Antagonist Compounds

Abstract

The present invention relates to compounds of formula I, as shown below: wherein R1, R2, R3, R4, R5 and R6 are each defined in the present application. The present invention also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or conditions in which adenosine A2a and / or A2b receptor activity is implicated, such as cancer. [Formula 1] JPEG2023537330000279.jpg69170

Description

[Technical Field]

[0001] The present invention relates to certain compounds that function as antagonists of the adenosine A2a receptor. Furthermore, some of the compounds are antagonists of both the A2a and A2b receptors. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions containing them, and their use in treating diseases or conditions in which adenosine A2a and / or A2b receptor activity is implicated, such as cancer. [Background technology]

[0002] Numerous immunosuppressive pathways are active in the tumor microenvironment, allowing tumor cells to evade cytotoxic T cell elimination and reducing patient clinical responses to anti-checkpoint antibody immunotherapy. The anti-PD-1 antibodies pembrolizumab and nivolumab, as well as the anti-PD-L1 antibodies durvalumab, avelumab, and atezolizumab, are approved for the treatment of many solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma. However, only 20–30% of patients respond to checkpoint blockade, and the treatment is associated with significant side effects (Sukari et al., 2016). For this reason, other methods to enhance the cytotoxicity of the tumor microenvironment are actively being investigated. These include agents that can be used as monotherapy or, more likely, in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy.

[0003] One approach that has gained attention is to disrupt the production and / or action of adenosine in the tumor microenvironment (Vijayan et al., 2017). Adenosine has immunosuppressive properties and is present in high concentrations in the tumor microenvironment. Recent studies have estimated that the human adenosine concentration is approximately 10 μM in tumors, compared with <1 μM in normal tissues (Houthuys et al., 2017). Adenosine is formed at both intracellular and extracellular sites by two distinct pathways involving two different substrates. Intracellular adenosine is derived from AMP and S-adenosylhomocysteine, whereas high extracellular adenosine concentrations observed during metabolic stress are associated with the release and degradation of precursor adenine nucleotides (ATP, ADP, and AMP) through the coordinated action of CD39 and CD73 (Vijayan et al., 2017).

[0004] CD39 and CD73 are upregulated in the tumor microenvironment in response to hypoxia. CD73 represents a putative patient stratification method for adenosine antagonists, as its expression on tumor cells is also associated with poor overall prognosis in many different cancer types, suggesting that adenosine production is involved in the undesirable immunosuppressive phenotype of the tumor microenvironment (Gao et al., 2014; Loi et al., 2013). CD73 expression by tumor-infiltrating immune cells is also important in promoting tumor immunosuppression, as CD73-negative Treg cells are unable to suppress effector T cell function (Deaglio et al., 2007; Reinhardt et al., 2017). Furthermore, patients resistant to anti-PD1 therapy have elevated levels of CD73 (Reinhardt et al., 2017).

[0005] Adenosine regulates cellular function by occupying specific GPCRs on the cell surface of the P1 purinoceptor subtype. The P1 receptor family is further subdivided into A1, A2a, A2b, and A3.

[0006] A2 receptors are subdivided into A2a and A2b receptors based on their high and low affinity for adenosine, respectively. A2a is expressed by lymphocytes, and its activation leads to the suppression of cytokine production and other effector functions. Tumor growth has been inhibited by genetic ablation of A2a in syngeneic mouse models, demonstrating this effect is due to enhanced lymphocyte activation and cytotoxic function (Ohta et al., 2006; Waickman et al., 2012; Beavis et al., 2013; Mittal et al., 2014; Cekic et al., 2014). A2a- / - mice show increased response to inhibition of checkpoint pathways such as PD-1, improving both tumor-free and overall survival. Adenosine-mediated A2a activation also limits the efficacy of anti-CTLA4 therapy (Iannone et al., 2014).

[0007] The effects of genetic deletion of A2a in mouse models can be mimicked by pharmacological blockade of A2a. A2a antagonists have been shown to enhance cytotoxic CD8+ T cells and the ability of NK cells to prevent metastasis of CD73-expressing tumors (Beavis et al., 2013). Importantly, A2a antagonists enhance the efficacy of anti-PD1 antibodies (Beavis et al., 2015).

[0008] These findings prompted the development of selective A2a antagonists for use in cancer immunotherapy, and clinical trials are underway with CPI-444, the first selective A2a antagonist evaluated in cancer, used as monotherapy and in combination with the anti-PDL1 antibody atezolizumab. Preliminary data indicated that this compound was well tolerated and showed early signs of reducing tumor size and enhancing CD8+ T cell infiltration into tumor tissue.

[0009] The adenosine A2b receptor also plays an important role in cancer progression through regulation of the tumor microenvironment. A2b is expressed by cells of myeloid origin, and high concentrations of adenosine found within the tumor microenvironment can alter the behavior of tumor-associated macrophages, myeloid-derived suppressor cells, and dendritic cells. Activation of A2b leads to the polarization of immunosuppressive M2 macrophages (Csoka et al., 2012), the formation of myeloid-derived suppressor cells (Rhyzov et al., 2011), and promotes the immunosuppressive and proangiogenic phenotype of dendritic cells (Novitskiy et al., 2008; Wilson et al., 2009). Blockade of A2b has been shown to reduce tumor size in many mouse cancer models (Cekic et al., 2012; Sorrentino et al., 2015; Iannone et al., 2013), an effect associated with reduced MDSC infiltration and VEGF production (Sorrentino et al., 2015; Iannone et al., 2013).

[0010] Therefore, dual inhibition of both A2a and A2b is an attractive approach to reduce immune suppression within the tumor microenvironment and inhibit proliferation. Summary of the Invention [Means for solving the problem]

[0011] According to a first aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0012] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0013] According to a further aspect of the invention there is provided a method of antagonizing adenosine A2a receptors, or A2a and A2b receptors, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0014] According to a further aspect of the invention there is provided a method of selectively antagonising adenosine A2a receptors, or A2a and A2b receptors, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0015] According to a further aspect of the present invention there is provided a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0016] According to a further aspect of the present invention there is provided a method of treating a disease or disorder associated with adenosine A2a and / or A2b receptor activity in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0017] According to a further aspect of the present invention there is provided a method of treating a cell proliferative disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0018] According to a further aspect of the present invention there is provided a method of treating cancer in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., a checkpoint inhibitor and / or a cytotoxic agent).

[0019] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

[0020] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a cell proliferative condition. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0021] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer. In certain embodiments, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0022] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use as an adenosine A2a and / or A2b antagonist, hi one embodiment the compound of the invention is a selective adenosine A2a and A2b antagonist.

[0023] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which adenosine A2a and / or A2b is involved.

[0024] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a cell proliferative condition. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0025] According to a further aspect of the present invention, there is provided the use of a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of cancer. Preferably, the cancer is a human cancer. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0026] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use as an adenosine A2a and / or A2b antagonist.

[0027] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which adenosine A2a is involved.

[0028] According to a further aspect of the present invention there is provided a process for preparing a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0029] According to a further aspect of the present invention there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, obtainable by, or obtained or directly obtained by, a process for preparing a compound as defined herein.

[0030] According to a further aspect of the present invention, there is provided a novel intermediate as defined herein, which is suitable for use in any one of the synthetic methods described herein.

[0031] Features, including any suitable and preferred features, associated with one aspect of the invention may also be features, including any suitable and preferred features, associated with any other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0032] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0033] References to "treating" or "treatment" should be understood to include prophylaxis, as well as the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition that occurs in humans who may be afflicted with or predisposed to the condition, disorder, or condition, but who have not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition; (2) arresting the condition, disorder, or condition, i.e., preventing, alleviating, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0034] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0035] As used herein, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups, such as "propyl," are specific to the straight-chain version only, and references to individual branched-chain alkyl groups, such as "isopropyl," are specific to the branched-chain version only. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl. Similar rules apply to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0036] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0037] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups. Thus, "(1-6C)alkylene" means a divalent linear saturated hydrocarbon group of 1 to 6 carbon atoms or a divalent branched saturated hydrocarbon group of 3 to 6 carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc.

[0038] "(2-6C)alkenylene" means a divalent linear hydrocarbon group of 2 to 6 carbon atoms or a divalent branched hydrocarbon group of 3 to 6 carbon atoms containing at least one double bond, such as ethenylene and 2,4-pentadienylene.

[0039] "(2-6C)alkynylene" means a divalent linear hydrocarbon group of 2 to 6 carbon atoms or a divalent branched hydrocarbon group of 3 to 6 carbon atoms containing at least one triple bond, such as, for example, ethynylene, propynylene, and butynylene.

[0040] "(3-8C)cycloalkyl" means a hydrocarbon ring containing 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

[0041] "(3-8C)cycloalkenyl" means a hydrocarbon ring containing at least one double bond, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, for example, 3-cyclohexen-1-yl or cyclooctenyl.

[0042] "(3-8C)cycloalkyl-(1-6C)alkylene" means a (3-8C)cycloalkyl group covalently linked to a (1-6C)alkylene group, both of which are defined herein.

[0043] The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0044] The terms "heterocyclyl," "heterocyclic," or "heterocycle" refer to a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system. Monocyclic heterocycles contain about 3 to 12 (preferably 3 to 7) ring atoms, with 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocycles contain 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocycles can be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Representative sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Sulfur-containing heterocycles also include oxidized sulfur heterocycles containing SO or SO groups. Examples include sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for a heterocyclyl group having one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl, 1,1-dioxide, thiomorpholinyl, thiomorpholinyl, 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As will be appreciated by those skilled in the art, a heterocycle can be linked to another group through any suitable atom, for example, a carbon or nitrogen atom. However, references herein to piperidino or morpholino refer to a piperidin-1-yl or morpholin-4-yl ring linked via the ring nitrogen.

[0045] "Bridged ring system" means a ring system in which two rings share three or more atoms, e.g., Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0046] "Spirobicyclic ring system" means that two ring systems share one common spiro carbon atom, i.e., a heterocycle is linked to an additional carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0047] "Heterocyclyl(1-6C)alkyl" means a heterocyclyl group covalently linked to a (1-6C)alkylene group, both of which are defined herein.

[0048] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic ring incorporating one or more (e.g., 14, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term "heteroaryl" includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more typically 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, e.g., a fused 5-membered and 6-membered ring, or a bicyclic structure formed from two fused 6-membered rings. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring contains up to three heteroatoms, more typically up to two heteroatoms, e.g., a single heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of an indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents on the ring, will be fewer than five.

[0049] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, and isoxazolyl. Examples include noryl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthidinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3b]-furanyl-, 2H-furo[3,2b]-pyranyl-, 5H-pyrido[2,3-d]-oxazinyl-, 1H-pyrazolo[4,3-d]-oxazinyl, 4H-imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, -imidazo[2,1b]thiazolyl, and -imidazo[1,2b][1,2,4]-triazinyl. "Heteroaryl" also includes partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other rings is non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2b][1,4]oxazinyl, and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl.

[0050] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0051] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0052] The bicyclic heteroaryl group can be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; and A cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms.

[0053] Particular examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0054] Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0055] "Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently linked to a (1-6C)alkylene group, both of which are defined herein. Examples of heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0056] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In certain embodiments, aryl is phenyl.

[0057] The term "aryl(1-6C)alkyl" means an aryl group covalently linked to a (1-6C)alkylene group, both of which are defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.

[0058] This specification also uses some compound terms to describe groups containing two or more functional groups. Such terms will be understood by those skilled in the art. For example, heterocyclyl(m-nC)alkyl includes (m-nC)alkyl substituted with heterocyclyl.

[0059] The term "optionally substituted" refers to groups, structures, or molecules that are substituted and to groups, structures, or molecules that are not substituted. 1 The term "one / any CH, CH, CH group or heteroatom (i.e., NH) within the group may be substituted" preferably refers to R 1 It means that (any) one of the hydrogen radicals of the group is replaced by the associated defined group.

[0060] Where optional substituents are selected from "one or more" groups, this definition is understood to include all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

[0061] The phrase "compounds of the invention" refers both generically and specifically to the compounds disclosed herein.

[0062] Compounds of the Invention In a first aspect, the present invention relates to a compound having structural formula I, as shown below, or a pharmaceutically acceptable salt, hydrate, or solvate thereof: [ka] [In the formula, R x is selected from methyl, CD3, chloro and CF3; R1 is (1-3C) alkyl, halo, (1-3C) haloalkyl, (1-3C) haloalkoxy, (1-3C) hydroxyalkyl, cyano, cyclopropyl, oxetan-3-yl, -(CR 1C R 1D ) q1 -OR 1A , -(CR 1C R 1D ) q1 -C(O)R 1A , -(CR 1C R 1D ) q1 -C(O)OR 1A , -(CR 1C R 1D ) q1 -OC(O)R 1A , -(CR 1C R 1D ) q1 -C(O)N(R 1B )R 1A , -(CR 1C R 1D ) q1 -N(R 1B )C(O)R 1A , -(CR 1C R 1D ) q1 -S(O) p R 1A (wherein p is 0, 1 or 2), (CR 1C R 1D ) q1 -SO2N(R 1B )R 1A , or -(CR 1C R 1D ) q1 -N(R 1B )SO2R 1A Selected from (wherein q1 is 0, 1 or 2; R 1A and R 1B are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; R 1C and R 1D are each independently selected from hydrogen or (1-2C)alkyl; R2 and R3 are both hydrogen, or one of R2 and R3 is hydrogen and the other is selected from fluoro, methyl, or methoxy; R4 and R5, together with the nitrogen atom to which they are attached, form one or more R 10C are linked to form a heterocycle which may be substituted on any available carbon atom by a substituent; (where R 10C is an oxo, thioxo, halo, or cyano substituent, or a group of the formula: -[CR 7a R 7b ] n -LZ is selected from the group (In the formula, n is 0 to 6; R 7a and R 7b are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)N(R b )-, -C(S)N(R a )-, -N(R a )C(S)-, -N(R a )C(S)N(R b )-, -S(O)2N(R a )- or -N(R a )SO2- (where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl, or heteroaryl(1-2C)alkyl; Z is (1-6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, nitro, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1, 2, or 3) or oxo; The alkyl portion of the substituent on Z may be further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy, and R c and R d are each independently selected from hydrogen, (1-6C) alkyl, (1-6C) haloalkyl, or (3-6C) cycloalkyl); and wherein any available N atom, even in the form of an N-oxide, is substituted with one or more R 10N may be replaced by (where R 10N is —S(O)2NH2, or (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R8b ] 1~6 -L 1b -Z1 Selected from (In the formula, R 8a and R 8b are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L 1a -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 )-, -S(O)2N(R a1 )- or N(R a1 )-selected from (where R a1 is selected from hydrogen or (1-2C) alkyl; L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -C(S)N(R a2 )-, -N(R a2 )C(S)-, -N(R a2 )C(S)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )SO2 (where R a2 and R b2 are each independently selected from hydrogen or (1-2C)alkyl; Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclyl(1-2C)alkyl or heteroaryl(1-2C)alkyl (provided that when Z1 is a heterocyclyl group directly linked to an N atom, it is a carbon-linked heterocyclyl); Z1 is (1-6C)alkyl, halo, (1-6C)haloalkoxy, cyano, nitro, -NR e R f, -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR e R f (wherein z is 1, 2 or 3) or oxo; e and R f are each independently selected from hydrogen, (1-6C) alkyl, (1-6C) haloalkyl, or (3-6C) cycloalkyl); In addition, in the formula, any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR e ) (where R e may be present as R selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl; R is selected from hydrogen, halo, methyl, methoxy and trifluoromethyl.

[0063] In a second aspect, the present invention relates to a compound having structural formula I′ (a subdefinition of formula I) as shown below, or a pharmaceutically acceptable salt, hydrate, or solvate thereof: [ka] [In formula: R1 is (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, -(CH2) q1 -OR 1A , -(CH2) q1 -C(O)R 1A , -(CH2) q1 -C(O)OR 1A, -(CH2) q1 -OC(O)R 1A , -(CH2) q1 -C(O)N(R 1B )R 1A , -(CH2) q1 -N(R 1B )C(O)R 1A , -(CH2) q1 -S(O) p R 1A (wherein p is 0, 1 or 2), -(CH2) q1 -SO2N(R 1B )R 1A , or -(CH2) q1 -N(R 1B )SO2R 1A Selected from (wherein q1 is 0, 1 or 2; R 1A and R 1B are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; R2 and R3 are both hydrogen, or one of R2 and R3 is hydrogen and the other is selected from fluoro, methyl, or methoxy; R4 and R5, together with the nitrogen atom to which they are attached, form one or more R 10C are linked to form a heterocycle which may be substituted on any available carbon atom by a substituent; (where R 10C is an oxo, thioxo, halo, or cyano substituent, or a group of the formula: -[CR 7a R 7b ] n -LZ is selected from the group (In the formula, n is 0 to 6; R 7a and R 7b are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a)-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)N(R b )-, -C(S)N(R a )-, -N(R a )C(S)-, -N(R a )C(S)N(R b )-, -S(O)2N(R a )- or -N(R a )SO2- (where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl, or heteroaryl(1-2C)alkyl; Z is (1-6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, nitro, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1, 2, or 3) or oxo; The alkyl portion of the substituent on Z may be further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy, and R c and R d are each independently selected from hydrogen, (1-6C) alkyl, (1-6C) haloalkyl, or (3-6C) cycloalkyl); and wherein any available N atom, even in the form of an N-oxide, is substituted with one or more R 10N may be replaced by (where R 10N is —S(O)2NH2, or (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~6 -L 1b -Z1 Selected from (In the ceremony R 8a and R 8b are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L 1a -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 )-, -S(O)2N(R a1 )- or N(R a1 )-selected from (where R a1 is selected from hydrogen or (1-2C) alkyl; L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -C(S)N(R a2 )-, -N(R a2 )C(S)-, -N(R a2 )C(S)N(R b2)-, -S(O)2N(R a2 )- or -N(R a2 )SO2 (where R a2 and R b2 are each independently selected from hydrogen or (1-2C)alkyl; Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclyl(1-2C)alkyl or heteroaryl(1-2C)alkyl (provided that when Z1 is a heterocyclyl group directly linked to an N atom, it is a carbon-linked heterocyclyl); Z1 is (1-6C)alkyl, halo, (1-6C)haloalkoxy, cyano, nitro, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR e R f (wherein z is 1, 2 or 3) or oxo; e and R f are each independently selected from hydrogen, (1-6C) alkyl, (1-6C) haloalkyl, or (3-6C) cycloalkyl); In addition, in the formula, any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR e ) (where R emay be present as hydrogen, (1-3C) alkyl or (2-3C) alkanoyl; R6 is selected from hydrogen, halo, methyl, methoxy and trifluoromethyl.

[0064] Particular compounds of the present invention include, for example, compounds of Formula I, or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise specified, R x , R1, R2, R3, R4, R5 and R6 each have one of the meanings defined above or in any of the following paragraphs (1) to (32): (1) R1 is (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, -(CH2) q1 -OR 1A and (CH2) q1 -C(O)R 1A Selected from (where q1 is 0 or 1; R 1A is selected from hydrogen or (1-2C) alkyl; (1a) R1 is (1-3C) alkyl, halo, (1-3C) haloalkyl, (1-3C) haloalkoxy, (1-3C) hydroxyalkyl, cyano, cyclopropyl, oxetan-3-yl, -(CH2) q1 -OR 1A and (CH2) q1 -C(O)R 1A Selected from (where q1 is 0 or 1; R 1A is selected from hydrogen or (1-2C) alkyl; (2) R1 is (1-2C) alkyl, halo, (1-2C) haloalkyl, and C(O)R 1A Selected from; (where R 1A is selected from hydrogen or methyl); (2a) R1 is (1-3C) alkyl, halo, (1-3C) haloalkyl, (1-3C) haloalkoxy, (1-3C) hydroxyalkyl, cyano, cyclopropyl, oxetan-3-yl, and OR 1A Selected from; (3) R1 is selected from methyl, halo, and CF3; (3a) R1 is selected from methyl, CD3, isopropyl, halo, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxetan-3-yl, -OMe, -CH2F, -CHF2, and CF3; (3b) R1 is selected from methyl, CD3, isopropyl, halo, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxetan-3-yl, -OMe, -CHF2, and CF3; (4) R1 is selected from methyl and halo; (4a) R1 is selected from methyl, CD3, isopropyl, hydroxymethyl, 2-hydroxyisopropyl, cyclopropyl, oxetan-3-yl, and halo; (5) R1 is selected from methyl, fluoro, or chloro; (6) R1 is selected from methyl or chloro; (7) R1 is methyl; (7a) R1 is methyl or CD3; (8) R1 is chloro; (8a) R1 is CD3; (8b) R1 is isopropyl; (8c) R1 is hydroxymethyl; (8d) R1 is 2-hydroxyisopropyl; (8e) R1 is cyclopropyl; (8f) R1 is oxetan-3-yl; (9) R2 and R3 are both hydrogen, or one of R2 and R3 is hydrogen and the other is fluoro or methyl; (10) R2 and R3 are both hydrogen; (11) R4 and R5, together with the nitrogen atom to which they are attached, may form one or more R10C are linked to form a heterocycle which may be substituted on any available carbon atom by a substituent, where R 10C is an oxo, thioxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group (In the ceremony n is 0 to 4; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)N(R b )-, -S(O)2N(R a )- or -N(R a )SO2- (where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl, or heteroaryl(1-2C)alkyl; Z is (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, nitro, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2Rd , -(CH2) z NR c R d (wherein z is 1, 2, or 3) or oxo; The alkyl portion of the substituent on Z may be further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy, and R c and R d are each independently selected from hydrogen, (1-4C)alkyl, (1-6C)haloalkyl, or (3-4C)cycloalkyl; and any available N atom, even in the form of an N-oxide, may be bonded to one or more R 10N where R 10N is -S(O)2NH2, or: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~4 -L 1b -Z1 Selected from (In the formula, R 8a and R 8b are both hydrogen; L 1a -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 )- or S(O)N(R a1 )-selected from (where R a1 is hydrogen or methyl); L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -C(S)N(R a2 )-, -N(Ra2 )C(S)-, -N(R a2 )C(S)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )SO2 (where R a2 and R b2 are each independently selected from hydrogen or methyl; Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclyl(1-2C)alkyl or heteroaryl(1-2C)alkyl (provided that when Z1 is a heterocyclyl group directly linked to an N atom, it is a carbon-linked heterocyclyl); Z1 is (1-4C)alkyl, halo, (1-4C)haloalkoxy, cyano, nitro, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR e R f (wherein z is 1, 2 or 3) or oxo; e and R f are each independently selected from hydrogen, (1-4C) alkyl, (1-4C) haloalkyl, or (3-6C) cycloalkyl); In addition, in the formula, any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR e ) (where Re may be present as hydrogen, (1-3C) alkyl or (2-3C) alkanoyl); (12) R4 and R5, together with the nitrogen atom to which they are attached, may form one or more R 10C are linked to form a heterocycle, optionally substituted on any available carbon atom by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group (In the formula, n is 0 to 2; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )SO2 (where R a2 and R b2 are each independently selected from hydrogen or methyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, heterocyclyl, or heteroaryl(1-2C)alkyl; Z is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(Rc )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1 or 2) or oxo; The alkyl portion of the substituent on Z1 may be further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C) alkyl, or (1-2C) alkoxy; R c and R d are each independently selected from hydrogen, (1-2C) alkyl, (1-2C) haloalkyl, or (3-6C) cycloalkyl); and any available N atom, even in the form of an N-oxide, may be bonded to one or more R 10N where R 10N is -S(O)2NH2, or: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~2 -L 1b -Z1 Selected from (In the formula, R 8a and R 8b are both hydrogen; L 1a is -C(O)-, -S(O)2- or S(O)2N(R a1 )-selected from (where R a1 is hydrogen or methyl); L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -S(O)2N(Ra2 )- or -N(R a2 )SO2 (where R a2 and R b2 are each independently selected from hydrogen or methyl; Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl or aryl(1-2C)alkyl (provided that when Z1 is a heterocyclyl group directly linked to an N atom, it is a carbon-linked heterocyclyl); Z1 is (1-2C)alkyl, halo, (1-2C)haloalkoxy, cyano, nitro, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR e R f (wherein z is 1, 2 or 3) or oxo; e and R f are each independently selected from hydrogen or (1-2C) alkyl); In addition, in the formula, any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR e ) (where R e may be present as hydrogen, (1-3C) alkyl or (2-3C) alkanoyl); (13) R4 and R5, together with the nitrogen atom to which they are attached, may be one or more R 10Care linked to form a heterocycle, optionally substituted on any available carbon atom by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group (In the formula, n is 0 to 2; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)N(R b )-, -S(O)2N(R a )- or -N(R a )SO2 (where R a and R b is hydrogen); Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, or heteroaryl; Z is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, —NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1 or 2) or oxo; Rc and R d are each independently selected from hydrogen, (1-2C) alkyl, or (1-2C) haloalkyl); and any available N atom, even in the form of an N-oxide, may be bonded to one or more R 10N where R 10N is -S(O)2NH2, or: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~2 -L 1b -Z1 Selected from (In the formula, R 8a and R 8b are both hydrogen; L 1a is -C(O)-, -S(O)2- or S(O)2N(R a1 )-selected from (where R a1 is hydrogen); L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -S(O)2N(R a2 )- or -N(R a2 )SO2 (where R a2 is hydrogen); Z1 is selected from (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl, heteroaryl (provided that when Z1 is a heterocyclyl group directly linked to an N atom, it is a carbon-linked heterocyclyl); Z1 is (1-2C) alkyl, halo, (1-2C) haloalkoxy, cyano, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e, -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR c R d (wherein z is 1 or 2), and R e and R f are each independently selected from hydrogen or methyl); In addition, in the formula, any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR e ) (where R e may be present as hydrogen, (1-2C) alkyl or (2C) alkanoyl; (14) R4 and R5, together with the nitrogen atom to which they are attached, may form one or more R 10C are linked to form a heterocycle which may be substituted on any available carbon atom by a substituent; (where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group (In the formula, n is 0 to 2; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -S(O)2N(R a )- or -N(R a )SO2 (where R a and R b is hydrogen); Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, or 5- or 6-membered heteroarylalkyl; Z is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, —NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1 or 2) or oxo; R c and R d are each independently selected from hydrogen or (1-2C) alkyl); and any available N atom, even in the form of an N-oxide, may be bonded to one or more R 10N where R 10N is -S(O)2NH2, or: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~2 -L 1b -Z1 Selected from (In the formula, R 8a and R 8b are both hydrogen; L 1ais -C(O)-, -S(O)2- or S(O)2N(R a1 )-selected from (where R a1 is hydrogen); L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -S(O)2N(R a2 )- or -N(R a2 )SO2 (where R a2 is hydrogen); Z1 is selected from (1-4C) alkyl, phenyl, 4- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl (provided that when Z1 is a heterocyclyl group directly linked to an N atom, it is a carbon-linked heterocyclyl); Z1 is (1-2C) alkyl, halo, (1-2C) haloalkoxy, cyano, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR c R d (wherein z is 1 or 2); R e and R f are each independently selected from hydrogen or methyl); In addition, in the formula, any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR e ) (where R emay be present as hydrogen, (1-2C) alkyl or (2C) alkanoyl; (15) R4 and R5, together with the nitrogen atom to which they are attached, may form one or more R 10C are linked to form a heterocycle, optionally substituted on any available carbon atom by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group (In the formula, n is 0 to 2; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -S(O)2N(R a )- or -N(R a )SO2 (where R a and R b is hydrogen); Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, or 5- or 6-membered heteroarylalkyl; Z is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, —NR c R d , -OR c , -C(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d or -S(O) y R c (wherein y is 0, 1 or 2) or oxo; R c and R d are each independently selected from hydrogen or (1-2C) alkyl); and any available N atom, even in the form of an N-oxide, may be bonded to one or more R 10N where R 10N is -S(O)2NH2, or: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~6 -L 1b -Z1 Selected from (In the formula, R 8a and R 8b are both hydrogen; L 1a is -C(O)-, -S(O)2- or S(O)2N(R a1 )-selected from (where R a1 is hydrogen); L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -S(O)2N(R a2 )- or -N(R a2 )SO2 (where R a2 is hydrogen); Z1 is selected from (1-4C) alkyl, phenyl, 4- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl (provided that when Z1 is a heterocyclyl group directly linked to an N atom, it is a carbon-linked heterocyclyl); Z1 is (1-2C) alkyl, halo, (1-2C) haloalkoxy, cyano, -NR e R f , -OR e , -C(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e(wherein y is 0, 1 or 2); R e and R f are each independently selected from hydrogen or methyl); In addition, in the formula, any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR e ) (where R e may be present as hydrogen, methyl or (2C)alkanoyl); (15a) R4 and R5, together with the nitrogen atom to which they are attached, represent one or more R 10C are linked to form a heterocycle, optionally substituted on any available carbon atom by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group (In the formula, n is 0 to 2; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -S(O)2N(R a )- or -N(R a )SO2 (where R a and R b is hydrogen); Z is selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl; Z is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, —NR c R d , -OR c , -C(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d or -S(O) y R c(wherein y is 0, 1 or 2) or oxo; R c and R d are each independently selected from hydrogen or (1-2C) alkyl); and any available N atom, even in the form of an N-oxide, may be bonded to one or more R 10N where R 10N is -S(O)2NH2, or: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~2 -L 1b -Z1 Selected from (In the formula, R 8a and R 8b are both hydrogen; L 1a is -C(O)-, -S(O)2- or S(O)2N(R a1 )-selected from (where R a1 is hydrogen); L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -S(O)2N(R a2 )- or -N(R a2 )SO2 (where R a2 is hydrogen); Z1 is selected from (1-4C) alkyl; Z1 is selected from (1-2C) alkyl, halo, (1-2C) haloalkoxy, cyano, -NR e R f , -OR e , -C(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O)y R e (wherein y is 0, 1 or 2); R e and R f are each independently selected from hydrogen or methyl); In addition, in the formula, any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR e ) (where R e may be present as hydrogen, methyl or (2C)alkanoyl); (15b) R4 and R5, together with the nitrogen atom to which they are attached, form one or more R 10C are linked to form a heterocycle which may be substituted on any available carbon atom by a substituent, where R 10C is an oxo, halo, or cyano substituent, or formula: -LZ is selected from the group (In the formula, L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -S(O)2N(R a )- or -N(R a )SO2 (where R a and R b is hydrogen); Z is selected from hydrogen, (1-4C) alkyl or (3-6C) cycloalkyl); and any available N atom, even in the form of an N-oxide, may be bonded to one or more R 10N where R 10N is —S(O)2NH2 or (1-4C)alkyl): In addition, in the formula, any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR e ) (where R emay be present as hydrogen, methyl or (2C)alkanoyl); (15c) R4 and R5, together with the nitrogen atom to which they are attached, form one or more R 10C are linked to form a heterocycle, optionally substituted on any available carbon atom by a substituent, where R 10C is selected from oxo, halo, cyano, (1-4C) alkyl or (3-6C) cycloalkyl: and any available N atom, even in the form of an N-oxide, may be bonded to one or more R 10N where R 10N is —S(O)2NH2 or (1-4C)alkyl): Any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR e ) (where R e may be present as hydrogen, methyl or (2C)alkanoyl); (16) R4 and R5 are linked together with the nitrogen atom to which they are attached to form a 4- to 12-membered heterocycle, and the heterocycle is formed from one or more R 10C or R 10N may be substituted with a substituent (wherein R 10C and R 10N is as defined in any one of paragraphs (11) to (15c) above); (17) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a 4- to 8-membered monocyclic or bridged heterocycle, or a 7- to 12-membered bicyclic or spiro-bicyclic heterocycle, and the heterocycle is 10C or R 10N may be substituted with a substituent (wherein R 10C and R 10N is as defined in any one of paragraphs (11) to (15c) above); (18) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a 4- to 7-membered monocyclic or bridged heterocycle, or a 7- to 11-membered bicyclic or spiro-bicyclic heterocycle, and the heterocycle is 10C or R 10N may be substituted with a substituent (wherein R 10C and R 10N is as defined in any one of paragraphs (11) to (15c) above); (19) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a 5- or 6-membered monocyclic heterocycle, or a 7- to 10-membered bicyclic heterocycle or spiro-bicyclic heterocycle, and the heterocycle is 10C or R 10N may be substituted with a substituent (wherein R 10C and R 10N is as defined in any one of paragraphs (11) to (15c) above); (20) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] (In the formula, * indicates the N atom to which R4 and R5 are attached; Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q2 is -CH2-, -CHR 10C -, -C(R 10C )2-, -CHR 10C -CH2-, -CH2-CHR 10C -, -CHR 10C -CHR 10C -, -C(R 10C )2-CH2- or CH2-C(R 10C )2- and; Q3 is CH, CR10C or N; Ring A is a spiro-fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; Ring B is a fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; where R e is selected from hydrogen or methyl; Each heterocyclic ring system may be one or more R as defined in any one of paragraphs (11) to (15c) above. 10C or R 10N optionally substituted with a substituent); (20a) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] (In the formula, * indicates the N atom to which R4 and R5 are attached; Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q2 is -CH2-, -CHR 10C -, -C(R 10C )2-, -CHR 10C -CH2-, -CH2-CHR 10C -, -CHR 10C -CHR 10C -, -C(R 10C )2-CH2- or CH2-C(R 10C )2- and; Q3 is CH, CR 10C or N; Ring A is a spiro-fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; Ring B is a fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; where R e is selected from hydrogen or methyl; Each heterocyclic ring system may be one or more R as defined in any one of paragraphs (11) to (15c) above.10C or R 10N optionally substituted with a substituent); (21) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] (In the formula, * indicates the N atom to which R4 and R5 are attached; Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q2 is -CH2-, -CHR 10C - or C(R 10C )2- and; Q3 is CH, CR 10C or N; Ring A is a spiro-fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; Ring B is a fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; where R e is selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl; Each heterocyclic ring system may be one or more R as defined in any one of paragraphs (11) to (15c) above. 10C or R 10N optionally substituted with a substituent); (21a) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] (In the formula, * indicates the N atom to which R4 and R5 are attached; Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR10C or C(R 10C )2; Q2 is -CH2-, -CHR 10C - or C(R 10C )2- and; Q3 is CH, CR 10C or N; Ring A is a spiro-fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; Ring B is a fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; where R e is selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl; Each heterocyclic ring system may be one or more R as defined in any one of paragraphs (11) to (15c) above. 10C or R 10N optionally substituted with a substituent); (21b) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] (In the formula, * indicates the N atom to which R4 and R5 are attached; Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q2 is -CH2-; Q3 is CH, CR 10C or N; Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q5 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R10C )2; Q6 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q7 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; where R e is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; Each heterocyclic ring system may be one or more R as defined in any one of paragraphs (11) to (15c) above. 10C or R 10N optionally substituted with a substituent); (22) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] (In the formula, * indicates the N atom to which R4 and R5 are attached; Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q2 is -CH2-; Q3 is CH, CR 10C or N; Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q5 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N, CH2, CHR 10C or C(R 10C )2; Q6 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q7 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; where R e is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; Each heterocyclic ring system may be one or more R as defined in any one of paragraphs (11) to (15c) above. 10C or R 10N optionally substituted with a substituent); (22a) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] (In the formula, * indicates the N atom to which R4 and R5 are attached; Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; where R e is selected from hydrogen, (1-2C) alkyl, or (2C) alkanoyl; each of the heterocyclic ring systems is selected from one or more R as defined in any one of paragraphs (11) to (15c) above.10C or R 10N optionally substituted with a substituent); (22b) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] (In the formula, * indicates the N atom to which R4 and R5 are attached; Q1 is O, NH, NR 10N , CH2, CHR 10C or C(R 10C )2; Q4 is O, NH, NR 10N , CH2, CHR 10C or C(R 10C )2; where R e is selected from hydrogen, methyl or (2C)alkanoyl; R 10c or R 10N is as defined in any one of paragraphs (11) to (15c) above); (23) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] (In the formula, * indicates the N atom to which R4 and R5 are attached; Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10C )2; Q2 is -CH2-; where R e is selected from hydrogen, methyl or (2C)alkanoyl; R 10c or R 10Nis as defined in any one of paragraphs (11) to (15c) above); (24) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle of the following structure: [ka] (In the formula, * indicates the N atom to which R4 and R5 are attached; Each R 10c are independently selected from the alternatives defined in any one of paragraphs (11) to (15c) above); (25) R6 is selected from hydrogen, halo, or methyl; (26) R6 is selected from hydrogen or methyl; (27) R6 is hydrogen; (28)R x is selected from methyl, CD3 or chloro; (29)R x is selected from methyl or CD3; (30)R x is methyl; (31)R x is CD3 (32)R x is chloro;

[0065] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or a monocyclic, bicyclic, spiro bicyclic or bridged heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0066] Suitably, the heteroaryl is a 5 or 6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0067] Preferably, the heterocyclyl group is a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, O, or S. Most preferably, the heterocyclyl group is a 5-, 6-, or 7-membered ring containing 1, 2, or 3 heteroatoms selected from N, O, or S [e.g., morpholinyl (e.g., 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl, or pyrrolidinonyl], or a 7-, 8-, 9-, or 10-membered spiro bicyclic ring system containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0068] Preferably, the aryl group is phenyl.

[0069] Suitably, R1 is as defined above in paragraphs (1) to (8). In one embodiment, R1 is as defined above in paragraph (6).

[0070] Preferably, R1 is as defined in paragraphs (1) to (8f) above. More preferably, R1 is as defined in paragraphs (1a), (2a), (3a), (3b), (4a), (7a), (8a), (8b), (8c), (8d), (8e), or (8f) above. In one embodiment, R1 is as defined in paragraph (4a) or (7a) above.

[0071] Preferably, R2 and R3 are as defined in any one of paragraphs (9) or (10) above. Most preferably, R2 and R3 are as defined in paragraph (10) above.

[0072] Preferably, R4 and R5 are as defined in any one of paragraphs (11) to (24) above. More preferably, R4 and R5 are as defined in paragraphs (15), (15a), (15b) or (15c), (20a), (21a), (21b), (22a) or (22b) above. In particular groups of compounds of the invention, R4 and R5 are as defined in paragraphs (16), (17), (18), (20), (21), (22), (23), (24), (20a), (21a), (21b), (22a) or (22b) above.

[0073] Preferably, R4 and R5 are as defined in any one of paragraphs (11) to (24) above. More preferably, R4 and R5 are as defined in paragraph (15) above. Even more preferably, R4 and R5 are as defined in paragraphs (16), (17), or (18) above. In particular groups of compounds of the invention, R4 and R5 are as defined in paragraphs (20), (21), (22), (23), or (24) above.

[0074] Preferably, R x is as defined in any one of paragraphs (28) to (31) above. Most preferably, R x is as defined in paragraph (29) above.

[0075] Preferably, R 10c and R 10N is as defined in any one of paragraphs (11) to (15c) above. More preferably, R 10c and R 10N is as defined in any one of paragraphs (15) to (15c) above. Even more preferably, R 10c and R 10N is as defined in any one of paragraphs (15a), (15b) or (15c) above.

[0076] Preferably, R6 is as defined in any one of paragraphs (25) to (27) above. More preferably, R6 is as defined in paragraph (27) above.

[0077] In certain groups of compounds of formula I above, R1 is as defined in any one of paragraphs (1), (2), (3), (4), (5), (6), (7) or (8), and R2, R3, R4, R5 and R6 each have any one of the definitions described herein.

[0078] In particular groups of compounds of formula I above, R1 is as defined in any one of paragraphs (1a), (2a), (3a), (3b), (4a), (7a), (8a), (8b), (8c), (8d), (8e), (8f) above, and R z R2, R3, R4, R5 and R6 each have one of the definitions described herein.

[0079] In a particular group of compounds of formula I above, R2 and R3 are hydrogen, i.e., the compounds have structural formula IA (a subformula of formula I) as shown below: [ka] (In the formula, R x , R1, R4, R5, R6 and R x each having one of the definitions described herein).

[0080] In an embodiment of the compound of formula IA, R x is as defined in any one of paragraphs (28) to (31) above; R1 is as defined in any one of paragraphs (1) through (8f) above; R4 and R5 are as defined in any one of paragraphs (11) to (24) above; R6 is as defined in any one of paragraphs (25) to (27) above;

[0081] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (1a), (2a), (3a), (3b), (4a), (7a), (8a), (8b), (8c), (8d), (8e) or (8f) above; R4 and R5 are as defined in paragraph (12) above; R6 is as defined in paragraph (25) above.

[0082] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraphs (15), (15a), (15b), (15c) or (16) above; R6 is as defined in paragraph (27) above.

[0083] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (16) above; R6 is as defined in paragraph (27) above.

[0084] In another embodiment of the compound of formula IA', R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (17) above; R6 is as defined in paragraph (27) above.

[0085] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (18) above; R6 is as defined in paragraph (27) above.

[0086] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (19) above; R6 is as defined in paragraph (27) above.

[0087] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (20) above; R6 is as defined in paragraph (27) above.

[0088] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (21) above; R6 is as defined in paragraph (27) above.

[0089] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (22) above; R6 is as defined in paragraph (27) above.

[0090] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (23) above; R6 is as defined in paragraph (27) above.

[0091] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (24) above; R6 is as defined in paragraph (27) above.

[0092] In another embodiment of the compound of formula IA, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraphs (20a), (21a), (21b), (22a) or (22b) above; R6 is as defined in paragraph (27) above.

[0093] In a particular group of compounds of formula I above, R6 is hydrogen, i.e., the compound has structural formula IB (a subformula of formula I') as shown below: [ka] (In the formula, R x , R1, R2, R3, R4 and R5 each have one of the definitions described herein).

[0094] In one embodiment of the compound of formula IB, R x is as defined in any one of paragraphs (28) to (31) above; R1 is as defined in any one of paragraphs (1) through (8f) above; R2 and R3 are as defined in paragraph (9) or (10); R4 and R5 are as defined in any one of paragraphs (11) to (24) above.

[0095] In another embodiment of the compound of formula IB, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (1a), (2a), (3a), (3b), (4a), (7a), (8a), (8b), (8c), (8d), (8e) or (8f) above; R2 and R3 are as defined in paragraph (9). R4 and R5 are as defined in paragraph (12) above.

[0096] In another embodiment of the compound of formula IB, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined in paragraphs (15), (15a), (15b) or (15c) above.

[0097] In another embodiment of the compound of formula IB, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined in paragraph (16) above.

[0098] In another embodiment of the compound of formula IB, R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined in paragraph (17) above.

[0099] In another embodiment of the compound of formula IB, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (18).

[0100] In another embodiment of the compound of formula IB, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined in paragraph (19) above.

[0101] In another embodiment of the compound of formula IB, R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (20).

[0102] In another embodiment of the compound of formula IB, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (21).

[0103] In another embodiment of the compound of formula IB, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (22).

[0104] In another embodiment of the compound of formula IB, R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (23).

[0105] In another embodiment of the compound of formula IB, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (24).

[0106] In another embodiment of the compound of formula IB, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined in paragraphs (20a), (21a), (21b), (22a) or (22b) above.

[0107] In a particular group of compounds of formula I above, R2, R3 and R6 are hydrogen, i.e., the compound has the structural formula IC (a subformula of formula I) shown below: [ka] (In the formula, R x , R1, R4 and R5 each have one of the definitions described herein).

[0108] In one embodiment of the compound of formula IC, R x is as defined in any one of paragraphs (28) to (31) above; R1 is as defined in any one of paragraphs (1) through (8f) above; R4 and R5 are as defined in any one of paragraphs (11) to (24) above.

[0109] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (1a), (2a), (3a), (3b), (4a), (7a), (8a), (8b), (8c), (8d), (8e) or (8f) above; R4 and R5 are as defined in paragraph (12) above.

[0110] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraphs (15), (15a), (15b) or (15c) above.

[0111] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (16) above.

[0112] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (17) above.

[0113] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined above in paragraph (18).

[0114] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraph (19) above.

[0115] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined above in paragraph (20).

[0116] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined above in paragraph (21).

[0117] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined above in paragraph (22).

[0118] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined above in paragraph (23).

[0119] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined above in paragraph (24).

[0120] In another embodiment of the compound of formula IC, R x is as defined in paragraph (29) above; R1 is as defined in paragraph (4a) above; R4 and R5 are as defined in paragraphs (20a), (21a), (21b), (22a) or (22b) above.

[0121] In a particular group of compounds of formula I above, R2 and R3 are hydrogen, i.e., the compound has the structural formula IA' (a subformula of formula I) shown below: [ka] (wherein R1, R4, R5 and R6 each have one of the definitions described herein).

[0122] In one embodiment of the compound of formula IA': R1 is as defined in any one of paragraphs (1) through (8) above; R4 and R5 are as defined in any one of paragraphs (11) to (24) above; R6 is as defined in any one of paragraphs (25) to (27) above.

[0123] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (2) above; R4 and R5 are as defined in paragraph (12) above; R6 is as defined in paragraph (25) above.

[0124] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraphs (15), (15a), (15b) or (15c) above; R6 is as defined in paragraph (27) above.

[0125] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (16) above; R6 is as defined in paragraph (27) above.

[0126] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (17) above; R6 is as defined in paragraph (27) above.

[0127] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (18) above; R6 is as defined in paragraph (27) above.

[0128] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (19) above; R6 is as defined in paragraph (27) above.

[0129] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (20) above; R6 is as defined in paragraph (27) above.

[0130] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (21) above; R6 is as defined in paragraph (27) above.

[0131] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (22) above; R6 is as defined in paragraph (27) above.

[0132] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (23) above; R6 is as defined in paragraph (27) above.

[0133] In another embodiment of the compound of formula IA', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (24) above; R6 is as defined in paragraph (27) above.

[0134] In a particular group of compounds of formula I above, R6 is hydrogen, i.e., the compound has the structural formula IB' (a subformula of formula I) shown below: [ka] (wherein R1, R2, R3, R4 and R5 each have one of the definitions described herein).

[0135] In one embodiment of the compound of formula IB': R1 is as defined in any one of paragraphs (1) through (8) above; R2 and R3 are as defined in paragraph (9) or (10); R4 and R5 are as defined in any one of paragraphs (11) to (24) above.

[0136] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (2) above; R2 and R3 are as defined in paragraph (9); R4 and R5 are as defined in paragraph (12) above.

[0137] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined in paragraphs (15), (15a), (15b) or (15c) above.

[0138] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined in paragraph (16) above.

[0139] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined in paragraph (17) above.

[0140] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (18).

[0141] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined in paragraph (19) above.

[0142] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (20).

[0143] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (21).

[0144] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (22).

[0145] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (23).

[0146] In another embodiment of the compound of formula IB', R1 is as defined in paragraph (6) above; R2 and R3 are as defined in paragraph (10); R4 and R5 are as defined above in paragraph (24).

[0147] In a particular group of compounds of formula I above, R2, R3 and R6 are hydrogen, i.e., the compound has the structural formula IC' (a subformula of formula I) shown below: [ka] (wherein R1, R4 and R5 each have one of the definitions described herein).

[0148] In one embodiment of the compound of formula IC': R1 is as defined in any one of paragraphs (1) through (8) above; R4 and R5 are as defined in any one of paragraphs (11) to (24) above.

[0149] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (2) above; R4 and R5 are as defined in paragraph (12) above.

[0150] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraphs (15), (15a), (15b) or (15c) above.

[0151] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (16) above.

[0152] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (17) above.

[0153] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (6) above; R4 and R5 are as defined above in paragraph (18).

[0154] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (6) above; R4 and R5 are as defined in paragraph (19) above.

[0155] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (6) above; R4 and R5 are as defined above in paragraph (20).

[0156] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (6) above; R4 and R5 are as defined above in paragraph (21).

[0157] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (6) above; R4 and R5 are as defined above in paragraph (22).

[0158] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (6) above; R4 and R5 are as defined above in paragraph (23).

[0159] In another embodiment of the compound of formula IC', R1 is as defined in paragraph (6) above; R4 and R5 are as defined above in paragraph (24).

[0160] Particular compounds of the present invention include any of the compounds described in the Examples section of this application, or a pharmaceutically acceptable salt or solvate thereof, in particular any of the following: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]piperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]pyrrolidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-(2-hydroxy-2-methyl-propyl)pyrrolidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide (2S)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-hydroxy-4-methyl-piperidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-cyano-4-methyl-piperidine-1-carboxamide (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide (3R)-3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-piperazine-1-carboxamide N4-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]morpholine-2,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-3-oxo-piperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide 4-Acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methylsulfonyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-sulfamoyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methoxy-piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(hydroxymethyl)azetidine-1-carboxamide 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,1-dioxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxyazetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-hydroxyethyl)-3-oxo-piperazine-1-carboxamide 4,4-Dicyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-hydroxy-2-methyl-propyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-methyl-1,7-diazaspiro[3.4]octane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-hydroxy-1,1-dimethyl-ethyl)piperazine-1-carboxamide (8aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxamide (8aR)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxy-pyrrolidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(methoxymethyl)piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-fluoro-piperidine-1-carboxamide (3S)-3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxy-3-methyl-azetidine-1-carboxamide (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid Methyl (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylate (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide (1S,4S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (3R)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]piperazine-1,3-dicarboxamide (3S)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]piperazine-1,3-dicarboxamide 4-Amino-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (1R,4R)-5-Acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (1S,4S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-2-oxo-1,3,8-triazospiro[4.5]decane-8-carboxamide N-[5-[2,6-bis(trideuteriomethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-9-methyl-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxo-1,3,8-triazospiro[4.5]decane-8-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetan-3-yl)-4-pyridyl]thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetan-3-yl)-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-morpholino-azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-tetrahydropyran-4-yl-piperazine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-pyrrolidin-1-yl-azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(dimethylamino)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(morpholinomethyl)piperidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,4-diazabicyclo[3.2.1]octane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,2-dioxo-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]thiazine-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-oxo-3,6,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-9-oxo-3,4,6,7,8,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-1,3,4,8,9,9a-hexahydropyrazino[1,2-c][1,3]oxazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-sulfamoyl-pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-pyrazol-1-yl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(1,2,4-oxazol-3-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazine-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(1H-imidazol-2-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-N4-methyl-piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-8-oxa-2-azaspiro[4.5]decane-2-carboxamide (3S)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]pyrrolidine-1,3-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-oxoimidazolidin-1-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(1,2,4-oxazol-5-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-methylimino-1-oxo-1,4-thiazinane-4-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-N4-(2-hydroxyethyl)piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-7-oxa-2,5-diazaspiro[3.5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6,9-dioxo-1,3,4,7,8,9a-hexahydropyrazino[1,2-a]pyrazine-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-oxo-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-8-methyl-6,9-dioxo-3,4,7,9a-tetrahydro-1H-pyrazino[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-2,9-diazaspiro[5.5]undecane-9-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(1-hydroxy-1-methyl-ethyl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrazino[1,2-c]pyrimidine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,2-dioxo-2lambda^{6}-thia-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide (3aR,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrole-5-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxo-3-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide (1S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-methyl-3,6-diazabicyclo[3.2.2]nonane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-methyl-2-oxo-1,3,8-triazospiro[4.5]decane-8-carboxamide (3aS,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-7-oxa-2-azaspiro[3.5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-2,7-diazaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-2,5,7-triazospiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-ethyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]piperidine-4-carboxylic acid (3S)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(hydroxymethyl)azetidine-1-carboxamide (3R)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid 4-Cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxy-3-methyl-azetidine-1-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-azetidine-1-carboxamide 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]azetidine-3-carboxylic acid (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-azetidine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)azetidine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-morpholine-4-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-azetidine-1-carboxamide N-[4-(3-cyano-2-methyl-phenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (3R)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]pyrrolidine-1,3-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-7-azaspiro[4.4]nonane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-7-azaspiro[3.4]octane-7-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azetidine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-morpholino-pyrrolidine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-5-oxo-piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxa-1-azaspiro[3.3]heptane-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,3-dimethyl-2-oxo-1,3,8-triazospiro[4.5]decane-8-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-5-oxo-piperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-methyl-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-methyl-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methylsulfonyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-hydroxy-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (4aR,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide 4-Amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxamide cis-(2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,6-dimethyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,2-dimethyl-piperazine-1-carboxamide 1-Acetylamino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamide 4,4-Dicyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methoxy-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide 1-Cyanoimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide rac-(3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,5-dimethyl-piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(trifluoromethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(trifluoromethyl)piperazine-1-carboxamide (3S)-3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide (3R)-3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4,7-diazaspiro[2.5]octane-7-carboxamide (3S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,5-dimethyl-piperazine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-piperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-3-methyl-piperazine-1-carboxamide (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-cyclopropyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,3-dimethyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dichloro-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetan-3-yl)-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[5-(2-cyano-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(fluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2-cyclopropyl-6-methyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2-isopropyl-6-methyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2-ethyl-6-methyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide 4-Cyano-N-[4-(3-cyano-2-methyl-phenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide N-[5-(2-acetamido-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[5-[2-(acetamidomethyl)-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-methoxyethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[5-[2-chloro-6-(1-hydroxy-1-methyl-ethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide N-[5-[2,6-bis(trideuteriomethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-4-cyano-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-[(1S)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (3R)-3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide (3S)-3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide.

[0161] Particular compounds of the present invention include any of the compounds described in the Examples section of this application, or a pharmaceutically acceptable salt or solvate thereof, in particular any of the following: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide; (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]piperazine-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]pyrrolidine-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-(2-hydroxy-2-methyl-propyl)pyrrolidine-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide; (2S)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-hydroxy-4-methyl-piperidine-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-cyano-4-methyl-piperidine-1-carboxamide; (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide formate; (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide formate N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide; 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide; (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxy-pyrrolidine-1-carboxamide; 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(methoxymethyl)piperidine-1-carboxamide; 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-fluoro-piperidine-1-carboxamide; (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]pyrrolidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxy-3-methyl-azetidine-1-carboxamide; (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]pyrrolidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-piperazine-1-carboxamide N4-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]morpholine-2,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-3-oxo-piperazine-1-carboxamide; (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide; 4-acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methylsulfonyl-piperazine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-sulfamoyl-piperazine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8-carboxamide; (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide; 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methoxy-piperidine-1-carboxamide; 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(hydroxymethyl)azetidine-1-carboxamide; 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]azetidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,1-dioxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxyazetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-hydroxyethyl)-3-oxo-piperazine-1-carboxamide; 4,4-dicyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)azetidine-1-carboxamide; (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid; Methyl (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylate; (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide; (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide; (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide; (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide; (1S,4S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide; (3R)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]piperazine-1,3-dicarboxamide; (3S)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]piperazine-1,3-dicarboxamide; 4-Amino-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide; 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide; (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide; 4-Amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide; 1-Acetylamino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide.

[0162] The various functional groups and substituents comprising the compound of formula (I) are generally selected so that the molecular weight of the compound of formula (I) does not exceed 1000. More generally, the molecular weight of the compound is less than 900, for example, less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, for example, 550 or less.

[0163] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of compounds of the present invention that are sufficiently basic, for example, acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris(2hydroxyethyl)amine.

[0164] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0165] The compounds of the present invention may have one or more asymmetric centers, and such compounds can therefore be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers, e.g., by synthesis from optically active starting materials or by resolution of racemates, are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomeric centers (E and Z isomers). It is understood that the present invention encompasses all optical, diastereomeric, and geometric isomers, and mixtures thereof, that possess antiproliferative activity.

[0166] The present invention also encompasses compounds of the present invention as defined herein that contain one or more isotopic substitutions. For example, H can be in any isotopic form, including 1H, 2H (D), and 3H (T), C can be in any isotopic form, including 12C, 13C, and 14C, and O can be in any isotopic form, including 16O and 18O.

[0167] It is also to be understood that certain compounds of formula (I) can exist in solvated as well as unsolvated forms, for example, hydrated forms, and it is to be understood that the present invention encompasses all such solvated forms that possess antiproliferative activity.

[0168] It will also be understood that certain compounds of formula I may exhibit polymorphism and that the invention encompasses all such forms which possess antiproliferative activity.

[0169] Compounds of Formula I can exist in many different tautomeric forms, and reference to a compound of Formula I includes all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all others are nevertheless encompassed by Formula I. Examples of tautomeric forms include keto, enol, and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. [ka]

[0170] Compounds of Formula I containing an amine functional group can also form N-oxides. Reference herein to compounds of Formula I containing an amine functional group also includes N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). See, for example, Jerry March, Advanced Organic Chemistry, 4th Edition, Wiley Interscience, pages 1977-1989. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0171] The compounds of formula (I) can be administered in the form of prodrugs, which are broken down in the human or animal body to release the compounds of the present invention. Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at a carboxy or hydroxy group in the compounds of formula (I), and in vivo cleavable amide derivatives that can be formed at a carboxy or amino group in the compounds of formula (I).

[0172] Thus, the present invention includes compounds of formula (I) as defined above when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present invention includes compounds of formula I produced by organic synthetic means as well as such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., compounds of formula (I) can be synthetically produced compounds or metabolically produced compounds.

[0173] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) are those that, based on sound medical judgment, have no undesirable pharmacological activity and are not excessively toxic and are suitable for administration to the human or animal body.

[0174] Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, H. Bundgaard p.113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0175] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a carboxy group are, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula I containing a carboxy group are, for example, pharmaceutically acceptable esters which are cleaved in the human or animal body to yield the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C1-6 alkyl esters such as methyl, ethyl and tert-butyl, C1-6 alkoxymethyl esters such as methoxymethyl ester, C1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl ester, C3-8 cycloalkylcarbonyloxy-C1-6 alkyl esters such as pivaloyloxymethyl ester, 3-phthalidyl ester, cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and C1-6 alkoxycarbonyloxyC1-6 alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl ester.

[0176] Suitable pharmaceutically acceptable prodrugs of a compound of formula (I) having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. An in vivo cleavable ester or ether of a compound of formula (I) containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramido cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include C1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, and C1-10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-6)2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0177] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having a carboxy group are, for example, in vivo cleavable amides thereof, for example amides formed with amines such as ammonia, C1-4 alkylamines such as methylamine, (C1-4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-4 alkoxy-C2-4 alkylamines such as 2-methoxyethylamine, phenyl-C1-4 alkylamines such as benzylamine, and amino acids such as glycine or its esters.

[0178] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, amides formed with C1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-4 alkyl)piperazin-1-ylmethyl.

[0179] The in vivo effects of the compounds of formula (I) may be exerted in part by one or more metabolic products formed in the human or animal body following administration of the compounds of formula (I). As noted above, the in vivo effects of the compounds of formula (I) may also be exerted by metabolism of precursor compounds (prodrugs).

[0180] The present invention may relate to any compound or particular group of compounds defined herein by any preferred or suitable feature or with respect to a particular embodiment, but the present invention may also relate to any compound or particular group of compounds that specifically excludes said any preferred or suitable feature or particular embodiment.

[0181] Preferably, the present invention excludes any individual compound that does not have biological activity as defined herein.

[0182] synthesis The compounds of the present invention may be prepared by any suitable method known in the art. Particular methods for forming compounds of formula I as defined herein are illustrated in the accompanying Examples.

[0183] In the descriptions of synthetic methods described herein, and in any reference synthetic methods used to prepare starting materials, it is understood that all suggested reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, can be selected by one of ordinary skill in the art.

[0184] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0185] It will be appreciated that during the synthesis of the compounds of the invention, or of particular starting materials in the processes defined herein, it may be desirable to protect certain substituents to prevent their undesired reactions. The skilled chemist will understand when such protection is required and how such protecting groups may be put in place and subsequently removed.

[0186] For examples of protecting groups, see one of the many general texts on the subject, for example, "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such method being chosen so as to remove the protecting group with minimal interference with groups elsewhere in the molecule.

[0187] Thus, where reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0188] For example, suitable protecting groups for amino or alkylamino groups include acyl groups, such as alkanoyl groups (e.g., acetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl). The deprotection conditions for the above-mentioned protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, e.g., lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, such as t-butoxycarbonyl groups, can be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups, can be removed by hydrogenation with a catalyst, e.g., palladium on carbon, or by treatment with a Lewis acid, e.g., borontris (trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0189] Suitable protecting groups for hydroxy groups are, for example, acyl groups, e.g., alkanoyl groups such as acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed by hydrolysis with a suitable base such as, for example, an alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation over a catalyst such as, for example, palladium on carbon.

[0190] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group which may be removed by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed by treatment with an acid, for example an organic acid, such as trifluoroacetic acid, or for example a benzyl group which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0191] Resins can also be used as protecting groups.

[0192] The methodology used to synthesize compounds of formula (I) will vary depending on the nature of R1, R2, R3, R4, R5 and R6 and any substituents associated therewith, and suitable processes for their preparation are further described in the accompanying Examples.

[0193] Once a compound of formula (I) has been synthesised by any one of the processes defined herein, the process may then further comprise one or more of the following additional steps: (i) removing any protecting groups present; (ii) converting a compound of formula (I) into another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate of a compound of formula I; and / or (iv) forming a prodrug of a compound of formula I.

[0194] An example of (ii) above is where a compound of formula (I) is synthesised and then one or more of the groups R1, R2, R3, R4, R5 and R6 are further reacted to change the nature of the group to provide an alternative compound of formula (I).

[0195] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0196] biological activity The biological assays described in the Examples section (Biological Examples 1-3) can be used to measure the pharmacological effects of the compounds of the present invention.

[0197] Although the pharmacological properties of compounds of formula I vary, as would be expected, with structural changes, the compounds of the invention were found to be active in the assays described in Biological Examples 1, 2 and 3.

[0198] Generally, with respect to adenosine A2a antagonism, compounds of the present invention have an IC2A activity of 1 μM or less in the assay described in Biological Example 1. 50 and preferred compounds of the present invention exhibit an IC 50 and the most preferred compounds of the present invention exhibit an IC of 50 nM or less. 50 Shows.

[0199] Generally, with respect to adenosine A2b antagonism, compounds of the present invention have an IC of 1 μM or less in the assay described in Biological Example 1. 50 and preferred compounds of the present invention exhibit an IC 50 and the most preferred compounds of the present invention exhibit an IC of 50 nM or less. 50 Shows.

[0200] Suitably, the compounds of the invention have an IC50 at adenosine A1 or A3 receptors in the assay described in Biological Example 1. 50 IC at adenosine A2a receptors 50 Preferably, the ion exchange rate is at least two times higher, more preferably at least five times higher, and even more preferably at least ten times higher.

[0201] Pharmaceutical Composition According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0202] Compositions of the invention may be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0203] The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0204] An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the proliferative conditions referred to herein.

[0205] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g of active agent (more preferably, 0.5 to 100 mg, e.g., 1 to 30 mg), mixed with an appropriate and convenient amount of excipient, which may vary from about 5 to about 98% by weight of the total composition.

[0206] The magnitude of a dose of a compound of formula I for therapeutic or prophylactic purposes will, of course, vary with the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0207] When used for therapeutic or prophylactic purposes, the compounds of the present invention are generally administered at a daily dose ranging, for example, from 0.1 mg / kg to 75 mg / kg of body weight, given in divided doses if necessary. Generally, when parenteral administration is used, lower doses are administered. Thus, for example, for intravenous or intraperitoneal administration, doses ranging, for example, from 0.1 mg / kg to 30 mg / kg of body weight are generally used. Similarly, for administration by inhalation, doses ranging, for example, from 0.05 mg / kg to 25 mg / kg of body weight are used. Oral administration, particularly in tablet form, may also be suitable. Typically, a unit dosage form contains about 0.5 mg to 0.5 g of a compound of the present invention.

[0208] Therapeutic Uses and Applications The present invention provides compounds that function as antagonists of adenosine A2 receptors, particularly adenosine A2a receptors.

[0209] According to a further aspect of the present invention there is provided a method of antagonizing adenosine A2a receptors in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0210] According to a further aspect of the present invention there is provided a method of selectively antagonizing adenosine A2a receptors in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0211] According to a further aspect of the present invention there is provided a method of inhibiting proliferation of a cell in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0212] According to a further aspect of the present invention there is provided a method of treating a disease or disorder associated with adenosine A2a receptor activity in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0213] According to a further aspect of the present invention there is provided a method of treating a cell proliferative disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0214] According to a further aspect of the present invention there is provided a method of treating cancer in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., a checkpoint inhibitor and / or a cytotoxic agent).

[0215] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

[0216] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a cell proliferative condition. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0217] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer. In certain embodiments, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0218] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use as an adenosine A2a antagonist. In one embodiment, the compound of the present invention is a selective adenosine A2a antagonist. In an alternative embodiment, certain compounds of the present invention are selective adenosine A2a antagonists and adenosine A2b antagonists.

[0219] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which adenosine A2a is involved.

[0220] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a cell proliferative condition. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0221] According to a further aspect of the present invention, there is provided the use of a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of cancer. Preferably, the cancer is a human cancer. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0222] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use as an adenosine A2a antagonist.

[0223] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use as an adenosine A2a antagonist.

[0224] According to a further aspect of the present invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which adenosine A2a receptor activity is implicated.

[0225] The term "proliferative disorder" is used interchangeably herein and refers to unwanted or uncontrolled cell proliferation of unwanted, excessive, or abnormal cells, such as neoplastic or hyperplastic growth, in vitro or in vivo. Examples of cell proliferative conditions include, but are not limited to, premalignant and malignant cell proliferation, including, but not limited to, malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis. Any type of cell can be treated, including, but not limited to, lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

[0226] The antiproliferative effects of the compounds of the present invention have particular application in the treatment of human cancers (due to their adenosine A2a antagonist activity).

[0227] More particularly, there is provided compounds of general formula (I) for use in the treatment of cancer, in particular solid tumors such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma.

[0228] More particularly, there is provided a compound of general formula (I) for use in the treatment of cancer, for example lung cancer, such as small cell lung cancer or non-small cell lung cancer.

[0229] There is also provided the use of a compound of general formula (I) in the manufacture of a medicament for use in the treatment of cancer, in particular solid tumours such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma.

[0230] The present invention further provides a method for the treatment of cancer, in particular solid tumors such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma, which comprises administering to a patient in need of such treatment an effective amount of a compound of general formula (I).

[0231] The patient to be treated is preferably a mammal, more preferably a human.

[0232] Route of administration The compounds of the present invention or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, to the desired site of action).

[0233] Routes of administration include, but are not limited to, oral (e.g., by ingestion), buccal, sublingual, transdermal (e.g., by patch, plaster, etc.), transmucosal (e.g., by patch, plaster, etc.), intranasal (e.g., by nasal spray), intraocular (e.g., by eye drops), pulmonary (e.g., by aerosol, e.g., by inhalation or insufflation therapy through the mouth or nose), rectal (e.g., by suppository or enema), vaginal (e.g., by pessary), parenteral (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intrathecal, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, substernal, and intratumoral, and by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly).

[0234] The compounds of the present invention or pharmaceutical compositions containing these compounds can be administered by intratumoral delivery.

[0235] Combination therapy The compounds of formula I are useful for the treatment and / or prevention of cell proliferative disorders, such as, for example, cancer. The compounds of formula I as defined herein may be used in combination with one or more additional anti-proliferative / anti-cancer therapies, such as, for example, chemotherapy with one or more additional anti-proliferative / anti-cancer agents, radiation therapy, and / or conventional surgery.

[0236] The additional anti-proliferative / anti-cancer agent may be included in a pharmaceutical composition together with a compound of formula (I) as defined herein or may be administered separately, either simultaneously with, earlier or later than, a compound of formula (I).

[0237] Thus, in a further aspect of the present invention there is provided a product comprising a compound of general formula (I) and an additional agent useful in the treatment or prevention of cancer as a combined preparation for simultaneous, sequential or separate use in the treatment of cancer.

[0238] The present invention also provides compounds of general formula (I) in combination with one or more additional anti-proliferative / anti-cancer agents for use in the treatment of cancer, as a combined preparation for simultaneous, sequential or separate use in the treatment of cancer.

[0239] In particular, the combination therapy defined herein is suitable for the treatment of solid tumors, such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma.

[0240] Suitable additional antiproliferative / anticancer agents that may be used in combination with compounds of formula I as defined herein (either separately or as part of a pharmaceutical composition combined with a compound of general formula (I) or as part of a combined preparation) include: 1) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents; 2) adenosine pathway modulators (including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors); 3) anti-PD-1 and PDL-1 antibodies (including, but not limited to, cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab); and 4) Anti-CTLA4 antibodies (including but not limited to ipilimumab).

[0241] The compounds of Formula I defined herein are particularly suitable for use in combination with anti-PD-1 and anti-PDL-1 antibodies (including, but not limited to, cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab). Preferably, the anti-PD-1 antibody is one of the antibodies disclosed in U.S. Patent Application Publication No. 2019 / 0225689 or U.S. Patent Application Publication No. 2017 / 0121409 (incorporated herein by reference in their entireties), such as cetrelimab. Cetrelimab (JNJ-63723283, CET) is a fully human immunoglobulin (Ig) G4 kappa monoclonal antibody that binds to programmed death receptor-1 (PD-1) with high affinity and specificity. Cetrelimab has demonstrated activity in solid tumors. Rutkowski P, et al.Journal of Clinical Oncology.2019;37(8):31.

[0242] The compounds of formula I as defined herein are particularly suitable for use in combination with adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors and CD39 inhibitors.

[0243] The A2a antagonists of general formula (I) may also be used in combination with cell-based immunotherapies, including but not limited to CAR-T cell therapy, and cancer vaccines.

[0244] Examples of additional anti-proliferative / anti-cancer chemotherapeutic agents include, but are not limited to, any one or more of the following: Tauromustine; Tazarotene; Tecogalan sodium; Tegafur; Terlapyrylium; Telomerase inhibitors; Temoporfin; Temozolomide; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Taliblastine; Thiocoraline; Thrombopoietin; Thrombopoietin mimetics; Thymalfadine; Thymopoietin receptor agonists; Thymotrin; Thyroid-stimulating hormone; Tin ethyl etiopurpurin; Tirapazamine; Titanocene dichloride; Topsentin; Toremifene; Totipotent stem cell factor; Translation inhibitors; Tretinoin; Triacetyluridine; Triciribine; Toxin Rimetrexate; Triptorelin; Tropisetron; Turosteride; Tyrosine kinase inhibitors; Tyrphostin; UBC inhibitors; Ubenimex; Urogenital sinus-derived growth inhibitor; Urokinase receptor antagonists; Vapreotide; Variolin B; Vector systems, erythrocyte gene therapy drugs; Veraresol; Veramine; Verdine; Verteporfin; Vinorelbine; Vinoxacin; Vitaxin; Vorozole; Zanoterone; Zeniplatin; Zilascorub; Zinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin,Acivicin; Aclarubicin; Acodazole hydrochloride; Acronine; Adzelesin; Aldesleukin; Altretamine; Ambomycin; Amethantrone acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene hydrochloride; Bisnafide dimesylate; Bizeresin; Sulfate Bleomycin;Brequinar sodium;Bropirimine;Busulfan;Cactinomycin;Calsterone;Caracemide;Carbetimer;Carboplatin;Carmustine;Carubicin hydrochloride;Carzelcin;Cedefingol;Chlorambucil;Ciloremycin;Cladribine;Crisnatol mesylate;Cyclophosphamide;Cytarabine;Dacarbazine;Daunorubicin hydrochloride;Decitabine;Dexolomaplatin;Dezaguamine;De Zaguamine mesylate; Diazicon; Doxorubicin; Doxorubicin hydrochloride; Droloxifene; Droloxifene citrate; Dromostanolone propionate; Duazomycin; Edatrexate; Eflornithine hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropizin; Epirubicin hydrochloride; Elbrozole; Esorubicin hydrochloride; Estramustine; Estramustine phosphate sodium; Ethanidazole ru; etoposide; etoposide phosphate; etopurine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; foscidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin 2 or rlL.sub.2),Interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-la; interferon gamma-lb; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; Methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocalcin; mitochromin; mitogillin; mitomarcine; mitomycin; mitosperm; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisulan; pegaspargase; periomycin; pentamstine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; promestane; porfimer sodium; Porfiromycin;Prednimustine;Procarbazine hydrochloride;Puromycin;Puromycin hydrochloride;Pyrazofurin;Rivopurin;Rogletimide;Safingol;Safingol hydrochloride;Semustine;Simtrazene;Sparfosate sodium;Sparsomycin;Spirogermanium hydrochloride;Spiromustine;Spiroplatin;Streptonigrin;Streptozocin;Sulofenur;Tallysomycin;Tecogalan sodium;Tegafur;Teloxantrone hydrochloride;Temoporfin;Teniposide;Teroxylon;Testolactone;Thiamiprine;Thiaminoprine Oguanine; Thiotepa; Tiazofurin; Tirapazamine; Toremifene citrate; Trestrone acetate; Trisibirine phosphate; Trimetrexate; Trimetrexate glucuronate; Triptorelin; Tubrozole hydrochloride; Uracil mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Binepidine sulfate; Vingrisinate sulfate; Vinleurosine sulfate; Vinorelbine tartrate; Vinrocidine sulfate; Vinzoquidine sulfate; Vorozole; Zeniplatin; Zinostatin; Zorubicin hydrochloride,Agents that arrest cells in the G2-M phase and / or modulate the formation or stability of microtubules (e.g., Taxol™ (i.e., paclitaxel)), Taxotere™ (compounds containing a taxane skeleton), elbrozole (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobulin isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), altritol (e.g., Altritol), altritin A and altritin C), spongistatins (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilones (e.g., epothilone A, epothilone B, epothilone C (i.e., desoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-3-10705), 21-hydroxyepothilone D (i.e., desoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), vincristine sulfate, cryptophycin 52 (i.e., LY-355703), bitilebamide, tublysin A, canadensol, sendaureidin (i.e., NSC-106969), oncocidin A1 (i.e., BTO-956 and DF-106969), E), Physianolide B, Laulimalide, Narcosine (also known as NSC-5366), Nascapine, Hemiasterin, Vanadocene acetylacetonate, Monsatrol, Inanosin (i.e., NSC-698666), Eleutherobin (Desmethyleleutherobin, Desaetyleleutherobin,leuruterobin A and Z), caribeoside, caribaeolin, halichondrin B, diazonamide A, taccalonolide A, diozostatin, (-)-phenylahistine (i.e., NSCL-96F037), myoseverin B, resberastatin sodium phosphate, steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-Fc anti-ER2, anti-CD52, anti-ULA-DR and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapeutic agents (e.g., anti-CD20 monoclonal antibody conjugated to ln, 0Y or I), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine , sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992,CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or hormone therapy, etc.

[0245] As noted above, combination therapies of the present invention may be achieved by the simultaneous, sequential, or separate administration of the individual components of the treatment. Such combination products utilize the compounds of this invention within the dosage ranges described above and the other pharmaceutically active agent(s) within their approved dosage ranges.

[0246] According to this aspect of the invention there is provided a combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more further anti-proliferative / anti-cancer agents for use in the treatment of cancer (e.g. cancer involving solid tumours).

[0247] According to this aspect of the invention there is also provided a combination for use in the treatment of a cell proliferative condition such as cancer (e.g. cancer involving solid tumours), comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-proliferative / anti-cancer agents selected from those listed above.

[0248] In a further aspect of the present invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of cancer in combination with another anti-tumour agent selected from any of those listed hereinabove.

[0249] When the term "combination" is used herein, it should be understood to refer to simultaneous, separate or sequential administration. In one aspect of the present invention, "combination" refers to simultaneous administration. In another aspect of the present invention, "combination" refers to separate administration. In a further aspect of the present invention, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such that the beneficial effect of the combination is lost.

[0250] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumor agent (selected from any of those listed herein above), in combination with a pharmaceutically acceptable diluent or carrier. [Example]

[0251] General conditions: Mass spectra were performed on LC-MS systems using electrospray ionization. These were performed using either a Waters Acquity H-Class UPLC with PDA and QDa mass detection, a Waters Acquity Classic UPLC with PDA and SQ mass detection, an Acquity LC (binary pump / PDA detector) with a ZQ mass spectrometer, or an Acquity i-Class (quaternary pump / PDA detector) with a Quattro Micro mass spectrometer, a Waters Acquity LC system equipped with a Waters PDA and ELS detector, or a Shimadzu LCMS-2010EV system. [M+H]+ refers to the monoisotopic molecular weight.

[0252] NMR spectra were performed on a Bruker Ultrashield 500 MHz NMR spectrometer, a Bruker Avance III HD 400 MHz NMR spectrometer, or a Bruker Avance III HD 500 MHz. Spectra were recorded at 298 K and referenced to the solvent peak.

[0253] The following examples illustrate the present invention, but are not intended to be limiting. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporations are carried out under vacuum, preferably at about 15 to 100 mmHg (= 20 to 133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, such as microanalysis and spectroscopic properties, e.g., MS, IR, and NMR. Abbreviations used are conventional in the art. Unless defined, these terms have their generally accepted meanings.

[0254] Abbreviation Appearance br Broad CDI 1,1'-carbonyldiimidazole d double line dd compound double line DCM dichloromethane DIPEA Diisopropylethylamine DMF N,N-dimethylformamide DMA Dimethylacetamide EtOAc ethyl acetate HPLC High-Performance Liquid Chromatography LC-MS Liquid Chromatography Mass Spectrometry Meoh Meoh MeCN acetonitrile MS mass spectrometry m multiplet mins minutes mL milliliter m / z mass-to-charge ratio NMR nuclear magnetic resonance ppm parts per million Rt retention time s single line t multiplet TBAF Tetra-n-butylammonium fluoride TFA trifluoroacetic acid THF tetrahydrofuran

[0255] For the examples that follow, compounds of preferred embodiments were synthesized using methods described herein or other methods known in the art.

[0256] The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified, if necessary, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purification. Salts can be prepared from compounds by known salt-forming procedures.

[0257] Unless otherwise stated, analytical HPLC conditions were as follows:

[0258] Method 2A Column: Kinetex Core-Shell C18 2.1 x 50 mm 5 μm Column temperature: 40°C Eluent: A: H2O + 0.1% formic acid, B: MeCN + 0.1% formic acid Flow rate: 1.2mL / min Gradient: 0-1.83 min 5-100% B, 1.83-2.25 min 100% B, 2.25-2.26 min 100-5% B

[0259] Method 2.5B Column: Phenomenex Gemini-NX C18 2 x 50 mm 3 μm Column temperature: 40℃ Eluents: A: 2 mM ammonium bicarbonate buffered to pH 10, B: MeCN Flow rate: 1mL / min Gradient: 0-1.80 min 1-100% B, 1.80-2.10 min 100% B, 2.10-2.30 min 100-1% B

[0260] Method 2B Column: Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 μm Column temperature: 50℃ Eluent: A: H2O, 0.1% formic acid B: MeCN Flow rate: 0.8mL / min Gradient: 0.0-1.8 min 2-98%B, 1.8-2.1 min 98%B, 2.1-2.5 min 98%A

[0261] Method 3A Column: Acquity LC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Eluent: A: HO, 0.1% formic acid, B: MeCN Flow rate: 0.6mL / min Gradient: 0.2-2.5 min 2-98% B, 2.5-3.3 min 98% B, 3.3-3.5 min 98% A

[0262] Method 3B Column: Acquity LC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Eluent: A: H2O, 0.1% ammonia, B: MeCN Flow rate: 0.6mL / min Gradient: 0.2-2.5 min 2-98% B, 2.5-3.3 min 98% B, 3.3-3.5 min 98% A

[0263] Method 5A Column: YMC-Triart C18 2 x 50 mm, 5 μm Flow rate: 0.8mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% formic acid Gradient: 0.0–4.0 min 0–95% B, 5% C; 4.0–4.4 min 95% B, 5% C; 4.4–4.5 min 95% A, 5% B

[0264] Method 5B Column: Waters Alliance ZQ MS, YMC-Triart C18 50×2mm, 5μm Column temperature: room temperature Eluent: A: H2O, B: CH3CN, C: 50% H2O / 50% CH3CN + 1.0% ammonia (aqueous) Flow rate: 0.8mL / min Gradient: 0.0–4.0 min 0–95% B, 5% C; 4.0–4.4 min 95% B, 5% C; 4.4–4.5 min 95% A, 5% B

[0265] Method 7A Column: Phenomenex Kinetix-XB C18 2.1 x 100 mm, 1.7 μm Column temperature: 40℃ Eluent: A: HO + 0.1% formic acid, B: MeCN + 0.1% formic acid Flow rate: 0.6mL / min Gradient: 0-5.3.0 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82-7.00 min 5% B

[0266] Method 7B Column: Waters LC® BEH™ C18, 2.1 mm x 100 mm, 1.7 μm Column temperature: 40℃ Eluents: A: 2 mM ammonium bicarbonate buffered to pH 10, B: MeCN Flow rate: 0.6mL / min Gradient: 0-5.3.0 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82-7.00 min 5% B

[0267] Method 8A Column: Acquity UPLC BEH C18 2.1 x 100 mm, 1.7 μm Column temperature: 50℃ Eluent: A: H2O, 0.1% formic acid B: MeCN Flow rate: 0.6mL / min Gradient: 0.5-6.5 min 2-98%B, 6.5-7.5 min 98%B

[0268] Method 8B Column: Acquity UPLC BEH C18 2.1 x 100 mm, 1.7 μm Column temperature: 50℃ Eluent: A: H2O, 0.1% ammonia B: MeCN Flow rate: 0.6mL / min Gradient: 0.5-6.5 min 2-98%B, 6.5-7.5 min 98%B

[0269] Method 15A Column: YMC-Triart C18 2 x 50 mm, 5 μm Flow rate: 0.8mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% formic acid Gradient: 0.0–12.0 min 0–95% B, 5% C; 12.0–14.0 min 95% B, 5% C; 14.0–14.2 min 95% A, 5% B

[0270] Method 15B Column: YMC-Triart C18 50 x 2 mm, 5 μm Flow rate: 0.8mL / min Eluents: A: HO, B: MeCN, C: 50% HO / 50% MeCN + 1.0% ammonia (aqueous) Gradient: 0.0–12.0 min 0–95% B, 5% C; 12.0–14.0 min 95% B, 5% C; 14.0–14.2 min 95% A, 5% B

[0271] Preparative HPLC with acidic pH, early elution method Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature) and a gradient from 10 to 95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in MeCN) over 14.44 min, followed by 95% B over 2.11 min, with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0272] Preparative HPLC with alkaline pH, early elution method Purification by preparative HPLC (alkaline pH, fast elution method) was performed on a Gilson LC system using a Waters Xbridge C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) and a gradient of 10 to 95% B (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in MeCN) over 14.44 min, followed by 95% B over 2.11 min, with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0273] Example 1 N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide [ka] Step 1: N-[4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide [ka] To a stirred solution of 3-(2-aminothiazol-4-yl)benzonitrile (Intermediate A) (653 mg, 3.08 mmol) in THF (10 mL) at 0° C. was added sodium hydride (60% in mineral oil) (150 mg, 3.75 mmol). After stirring at room temperature for 20 minutes, morpholine-4-carbonyl chloride (520 μL, 4.55 mmol) was added and stirring was continued for 18 hours. The resulting mixture was diluted with THF (10 mL) and then re-treated with sodium hydride (60% in mineral oil) (150 mg, 3.75 mmol). After stirring for 10 minutes, morpholine-4-carbonyl chloride (520 μL, 4.55 mmol) was added and stirring was continued for 4 hours. The reaction was quenched with water (20 mL) and extracted with EtOAc (2×40 mL). The aqueous layer was acidified to pH 5 with 1 M HCl and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo. The resulting brown oil was purified by silica chromatography eluting with 0-100% EtOAc / heptane to afford the title compound as a beige solid. LC-MS (Method 2A): Rt1.06 min; MS m / z315.1=[M+H]+ 11 H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.31(t,J=1.5Hz,1H),8.21(dt,J=7.9,1.3Hz,1H),7.76(dt,J=7.7,1 .3Hz,1H),7.73(s,1H),7.63(t,J=7.8Hz,1H),3.67-3.58(m,4H),3.56-3.48(m,4H).

[0274] Step 2: N-[5-bromo-4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide [ka] To a solution of N-[4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide (Step 1) (790 mg, 2.34 mmol) in THF (20 mL) was added NBS (499 mg, 2.8 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with EtOAc (50 mL) and washed with water (30 mL), saturated NaHCO solution (2 × 30 mL), and brine (30 mL). The organic layer was dried over MgSO and concentrated in vacuo to give the title compound as a yellow solid. LC-MS (Method 2A): Rt1.18 min; MS m / z393.0 / 395.0=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 11.35(s,1H),8.25(t,J=1.5Hz,1H),8.21(dt,J=8.0,1.4Hz,1H),7.88(dt,J= 7.7,1.3Hz,1H),7.71(t,J=7.9Hz,1H),3.63-3.56(m,4H),3.55-3.48(m,4H).

[0275] Step 3: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide A stirred solution of N-[5-bromo-4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide (Step 2) (50 mg, 0.13 mmol), (2-chloro-6-methyl-4-pyridyl)boronic acid (87 mg, 0.51 mmol), and cesium carbonate (124 mg, 0.38 mmol) in monoglyme (3 mL) and water (0.5 mL) was degassed with nitrogen for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.03 mmol) was added, and the reaction mixture was heated at 85° C. for 7.5 hours. After cooling to room temperature, the mixture was diluted with DCM (5 mL) and water (5 mL). The organic layer was separated, passed through a hydrophobic frit, and concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with acetonitrile / water / 0.1% formic acid, followed by further purification by C18 reverse phase chromatography eluting with acetonitrile / water / 0.1% ammonia to give the title compound as a bright yellow powder. LC-MS (Method 2.5B): Rt3.58 min; MS m / z440.1 / 442.1=[M+H]+ 1 H NMR(400MHz,DMSO-d6)δ 11.40(br s,1H),7.90(t,J=1.4Hz,1H),7.84(dt,J=7.7,1.3Hz,1H),7.72(dt,J=7.9,1.3Hz,1H),7.58( t,J=7.9Hz,1H),7.14(s,1H),7.01(s,1H),3.62-3.57(m,4H),3.54-3.49(m,4H),2.39(s,3H)

[0276] Example 2 N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide [ka] Step 1: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]imidazole-1-carboxamide [ka] A solution of 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate D) (73 mg, 0.17 mmol) and CDI (55 mg, 0.34 mmol) in DMA (0.5 mL) was stirred at room temperature for 24 hours. An additional portion of CDI (55 mg, 0.34 mmol) was added, and stirring was continued at room temperature for 2 hours, then at 50° C. for 1 hour. After cooling to room temperature, the resulting precipitate was collected by vacuum filtration to give the title compound as a pale yellow solid. LC-MS (Method 7B): Rt 3.76 min; MS M / z 385.1 = [M-(C3N2H5)+(OCH3)]+; methyl carbamate observed from reaction of the title compound with MeOH. 1 H NMR(400MHz,DMSO-d6)δ 8.43(s,1H),8.11(d,J=3.6Hz,1H),7.90(d,J=1.5Hz,1H),7.84(d,J=1.4Hz,1H),7.83-7.79(m,1H),7.76 -7.72(m,1H),7.69(dt,J=7.9,1.4Hz,1H),7.56(t,J=7.8Hz,1H),7.01(s,1H),6.91(s,1H),2.35(s,3H).

[0277] Step 2: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide To a stirred solution of N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]imidazole-1-carboxamide (Step 1) (59 mg, 0.09 mmol) in DMA (0.5 mL) was added 2-pyrrolidin-3-ylpropan-2-ol (22 mg, 0.17 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. An additional portion of 2-pyrrolidin-3-ylpropan-2-ol (22 mg, 0.17 mmol) was added, and stirring was continued for 3 days. DIPEA (30 μL, 0.17 mmol) was added, followed by additional 2-pyrrolidin-3-ylpropan-2-ol (22 mg, 0.17 mmol), and the mixture was heated to 50° C. for 18 hours. The resulting mixture was diluted with water (3 mL) and extracted with EtOAc (3×3 mL). The combined organic extracts were filtered through a phase separation cartridge and concentrated in vacuo. The crude product was purified by silica chromatography eluting with 0-100% EtOAc / DCM followed by 0-10% MeOH / EtOAc to give the title compound as an off-white solid. LC-MS (Method 7B): Rt3.23 min; MS m / z482.3 / 484.2=[M+H]+ 1 H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),7.92(t,J=1.5Hz,1H),7.85(dt,J=7.7,1.4Hz,1H),7.73(dt,J=7.9,1.3Hz,1H),7.59(t,J=7.9Hz,1 H),7.18(s,1H),7.06(s,1H),4.37(s,1H),3.71-3.41(m,4H),2.40(s,3H),2.21(s,1H),1.83(s,2H),1.12(s,6H).

[0278] Example 3 (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide [ka] A solution of 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate D) (52 mg, 0.16 mmol) and CDI (31 mg, 0.19 mmol) in DMA (0.5 mL) was stirred at 50 °C for 22 h. Additional CDI (31 mg, 0.19 mmol) was added and stirring was continued at 50 °C for a total of 46 h. The resulting mixture was cooled to room temperature and then treated with 2-[(2R)-pyrrolidin-2-yl]propan-2-ol hydrochloride (40 mg, 0.24 mmol) and DIPEA (55 μL, The resulting orange solid was purified by silica chromatography eluting with 0-100% EtOAc / DCM, followed by a second purification by silica chromatography eluting with 0-100% EtOAc / heptane to give the title compound as an off-white solid. LC-MS (Method 7B): Rt3.62 min; MS m / z482.3 / 484.3=[M+H]+ 1 H NMR(400MHz,DMSO-d6)δ 12.00(s,1H),7.88(t,J=1.5Hz,1H),7.85(dt,J=7.7,1.4Hz,1H),7.69(dt,J=8.0,1.2Hz,1H),7.58(t,J=7.8Hz,1H),7.21-7. 16(m,1H),7.08-7.03(m,1H),4.01-3.82(m,3H),2.40(s,3H),2.11-2.00(m,1H),1.90-1.60(m,4H),1.19(s,3H),1.10(s,3H).

[0279] The compounds of the following table (Table Ex3) were prepared in analogy to Example 3 from 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate D) and the appropriate amine.

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[0283] Example 4 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide [ka] A solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) (50 mg, 0.16 mmol) and CDI (40 mg, 0.24 mmol) in DMA (0.5 mL) was stirred at 50° C. for 18 h. The resulting mixture was treated with 1-methylpiperazine (36 μL, 0.33 mmol) and stirring was continued at 50° C. for 1 h. After cooling to room temperature, the crude mixture was purified by preparative HPLC using acidic conditions, fast elution method to provide the title compound. LC-MS (Method 7B): Rt2.43 min; MS m / z433.3=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 11.27(br s,1H),7.89(t,J=1.5Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7.70(dt,J=8.0,1.2Hz,1H),7.56( t,J=7.8Hz,1H),6.93(s,2H),3.55-3.50(m,4H),2.36(s,6H),2.34-2.30(m,4H),2.20(s,3H).

[0284] Example 4.1 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide [ka] A solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) (50 mg, 0.16 mmol) and CDI (53 mg, 0.33 mmol) in DMA (0.5 mL) was stirred at 50 °C for 18 h. The resulting mixture was treated with piperidine-4-carbonitrile (36 mg, 0.33 mmol) and DIPEA (90 μL, 0.49 mmol), and stirring was continued at 50 °C for 30 min. After cooling to room temperature, the crude material was purified by C18 reverse-phase chromatography eluting with 5–20% MeCN / water (+0.1% ammonium hydroxide modifier) ​​to give a solid that was suspended in EtO (2 mL), collected by filtration, washed with EtO (2 × 1.5 mL), and dried to give the title compound as a yellow solid. LC-MS (Method 8B): Rt4.17 min; MS m / z443.3=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 11.28(s,1H),7.88(s,1H),7.81(d,J=7.9Hz,1H),7.70(d,J=7.9Hz,1H),7.56(t,J=7.9Hz,1H),6.92(s,2H), 3.83-3.76(m,2H),3.45-3.38(m,2H),3.14-3.08(m,1H),2.36(s,6H),1.95-1.86(m,2H),1.75-1.65(m,2H).

[0285] The compounds of the examples shown in the table below (Table Ex4) were prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and the appropriate amine in analogy to Example 4 or Example 4.1.

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[0296] Example 4.12 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] CDI (1.27 g, 7.83 mmol) and DIPEA (2.05 mL, 11.75 mmol) were added to a stirred solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) (1.2 g, 3.92 mmol) in DMA (12 mL), and the solution was heated at 50 °C overnight. 2-Oxa-6-azaspiro[3.3]heptane (0.73 mL, 7.83 mmol) and additional DIPEA (2.05 mL, 11.75 mmol) were added, and the solution was stirred at 50 °C for 40 min. The resulting mixture was cooled to room temperature, then diluted with EtOAc (150 mL), washed with 90% brine (100 mL), 50% brine (3 × 100 mL), dried over MgSO, and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 0-4% MeOH / DCM gave the title compound as an off-white solid. LC-MS (Method 8B): Rt2.82 min; MS m / z432.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.35(s,1H),7.88(t,J=1.7Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7.70(dt,J=8.0,1. 5Hz, 1H), 7.56 (t, J=7.8Hz, 1H), 6.93 (s, 2H), 4.68 (s, 4H), 4.21 (s, 4H), 2.36 (s, 6H).

[0297] Example 5: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid [ka] Example 5.1: Methyl (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylate [ka] Step 1: (2R)-1-tert-butoxycarbonyl-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid [ka] A solution of 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate D) (50 mg, 0.15 mmol) and CDI (50 mg, 0.31 mmol) in DMA (0.5 mL) was stirred at 50 °C for 20 h. The reaction mixture was treated with (2R)-1-tert-butoxycarbonylpiperazine-2-carboxylic acid (106 mg, 0.46 mmol) and DIPEA (53 μL, 0.31 mmol), and stirring was continued for 1 h with heating at 50 °C. After cooling to room temperature, the resulting mixture was diluted with water (2 mL) and extracted with EtOAc (3 × 2 mL). The combined organic extracts were filtered through a phase separation cartridge and concentrated in vacuo. The crude product was dissolved in DCM (4 mL), and heptane (10 mL) was added, resulting in the formation of a precipitate. The solid was collected by vacuum filtration to give the title compound as a brown solid. LC-MS (Method 2A): Rt1.25 min; MS m / z583.2 / 585.2=[M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (t, J = 1.5 Hz, 1H), 7.86 (dt, J = 7.7, 1.3 Hz, 1H), 7.72 (dt, J = 7.9, 1.3 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.06 (s, 1H), 4.68-4.57 (m, 1H), 4.51 (d, J = 30.0 Hz, 2H), 4.17-4.08 (m, 2H), 3.77-3.69 (m, 2H), 2.40 (s, 3H), 1.39 (d, J = 7.0 Hz, 9H). No NH or OH protons were observed.

[0298] Step 2: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid and methyl (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylate To a solution of (2R)-1-tert-butoxycarbonyl-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid (Step 1) (94 mg, 0.13 mmol) in DCM (2 mL) and MeOH (0.2 mL) was added 4 M HCl in 1,4-dioxane (322 μL, 1.29 mmol) and the reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated in vacuo and the crude mixture was purified by HPLC using acidic conditions, fast elution method to give the following compounds: Example 5: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid (as an off-white solid). LC-MS (Method 7A): Rt2.08 min; MS m / z483.2 / 485.1=[M+H]+(99%@215nm) 1 H NMR (500 MHz, DMSO-d6) δ 7.91 (t, J = 1.5 Hz, 1H), 7.85 (dt, J = 7.7, 1.3 Hz, 1H), 7.72 (dt, J = 7.9, 1.3 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.05 (s, 1H), 4.37 (dd, J = 10.9, 3.2 Hz, 2H), 4.02 (d, J = 13.0 Hz, 1H), 3.11 (dd, J = 9.5, 6.1 Hz, 1H), 2.92-2.85 (m, 1H), 2.40 (s, 3H). Two NH and COOH protons were not observed. Two CH signals were below the HO signal.

[0299] Example 5.1: Methyl (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylate (as an off-white solid). LC-MS (Method 7A): Rt2.10 min; MS m / z497.2 / 499.1=[M+H]+(99%@215nm) 1 H NMR (500 MHz, DMSO-d6) δ 7.92 (t, J = 1.5 Hz, 1H), 7.85 (dt, J = 7.7, 1.3 Hz, 1H), 7.72 (dt, J = 8.0, 1.4 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.06 (s, 1H), 4.07-4.00 (m, 1H), 3.74 (d, J = 12.9 Hz, 1H), 3.66 (s, 3H), 3.46 (dd, J = 8.3, 3.5 Hz, 1H), 3.22-3.17 (m, 1H), 2.91 (dt, J = 11.9, 3.3 Hz, 1H), 2.62-2.58 (m, 1H), 2.40 (s, 3H). Two NH protons were not observed. One CH signal was below the HO signal.

[0300] The compounds of the examples shown in the table below (Table Ex5) were prepared in analogy to Example 5 from 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate D) and the appropriate amine (Step 1), followed by deprotection using 4M HCl in 1,4-dioxane (Step 2).

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[0305] Example 6 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide [ka] A solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) (50 mg, 0.16 mmol) and CDI (40 mg, 0.24 mmol) in DMA (0.5 mL) was stirred at 50° C. for 18 hours. The resulting mixture was treated with 4-methylpiperidine-4-carbonitrile hydrochloride (52 mg, 0.33 mmol) and DIPEA (85 μL, 0.49 mmol), and stirring was continued at 50° C. for 1 hour. After cooling to room temperature, the crude mixture was purified by preparative HPLC using acidic conditions, fast elution method, to give the title compound as a colorless solid. Example 6 was also prepared using the following procedure:

[0306] CDI (1.27 g, 7.83 mmol) and DIPEA (2.05 mL, 11.75 mmol) were added to a stirred solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) (1.20 g, 3.92 mmol) in DMA (12 mL), and the solution was heated at 50° C. overnight. 4-Methylpiperidine-4-carbonitrile hydrochloride (1.26 g, 7.83 mmol) and additional DIPEA (2.05 mL, 11.75 mmol) were added, and the solution was stirred at 50° C. for 30 minutes. The resulting mixture was cooled to room temperature, then diluted with EtOAc (150 mL), washed with 90% aqueous brine solution (100 mL), 50% aqueous brine solution (3×100 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 1-3% MeOH / DCM gave a yellow solid. Addition of MeOH (15 mL) gave a white solid which was collected by filtration, washed with MeOH (2 mL), EtO (20 mL), and dried to give the title compound as a colorless solid. LC-MS (Method 8B): Rt3.24 min; MS m / z457.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.31(s,1H),7.89(t,J=1.8Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7.70(dt,J=8.0,1.5Hz,1H),7.56(t,J=7.9Hz,1H),6.93(s,2H) ,4.22(d,J=14.0Hz,2H),3.03(t,J=12.6Hz,2H),2.36(s,6H),1.92(d,J=13.4Hz,2H),1.53(td,J=13.2,4.0Hz,2H),1.37(s,3H).

[0307] The compounds of the examples shown in the table below (Table Ex6) were prepared in analogy to Example 6 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) or the appropriate starting intermediate and the appropriate amine.

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[0342] Example 7 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide [ka] Step 1: tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]piperazine-1-carboxylate [ka] A solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) (50 mg, 0.16 mmol) and CDI (40 mg, 0.24 mmol) in DMA (0.5 mL) was stirred at 50 °C for 18 h. The resulting mixture was treated with tert-butyl piperazine-1-carboxylate (61 mg, 0.33 mmol) and stirring was continued at 50 °C for 1 h. After cooling to room temperature, the crude mixture was diluted with water (10 mL) and the precipitate was collected by vacuum filtration. The solid was dissolved in DCM, filtered through a phase separation cartridge, and concentrated in vacuo. The crude product was purified by silica chromatography eluting with 0-100% EtOAc / DCM to give the title compound. LC-MS (Method 7A): Rt2.16 min; MS m / z519.3=[M+H]+ H NMR(500MHz,DMSO-d6)δ 11.30(s,1H),7.89(t,J=1.4Hz,1H),7.82(d,J=7.7Hz,1H),7.71(dt,J=8.0,1.2Hz,1H),7.56( t,J=7.8Hz,1H),6.93(s,2H),3.55-3.49(m,4H),3.39-3.34(m,4H),2.36(s,6H),1.42(s,9H).

[0343] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide A solution of tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]piperazine-1-carboxylate (Step 1) (70 mg, 0.14 mmol) in DCM (2 mL), MeOH (2 drops), and 4 M HCl in 1,4-dioxane (338 μL, 1.35 mmol) was stirred at room temperature for 22 h. The resulting mixture was concentrated in vacuo, and the crude product was purified by preparative HPLC using basic conditions, fast elution method, to give the title compound. LC-MS (Method 7A): Rt0.94 min; MS m / z419.2=[M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 6.92 (s, 2H), 3.50-3.43 (m, 4H), 2.74-2.68 (m, 4H), 2.36 (s, 6H). Two NH protons were not observed.

[0344] Example 7.1 (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide [ka] Step 1: tert-butyl (2R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2-methyl-piperazine-1-carboxylate [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl (2R)-2-methylpiperazine-1-carboxylate. LC-MS (Method 2A): Rt1.07 min; MS m / z533.3=[M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 11.30(s,1H),7.89(t,J=1.5Hz,1H),7.82(dt,J=7.7,1.7Hz,1H),7.71(dt,J =8.0,1.3Hz,1H),7.56(t,J=7.8Hz,1H),6.93(s,2H),4.20-4.09(m,2H),4.02 (d,J=13.7Hz,1H),3.78-3.69(m,1H),3.14(dd,J=13.7,4.1Hz,1H),3.09-3.0 0(m,1H),2.99-2.89(m,1H),2.36(s,6H),1.42(s,9H),1.07(d,J=6.7Hz,3H).

[0345] Step 2: (3R)—N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide The title compound was prepared in analogy to Step 2 of Example 7 from tert-butyl (2R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2-methyl-piperazine-1-carboxylate and 4M HCl in 1,4-dioxane. LC-MS (Method 7A): Rt1.00 min; MS m / z433.2=[M+H]+ 1 H NMR (400 MHz, DMSO-d₆) δ 7.89 (t, J = 1.5 Hz, 1H), 7.82 (dt, J = 7.7, 1.3 Hz, 1H), 7.73-7.69 (m, 1H), 7.56 (t, J = 7.8 Hz, 1H), 6.93 (s, 2H), 4.18-4.08 (m, 2H), 3.06 (d, J = 11.6 Hz, 1H), 3.02-2.91 (m, 2H), 2.88 (s, 1H), 2.82-2.73 (m, 1H), 2.36 (s, 6H), 1.08 (d, J = 6.3 Hz, 3H). Two NH protons were not observed.

[0346] Example 7.2 4-Amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide [ka] Step 1: tert-butyl N-[4-cyano-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-4-piperidyl]carbamate [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl N-(4-cyano-4-piperidyl)carbamate. LC-MS (Method 5B): Rt2.95 min; MS m / z558.2=[M+H]+ 1 H NMR (500 MHz, DMSO-d6) δ 11.34 (s, 1H), 7.88 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.77 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 6.92 (s, 2H), 3.94-3.86 (m, 2H), 2.36 (s, 6H), 2.23-2.17 (m, 2H), 1.87-1.81 (m, 2H), 1.43 (s, 9H). No CH2 signal was observed.

[0347] Step 2: 4-amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide The title compound was prepared in analogy to Step 2 of Example 7 from tert-butyl N-[4-cyano-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-4-piperidyl]-carbamate and 4M HCl in 1,4-dioxane. LC-MS (Method 8B): Rt3.30 min; MS m / z458.3=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 11.31(s,1H),7.88(s,1H),7.82(d,J=7.7Hz,1H),7.70(d,J=7.7Hz,1H),7.56(t,J=7.7Hz,1H),6.92(s,2H), 3.97-3.77(m,3H),2.77-2.65(m,2H),2.46-2.40(m,1H),2.36(s,6H),2.02-1.86(m,2H),1.70-1.53(m,2H).

[0348] Example 7.3 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide [ka] Step 1: tert-butyl 9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate. LC-MS (Method 2A): Rt0.77 min; MS m / z589.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.22(s,1H),7.89(t,J=1.5Hz,1H),7.82(dt,J=7.7,1.3Hz,1H),7.70(dt,J=8.0,1.3Hz,1H),7.56(t,J=7.9Hz,1H),6.92(s,2H),3.86 -3.78(m,2H),3.64-3.59(m,2H),3.36-3.32(m,2H),3.28-3.16(m,4H),2.36(s,6H),1.75-1.69(m,2H),1.52-1.44(m,2H),1.41(s,9H).

[0349] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide The title compound was prepared in a similar manner to Step 2 of Example 7 from tert-butyl 9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (Step 1) and 4M HCl in 1,4-dioxane. LC-MS (Method 7B): Rt2.68 min; MS m / z489.4=[M+H]+ H NMR (500 MHz, DMSO-d) δ 7.88 (t, J = 1.7 Hz, 1H), 7.81 (dt, J = 7.9, 1.4 Hz, 1H), 7.70 (dt, J = 8.2, 1.4 Hz, 1H), 7.55 (dd, J = 7.8, 7.8 Hz, 1H), 6.91 (s, 2H), 3.83 (dt, J = 13.2, 4.1 Hz, 2H), 3.56-3.52 (m, 2H), 3.23-3.15 (m, 2H), 2.64 (td, J = 3.9, 2.1 Hz, 2H), 2.54 (s, 2H), 2.35 (s, 6H), 1.89-1.83 (m, 2H), 1.45-1.37 (m, 2H). Two NH protons were not observed.

[0350] Example 7.4 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide [ka] Step 1: tert-butyl 8-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate. LC-MS (Method 2A): Rt0.77 min; MS m / z545.3=[M+H]+ 1H NMR(400MHz,DMSO-D6)δ 11.37(s,1H),7.88(d,J=1.7Hz,1H),7.82(dt,J=7.8,1.4Hz,1H),7.70(dt,J=8.1,1.4Hz,1H),7.56(dd,J=7.8,7.8Hz,1H),6.93(s,2H),4.6 0-4.49(m,2H),3.80-3.66(m,2H),3.09-3.02(m,1H),2.96-2.89(m,1H ),2.36(s,6H),1.89-1.80(m,2H),1.62(q,J=7.0Hz,2H),1.41(s,9H).

[0351] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide The title compound was prepared in a similar manner to Step 2 of Example 7 from tert-butyl 8-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Step 1) and 4M HCl in 1,4-dioxane. LC-MS (Method 7B): Rt2.57 min; MS m / z445.4=[M+H]+ H NMR (500 MHz, methanol-d) δ 7.91 (t, J = 1.7 Hz, 1H), 7.72 (dt, J = 7.9, 1.4 Hz, 1H), 7.68 (dt, J = 7.8, 1.4 Hz, 1H), 7.48 (dd, J = 7.8, 7.8 Hz, 1H), 7.01 (s, 2H), 4.43-4.37 (m, 2H), 2.98 (dd, J = 13.1, 2.0 Hz, 2H), 2.74 (dd, J = 13.1, 2.1 Hz, 2H), 2.44 (s, 6H), 2.05-1.98 (m, 4H). Two NH protons were not observed.

[0352] Example 7.5 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide [ka] Step 1: tert-butyl 6-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate. LC-MS (Method 2A): Rt0.70 min; MS m / z531.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.59(s,1H),7.87(t,J=1.7Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7.69(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8Hz,1H),6.92(s,2 H),4.53-4.35(m,2H),3.87-3.70(m,2H),3.42-3.34(m,2H),2.59(q,J=7.1Hz,1H),2.35(s,6H),1.45(d,J=8.9Hz,1H),1.38(s,9H).

[0353] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide The title compound was prepared in a similar manner to Step 2 of Example 7 from tert-butyl 6-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (Step 1) and 4M HCl in 1,4-dioxane. LC-MS (Method 7A): Rt0.98 min; MS m / z431.3=[M+H]+ H NMR (500 MHz, methanol-d) δ 7.90 (t, J = 1.7 Hz, 1H), 7.71 (dt, J = 8.0, 1.4 Hz, 1H), 7.68 (dt, J = 7.8, 1.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.01 (s, 2H), 4.43-4.38 (m, 2H), 3.48 (d, J = 13.2 Hz, 2H), 2.99 (dd, J = 13.0, 1.9 Hz, 2H), 2.76-2.70 (m, 1H), 2.44 (s, 6H), 1.84 (d, J = 8.8 Hz, 1H). Two NH protons were not observed.

[0354] Example 7.6 (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxamide [ka] Step 1: (1R,4R)-tert-butyl 5-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylate [ka] The title compound was prepared in analogy to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl (2R,5R)-5-ethyl-2-methyl-piperazine-1-carboxylate. LC-MS (Method 2A): Rt0.76 min; MS m / z545.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.07(s,1H),7.88(d,J=1.8Hz,1H),7.82(dt,J=7.8,1.5Hz,1H),7.71(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8Hz,1H),6 .93(s,2H),4.50-4.37(m,1H),4.23-4.13(m,1H),3.68-3.38(m,4H),2.36(s,6H),1.91-1.73(m,4H),1.41(d,J=3.3Hz,9H).

[0355] Step 2: (1R,4R)—N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxamide The title compound was prepared in analogy to Step 2 of Example 7 from tert-butyl (1R,4R)—N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (Step 1) and 4M HCl in 1,4-dioxane. LC-MS (Method 7A): Rt0.99 min; MS m / z445.3=[M+H]+ 1H NMR (500MHz, methanol-d4)δ 7.91(t,J=1.7Hz,1H),7.72(dt,J=8.0,1.5Hz,1H),7.68(dt,J=7.8,1.4Hz,1H),7.49 (dd,J=7.8,7.8Hz,1H),7.00(s,2H),4.27(s,1H),3.78(d,J=10.7Hz,1H),3.64(d,J=1 0.7 Hz, 1H), 3.28-3.23 (m, 1H), 3.22-3.18 (m, 1H), 3.11 (dd, J = 11.5, 1.9 Hz, 1H), 2.43 (s, 6H), 2.08-1.98 (m, 2H), 1.97-1.89 (m, 1H), 1.88-1.80 (m, 1H). Two NH protons were not observed.

[0356] Example 7.7 (2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide [ka] Step 1: (2S,5S)-tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,5-dimethyl-piperazine-1-carboxylate [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl cis-(2S,5S)-2,5-dimethylpiperazine-1-carboxylate. LC-MS (Method 7A): Rt0.80 min; MS m / z547.4=[M+H]+ 1H NMR (400MHz, DMSO-d6) δ 11.19(s,1H),7.89(t,J=1.7Hz,1H),7.82(dt,J=7.8,1.4Hz,1H),7.70(dt,J =8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8Hz,1H),6.93(s,2H),4.20-4.08(m,2H) ,3.95-3.84(m,2H),2.96(dd,J=14.6,11.2Hz,1H),2.88(dd,J=14.2,10.7Hz ,1H),2.36(s,6H),1.39(s,9H),1.10(d,J=6.1Hz,3H),1.06(d,J=6.1Hz,3H).

[0357] Step 2: (2S,5S)—N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide The title compound was prepared in analogy to Step 2 of Example 7 from tert-butyl (2S,5S)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,5-dimethyl-piperazine-1-carboxylate (Step 1) and 4M HCl in 1,4-dioxane. LC-MS (Method 7B): Rt2.72 min; MS m / z447.3=[M+H]+ 1H NMR (500MHz, methanol-d4) δ 7.91 (t, J = 1.7 Hz, 1H), 7.71 (dt, J = 7.9, 1.4 Hz, 1H), 7.69 (dt, J = 7.8, 1.4 Hz, 1H), 7.49 (dd, J = 7.8, 7.8 Hz, 1H), 7.00 (s, 2H), 4.37-4.29 (m, 1H), 3.98-3.90 (m, 1H), 2.99 (dd, J = 12.9, 4.2 Hz, 1H), 2.90 (dd, J = 12.9, 1.5 Hz, 1H), 2.78-2.69 (m, 2H), 2.43 (s, 6H), 1.31 (d, J = 6.9 Hz, 3H), 1.16 (d, J = 5.8 Hz, 3H). Two NH protons were not observed.

[0358] Example 7.8 (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,6-dimethyl-piperazine-1-carboxamide [ka] Step 1: (3R,5R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3,5-dimethyl-piperazine-1-carboxylate tert-butyl [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl (3R,5R)-3,5-dimethylpiperazine-1-carboxylate. LC-MS (Method 2A): Rt0.81 min; MS m / z547.3=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.16(s,1H),7.90(t,J=1.7Hz,1H),7.82(dt,J=7.8,1.2Hz,1H),7.71(dt,J=8.3,1.2Hz,1H),7.56(dd,J=7.8 ,7.8Hz,1H),6.92(s,2H),4.39-4.29(m,2H),3.61-3.45(m,4H),2.35(s,6H),1.43(s,9H),1.23-1.17(m,6H).

[0359] Step 2: (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,6-dimethyl-piperazine-1-carboxamide The title compound was prepared in analogy to Step 2 of Example 7 from tert-butyl rac-(3R,5R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3,5-dimethyl-piperazine-1-carboxylate (Step 1) and 4M HCl in 1,4-dioxane. LC-MS (Method 7B): Rt2.73 min; MS m / z447.4=[M+H]+ H NMR (400 MHz, methanol-d) δ 7.91 (t, J = 1.7 Hz, 1H), 7.72 (dt, J = 8.0, 1.5 Hz, 1H), 7.69 (dt, J = 7.8, 1.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.01 (s, 2H), 4.02-3.95 (m, 2H), 3.21 (dd, J = 13.0, 3.9 Hz, 2H), 2.78 (dd, J = 13.1, 4.5 Hz, 2H), 2.44 (s, 6H), 1.34 (d, J = 6.5 Hz, 6H). Two NH protons were not observed.

[0360] Example 7.9 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,2-dimethyl-piperazine-1-carboxamide [ka] Step 1: tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3,3-dimethyl-piperazine-1-carboxylate [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl 3,3-dimethylpiperazine-1-carboxylate. LC-MS (Method 2A): Rt0.83 min; MS m / z547.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.24(s,1H),7.87(t,J=1.7Hz,1H),7.82(dt,J=7.7,1.5Hz,1H),7.70(dt,J=8.1,1.4Hz,1H),7.56(dd,J= 7.8,7.8Hz,1H),6.92(s,2H),3.71-3.65(m,2H),3.45-3.36(m,4H),2.35(s,6H),1.42(s,9H),1.39(s,6H).

[0361] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,2-dimethyl-piperazine-1-carboxamide The title compound was prepared in analogy to Step 2 of Example 7 from tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3,3-dimethyl-piperazine-1-carboxylate (Step 1) and 4M HCl in 1,4-dioxane. LC-MS (Method 7B): Rt2.88 min; MS m / z447.4=[M+H]+ H NMR (400 MHz, methanol-d) δ 7.89 (t, J = 1.5 Hz, 1H), 7.72-7.67 (m, 2H), 7.49 (dd, J = 7.8, 7.8 Hz, 1H), 7.00 (s, 2H), 3.50-3.45 (m, 2H), 2.99-2.93 (m, 2H), 2.69 (s, 2H), 2.44 (s, 6H), 1.47 (s, 6H). Two NH protons were not observed.

[0362] Example 7.10 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide [ka] Step 1: tert-butyl 5-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-5,8-diazaspiro[3.5]nonane-8-carboxylate [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl 5,8-diazaspiro[3.5]nonane-8-carboxylate. LC-MS (Method 2A): Rt0.83 min; MS m / z559.3=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.40(s,1H),7.87(t,J=1.7Hz,1H),7.82(dt,J=7.8,1.5Hz,1H),7.70(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8Hz,1H),6.93(s,2H) ,3.53(s,2H),3.50-3.44(m,2H),3.29-3.25(m,2H),2.35(s,6H),2.28-2.16(m,3H),2.04-1.97(m,2H),1.81-1.75(m,1H),1.42(s,9H).

[0363] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide The title compound was prepared in a similar manner to Step 2 of Example 7 from tert-butyl 5-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-5,8-diazaspiro[3.5]nonane-8-carboxylate (Step 1) and 4M HCl in 1,4-dioxane. LC-MS (Method 7B): Rt2.48 min; MS m / z459.3=[M+H]+ H NMR (400 MHz, methanol-d) δ 7.89 (t, J = 1.7 Hz, 1H), 7.72-7.66 (m, 2H), 7.48 (dd, J = 7.8, 0.6 Hz, 1H), 6.99 (s, 2H), 3.51-3.47 (m, 2H), 3.01 (s, 2H), 2.73-2.69 (m, 2H), 2.43 (s, 6H), 2.33-2.25 (m, 4H), 1.88-1.69 (m, 2H). Two NH protons were not observed.

[0364] Example 7.11 trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide [ka] Step 1: tert-butyl trans-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,5-dimethyl-piperazine-1-carboxylate [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl trans-2,5-dimethylpiperazine-1-carboxylate. LC-MS (Method 2A): Rt0.81 min; MS m / z547.3=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.29(s,1H),7.89(t,J=1.7Hz,1H),7.85-7.78(m,1H),7.70(dt,J=8.2,1.6Hz,1H),7.56(dd,J=7.8,7.8Hz,1H),6.92(s,2H),4.44(d,J =21.6Hz,2H),4.31-4.21(m,1H),4.21-4.11(m,1H),3.92-3.85(m,1H),3.65-3.56(m,1H),2.36(s,6H),1.42(s,9H),1.15-1.01(m,6H).

[0365] Step 2: trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide The title compound was prepared in analogy to Step 2 of Example 7 from tert-butyl trans-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,5-dimethyl-piperazine-1-carboxylate (Step 1) and 4M HCl in 1,4-dioxane. LC-MS (Method 7A): Rt1.10 min; MS m / z447.3=[M+H]+ H NMR (400 MHz, methanol-d) δ 7.91 (t, J = 1.7 Hz, 1H), 7.74-7.67 (m, 2H), 7.49 (dd, J = 7.8, 7.8 Hz, 1H), 7.00 (s, 2H), 4.33-4.26 (m, 1H), 3.74 (dd, J = 14.0, 2.2 Hz, 1H), 3.40 (dd, J = 13.6, 4.0 Hz, 1H), 3.26-3.17 (m, 2H), 2.60 (dd, J = 13.5, 2.9 Hz, 1H), 2.43 (s, 6H), 1.33 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H). Two NH protons were not observed.

[0366] Example 8 1-Acetylimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide [ka] To a suspension of N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide (Example 4.2) (50 mg, 0.11 mmol) in DCM (2.5 mL) was added triethylamine (37 μL, 0.27 mmol) followed by acetyl chloride (10 μL, 0.14 mmol) at 0° C., and the mixture was stirred for 1 h. An additional acetyl chloride (10 μL, 0.14 mmol) was added, and the reaction mixture was stirred at 0° C. for 30 min, after which an additional acetyl chloride (4 μL, 0.05 mmol) was added, and the reaction mixture was stirred at 0° C. for 15 min. The resulting mixture was concentrated in vacuo and then partitioned between 10% MeOH in EtOAc (20 mL) and water (20 mL). The layers were separated and the aqueous layer was further extracted with 10% MeOH in EtOAc (2 x 20 mL). The combined organic extracts were concentrated in vacuo and the crude material was purified by C18 reverse phase chromatography eluting with 5-15% MeCN / water (+0.1% ammonium hydroxide modifier) ​​to afford the title compound as an off-white solid. LC-MS (Method 8B): Rt2.16 min; MS m / z509.3=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 11.58(s,1H),7.88(s,1H),7.83(d,J=7.8Hz,1H),7.70(d,J=7.8Hz,1H),7.56(t,J=7.8Hz,1H), 6.92(s,2H),4.26-4.18(m,2H),3.77-3.65(m,4H),3.53-3.47(m,2H),2.36(s,6H),1.99(s,3H).

[0367] Example 9 N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] A solution of 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate I) (60 mg, 0.13 mmol) and CDI (49 mg, 0.30 mmol) in DMA (0.5 mL) was stirred at 50 °C overnight. The resulting mixture was treated with 2-oxa-6-azaspiro[3.3]heptane (30 mg, 0.30 mmol) in DMA (0.1 mL) and DIPEA (78 μL, 0.45 mmol), and stirring was continued at 50 °C for 30 min. The reaction mixture was cooled to room temperature, and 1 M TBAF in THF (211 μL, 0.21 mmol) was added. After stirring for 15 minutes, the resulting mixture was purified by C18 reverse-phase chromatography eluting with a gradient of 5-15% MeCN / water (+0.1% ammonium hydroxide modifier). Product fractions were combined, concentrated, and loaded onto an Isolute® SCX cartridge. The column was flushed with MeOH (30 mL), and the product was eluted with 0.7 M NH3 in MeOH (30 mL). The solvent was removed in vacuo, and the resulting material was triturated with 2:1 hexane / diethyl ether (1 mL) to give a solid. The solid was further purified by silica chromatography eluting with a gradient of 0-4% MeOH / DCM to give the title compound as a yellow solid. LC-MS (Method 8B): Rt2.93 min; MS m / z448.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),7.87(d,J=1.5Hz,1H),7.81(d,J=7.8Hz,1H),7.71(dt,J=7.8,1.5Hz,1H),7.55(t,J=7.8Hz,1H), 7.13(s,1H),6.96(s,1H),5.32(t,J=5.8Hz,1H),4.67(s,4H),4.46(d,J=5.8Hz,2H),4.19(s,4H),2.36(s,3H).

[0368] The compounds of the examples shown in the table below (Table Ex9) were prepared in a similar manner to Example 9 from 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate I) and the appropriate amine.

[0369] JPEG0007805350000110.jpg241170

[0370] JPEG0007805350000111.jpg186170

[0371] JPEG0007805350000112.jpg128170

[0372] Example 10 N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate M) and 1,4-thiazinane 1-oxide hydrochloride. LC-MS (Method 8A): Rt2.64 min; MS m / z470.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.51(s,1H),7.89(s,1H),7.81(d,J=7.8Hz,1H),7.67(d,J=7.8Hz,1H),7.55(t,J=7.8Hz,1H),7.11(d,J=4.9Hz,1H ),4.12(d,J=14.7Hz,2H),3.79(t,J=13.1Hz,2H),2.94(t,J=12.5Hz,2H),2.75(d,J=13.6Hz,2H),2.41-2.32(m,6H).

[0373] Example 11 1-Cyanoimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide [ka] To a suspension of N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide (Example 4.2) (50 mg, 0.11 mmol) in DCM (2 mL) at 0° C., DMAP (14 mg, 0.12 mmol) was added, followed by cyanogen bromide (23 mg, 0.21 mmol), and the mixture was stirred at 0° C. for 1 hour and 10 minutes. Additional cyanogen bromide (3 mg, 0.03 mmol) and DMAP (2 mg, 0.02 mmol) were added, and stirring was continued at 0° C. for 1 hour. Additional cyanogen bromide (6 mg, 0.05 mmol) and DMAP (3 mg, 0.03 mmol) were added, and after stirring for 45 minutes, the mixture was concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with 5-40% MeCN / water (with 0.1% ammonium hydroxide modifier), further purified by silica chromatography eluting with a gradient of 0-5% MeOH / DCM, and then purified by silica chromatography eluting with a gradient of 0-80% EtOAc / DCM to give the title compound as a yellow solid. LC-MS (Method 8B): Rt4.70 min; MS m / z492.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.64(s,1H),7.89(s,1H),7.84(d,J=7.8Hz,1H),7.70(d,J=7.8Hz,1H),7.57(t,J=7.8Hz,1 H),6.93(s,2H),4.40(d,J=13.7Hz,2H),3.82-3.73(m,4H),3.70-3.63(m,2H),2.36(s,6H).

[0374] Example 12 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide [ka] Step 1: 4-cyano-N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate J) and 4-methylpiperidine-4-carbonitrile. LC-MS (Method 3B): Rt2.37 min; MS m / z621.4=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.34(s,1H),7.84(t,J=1.8Hz,1H),7.75-7.69(m,2H),7.52(t,J=7.9Hz,1H),7.18-7.13(m,2H),7.00-6.95(m,2H),6.86-6.80(m,2H),4. 25-4.18(m,2H),4.11(s,2H),3.75(s,3H),3.08-2.99(m,2H),2.48(s ,3H),1.95-1.88(m,2H),1.57-1.50(m,2H),1.45(s,6H),1.37(s,3H).

[0375] Step 2: 4-cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide To a solution of 4-cyano-N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide (Step 1) (77 mg, 0.12 mmol) in DCM (3.6 mL) was added trifluoroacetic acid (0.38 mL, 4.96 mmol), and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with DCM (15 mL), washed with saturated NaHCO solution (2 x 20 mL), then dried over NaSO, and the solvent was removed in vacuo. Purification by silica chromatography eluting with 3% MeOH / DCM gave an oil, which was suspended in 10% EtO / hexane to form a precipitate, which was collected by filtration and dried to give the title compound as an off-white solid. LC-MS (Method 8B): Rt4.20 min; MS m / z501.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.33(s,1H),7.85(s,1H),7.83(d,J=7.8Hz,1H),7.77(d,J=7.8Hz,1H),7.59(t,J=7.8Hz,1H),7.29(s,1H),7.03(s,1H),5.09(s,1H),4.23(apr d,J=14.1Hz,2H),3.04(apr t,J=13.1Hz,2H),2.43(s,3H),1.93(apr d,J=13.6Hz,2H),1.58-1.50(m,2H),1.38(s,3H),1.36(s,6H).

[0376] Example 12.1 N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide [ka] Step 1: N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate J) and 6-oxa-2-azaspiro[3.4]octane. LC-MS (Method 3B): Rt2.17 min; MS m / z610.3=[M+H]+ 1H NMR (500MHz, methanol-d4) δ 7.82 (t, J = 1.6 Hz, 1H), 7.69 (dt, J = 7.8, 1.6 Hz, 1H), 7.51 (dt, J = 7.8, 1.6 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 7.05-7.01 (m, 2H), 6.86-6.80 (m, 2H), 4.16 (s, 2H), 4.11 (s, 4H), 3.89 (s, 2H), 3.86 (t, J = 7.0 Hz, 2H), 3.80 (s, 3H), 2.54 (s, 3H), 2.23 (t, J = 7.0 Hz, 2H), 1.54 (s, 6H). The NH proton was not observed.

[0377] Step 2: N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide The title compound was prepared in analogy to Step 2 of Example 12 from N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide (Step 1) and TFA. LC-MS (Method 8B): Rt3.18 min; MS m / z490.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),7.85-7.81(m,2H),7.76(dt,J=7.8,1.6Hz,1H),7.60-7.56(m,1H),7.29(d,J=1.6Hz,1H),7.02(d,J=1.6 Hz,1H),5.09(s,1H),4.02(s,4H),3.78(s,2H),3.72(t,J=7.0Hz,2H),2.42(s,3H),2.13(t,J=7.0Hz,2H),1.36(s,6H).

[0378] Example 12.2 N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] Step 1: N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate J) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS (Method 3B): Rt2.06 min; MS m / z596.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.37(br s,1H),7.83(br t,J=1.7Hz,1H),7.74-7.71(m,1H),7.73-7.68(m,1H),7.52(apr t,J=7.8Hz,1H),7.16-7.12(m,2H),6.99-6.95(m,2H),6.85-6.81(m,2H),4. 67(s,4H),4.20(s,4H),4.10(s,2H),3.75(s,3H),2.48(s,3H),1.45(s,6H).

[0379] Step 2: N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide The title compound was prepared in analogy to Step 2 of Example 12 from N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (Step 1) and TFA. LC-MS (Method 8B): Rt3.68 min; MS m / z476.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.35(s,1H),7.85-7.79(m,2H),7.75(dt,J=7.9,1.4Hz,1H),7.61-7.54(m,1H),7.27(d,J=1.6 Hz,1H),7.01(d,J=1.6Hz,1H),5.08(s,1H),4.67(s,4H),4.20(s,4H),2.41(s,3H),1.35(s,6H).

[0380] Example 12.3 N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] Step 1: N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]ethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]ethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate PA) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS (Method 3B): Rt1.81 min; MS m / z580.4=[MH]- 1H NMR(500MHz,DMSO-d6)δ 11.38(br s,1H),7.85(t,J=1.7Hz,1H),7.75-7.71(m,2H),7.53(apr t,J=7.8Hz,1H),7.16(br d,J=1.6Hz,1H),7.06-7.02(m,2H),6.98(br d,J=1.6Hz,1H),6.88-6.84(m,2H),4.67(s,4H),4.42(q,J=6.5Hz,1H),4.23-4.1 8(m,5H),4.16(d,J=11.5Hz,1H),3.75(s,3H),2.46(s,3H),1.27(d,J=6.5Hz,3H).

[0381] Step 2: N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide The title compound was prepared in a similar manner to Step 2 of Example 12 from N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]ethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (Step 1) and TFA. LC-MS (Method 8B): Rt3.67 min; MS m / z462.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),7.84(br t,J=1.5Hz,1H),7.82(br dt,J=7.7,1.5Hz,1H),7.74(br dt,J=8.0,1.5Hz,1H),7.57(apr t,J=7.8Hz,1H),7.12(s,1H),7.01(s,1H),5.23(d,J=4.5Hz,1H),4.67(s ,4H),4.65-4.56(m,1H),4.21(s,4H),2.40(s,3H),1.26(d,J=6.6Hz,3H).

[0382] Example 12.3a and Example 12.3b Racemic N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (Example 12.3) was dissolved in EtOH / DCM (4:1) at 50 mg / mL and purified by SFC to give the individual enantiomers:

[0383] Purification conditions Column details: Lux iC5 (21.2 mm x 250 mm, 5 μm) Column temperature: 40°C Flow rate 50mL / min BPR 100BarG Detector wavelength: 218nm Injection volume 250μL (2mg) Isocratic conditions 50:50 EtOH:CO2

[0384] Chiral purity analysis conditions Column details: Lux iC5 (4.6 mm x 250 mm, 5 μm) Column temperature: 40°C Flow rate: 4 mL / min Detector wavelength: 210-400 nm Injection volume 1.0μL BPR 125BarG Isocratic conditions: 50:50 EtOH:CO2 (0.2% v / v NH3)

[0385] Example 12.3a N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide or N-[4-(3-cyanophenyl)-5-[2-[(1S)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] First eluting peak: Chiral LCMS retention time: = 3.12 min LC-MS (Method 8B): Rt2.56 min; MS m / z462.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),7.84(t,J=1.6Hz,1H),7.82(dt,J=7.8,1.6Hz,1H),7.74(dt,J=7.8,1.6Hz,1H),7.57(t,J=7.8Hz,1H),7.12(d,J=1.7Hz,1H),7.01 (d,J=1.7Hz,1H),5.23(d,J=4.5Hz,1H),4.67(s,4H),4.60(td,J=6.5,4.5Hz,1H),4.21(s,4H),2.40(s,3H),1.26(d,J=6.5Hz,3H).

[0386] Example 12.3b N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaaspiro[3.3]heptane-6-carboxamide or N-[4-(3-cyanophenyl)-5-[2-[(1S)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaaspiro[3.3]heptane-6-carboxamide [ka] Second eluting peak: Chiral LCMS retention time: = 4.12 min LC-MS (Method 8B): Rt2.74 min; MS m / z462.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),7.84(t,J=1.6Hz,1H),7.82(dt,J=7.8,1.6Hz,1H),7.74(dt,J=7.8,1.6Hz,1H),7.57(t,J=7.8Hz,1H),7.12(d,J=1.7H) z,1H),7.01(d,J=1.7Hz,1H),5.23(d,J=4.4Hz,1H),4.67(s,4H),4.63-4.58(m,1H),4.21(s,4H),2.40(s,3H),1.26(d,J=6.5Hz,3H).

[0387] Example 13 (3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,5-dimethyl-piperazine-1-carboxamide [ka] Step 1: tert-butyl rac-(2S,6R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,6-dimethyl-piperazine-1-carboxylate The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate. LC-MS (Method 2B): Rt1.69 min; MS m / z547.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.39(s,1H),7.90(d,J=1.8Hz,1H),7.83(dt,J=7.8,1.5Hz,1H),7.72(dt,J=8.0,1.5Hz,1H),7.57(t,J=7.8Hz,1H),6.9 4(s,2H),4.17(d,J=13.4Hz,2H),4.13-4.01(m,2H),3.12-3.04(m,2H),2.37(s,6H),1.43(s,9H),1.15(d,J=2.5Hz,6H).

[0388] Step 2: (3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,5-dimethyl-piperazine-1-carboxamide To a stirred solution of tert-butyl (2S,6R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,6-dimethyl-piperazine-1-carboxylate (Step 1) (100 mg, 0.14 mmol) in chloroform (2 mL), trimethylsilyl iodide (0.08 mL, 0.58 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under a nitrogen flow, and chloroform (2 mL) was added and concentrated again. After purification by C18 reverse-phase chromatography eluting with a gradient of 15-40% MeCN / water (+0.1% ammonium hydroxide modifier), the product fractions were lyophilized to afford the title compound as a white solid. LC-MS (Method 8B): Rt3.04 min; MS m / z447.2=[M+H]+ H NMR (500 MHz, DMSO-d) δ 11.16 (s, 1H), 7.90 (t, J = 1.8 Hz, 1H), 7.82 (dt, J = 7.7, 1.5 Hz, 1H), 7.71 (dt, J = 8.0, 1.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 6.93 (s, 2H), 4.10 (d, J = 12.5 Hz, 2H), 2.74-2.57 (m, 2H), 2.37 (s, 6H), 2.35-2.27 (m, 2H), 0.99 (d, J = 6.2 Hz, 6H). No NH protons were observed.

[0389] The compounds of the examples shown in the table below (Table Ex13) were prepared in analogy to Example 13 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C)) and the appropriate amine (Step 1) followed by deprotection using trimethylsilyl iodide (Step 2).

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[0400] Example 14 (3R)N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-3-methyl-piperazine-1-carboxamide [ka] Step 1: tert-butyl (2R)-4-[[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]carbamoyl]-2-methyl-piperazine-1-carboxylate [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate H) and tert-butyl (2R)-2-methylpiperazine-1-carboxylate. LC-MS (Method 5B): Rt3.29 min; MS m / z587.5=[M+H]+ H NMR (500 MHz, DMSO-d) δ 11.46 (s, 1H), 7.92 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.53 (s, 1H), 7.33 (s, 1H), 4.22-4.11 (m, 2H), 4.06-4.00 (m, 1H), 3.77-3.71 (m, 1H), 3.17-3.1 (m, 1H), 3.08-3.00 (m, 1H), 2.99-2.90 (m, 1H), 1.41 (s, 9H), 1.07 (d, J = 6.7 Hz, 3H). No CH signal was observed.

[0401] Step 2: (3R)N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-3-methyl-piperazine-1-carboxamide To a solution of tert-butyl (2R)-4-[[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]carbamoyl]-2-methyl-piperazine-1-carboxylate (Step 1) (83 mg, 0.14 mmol) in DCM (3.6 mL) was added TFA (0.71 mL, 9.27 mmol), and the reaction mixture was stirred at room temperature for 1 h. EtOAc (20 mL) and 1 M NaOH (aq) (20 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (4 × 15 mL), and the combined organic extracts were dried over NaSO and concentrated in vacuo to give a yellow oil. The crude product was purified by C18 reverse-phase chromatography eluting with a gradient of 10–30% MeCN / water (+0.1% ammonium hydroxide modifier) ​​to give the title compound as a white solid. LC-MS (Method 8B): Rt4.37 min; MS m / z487.2=[M+H]+ H NMR (500 MHz, methanol-d) δ 7.92 (s, 1H), 7.72 (t, J = 9.1 Hz, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.36 (s, 1H), 4.14 (d, J = 12.9 Hz, 2H), 3.07-2.95 (m, 2H), 2.84-2.76 (m, 2H), 2.64 (t, J = 11.9 Hz, 1H), 2.55 (s, 3H), 1.14 (d, J = 6.4 Hz, 3H). Two NH protons were not observed.

[0402] Example 14.1 rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate [ka] Step 1: tert-butyl rac-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate G) and tert-butyl rac-(4aS,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylate. LC-MS (Method 2B): Rt1.49 min; MS m / z597.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.61(s,1H),7.91(s,1H),7.87(d,J=7.8Hz,1H),7.78-7.72(m,1H),7.60(t,J=7.8Hz, 1H),7.41(s,1H),7.22(s,1H),6.84(t,J=54.9Hz,1H),4.21(p,J=7.1,6.6Hz,1H),4.14( d,J=12.7Hz,1H),4.08-3.97(m,1H),3.78-3.60(m,2H),3.55(ddd,J=9.3,7.2,3.7Hz,1 H),3.29-3.09(m,3H),3.01(dt,J=22.4,9.8Hz,1H),2.49(s,3H),1.43(d,J=9.2Hz,9H).

[0403] Step 2: rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate The title compound was prepared in a similar manner to Step 2 of Example 14 from tert-butyl rac-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate (Step 1) and TFA. LC-MS (Method 8B): Rt2.35 min; MS m / z497.1=[M+H]+ H NMR (500 MHz, DMSO-d) δ 11.72 (s, 1H), 9.00 (s, 2H), 7.93-7.86 (m, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.38 (s, 1H), 7.22 (s, 1H), 6.85 (t, J = 54.9 Hz, 1H), 4.23-3.97 (m, 3H), 3.80-3.59 (m, 2H), 3.46 (dd, J = 10.9, 7.3 Hz, 1H), 3.27-3.12 (m, 3H), 2.97 (t, J = 11.0 Hz, 1H). No exchangeable protons were observed.

[0404] Example 14.2 rac-(4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate [ka] Step 1: tert-butyl rac-(4aS,7aR)-6-[[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate G) and tert-butyl rac-(4aS,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylate. LC-MS (Method 2B): Rt1.48 min; MS m / z597.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.23(s,1H),7.91(d,J=1.7Hz,1H),7.86(dt,J=7.7,1.4Hz,1H),7.74(dt,J=7.9,1.5Hz,1H),7.59(t,J=7.8Hz,1H),7.39(s,1H),7.22(d,J=1 .6Hz,1H),6.85(t,J=54.9Hz,1H),4.44(s,1H),3.99(s,1H),3.86(s,2H) ),3.75-3.41(m,5H),3.05(d,J=59.6Hz,1H),2.49(s,3H),1.44(s,9H).

[0405] Step 2: rac-(4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate The title compound was prepared in a similar manner to Step 2 of Example 14 from tert-butyl rac-(4aS,7aR)-6-[[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate (Step 1) and TFA. LC-MS (Method 8B): Rt2.73 min; MS m / z467.1=[M+H]+ H NMR (500 MHz, methanol-d) δ 7.94 (t, J = 1.7 Hz, 1H), 7.74 (ddt, J = 8.2, 6.9, 1.4 Hz, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.33 (s, 1H), 6.63 (t, J = 55.2 Hz, 1H), 4.45 (s, 1H), 4.15-4.04 (m, 2H), 4.00 (t, J = 9.4 Hz, 1H), 3.95-3.80 (m, 2H), 3.78 (s, 2H), 3.51-3.42 (m, 1H), 3.24 (ddt, J = 12.6, 1.5 Hz, 1H), 2.55 (s, 3H). No exchangeable protons were observed.

[0406] Example 14.3 rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate [ka] Step 1: tert-butyl rac-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl rac-(4aS,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylate. LC-MS (Method 3B): Rt1.70 min; MS m / z559.4=[MH]+ 1H NMR(500MHz,DMSO-d6)δ 11.51(s,1H),7.89(t,J=1.6Hz,1H),7.83(dt,J=7.8,1.6Hz,1H),7.73-7.69(m, 1H),7.57(t,J=7.8Hz,1H),6.94(s,2H),4.20(dd,J=10.1,6.5Hz,1H),4.13(d,J =12.7Hz,1H),4.07-4.02(m,1H),3.72-3.60(m,2H),3.56-3.51(m,1H),3.28-3. 20(m,1H),3.20-3.07(m,2H),3.06-2.95(m,1H),2.36(s,6H),1.46-1.37(m,9H).

[0407] Step 2: rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate The title compound was prepared in a similar manner to Step 2 of Example 14 from tert-butyl rac-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate (Step 1) and TFA. LC-MS (Method 8A): Rt1.76 min; MS m / z461.1=[M+H]+ 1H NMR (500MHz, methanol-d4)δ 7.96(t,J=1.7Hz,1H),7.83-7.78(m,2H),7.59(t,J=7.8Hz,1H),7.46(s,2H ),4.30(dd,J=11.8,7.1Hz,1H),4.18(ddd,J=11.8,3.7,1.5Hz,1H),4.06(br d, J = 12.9 Hz, 1H), 3.87 (td, J = 11.8, 3.2 Hz, 1H), 3.79 (ddd, J = 11.2, 9.6, 7.4 Hz, 1H), 3.57 (dd, J = 11.2, 7.4 Hz, 1H), 3.46 (t, J = 11.8 Hz, 1H), 3.29-3.21 (m, 2H), 3.13 (t, J = 11.2 Hz, 1H), 2.61 (s, 6H). No exchangeable protons were observed.

[0408] Example 14.4 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-cyclopropyl-piperazine-1-carboxamide [ka] Step 1: tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3-cyclopropyl-piperazine-1-carboxylate [ka] The title compound was prepared in a similar manner to Example 4 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl 3-cyclopropyl-piperazine-1-carboxylate. LC-MS (Method 2.5A): Rt0.80 min; MS m / z559.3=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.21(s,1H),7.88(t,J=1.8Hz,1H),7.82(dt,J=7.7,1.5Hz,1H),7.70(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8Hz,1H),6.92(s,2H),4. 10-3.92(m,3H),3.71-3.61(m,1H),3.25-3.15(m,1H),3.07-2.80(m, 2H), 2.36 (s, 6H), 1.42 (s, 9H), 1.25-1.19 (m, 1H), 0.54-0.38 (m, 4H).

[0409] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-cyclopropyl-piperazine-1-carboxamide The title compound was prepared in a similar manner to Step 2 of Example 14 from tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3-cyclopropyl-piperazine-1-carboxylate (Step 1) and TFA. LC-MS (Method 7B): Rt2.80 min; MS m / z459.4=[M+H]+ 1H NMR (500MHz, methanol-d4)δ 7.90(t,J=1.7Hz,1H),7.71(dt,J=8.0,1.5Hz,1H),7.69(dt,J=7.8,1.4Hz,1H),7.49(dd,J=7.8,7. 8Hz,1H),7.00(s,2H),4.00-3.94(m,1H),3.49(dd,J=10.3,3.8Hz,1H),3.38(td,J=13.0,3.2Hz,1H) , 3.13-3.09 (m, 1H), 3.08-3.02 (m, 1H), 2.93-2.88 (m, 1H), 2.73 (td, J=12.6, 3.6 Hz, 1H), 2.43 (s, 6H), 1.68-1.60 (m, 1H), 0.67-0.60 (m, 1H), 0.56-0.49 (m, 2H), 0.40-0.34 (m, 1H). Two NH protons were not observed.

[0410] Example 14.5 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide [ka] Step 1: tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3-(cyclopropylmethyl)piperazine-1-carboxylate [ka] The title compound was prepared in a similar manner to Example 4 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl 3-(cyclopropylmethyl)piperazine-1-carboxylate. LC-MS (Method 2A): Rt0.87 min; MS m / z573.3=[M+H]+ 1H NMR (400MHz, DMSO-d6) δ 11.28 (s, 1H), 7.88 (t, J = 1.7 Hz, 1H), 7.82 (dt, J = 7.7, 1.4 Hz, 1H), 7.71 (dt, J = 8.0, 1.4 Hz, 1H), 7.56 (dd, J = 7.8, 7.8 Hz, 1H), 6.92 (s, 2H), 4.44-4.36 (m, 1H), 4.03-3.82 (m, 3H), 3.08-2.95 (m, 2H), 2.35 (s, 6H), 1.42 (s, 9H), 0.84 (dd, J = 6.6, 2.4 Hz, 2H), 0.70-0.62 (m, 1H), 0.44-0.33 (m, 2H), 0.13-0.03 (m, 2H). No CH protons were observed.

[0411] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide The title compound was prepared in a similar manner to Step 2 of Example 14 from tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-3-(cyclopropylmethyl)piperazine-1-carboxylate (Step 1) and TFA. LC-MS (Method 7B): Rt3.14 min; MS m / z473.4=[M+H]+ 1H NMR (400MHz, methanol-d4) δ 7.90 (t, J = 1.4 Hz, 1H), 7.73-7.70 (m, 1H), 7.70-7.66 (m, 1H), 7.49 (dd, J = 7.8, 7.8 Hz, 1H), 7.00 (s, 2H), 4.36-4.29 (m, 1H), 3.96-3.89 (m, 1H), 3.14-3.04 (m, 2H), 3.03-2.97 (m, 1H) 1H), 2.92 (dd, J = 13.0, 4.2 Hz, 1H), 2.71 (td, J = 12.6, 3.7 Hz, 1H), 2.43 (s, 6H), 1.79-1.62 (m, 2H), 0.74-0.65 (m, 1H), 0.48-0.42 (m, 2H), 0.17-0.10 (m, 2H). - 2 × NH protons were not observed.

[0412] Example 14.6 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,3-dimethyl-piperazine-1-carboxamide [ka] Step 1: tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,2-dimethyl-piperazine-1-carboxylate [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl 2,2-dimethylpiperazine-1-carboxylate. LC-MS (Method 2B): Rt1.62 min; MS m / z547.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 10.97(v br s,1H),7.89(t,J=1.8Hz,1H),7.82(dt,J=7.7,1.5Hz,1H),7.71(dt,J=7.9,1.5Hz,1H),7.56(t,J=7.8Hz,1H),6.93 (s,2H),3.71-3.65(m,2H),3.65-3.57(m,2H),3.57-3.51(m,2H),2.36(s,6H),1.42(d,J=2.9Hz,9H),1.34(s,6H).

[0413] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,2-dimethyl-piperazine-1-carboxamide The title compound was prepared in analogy to Step 2 of Example 14 from tert-butyl 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-2,2-dimethyl-piperazine-1-carboxylate (Step 1) and TFA. LC-MS (Method 8B): Rt2.82 min; MS m / z447.1=[M+H]+ H NMR (500 MHz, methanol-d₄) δ 7.92 (t, J = 1.7 Hz, 1H), 7.73 (dt, J = 8.0, 1.5 Hz, 1H), 7.70 (dt, J = 7.7, 1.4 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.02 (s, 2H), 3.63-3.55 (m, 2H), 3.40 (s, 2H), 3.02-2.85 (m, 2H), 2.45 (s, 6H), 1.19 (s, 6H). Two NH protons were not observed.

[0414] Example 14.7 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide [ka] Step 1: tert-butyl 9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-4-oxa-1,9-diazaspiro[5.5]undecane-1-carboxylate [ka] The title compound was prepared in a similar manner to Example 4 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and tert-butyl 4-oxa-1,9-diazaspiro[5.5]undecane-1-carboxylate. LC-MS (Method 2A): Rt0.74 min; MS m / z589.2=[M+H]+ 1H NMR (500MHz, CDCl3) δ 8.11(s,1H),7.76(t,J=1.6Hz,1H),7.69(dt,J=7.6,1.4Hz,1H),7.55(dt,J=7. 9,1.5Hz,1H),7.48(t,J=7.8Hz,1H),6.90(s,2H),3.91(dt,J=11.6,5.1Hz,2H), 3.77(t,J=5.3Hz,2H),3.60(s,2H),3.54(t,J=5.3Hz,2H),3.49-3.41(m,2H),2 .60(ddd,J=14.0,9.6,4.5Hz,2H),2.54(s,6H),1.84-1.74(m,2H),1.45(s,9H).

[0415] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide The title compound was prepared in a similar manner to Step 2 of Example 14 from tert-butyl 9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]-4-oxa-1,9-diazaspiro[5.5]undecane-1-carboxylate (Step 1) and TFA. LC-MS (Method 7A): Rt1.16 min; MS m / z489.3=[M+H]+ H NMR (400 MHz, MeOD) δ 7.90 (t, J = 1.7 Hz, 1H), 7.73-7.66 (m, 2H), 7.48 (dd, J = 7.8, 7.8 Hz, 1H), 7.00 (s, 2H), 3.70-3.62 (m, 4H), 3.63-3.56 (m, 2H), 3.54 (s, 2H), 2.92-2.87 (m, 2H), 2.43 (s, 6H), 1.73 (t, J = 5.9 Hz, 4H). Two NH protons were not observed.

[0416] Example 16 N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide [ka] To a solution of 3-[2-amino-5-(2-methoxy-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate K) (75 mg, 0.23 mmol) and CDI (75 mg, 0.47 mmol) in DMA (1.2 mL) was added DIPEA (0.12 mL, 0.70 mmol), and the reaction mixture was stirred at 50 °C overnight. 1-Imino-1,4-thiazinane 1-oxide (47 mg, 0.35 mmol) was added, and stirring was continued at 50 °C for an additional 1 h. The resulting mixture was purified by C18 reverse-phase chromatography eluting with a gradient of 5-20% MeCN / water (+0.1% ammonium hydroxide modifier) ​​to afford the title compound as a white solid. LC-MS (Method 8B): Rt3.55 min; MS m / z483.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.53(s,1H),7.91(s,1H),7.84(d,J=7.7Hz,1H),7.72(d,J=8.0Hz,1H),7.58(t,J=7.8Hz,1H),6.74(s,1H),6.42 (s,1H),4.11(d,J=14.4Hz,2H),3.84(s,1H),3.81(s,3H),3.78-3.68(m,2H),3.08(d,J=5.4Hz,4H),2.34(s,3H).

[0417] The compounds of the following tabulated examples (Table Ex16) were prepared in a manner analogous to Example 16 from the appropriate starting compounds and amines as indicated in the table.

[0418] JPEG0007805350000153.jpg240170

[0419] JPEG0007805350000154.jpg166170

[0420] JPEG0007805350000155.jpg225170

[0421] JPEG0007805350000156.jpg141170

[0422] Example 17 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] Step 1: 3-[2-amino-5-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)thiazol-4-yl]benzonitrile [ka] mCPBA (110 mg, 0.49 mmol) was added to a suspension of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) (100 mg, 0.33 mmol) in DCM (2 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. Additional mCPBA (73 mg, 0.33 mmol) was added, and stirring was continued for 1 h. The resulting solution was diluted with DCM (10 mL) and washed with saturated NaHCO solution (2 × 20 mL). The organics were dried over NaSO and concentrated in vacuo to give a red oil. The oil was dry-loaded onto silica and purified by silica chromatography eluting with a gradient of 0–5% MeOH / DCM to give a solid that was triturated with EtO, filtered, and washed with EtO (3 × 2 mL) to give the title compound as a yellow solid. LC-MS (Method 5A): Rt1.86 min; MS m / z323.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.86(d,J=1.9Hz,1H),7.77(d,J=7.7Hz,1H),7.69(d,J=7.9Hz,1H),7.55-7.49(m,1H),7.46-7.39(m,2H),7.14(s,2H),2.27(s,6H).

[0423] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide The title compound was prepared in analogy to Example 6 from 3-[2-amino-5-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)thiazol-4-yl]benzonitrile (step 1) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS (Method 8A): Rt2.53 min; MS m / z448.2=[M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.20 (s, 2H), 4.67 (s, 4H), 4.13 (s, 4H), 2.29 (s, 6H). No NH protons were observed.

[0424] Example 18 4-Cyano-N-[4-(3-cyano-2-methyl-phenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]-2-methyl-benzonitrile (Intermediate O) and 4-methylpiperidine-4-carbonitrile hydrochloride. LC-MS (Method 8B): Rt4.25 min; MS m / z471.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),7.89(d,J=7.7Hz,1H),7.53(d,J=7.6Hz,1H),7.44(t,J=7.7Hz,1H),6.67(s,2H),4.23(d,J=14.0Hz, 2H),3.03(t,J=13.1Hz,2H),2.29-2.25(m,9H),1.92(d,J=13.5Hz,2H),1.53(td,J=13.2,3.9Hz,2H),1.38(s,3H).

[0425] Example 19 N-[5-(2-acetamido-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from N-[4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-6-methyl-2-pyridyl]acetamide (Intermediate KG) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS (Method 8B): Rt2.89 min; MS m / z475.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.35(s,1H),10.49(s,1H),7.87(d,J=1.8Hz,1H),7.85(s,1H),7.81(dt,J=7.8,1.5Hz,1H),7.73(dt,J=7.8, 1.5Hz,1H),7.55(t,J=7.8Hz,1H),6.82(d,J=1.5Hz,1H),4.67(s,4H),4.20(s,4H),2.33(s,3H),2.02(s,3H).

[0426] Example 20 N-[5-[2-(acetamidomethyl)-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from N-[[4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-6-methyl-2-pyridyl]methyl]acetamide (Intermediate KH) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS (Method 8B: Rt2.59 min; MS m / z489.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.37(s,1H),8.30(t,J=6.0Hz,1H),7.88-7.81(m,2H),7.68(dt,J=8.0,1.5Hz,1H),7.55(t,J=7.8Hz Contains 1% Et2O

[0427] Example 21 N-[4-(3-cyanophenyl)-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate KI) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS (Method 8B): Rt3.30 min; MS m / z462.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.38(s,1H),7.87(s,1H),7.83(dt,J=7.7,1.5Hz,1H),7.73(dt,J=8.0,1.5Hz,1H),7.58(t,J=7.8 Hz,1H),7.08(s,1H),6.99(s,1H),4.68(s,4H),4.39(s,2H),4.21(s,4H),3.23(s,3H),2.41(s,3H).

[0428] Example 22 N-[4-(3-cyanophenyl)-5-[2-(1-methoxyethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate P) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS (Method 8B): Rt3.92 min; MS m / z476.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.45(s,1H),7.91-7.87(m,2H),7.83(dt,J=7.9,1.5Hz,1H),7.67-7.63(m,1H),7.21(d,J=1.6Hz,1H), 6.95(d,J=1.6Hz,1H),4.74(s,4H),4.33-4.20(m,5H),3.10(s,3H),2.51(s,3H),1.28(d,J=6.5Hz,3H).

[0429] Example 23 N-[5-[2-chloro-6-(1-hydroxy-1-methyl-ethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-chloro-6-(1-hydroxy-1-methyl-ethyl)-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate Q) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS (Method 8B): Rt3.40 min; MS m / z496.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.47(s,1H),7.88(t,J=1.6Hz,1H),7.86(dt,J=7.8,1.6Hz,1H),7.76(dt,J=7.9,1.6Hz,1H),7.61(apr t,J=7.8Hz,1H),7.46(d,J=1.5Hz,1H),7.15(d,J=1.5Hz,1H),5.26(s,1H),4.67(s,4H),4.21(s,4H),1.36(s,6H).

[0430] Example 24 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide [ka] Step 1: N-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-4-cyano-4-methyl-piperidine-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 6 from 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate I) and 4-methylpiperidine-4-carbonitrile hydrochloride. LC-MS (Method 3B): Rt2.34 min; MS m / z587.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.35(s,1H),7.85(s,1H),7.82(d,J=7.8Hz,1H),7.72(d,J=7.9Hz,1H),7.56(t,J=7.8Hz,1H),7.12(s,1H),7.01(s,1H),4.62(s,2H),4.22 (d,J=14.0Hz,2H),3.03(t,J=12.9Hz,2H),2.42(s,3H),1.92(d,J=13.6Hz,2H),1.58-1.49(m,2H),1.37(s,3H),0.77(s,9H),-0.02(s,6H).

[0431] Step 2: 4-cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide To a solution of N-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-4-cyano-4-methyl-piperidine-1-carboxamide (Step 1) (188 mg, 0.32 mmol) in THF (6.4 mL) was added TBAF (0.64 mL, 0.64 mmol), and the reaction mixture was stirred at room temperature for 90 min. Additional TBAF (0.64 mL, 0.64 mmol) was added, and stirring was continued for an additional 2.5 h. The resulting mixture was diluted with EtOAc (50 mL) and water (50 mL). The layers were separated, and the aqueous phase was further extracted with EtOAc (40 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by silica chromatography eluting with 0-30% MeOH / EtOAc gave a yellow solid. The solid was further purified by C18 reverse phase chromatography eluting with a gradient of 10-35% MeCN / water (+0.1% ammonium hydroxide) to give a solid which was triturated with Et2O and filtered to give the title compound as a white solid. LC-MS (Method 8B): Rt3.75 min; MS m / z473.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.32(s,1H),7.89(s,1H),7.82(d,J=7.7Hz,1H),7.72(d,J=7.8Hz,1H), 7.56(t,J=7.8Hz,1H),7.14(s,1H),6.98(s,1H),5.33(t,J=5.9Hz,1H),4. 46(d,J=5.9Hz,2H),4.23(d,J=14.0Hz,2H),3.02(t,J=13.1Hz,2H),2.37( s,3H),1.92(d,J=13.6Hz,2H),1.52(dt,J=13.4,7.1Hz,2H),1.37(s,3H).

[0432] Example 26 N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide [ka] The title compound was prepared in a similar manner to Example 9 from 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(trifluoromethyl)-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate IA) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS (Method 8B): Rt3.49 min; MS m / z502.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.52(s,1H),7.92(t,J=1.8Hz,1H),7.88(dt,J=7.8,1.4Hz,1H),7.76(dt,J=8.0,1.4Hz,1H),7.65(d,J=1.5Hz,1H), 7.61(t,J=7.8Hz,1H),7.39(d,J=1.6Hz,1H),5.63(t,J=5.9Hz,1H),4.68(s,4H),4.60(d,J=5.9Hz,2H),4.23(s,4H).

[0433] Example 27 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide [ka] CDI (1.16 g, 7.18 mmol) and DIPEA (1.88 mL, 10.77 mmol) were added to a stirred solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) (1.1 g, 3.59 mmol) in DMA (11 mL), and the solution was heated at 50 °C overnight. 3-Methylpyrrolidine-3-carbonitrile hydrochloride (1.00 g, 6.82 mmol) and additional DIPEA (1.88 mL, 10.77 mmol) were added, and the solution was stirred at 50 °C for 30 minutes. The resulting mixture was cooled to room temperature and diluted with EtOAc (150 mL). The mixture was washed with 90% aqueous brine solution (100 mL) and 50% aqueous brine solution (3 × 100 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 1-2% MeOH / DCM gave a yellow solid. Addition of MeOH (10 mL) gave a white solid which was collected by filtration, washed with MeOH (2 mL) and EtO (20 mL), and dried to give the title compound as a white solid. LC-MS (Method 8B): Rt3.03 min; MS m / z443.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.24(s,1H),7.89(t,J=1.8Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7.71(dt,J=8.0,1.5Hz,1H),7.56(t,J=7.8Hz,1H),6.94(s,2H), 3.96-3.86(m,1H),3.64(d,J=34.3Hz,2H),3.42(d,J=11.1Hz,1H),2.43-2.38(m,1H),2.36(s,6H),2.14-2.02(m,1H),1.47(s,3H).

[0434] Example 27a and Example 27b Racemic 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide (Example 27) was dissolved in EtOH / DCM (4:1) at 50 mg / mL and purified by SFC. Fractions of each enantiomer were combined and evaporated to near dryness, then transferred to a final container with DCM, and the DCM was removed under a stream of compressed air at 35°C. The mixture was then stored in a vacuum oven at 35°C and 5 mbar until a constant weight was reached.

[0435] Purification conditions Column details: Lux iA3 (21.2 mm x 250 mm, 5 μm) Column temperature: 40°C Flow rate 50mL / min BPR 100BarG Detector wavelength: 216 nm Injection volume 250μL (12.5mg) Isocratic conditions: 35:65 EtOH:CO2 (0.2% v / v NH3)

[0436] Chiral purity analysis conditions Column details Chiralpak IG (4.6mm×250mm, 5μm) Column temperature: 40°C Flow rate: 4mL / min Detector wavelength: 210~400nm Injection volume 1.0μL BPR 125BarG Isocratic conditions: 25:75 EtOH:CO2 (0.2% v / v NH3)

[0437] Example 27a (3R)-3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide [ka] First eluting peak: Chiral LCMS retention time: = 7.05 min LC-MS (Method 8B): Rt3.04 min; MS m / z443.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.24(s,1H),7.89(t,J=1.6Hz,1H),7.82(dt,J=7.7,1.6Hz,1H),7.71(dt,J=8.0,1.6Hz,1H),7.56(apr t,J=7.8Hz,1H),6.93(s,2H),3.98-3.86(m,1H),3.72-3.63(m,1H),3.64-3.55(m,1H) ),3.46-3.38(m,1H),2.43-2.36(m,1H),2.36(s,6H),2.12-2.03(m,1H),1.47(s,3H).

[0438] Example 27b (3S)-3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide [ka] Second eluting peak: Chiral LCMS retention time: = 8.59 min LC-MS (Method 8B): Rt2.92 min; MS m / z443.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.24(s,1H),7.89(t,J=1.6Hz,1H),7.82(dt,J=7.7,1.6Hz,1H),7.71(dt,J=8.0,1.6Hz,1H),7.56(apr t,J=7.8Hz,1H),6.93(s,2H),3.98-3.87(m,1H),3.71-3.63(m,1H),3.64-3.55(m,1H) ),3.46-3.37(m,1H),2.43-2.38(m,1H),2.36(s,6H),2.13-2.02(m,1H),1.47(s,3H).

[0439] A further sample of Example 27b was obtained under the following conditions: Racemic 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide (Example 27) was dissolved in EtOH / DCM (4:1) at 25 mg / mL and purified by SFC. Fractions of each enantiomer were combined and evaporated to near dryness. The resulting solid was transferred to a final container with DCM, and the DCM was removed under a stream of compressed air at 35°C. It was then stored in a vacuum oven at 35°C and 5 mbar until a constant weight was reached. The material was triturated in EtO / MeOH under sonication, and the resulting thick suspension was filtered. The solid was washed with EtO / MeOH, dried on a sinter under vacuum, and then further dried in a vacuum oven at 50°C overnight to give the title compound as a cream-colored solid.

[0440] Purification conditions Column details: Lux iA3 (21.2 mm x 250 mm, 5 μm) Column temperature: 40°C Flow rate 50mL / min BPR 100BarG Detector wavelength: 217nm Injection volume 500μL (12.5mg) Isocratic conditions: 25:75 EtOH:CO2 (0.2% v / v NH3)

[0441] Chiral purity analysis conditions Column details Chiralpak IG (4.6mm×250mm, 5μm) Column temperature: 40°C Flow rate 4mL / min Detector wavelength: 210~400nm Injection volume 1.0μL BPR 125BarG Isocratic conditions: 25:75 EtOH:CO2 (0.2% v / v NH3)

[0442] Second eluting peak: Chiral LCMS retention time: = 9.73 min LC-MS (Method 8A): Rt2.37 min; MS m / z443.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.23(br s,1H),7.89(br t,J=1.5Hz,1H),7.82(br dt,J=7.7,1.5Hz,1H),7.71(br dt,J=8.0,1.5Hz,1H),7.56(apr t,J=7.8Hz,1H),6.93(s,2H),3.92(br s,1H),3.67(br s,1H),3.60(br s,1H),3.41(br d,J=11.2Hz,1H),2.39(s,1H),2.36(s,6H),2.12-2.03(m,1H),1.47(s,3H).

[0443] Alternatively, Examples 27a and 27b were prepared in a manner analogous to Example 6 from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile (Intermediate C) and (3R)-3-methylpyrrolidine-3-carbonitrile hydroiodide (Intermediate U) or (3S)-3-methylpyrrolidine-3-carbonitrile hydroiodide (Intermediate UA).

[0444] Example 28 N-[5-[2,6-bis(trideuteriomethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-4-cyano-4-methyl-piperidine-1-carboxamide [ka] 3-[2-Amino-5-[2,6-bis(trideuteriomethyl)-4-pyridyl]thiazol-4-yl]benzonitrile (Intermediate N) (465 mg, 1.49 mmol) and CDI (483 mg, 2.98 mmol) were dissolved in anhydrous DMA (7.5 mL) in a sealed tube under nitrogen. DIPEA (778 μL, 4.47 mmol) was added, and the resulting solution was stirred at 50° C. for 17 h. 4-Methylpiperidine-4-carbonitrile hydrochloride (478 mg, 2.98 mmol) and additional DIPEA (778 μL, 4.47 mmol) were added, and the mixture was stirred at 50° C. for 1 h. The mixture was cooled to room temperature, diluted with EtOAc (80 mL), and washed successively with 80% brine (80 mL), 20% brine (2×80 mL), and 50% brine (80 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the crude material as a pale yellow foam. Purification by silica chromatography eluting with a gradient of 1-2% MeOH / DCM gave a clear straw-colored glass which was triturated and azeotroped with Et2O to give the title compound as a cream-colored solid. LC-MS (Method 8B): Rt3.08 min; MS m / z463.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.31(s,1H),7.89(t,J=1.6Hz,1H),7.82(dt,J=7.8,1.6Hz,1H),7.70(dt,J=8.0,1.6Hz,1H),7.56(apr t,J=7.8Hz,1H),6.93(s,2H),4.22(d,J=13.9Hz,2H),3.03(t,J=13.3Hz,2H),1.92(d,J=13.9Hz,2H),1.53(td,J=13.3,4.0Hz,2H),1.37(s,3H).

[0445] Preparation of intermediates Intermediate A 3-(2-aminothiazol-4-yl)benzonitrile hydrobromide [ka] The following was prepared according to the procedure of Wang, Y. and Yang, T., as described in WO 2012 / 100734, page 24, Example 15, step 2:

[0446] To a flask containing 3-(2-bromoacetyl)benzonitrile (5 g, 22.32 mmol) in EtOH (50 mL), thiourea (1.87 g, 24.55 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The solvent volume was reduced by approximately 50% under reduced pressure to form a suspension. The suspension was sonicated, filtered, and dried to give the title compound as a colorless solid. LC-MS (Method 3B): Rt1.62 min; MS m / z202.3=[M+H]+ 11 H NMR (500 MHz, DMSO-d) δ 8.22 (t, J = 1.8 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H). No NH protons were observed.

[0447] 3-(2-aminothiazol-4-yl)benzonitrile can also be prepared as follows: To a flask containing thiourea (2.04 g, 26.78 mmol) in pyridine (50 mL) under nitrogen was added 3-(2-bromoacetyl)benzonitrile (3.0 g, 13.39 mmol), and the mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo. The crude product was purified by silica chromatography eluting with 0-100% EtOAc / DCM. The resulting solid was recrystallized from EtOAc to give 3-(2-aminothiazol-4-yl)benzonitrile as a pale yellow solid. LC-MS (Method 7A): Rt1.75 min; MS m / z202.1=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 8.20(t,J=1.5Hz,1H),8.11(dt,J=7.9,1.4Hz,1H),7.70(dt,J=7.7,1.3Hz,1H),7.58(t,J=7.6Hz,1H),7.26(s,1H),7.14(s,2H).

[0448] Intermediate B 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile [ka] The following was prepared according to the procedure of Wang, Y. and Yang, T., as described in WO 2012 / 100734, pages 24-25, Example 15, step 3:

[0449] To a solution of 3-(2-aminothiazol-4-yl)benzonitrile hydrobromide (Intermediate A) (2.6 g, 9.21 mmol) in THF (40 mL) was added NBS (1.97 g, 11.06 mmol), and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with EtOAc (60 mL) and washed with water (100 mL). The organic layer was separated, and the aqueous was further extracted with EtOAc (2 x 50 mL). The combined organics were dried over MgSO4 and concentrated in vacuo to give an orange solid. This solid was suspended in DCM (20 mL), filtered, washed with DCM, and dried to give the title compound as an off-white solid. LC-MS (Method 3B): Rt1.64 min; MS m / z279.9 / 281.9=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 8.16(t,J=1.7Hz,1H),8.15(dt,J=7.9,1.7Hz,1H),7.83(d,J=7.9Hz,1H),7.66(t,J=7.9Hz,1H),7.42(s,2H).

[0450] Intermediate C 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile [ka] A solution of potassium carbonate (43.1 g, 312.34 mmol) in water (210 mL) was added to a solution of 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) (35.0 g, 124.94 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (34.95 g, 149.93 mmol) in 1,4-dioxane (840 mL), and the mixture was deoxygenated by nitrogen sparging for 20 minutes. Bis(tri-tert-butylphosphine)palladium(0) (6.38 g, 12.49 mmol) was added, the flask was sealed, and the flask was evacuated and backfilled with nitrogen (three cycles). The reaction mixture was stirred at 80 °C for 1 hour and then cooled to room temperature. The mixture was diluted with EtOAc (500 mL) and water (200 mL), and the layers were separated. The organic layer was washed with 20% brine (500 mL), pure brine (200 mL), dried over Na2SO4, and filtered through a plug of Celite® (filter material), eluting with EtOAc (4 x 200 mL). The filtrate was concentrated in vacuo, and the resulting material was triturated in DCM (150 mL) with sonication. The solid was collected by filtration, washed with DCM (3 x 50 mL), and dried in vacuo to give the title compound as a pale yellow solid. LC-MS (Method 2B): Rt1.26 min; MS m / z307.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.81(br t,J=1.5Hz,1H),7.79(br dt,J=7.6,1.5Hz,1H),7.66(br dt,J=7.9,1.5Hz,1H),7.52(apr t,J=7.8Hz,1H),7.50-7.36(m,2H),6.80(s,2H),2.32(s,6H).

[0451] Intermediate D 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile [ka] A solution of 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) (710 mg, 2.53 mmol), 2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (649 mg, 2.56 mmol), and cesium carbonate (1652 mg, 5.07 mmol) in monoglyme (28.4 mL) and water (3.5 mL) was degassed with nitrogen for 5 minutes. Pd(dppf)Cl2·CHCl2 (517 mg, 0.63 mmol) was added, and the reaction mixture was heated at 80 °C under nitrogen for 1 hour. After cooling to room temperature, the resulting mixture was filtered, and the precipitate was washed with EtOAc (50 mL). The filtrate was partitioned between water (20 mL) and brine (20 mL), and the organic layer was separated, dried over MgSO4, and concentrated in vacuo. The crude product was purified by silica chromatography eluting with 0-50% EtOAc / DCM to give the title compound as a brown solid. LC-MS (Method 2A): Rt1.12 min; MS m / z327.0 / 329.0=[M+H]+ 1 H NMR(400MHz,DMSO-d6)δ 7.86-7.80(m,2H),7.69(dt,J=7.9,1.4Hz,1H),7.60(s,2H),7.59-7.54(m,1H),7.03-6.99(m,1H),6.92-6.89(m,1H),2.35(s,3H).

[0452] Intermediate E 4-(Hydroxymethyl)piperidine-4-carbonitrile Hydrochloride [ka] To a solution of tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (100 mg, 0.42 mmol) in DCM (1 mL) was added 4 M HCl in 1,4-dioxane (2.08 mL, 8.32 mmol), and the reaction mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo to give the title compound as a colorless solid. 1 H NMR(400MHz,DMSO-d6)δ 9.11(s,2H),5.66(t,J=5.8Hz,1H),3.52(d,J=5.8Hz,2H),3.41-3.34(m,2H ),2.90(td,J=13.1,3.0Hz,2H),2.04(d,J=14.2Hz,2H),1.85-1.73(m,2H).

[0453] Intermediate F Piperidine-4,4-dicarbonitrile hydrochloride [ka] Step 1: 1-benzylpiperidine-4,4-dicarbonitrile [ka] The following was prepared according to the procedure of Zahler, R. and Vath, J., as described in WO 2017 / 027684 A1, pages 56 and 57:

[0454] K2CO3 (1132 mg, 8.19 mmol) was added to a solution of propanedinitrile (0.23 mL, 3.72 mmol) in DMF (5 mL), and the reaction mixture was stirred at 65 °C for 2 h. To this mixture was added N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (1.0 g, 3.72 mmol) in DMF (5 mL), and stirring was continued at 65 °C for 16 h. After cooling to room temperature, the reaction was quenched with ice-cold water. The resulting mixture was extracted with EtOAc (3 × 10 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica chromatography eluting with 10–40% EtOAc / petroleum ether to give the title compound as a colorless oil. LC-MS (Method 8B): Rt4.31 min; MS m / z226.2=[M+H]+ 1 H NMR(500MHz,CDCl3)δ 7.37-7.25(m,5H),3.56(s,2H),2.64(s,4H),2.25(s,4H).

[0455] Step 2: Piperidine-4,4-dicarbonitrile hydrochloride 1-Chloroethyl carbonochloridate (0.36 mL, 3.31 mmol) was added dropwise to a stirred solution of 1-benzylpiperidine-4,4-dicarbonitrile (Step 1) (622 mg, 2.76 mmol) in DCE (5 mL) at 0° C. The reaction mixture was heated at reflux for 24 h and then concentrated in vacuo to give a colorless oil. Methanol (5 mL) was then added and the solution was heated at reflux for 3 h. The resulting mixture was concentrated in vacuo to give the title compound as a colorless solid. 1 H NMR(500MHz,DMSO-d6)δ 9.38(m,2H),3.21(s,4H),2.65-2.57(m,4H).

[0456] intermediate G 3-[2-amino-5-(2-difluoromethyl-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile [ka] The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 2-(difluoromethyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. LC-MS (Method 5B): Rt2.83 min; MS m / z343.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.84(dd,J=4.8,3.0Hz,2H),7.70(d,J=7.9Hz,1H),7.63(s,2H),7.56(t,J= 8.1Hz,1H),7.20(s,1H),7.07(s,1H),6.80(t,J=55.0Hz,1H),2.44(s,3H).

[0457] Intermediate H 3-[2-amino-5-(2-trifluoromethyl-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile [ka] The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine. LC-MS (Method 3B): Rt1.86 min; MS m / z359.3=[MH]- 1H NMR(500MHz,DMSO-d6)δ 7.88-7.81(m,2H),7.71(d,J=8.0Hz,1H),7.68(s,2H),7.57(dd,J=9.6,6.6Hz,1H),7.33(s,1H),7.15(s,1H),2.47(s,3H).

[0458] Intermediate I 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile [ka] Step 1: (4-Bromo-6-methyl-2-pyridyl)methoxy-tert-butyl-dimethyl-silane [ka] To a solution of (4-bromo-6-methyl-2-pyridyl)methanol (2.0 g, 9.9 mmol) in DMF (15 mL) at 0 °C, imidazole (0.03 mL, 12.87 mmol) was added, followed by tert-butyldimethylsilyl chloride (1.11 mL, 10.89 mmol), and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was partitioned between EtOAc (150 mL) and water (150 mL), and the layers were separated. The aqueous layer was further extracted with EtOAc (100 mL), and the combined organic extracts were washed with saturated NaHCO3 solution (150 mL), brine (150 mL), dried over MgSO4, and concentrated in vacuo to afford the title compound as a yellow oil, which slowly crystallized to give a yellow solid. 1H NMR(500MHz,DMSO-d6)δ 7.45(d,J=0.8Hz,1H),7.38(s,1H),4.70(s,2H),2.43(s,3H),0.91(s,9H),0.10(s,6H).

[0459] Step 2: 2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine [ka] A solution of (4-bromo-6-methyl-2-pyridyl)methoxy-tert-butyl-dimethyl-silane (Step 1) (2.96 g, 9.35 mmol), bis(pinacolato)diboron (3.56 g, 14.02 mmol), potassium acetate (5.16 g, 37.39 mmol), and Pd(dppf)Cl (889 mg, 1.22 mmol) in 1,4-dioxane (45 mL) was heated to 80 °C overnight. The resulting mixture was concentrated in vacuo, and the residue was dissolved in hexane (a small amount of DCM was added to aid dissolution). The mixture was filtered through Celite® (filter material) and concentrated in vacuo to give the title compound as a brown solid. 1H NMR(500MHz,DMSO-d6)δ 7.46(s,1H),7.31(s,1H),4.71(s,2H),2.44(s,3H),1.30(s,12H),0.91(s,9H),0.09(s,6H).

[0460] Step 3: 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile To a degassed mixture of 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) (1.0 g, 3.57 mmol), 2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine (Step 2) (2.59 g, 7.14 mmol), and potassium carbonate (1.97 g, 14.28 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added bis(tri-tert-butylphosphine)palladium(0) (182 mg, 0.36 mmol). The reaction mixture was stirred at 80 °C for 1 h and then cooled to room temperature. The resulting mixture was diluted with EtOAc (100 mL) and water (100 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 10-40% EtOAc / petroleum ether gave a solid which was triturated in diethyl ether (8 mL), collected by filtration, washed with diethyl ether (3 x 2 mL), and dried under vacuum overnight to give the title compound as a yellow solid. LC-MS (Method 3B): Rt2.28 min; MS m / z435.4=[MH]- 1H NMR(500MHz,DMSO-d6)δ 7.82-7.75(m,2H),7.68(dt,J=7.9,1.5Hz,1H),7.52(td,J=7.6,7.0,1.3Hz,1H),7.4 8(s,2H),6.94(d,J=2.8Hz,2H),4.59(s,2H),2.37(s,3H),0.78(s,9H),-0.02(s,6H).

[0461] Intermediate IA 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(trifluoromethyl)-4-pyridyl]thiazol-4-yl]benzonitrile [ka] Step 1: [4-Bromo-6-(trifluoromethyl)-2-pyridyl]methoxy-tert-butyl-dimethyl-silane [ka] The title compound was prepared in a similar manner to Step 1 of Intermediate I from [4-bromo-6-(trifluoromethyl)-2-pyridyl]methanol and tert-butyldimethylsilyl chloride. LC-MS (Method 3B): Rt2.84 min; MS m / z370.0 / 372.0=[M+H]+ 1H NMR (500 MHz, chloroform-d) δ 7.88 (s, 1H), 7.73-7.69 (m, 1H), 4.86 (s, 2H), 0.97 (s, 9H), 0.14 (s, 6H).

[0462] Step 2: tert-butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-2-pyridyl]methoxy]silane [ka] The title compound was prepared in analogy to Step 2 of Intermediate I from [4-bromo-6-(trifluoromethyl)-2-pyridyl]methoxy-tert-butyl-dimethyl-silane (Step 1) and bis(pinacolato)diboron. 1H NMR (500 MHz, chloroform-d) δ 8.04 (s, 1H), 7.88 (d, J = 0.9 Hz, 1H), 4.89 (s, 2H), 1.36 (s, 12H), 0.96 (s, 9H), 0.13 (s, 6H).

[0463] Step 3: 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(trifluoromethyl)-4-pyridyl]thiazol-4-yl]benzonitrile The title compound was prepared in analogy to Step 3 of Intermediate I from tert-butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-2-pyridyl]methoxy]silane (Step 2) and 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B). LC-MS (Method 3B): Rt2.38 min; MS m / z491.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.86(t,J=1.8Hz,1H),7.83(dt,J=7.7,1.5Hz,1H),7.75-7.68(m,3H),7.54(t,J=7.8Hz, 1H),7.36(d,J=1.6Hz,1H),7.29(d,J=1.6Hz,1H),4.70(s,2H),0.79(s,9H),0.00(s,6H).

[0464] Intermediate J 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile [ka] Step 1: 2-(4-bromo-6-methyl-2-pyridyl)propan-2-ol [ka] A solution of ethyl 4-bromo-6-methyl-pyridine-2-carboxylate (1.04 g, 4.25 mmol) in anhydrous THF (20 mL) was added dropwise over 10 minutes to a stirred solution of methylmagnesium bromide (3.4 M in 2-Me-THF) (2.75 mL, 9.36 mmol) under nitrogen at 0 °C and stirred for 5 minutes. The ice bath was removed, and the mixture was stirred at room temperature for 20 minutes. The resulting mixture was recooled to 5 °C, and the reaction was quenched by the addition of 1 M HCl (9 mL). The mixture was diluted with water (30 mL) and EtOAc (30 mL), and the pH of the aqueous layer was adjusted to pH 7 by the addition of saturated NaHCO solution, after which the layers were shaken and separated. The aqueous layer was extracted with EtOAc (30 mL) and the combined organic extracts were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the title compound as a pale yellow oil. LC-MS (Method 3B): Rt1.59 min; MS m / z230.1 / 232.1=[M+H]+ 1H NMR(500MHz,CDCl3)δ 7.33(d,J=1.0Hz,1H),7.24(d,J=1.0Hz,1H),5.08(s,1H),2.54(s,3H),1.51(s,6H).

[0465] Step 2: 4-Bromo-2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-pyridine [ka] NaH (60%, in oil) (229 mg, 5.74 mmol) was added to a solution of 2-(4-bromo-6-methyl-2-pyridyl)propan-2-ol (Step 1) (660 mg, 2.87 mmol) in anhydrous DMF (15 mL) under nitrogen, and the mixture was stirred at room temperature for 5 minutes. 4-Methoxybenzyl bromide (620 μL, 4.3 mmol) was added via syringe, and the resulting mixture was stirred at room temperature for 1 hour. Additional NaH (60%, in oil) (229 mg, 5.74 mmol) and 4-methoxybenzyl bromide (413 μL, 2.87 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction was quenched by the dropwise addition of water (1 mL) and then diluted with EtOAc (75 mL). The mixture was washed with 90% brine (75 mL), 50% brine (3×75 mL), brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification by silica chromatography eluting with 5% EtOAc / n-hexane afforded the title compound as a colorless oil. LC-MS (Method 3B): Rt2.46 min; MS m / z350.1 / 352.1=[M+H]+ 1H NMR (500MHz, chloroform-d) δ 7.62 (apr dd,J=1.7,0.7Hz,1H),7.30-7.27(m,2H),7.20(d,J=1.7Hz,1H),6.91-6.88(m,2H),4.29(s,2H),3.81(s,3H),2.52(s,3H),1.61(s,6H).

[0466] Step 3: 2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] The title compound was prepared in analogy to Step 2 of Intermediate I from 4-bromo-2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-pyridine (Step 2) and bis(pinacolato)diboron. LC-MS (Method 3B): Rt 1.19 min; MS m / z 316.2 = [M+H] + [NB - mass ion of parent boronic acid]. 1H NMR(500MHz,DMSO-d6)δ 7.62(s,1H),7.32(s,1H),7.27-7.23(m,2H),6.90-6.86(m,2H),4.19(s,2H),3.74(s,3H),2.49(s,3H),1.53(s,6H),1.30(s,12H).

[0467] Step 4: 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile A solution of K2CO3 (297 mg, 2.15 mmol) in water (1.5 mL) was added to a solution of 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) (215 mg, 0.77 mmol) and 2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Step 3) (396 mg, 1.0 mmol) in 1,4-dioxane (6 mL), and the mixture was degassed by nitrogen sparging for 10 minutes. Pd(tBu3P)2 (39 mg, 0.08 mmol) was added and heated at 50 °C for 1 hour. The resulting mixture was cooled to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water (30 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica chromatography eluting with 1% MeOH / DCM gave a yellow gummy foam which was dissolved in Et2O and concentrated to give the title compound as a yellow solid. LC-MS (Method 3B): Rt2.21 min; MS m / z471.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.78(t,J=1.8Hz,1H),7.68(dd,J=7.8,1.8Hz,2H),7.50(t,J=7.8Hz,1H),7.47(s,2H),7.06(d,J=1.7Hz,1H),7 .01(d,J=1.7Hz,1H),6.99-6.94(m,2H),6.85-6.81(m,2H),4.09(s,2H),3.75(s,3H),2.44(s,3H),1.43(s,6H).

[0468] Intermediate K 3-[2-amino-5-(2-methoxy-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile [ka] The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. LC-MS (Method 3B): Rt1.81 min; MS m / z321.2=[MH]- 1H NMR(500MHz,DMSO-d6)δ 7.82(s,1H),7.79(d,J=7.7Hz,1H),7.67(d,J=8.1Hz,1H),7.54(t,J=7.8 Hz,1H),7.46(s,2H),6.60(s,1H),6.29(s,1H),3.34(s,3H),2.29(s,3H).

[0469] Intermediate KA 3-[2-amino-5-(2-cyano-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile [ka] The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile. LC-MS (Method 3B): Rt1.53 min; MS m / z318.0=[MH]+ 1H NMR(500MHz,DMSO-d6)δ 7.86(s,1H),7.85(s,1H),7.69(s,2H),7.67(s,1H),7.57(t,J=7.8Hz,1H),7.47(s,1H),7.32(s,1H),2.42(s,3H).

[0470] Intermediate KB 3-[2-amino-5-[2-(fluoromethyl)-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile [ka] Step 1: 4-Bromo-2-(fluoromethyl)-6-methyl-pyridine [ka] To a solution of (4-bromo-6-methyl-2-pyridyl)methanol (500 mg, 2.47 mmol) in DCM (5 mL) was added diethylaminosulfur trifluoride (0.36 mL, 2.72 mmol) dropwise at −40° C. The mixture was stirred at −40° C. for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with DCM (5 mL), water (5 mL), and saturated NaHCO solution (5 mL). The layers were separated, and the aqueous layer was further extracted with DCM (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried over NaSO, and the solvent was removed in vacuo. Purification by silica chromatography eluting with a gradient of 1–20% EtOAc / petroleum ether afforded the title compound as a white solid. LC-MS (Method 3B): Rt1.66 min; MS m / z204.0 / 205.9=[M+H]+ 1H NMR (500 MHz, chloroform-d) δ 7.50-7.42 (m, 1H), 7.31-7.29 (m, 1H), 5.42 (d, J = 46.6 Hz, 2H), 2.52 (s, 3H).

[0471] Step 2: 2-(fluoromethyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] A mixture of 4-bromo-2-(fluoromethyl)-6-methyl-pyridine (Step 1) (370 mg, 1.81 mmol), bis(pinacolato)diboron (553 mg, 2.18 mmol), and AcOK (534 mg, 5.44 mmol) in 1,4-dioxane (10 mL) was degassed under nitrogen for 10 minutes. Pd(dppf)C l2(133 mg, 0.18 mmol) was added and the flask was purged and backfilled with nitrogen (×3). The reaction mixture was stirred at 95° C. for 16 h and then cooled to room temperature. The resulting mixture was diluted with EtOAc (50 mL) and filtered through Celite® (filter material), eluting with EtOAc. The filtrate was concentrated in vacuo to give the title compound as a brown oil. 1H NMR(500MHz,DMSO-d6)δ 7.93(s,1H),7.45(d,J=11.9Hz,1H),5.44(d,J=47.1Hz,2H),3.57(s,3H),1.31(s,12H).

[0472] Step 3: 3-[2-amino-5-[2-(fluoromethyl)-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 2-(fluoromethyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Step 2). LC-MS (Method 3B): Rt1.56 min; MS m / z325.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.84-7.79(m,2H),7.68(dt,J=8.0,1.4Hz,1H),7.56-7.51(m,3H),6.98(d,J=15.9Hz,2H),5.32(d,J=46.9Hz,2H),2.38(s,3H).

[0473] Intermediate KC 3-[2-amino-5-(2-cyclopropyl-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile [ka] The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 2-cyclopropyl-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. LC-MS (Method 3B): Rt1.33 min; MS m / z333.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.81(t,J=1.5Hz,1H),7.79(dt,J=7.7,1.5Hz,1H),7.67(dt,J=8.0,1.5Hz,1H),7.54(apr t,J=7.8Hz,1H),7.44(s,2H),6.76(d,J=1.6Hz,1H),6.75(d,J=1.6Hz,1H),2. 28(s,3H),1.92(tt,J=8.1,4.8Hz,1H),0.87-0.83(m,2H),0.79-0.74(m,2H).

[0474] Intermediate KD 3-[2-amino-5-(2-isopropyl-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile [ka] The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 2-isopropyl-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. LC-MS (Method 5B): Rt2.86 min; MS m / z335.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.80(dd,J=7.8,1.5Hz,1H),7.77(d,J=1.8Hz,1H),7.71(dt,J=7.9,1.5Hz,1H),7.55(t,J=7.8Hz,1H),7. 45(s,2H),6.89(d,J=1.6Hz,1H),6.68(d,J=1.5Hz,1H),3.92(s,3H),2.79(h,J=6.8Hz,1H),1.05(s,6H).

[0475] Intermediate KE 3-[2-amino-5-(2-ethyl-6-methyl-4-pyridyl)thiazol-4-yl]benzonitrile [ka] The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 2-ethyl-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. LC-MS (Method 5B): Rt2.64 min; MS m / z321.1=[M+H]+ 1H NMR(500MHz,CDCl3)δ 7.86(t,J=1.5Hz,1H),7.66(dt,J=7.9,1.5Hz,1H),7.59(dt,J=7.7,1.5Hz,1H),7.38(apr t,J=7.8Hz,1H),6.82(s,1H),6.76(s,1H),5.10-4.98(m,2H),2.70(q,J=7.6Hz,2H),2.47(s,3H),1.18(t,J=7.6Hz,3H).

[0476] Intermediate KF 3-[2-amino-5-(2,6-dichloro-4-pyridyl)thiazol-4-yl]benzonitrile [ka] The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. LC-MS (Method 5B): Rt3.10 min; MS m / z346.9=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.91(s,1H),7.87(d,J=7.8Hz,1H),7.77(s,2H),7.74(d,J=7.8Hz,1H),7.59(t,J=7.8Hz,1H),7.15(s,2H).

[0477] Intermediate KG N-[4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-6-methyl-2-pyridyl]acetamide [ka] Step 1: N-(4-bromo-6-methyl-2-pyridyl)acetamide [ka] Triethylamine (0.45 mL, 3.23 mmol) and acetic anhydride (0.75 mL, 7.94 mmol) were added to a stirred solution of 4-bromo-6-methyl-pyridin-2-amine (550 mg, 2.94 mmol) in THF (20 mL) and heated to 50 °C for 22 h, followed by reflux for 2 h. The resulting mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and saturated NaHCO solution (100 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 100 mL). The combined organic extracts were dried over MgSO and concentrated in vacuo to give an off-white solid. The solid was dry-loaded onto silica and purified by silica chromatography eluting with a gradient of 0–8% MeOH to give the title compound as a white solid. LC-MS (Method 5A): Rt2.28 min; MS m / z228.9 / 230.9=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 10.66(s,1H),8.13(d,J=1.6Hz,1H),7.25(d,J=1.6Hz,1H),2.39(s,3H),2.07(s,3H).

[0478] Step 2: N-[6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]acetamide [ka] The title compound was prepared from N-(4-bromo-6-methyl-2-pyridyl)acetamide (Step 1) and bis(pinacolato)diboron in analogy to Step 2 of Intermediate KB. 1H NMR (500 MHz, chloroform-d) δ 9.12 (s, 1H), 8.39 (s, 1H), 7.27 (s, 1H), 2.49 (s, 3H), 2.21 (s, 3H), 1.32 (s, 12H).

[0479] Step 3: N-[4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-6-methyl-2-pyridyl]acetamide The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and N-[6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridyl]acetamide (Step 2). LC-MS (Method 5B): Rt2.29 min; MS m / z350.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 10.41(s,1H),7.81(d,J=1.7Hz,1H),7.80-7.74(m,2H),7.69(ddd,J=7.8,1.7,1.5Hz,1 H),7.52(t,J=7.8Hz,1H),7.45(s,2H),6.69(d,J=1.5Hz,1H),2.29(s,3H),2.01(s,3H).

[0480] Intermediate KH N-[[4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-6-methyl-2-pyridyl]methyl]acetamide [ka] Step 1: N-[(4-bromo-6-methyl-2-pyridyl)methyl]acetamide [ka] Triethylamine (0.52 mL, 4.08 mmol) and acetic anhydride (0.46 mL, 4.89 mmol) were added to a stirred solution of (4-bromo-6-methyl-2-pyridyl)methanamine (410 mg, 2.04 mmol) in DCM (15 mL) at 0 °C. The solution was warmed to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo to give an orange residue, which was diluted with water (10 mL). The solution was partitioned between saturated NaHCO3 solution (20 mL) and EtOAc (20 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 0–60% EtOAc / DCM afforded the title compound as a white solid. LC-MS (Method 3B): Rt1.28 min; MS m / z245.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 8.44(t,J=6.1Hz,1H),7.44(d,J=1.7Hz,1H),7.28(d,J=1.7Hz,1H),4.28(d,J=6.0Hz,2H),2.44(s,3H),1.91(s,3H).

[0481] Step 2: N-[[6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]methyl]acetamide [ka] The title compound was prepared from N-[(4-bromo-6-methyl-2-pyridyl)methyl]acetamide (Step 1) and bis(pinacolato)diboron in a manner analogous to Step 2 of Intermediate KB. 1H NMR(500MHz,DMSO-d6)δ 8.44(t,J=6.0Hz,1H),7.32(s,1H),7.27(s,1H),4.30(d,J=6.0Hz,2H),2.46(s,3H),1.89(s,3H),1.30(s,12H).

[0482] Step 3: N-[[4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-6-methyl-2-pyridyl]methyl]acetamide The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and N-[[6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridyl]methyl]acetamide (Step 2). LC-MS (Method 2B): Rt1.07 min; MS m / z364.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 8.26(t,J=6.0Hz,1H),7.84-7.77(m,2H),7.65(dt,J=8.0,1.5Hz,1H),7.53(d,J=7.8Hz,1H),7.48(s ,2H),6.90(d,J=1.5Hz,1H),6.75(d,J=1.6Hz,1H),4.17(d,J=6.0Hz,2H),2.37(s,3H),1.75(s,3H).

[0483] Intermediate KI 3-[2-amino-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile [ka] Step 1: 4-Bromo-2-(methoxymethyl)-6-methyl-pyridine [ka] MeI (0.18 mL, 2.97 mmol) was added dropwise to a stirred solution of (4-bromo-6-methyl-2-pyridyl)methanol (300 mg, 1.48 mmol) and KOH (167 mg, 2.97 mmol), and the mixture was stirred at room temperature for 16 h. Further MeI (0.18 mL, 2.97 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with EtOAc (20 mL), washed with brine (3 × 20 mL), dried over NaSO, and concentrated in vacuo to give the title compound as a brown oil. LC-MS (Method 3B): Rt1.62 min; MS m / z218.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.48(d,J=1.8Hz,1H),7.40(d,J=1.7Hz,1H),4.45(s,2H),3.36(s,3H),2.45(s,3H).

[0484] Step 2: 2-(methoxymethyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] The title compound was prepared from 4-bromo-2-(methoxymethyl)-6-methyl-pyridine (step 1) and bis(pinacolato)diboron in analogy to step 2 of intermediate KB. 1H NMR(500MHz,DMSO-d6)δ 7.41(s,1H),7.34(s,1H),4.45(d,J=4.3Hz,2H),3.36(s,3H),2.45(d,J=6.7Hz,3H),1.31(s,12H).

[0485] Step 3: 3-[2-amino-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazol-4-yl]benzonitrile The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 2-(methoxymethyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Step 2). LC-MS (Method 3B): Rt1.50 min; MS m / z337.5=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.83-7.78(m,2H),7.70(dt,J=7.9,1.5Hz,1H),7.55(t,J=7.8Hz,1H),7.49(s,2H), 6.94(d,J=1.7Hz,1H),6.88(d,J=1.7Hz,1H),4.35(s,2H),3.21(s,3H),2.37(s,3H).

[0486] Intermediate L 3-[2-amino-5-[2-methyl-6-(oxetan-3-yl)-4-pyridyl]thiazol-4-yl]benzonitrile [ka] The title compound was prepared in analogy to Intermediate C from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) and 2-methyl-6-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. LC-MS (Method 2B): Rt1.22 min; MS m / z349.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.83-7.81(m,1H),7.80(dt,J=7.6,1.4Hz,1H),7.68(dt,J=8.0,1.4Hz,1H),7.54(apr t,J=7.8Hz,1H),7.48(s,2H),6.92(d,J=1.6Hz,1H),6.84(d,J=1.6Hz,1H),4.78(dd,J= 8.5,5.6Hz,2H),4.62(dd,J=6.8,5.6Hz,2H),4.22(tt,J=8.5,6.8Hz,1H),2.40(s,3H).

[0487] Intermediate M 3-[2-amino-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-4-yl]benzonitrile [ka] A mixture of 4-bromo-3-fluoro-2,6-dimethyl-pyridine (100 mg, 0.36 mmol), bis(pinacolato)diboron (181 mg, 0.71 mmol), and AcOK (193 mg, 1.96 mmol) in 1,4-dioxane (6 mL) was degassed under a nitrogen flow. Pd(dppf)Cl (47 mg, 0.06 mmol) was added, and the reaction was heated to 100 °C overnight. The resulting mixture was cooled to room temperature, filtered, and washed with DCM (2 × 5 mL). The filtrate was concentrated in vacuo, and the boronate was taken up in 1,4-dioxane (2.5 mL) and water (0.5 mL). 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) (100 mg, 0.36 mmol) and K2CO3 (197 mg, 1.43 mmol) were added and the mixture was degassed under a flow of nitrogen. Bis(tri-tert-butylphosphine)palladium(0) (18 mg, 0.04 mmol) was added and the reaction mixture was heated to 80° C. for 45 min. After cooling to room temperature, the resulting mixture was concentrated in vacuo and purified by silica chromatography eluting with a gradient of 0-3% MeOH / DCM to give the title compound as a brown solid. LC-MS (Method 3B): Rt1.55 min; MS m / z325.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.80(s,1H),7.77(d,J=7.7Hz,1H),7.62(d,J=8.0Hz,1H),7.56-7.47(m,3H),6.99(d,J=5.0Hz,1H),2.39-2.30(m,6H).

[0488] Intermediate N( 3-[2-amino-5-[2,6-bis(trideuteriomethyl)-4-pyridyl]thiazol-4-yl]benzonitrile [ka] Step 1: 2,6-Bis(trideuteriomethyl)pyridine [ka] 2,6-Dichloropyridine (5.0 g, 33.79 mmol) and NiCl(dppp) (916 mg, 1.69 mmol) were placed under nitrogen, and anhydrous THF (68 mL) was added via syringe. The mixture was cooled to 0 °C and treated dropwise over 20 min with a solution of methyl-d-magnesium iodide (1 M, in EtO) (100 mL, 100 mmol). The reaction mixture was stirred and heated to reflux for 1.5 h and cooled to room temperature. The reaction was quenched by the careful addition of MeOH (15 mL), followed by 1 M aqueous HCl (125 mL). The resulting biphasic mixture was stirred vigorously for 5 min until all solids were dissolved and effervescence had completely ceased. The mixture was diluted with EtO (125 mL), and the layers were separated. The organic layer was extracted with water (125 mL), and the combined aqueous layers were adjusted to pH 10 with 10% aqueous NaOH, after which the mixture was extracted with EtOAc (2 × 300 mL), and the combined organic extracts were washed with brine (200 mL), dried over NaSO, and carefully concentrated at 35-38 °C and 170-190 mbar, followed by brief concentration at 40 °C and 100 mbar to give the crude material as a pale orange-brown oil. The oil was purified by reduced pressure distillation (120-140 °C at rough vacuum) to give the title compound as a clear, colorless oil. LC-MS (Method 2B): Rt1.05 min; MS m / z114.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.54(t,J=7.6Hz,1H),7.02(d,J=7.6Hz,2H)

[0489] Step 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-bis(trideuteriomethyl)pyridine [ka] Methoxy(cyclooctadiene)iridium(I) dimer (789 mg, 1.19 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (639 mg, 2.38 mmol), and bis(pinacolato)diboron (10.07 g, 39.67 mmol) were placed in a sealed flask, which was then evacuated and backfilled with nitrogen (three cycles). Freshly deoxygenated anhydrous cyclohexane (50 mL) was added via syringe, and the resulting mixture was sonicated briefly to dissolve most of the solids and form a deep reddish-brown solution. The mixture was stirred vigorously at room temperature for 1 hour, and then a solution of 2,6-bis(trideuteriomethyl)pyridine (Step 1) (4.49 g, 39.67 mmol) in deoxygenated anhydrous cyclohexane (50 mL) was added via syringe under nitrogen. The resulting mixture was stirred at room temperature for 19.5 hours, then additional bis(pinacolato)diboron (2.01 g, 7.93 mmol) in deoxygenated anhydrous cyclohexane (10 mL) was added via syringe under nitrogen. After the mixture was stirred at room temperature for 2 hours, additional methoxy(cyclooctadiene)iridium(I) dimer (263 mg, 0.40 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (213 mg, 0.79 mmol) were added. Stirring was continued at room temperature under nitrogen for an additional 17.5 hours, after which the mixture was concentrated in vacuo to give the title compound as a dark brown solid. LC-MS (Method 2B): Rt0.92 min; MS m / z240.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.22(s,2H),1.29(s,12H).

[0490] Step 3: 3-[2-amino-5-[2,6-bis(trideuteriomethyl)-4-pyridyl]thiazol-4-yl]benzonitrile A solution of K2CO3 (10.74 g, 77.68 mmol) in water (60 mL) was added to a solution of 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate B) (8.7 g, 31.07 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-bis(trideuteriomethyl)pyridine (Step 2) (8.92 g, 37.29 mmol) in 1,4-dioxane (240 mL), and the reaction mixture was deoxygenated by nitrogen sparging for 10 min. Pd(tBu3P)2 (1.59 g, 3.11 mmol) was added, the flask was sealed, and the flask was evacuated and backfilled with nitrogen (three cycles). The reaction mixture was stirred at 50 °C for 1 h and then cooled to room temperature. The resulting mixture was diluted with EtOAc (500 mL), washed with water (250 mL), brine (250 mL), dried over NaSO, and concentrated in vacuo. The crude material was redissolved in approximately 9:1 chloroform / MeOH (250 mL) and passed through a brief, pre-wetted plug of Celite® (filter material), eluting with chloroform. The filtrate was concentrated in vacuo to give a dark brown residue, which was triturated in a 5:2 mixture of EtO / DCM (70 mL) under sonication. The resulting solid was filtered, washed with DCM (5 × 10 mL), and dried in vacuo to give the title compound as a cream-colored solid. LC-MS (Method 2B): Rt1.29 min; MS m / z313.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.81(br t,J=1.5Hz,1H),7.79(br dt,J=7.6,1.5Hz,1H),7.66(br dt,J=7.9,1.5Hz,1H),7.52(apr t,J=7.8Hz,1H),7.48-7.39(m,2H),6.80(s,2H).

[0491] Intermediate O 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazol-4-yl]-2-methyl-benzonitrile [ka] Step 1: 3-(2-aminothiazol-4-yl)-2-methyl-benzonitrile [ka] Bis(tri-tert-butylphosphine)palladium(0) (29 mg, 0.06 mmol) was added to a degassed solution of 4-bromothiazol-2-amine (100 mg, 0.56 mmol), (3-cyano-2-methyl-phenyl)boronic acid (180 mg, 1.12 mmol), and potassium carbonate (154 mg, 1.12 mmol) in 1,4-dioxane (4 mL) and water (0.8 mL). The flask was evacuated and filled with nitrogen (×3), and the reaction mixture was stirred at 80 °C overnight. The resulting mixture was cooled to room temperature and partitioned between EtOAc and 70% brine. The organic layer was separated, washed with 70% brine, dried over Na SO , and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 2–5% MeOH / DCM gave a brown solid, which ...

Claims

1. A compound having structural formula I shown below, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, R ｘ is methyl, CD ３ , chloro and CF ３ Selected from: R １ is (1-3C) alkyl, halo, (1-3C) haloalkyl, (1-3C) haloalkoxy, (1-3C) hydroxyalkyl, cyano, cyclopropyl, oxetan-3-yl, -(CR １Ｃ R １Ｄ ) ｑ１ -OR １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -C(O)R １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -C(O)OR １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -OC(O)R １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -C(O)N(R １Ｂ ) R １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -N(R １Ｂ ) C(O)R １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -S(O) ｐ R １Ａ (wherein p is 0, 1 or 2), (CR １Ｃ R １Ｄ ) ｑ１ -SO ２ N (R １Ｂ ) R １Ａ , or -(CR １Ｃ R １Ｄ ) ｑ１ -N(R １Ｂ ) SO ２ R １Ａ Selected from (wherein q1 is 0, 1 or 2; R １Ａ and R １Ｂ are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; R １Ｃ and R １Ｄ are each independently selected from hydrogen or (1-2C)alkyl; R ２ and R ３ are all hydrogen, or R ２ and R ３ one of which is hydrogen and the other is selected from fluoro, methyl or methoxy; R ４ and R ５ together with the nitrogen atom to which they are attached, form one or more R １０Ｃ are linked to form a heterocycle which may be substituted on any available carbon atom by a substituent; (where R １０Ｃ is an oxo, thioxo, halo, or cyano substituent, or a group of the formula: -[CR ７ａ R ７ｂ ] ｎ -L-Z is selected from the group (In the formula, n is 0 to 6; R ７ａ and R ７ｂ are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L is absent or is —O—, —S—, —SO—, or —SO ２ -, -N(R ａ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ ) -, -N(R ａ )C(O)-,-N(R ａ )C(O)N(R ｂ )-, -C(S)N(R ａ ) -, -N(R ａ )C(S)-,-N(R ａ ) C(S)N(R ｂ ) -, -S(O) ２ N (R ａ )- or -N(R ａ ) SO ２ - (wherein R ａ and R ｂ are each independently selected from hydrogen or (1-2C)alkyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl, or heteroaryl(1-2C)alkyl; Z is (1-6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, nitro, —NR ｃ R ｄ , -OR ｃ , -C(O)R ｃ , -C(O)OR ｃ , -OC(O)R ｃ , -C(O)N(R ｃ ) R ｄ , -N(R ｃ ) C(O)R ｄ , -S(O) ｙ R ｃ (wherein y is 0, 1 or 2), -SO ２ N (R ｃ ) R ｄ , -N(R ｃ ) SO ２ R ｄ , -(CH ２ ) ｚ NR ｃ R ｄ (wherein z is 1, 2 or 3) or oxo; The alkyl portion of the substituent on Z may be further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C) alkyl or (1-2C) alkoxy; R ｃ and R ｄ are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl; and wherein any available N atom, even in the form of an N-oxide, is bonded to one or more R １０Ｎ may be replaced by (where R １０Ｎ is -S(O) ２ NH ２ or (i)-Z １ ; (ii)-L １ａ -Z １ or (iii)-[CR ８ａ R ８ｂ ] １～６ -L １ｂ -Z １ Selected from (In the formula, R8a and R8b are each independently selected from hydrogen, fluoro, or (1-2C) alkyl; L １ａ is -C(O)-, -S(O) ２ -, -C(O)O-, -C(O)N(R ａ１ ) -, -S(O) ２ N (R ａ１ )- or N(R ａ１ )—wherein R ａ１ is selected from hydrogen or (1-2C) alkyl; L １ｂ is absent or is —O—, —S—, —SO—, —SO ２ -, -N(R ａ２ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ２ ) -, -N(R ａ２ )C(O)-,-N(R ａ２ )C(O)N(R ｂ２ )-, -C(S)N(R ａ２ ) -, -N(R ａ２ )C(S)-,-N(R ａ２ ) C(S)N(R ｂ２ ) -, -S(O) ２ N (R ａ２ )- or -N(R ａ２ ) SO ２ where R ａ２ and R ｂ２ are each independently selected from hydrogen or (1-2C)alkyl; Z １ is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclyl(1-2C)alkyl or heteroaryl(1-2C)alkyl, with the proviso that Z １ is a heterocyclyl group directly linked to an N atom, then it is a carbon-linked heterocyclyl); Z １ is (1-6C) alkyl, halo, (1-6C) haloalkoxy, cyano, nitro, —NR ｅ R ｆ , -OR ｅ , -C(O)R ｅ , -C(O)OR ｅ , -OC(O)R ｅ , -C(O)N(R ｅ ) R ｆ , -N(R ｅ ) C(O)R ｆ , -S(O) ｙ R ｅ (wherein y is 0, 1 or 2), -SO ２ N (R ｅ ) R ｆ , -N(R ｅ ) SO ２ R ｆ , -(CH ２ ) ｚ NR ｅ R ｆ (wherein z is 1, 2 or 3) or oxo; ｅ and R ｆ are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl; In addition, in the formula, any S atom present in the heterocycle may be S(=O), S(=O) ２ or S(=O)(=NR ｅ ) (where R ｅ may be present as hydrogen, (1-3C) alkyl or (2-3C) alkanoyl; R ６ is selected from hydrogen, halo, methyl, methoxy and trifluoromethyl.

2. R ｘ is methyl or CD ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from:

3. R １ is (1-3C) alkyl, halo, (1-3C) haloalkyl, (1-3C) haloalkoxy, (1-3C) hydroxyalkyl, cyano, cyclopropyl, oxetan-3-yl, -(CH ２ ) ｑ１ -OR １Ａ and -(CH ２ ) ｑ１ -C(O)R １Ａ Selected from: q1 is 0 or 1; R １Ａ is selected from hydrogen or (1-2C) alkyl; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R １ is methyl, CD ３ , isopropyl, halo, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxetan-3-yl, -OMe, -CH ２ F, -CHF ２ or CF ３ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from:

5. R ２ and R ３ are all hydrogen, or R ２ and R ３ The compound according to any one of claims 1 to 4, wherein one of is hydrogen and the other is fluoro or methyl, or a pharmaceutically acceptable salt thereof.

6. R ２ and R ３ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each of

7. R ４ and R ５ together with the nitrogen atom to which they are attached, form one or more R １０Ｃ are linked to form a heterocycle which may be substituted on any available carbon atom with a substituent; Here, R １０Ｃ is an oxo, halo, or cyano substituent, or a group of the formula: -[CH ２ ] ｎ -L-Z is selected from the group (In the ceremony n is 0 to 2; L is absent or is —O—, —S—, —SO—, or —SO ２ -, -N(R ａ２ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ２ ) -, -N(R ａ２ )C(O)-,-N(R ａ２ )C(O)N(R ｂ２ ) -, -S(O) ２ N (R ａ２ )- or -N(R ａ２ ) SO ２ - (wherein R ａ２ and R ｂ２ are each independently selected from hydrogen or methyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, heterocyclyl, or heteroaryl; Z is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, —NR ｃ R ｄ , -OR ｃ , -C(O)R ｃ , -C(O)OR ｃ , -OC(O)R ｃ , -C(O)N(R ｃ ) R ｄ , -N(R ｃ ) C(O)R ｄ , -S(O) ｙ R ｃ (wherein y is 0, 1 or 2), -SO ２ N (R ｃ ) R ｄ , -N(R ｃ ) SO ２ R ｄ , -(CH ２ ) ｚ NR ｃ R ｄ (wherein z is 1 or 2) or oxo; Z １ The alkyl portion of any of the above substituents may be further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C) alkyl, or (1-2C) alkoxy; R ｃ and R ｄ are each independently selected from hydrogen, (1-2C)alkyl, (1-2C)haloalkyl, or (3-6C)cycloalkyl; and any available N atom, even in the form of an N-oxide, may be bonded to one or more R １０Ｎ where R １０Ｎ Ha-S(O) ２ NH ２ or: (i)-Z １ ; (ii)-L １ａ -Z １ or (iii)-[CR ８ａ R ８ｂ ] １～２ -L １ｂ -Z １ Selected from (In the formula, R8a and R8b are both hydrogen; L １ａ is -C(O)-, -S(O) ２ - or S(O) ２ N (R ａ１ )—wherein R ａ１ is hydrogen or methyl); L １ｂ is absent or is —O—, —S—, —SO—, —SO ２ -, -N(R ａ２ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ２ ) -, -N(R ａ２ )C(O)-,-N(R ａ２ )C(O)N(R ｂ２ ) -, -S(O) ２ N (R ａ２ )- or -N(R ａ２ ) SO ２ where R ａ２ and R ｂ２ are each independently selected from hydrogen or methyl; Z １ is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl or aryl(1-2C)alkyl, provided that Z １ is a heterocyclyl group directly linked to an N atom, then it is a carbon-linked heterocyclyl); Z １ is (1-2C) alkyl, halo, (1-2C) haloalkoxy, cyano, nitro, —NR ｅ R ｆ , -OR ｅ , -C(O)R ｅ , -C(O)OR ｅ , -OC(O)R ｅ , -C(O)N(R ｅ ) R ｆ , -N(R ｅ ) C(O)R ｆ , -S(O) ｙ R ｅ (wherein y is 0, 1 or 2), -SO ２ N (R ｅ ) R ｆ , -N(R ｅ ) SO ２ R ｆ , -(CH ２ ) ｚ NR ｅ R ｆ (wherein z is 1, 2 or 3) or oxo; ｅ and R ｆ are each independently selected from hydrogen or (1-2C) alkyl; And any S atom present in the heterocycle may be S(=O), S(=O) ２ or S(=O)(=NR ｅ ) (where R ｅ is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. R ４ and R ５ together with the nitrogen atom to which they are attached, form one or more R １０Ｃ are linked to form a heterocycle which may be substituted on any available carbon atom with a substituent; Here, R １０Ｃ is an oxo, halo, or cyano substituent, or a group of the formula: -[CH ２ ] ｎ -L-Z is selected from the group (In the ceremony n is 0 to 2; L is absent or is —O—, —S—, —SO—, or —SO ２ -, -N(R ａ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ ) -, -N(R ａ )C(O)-,-S(O) ２ N (R ａ )- or -N(R ａ ) SO ２ where R ａ and R ｂ is hydrogen); Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 4- to 7-membered heterocyclyl, or 5- or 6-membered heteroarylalkyl; Z is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, —NR ｃ R ｄ , -OR ｃ , -C(O)R ｃ , -C(O)N(R ｃ ) R ｄ , -N(R ｃ ) C(O)R ｄ or -S(O) ｙ R ｃ (wherein y is 0, 1 or 2) or oxo; R ｃ and R ｄ are each independently selected from hydrogen or (1-2C) alkyl; and any available N atom, even in the form of an N-oxide, may be bonded to one or more R １０Ｎ where R １０Ｎ Ha-S(O) ２ NH ２ or: (i)-Z １ ; (ii)-L １ａ -Z １ or (iii)-[CR ８ａ R ８ｂ ] １～２ -L １ｂ -Z １ Selected from (In the formula, R8a and R8b are both hydrogen; L １ａ is -C(O)-, -S(O) ２ - or S(O) ２ N (R ａ１ )—wherein R ａ１ is hydrogen); L １ｂ is absent or is —O—, —S—, —SO—, —SO ２ -, -N(R ａ２ )-, -C(O)N(R ａ２ ) -, -N(R ａ２ )C(O)-,-S(O) ２ N (R ａ２ )- or -N(R ａ２ ) SO ２ where R ａ２ is hydrogen); Z １ is selected from (1-4C) alkyl, phenyl, 4- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl, provided that Z １ is a heterocyclyl group directly linked to an N atom, then it is a carbon-linked heterocyclyl); Z １ is (1-2C) alkyl, halo, (1-2C) haloalkoxy, cyano, —NR ｅ R ｆ , -OR ｅ , -C(O)R ｅ , -C(O)N(R ｅ ) R ｆ , -N(R ｅ ) C(O)R ｆ , -S(O) ｙ R ｅ (wherein y is 0, 1 or 2); R ｅ and R ｆ are each independently selected from hydrogen or methyl); And any S atom present in the heterocycle may be S(=O), S(=O) ２ or S(=O)(=NR ｅ ) (where R ｅ is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. R ４ and R ５ together with the nitrogen atom to which they are attached, form one or more R １０Ｃ are linked to form a heterocycle, optionally substituted on any available carbon atom by a substituent, where R １０Ｃ is selected from oxo, halo, cyano, (1-4C)alkyl or (3-6C)cycloalkyl; and any available N atom, even in the form of an N-oxide, may be bonded to one or more R １０Ｎ where R １０Ｎ is -S(O) ２ NH ２ or (1-4C) alkyl): And any S atom present in the heterocycle may be S(=O), S(=O) ２ or S(=O)(=NR ｅ ) (where R ｅ is selected from hydrogen, methyl or (2C)alkanoyl; The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. R ４ and R ５ are linked together with the nitrogen atom to which they are attached to form a heterocycle selected from any one of the following options: 【Chemistry 2】 (In the formula, ＊ is R ４ and R ５ indicates the N atom to which Q １ is O, NH, S, S(O), S(O) ２ , S(O)(=NR ｅ ), N-R １０Ｎ , C.H. ２ , CHR １０Ｃ or C(R １０Ｃ ) ２ and Q ２ is -CH ２ --, --CHR １０Ｃ -, -C(R １０Ｃ ) ２ --, --CHR １０Ｃ -CH ２ -, -CH ２ -CHR １０Ｃ --, --CHR １０Ｃ -CHR １０Ｃ -, -C(R １０Ｃ ) ２ -CH ２ - or -CH ２ -C(R １０Ｃ ) ２ - and; Q ３ , CH, CR １０Ｃ or N; Ring A is a spiro-fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; Ring B is a fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; Here, R ｅ is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; Each heterocyclic ring system may comprise one or more R as defined in any one of claims 1, 6, 7 or 8. １０Ｃ or R １０Ｎ optionally substituted with a substituent), The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. R ４ and R ５ are linked together with the nitrogen atom to which they are attached to form a heterocycle selected from any one of the following options: 【Transformation 3】 (In the formula, ＊ is R ４ and R ５ indicates the N atom to which Q １ is O, NH, S, S(O), S(O) ２ , S(O)(=NR ｅ ), N-R １０Ｎ , C.H. ２ , CHR １０Ｃ or C(R １０Ｃ ) ２ and Q ２ is -CH ２ - and; Here, R ｅ is selected from hydrogen, methyl or (2C)alkanoyl; R １０Ｃ or R １０Ｎ is as defined in any one of claims 1, 6, 7 or 8), The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R ４ and R ５ together with the nitrogen atom to which they are attached, form the structure: 【Chemistry 4】 (In the formula, ＊ is R ４ and R ５ represents the N atom to which each R １０Ｃ are independently selected from the alternatives defined in any one of claims 1, 6, 7 or 8 above. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

13. R ６ The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen, halo, or methyl.

14. R ６ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

15. A compound of formula IA, IB or IC: 【Transformation 5】 (In the formula, R ｘ , R １ , R ２ , R ３ , R ４ , R ５ and R ６ are each as defined in any one of claims 1 to 12).

16. A compound selected from any one of the following, or a pharmaceutically acceptable salt thereof: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]piperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]pyrrolidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-(2-hydroxy-2-methyl-propyl)pyrrolidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide (2S)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-hydroxy-4-methyl-piperidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-cyano-4-methyl-piperidine-1-carboxamide (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-piperazine-1-carboxamide N4-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]morpholine-2,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-3-oxo-piperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide 4-acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methylsulfonyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-sulfamoyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methoxy-piperidine-1-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(hydroxymethyl)azetidine-1-carboxamide 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,1-dioxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxy-azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-hydroxyethyl)-3-oxo-piperazine-1-carboxamide 4,4-dicyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-hydroxy-2-methyl-propyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-methyl-1,7-diazaspiro[3.4]octane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-hydroxy-1,1-dimethyl-ethyl)piperazine-1-carboxamide (8aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxamide (8aR)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxy-pyrrolidine-1-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(methoxymethyl)piperidine-1-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-fluoro-piperidine-1-carboxamide (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxy-3-methyl-azetidine-1-carboxamide (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylic acid Methyl (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]carbamoyl]piperazine-2-carboxylate (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide (1S,4S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (3R)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]piperazine-1,3-dicarboxamide (3S)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]piperazine-1,3-dicarboxamide 4-amino-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (1R,4R)-5-acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (1S,4S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-2-oxo-1,3,8-triazospiro[4.5]decane-8-carboxamide N-[5-[2,6-bis(trideuteriomethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-9-methyl-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxo-1,3,8-triazospiro[4.5]decane-8-carboxamide 3-cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetan-3-yl)-4-pyridyl]thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetan-3-yl)-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-morpholino-azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-tetrahydropyran-4-yl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-pyrrolidin-1-yl-azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(dimethylamino)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(morpholinomethyl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,4-diazabicyclo[3.2.1]octane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,2-dioxo-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]thiazine-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-oxo-3,6,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-9-oxo-3,4,6,7,8,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-1,3,4,8,9,9a-hexahydropyrazino[1,2-c][1,3]oxazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-sulfamoyl-pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-pyrazol-1-yl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(1,2,4-oxazol-3-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazine-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(1H-imidazol-2-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-N4-methyl-piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-8-oxa-2-azaspiro[4.5]decane-2-carboxamide (3S)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]pyrrolidine-1,3-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(2-oxoimidazolidin-1-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(1,2,4-oxazol-5-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-methylimino-1-oxo-1,4-thiazinane-4-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-N4-(2-hydroxyethyl)piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-7-oxa-2,5-diazaspiro[3.5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6,9-dioxo-1,3,4,7,8,9a-hexahydropyrazino[1,2-a]pyrazine-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-oxo-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-8-methyl-6,9-dioxo-3,4,7,9a-tetrahydro-1H-pyrazino[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-2,9-diazaspiro[5.5]undecane-9-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-(1-hydroxy-1-methyl-ethyl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrazino[1,2-c]pyrimidine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,2-dioxo-2λ^{6}-thia-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide (3aR,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrole-5-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxo-3-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide (1S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-methyl-3,6-diazabicyclo[3.2.2]nonane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-methyl-2-oxo-1,3,8-triazospiro[4.5]decane-8-carboxamide (3aS,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-7-oxa-2-azaspiro[3.5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-2,7-diazaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxo-2,5,7-triazospiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-ethyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]piperidine-4-carboxylic acid (3S)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(hydroxymethyl)azetidine-1-carboxamide (3R)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid 4-cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-hydroxy-3-methyl-azetidine-1-carboxamide 3-cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-azetidine-1-carboxamide 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]carbamoyl]azetidine-3-carboxylic acid (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-azetidine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)azetidine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-morpholine-4-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-azetidine-1-carboxamide N-[4-(3-cyano-2-methyl-phenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (3R)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]pyrrolidine-1,3-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-7-azaspiro[4.4]nonane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-oxa-7-azaspiro[3.4]octane-7-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azetidine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-morpholino-pyrrolidine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-5-oxo-piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxa-1-azaspiro[3.3]heptane-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1,3-dimethyl-2-oxo-1,3,8-triazospiro[4.5]decane-8-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-5-oxo-piperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-methyl-5-oxo-2,6-diazaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-methyl-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methylsulfonyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-hydroxy-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (4aR,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide 4-amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxamide cis-(2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,6-dimethyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2,2-dimethyl-piperazine-1-carboxamide 1-acetylamino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]piperidine-1-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamide 4,4-dicyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]piperidine-1-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methoxy-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide 1-cyanoimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,5-dimethyl-piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(trifluoromethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-(trifluoromethyl)piperazine-1-carboxamide (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4,7-diazaspiro[2.5]octane-7-carboxamide (3S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,5-dimethyl-piperazine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-piperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-methyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-3-methyl-piperazine-1-carboxamide (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-cyclopropyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3,3-dimethyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl)thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dichloro-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetan-3-yl)-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[5-(2-cyano-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(fluoromethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2-cyclopropyl-6-methyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2-isopropyl-6-methyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2-ethyl-6-methyl-4-pyridyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide 4-cyano-N-[4-(3-cyano-2-methyl-phenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide N-[5-(2-acetamido-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[5-[2-(acetamidomethyl)-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-methoxyethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[5-[2-chloro-6-(1-hydroxy-1-methyl-ethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazol-2-yl]-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide N-[5-[2,6-bis(trideuteriomethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazol-2-yl]-4-cyano-4-methyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-[(1S)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide (3S)-3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use in therapy.

19. A pharmaceutical composition comprising the compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, (i) treatment of cell proliferative conditions; (ii) the treatment of cancer; (iii) the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents; (iv) the treatment of cancer, wherein said compound or pharmaceutical composition is 1) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents; 2) adenosine pathway modulators; 3) anti-PD-1 and PDL-1 antibodies; and 4) Anti-CTLA4 antibody and (iii) administering the compound in combination with one or more additional anti-cancer agents selected from the group consisting of: A pharmaceutical composition for use in

20. 20. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cell proliferative disorder.

21. 20. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

22. 20. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in combination with one or more additional anti-cancer agents, in the manufacture of a medicament for the treatment of a cell proliferative disorder.

23. the one or more additional anti-cancer agents 1) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents; 2) adenosine pathway modulators; 3) anti-PD-1 and PDL-1 antibodies; and 4) Anti-CTLA4 antibody 23. The use according to claim 22, wherein the compound is selected from the group consisting of:

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