-alkyl)amino, di(C1-4-haloalkyl)amino, N-(C1-4-alkyl)-N-(C1-4-haloalkyl)amino, C1-4-alkoxy, C1-4-haloalkoxy, C3-6-cycloalkyloxy, (C1-4-alkyl)aminocarbonyl, (C1-4-haloalkyl)aminocarbonyl, di(C1-4-alkyl)aminocarbonyl, di(C1-4-haloalkyl)aminocarbonyl, N-(C1-4-alkyl)-N-(C1-4-haloalkyl)aminocarbonyl, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, C6-10-aryl, heteroaryl, and heterocyclyl; wherein these substituents are optionally substituted by one or more group selected preferably
from halo, cyano, oxo, hydroxy, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl, C1-4-alkoxy, C1-4-haloalkoxy, amino, C1-4-alkylamino, C1-4-haloalkylamino, di(C1-4-alkyl)amino, di(C1-4-haloalkyl)amino, N-(C1-4-alkyl)-N-(C1-4-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. [0105] 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-hydroxyethylamino, dimethylamino, N-methyl-N-ethylamino, N- methyl-N-(2,2,2-trifluoroethyl)amino, N-methyl-N-(trifluoromethyl)amino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclobutoxy, methyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, 1-propynyl, pyrazolyl, imidazolyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 3-methyl-2-oxoimidazolidin-1-yl, 2-oxopyrrolidin-1-yl, 4- methylpiperazin-1-yl, 2-methylpyrrolidin-1-yl, 3-methylazetidin-1-yl, 3,3- difluoroazetidin-1-yl, 3-methoxyazetidin-1-yl, 3-(difluoromethyl)azetidin-1-yl, 3,3- dimethylpyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, 3- fluoropyrrolidin-1-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, 1,1-difluoro-5-azaspiro[2.3]hexan- 5-yl, and 5-azaspiro[2.4]heptan-5-yl. [0106] According to one embodiment, Ar2 is preferably selected from:
wherein R13, R14, R15, R17, R18, R19, R20, and R21, are each independently selected from H, halo, cyano, oxo, hydroxy, amino, C1-4-alkylamino, C1-4-haloalkylamino, di(C1-4-alkyl)amino, di(C1-4-haloalkyl)amino,
N-(C1-4-alkyl)-N-(C1-4-haloalkyl)amino, C1-4-alkoxy, C1-4-haloalkoxy, C3-6-cycloalkyloxy, (C1-4-alkyl)aminocarbonyl, (C1-4-haloalkyl)aminocarbonyl, di(C1-4-alkyl)aminocarbonyl, di(C1-4-haloalkyl)aminocarbonyl, N-(C1-4-alkyl)-N-(C1-4-haloalkyl)aminocarbonyl, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl, C2-4-alkynyl, C6-10-aryl, heteroaryl, and heterocyclyl; wherein these substituents are optionally substituted by one or more group selected preferably from halo, cyano, oxo, hydroxy, C1-4-alkyl, C1-4-haloalkyl, C3-6-cycloalkyl, C1-4-alkoxy, C1-4-haloalkoxy, amino, C1-4-alkylamino, C1-4-haloalkylamino, di(C1-4-alkyl)amino, di(C1-4-haloalkyl)amino, N-(C1-4-alkyl)-N-(C1-4-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(C1-4-alkyl)amino, C1-4-alkoxy, C3-6-cycloalkyl, and heterocyclyl; and represents the point of attachment to the rest of the compound. [0107] In one embodiment, R13, R14, R15, R17, R18, R19, R20, and R21, are each independently selected from H, dimethylamino, methoxy, cyclopropyl, and pyrrolidinyl. [0108] According to one embodiment, Ar2 is selected from:
wherein represents the point of attachment to the rest of the compound. [0109] According to one embodiment, Ar2 preferably is selected from:
wherein represents the point of attachment to the rest of the compound. Subformulae [0110] In one embodiment, the compounds of the invention are of formula (Ia) or (Ia’):
or pharmaceutically acceptable salts and/or solvates thereof, wherein m, R1, R2, R3, R4, R5, L, Ar1 and Ar2 are as defined above.
[0111] In one embodiment, the compounds of the invention of formula (Ib) or (Ib’):
wherein m, R1, R2, R3, R4, R5, L, Ar1 and Ar2 are as defined above. [0112] 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, L, Ar1 and Ar2 are as defined herein. [0113] 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, Ar1 and Ar2 are as defined above. [0114] In one embodiment, the compounds of the invention are of formula (Ie) or (Ie’):
or pharmaceutically acceptable salts and/or solvates thereof, wherein R1, R2, R4, R5, Ar1 and Ar2 are as defined above. [0115] In one embodiment, the compounds of the invention are of formula (If) or (If’):
or pharmaceutically acceptable salts and/or solvates thereof, wherein R1, R2, R4, R5, L3, Ar1 and Ar2 are as defined above. [0116] In one embodiment, in formula (I-3), L3 is preferably selected from:
wherein • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2. [0117] In one embodiment, in formula (I-3), L3 is more preferably selected from:
wherein • represents the point of attachment to the -CR4R5- moiety; and •• represents the point of attachment to Ar2. [0118] Unless otherwise specified, when it is referred to formula (I), it also encompasses any of above subformulae thereof. [0119] According to one embodiment, the compound according to the invention is selected from those listed in Table 1: Table 1 001 (R)-N-(cyclobutylmethyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine
(R)-N-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (R)-N-(cyclobutylmethyl)-1-(6-((4-(imidazo[1,5-a]pyridin-8-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine (R)-N-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-5-methoxynicotinamide (R)-N-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-6-methoxy-1H-indazole-4-carboxamide 4-(1-((6-(4,4-dimethyl-[1,3'-bipiperidin]-1'-yl)pyridazin-3-yl)methyl)-1H- 1,2,3-triazol-4-yl)-6-methoxy-1H-indazole 6-methoxy-4-(1-((6-(4-methyl-[1,3'-bipiperidin]-1'-yl)pyridazin-3- yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazole 4-(1-((6-(3-(6-azaspiro[3.4]octan-6-yl)piperidin-1-yl)pyridazin-3-yl)methyl)- 1H-1,2,3-triazol-4-yl)-6-methoxy-1H-indazole (R)-1-(6-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)-N-(cyclobutylmethyl)piperidin-3-amine (R)-N-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-7-carboxamide N-((6-(3-(((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)piperidin-1- yl)pyridazin-3-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (R)-N-(cyclobutylmethyl)-1-(6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(6-((4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)- 1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine N-((6-(3-(6-azaspiro[2.5]octan-6-yl)piperidin-1-yl)pyridazin-3-yl)methyl)-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (R)-N-(cyclopropylmethyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine (R)-N-((6-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide
(R)-2-(1-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-1H-1,2,3-triazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (R)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1-(6-((4-(6-methoxy-1H- indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine (R)-3-(1-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-1H-1,2,3-triazol-4-yl)-5-methoxypicolinonitrile 1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)-N-((3-methylbicyclo[1.1.1]pentan-1- yl)methyl)piperidin-3-amine (R)-5-(1-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-1H-1,2,3-triazol-4-yl)nicotinonitrile (R)-N-(cyclobutylmethyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridazin-3-yl)-N-methylpiperidin-3-amine (R)-N-cyclopentyl-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)piperidin-3-amine (R)-N-(3,3-dimethylbutyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine 1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)-N-(spiro[2.3]hexan-1-yl)piperidin-3-amine N-(cyclobutylmethyl)-1-(5-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)thiazol-2-yl)piperidin-3-amine 4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-((4-(6-methoxy-1H- indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2(1H)-one 5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-2-((4-(6-methoxy-1H- indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3(2H)-one (R)-2-(1-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-1H-1,2,3-triazol-4-yl)quinazolin-4(3H)-one (R)-N-cyclobutyl-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)piperidin-3-amine (R)-N-isobutyl-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)piperidin-3-amine
(R)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)-N-neopentylpiperidin-3-amine (3R)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)-N-(tetrahydrofuran-3-yl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(6-((4-(imidazo[5,1-b]thiazol-3-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine 4-(1-((6-(3-(2-azaspiro[3.3]heptan-2-yl)piperidin-1-yl)pyridazin-3- yl)methyl)-1H-1,2,3-triazol-4-yl)-6-methoxy-1H-indazole N-(cyclobutylmethyl)-1-(5-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)-1,3,4-thiadiazol-2-yl)piperidin-3-amine (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(6-methoxy-1H-indazol-4-yl)-1H- 1,2,3-triazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (3R,6S)-N-(cyclobutylmethyl)-1-(6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridazin-3-yl)-6-methylpiperidin-3-amine (R)-6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-3-((4-(6-methoxy-1H- indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-4(1H)-one (R)-N-(cyclobutylmethyl)-1-(5-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-2-yl)piperidin-3-amine (R)-6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-3-((4-(6-methoxy-1H- indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyrimidin-4(3H)-one (R)-N-(cyclobutylmethyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)piperidin-3-amine N-(cyclobutylmethyl)-1-(2-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyrimidin-5-yl)piperidin-3-amine (3R)-N-(1-cyclobutylethyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine (3R)-N-(1-cyclopropylethyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H- 1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine N-(cyclobutylmethyl)-1-(5-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyrimidin-2-yl)piperidin-3-amine
N-(cyclobutylmethyl)-1-(5-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)pyrazin-2-yl)piperidin-3-amine (R)-3-(1-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-1H-1,2,3-triazol-4-yl)isoquinolin-1(2H)-one N-(cyclobutylmethyl)-1-(2-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3- triazol-1-yl)methyl)thiazol-5-yl)piperidin-3-amine 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-methoxy-1H- indazol-4-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one N-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)ethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 3-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-6-((4-(6-methoxy-1H- indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2(1H)-one N-(cyclobutylmethyl)-1-(6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)-3-methylpiperidin-3-amine 4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-5-fluoro-1-((4-(6-methoxy- 1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (3R,5S)-N-(cyclobutylmethyl)-5-fluoro-1-(6-((4-(5-methoxypyridin-3-yl)- 1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine (R)-1-(6-((4-(6-chloro-1H-indazol-4-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)-N-(cyclobutylmethyl)piperidin-3-amine N-(1-(5-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)ethyl)- 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-(cyclobutylmethyl)-4,4-difluoro-1-(6-((4-(5-methoxypyridin-3-yl)-1H- 1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine (R)-N-((5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)methyl)- 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (R)-N-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-3-yl)methyl)- 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide
(R)-5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-2-((4-(5-methoxypyridin- 3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3(2H)-one (R)-4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-((4-(5-methoxypyridin- 3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2(1H)-one (3R)-N-(cyclobutylmethyl)-1-(6-(2,2,2-trifluoro-1-(4-(5-methoxypyridin-3- yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine N-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)- 2,2,2-trifluoroethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine 5-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-2-(1-(4-(5- methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridazin-3(2H)-one (R)-N-(cyclobutylmethyl)-1-(4-((4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)methyl)phenyl) piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(6-((5-(5-methoxypyridin-3-yl)-4H-1,2,4- triazol-3-yl)methyl)pyridazin-3-yl)piperidin-3-amine (R)-N-(4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)benzyl)-4-oxo-4H- pyrido[1,2-a]pyrimidine-2-carboxamide (3R)-N-(cyclobutylmethyl)-1-(5-(1-(4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)ethyl)pyridin-2-yl)piperidin-3-amine N-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-3-yl)ethyl)- 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)ethyl)pyridin-3-yl)piperidin-3-amine N-((S)-1-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)phenyl)ethyl)- 4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (R)-4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-((1-(5-methoxypyridin- 3-yl)-1H-1,2,3-triazol-4-yl)methyl)pyridin-2(1H)-one (3R)-N-(cyclobutylmethyl)-1-(4-(1-(4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)ethyl)phenyl)piperidin-3-amine
(R)-4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-((5-(5-methoxypyridin- 3-yl)-1,3,4-thiadiazol-2-yl)methyl)pyridin-2(1H)-one 1-(1-(4-(5-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)-4-((R)-3- ((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(pyridin-3-yl)- 1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (R)-N-(cyclobutylmethyl)-1-(6-((4-(5-methoxypyridin-3-yl)-1H-imidazol-1- yl)methyl)pyridazin-3-yl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(6-(2-(4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)propan-2-yl)pyridazin-3-yl)piperidin-3-amine N-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)propyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (3R)-N-(cyclobutylmethyl)-1-(6-(cyclopropyl(4-(5-methoxypyridin-3-yl)- 1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)propyl)pyridazin-3-yl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(5-((4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-2-yl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)piperidin-3-amine 2-(1-(1-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-2-oxopyridin- 1(2H)-yl)ethyl)-1H-1,2,3-triazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 2-(1-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)ethyl)-1H-1,2,3-triazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 7-chloro-2-(1-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1- yl)pyridazin-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4- one
N-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)ethyl)-8-(methylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2- carboxamide N-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)ethyl)-7-methoxy-1H-indazole-4-carboxamide 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- methoxypyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-fluoropyridin- 3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (R)-4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-((5-(5-methoxypyridin- 3-yl)-1H-pyrazol-3-yl)methyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (methylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (R)-4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-((2-(5-methoxypyridin- 3-yl)thiazol-5-yl)methyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- methoxypyridin-3-yl)-1H-imidazol-1-yl)ethyl)pyridin-2(1H)-one 2-(1-(1-(5-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2- yl)ethyl)-1H-1,2,3-triazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one N-(1-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)phenyl)ethyl)-4- oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-(cyclobutylmethyl)-1-(6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1- yl)methyl)pyridazin-3-yl)azepan-3-amine 2-(1-(1-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)phenyl)ethyl)- 1H-1,2,3-triazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-ethoxypyridin- 3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-methoxy-6- methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6- methoxypyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one
4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(5-(5- methoxypyridin-3-yl)-2H-tetrazol-2-yl)ethyl)pyridin-2(1H)-one (R)-4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-((1-(5-methoxypyridin- 3-yl)-1H-pyrazol-4-yl)methyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-methoxy-4- methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 3-(1-(1-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-2-oxopyridin- 1(2H)-yl)ethyl)-1H-1,2,3-triazol-4-yl)-5-methoxypicolinonitrile N-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)ethyl)-4-thioxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)ethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbothioamide N-(1-(5-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2- yl)ethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (dimethylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-methoxy-2- methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)cyclopropyl)pyridazin-3-yl)piperidin-3-amine 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-((R)-1-(4-(5- methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridine-2(1H)-thione N-(1-(5-((R)-3-(cyclopentylamino)piperidin-1-yl)pyridin-2-yl)ethyl)-4-oxo- 4H-pyrido[1,2-a]pyrimidine-2-carboxamide (R)-N-(cyclobutylmethyl)-1-(6-((4-(5-methoxypyridazin-3-yl)-1H-1,2,3- triazol-1-yl)methyl)pyridin-3-yl)piperidin-3-amine 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(5-(5-methoxy pyridin-3-yl)-1,3,4-thiadiazol-2-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(1-(5-methoxy pyridin-3-yl)-1H-pyrazol-4-yl)ethyl)pyridin-2(1H)-one
4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-(methyl amino)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(methyl amino)pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (R)-N-(cyclobutylmethyl)-1-(4-((4-(6-methoxy-1H-indazol-4-yl)-1-1,2,3- triazol-1-yl)methyl)phenyl)piperidin-3-amine 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(imidazo[1,5- a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(3-(5- methoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-3-fluoro-1-(1-(4-(5- methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (R)-2-(1-((5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl) methyl)-1H-1,2,3-triazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (R)-2-(1-(4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)benzyl)-1H-1,2,3- triazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- morpholinopyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(3-(5- methoxypyridin-3-yl)isoxazol-5-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (difluoromethoxy)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)- one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(1-(5- methoxypyridin-3-yl)-1H-1,2,3-triazol-4-yl)ethyl)pyridin-2(1H)-one 5-(1-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)ethyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylpyridin-3-amine (R)-N-(cyclobutylmethyl)-1-(4-(3-(4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)oxetan-3-yl)phenyl)piperidin-3-amine 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(3-(5- methoxypyridin-3-yl)-1H-1,2,4-triazol-1-yl)ethyl)pyridin-2(1H)-one
(R)-N-(cyclobutylmethyl)-1-(4-((4-(5-methoxypyridazin-3-yl)-1H-1,2,3- triazol-1-yl)methyl)phenyl)piperidin-3-amine (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(5-methoxypyridazin-3-yl)-1H-1,2,3- triazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (3R)-N-(cyclobutylmethyl)-1-(6-fluoro-5-(1-(4-(5-methoxypyridin-3-yl)-1H- 1,2,3-triazol-1-yl)ethyl)pyridin-2-yl)piperidin-3-amine (R)-5-(1-((5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2- yl)methyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylpyridin-3-amine (R)-5-(1-(4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)benzyl)-1H-1,2,3- triazol-4-yl)-N,N-dimethylpyridin-3-amine 2-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)-N-(5- methoxypyridin-3-yl)propanamide 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (dimethylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 5-(1-(1-(5-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2- yl)ethyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylpyridin-3-amine (R)-N-(cyclobutylmethyl)-1-(4-((4-(5-methoxypyridin-3-yl)-1H-imidazol-1- yl)methyl)phenyl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(4-((5-(5-methoxypyridin-3-yl)-2H-tetrazol-2- yl)methyl)phenyl)piperidin-3-amine 1-(1-(4-(5-(1H-pyrazol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)-4- ((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2(1H)-one 1-(1-(4-(1H-pyrazolo[3,4-c]pyridin-4-yl)-1H-1,2,3-triazol-1-yl)ethyl)-4-((R)- 3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2(1H)-one (R)-5-(1-(3-(4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)phenyl)oxetan-3- yl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylpyridin-3-amine (R)-5-(1-(3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2- yl)oxetan-3-yl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylpyridin-3-amine (R)-N-(cyclobutylmethyl)-1-(6-(3-(4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine
4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (ethyl(methyl)amino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 1-(1-(4-(5-bromopyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)-4-((R)-3- ((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(3-methyl-2- oxoimidazolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(methyl(2,2,2- trifluoroethyl)amino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)- one (R)-5-(1-(1-(4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)phenyl)vinyl)- 1H-1,2,3-triazol-4-yl)-N,N-dimethylpyridin-3-amine 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(1-(5- (dimethylamino)pyridin-3-yl)-1H-pyrazol-4-yl)ethyl)pyridin-2(1H)-one 2-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)-N-(5- (dimethylamino)pyridin-3-yl)propanamide 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (isopropylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(2- oxopyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)- one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(pyrrolidin-1- yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 1-(1-(4-(5-(azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)-4-((R)-3- ((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2(1H)-one 2-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-2-oxopyridin-1(2H)- yl)-N-(5-(dimethylamino)pyridin-3-yl)propanamide (R)-4-(3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-((4-(5- (dimethylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-6- methylpyridin-2(1H)-one
4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6- (dimethylamino)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 1-(5-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-1-(2-(5- methoxypyridin-3-yl)thiazol-5-yl)ethan-1-ol 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (dimethylamino)pyridin-3-yl)-1H-imidazol-1-yl)ethyl)pyridin-2(1H)-one (3R)-N-(cyclobutylmethyl)-1-(6-(1-(2-(6-methoxy-1H-indazol-4-yl)thiazol- 5-yl)ethyl)pyridin-3-yl)piperidin-3-amine 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(4- methylpiperazin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 5-(5-(1-(5-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2- yl)ethyl)thiazol-2-yl)-N,N-dimethylpyridin-3-amine 2-(1-(1-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-2-oxopyridin- 1(2H)-yl)ethyl)-1H-imidazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(5-(5- (dimethylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(2- methylpyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 5-(1-(1-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)ethyl)-1H-imidazol-4-yl)-N,N-dimethylpyridin-3-amine (R)-4-(3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-((4-(5- (dimethylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2(1H)- one (R)-3-(5-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(5- (dimethylamino)pyridin-3-yl)oxetane-3-carboxamide 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(pyrrolidin- 1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one
4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(3- methylazetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)- one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(piperidin-1- yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(5-(5- (dimethylamino)pyridin-3-yl)-2H-tetrazol-2-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-(pyrrolidin- 1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (3R)-N-(cyclobutylmethyl)-1-(6-(1-(2-(5-methoxypyridin-3-yl)thiazol-5- yl)ethyl)pyridin-3-yl)piperidin-3-amine (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(5-methoxypyridin-3-yl)-1H- imidazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (R)-5-(1-((6-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridazin-3- yl)methyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylpyridin-3-amine (R)-5-(1-(3-(5-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2- yl)oxetan-3-yl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylpyridin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6- (dimethylamino)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(5-ethoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-methoxy-1H- indazol-4-yl)-1H-imidazol-1-yl)ethyl)pyridin-2(1H)-one 5-(1-(1-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)phenyl)ethyl)- 1H-1,2,3-triazol-4-yl)-N,N-dimethylpyridin-3-amine (3R)-N-(cyclobutylmethyl)-1-(6-(1-(5-(5-methoxypyridin-3-yl)-2H-tetrazol- 2-yl)ethyl)pyridazin-3-yl)piperidin-3-amine
1-(1-(4-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-3-yl)-1H-1,2,3-triazol- 1-yl)ethyl)-4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2(1H)- one (R)-6-(1-(3-(5-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2- yl)oxetan-3-yl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylpyrazin-2-amine 1-(1-(4-(5-(2-azaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-1,2,3-triazol-1- yl)ethyl)-4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2(1H)- one (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (R)-3-(5-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(5- (pyrrolidin-1-yl)pyridin-3-yl)oxetane-3-carboxamide 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(1-(5- (dimethylamino)pyridin-3-yl)-1H-pyrazol-4-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(3,3- difluoroazetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (dimethylamino)pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)- one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(3- methoxyazetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(2,2,2- trifluoroethoxy)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (R)-4-(3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-((4-(6-(pyrrolidin-1- yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2(1H)-one (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-(pyrrolidin-1-yl)pyridazin-3-yl)- 1H-1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine
4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (ethyl(methyl)amino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(3-(5- methoxypyridin-3-yl)isothiazol-5-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-((2- hydroxyethyl)amino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)- one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(pyrrolidin- 1-yl)pyridazin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (R)-N-(cyclopropylmethyl)-1-(5-(3-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-2-yl)piperidin-3-amine 2-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-2-oxopyridin-1(2H)- yl)-N-(5-(pyrrolidin-1-yl)pyridin-3-yl)propanamide 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(3- (difluoromethyl)azetidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1- yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-(1-(5-(6-methoxy-1H- indazol-4-yl)-2H-tetrazol-2-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(1,1- difluoro-5-azaspiro[2.3]hexan-5-yl)pyridin-3-yl)-1H-1,2,3-triazol-1- yl)ethyl)pyridin-2(1H)-one (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)pyridazin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)pyridazin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(6-(3,3-dimethylpyrrolidin-1- yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3- amine
(R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(6-(3,3-difluoropyrrolidin-1- yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3- amine (3R)-1-(6-(3-(4-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)-1H-1,2,3- triazol-1-yl)oxetan-3-yl)pyridin-3-yl)-N-(cyclopropylmethyl)piperidin-3- amine (R)-3-(5-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(4- oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide 1-(1-(4-(5-(1H-imidazol-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)-4- ((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(1-(5-(pyrrolidin- 1-yl)pyridazin-3-yl)-1H-pyrazol-4-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(1-(6-(pyrrolidin- 1-yl)pyrazin-2-yl)-1H-pyrazol-4-yl)ethyl)pyridin-2(1H)-one (R)-1-(6-(3-(4-(6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-2-yl)-1H-1,2,3- triazol-1-yl)oxetan-3-yl)pyridin-3-yl)-N-(cyclopropylmethyl)piperidin-3- amine (R)-1-(6-(3-(4-(6-(5-azaspiro[2.4]heptan-5-yl)pyrazin-2-yl)-1H-1,2,3-triazol- 1-yl)oxetan-3-yl)pyridin-3-yl)-N-(cyclopropylmethyl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(5-(3-(4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-2-yl)piperidin-3-amine 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(1-(5- (dimethylamino)pyridazin-3-yl)-1H-pyrazol-4-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(1-(6- (dimethylamino)pyrazin-2-yl)-1H-pyrazol-4-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-(pyrrolidin- 1-yl)pyrazin-2-yl)-1H-imidazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-(3,3- difluoropyrrolidin-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one
4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(5-(6-(pyrrolidin- 1-yl)pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6- (dimethylamino)pyrazin-2-yl)-1H-imidazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-(3,3- dimethylpyrrolidin-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(5-(6- (dimethylamino)pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(2-(6-(pyrrolidin- 1-yl)pyrazin-2-yl)thiazol-5-yl)ethyl)pyridin-2(1H)-one 1-(1-(4-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1- yl)ethyl)-4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2(1H)- one 1-(1-(4-(6-(5-azaspiro[2.4]heptan-5-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1- yl)ethyl)-4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2(1H)- one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (methyl(trifluoromethyl)amino)pyridin-3-yl)-1H-1,2,3-triazol-1- yl)ethyl)pyridin-2(1H)-one 1-(1-(4-(6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-2-yl)-1H-1,2,3-triazol- 1-yl)ethyl)-4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin- 2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-((R)-3- methylpyrrolidin-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one (R)-3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(4- oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide
4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-((S)-3- methylpyrrolidin-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-((S)-3- fluoropyrrolidin-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(2-(6-(pyrrolidin- 1-yl)pyrazin-2-yl)oxazol-5-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (dimethylamino)pyridazin-3-yl)-1H-imidazol-1-yl)ethyl)pyridin-2(1H)-one (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(6-((R)-3-methylpyrrolidin-1- yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3- amine 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-((R)-3- fluoropyrrolidin-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-(3- methoxyazetidin-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin- 2(1H)-one 1-(1-(4-(6-(5-azaspiro[2.3]hexan-5-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1- yl)ethyl)-4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2(1H)- one (R)-3-(5-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(6- (pyrrolidin-1-yl)pyrazin-2-yl)oxetane-3-carboxamide (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-methoxypyridin-3-yl)-1H-1,2,3- triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1H- imidazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine 2-(6-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)-N-(5- (pyrrolidin-1-yl)pyridin-3-yl)propanamide
4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5-(pyrrolidin- 1-yl)pyridin-3-yl)-1H-imidazol-1-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(1-(5-(pyrrolidin- 1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6-(1,1- difluoro-5-azaspiro[2.3]hexan-5-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1- yl)ethyl)pyridin-2(1H)-one 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(6- methylpyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3- triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H- 1,2,3-triazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(6-methoxypyrazin-2-yl)-1H-1,2,3- triazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)- 1H-1,2,3-triazol-1-yl)ethyl)pyridin-3-yl)piperidin-3-amine 6-(1-(1-(5-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2- yl)ethyl)-1H-1,2,3-triazol-4-yl)-N,N-dimethylpyrazin-2-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(4-(6-methoxypyrazin-2-yl)-1H-1,2,3- triazol-1-yl)ethyl)pyridin-3-yl)piperidin-3-amine (R)-3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(6- (pyrrolidin-1-yl)pyrazin-2-yl)oxetane-3-carboxamide (R)-3-(5-(3-(((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)piperidin-1- yl)pyridin-2-yl)-N-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3- carboxamide 2-(5-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(5- (pyrrolidin-1-yl)pyridin-3-yl)propanamide 2-(5-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(4- oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)propanamide
4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- (dimethylamino)pyridin-3-yl)-1H-imidazol-1-yl)ethyl)pyridin-2(1H)-one (R)-N-(cyclobutylmethyl)-1-(6-(3-(4-(5-methoxypyridin-3-yl)-1H-imidazol- 1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (R)-3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(6- cyclopentylpyrazin-2-yl)oxetane-3-carboxamide (R)-3-(5-(3-(((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)piperidin-1- yl)pyridin-2-yl)-N-(6-(pyrrolidin-1-yl)pyrazin-2-yl)oxetane-3-carboxamide N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)-3-(5-((R)-3- ((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)oxetane-3- carboxamide (R)-2-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(5- (pyrrolidin-1-yl)pyridin-3-yl)acetamide (R)-3-(5-(3-((cyclobutylmethyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)- N-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(6- methoxy-1H-indazol-4-yl)oxetane-3-carboxamide 2-(5-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(6- (pyrrolidin-1-yl)pyrazin-2-yl)propanamide 2-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)-N-(4- oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)propanamide (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(5-methoxypyridin-3-yl)-1H- imidazol-1-yl)ethyl)pyridin-3-yl)piperidin-3-amine (R)-2-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(6- (pyrrolidin-1-yl)pyrazin-2-yl)acetamide (R)-3-(4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)phenyl)-N-(4-oxo-4H- pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide 2-(6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)-N-(6- (pyrrolidin-1-yl)pyrazin-2-yl)propanamide (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1H- 1,2,3-triazol-1-yl)ethyl)pyridin-3-yl)piperidin-3-amine
(R)-3-(4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)phenyl)-N-(6- (pyrrolidin-1-yl)pyrazin-2-yl)oxetane-3-carboxamide (R)-N-(cyclobutylmethyl)-1-(6-((4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1H- 1,2,3-triazol-1-yl)methyl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(6-(3-(4-(6-cyclopropylpyrazin-2-yl)-1H-1,2,3- triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (3R)-1-(6-(1-(4-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)-1H-1,2,3- triazol-1-yl)ethyl)pyridazin-3-yl)-N-(cyclobutylmethyl)piperidin-3-amine (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1H- 1,2,3-triazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (3R)-1-(6-(1-(4-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)-1H-1,2,3- triazol-1-yl)ethyl)pyridin-3-yl)-N-(cyclobutylmethyl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(4-((4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1H- 1,2,3-triazol-1-yl)methyl)phenyl)piperidin-3-amine (3R)-1-(4-((4-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)-1H-1,2,3- triazol-1-yl)methyl)phenyl)-N-(cyclobutylmethyl)piperidin-3-amine (R)-1-(6-(3-(4-(6-(1H-pyrazol-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1- yl)oxetan-3-yl)pyridin-3-yl)-N-(cyclobutylmethyl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(6-(3-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (3R)-1-(6-(3-(4-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)-1H-1,2,3- triazol-1-yl)oxetan-3-yl)pyridin-3-yl)-N-(cyclobutylmethyl)piperidin-3- amine (3R)-N-(cyclobutylmethyl)-1-(6-(1-(4-(6-cyclopropylpyrazin-2-yl)-1H-1,2,3- triazol-1-yl)ethyl)pyridin-3-yl)piperidin-3-amine (3R)-1-(6-(1-(4-(6-(1H-pyrazol-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1- yl)ethyl)pyridin-3-yl)-N-(cyclobutylmethyl)piperidin-3-amine 2-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)phenyl)-N-(6- (pyrrolidin-1-yl)pyrazin-2-yl)propanamide (R)-1-(6-(3-(4-(6-(1H-pyrrol-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1- yl)oxetan-3-yl)pyridin-3-yl)-N-(cyclobutylmethyl)piperidin-3-amine
(3R)-N-(cyclobutylmethyl)-1-(4-(1-(4-(5-methoxypyridin-3-yl)-1H- imidazol-1-yl)ethyl)phenyl)piperidin-3-amine (R)-3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N- (quinoxalin-2-yl)oxetane-3-carboxamide (R)-3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-3-fluoropyridin-2-yl)- N-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(1H- pyrrolo[2,3-b]pyridin-5-yl)oxetane-3-carboxamide (3R)-N-(cyclobutylmethyl)-1-(6-(1-(1-(5-methoxypyridin-3-yl)-1H-pyrazol- 4-yl)ethyl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(4-(3-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)phenyl)piperidin-3-amine (R)-3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(1- oxo-1,2-dihydroisoquinolin-3-yl)oxetane-3-carboxamide (3R)-N-(cyclobutylmethyl)-1-(5-fluoro-6-(1-(4-(6-(pyrrolidin-1-yl)pyrazin- 2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-3-yl)piperidin-3-amine (3R)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1-(6-(1-(4-(6- (pyrrolidin-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-3- yl)piperidin-3-amine (3R)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1-(6-(1-(4-(6- (pyrrolidin-1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridazin-3- yl)piperidin-3-amine (R)-N-(cyclobutylmethyl)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3- triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (R)-1-(6-(3-(4-(5-cyclobutoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)oxetan-3- yl)pyridin-3-yl)-N-(cyclobutylmethyl)piperidin-3-amine (R)-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1-(6-(3-(4-(6-(pyrrolidin- 1-yl)pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin- 3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)- 1H-1,2,3-triazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine
(R)-3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(1- methyl-2-oxo-6-(pyrrolidin-1-yl)-1,2-dihydropyridin-4-yl)oxetane-3- carboxamide (R)-3-(5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(5- oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)oxetane-3-carboxamide (R)-1-(6-(3-(4-(5-cyclobutylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)oxetan-3- yl)pyridin-3-yl)-N-(cyclopropylmethyl)piperidin-3-amine (R)-1-(6-(3-(4-(5-cyclopentylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)oxetan-3- yl)pyridin-3-yl)-N-(cyclopropylmethyl)piperidin-3-amine (R)-4-(1-(3-(5-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2- yl)oxetan-3-yl)-1H-1,2,3-triazol-4-yl)-1-methyl-6-(pyrrolidin-1-yl)pyridin- 2(1H)-one (R)-N-(cyclopropylmethyl)-1-(6-(1-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3- triazol-1-yl)-3,3-difluorocyclobutyl)pyridin-3-yl)piperidin-3-amine (R)-2-(1-(3-(5-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-2- yl)oxetan-3-yl)-1H-1,2,3-triazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (3R)-N-(cyclopropylmethyl)-1-(6-(1-(4-(5-cyclopropylpyridin-3-yl)-1H- 1,2,3-triazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(4-(5-cyclopropylpyridin-3-yl)-1H- 1,2,3-triazol-1-yl)ethyl)-5-methylpyridin-3-yl)piperidin-3-amine (R)-3-(6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-3-yl)-N-(6- (pyrrolidin-1-yl)pyrazin-2-yl)oxetane-3-carboxamide 4-((R)-3-((cyclopropylmethyl)amino)piperidin-1-yl)-1-(1-(4-(5- cyclopropylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethyl)pyridin-2(1H)-one (R)-3-(6-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-3-yl)-N-(4- oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-3-(6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridin-3-yl)-N-(4- oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(6-cyclopropylpyrazin-2-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine
(R)-3-(6-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridin-3-yl)-N-(6- (pyrrolidin-1-yl)pyrazin-2-yl)oxetane-3-carboxamide (R)-3-(5-(3-((cyclopentylmethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(4- oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-3-(5-(3-(cyclopentylamino)piperidin-1-yl)pyridin-2-yl)-N-(4-oxo-4H- pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-3-(5-(3-(cyclobutylamino)piperidin-1-yl)pyridin-2-yl)-N-(4-oxo-4H- pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-N-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-3-(5-(3-(((1- (trifluoromethyl)cyclopropyl)methyl)amino)piperidin-1-yl)pyridin-2- yl)oxetane-3-carboxamide (R)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)oxetan-3- yl)pyridin-3-yl)-N-isobutylpiperidin-3-amine (R)-3-(5-(3-(((1-fluorocyclopropyl)methyl)amino)piperidin-1-yl)pyridin-2- yl)-N-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-3-(5-(3-(((1-methylcyclopropyl)methyl)amino)piperidin-1-yl)pyridin-2- yl)-N-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)oxetan-3- yl)pyridin-3-yl)-N-((1-fluorocyclopropyl)methyl)piperidin-3-amine (R)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)oxetan-3- yl)pyridin-3-yl)-N-((1-methylcyclopropyl)methyl)piperidin-3-amine (R)-N-cyclobutyl-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3-triazol-1- yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (R)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)oxetan-3- yl)pyridin-3-yl)-N-((1-(trifluoromethyl)cyclopropyl)methyl)piperidin-3- amine 3-(5-((3R)-3-((1-cyclobutylethyl)amino)piperidin-1-yl)pyridin-2-yl)-N-(4- oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-N-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-3-(5-(3-(((1- (trifluoromethyl)cyclobutyl)methyl)amino)piperidin-1-yl)pyridin-2- yl)oxetane-3-carboxamide
(R)-3-(5-(3-(((3,3-difluorocyclobutyl)methyl)amino)piperidin-1-yl)pyridin- 2-yl)-N-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)oxetane-3-carboxamide (R)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)oxetan-3- yl)pyridin-3-yl)-N-((1-(trifluoromethyl)cyclobutyl)methyl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)- 1H-imidazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (R)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)oxetan-3- yl)pyridin-3-yl)-N-((3,3-difluorocyclobutyl)methyl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(4-(5-cyclopropylpyridin-3-yl)-1H- imidazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-cyclopropylpyridazin-3-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(5-(5-cyclopropylpyridin-3-yl)-1,3,4- oxadiazol-2-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-(prop-1-yn-1-yl)pyridin-3-yl)-1H- 1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-(cyclopropylmethyl)pyridin-3-yl)- 1H-1,2,3-triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(5-(6-(pyrrolidin-1-yl)pyrazin-2-yl)- 1,3,4-oxadiazol-2-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (3R)-N-((1-methylcyclopropyl)methyl)-1-(6-(1-(4-(6-(pyrrolidin-1- yl)pyrazin-2-yl)-1H-imidazol-1-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3- triazol-1-yl)azetidin-3-yl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3- triazol-1-yl)-1-methylazetidin-3-yl)pyridin-3-yl)piperidin-3-amine (S)-N-(cyclopropylmethyl)-1-(6-(3-(4-(5-cyclopropylpyridin-3-yl)-1H-1,2,3- triazol-1-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(3-(5-(5-cyclopropylpyridin-3-yl)-1,3,4- thiadiazol-2-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine
(3R)-N-(cyclopropylmethyl)-1-(6-(1-(5-(6-(pyrrolidin-1-yl)pyrazin-2-yl)- 1,3,4-thiadiazol-2-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(1-(6-(pyrrolidin-1-yl)pyrazin-2-yl)- 1H-pyrazol-4-yl)ethyl)pyridin-3-yl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(4-(6-(pyrrolidin-1-yl)pyrazin-2-yl)- 1H-imidazol-1-yl)ethyl)pyridin-3-yl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(1-(5-cyclopropylpyridin-3-yl)-1H- pyrazol-4-yl)ethyl)pyridin-3-yl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(4-(5-cyclopropylpyridin-3-yl)-1H- 1,2,3-triazol-1-yl)ethyl)pyridin-3-yl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(5-(5-cyclopropylpyridin-3-yl)-1,3,4- thiadiazol-2-yl)ethyl)pyridazin-3-yl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(5-(5-cyclopropylpyridin-3-yl)-1,3,4- thiadiazol-2-yl)ethyl)pyridin-3-yl)piperidin-3-amine (3R)-N-(cyclopropylmethyl)-1-(6-(1-(5-(6-(pyrrolidin-1-yl)pyrazin-2-yl)- 1,3,4-thiadiazol-2-yl)ethyl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-((5-(6-(pyrrolidin-1-yl)pyrazin-2-yl)-1,3,4- thiadiazol-2-yl)methyl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-((5-(5-cyclopropylpyridin-3-yl)-1,3,4- thiadiazol-2-yl)methyl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(2-(5-(5-cyclopropylpyridin-3-yl)-1,3,4- thiadiazol-2-yl)propan-2-yl)pyridin-3-yl)piperidin-3-amine (R)-N-(cyclopropylmethyl)-1-(6-(2-(5-(6-(pyrrolidin-1-yl)pyrazin-2-yl)- 1,3,4-thiadiazol-2-yl)propan-2-yl)pyridin-3-yl)piperidin-3-amine (3R)-N-((1-methylcyclopropyl)methyl)-1-(6-(1-(4-(6-(pyrrolidin-1- yl)pyrazin-2-yl)-1H-imidazol-1-yl)ethyl)pyridin-3-yl)piperidin-3-amine (3R)-N-((1-methylcyclopropyl)methyl)-1-(6-(1-(5-(6-(pyrrolidin-1- yl)pyrazin-2-yl)-1,3,4-thiadiazol-2-yl)ethyl)pyridin-3-yl)piperidin-3-amine (R)-N-((1-methylcyclopropyl)methyl)-1-(6-(3-(5-(6-(pyrrolidin-1-yl)pyrazin- 2-yl)-1,3,4-thiadiazol-2-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine
368 (R)-1-(6-(3-(5-(5-cyclopropylpyridin-3-yl)-1,3,4-thiadiazol-2-yl)oxetan-3- yl)pyridin-3-yl)-N-((1-methylcyclopropyl)methyl)piperidin-3-amine 369 (R)-N-(cyclopropylmethyl)-1-(6-(3-(5-(6-(pyrrolidin-1-yl)pyrazin-2-yl)- 1,3,4-thiadiazol-2-yl)oxetan-3-yl)pyridin-3-yl)piperidin-3-amine and stereoisomers thereof, and pharmaceutically acceptable salts and/or solvates thereof. [0120] The compounds of Table 1 were named using ChemDraw 21® purchased from CambridgeSoft (Cambridge, MA, USA). [0121] In one particular embodiment, the compound of formula (I) is selected from compounds 001, 058, 068, 107, 142, 149, 160, 166, 171, 176, 180, 185, 194, 196, 212, 220, 239, 248, 250, 256, 259, 263, 309, 352, 361, 367, 368, as defined in Table 1, and stereoisomers thereof, and pharmaceutically acceptable salts and/or solvates thereof. [0122] 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. [0123] 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), subformulae 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.
[0124] Bonds from an asymmetric carbon in compounds are generally depicted using a solid line ( ), a solid wedge ( ), or a dotted wedge ( ).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. [0125] All references to compounds of formula (I) include references to isotopically-labelled compounds of formula (I), including deuterated compounds of formula (I). [0126] 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. [0127] 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. [0128] 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. [0129] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. [0130] 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 compounds are 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. [0131] 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. [0132] 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. [0133] 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. [0134] 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. BCL2 inhibitor [0135] The combination therapies of the invention comprise the administration of a BCL2 inhibitor. [0136] In one embodiment, any BCL2 inhibitor may be used in the combination therapy of the invention. In a preferred embodiment, any BCL2 inhibitor approved for therapeutic use may be used in the combination therapy of the invention. [0137] In one embodiment, the BLC2 inhibitor is selected from venetoclax, oblimersen, obatoclax, navitoclax, pelcitoclax, R-(-)-gossypol, and pharmaceutically acceptable salts thereof. [0138] Venetoclax, also known as ABT-199, GDC-0199 or RG-7601, corresponds to 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N- (3-nitro-4-{[(oxan-4-yl)methyl]amino}benzenesulfonyl)-2-{1H-pyrrolo[2,3-b]pyridin- 5-yloxy}benzamide (CAS number 1257044-40-8). [0139] Oblimersen, also known as G3139, is an antisense oligonucleotide. In one embodiment, oblimersen is used under the form of a sodium salt, referred to as oblimersen sodium (CAS number 190977-41-4). [0140] Obatoclax, also known as GX15-070, corresponds to 2-[(2Z)-2-[(3,5-dimethyl- 1H-pyrrol-2-yl)methylidene]-3-methoxy-2H-pyrrol-5-yl]-1H-indole (CAS number
803712-67-6). In one embodiment, obatoclax is used under the form of a mesylate salt, referred to as obatoclax mesylate (CAS number 803712-79-0). [0141] Navitoclax, also known as ABT-263, corresponds to 4-(4-{[2-(4-chlorophenyl)- 5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-(4-{[(2R)-4-(morpholin-4- yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-trifluoromethanesulfonylbenzene sulfonyl)benzamide (CAS number 923564-51-6). [0142] Pelcitoclax, also known as APG-1252, corresponds to (3-{1-[(3R)-3-[(4-{[4-(4- {3-[2-(4-chlorophenyl)-4-methanesulfonyl-5-methyl-1-(propan-2-yl)-1H-pyrrol-3-yl]-5- fluorophenyl}piperazin-1-yl)phenyl]sulfamoyl}-2-trifluoromethanesulfonylphenyl) amino]-4-(phenylsulfanyl)butyl]piperidine-4-carbonyloxy}propyl)phosphonic acid (CAS number 1619923-36-2). [0143] R-(-)-gossypol, also known as AT-101, corresponds to 7-(8-formyl-1,6,7- trihydroxy-3-methyl-5-propan-2-ylnaphthalen-2-yl)-2,3,8-trihydroxy-6-methyl-4- propan-2-ylnaphthalene-1-carbaldehyde (CAS number 303-45-7). In one embodiment, R-(-)-gossypol is used under the form of a salt of acetic acid, referred to as R-(-)-gossypol acetic acid (CAS number 866541-93-7). [0144] In a preferred embodiment, the BCL2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof. [0145] Suitable pharmaceutically acceptable salts are as those defined above with regards to compounds of formula (I). Combination [0146] In a first aspect, the invention thus relates to a combination comprising: (i) a BCL2 inhibitor, as defined above, or a pharmaceutically acceptable salt thereof; and (ii) a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and/or solvate thereof.
[0147] In one embodiment, the BCL2 inhibitor is a BCL2 inhibitor approved for therapeutic use, and the compound of formula (I) is as defined herein, or a pharmaceutically acceptable salt and/or solvate thereof. [0148] In one embodiment, the BCL2 inhibitor is selected from venetoclax, oblimersen, obatoclax, navitoclax, pelcitoclax, R-(-)-gossypol, and pharmaceutically acceptable salts thereof; and the compound of formula (I) is as defined herein, or a pharmaceutically acceptable salt and/or solvate thereof. [0149] In one embodiment, the BCL2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof; and the compound of formula (I) is as defined herein, or a pharmaceutically acceptable salt and/or solvate thereof. [0150] In one embodiment, the BCL2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof; and the compound of formula (I) is selected from any one of the compounds of the Table 1, and stereoisomers thereof, and pharmaceutically acceptable salts and/or solvates thereof. [0151] In one embodiment, the BCL2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof; and the compound of formula (I) is selected from compounds 001, 058, 068, 107, 142, 149, 160, 166, 171, 176, 180, 185, 194, 196, 212, 220, 239, 248, 250, 256, 259, 263, 309, 352, 361, 367, 368, as defined in Table 1, and stereoisomers thereof, and pharmaceutically acceptable salts and/or solvates thereof. [0152] In the combination of the invention, a METTL3 inhibitor of formula (I) as defined herein, or a pharmaceutically acceptable salt and/or solvate thereof, is administered “in combination with” a BCL2 inhibitor, or a pharmaceutically acceptable salt thereof, or vice versa, which includes, unless otherwise stated otherwise, the both agents being administered sequentially, separately or simultaneously with one another. [0153] As used herein “simultaneous administration” refers to therapy in which the both agents (e.g. a compound of formula (I) as defined herein, and a BCL2 inhibitor) are administered at the same time.
[0154] As used herein, “separate administration” means that one agent is administered after the other, however, the time period between administration is such that the first administered agent is no longer present at a therapeutically effective amount when the second agent is administered. Accordingly, the two agents exert their therapeutic effects separately. Nevertheless, the overall therapeutic effect observed when the two agents separately act therapeutically may be greater than either agent used alone. [0155] As used herein “sequential administration” means that one agent is administered after the other, however, the time period between the administration of each agent is such that both agents are capable of acting therapeutically concurrently. Thus, administration “sequentially” may permit one agent to be administered within seconds, minutes, or a matter of hours after the other, provided the circulatory half-life of the first administered agent is such that they are both concurrently present in therapeutically effective amounts. The time delay between the administration of the agents may vary depending on the exact nature of the agents, the interaction there between, and their respective half-lives. [0156] The administration of the both agents may occur with similar or different numbers of administration for each agent. The administration of the both agents may occur either at the same site of administration or at different sites of administration, under similar or different dosage forms. [0157] 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. Pharmaceutical products [0158] In a second aspect, the invention thus relates to a pharmaceutical product comprising a combination according to the invention, i.e. a combination of (i) a BCL2 inhibitor (e.g. venetoclax), as defined above, or a pharmaceutically acceptable salt
thereof; and (ii) a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and/or solvate thereof. [0159] In one embodiment, the pharmaceutical product may comprise one or more unit dosage forms (e.g. vials, tablets or capsules in a blister pack). In one embodiment, each unit dose comprises only one agent selected from the BCL2 inhibitor (e.g. venetoclax), as defined above, and the compound of formula (I) as defined above. In another embodiment, the unit dosage form comprises both the BCL2 inhibitor (e.g. venetoclax), as defined above, and the compound of formula (I) as defined above. [0160] In one embodiment, the pharmaceutical product may comprise a kit of parts comprising separate formulations of (i) a BCL2 inhibitor (e.g. venetoclax), as defined above, or a pharmaceutically acceptable salt thereof; and (ii) a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and/or solvate thereof. The separate formulations may be administered sequentially, separately and/or simultaneously, as detailed above. [0161] In one embodiment, the pharmaceutical product is a kit of parts which comprises: (a) a first part comprising a BCL2 inhibitor, or a pharmaceutically acceptable salt thereof, as defined herein; and (b) a second part comprising a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt and/or solvate thereof. [0162] In one embodiment, the kit of parts comprises: (a) a first container comprising a BCL2 inhibitor, or a pharmaceutically acceptable salt thereof, as defined herein, and one or more pharmaceutically acceptable carrier; (b) a second container comprising a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt and/or solvate thereof, and one or more pharmaceutically acceptable carrier; and (c) a container means for containing said first and second containers.
[0163] In another embodiment, the pharmaceutical product is a pharmaceutical composition comprising a combination according to the invention, and one or more pharmaceutically acceptable carrier. [0164] In one embodiment, the pharmaceutical product is a pharmaceutical composition comprises: (i) a BCL2 inhibitor, as defined above, or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (I) as defined above, or a pharmaceutically acceptable salt and/or solvate thereof; and (iii) one or more pharmaceutically acceptable carrier. [0165] In one embodiment the pharmaceutical product further comprises means for facilitating compliance with a dosage regimen, for instance instructions detailing how to administer the combination. [0166] In one embodiment, the pharmaceutical product further comprises instructions indicating that the combination, as defined herein, can be used in the treatment of cancer. Pharmaceutical formulations and administration [0167] As detailed above, the pharmaceutical product of the invention can be a kit of part wherein each agent of the combination is in a separate pharmaceutical formulation, or the pharmaceutical product of the invention can be a single pharmaceutical formulation comprising the both agents of the combination of the invention (i.e. a pharmaceutical composition). [0168] The pharmaceutical formulations may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for
intravenous, subcutaneous, intramuscular or intraperitoneal dosing, or as a suppository for rectal dosing). [0169] The pharmaceutical formulations may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, formulations intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. [0170] The pharmaceutical formulations 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 agent into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical formulations are prepared by uniformly and intimately bringing the active agent into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired dosage form. [0171] An effective amount of each component of the combination therapy is present. Such an amount is an amount sufficient to treat or prevent a cancer condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition. [0172] The amount of active agent that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. [0173] The size of the dose for therapeutic or prophylactic purposes of a combination of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the patient and the route of administration, according to well-known principles of medicine. [0174] In using a combination of the invention for therapeutic or prophylactic purposes it will generally be administered within a therapeutically effective dose of the particular agent concerned. These dosages are known in the art and will vary from one agent to another. Suitable dosing schedules are known in the art. For example, 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 active agents 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. Therapeutic uses [0175] In a third aspect, the invention also relates to the use of the combination of the invention and its related products, i.e. the pharmaceutical product, kit of part and pharmaceutical composition, in the treatment of cancer. [0176] The invention thus relates to the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, for use in the treatment of cancer in a patient in need thereof. The invention also relates to the use of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment of cancer in a patient in need thereof. The invention further relates to a method of treatment of cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention. [0177] In one embodiment, the invention also relates a compound of formula (I) as herein defined, for use in the treatment of cancer in a patient in need thereof, wherein the compound of formula (I) is for administration in combination with a BCL2 inhibitor as herein defined. The invention also relates to the use of a compound of formula (I) as
herein defined, in the manufacture of a medicament for use in the treatment of cancer in a patient in need thereof, wherein the compound of formula (I) is for administration in combination with a BCL2 inhibitor as herein defined. The invention further relates to a method of treatment of cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) as herein defined, in combination with a BCL2 inhibitor as herein defined. [0178] In another embodiment, the invention also relates a BCL2 inhibitor as herein defined, for use in the treatment of cancer in a patient in need thereof, wherein the BCL2 inhibitor is for administration in combination with a compound of formula (I) as herein defined. The invention also relates to the use of a BCL2 inhibitor as herein defined, in the manufacture of a medicament for use in the treatment of cancer in a patient in need thereof, wherein the a BCL2 inhibitor is for administration in combination with a compound of formula (I) as herein defined. The invention further relates to a method of treatment of cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a BCL2 inhibitor as herein defined, in combination with a compound of formula (I) as herein defined. [0179] By “administration in combination with” it is meant that the agents are being administered sequentially, separately or simultaneously with one another. [0180] In one embodiment, the treated cancer is a cancer in which METTL3 and/or BCL2 activity is implicated. In one embodiment, the treated cancer is a cancer in which METTL3 activity is implicated. In one embodiment, the treated cancer is a cancer in which BCL2 activity is implicated. In one embodiment, the treated cancer is a cancer in which METTL3 and BCL2 activities are implicated. [0181] In one embodiment, the treated cancer is a hematological cancer. [0182] Hematological cancers begin in the cells of the immune system or in blood- forming tissue, such as the bone marrow. Common types of hematologic cancer are lymphoma, myeloma, and leukemia.
[0183] Lymphomas start in the lymph system, the part of the immune system that fights infection. Because the lymph system is found throughout the body, lymphoma can begin almost anywhere. The two main types are Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma (NHL). Example of NHL include Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL). [0184] Myeloma is a cancer of the plasma cells, the white blood cells that make antibodies that protect against infection. Examples of myelomas include multiple myeloma (MM). [0185] Leukemia is a cancer of the blood cells and bone marrow (the soft, sponge-like tissue in the center of most bones that makes blood cells). There are several types of leukemia, grouped by whether it grows faster (acute) or slower (chronic) and whether it starts in lymphocytic cells or myelogenous cells. Examples of leukemias include acute myeloid leukaemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukaemia (CLL), myelodysplastic syndromes (MDS). [0186] Examples of hematological cancers include acute myeloid leukaemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndromes (MDS), non-Hodgkin lymphoma (NHL), Burkitt lymphoma, diffuse large B- cell lymphoma (DLBCL), Hodgkin lymphoma (cHL), myeloma, multiple myeloma (MM). [0187] In one embodiment, the treated cancer is selected from lymphomas, myelomas, and leukemias. [0188] In one embodiment, the treated cancer is selected from acute myeloid leukaemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukaemia, small lymphocytic lymphoma, myelodysplastic syndromes, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, myeloma, and multiple myeloma.
[0189] In another aspect, the invention also relates to the use of the combination of the invention and its related products, i.e. the pharmaceutical product, kit of part and pharmaceutical composition, in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer). [0190] The invention thus relates to the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial, in a patient in need thereof. The invention also relates to the use of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial, in a patient in need thereof. The invention further relates to a method of treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention. [0191] In one embodiment, the invention also relates a compound of formula (I) as herein defined, for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial, in a patient in need thereof, wherein the compound of formula (I) is for administration in combination with a BCL2 inhibitor as herein defined. The invention also relates to the use of a compound of formula (I) as herein defined, in the manufacture of a medicament for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial, in a patient in need thereof, wherein the compound of formula (I) is for administration in combination with a BCL2 inhibitor as herein defined. The invention further relates to a method of treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) as herein defined, in combination with a BCL2 inhibitor as herein defined. [0192] In another embodiment, the invention also relates a BCL2 inhibitor as herein defined, for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial, in a patient in need thereof, wherein the BCL2 inhibitor is for administration
in combination with a compound of formula (I) as herein defined. The invention also relates to the use of a BCL2 inhibitor as herein defined, in the manufacture of a medicament for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial, in a patient in need thereof, wherein the a BCL2 inhibitor is for administration in combination with a compound of formula (I) as herein defined. The invention further relates to a method of treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a BCL2 inhibitor as herein defined, in combination with a compound of formula (I) as herein defined. [0193] In another aspect, the combination of the invention and its related products, i.e. the pharmaceutical product, kit of part and pharmaceutical composition, are particularly useful for treating patients overexpressing MCL1. Indeed, as mentioned above, MCL1 is the most prominent anti-apoptotic alternative to BCL2 in hematologic cancers. [0194] The invention thus relates to the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, for use in the treatment of cancer in a patient in need thereof, wherein the patient is overexpressing MCL1. The invention also relates to the use of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment of cancer in a patient in need thereof, wherein the patient is overexpressing MCL1. The invention further relates to a method of treatment of cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, wherein the patient is overexpressing MCL1. [0195] By “patient overexpressing MCL1”, it is referred to a patient in whom the amount of MCL1 is increased compared to the amount of MCL1 in a healthy subject. The determination of the overexpression of MCL1 in the patients and/or subjects can be conducted by methods well known in the art. For example, determination of the overexpression of MCL1 can be conducted by immunochemistry or western blot.
[0196] In another aspect, the combination of the invention and its related products, i.e. the pharmaceutical product, kit of part and pharmaceutical composition, are also particularly useful for treating patients who are resistant or refractory to a BCL2 inhibitor therapy (e.g. venetoclax), especially patients who show resistance to a BCL2 inhibitor therapy by upregulation of MCL1. In one embodiment, the combination of the invention and its related products, i.e. the pharmaceutical product, kit of part and pharmaceutical composition, are particularly useful for treating patients who are refractory to a BCL2 inhibitor therapy (e.g. venetoclax). In one embodiment, the combination of the invention and its related products, i.e. the pharmaceutical product, kit of part and pharmaceutical composition, are particularly useful for treating patients who are resistant to a BCL2 inhibitor therapy (e.g. venetoclax), especially patients who show resistance to a BCL2 inhibitor therapy by upregulation of MCL1. [0197] By “patient refractory to a BCL2 inhibitor therapy”, it is referred to a patient that was never respondent to the BCL2 inhibitor therapy. [0198] By “patient resistant to a BCL2 inhibitor therapy”, it is referred to a patient that was respondent to the BCL2 inhibitor therapy at the beginning of the treatment, but for who a resistance appeared overtime, such that the patient is then no longer respondent to the BCL2 inhibitor therapy, or no longer as respondent to the BCL2 inhibitor therapy as at the beginning of the treatment. One of the mechanism of resistance to BCL2 inhibitor is by an upregulation of MCL1. [0199] The invention thus relates to the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, for use in the treatment of cancer in a patient in need thereof, wherein the patient is resistant or refractory to a BCL2 inhibitor therapy, especially the patient is resistant or refractory to a BCL2 inhibitor therapy by upregulation of MCL1. The invention also relates to the use of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment of cancer in a patient in need thereof, wherein the patient is resistant or refractory to a BCL2 inhibitor therapy, especially the patient is resistant or refractory to a BCL2 inhibitor therapy by upregulation of MCL1. The invention further relates to a method of treatment
of cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, wherein the patient is resistant or refractory to a BCL2 inhibitor therapy, especially the patient is resistant or refractory to a BCL2 inhibitor therapy by upregulation of MCL1. [0200] The invention thus relates to the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, for use in the treatment of cancer in a patient in need thereof, wherein the patient is resistant to a BCL2 inhibitor therapy, especially the patient is resistant to a BCL2 inhibitor therapy by upregulation of MCL1. The invention also relates to the use of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment of cancer in a patient in need thereof, wherein the patient is resistant to a BCL2 inhibitor therapy, especially the patient is resistant to a BCL2 inhibitor therapy by upregulation of MCL1. The invention further relates to a method of treatment of cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, wherein the patient is resistant to a BCL2 inhibitor therapy, especially the patient is resistant to a BCL2 inhibitor therapy by upregulation of MCL1. [0201] The invention thus relates to the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, for use in the treatment of cancer in a patient in need thereof, wherein the patient is refractory to a BCL2 inhibitor therapy, especially the patient is refractory to a BCL2 inhibitor therapy by upregulation of MCL1. The invention also relates to the use of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment of cancer in a patient in need thereof, wherein the patient is refractory to a BCL2 inhibitor therapy, especially the patient is refractory to a BCL2 inhibitor therapy by upregulation of MCL1. The invention further relates to a method of treatment of cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the combination, the
pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, wherein the patient is refractory to a BCL2 inhibitor therapy, especially the patient is refractory to a BCL2 inhibitor therapy by upregulation of MCL1. [0202] In another aspect, the combination of the invention and its related products, i.e. the pharmaceutical product, kit of part and pharmaceutical composition, are also particularly useful for sensitizing patients who are resistant or refractory to a BCL2 inhibitor therapy (e.g. venetoclax). In one embodiment, the combination of the invention and its related products, i.e. the pharmaceutical product, kit of part and pharmaceutical composition, are also particularly useful for sensitizing patients who are resistant to a BCL2 inhibitor therapy (e.g. venetoclax). In one embodiment, the combination of the invention and its related products, i.e. the pharmaceutical product, kit of part and pharmaceutical composition, are also particularly useful for sensitizing patients who are refractory to a BCL2 inhibitor therapy (e.g. venetoclax) [0203] By “sensitizing a patient who is refractory to a BCL2 inhibitor therapy”, it is meant that a patient that was never respondent to the BCL2 inhibitor therapy becomes respondent. [0204] By “sensitizing a patient who is resistant to a BCL2 inhibitor therapy”, it is meant that a patient that developed a resistance to the BCL2 inhibitor therapy becomes respondent again, i.e. the resistance to the BCL2 inhibitor therapy is overcome. [0205] The invention thus relates to the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, for use in the treatment of cancer in a patient in need thereof, wherein it is for sensitizing a patient who is resistant or refractory to a BCL2 inhibitor therapy. The invention also relates to the use of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment of cancer in a patient in need thereof, wherein it is for sensitizing a patient who is resistant or refractory to a BCL2 inhibitor therapy. The invention further relates to a method for sensitizing a patient who is resistant or refractory to a BCL2 inhibitor therapy, comprising administering to said patient a therapeutically effective amount of the combination, the
pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention. [0206] The invention thus relates to the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, for use in the treatment of cancer in a patient in need thereof, wherein it is for sensitizing a patient who is refractory to a BCL2 inhibitor therapy. The invention also relates to the use of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment of cancer in a patient in need thereof, wherein it is for sensitizing a patient who is refractory to a BCL2 inhibitor therapy. The invention further relates to a method for sensitizing a patient who is refractory to a BCL2 inhibitor therapy, comprising administering to said patient a therapeutically effective amount of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention. [0207] The invention thus relates to the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, for use in the treatment of cancer in a patient in need thereof, wherein it is for sensitizing a patient who is resistant to a BCL2 inhibitor therapy. The invention also relates to the use of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention, in the manufacture of a medicament for use in the treatment of cancer in a patient in need thereof, wherein it is for sensitizing a patient who is resistant to a BCL2 inhibitor therapy. The invention further relates to a method for sensitizing a patient who is resistant to a BCL2 inhibitor therapy, comprising administering to said patient a therapeutically effective amount of the combination, the pharmaceutical product, the kit of part, or the pharmaceutical composition of the invention. BRIEF DESCRIPTION OF THE DRAWINGS [0208] Figure 1: MCL-1 content in Kasumi-1 cells: western blot analysis of Kasumi cells after 48h treatment with IC50 concentrations of compounds of formula (I) (compounds 142*, 239, 256 and 309*) or DMSO, using GAPDH as loading control.
EXAMPLES [0209] The present invention is further illustrated by the following examples. [0210] The compounds of formula (I) used in the examples were synthesized as described in PCT/EP2024/051219. 1: Viability assays to evaluate
with venetoclax Purpose [0211] The sensitivity of AML cells lines to combinations of METTL3 inhibitors of formula (I) and venetoclax was evaluated. Method [0212] AML cell lines Kasumi-1 or MV-4-11 are treated with venetoclax (Abcam, Cat.N° ab217298) alone or in combination with different concentrations of METTL3 inhibitors of formula (I). After 72h of treatment, an ATP-lite One Step (Perkin Elmer, 6016739) viability assay is performed according the supplier’s instructions. Each point is measured in duplicate. The raw data are generated in relative light unit (RLU). Then, the results were expressed in % of viability relative to 0.05% DMSO control wells (=100% viability). The website application SynergyFinder is used to determine the potential synergism between venetoclax and METTL3 inhibitors. https://synergyfinder.fimm.fi/synergy/20240513132947258962/ [0213] The IC50 for venetoclax alone or in combination with METTL3 inhibitors is determined with GraphPadPrism. The concentration of venetoclax were assessed in the range 10-5.5M to 10-9M for Kasumi cells and 10-7M to 10-9M for MV-4-11 cells. The concentrations of METTL3 inhibitors used for tables of results below are chosen in the most synergistic area determined by SynergyFinder. Synergistic interactions occur when IC50 values of venetoclax decrease in the presence of the METTL3 inhibitor. [0214] The method was the following: - Prepare the solutions of the compounds of formula (I) and venetoclax (4-fold concentrated each);
- Seed cells in cell culture microplate, 96w, PS, F-Bottom white, CELLSTAR (Greiner 655083): 50µl of suspension cell/well; Cat. N° Culture medium Cells/well RPMI-1640 (Gibco A10491- Kasumi-1 ATCC CRL-2724 01) + 10% FBS 15000 (Gibco A526701) 5 RPMI-1640 (Gibco A10491- MV-4-11 ATCC CRL-9591 01) + 10% FBS 10000 (Gibco A526701) - Add 25µl of DMSO + 25µL of compound of formula (I) or venetoclax for treatment of cells with one agent alone; or Add 25µl of compound of formula (I) + 25µL of venetoclax for treatment of cells with a combination of both agents; - Put a gas permeable sealing membrane (Sigma Z380059-1PK) on the plate to prevent evaporation; - Incubation at 37°C, 5% CO2, 80%RH for 72h; - Proceed to ATP-lite One Step viability assay: o Equilibrate the substrate vial and the buffer solution at RT before reconstitution; o Reconstitute the lyophilized substrate solution by adding 250mL of buffer to the vial; o Mix the contents of the vial by inversion and leave the solution to stand for 5 minutes; o After incubation, take the plates out the incubator and let them at RT few minutes; o Stick a black bottom seal under the plates; o Remove the top seal and add 100µl of the reconstituted reagent directly to each well containing cells; o Shake the plate for 2 minutes at 700 rpm; o Place the plate in the dark for 10 minutes to reduce plate phosphorescence; o Measure luminescence with Envision.
Results [0215] The IC50 of venetoclax alone or in combination with tested compounds of formula (I) in Kasumi cells are reported in Table 2 below. For each tested compound of formula (I) (referred to as “Cpd xxx”, as detailed in Table 1 above), the IC50 of venetoclax is provided in absence of the compound (second column – “0 nM – Cpd xxx”), and in presence of two different concentrations of the compound (third and fourth column). Table 2 Cpd 001 0 nM – Cpd 001 300 nM – Cpd 001 1 µM – Cpd 001 IC50 venetoclax 319 28 10 (nM) Cpd 058* 0 nM – Cpd 058* 1 µM – Cpd 058* 3 µM – Cpd 058* IC50 venetoclax 821 274 56 (nM) Cpd 068 0 nM – Cpd 068 1 µM – Cpd 068 3 µM – Cpd 068 IC50 venetoclax 691 194 28 (nM) Cpd 107 0 nM – Cpd 107 300 nM – Cpd 107 1 µM – Cpd 107 IC50 venetoclax 502 128 24 (nM) Cpd 142* 0 nM – Cpd 142* 30 nM – Cpd 142* 100 nM – Cpd 142* IC50 venetoclax (nM) 582 67 20 Cpd 149 0 nM – Cpd 149 30 nM – Cpd 149 100 nM – Cpd 149 IC50 venetoclax (nM) 792 95 13 Cpd 160* 0 nM – Cpd 160* 10 nM – Cpd 160* 30 nM – Cpd 160* IC50 venetoclax 874 126 26 (nM) Cpd 166* 0 nM – Cpd 166* 10 nM – Cpd 166* 30 nM – Cpd 166* IC50 venetoclax 568 288 116 (nM)
Cpd 171* 0 nM – Cpd 171* 30 nM – Cpd 171* 100 nM – Cpd 171* IC50 venetoclax 791 168 31 (nM) Cpd 176* 0 nM – Cpd 176* 10nM – Cpd 176* 30 nM – Cpd 176* IC50 venetoclax 966 170 21 (nM) Cpd 180* 0 nM – Cpd 180* 10nM – Cpd 180* 30 nM – Cpd 180* IC50 venetoclax 920 133 36 (nM) Cpd 185 0 nM – Cpd 185 10nM – Cpd 185 30 nM – Cpd 185 IC50 venetoclax (nM) 1000 326 109 Cpd 194 0 nM – Cpd 194 10nM – Cpd 194 30 nM – Cpd 194 IC50 venetoclax 728 133 30 (nM) Cpd 196* 0 nM – Cpd 196* 10nM – Cpd 196* 30 nM – Cpd 196* IC50 venetoclax 1100 253 37 (nM) Cpd 212 0 nM – Cpd 212 30 nM – Cpd 212 100 nM – Cpd 212 IC50 venetoclax 535 42 13 (nM) Cpd 220* 0 nM – Cpd 220* 10 nM – Cpd 220* 30 nM – Cpd 220* IC50 venetoclax 546 29 5 (nM) Cpd 239 0 nM – Cpd 239 30nM – Cpd 239 100 nM – Cpd 239 IC50 venetoclax (nM) 586 76 25 Cpd 248 0 nM – Cpd 248 100nM – Cpd 248 300 nM – Cpd 248 IC50 venetoclax (nM) 584 92 27 Cpd 250 0 nM – Cpd 250 100nM – Cpd 250 300 nM – Cpd 250 IC50 venetoclax 471 86 18 (nM)
Cpd 256 0 nM – Cpd 256 30 nM – Cpd 256 100 nM – Cpd 256 IC50 venetoclax 820 88 29 (nM) Cpd 259* 0 nM – Cpd 259* 30 nM – Cpd 259* 100 nM – Cpd 259* IC50 venetoclax 451 55 20 (nM) Cpd 263 0 nM – Cpd 263 100 nM – Cpd 263 300 nM – Cpd 263 IC50 venetoclax 683 66 29 (nM) Cpd 309* 0 nM – Cpd 309* 30 nM – Cpd 309* 100 nM – Cpd 309* IC50 venetoclax (nM) 557 81 24 Cpd 352 0 nM – Cpd 352 30 nM – Cpd 352 100 nM – Cpd 352 IC50 venetoclax 261 29 7.8 (nM) Cpd 361 0 nM – Cpd 361 30 nM – Cpd 361 100 nM – Cpd 361 IC50 venetoclax 390 23 5.6 (nM) Cpd 367 0 nM – Cpd 367 10 nM – Cpd 367 30 nM – Cpd 367 IC50 venetoclax 339 46 8 (nM) Cpd 368 0 nM – Cpd 368 30 nM – Cpd 368 100 nM – Cpd 368 IC50 venetoclax 330 63 9.4 (nM) wherein * 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 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. [0216] Similarly, the IC50 of venetoclax alone or in combination with tested compounds of formula (I) in MV-4-11 cells are reported in Table 3 below.
Table 3 Cpd 001 0 nM – Cpd 001 1 µM – Cpd 001 3 µM – Cpd 001 IC50 venetoclax 9.23 1.67 0.88 (nM) Cpd 058* 0 nM – Cpd 058* 3 µM – Cpd 058* 10 µM – Cpd 058* IC50 venetoclax (nM) 3.35 2.36 1.53 Cpd 068 0 nM – Cpd 068 3 µM – Cpd 068 10 µM – Cpd 068 IC50 venetoclax (nM) 3.64 1.98 0.77 Cpd 107 0 nM – Cpd 107 3 µM – Cpd 107 10 µM – Cpd 107 IC50 venetoclax 1.98 1.09 0.66 (nM) Cpd 142* 0 nM – Cpd 142* 100 nM – Cpd 142* 300 nM – Cpd 142* IC50 venetoclax 4.7 1.37 0.67 (nM) Cpd 149 0 nM – Cpd 149 300 nM – Cpd 149 1 µM – Cpd 149 IC50 venetoclax 3 1.53 0.6 (nM) Cpd 160* 0 nM – Cpd 160* 100 nM – Cpd 160* 300 nM – Cpd 160* IC50 venetoclax 2.84 0.46 0.73 (nM) Cpd 166* 0 nM – Cpd 166* 100 nM – Cpd 166* 300 nM – Cpd 166* IC50 venetoclax (nM) 1.94 0.91 0.72 Cpd 171* 0 nM – Cpd 171* 300 nM – Cpd 171* 3 µM – Cpd 171* IC50 venetoclax (nM) 6 1.34 1.03 Cpd 176* 0 nM – Cpd 176* 30 nM – Cpd 176* 100 nM – Cpd 176* IC50 venetoclax 1.38 0.64 0.44 (nM) Cpd 180* 0 nM – Cpd 180* 30 nM – Cpd 180* 100 nM – Cpd 180* IC50 venetoclax 1.28 0.61 0.41 (nM)
Cpd 185 0 nM – Cpd 185 300 nM – Cpd 185 1 µM – Cpd 185 IC50 venetoclax 1.53 0.55 0.2 (nM) Cpd 194 0 nM – Cpd 194 300 nM – Cpd 194 1 µM – Cpd 194 IC50 venetoclax 1.44 0.49 0.21 (nM) Cpd 196* 0 nM – Cpd 196* 100 nM – Cpd 196* 300 nM – Cpd 196* IC50 venetoclax 2.17 0.53 0.33 (nM) Cpd 212 0 nM – Cpd 212 300 nM – Cpd 212 1 µM – Cpd 212 IC50 venetoclax (nM) 2.3 0.77 0.38 Cpd 220* 0 nM – Cpd 220* 30 nM – Cpd 220* 100 nM – Cpd 220* IC50 venetoclax 2.29 0.73 0.57 (nM) Cpd 239 0 nM – Cpd 239 300 nM – Cpd 239 1 µM – Cpd 239 IC50 venetoclax 5.36 1.99 1.41 (nM) Cpd 248 0 nM – Cpd 248 300 nM – Cpd 248 1 µM – Cpd 248 IC50 venetoclax 7.53 3.32 1.15 (nM) Cpd 250 0 nM – Cpd 250 300 nM – Cpd 250 1 µM – Cpd 250 IC50 venetoclax 7.39 2.93 1.12 (nM) Cpd 256 0 nM – Cpd 256 300 nM – Cpd 256 1 µM – Cpd 256 IC50 venetoclax (nM) 3.66 2.08 0.65 Cpd 352 0 nM – Cpd 352 300 nM – Cpd 352 1 µM – Cpd 352 IC50 venetoclax (nM) 10 1.45 0.81 Cpd 361 0 nM – Cpd 361 300 nM – Cpd 361 1 µM – Cpd 361 IC50 venetoclax 6.3 2.2 0.94 (nM)
Cpd 367 0 nM – Cpd 367 100 nM – Cpd 367 300 nM – Cpd 367 IC50 venetoclax 5.3 2.2 1.1 (nM) Cpd 368 0 nM – Cpd 368 300 nM – Cpd 368 1µM – Cpd 368 IC50 venetoclax 5.3 3 0.82 (nM) wherein * has the same meaning as detailed above for Table 2. Conclusion [0217] As evidenced in above Table 2 and Table 3, tested compounds of formula (I) show a synergistic interaction with venetoclax in Kasumi and MV-4-11 AML cell lines, since increasing concentrations of tested compounds of formula (I) lead to decreasing IC50 of venetoclax. Example 2: Reduction of MCL1 content in AML cell lines by compounds of formula (I) Purpose [0218] The effect of the compounds of formula (I) of the invention on anti-apoptotic biomarker MCL1 was evaluated by western blot on AML cell lines. Method [0219] Western blots were performed on two AML cell lines (Kasumi-1 cells and MV-4-11 cells) treated for 48 hours with IC50 concentrations of compounds of formula (I) or with DMSO, as vehicle control. MCL1-content was analyzed by western blot and GAPDH was used as loading control. RIPA-extracts (45 µg of total protein) were separated by SDS-PAGE electrophoresis then transferred onto a PVDF membrane. MCL1-specific antibody (SCBT, sc-12756) was probed ON at 4°C then detected by HRP- conjugated secondary antibodies (1hr, RT). GAPDH was probed as loading control (CST, 8884). HRP-chemiluminescence was recorded by a C-digit scanner (Li-Cor). [0220] Tested compounds of formula (I) are compounds 142*, 239, 256 and 309*, wherein * has the same meaning as detailed in Example 1.
Results [0221] The compounds of invention associate with an impressive reduction of MCL1- content in Kasumi-1 cells, as shown in Figure 1. MCL1 reduction was also confirmed in the same extend for the other tested AML cell line, MV-4-11. [0222] MCL1 is the most prominent antiapoptotic alternative to BCL2 in hematologic cancers. Without willing to be bound by a theory, the reduction of MCL1 content might be the likely mechanism by which compounds of formula (I) sensitize AML cell lines to the BLC2-inhibitor venetoclax, as demonstrated in synergism assays of Example 1.