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 as defined in the application. The 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 associated with adenosine A2a and / or A2b receptor activity, such as for example cancer.

Description

[0001] introduction

[0002] This invention relates to certain compounds used as adenosine A2a receptor antagonists. Additionally, some of these compounds are also antagonists of both A2a and A2b receptors. The invention also relates to methods for preparing these compounds, pharmaceutical compositions comprising them, and their use in the treatment of diseases or conditions related to adenosine A2a and / or A2b receptor activity, such as, for example, cancer. Background Technology

[0003] Many immunosuppressive pathways are active in the tumor microenvironment, enabling tumor cells to evade elimination by cytotoxic T cells and reducing clinical response to anti-checkpoint antibody immunotherapy. Anti-PD-1 antibodies pembrolizumab and nivolumab, as well as anti-PD-L1 antibodies durvalumab, avelumab, and atezolizumab, are approved for the treatment of various 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 side effects of such treatments are significant (Sukari et al., 2016). Therefore, other approaches to enhance the cytotoxic potential of the tumor microenvironment are being actively investigated. This includes agents that can be used as monotherapy, or agents that are more likely to be used in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy.

[0004] One approach of interest is to interfere with the production and / or function 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 estimate adenosine concentrations in human tumors to be approximately 10 μM, compared to <1 μM in normal tissues (Houthuys et al., 2017). Adenosine is formed at intracellular and extracellular sites through two distinct pathways involving two different substrates. Intracellular adenosine originates from AMP and S-adenosine homocysteine, while the high extracellular adenosine concentrations observed during metabolic stress are associated with the release and degradation of precursor adenine nucleotides (ATP, ADP, and AMP) via the synergistic action of CD39 and CD73 (Vijayan et al., 2017).

[0005] In response to hypoxia, CD39 and CD73 are upregulated in the tumor microenvironment. CD73 represents a putative approach to patient stratification 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 contributes to an unfavorable immunosuppressive phenotype in the tumor microenvironment (Gao et al., 2014; Loi et al., 2013). CD73 expression on tumor-infiltrating immune cells is also important for promoting tumor immunosuppression, as CD73-negative Treg cells fail to suppress effector T cell function (Deaglio et al., 2007; Reinhardt et al., 2017). Furthermore, CD73 levels are elevated in patients resistant to anti-PD1 therapy (Reinhardt et al., 2017).

[0006] Adenosine regulates cellular function by occupying specific GPCRs on the cell surface of the P1 purine receptor subtype. The P1 receptor family is further subdivided into A1, A2a, A2b, and A3.

[0007] The A2 receptor is further subdivided into A2a and A2b based on its high and low affinity for adenosine, respectively. A2a is expressed by lymphocytes, and activation of A2a leads to the inhibition of cytokine production and other effector functions. In syngeneic mouse models, gene ablation of A2a inhibits tumor growth, and this effect has been shown to be due to enhanced lymphocyte activation and cytotoxicity (Ohta et al., 2006; Waickman et al., 2012; Beavis et al., 2013; Mittal et al., 2014; Cekic et al., 2014). A2a- / - mice show enhanced responses to checkpoint pathway (e.g., PD-1) inhibition, with improved disease-free survival and overall survival. Adenosine-mediated A2a activation also limits the efficacy of anti-CTLA4 therapy (Iannone et al., 2014).

[0008] The effects of A2a gene deficiency in mouse models are modeled through pharmacological blockade of A2a. A2a antagonists have been shown to enhance cytotoxic CD8+ T cells and improve 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).

[0009] These findings spurred the development of selective A2a antagonists for cancer immunotherapy, and clinical trials of CPI-444 are underway. CPI-444 is the first selective A2a antagonist evaluated in cancer, both as monotherapy and in combination with the anti-PDL1 antibody atezolizumab. Preliminary data indicate that the compound is well-tolerated and shows early signs of shrinking tumor size and enhancing CD8+ T cell infiltration into tumor tissue.

[0010] Adenosine A2b receptors also play a crucial role in cancer progression by modulating the tumor microenvironment. A2b is expressed by bone marrow-derived cells, and high concentrations of adenosine found in the tumor microenvironment can alter the behavior of tumor-associated macrophages, bone marrow-derived suppressor cells, and dendritic cells. Activation of A2b leads to polarization of immunosuppressive M2 macrophages (Csoka et al., 2012), formation of bone marrow-derived suppressor cells (Rhyzov et al., 2011), and promotes immunosuppressive and pro-angiogenic phenotypes in 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), and is associated with reduced MDSC infiltration and VEGF production (Sorrentino et al., 2015; Iannone et al., 2013).

[0011] Therefore, dual inhibition of A2a and A2b is an attractive approach to reduce immunosuppression within the tumor microenvironment to inhibit growth. Summary of the Invention

[0012] According to a first aspect of the invention, a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof is provided.

[0013] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, mixed with a pharmaceutically acceptable diluent or carrier.

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

[0015] According to another aspect of the invention, a method is provided for selectively antagonizing adenosine A2a receptors, or A2a and A2b receptors, in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0016] According to another aspect of the invention, a method for inhibiting cell proliferation in vitro or in vivo is provided, the method comprising contacting cells 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 antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0017] According to another aspect of the invention, there is provided a method for treating a patient in need of such treatment with a disease or disorder related to adenosine A2a and / or A2b receptor activity, the method 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.

[0018] According to another aspect of the invention, a method for treating a patient requiring such treatment for a proliferative disorder is provided, the method 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0019] According to another aspect of the invention, a method for treating cancer in a patient requiring such treatment is provided, the method 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0020] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions thereof, are provided for use in therapy.

[0021] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, are provided for use in the treatment of proliferative disorders. Suitably, the compounds or pharmaceutical compositions are administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0022] According to another aspect of the invention, compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, are provided for use in the treatment of cancer. In a specific embodiment, the cancer is human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0023] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided for use as adenosine A2a and / or A2b antagonists. In embodiments, the compounds of the invention are selective adenosine A2a and A2b antagonists.

[0024] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided for use in the treatment of diseases or disorders associated with adenosine A2a and / or A2b.

[0025] According to another aspect of the invention, use is provided in the manufacture of a medicament for treating proliferative disorders, in the form of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvation thereof. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0026] According to another aspect of the invention, use is provided in the manufacture of a medicament for treating cancer, as defined herein, of a compound or a pharmaceutically acceptable salt, hydrate, or solvation thereof. Suitably, the cancer is human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0027] According to another aspect of the invention, 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 is provided.

[0028] According to another aspect of the invention, the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the manufacture of a medicament for treating diseases or disorders associated with adenosine A2a is provided.

[0029] According to another aspect of the invention, a method is provided for preparing compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0030] According to another aspect of the invention, there are provided compounds or pharmaceutically acceptable salts, hydrates or solvates thereof that are obtainable by, or obtained by, or directly obtained by, methods of preparation of compounds as defined herein.

[0031] According to another aspect of the invention, novel intermediates as defined herein are provided that are suitable for any of the synthetic methods described herein.

[0032] Features relating to one aspect of the invention (including optional, suitable, and preferred features) can also be features relating to any other aspect of the invention (including optional, suitable, and preferred features). Detailed Implementation

[0033] definition

[0034] Unless otherwise stated, the following terms used in the specification and claims have the same meanings as stated below.

[0035] It should be understood that the term “treating” as used here includes prevention and relief of established symptoms of a condition. “Treating” of a state, disorder, or symptom includes: (1) preventing or delaying the onset of clinical symptoms of a state, disorder, or symptom that develops in a person who may have or is susceptible to the state, disorder, or symptom but has not yet experienced or shown clinical or subclinical symptoms of the state, disorder, or symptom; (2) suppressing the state, disorder, or symptom, i.e., preventing, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance therapy) or at least one of its clinical or subclinical symptoms; or (3) alleviating or slowing the disease, i.e. causing the disappearance of the state, disorder, or symptom or at least one of its clinical or subclinical symptoms.

[0036] "Therapeutic effective dose" refers to the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to achieve the desired therapeutic effect. The "therapeutic effective dose" varies depending on the compound, the disease and its severity, and the age and weight of the mammal being treated.

[0037] In this specification, the term "alkyl" includes both straight-chain and branched alkyl groups. References to a single alkyl group, such as "propyl," are specific only to the straight-chain form, and references to a single branched alkyl group, such as "isopropyl," are specific only to the branched form. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl. Similar convention applies to other groups; for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0038] The terms “(m-nC)” or “(m-nC) group” used alone or as a prefix refer to any group having m to n carbon atoms.

[0039] "alkylene", "alkenylene", or "alkynylene" groups are alkyl, alkenyl, or alkynyl groups located between two other chemical groups and used to connect these two other chemical groups. Therefore, "(1-6C)alkylene" means a straight-chain saturated divalent hydrocarbon group having one to six carbon atoms or a branched saturated divalent hydrocarbon group having three to six carbon atoms, such as methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc.

[0040] "(2-6C)-olefin" refers to a straight-chain divalent hydrocarbon group with two to six carbon atoms containing at least one double bond, or a branched divalent hydrocarbon group with three to six carbon atoms, such as vinylidene, 2,4-pentadienylidene, etc.

[0041] "(2-6C)-ynyl" refers to a straight-chain divalent hydrocarbon group with two to six carbon atoms containing at least one triple bond, or a branched divalent hydrocarbon group with three to six carbon atoms, such as ynylene, ynylene, and ynylene.

[0042] “(3-8C)cycloalkyl” means a hydrocarbon ring containing 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclic [2.2.1]heptyl.

[0043] "(3-8C)cycloalkenyl" refers to a hydrocarbon ring containing at least one double bond, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl (e.g., 3-cyclohexen-1-yl) or cyclooctenyl.

[0044] "(3-8C)cycloalkyl-(1-6C)alkylene" means a (3-8C)cycloalkyl group covalently attached to a (1-6C)alkylene group, both of which are defined herein.

[0045] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0046] The terms "heterocyclic group," "heterocyclic," or "heterocyclic" refer to one or more non-aromatic, saturated or partially saturated monocyclic, fused, bridged, or spirobicyclic heterocyclic systems. Monocyclic heterocycles contain about 3 to 12 (suitably 3 to 7) ring atoms, with 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocycles contain 7 to 17 member atoms, suitably 7 to 12 member atoms. One or more bicyclic heterocycles can be fused, spirocyclic, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as ethylene oxide, oxetyl, tetrahydrofuranyl, dioxyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, aziridine, pyrrolidinyl, piperidinyl, piperazine, tetrahydrotriazine, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiaran, and hexahydrothiophene. (hexahydrothiepine). Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, sulfur oxide heterocycles containing SO or SO2 groups are also included. Examples include tetrahydrothiophene and thiomorpholinyl in sulfoxide and sulfone forms, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for heterocyclic groups with one or two oxo (=O) or thio (=S) substituents are, for example, 2-oxopyrrolyl, 2-thiopyrrolyl, 2-oxoimidazoyl, 2-thioimidazoyl, 2-oxopyridinyl, 2,5-dioxopyrrolyl, 2,5-dioxoimidazoyl, or 2,6-dioxopyridinyl. Specific heterocyclic groups are saturated monocyclic 3- to 7-membered heterocyclic groups containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur, such as azobutyryl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, morpholinyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazine, or homopiperazine. As those skilled in the art will understand, any heterocycle can be attached to another group via any suitable atom (such as via a carbon or nitrogen atom). However, the references to piperidinium or morpholinium herein refer to piperidin-1-yl or morpholin-4-yl rings linked via a cyclic nitrogen atom.

[0047] "Bridged ring system" refers to a ring system in which two rings share more than two atoms. See, for example, *Advanced Organic Chemistry*, edited by Jerry March, 4th edition, Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclic ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, and quinine rings.

[0048] A "spirobicyclic system" refers to a system in which two rings share a common spirocarbon atom, meaning that a heterocycle is connected to another carbon ring or heterocycle through a single common spirocarbon atom. Examples of spirocyclic 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.

[0049] "Heterocyclic (1-6C)alkyl" means a heterocyclic group covalently attached to a (1-6C)alkylene group, both of which are defined herein.

[0050] The term "heteroaryl" or "heteroaromatic" refers to a monocyclic, bicyclic, or polycyclic aromatic group containing 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 substances. Examples of heteroaryls are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members. Heteroaryls can be, for example, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic, such as a bicyclic structure formed by fused 5- and 6-membered rings or two fused 6-membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group (including any amino substituent in the ring) will be less than five.

[0051] Examples of heteroaryl groups include furanyl, pyrroleyl, thiophenyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenoyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, benzothiazolyl, indolyl, purinyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxolinyl, and quinoxolinyl. The terms "heteroaryl" also encompass partially aromatic bicyclic or polycyclic systems, wherein at least one ring is an aromatic ring and one or more other rings are non-aromatic, saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of some aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxacyclopentenyl, 2,2-dioxo-1,3-dihydro-2-benzothiophene, 4,5,6,7-tetrahydrobenzofuranyl, dihydroindolyl, 1,2,3,4-tetrahydro-1,8-naphthidyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl.

[0052] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, furazonyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0053] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl.

[0054] The bicyclic heteroaryl group can be, for example, selected from the following groups:

[0055] A benzene ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

[0056] A pyridine ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

[0057] A pyrimidine ring fused with a 5- or 6-membered ring containing one or two heteroatoms;

[0058] Pyrrole rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0059] A pyrazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0060] Pyrazine rings fused with 5- or 6-membered rings containing 1 or 2 heteroatoms;

[0061] Imidazole rings fused with 5- or 6-membered rings containing 1 or 2 heteroatoms;

[0062] Oxazole rings fused with 5- or 6-membered rings containing 1 or 2 heteroatoms;

[0063] An isoxazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0064] Thiazole rings fused with 5- or 6-membered rings containing 1 or 2 heteroatoms;

[0065] An isothiazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0066] Thiophene rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0067] Furan rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0068] Cyclohexyl rings fused with 5- or 6-membered heteroaromatic rings containing 1, 2, or 3 cyclic heteroatoms; and

[0069] A cyclopentyl ring fused with a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms.

[0070] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused with a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, inazinyl, dihydroindolyl, isodihydroindolyl, purine (e.g., adenine, guanine), indolyl, benzodioxanepentenyl, and pyrazolopyridyl.

[0071] Specific 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, benzodioxane, quinazinyl, benzooxazinyl, benzodiazinyl, pyridinylpyridinyl, quinoxolinyl, quinazolinyl, terolinyl, phthalazinyl, naphthidyl, and pteridinyl.

[0072] "Heteroaryl(1-6C)alkyl" refers to a heteroaryl group covalently attached to a (1-6C)alkylene group, both of which are defined herein. Examples of heteroaryl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, etc.

[0073] The term "aryl" refers to a ring or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent substances. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In a specific embodiment, the aryl group is phenyl.

[0074] The term “aryl(1-6C)alkyl” refers to an aryl group covalently attached to a (1-6C)alkylene group, both of which are defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, etc.

[0075] This specification also uses several compound terms to describe groups containing more than one functionality. Such terms will be understood by those skilled in the art. For example, heterocyclic (m-nC) alkyl includes (m-nC) alkyl groups substituted with heterocyclic groups.

[0076] The term "optionally substituted" refers to both the substituted group, structure, or molecule and the unsubstituted group, structure, or molecule. The term "wherein R..." 1 "One or any CH, CH2, CH3 group or heteroatom (i.e., NH) within the group is optionally substituted" appropriately means R 1 Any one of the hydrogen groups in the group is replaced by a group specified in the relevant regulations.

[0077] When the optional substituent is selected from "one or more" groups, it should be understood that the definition includes all substituents selected from one of the specified groups or substituents selected from two or more specified groups.

[0078] The phrase “compounds of the present invention” means those compounds disclosed herein, both generally and specifically.

[0079] The compounds of the present invention

[0080] In a first aspect, the present invention relates to compounds having the following structural formula I, or pharmaceutically acceptable salts, hydrates, or solvates thereof:

[0081]

[0082] in:

[0083] R x Selected from methyl, CD3, chlorine and CF3;

[0084] R1 is selected from (1-3C)alkyl, halogen, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C) hydroxyalkyl, cyano, cyclopropyl, oxetane-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 (where 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 ,

[0085] Where q1 is 0, 1, or 2; and

[0086] Where R 1A and R 1B Each is independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl;

[0087] Where R 1C and R 1D Each is independently selected from hydrogen or (1-2C) alkyl;

[0088] R2 and R3 are both hydrogen, or one of R2 and R3 is hydrogen and the other is selected from fluorine, methyl or methoxy.

[0089] The R4 and R5 connections allow them to form, together with the attached nitrogen atom, on any available carbon atom, optionally bounded by one or more R atoms. 10C Heterocyclic compounds with substituents

[0090] Where R 10C Selected from oxo groups, thio groups, halogens, or cyano substituents, or groups having the following formula:

[0091] –[CR 7a R 7b ] n –L–Z

[0092] in

[0093] n is between 0 and 6;

[0094] R 7a and R 7b Each is independently selected from hydrogen, fluorine, or (1-2C)alkyl;

[0095] L does not exist or is selected from -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 Each is independently selected from hydrogen or (1-2C)alkyl; and

[0096] Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclic, heterocyclic(1-2C)alkyl, heteroaryl or heteroaryl(1-2C)alkyl; and wherein Z is optionally substituted by one or more substituents selected from: (1-6C)alkyl, halogen, (1-6C) haloalkyl, (1-6C) haloalkoxy, cyano, nitro, -NR c R d -ORc -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 (where y is 0, 1, or 2), -SO2N(R) c )R d -N(R) c SO2R d -(CH2) z NR c R d (where z is 1, 2, or 3) or an oxo group,

[0097] Any alkyl moiety in the substituents on Z is optionally further substituted with a cyano, halogen, hydroxyl, amino, oxo, (1-2C)alkyl, or (1-2C)alkoxy group, and R c and R d Each is independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl;

[0098] And any available N atoms therein are optionally in the form of N-oxides or optionally surrounded by one or more R atoms. 10N replace,

[0099] Where R 10N It is -S(O)2NH2 or selected from:

[0100] (i)–Z1;

[0101] (ii)–L 1a –Z1; or

[0102] (iii)–[CR 8a R 8b ] 1-6 –L 1b –Z1;

[0103] in

[0104] R 2a and R 2b Each is independently selected from hydrogen, fluorine, or (1-2C)alkyl;

[0105] L 1a Selected from -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R) a1 )-、-S(O)2N(Ra1 - or -N(R) a1 )-, where R a1 Selected from hydrogen or (1-2C) alkyl;

[0106] L 1b It does not exist or is selected from -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 Each is independently selected from hydrogen or (1-2C)alkyl; and

[0107] Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclic, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclic(1-2C)alkyl, or heteroaryl(1-2C)alkyl, provided that when Z1 is a heterocyclic group directly attached to the N atom, it is a carbon-linked heterocyclic group; and wherein Z1 is optionally substituted by one or more substituents selected from: (1-6C)alkyl, halogen, (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 (where y is 0, 1, or 2), -SO2N(R) e )R f -N(R) e SO2R f -(CH2) z NR e R f(where z is 1, 2, or 3) or an oxo group, and where R e and R f Each is independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl;

[0108] Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen, (1-3C)alkyl, or (2-3C)alkanoyl; and

[0109] R6 is selected from hydrogen, halogen, methyl, methoxy, and trifluoromethyl.

[0110] In a second aspect, the present invention relates to compounds having the following structural formula I' (a sub-definition of formula I) or pharmaceutically acceptable salts, hydrates or solvates thereof:

[0111]

[0112] in:

[0113] R1 is selected from (1-2C)alkyl, halogen, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, and -(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 (where p is 0, 1, or 2), -(CH2) q1 -SO2N(R 1B )R 1A or -(CH2) q1 -N(R 1B SO2R 1A ,

[0114] Where q1 is 0, 1, or 2; and

[0115] Where R1A and R 1B Each is independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl;

[0116] R2 and R3 are both hydrogen, or one of R2 and R3 is hydrogen and the other is selected from fluorine, methyl or methoxy.

[0117] The R4 and R5 connections allow them to form, together with the attached nitrogen atom, on any available carbon atom, optionally bounded by one or more R atoms. 10C Heterocyclic compounds with substituents

[0118] Where R 10C Selected from oxo groups, thio groups, halogens, or cyano substituents, or groups having the following formula:

[0119] –[CR 7a R 7b ] n –L–Z

[0120] in

[0121] n is between 0 and 6;

[0122] R 7a and R 7b Each is independently selected from hydrogen, fluorine, or (1-2C)alkyl;

[0123] L does not exist or is selected from -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 Each is independently selected from hydrogen or (1-2C)alkyl; and

[0124] Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclic, heterocyclic(1-2C)alkyl, heteroaryl or heteroaryl(1-2C)alkyl; and wherein Z is optionally substituted by one or more substituents selected from: (1-6C)alkyl, halogen, (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 (where y is 0, 1, or 2), -SO2N(R) c )R d -N(R) c SO2R d -(CH2) z NR c R d (where z is 1, 2, or 3) or an oxo group,

[0125] Any alkyl moiety in the substituents on Z is optionally further substituted with a cyano, halogen, hydroxyl, amino, oxo, (1-2C)alkyl, or (1-2C)alkoxy group, and R c and R d Each is independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl;

[0126] And any available N atoms therein are optionally in the form of N-oxides or optionally surrounded by one or more R atoms. 10N replace,

[0127] Where R 10N It is -S(O)2NH2 or selected from:

[0128] (i)–Z1;

[0129] (ii)–L 1a –Z1; or

[0130] (iii)–[CR 8a R 8b ] 1-6 –L 1b –Z1;

[0131] in

[0132] R 2a and R 2b Each is independently selected from hydrogen, fluorine, or (1-2C)alkyl;

[0133] L 1a Selected from -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R) a1 )-、-S(O)2N(R a1 - or -N(R) a1 )-, where R a1 Selected from hydrogen or (1-2C) alkyl;

[0134] L 1b It does not exist or is selected from -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 Each is independently selected from hydrogen or (1-2C)alkyl; and

[0135] Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclic, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclic(1-2C)alkyl, or heteroaryl(1-2C)alkyl, provided that when Z1 is a heterocyclic group directly attached to the N atom, it is a carbon-linked heterocyclic group; and wherein Z1 is optionally substituted by one or more substituents selected from: (1-6C)alkyl, halogen, (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 (where y is 0, 1, or 2), -SO2N(R) e )R f -N(R) e SO2R f -(CH2) z NR e R f (where z is 1, 2, or 3) or an oxo group, and where R e and R f Each is independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl;

[0136] Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen, (1-3C)alkyl, or (2-3C)alkanoyl; and

[0137] R6 is selected from hydrogen, halogen, methyl, methoxy, and trifluoromethyl.

[0138] Specific compounds of the present invention include, for example, compounds having Formula I or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise specified, R x Each of R1, R2, R3, R4, R5, and R6 has any meaning as defined above or in any of the following paragraphs (1) to (32):

[0139] (1) R1 is selected from (1-2C)alkyl, halogen, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, -(CH2). q1 -OR 1A and -(CH2) q1 -C(O)R 1A ;

[0140] Where q1 is 0 or 1; and

[0141] Where R 1A Selected from hydrogen or (1-2C) alkyl;

[0142] (1a) R1 is selected from (1-3C)alkyl, halogen, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxetane-3-yl, -(CH2). q1 -OR 1A and -(CH2) q1 -C(O)R1A ;

[0143] Where q1 is 0 or 1; and

[0144] Where R 1A Selected from hydrogen or (1-2C) alkyl;

[0145] (2) R1 is selected from (1-2C)alkyl, halogen, (1-2C)haloalkyl and -C(O)R 1A ;

[0146] Where R 1A Selected from hydrogen or methyl;

[0147] (2a) R1 is selected from (1-3C)alkyl, halogen, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C) hydroxyalkyl, cyano, cyclopropyl, oxetane-3-yl and -OR 1A ;

[0148] (3) R1 is selected from methyl, halogen and -CF3;

[0149] (3a) R1 is selected from methyl, CD3, isopropyl, halogen, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxetane-3-yl, -OMe, -CH2F, -CHF2 and -CF3;

[0150] (3b) R1 is selected from methyl, CD3, isopropyl, halogen, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxetane-3-yl, -OMe, CHF2 and -CF3;

[0151] (4) R1 is selected from methyl and halogen;

[0152] (4a) R1 is selected from methyl, CD3, isopropyl, hydroxymethyl, 2-hydroxyisopropyl, cyclopropyl, oxetane-3-yl and halogen;

[0153] (5) R1 is selected from methyl, fluorine or chlorine;

[0154] (6) R1 is selected from methyl or chlorine;

[0155] (7) R1 is a methyl group;

[0156] (7a) R1 is a methyl group or CD3;

[0157] (8) R1 is chlorine;

[0158] (8a) R1 is CD3;

[0159] (8b) R1 is isopropyl;

[0160] (8c)R1 is hydroxymethyl;

[0161] (8d)R1 is 2-hydroxyisopropyl;

[0162] (8e)R1 is cyclopropyl;

[0163] (8f)R1 is an oxetane-3-yl group

[0164] (9) Both R2 and R3 are hydrogen, or one of R2 and R3 is hydrogen and the other is fluorine or methyl;

[0165] (10) Both R2 and R3 are hydrogen;

[0166] (11) The connection of R4 and R5 allows them to form, together with the nitrogen atom to which they are attached, on any available carbon atom, optionally by one or more R... 10C Substituent-substituted heterocycles, wherein R 10C Selected from oxo groups, thio groups, halogens, or cyano substituents, or groups having the following formula:

[0167] –[CH2] n –L–Z

[0168] in

[0169] n is between 0 and 4;

[0170] L does not exist or is selected from -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 Each is independently selected from hydrogen or (1-2C)alkyl; and

[0171] Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclic, heterocyclic(1-2C)alkyl, heteroaryl or heteroaryl(1-2C)alkyl; and wherein Z is optionally substituted by one or more substituents selected from: (1-4C)alkyl, halogen, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, nitro, -NR c R d -OR c -C(O)R c -C(O)ORc -OC(O)R c -C(O)N(R) c )R d -N(R) c )C(O)R d -S(O) y R c (where y is 0, 1, or 2), -SO2N(R) c )R d -N(R) c SO2R d -(CH2) z NR c R d (where z is 1, 2, or 3) or an oxo group,

[0172] Any alkyl moiety in the substituents on Z is optionally further substituted with a cyano, halogen, hydroxyl, amino, oxo, (1-2C)alkyl, or (1-2C)alkoxy group, and R c and R d Each is independently selected from hydrogen, (1-4C)alkyl, (1-4C)haloalkyl, or (3-6C)cycloalkyl;

[0173] And any available N atoms therein are optionally in the form of N-oxides or optionally surrounded by one or more R atoms. 10N Replace, where R 10N It is -S(O)2NH2 or selected from:

[0174] (i)–Z1;

[0175] (ii)–L 1a –Z1; or

[0176] (iii)–[CR 8a R 8b ] 1-4 –L 1b –Z1;

[0177] in

[0178] R 2a and R 2b They are all hydrogen;

[0179] L 1a Selected from -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R) a1 )-or-S(O)2N(R a1 )-, where R a1 It is hydrogen or methyl;

[0180] L 1bIt does not exist or is selected from -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 Each is independently selected from hydrogen or methyl; and

[0181] Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclic, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclic(1-2C)alkyl, or heteroaryl(1-2C)alkyl, provided that when Z1 is a heterocyclic group directly attached to the N atom, it is a carbon-linked heterocyclic group; and wherein Z1 is optionally substituted by one or more substituents selected from: (1-4C)alkyl, halogen, (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 (where y is 0, 1, or 2), -SO2N(R) e )R f -N(R) e SO2R f -(CH2) z NR e R f (where z is 1, 2, or 3) or an oxo group, and where R e and R f Each is independently selected from hydrogen, (1-4C)alkyl, (1-4C)haloalkyl, or (3-6C)cycloalkyl;

[0182] Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen, (1-3C)alkyl, or (2-3C)alkylyl;

[0183] (12) The connection of R4 and R5 allows them to form, together with the nitrogen atom to which they are attached, on any available carbon atom, optionally by one or more R... 10C Substituent-substituted heterocycles, wherein R 10C Selected from oxo groups, halogens, or cyano substituents, or groups having the following formula:

[0184] –[CH2] n –L–Z

[0185] in

[0186] n is between 0 and 2;

[0187] L does not exist or is selected from -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 Each is independently selected from hydrogen or methyl; and

[0188] Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, heterocyclic, or heteroaryl; and wherein Z is optionally substituted by one or more substituents selected from: (1-2C)alkyl, halogen, (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(where y is 0, 1, or 2), -SO2N(R) c )R d -N(R) c SO2R d -(CH2) z NR c R d (where z is 1 or 2) or an oxo group;

[0189] Any alkyl moiety in the substituents on Z1 may optionally be further substituted with a cyano, halogen, hydroxyl, amino, oxo, (1-2C)alkyl, or (1-2C)alkoxy group, and R c and R d Each is independently selected from hydrogen, (1-2C)alkyl, (1-2C)haloalkyl, or (3-6C)cycloalkyl;

[0190] And any available N atoms therein are optionally in the form of N-oxides or optionally surrounded by one or more R atoms. 10N Replace, where R 10N It is -S(O)2NH2 or selected from:

[0191] (i)–Z1;

[0192] (ii)–L 1a –Z1; or

[0193] (iii)–[CR 8a R 8b ] 1-2 –L 1b –Z1;

[0194] in

[0195] R 2a and R 2b They are all hydrogen;

[0196] L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R) a1 )-, where R a1 It is hydrogen or methyl;

[0197] L 1b It does not exist or is selected from -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 Each is independently selected from hydrogen or methyl; and

[0198] Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclic, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, or aryl(1-2C)alkyl, provided that when Z1 is a heterocyclic group directly attached to the N atom, it is a carbon-linked heterocyclic group; and wherein Z1 is optionally substituted by one or more substituents selected from: (1-2C)alkyl, halogen, (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 (where y is 0, 1, or 2), -SO2N(R) e )R f -N(R) e SO2R f -(CH2) z NR e R f (where z is 1, 2, or 3) or an oxo group, and where R e and R f Each is independently selected from hydrogen or (1-2C) alkyl;

[0199] Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen, (1-3C)alkyl, or (2-3C)alkylyl;

[0200] (13) The R4 and R5 connections allow them to form, together with the nitrogen atom to which they are attached, on any available carbon atom, optionally by one or more R... 10C Substituent-substituted heterocycles, wherein R 10C Selected from oxo groups, halogens, or cyano substituents, or groups having the following formula:

[0201] –[CH2] n –L–Z

[0202] in

[0203] n is between 0 and 2;

[0204] L does not exist or is selected from -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 It is hydrogen; and

[0205] Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclic, or heteroaryl; and wherein Z is optionally substituted by one or more substituents selected from: (1-2C)alkyl, halogen, (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 (where y is 0, 1, or 2), -SO2N(R) c )R d -N(R) c SO2R d -(CH2) z NR c R d (where z is 1 or 2) or an oxo group;

[0206] Where R c and R d Each is independently selected from hydrogen, (1-2C)alkyl, or (1-2C)haloalkyl;

[0207] And any available N atoms therein are optionally in the form of N-oxides or optionally surrounded by one or more R atoms. 10N Replace, where R 10N It is -S(O)2NH2 or selected from:

[0208] (i)–Z1;

[0209] (ii)–L 1a –Z1; or

[0210] (iii)–[CR 8a R 8b ] 1-2 –L 1b –Z1;

[0211] in

[0212] R 2a and R 2b They are all hydrogen;

[0213] L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R) a1 )-, where R a1 It is hydrogen;

[0214] L 1b It does not exist or is selected from -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 It is hydrogen; and

[0215] Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclic, and heteroaryl, provided that when Z1 is a heterocyclic group directly attached to the N atom, it is a carbon-linked heterocyclic group; and wherein Z1 is optionally substituted by one or more substituents selected from: (1-2C)alkyl, halogen, (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 (where y is 0, 1, or 2), -SO2N(R) e )R f -N(R) e SO2R f-(CH2) z NR c R d (where z is 1 or 2); and where R e and R f Each is independently selected from hydrogen or methyl;

[0216] Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen, (1-2C)alkyl, or (2C)alkanoyl;

[0217] (14) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form on any available carbon atom, optionally by one or more R... 10C Heterocyclic compounds with substituents

[0218] Where R 10C Selected from oxo groups, halogens, or cyano groups, or groups having the following formula:

[0219] –[CH2] n –L–Z

[0220] in

[0221] n is between 0 and 2;

[0222] L does not exist or is selected from -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 It is hydrogen; and

[0223] Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 4-7-membered heterocyclic, or 5- or 6-membered heteroaryl; and wherein Z is optionally substituted by one or more substituents selected from: (1-2C)alkyl, halogen, (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 )Rd -N(R) c )C(O)R d -S(O) y R c (where y is 0, 1, or 2), -SO2N(R) c )R d -N(R) c SO2R d -(CH2) z NR c R d (where z is 1 or 2) or an oxo group;

[0224] Where R c and R d Each is independently selected from hydrogen or (1-2C) alkyl;

[0225] And any available N atoms therein are optionally in the form of N-oxides or optionally surrounded by one or more R atoms. 10N Replace, where R 10N It is -S(O)2NH2 or selected from:

[0226] (i)–Z1;

[0227] (ii)–L 1a –Z1; or

[0228] (iii)–[CR 8a R 8b ] 1-2 –L 1b –Z1;

[0229] in

[0230] R 2a and R 2b They are all hydrogen;

[0231] L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R) a1 )-, where R a1 It is hydrogen;

[0232] L 1b It does not exist or is selected from -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 It is hydrogen; and

[0233] Z1 is selected from (1-4C) alkyl, phenyl, 4-7-membered heterocyclic, or 5- or 6-membered heteroaryl, provided that when Z1 is a heterocyclic group directly attached to the N atom, it is a carbon-linked heterocyclic group; and wherein Z1 is optionally substituted by one or more substituents selected from: (1-2C) alkyl, halogen, (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 (where y is 0, 1, or 2), -SO2N(R) e )R f -N(R) e SO2R f -(CH2) z NR c R d (where z is 1 or 2); and where R e and R f Each is independently selected from hydrogen or methyl;

[0234] Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen, (1-2C)alkyl, or (2C)alkanoyl;

[0235] (15) The connection of R4 and R5 allows them to form, together with the nitrogen atom to which they are attached, on any available carbon atom, optionally by one or more R... 10C Substituent-substituted heterocycles, wherein R 10C Selected from oxo groups, halogens, or cyano substituents, or groups having the following formula:

[0236] –[CH2] n –L–Z

[0237] in

[0238] n is between 0 and 2;

[0239] L does not exist or is selected from -O-, -S-, -SO-, -SO2-, -N(R) a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(Ra )-、-N(R a C(O)-、-S(O)2N(R) a - or -N(R) a SO2-, where R a and R b It is hydrogen; and

[0240] Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 4-7-membered heterocyclic, or 5- or 6-membered heteroaryl; and wherein Z is optionally substituted by one or more substituents selected from: (1-2C)alkyl, halogen, (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 (where y is 0, 1, or 2) or an oxo group;

[0241] Where R c and R d Each is independently selected from hydrogen or (1-2C) alkyl;

[0242] And any available N atoms therein are optionally in the form of N-oxides or optionally surrounded by one or more R atoms. 10N Replace, where R 10N It is -S(O)2NH2 or selected from:

[0243] (i)–Z1;

[0244] (ii)–L 1a –Z1; or

[0245] (iii)–[CR 8a R 8b ] 1-2 –L 1b –Z1;

[0246] in

[0247] R 2a and R 2b They are all hydrogen;

[0248] L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R) a1 )-, where R a1 It is hydrogen;

[0249] L 1b It does not exist or is selected from -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 It is hydrogen; and

[0250] Z1 is selected from (1-4C) alkyl, phenyl, 4-7-membered heterocyclic, or 5- or 6-membered heteroaryl, provided that when Z1 is a heterocyclic group directly attached to the N atom, it is a carbon-linked heterocyclic group; and wherein Z1 is optionally substituted by one or more substituents selected from: (1-2C) alkyl, halogen, (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 (where y is 0, 1, or 2); and where R e and R f Each is independently selected from hydrogen or methyl;

[0251] Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen, methyl, or (2C) alkyl group;

[0252] (15a) The connection of R4 and R5 such that they, together with the nitrogen atom to which they are attached, form on any available carbon atom, optionally by one or more R... 10C Substituent-substituted heterocycles, wherein R 10C Selected from oxo groups, halogens, or cyano substituents, or groups having the following formula:

[0253] –[CH2] n –L–Z

[0254] in

[0255] n is between 0 and 2;

[0256] L does not exist or is selected from -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 It is hydrogen; and

[0257] Z is selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl; and wherein Z is optionally substituted by one or more substituents selected from: (1-2C)alkyl, halogen, (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 (where y is 0, 1, or 2) or an oxo group;

[0258] Where R c and R d Each is independently selected from hydrogen or (1-2C) alkyl;

[0259] And any available N atoms therein are optionally in the form of N-oxides or optionally surrounded by one or more R atoms. 10N Replace, where R 10N It is -S(O)2NH2 or selected from:

[0260] (i)–Z1;

[0261] (ii)–L 1a –Z1; or

[0262] (iii)–[CR 8a R 8b ] 1-2 –L 1b –Z1;

[0263] in

[0264] R 2a and R 2b They are all hydrogen;

[0265] L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R) a1)-, where R a1 It is hydrogen;

[0266] L 1b It does not exist or is selected from -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 It is hydrogen; and

[0267] Z1 is selected from (1-4C) alkyl, wherein Z1 is optionally substituted by one or more substituents selected from: (1-2C) alkyl, halogen, (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 (where y is 0, 1, or 2); and where R e and R f Each is independently selected from hydrogen or methyl;

[0268] Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen, methyl, or (2C) alkyl group;

[0269] (15b) The R4 and R5 connections cause them, together with the nitrogen atom to which they are attached, to form on any available carbon atom, optionally by one or more R... 10C Substituent-substituted heterocycles, wherein R 10C Selected from oxo groups, halogens, or cyano substituents, or groups having the following formula:

[0270] –L–Z

[0271] in

[0272] L does not exist or is selected from -O-, -S-, -SO-, -SO2-, -N(R) a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-、-N(R aC(O)-、-S(O)2N(R) a - or -N(R) a SO2-, where R a and R b It is hydrogen; and

[0273] Z is selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0274] And any available N atoms therein are optionally in the form of N-oxides or optionally surrounded by one or more R atoms. 10N Replace, where R 10N It is -S(O)2NH2 or (1-4C) alkyl.

[0275] Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen, methyl, or (2C) alkyl group;

[0276] (15c) The R4 and R5 connections cause them, together with the nitrogen atom to which they are attached, to form on any available carbon atom, optionally by one or more R... 10C Substituent-substituted heterocycles, wherein R 10C Selected from oxogroups, halogens, cyanogroups, (1-4C)alkyl groups, or (3-6C)cycloalkyl groups;

[0277] And any available N atoms therein are optionally in the form of N-oxides or optionally surrounded by one or more R atoms. 10N Replace, where R 10N It is -S(O)2NH2 or (1-4C) alkyl.

[0278] Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen, methyl, or (2C) alkyl group;

[0279] (16) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a 4- to 12-membered heterocycle, wherein the heterocycle is optionally connected by one or more R 10C Or R 10N Substituent substitution, where R 10C and R 10N It is as defined in any of the paragraphs (11) to (15c) above;

[0280] (17) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a 4- to 8-membered monocyclic or bridging heterocyclic or a 7- to 12-membered bicyclic or spirobicyclic heterocyclic, wherein the heterocyclic is optionally connected by one or more R 10C Or R 10N Substituent substitution, where R 10C and R 10N It is as defined in any of the paragraphs (11) to (15c) above;

[0281] (18) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a 4- to 7-membered monocyclic or bridging heterocyclic or a 7- to 11-membered bicyclic or spirobicyclic heterocyclic, wherein the heterocyclic is optionally connected by one or more R4 and R5. 10C Or R 10N Substituent substitution, where R 10C and R 10N It is as defined in any of the paragraphs (11) to (15c) above;

[0282] (19) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a 5- or 6-membered monocyclic heterocycle or a 7- to 10-membered bicyclic or spirobicyclic heterocycle, wherein the heterocycle is optionally connected by one or more R4 and R5. 10C Or R 10N Substituent substitution, where R 10C and R 10N It is as defined in any of the paragraphs (11) to (15c) above;

[0283] (20) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a heterocycle selected from any of the following options:

[0284]

[0285] The asterisk (*) indicates the N atom attached to R4 and R5;

[0286] Q1 is O, NH, S, S(O), S(O)2, S(O) (=NR) e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0287] 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-;

[0288] Q3 is CH, CR 10C Or N;

[0289] Ring A is a spiro-fused 4, 5, or 6-membered carbon ring or heterocycle;

[0290] Ring B is a fused 4, 5, or 6-membered carbon ring or heterocycle;

[0291] Where R e Selected from hydrogen or methyl;

[0292] Furthermore, each of the heterocyclic systems is optionally defined by one or more R as described in any of paragraphs (11) to (15c) above. 10c Or R 10N Substituent substitution;

[0293] (20a) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a heterocycle selected from any of the following options:

[0294]

[0295]

[0296] The asterisk (*) indicates the N atom attached to R4 and R5;

[0297] Q1 is O, NH, S, S(O), S(O)2, S(O) (=NR) e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0298] 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-;

[0299] Q3 is CH, CR 10C Or N;

[0300] Ring A is a spiro-fused 4, 5, or 6-membered carbon ring or heterocycle;

[0301] Ring B is a fused 4, 5, or 6-membered carbon ring or heterocycle;

[0302] Where R e Selected from hydrogen or methyl;

[0303] Furthermore, each of the heterocyclic systems is optionally defined by one or more R as described in any of paragraphs (11) to (15c) above. 10c Or R 10N Substituent substitution;

[0304] (21) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a heterocycle selected from any of the following options:

[0305]

[0306]

[0307] The asterisk (*) indicates the N atom attached to R4 and R5;

[0308] Q1 is O, NH, S, S(O), S(O)2, S(O) (=NR) e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0309] Q2 is -CH2-, -CHR 10C - or -C(R) 10c )2-;

[0310] Q3 is CH, CR 10C Or N;

[0311] Ring A is a spiro-fused 4, 5, or 6-membered carbon ring or heterocycle;

[0312] Ring B is a fused 4, 5, or 6-membered carbon ring or heterocycle;

[0313] Where R e Selected from hydrogen, (1-3C)alkyl, or (2-3C)alkylyl;

[0314] Furthermore, each of the heterocyclic systems is optionally defined by one or more R as described in any of paragraphs (11) to (15c) above. 10c Or R 10N Substituent substitution;

[0315] (21a) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a heterocycle selected from any of the following options:

[0316]

[0317]

[0318] The asterisk (*) indicates the N atom attached to R4 and R5;

[0319] Q1 is O, NH, S, S(O), S(O)2, S(O) (=NR) e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0320] Q2 is -CH2-, -CHR 10C - or -C(R) 10c )2-;

[0321] Q3 is CH, CR 10C Or N;

[0322] Ring A is a spiro-fused 4, 5, or 6-membered carbon ring or heterocycle;

[0323] Ring B is a fused 4, 5, or 6-membered carbon ring or heterocycle;

[0324] Where R e Selected from hydrogen, (1-3C)alkyl, or (2-3C)alkylyl;

[0325] Furthermore, each of the heterocyclic systems is optionally defined by one or more R as described in any of paragraphs (11) to (15c) above. 10c Or R 10N Substituent substitution;

[0326] (21b) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a heterocycle selected from any of the following options:

[0327]

[0328]

[0329] The asterisk (*) indicates the N atom attached to R4 and R5;

[0330] Q1 is O, NH, S, S(O), S(O)2, S(O) (=NR) e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0331] Q2 is -CH2-;

[0332] Q3 is CH, CR 10C Or N;

[0333] Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0334] Q5 is O, NH, S, S(O), S(O)2, S(O) (=NR) e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0335] Q6 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0336] Q7 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0337] Where R e Selected from hydrogen, (1-2C)alkyl, or (2C)alkanoyl;

[0338] Furthermore, each of the heterocyclic systems is optionally defined by one or more R as described in any of paragraphs (11) to (15c) above. 10c Or R 10N Substituent substitution;

[0339] (22) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a heterocycle selected from any of the following options:

[0340]

[0341] The asterisk (*) indicates the N atom attached to R4 and R5;

[0342] Q1 is O, NH, S, S(O), S(O)2, S(O) (=NR) e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0343] Q2 is -CH2-;

[0344] Q3 is CH, CR10C Or N;

[0345] Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0346] Q5 is O, NH, S, S(O), S(O)2, S(O) (=NR) e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0347] Q6 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0348] Q7 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0349] Where R e Selected from hydrogen, (1-2C)alkyl, or (2C)alkanoyl;

[0350] Furthermore, each of the heterocyclic systems is optionally defined by one or more R as described in any of paragraphs (11) to (15c) above. 10c Or R 10N Substituent substitution;

[0351] (22a) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a heterocycle selected from any of the following options:

[0352]

[0353] The asterisk (*) indicates the N atom attached to R4 and R5;

[0354] Q1 is O, NH, S, S(O), S(O)2, S(O) (=NR) e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0355] Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N CH2, CHR 10C or C(R) 10c )2;

[0356] Where R e Selected from hydrogen, (1-2C)alkyl, or (2C)alkanoyl;

[0357] Furthermore, each of the heterocyclic systems is optionally defined by one or more R as described in any of paragraphs (11) to (15c) above. 10c Or R 10N Substituent substitution;

[0358] (22b) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a heterocycle selected from any of the following options:

[0359]

[0360] The asterisk (*) indicates the N atom attached to R4 and R5;

[0361] Q1 is O, NH, NR 10N CH2, CHR 10C or C(R) 10c )2;

[0362] Q4 is O, NH, NR 10N CH2, CHR 10C or C(R) 10c )2;

[0363] Where R e Selected from hydrogen, methyl, or (2C) alkyl group;

[0364] And R 10c Or R 10N It is as defined in any of the paragraphs (11) to (15c) above;

[0365] (23) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a heterocycle selected from any of the following options:

[0366]

[0367] The asterisk (*) indicates the N atom attached to R4 and R5;

[0368] Q1 is O, NH, S, S(O), S(O)2, S(O) (=NR) e ), NR 10N CH2, CHR 10Cor C(R) 10c )2;

[0369] Q2 is -CH2-;

[0370] Where R e Selected from hydrogen, methyl, or (2C) alkyl group;

[0371] And R 10c Or R 10N It is as defined in any of the paragraphs (11) to (15c) above;

[0372] (24) The connection of R4 and R5 causes them, together with the nitrogen atom to which they are attached, to form a heterocycle with the following structure:

[0373]

[0374] The asterisk (*) indicates the N atom attached to R4 and R5;

[0375] And each R 10c Choose independently the option defined in any one of paragraphs (11) to (15c) above;

[0376] (25) R6 is selected from hydrogen, halogen or methyl;

[0377] (26) R6 is selected from hydrogen or methyl;

[0378] (27) R6 is hydrogen;

[0379] (28)R x Selected from methyl, CD3 or chlorine;

[0380] (29)R x Selected from methyl or CD3;

[0381] (30)R x It is methyl;

[0382] (31)R x It's CD3

[0383] (32)R x It is chlorine;

[0384] Suitablely, a heteroaryl or heterocyclic group as defined herein is a monocyclic heteroaryl or monocyclic, bicyclic, spirobicyclic or bridging heterocyclic group containing one, two or three heteroatoms selected from N, O or S.

[0385] Suitablely, a heteroaryl is a 5- or 6-membered heteroaryl ring containing one, two, or three heteroatoms selected from N, O, or S.

[0386] Suitablely, the heterocyclic group is a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclic ring containing one, two, or three heteroatoms selected from N, O, or S. Most suitablely, the heterocyclic group is a 5-, 6-, or 7-membered ring [e.g., morpholino (e.g., 4-morpholino), pyridino, piperazino, homopiperazino, or pyrrolidone] or a 7-, 8-, 9-, or 10-membered spirobicyclic system containing one, two, or three heteroatoms selected from N, O, or S.

[0387] Appropriately, the aryl group is phenyl.

[0388] Appropriately, R1 is defined as in paragraphs (1) to (8) above. In the embodiment, R1 is defined as in paragraph (6) above.

[0389] Suitablely, R1 is as defined in paragraphs (1) through (8f) above. Most preferably, R1 is as defined in paragraphs (1a), (2a), (3a), (3b), (4a), (7a), (8a), (8b), (8c), (8d), (8e), or (8f) above. In an embodiment, R1 is as defined in paragraph (4a) or (7a) above.

[0390] Appropriately, R2 and R3 are as defined in either paragraph (9) or (10) above. Most appropriately, R2 and R3 are as defined in paragraph (10) above.

[0391] Suitablely, R4 and R5 are as defined in any of paragraphs (11) to (24) above. More suitably, R4 and R5 are as defined in paragraphs (15), (15a), (15b) or (15c), (20a), (21a), (21b), (22a) or (22b) above. In certain groups of compounds of the present invention, R4 and R5 are as defined in paragraphs (16), (17), (18), (20), (21), (22), (23), (24), (20a), (21a), (21b), (22a) or (22b) above.

[0392] Suitablely, R4 and R5 are as defined in any of paragraphs (11) to (24) above. More suitablely, R4 and R5 are as defined in paragraph (15) above. Even more suitablely, R4 and R5 are as defined in paragraphs (16), (17), or (18) above. In certain groups of the compounds of the present invention, R4 and R5 are as defined in paragraphs (20), (21), (22), (23), or (24) above.

[0393] Appropriately, R xIt is as defined in any of the paragraphs (28) to (31) above. Most appropriately, R x It is as defined in paragraph (29) above.

[0394] Appropriately, R 10c and R 10N It is as defined in any of the paragraphs (11) to (15c) above. More appropriately, R 10c and R 10N It is as defined in any of the paragraphs (15) to (15c) above. Even more appropriately, R 10c and R 10N It is as defined in any of the paragraphs (15a), (15b) or (15c) above.

[0395] Appropriately, R6 is as defined in any of paragraphs (25) to (27) above. More appropriately, R6 is as defined in paragraph (27) above.

[0396] In the specific group of compounds having Formula I mentioned above, R 1是 As defined in any of paragraphs (1), (2), (3), (4), (5), (6), (7) or (8), and R2, R3, R4, R5 and R6 each have any of the definitions stated herein.

[0397] In the specific group of compounds having 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 R1, R2, R3, R4, R5, and R6 each have any of the definitions stated herein.

[0398] In the specific group of compounds having Formula I above, R2 and R3 are hydrogen, that is, the compounds have the following structural formula IA (a sub-formula of Formula I):

[0399]

[0400] Where R x R1, R4, R5, R6 and R x Each has one of the definitions stated in this article.

[0401] In examples of compounds having formula IA:

[0402] R x It is as defined in any of the paragraphs (28) to (31) above.

[0403] R1 is as defined in any of the paragraphs (1) to (8f) above;

[0404] R4 and R5 are as defined in any of the paragraphs (11) to (24) above; and

[0405] R6 is as defined in any of paragraphs (25) to (27) above;

[0406] In another embodiment of the compound having formula IA:

[0407] R x It is as defined in paragraph (29) above;

[0408] R1 is as defined in paragraphs (1a), (2a), (3a), (3b), (4a), (7a), (8a), (8b), (8c), (8d), (8e), or (8f) above;

[0409] R4 and R5 are as defined in paragraph (12) above; and

[0410] R6 is defined as in paragraph (25) above.

[0411] In another embodiment of the compound having formula IA:

[0412] R x It is as defined in paragraph (29) above;

[0413] R1 is as defined in paragraph (4a) above;

[0414] R4 and R5 are as defined in paragraphs (15), (15a), (15b), (15c), or (16) above; and

[0415] R6 is defined as in paragraph (27) above.

[0416] In another embodiment of the compound having formula IA:

[0417] R x It is as defined in paragraph (29) above;

[0418] R1 is as defined in paragraph (4a) above;

[0419] R4 and R5 are as defined in paragraph (16) above; and

[0420] R6 is defined as in paragraph (27) above.

[0421] In another embodiment of the compound having formula IA':

[0422] Rx It is as defined in paragraph (29) above;

[0423] R1 is as defined in paragraph (4a) above;

[0424] R4 and R5 are as defined in paragraph (17) above; and

[0425] R6 is defined as in paragraph (27) above.

[0426] In another embodiment of the compound having formula IA:

[0427] R x It is as defined in paragraph (29) above;

[0428] R1 is as defined in paragraph (4a) above;

[0429] R4 and R5 are as defined in paragraph (18) above; and

[0430] R6 is defined as in paragraph (27) above.

[0431] In another embodiment of the compound having formula IA:

[0432] R x It is as defined in paragraph (29) above;

[0433] R1 is as defined in paragraph (4a) above;

[0434] R4 and R5 are as defined in paragraph (19) above; and

[0435] R6 is defined as in paragraph (27) above.

[0436] In another embodiment of the compound having formula IA:

[0437] R x It is as defined in paragraph (29) above;

[0438] R1 is as defined in paragraph (4a) above;

[0439] R4 and R5 are as defined in paragraph (20) above; and

[0440] R6 is defined as in paragraph (27) above.

[0441] In another embodiment of the compound having formula IA:

[0442] R x It is as defined in paragraph (29) above;

[0443] R1 is as defined in paragraph (4a) above;

[0444] R4 and R5 are as defined in paragraph (21) above; and

[0445] R6 is defined as in paragraph (27) above.

[0446] In another embodiment of the compound having formula IA:

[0447] R x It is as defined in paragraph (29) above;

[0448] R1 is as defined in paragraph (4a) above;

[0449] R4 and R5 are as defined in paragraph (22) above; and

[0450] R6 is defined as in paragraph (27) above.

[0451] In another embodiment of the compound having formula IA:

[0452] R x It is as defined in paragraph (29) above;

[0453] R1 is as defined in paragraph (6) above;

[0454] R4 and R5 are as defined in paragraph (23) above; and

[0455] R6 is defined as in paragraph (27) above.

[0456] In another embodiment of the compound having formula IA:

[0457] R x It is as defined in paragraph (29) above;

[0458] R1 is as defined in paragraph (4a) above;

[0459] R4 and R5 are as defined in paragraph (24) above; and

[0460] R6 is defined as in paragraph (27) above.

[0461] In another embodiment of the compound having formula IA:

[0462] R x It is as defined in paragraph (29) above;

[0463] R1 is as defined in paragraph (4a) above;

[0464] R4 and R5 are as defined in paragraphs (20a), (21a), (21b), (22a), or (22b) above; and

[0465] R6 is defined as in paragraph (27) above.

[0466] In the specific group of compounds having Formula I above, R6 is hydrogen, that is, the compound has the following structural formula IB (a sub-formula of Formula I'):

[0467]

[0468] Where R x R1, R2, R3, R4 and R5 each have any of the definitions stated herein.

[0469] In examples of compounds having formula IB:

[0470] R x It is as defined in any of the paragraphs (28) to (31) above.

[0471] R1 is as defined in any of the paragraphs (1) to (8f) above;

[0472] R2 and R3 are as defined in paragraphs (9) or (10); and

[0473] R4 and R5 are as defined in any of the paragraphs (11) to (24) above.

[0474] In another embodiment of the compound having formula IB:

[0475] R x It is as defined in paragraph (29) above;

[0476] R1 is as defined in paragraphs (1a), (2a), (3a), (3b), (4a), (7a), (8a), (8b), (8c), (8d), (8e), or (8f) above;

[0477] R2 and R3 are as defined in paragraph (9); and

[0478] R4 and R5 are defined as in paragraph (12) above.

[0479] In another embodiment of the compound having formula IB:

[0480] R x It is as defined in paragraph (29) above;

[0481] R1 is as defined in paragraph (4a) above;

[0482] R2 and R3 are as defined in paragraph (10); and

[0483] R4 and R5 are as defined in paragraphs (15), (15a), (15b), or (15c) above.

[0484] In another embodiment of the compound having formula IB:

[0485] R x It is as defined in paragraph (29) above;

[0486] R1 is as defined in paragraph (4a) above;

[0487] R2 and R3 are as defined in paragraph (10); and

[0488] R4 and R5 are as defined in paragraph (16) above.

[0489] In another embodiment of the compound having formula IB:

[0490] R1 is as defined in paragraph (6) above;

[0491] R2 and R3 are as defined in paragraph (10); and

[0492] R4 and R5 are defined as in paragraph (17) above.

[0493] In another embodiment of the compound having formula IB:

[0494] R x It is as defined in paragraph (29) above;

[0495] R1 is as defined in paragraph (4a) above;

[0496] R2 and R3 are as defined in paragraph (10); and

[0497] R4 and R5 are as defined in paragraph (18) above.

[0498] In another embodiment of the compound having formula IB:

[0499] R x It is as defined in paragraph (29) above;

[0500] R1 is as defined in paragraph (4a) above;

[0501] R2 and R3 are as defined in paragraph (10); and

[0502] R4 and R5 are defined as in paragraph (19) above.

[0503] In another embodiment of the compound having formula IB:

[0504] R1 is as defined in paragraph (6) above;

[0505] R2 and R3 are as defined in paragraph (10); and

[0506] R4 and R5 are as defined in paragraph (20) above.

[0507] In another embodiment of the compound having formula IB:

[0508] R x It is as defined in paragraph (29) above;

[0509] R1 is as defined in paragraph (4a) above;

[0510] R2 and R3 are as defined in paragraph (10); and

[0511] R4 and R5 are defined as in paragraph (21) above.

[0512] In another embodiment of the compound having formula IB:

[0513] R x It is as defined in paragraph (29) above;

[0514] R1 is as defined in paragraph (4a) above;

[0515] R2 and R3 are as defined in paragraph (10); and

[0516] R4 and R5 are defined as in paragraph (22) above.

[0517] In another embodiment of the compound having formula IB:

[0518] R1 is as defined in paragraph (6) above;

[0519] R2 and R3 are as defined in paragraph (10); and

[0520] R4 and R5 are defined as in paragraph (23) above.

[0521] In another embodiment of the compound having formula IB:

[0522] R x It is as defined in paragraph (29) above;

[0523] R1 is as defined in paragraph (4a) above;

[0524] R2 and R3 are as defined in paragraph (10); and

[0525] R4 and R5 are defined as in paragraph (24) above.

[0526] In another embodiment of the compound having formula IB:

[0527] R x It is as defined in paragraph (29) above;

[0528] R1 is as defined in paragraph (4a) above;

[0529] R2 and R3 are as defined in paragraph (10); and

[0530] R4 and R5 are as defined in paragraphs (20a), (21a), (21b), (22a), or (22b) above.

[0531] In the specific group of compounds having Formula I above, R2, R3, and R6 are hydrogen, meaning the compounds have the following structural formula IC (a sub-formula of Formula I):

[0532]

[0533] Where R x R1, R4 and R5 each have any of the definitions stated in this document.

[0534] In examples of compounds having formula IC:

[0535] R x It is as defined in any of the paragraphs (28) to (31) above.

[0536] R1 is as defined in any of paragraphs (1) to (8f) above; and

[0537] R4 and R5 are as defined in any of the paragraphs (11) to (24) above.

[0538] In another embodiment of the compound having formula IC:

[0539] R x It is as defined in paragraph (29) above;

[0540] R1 is as defined in paragraphs (1a), (2a), (3a), (3b), (4a), (7a), (8a), (8b), (8c), (8d), (8e), or (8f) above; and

[0541] R4 and R5 are defined as in paragraph (12) above.

[0542] In another embodiment of the compound having formula IC:

[0543] R x It is as defined in paragraph (29) above;

[0544] R1 is as defined in paragraph (4a) above; and

[0545] R4 and R5 are as defined in paragraphs (15), (15a), (15b), or (15c) above.

[0546] In another embodiment of the compound having formula IC:

[0547] R x It is as defined in paragraph (29) above;

[0548] R1 is as defined in paragraph (4a) above; and

[0549] R4 and R5 are as defined in paragraph (16) above.

[0550] In another embodiment of the compound having formula IC:

[0551] R x It is as defined in paragraph (29) above;

[0552] R1 is as defined in paragraph (4a) above; and

[0553] R4 and R5 are defined as in paragraph (17) above.

[0554] In another embodiment of the compound having formula IC:

[0555] R x It is as defined in paragraph (29) above;

[0556] R1 is as defined in paragraph (4a) above; and

[0557] R4 and R5 are as defined in paragraph (18) above.

[0558] In another embodiment of the compound having formula IC:

[0559] R x It is as defined in paragraph (29) above;

[0560] R1 is as defined in paragraph (4a) above; and

[0561] R4 and R5 are defined as in paragraph (19) above.

[0562] In another embodiment of the compound having formula IC:

[0563] R x It is as defined in paragraph (29) above;

[0564] R1 is as defined in paragraph (4a) above; and

[0565] R4 and R5 are as defined in paragraph (20) above.

[0566] In another embodiment of the compound having formula IC:

[0567] R x It is as defined in paragraph (29) above;

[0568] R1 is as defined in paragraph (4a) above; and

[0569] R4 and R5 are defined as in paragraph (21) above.

[0570] In another embodiment of the compound having formula IC:

[0571] R x It is as defined in paragraph (29) above;

[0572] R1 is as defined in paragraph (4a) above; and

[0573] R4 and R5 are defined as in paragraph (22) above.

[0574] In another embodiment of the compound having formula IC':

[0575] R x It is as defined in paragraph (29) above;

[0576] R1 is as defined in paragraph (4a) above; and

[0577] R4 and R5 are defined as in paragraph (23) above.

[0578] In another embodiment of the compound having formula IC:

[0579] R x It is as defined in paragraph (29) above;

[0580] R1 is as defined in paragraph (4a) above; and

[0581] R4 and R5 are defined as in paragraph (24) above.

[0582] In another embodiment of the compound having formula IC:

[0583] R x It is as defined in paragraph (29) above;

[0584] R1 is as defined in paragraph (4a) above; and

[0585] R4 and R5 are as defined in paragraphs (20a), (21a), (21b), (22a), or (22b) above; and

[0586] In the specific group of compounds having Formula I above, R2 and R3 are hydrogen, that is, the compounds have the following structural formula IA' (a sub-formula of Formula I):

[0587]

[0588] R1, R4, R5, and R6 each have one of the definitions stated in this paper.

[0589] In examples of compounds having formula IA':

[0590] R1 is as defined in any of paragraphs (1) to (8) above;

[0591] R4 and R5 are as defined in any of the paragraphs (11) to (24) above; and

[0592] R6 is as defined in any of paragraphs (25) to (27) above.

[0593] In another embodiment of the compound having formula IA':

[0594] R1 is as defined in paragraph (2) above;

[0595] R4 and R5 are as defined in paragraph (12) above; and

[0596] R6 is defined as in paragraph (25) above.

[0597] In another embodiment of the compound having formula IA':

[0598] R1 is as defined in paragraph (6) above;

[0599] R4 and R5 are as defined in paragraphs (15), (15a), (15b), or (15c) above; and

[0600] R6 is defined as in paragraph (27) above.

[0601] In another embodiment of the compound having formula IA':

[0602] R1 is as defined in paragraph (6) above;

[0603] R4 and R5 are as defined in paragraph (16) above; and

[0604] R6 is defined as in paragraph (27) above.

[0605] In another embodiment of the compound having formula IA':

[0606] R1 is as defined in paragraph (6) above;

[0607] R4 and R5 are as defined in paragraph (17) above; and

[0608] R6 is defined as in paragraph (27) above.

[0609] In another embodiment of the compound having formula IA':

[0610] R1 is as defined in paragraph (6) above;

[0611] R4 and R5 are as defined in paragraph (18) above; and

[0612] R6 is defined as in paragraph (27) above.

[0613] In another embodiment of the compound having formula IA':

[0614] R1 is as defined in paragraph (6) above;

[0615] R4 and R5 are as defined in paragraph (19) above; and

[0616] R6 is defined as in paragraph (27) above.

[0617] In another embodiment of the compound having formula IA':

[0618] R1 is as defined in paragraph (6) above;

[0619] R4 and R5 are as defined in paragraph (20) above; and

[0620] R6 is defined as in paragraph (27) above.

[0621] In another embodiment of the compound having formula IA':

[0622] R1 is as defined in paragraph (6) above;

[0623] R4 and R5 are as defined in paragraph (21) above; and

[0624] R6 is defined as in paragraph (27) above.

[0625] In another embodiment of the compound having formula IA':

[0626] R1 is as defined in paragraph (6) above;

[0627] R4 and R5 are as defined in paragraph (22) above; and

[0628] R6 is defined as in paragraph (27) above.

[0629] In another embodiment of the compound having formula IA':

[0630] R1 is as defined in paragraph (6) above;

[0631] R4 and R5 are as defined in paragraph (23) above; and

[0632] R6 is defined as in paragraph (27) above.

[0633] In another embodiment of the compound having formula IA':

[0634] R1 is as defined in paragraph (6) above;

[0635] R4 and R5 are as defined in paragraph (24) above; and

[0636] R6 is defined as in paragraph (27) above.

[0637] In the specific group of compounds having Formula I above, R6 is hydrogen, that is, the compound has the following structural formula IB' (a sub-formula of Formula I):

[0638]

[0639] R1, R2, R3, R4, and R5 each have one of the definitions stated in this paper.

[0640] In examples of compounds having formula IB':

[0641] R1 is as defined in any of paragraphs (1) to (8) above;

[0642] R2 and R3 are as defined in paragraphs (9) or (10); and

[0643] R4 and R5 are as defined in any of the paragraphs (11) to (24) above.

[0644] In another embodiment of the compound having formula IB':

[0645] R1 is as defined in paragraph (2) above;

[0646] R2 and R3 are as defined in paragraph (9); and

[0647] R4 and R5 are defined as in paragraph (12) above.

[0648] In another embodiment of the compound having formula IB':

[0649] R1 is as defined in paragraph (6) above;

[0650] R2 and R3 are as defined in paragraph (10); and

[0651] R4 and R5 are as defined in paragraphs (15), (15a), (15b), or (15c) above.

[0652] In another embodiment of the compound having formula IB':

[0653] R1 is as defined in paragraph (6) above;

[0654] R2 and R3 are as defined in paragraph (10); and

[0655] R4 and R5 are as defined in paragraph (16) above.

[0656] In another embodiment of the compound having formula IB':

[0657] R1 is as defined in paragraph (6) above;

[0658] R2 and R3 are as defined in paragraph (10); and

[0659] R4 and R5 are defined as in paragraph (17) above.

[0660] In another embodiment of the compound having formula IB':

[0661] R1 is as defined in paragraph (6) above;

[0662] R2 and R3 are as defined in paragraph (10); and

[0663] R4 and R5 are as defined in paragraph (18) above.

[0664] In another embodiment of the compound having formula IB':

[0665] R1 is as defined in paragraph (6) above;

[0666] R2 and R3 are as defined in paragraph (10); and

[0667] R4 and R5 are defined as in paragraph (19) above.

[0668] In another embodiment of the compound having formula IB':

[0669] R1 is as defined in paragraph (6) above;

[0670] R2 and R3 are as defined in paragraph (10); and

[0671] R4 and R5 are as defined in paragraph (20) above.

[0672] In another embodiment of the compound having formula IB':

[0673] R1 is as defined in paragraph (6) above;

[0674] R2 and R3 are as defined in paragraph (10); and

[0675] R4 and R5 are defined as in paragraph (21) above.

[0676] In another embodiment of the compound having formula IB':

[0677] R1 is as defined in paragraph (6) above;

[0678] R2 and R3 are as defined in paragraph (10); and

[0679] R4 and R5 are defined as in paragraph (22) above.

[0680] In another embodiment of the compound having formula IB':

[0681] R1 is as defined in paragraph (6) above;

[0682] R2 and R3 are as defined in paragraph (10); and

[0683] R4 and R5 are defined as in paragraph (23) above.

[0684] In another embodiment of the compound having formula IB':

[0685] R1 is as defined in paragraph (6) above;

[0686] R2 and R3 are as defined in paragraph (10); and

[0687] R4 and R5 are defined as in paragraph (24) above.

[0688] In the specific group of compounds having Formula I above, R2, R3, and R6 are hydrogen, meaning the compounds have the following structural formula IC' (a sub-formula of Formula I):

[0689]

[0690] R1, R4, and R5 each have one of the definitions stated in this paper.

[0691] In examples of compounds having formula IC':

[0692] R1 is as defined in any of paragraphs (1) to (8) above; and

[0693] R4 and R5 are as defined in any of the paragraphs (11) to (24) above.

[0694] In another embodiment of the compound having formula IC':

[0695] R1 is as defined in paragraph (2) above; and

[0696] R4 and R5 are defined as in paragraph (12) above.

[0697] In another embodiment of the compound having formula IC':

[0698] R1 is as defined in paragraph (6) above; and

[0699] R4 and R5 are as defined in paragraphs (15), (15a), (15b), or (15c) above.

[0700] In another embodiment of the compound having formula IC':

[0701] R1 is as defined in paragraph (6) above; and

[0702] R4 and R5 are as defined in paragraph (16) above.

[0703] In another embodiment of the compound having formula IC':

[0704] R1 is as defined in paragraph (6) above; and

[0705] R4 and R5 are defined as in paragraph (17) above.

[0706] In another embodiment of the compound having formula IC':

[0707] R1 is as defined in paragraph (6) above; and

[0708] R4 and R5 are as defined in paragraph (18) above.

[0709] In another embodiment of the compound having formula IC':

[0710] R1 is as defined in paragraph (6) above; and

[0711] R4 and R5 are defined as in paragraph (19) above.

[0712] In another embodiment of the compound having formula IC':

[0713] R1 is as defined in paragraph (6) above; and

[0714] R4 and R5 are as defined in paragraph (20) above.

[0715] In another embodiment of the compound having formula IC':

[0716] R1 is as defined in paragraph (6) above; and

[0717] R4 and R5 are defined as in paragraph (21) above.

[0718] In another embodiment of the compound having formula IC':

[0719] R1 is as defined in paragraph (6) above; and

[0720] R4 and R5 are defined as in paragraph (22) above.

[0721] In another embodiment of the compound having formula IC':

[0722] R1 is as defined in paragraph (6) above; and

[0723] R4 and R5 are defined as in paragraph (23) above.

[0724] In another embodiment of the compound having formula IC':

[0725] R1 is as defined in paragraph (6) above; and

[0726] R4 and R5 are defined as in paragraph (24) above.

[0727] Specific compounds of the present invention include any compound described in the Examples section of this application or a pharmaceutically acceptable salt or solvation thereof, and, in particular, any one of the following:

[0728] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]morpholine-4-carboxamide

[0729] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide

[0730] (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide

[0731] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]piperazine-1-carboxamide

[0732] (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide

[0733] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-(oxetane-3-yl)piperazine-1-carboxamide

[0734] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide

[0735] N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]pyrrolidine-1-carboxamide

[0736] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-2-(2-hydroxy-2-methyl-propyl)pyrrolidine-1-carboxamide

[0737] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide

[0738] (2S)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]carbamoyl]piperazine-2-carboxylic acid

[0739] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-methylpiperazin-1-carboxamide

[0740] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-hydroxy-4-methylpiperidine-1-carboxamide

[0741] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-cyano-4-methyl-piperidin-1-carboxamide

[0742] (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide

[0743] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-methylpiperazine-1-carboxamide

[0744] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide

[0745] (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]pyrrolidine-1-carboxamide

[0746] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxamide

[0747] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0748] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-oxo-piperazin-1-carboxamide

[0749] N4-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]morpholine-2,4-dicarboxamide

[0750] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-methyl-3-oxo-piperazin-1-carboxamide

[0751] (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide

[0752] 4-Acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperazine-1-carboxamide

[0753] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methylsulfonyl-piperazine-1-carboxamide

[0754] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-aminosulfonyl-piperazine-1-carboxamide

[0755] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide

[0756] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide

[0757] (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide

[0758] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methoxy-piperidine-1-carboxamide

[0759] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamide

[0760] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide

[0761] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(hydroxymethyl)azacyclobutane-1-carboxamide

[0762] 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]azacyclobutane-1-carboxamide

[0763] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1,1-dioxo-1,4-thiazinane-4-carboxamide

[0764] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide

[0765] N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperidine-1,4-dicarboxamide

[0766] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide

[0767] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-azacyclobutane-1-carboxamide

[0768] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-(2-hydroxyethyl)-3-oxo-piperazin-1-carboxamide

[0769] 4,4-Dicyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide

[0770] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-(1-hydroxy-1-methyl-ethyl)azacyclobutane-1-carboxamide

[0771] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(2-hydroxy-2-methyl-propyl)piperazine-1-carboxamide

[0772] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-methyl-1,7-diazaspiro[3,4]octane-7-carboxamide

[0773] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(2-hydroxy-1,1-dimethyl-ethyl)piperazine-1-carboxamide

[0774] (8aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-carboxamide

[0775] (8aR)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-carboxamide

[0776] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-(oxetane-3-yl)piperazine-1-carboxamide

[0777] (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-pyrrolidine-1-carboxamide

[0778] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(methoxymethyl)piperidine-1-carboxamide

[0779] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-fluoro-piperidine-1-carboxamide

[0780] (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]pyrrolidine-1-carboxamide

[0781] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-3-methyl-azacyclobutane-1-carboxamide

[0782] (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]carbamoyl]piperazine-2-carboxylic acid

[0783] (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]carbamoyl]piperazine-2-carboxylic acid methyl ester

[0784] (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide

[0785] (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide

[0786] (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-methylpiperazin-1-carboxamide

[0787] (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-methylpiperazine-1-carboxamide

[0788] (1S,4S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

[0789] (3R)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]piperazine-1,3-dicarboxamide

[0790] (3S)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]piperazine-1,3-dicarboxamide

[0791] 4-Amino-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide

[0792] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methyl-piperidine-1-carboxamide

[0793] (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide

[0794] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide

[0795] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0796] (1R,4R)-5-acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

[0797] (1S,4S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

[0798] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide

[0799] N-[5-[2,6-bis(trideuteratedmethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0800] N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0801] (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide

[0802] N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-9-methyl-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide

[0803] N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide

[0804] (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide

[0805] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide

[0806] 3-Cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxecyclobutan-3-yl)-4-pyridyl]thiazolyl-2-yl]-3-methyl-pyrrolidine-1-carboxamide

[0807] 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxecyclobutane-3-yl)-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide

[0808] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-morpholino-azacyclobutane-1-carboxamide

[0809] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-4-tetrahydropyran-4-yl-piperazin-1-carboxamide;

[0810] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-3-pyrrolidine-1-yl-azacyclobutane-1-carboxamide

[0811] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(dimethylamino)azacyclobutane-1-carboxamide

[0812] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-(morpholinomethyl)piperidine-1-carboxamide;

[0813] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide

[0814] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxamide

[0815] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1,4-diazabicyclo[3.2.1]octane-4-carboxamide

[0816] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxamide

[0817] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazo-2-yl]-2,2-dioxo-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]thiazine-8-carboxamide

[0818] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-4-oxo-3,6,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-carboxamide

[0819] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-9-oxo-3,4,6,7,8,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-carboxamide

[0820] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxo-1,3,4,8,9,9a-hexahydropyrazino[1,2-c][1,3]oxazine-2-carboxamide

[0821] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-carboxamide

[0822] N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazo-2-yl]-1-oxo-1,4-thiazinyl-4-carboxamide

[0823] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-aminosulfonyl-pyrrolidine-1-carboxamide

[0824] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide

[0825] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazo-2-yl]-4-pyrazol-1-yl-piperidine-1-carboxamide

[0826] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide

[0827] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1,3-dioxo-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazine-7-carboxamide

[0828] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide

[0829] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(1H-imidazol-2-yl)piperidine-1-carboxamide

[0830] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxamide

[0831] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxamide

[0832] N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-N4-methylpiperidine-1,4-dicarboxamide

[0833] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-8-oxa-2-azaspiro[4.5]decane-2-carboxamide

[0834] (3S)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]pyrrolidine-1,3-dicarboxamide

[0835] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(2-oxoimidazolidine-1-yl)piperidine-1-carboxamide

[0836] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide

[0837] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-methylimino-1-oxo-1,4-thiazinane-4-carboxamide

[0838] N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-N4-(2-hydroxyethyl)piperidine-1,4-dicarboxamide

[0839] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxo-7-oxa-2,5-diazaspiro[3,5]nonane-2-carboxamide

[0840] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-6,9-dioxo-1,3,4,7,8,9a-hexahydropyrazino[1,2-a]pyrazin-2-carboxamide

[0841] (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide

[0842] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-oxo-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxamide

[0843] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-methyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide

[0844] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-8-methyl-6,9-dioxo-3,4,7,9a-tetrahydro-1H-pyrazino[1,2-a]pyrazin-2-carboxamide

[0845] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide

[0846] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-oxo-2,9-diazaspiro[5.5]undecane-9-carboxamide

[0847] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(1-hydroxy-1-methyl-ethyl)piperidine-1-carboxamide

[0848] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrazino[1,2-c]pyrimidine-2-carboxamide

[0849] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-carboxamide

[0850] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxamide

[0851] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide

[0852] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,2-dioxo-2λ^{6}-thia-6-azaspiro[3.3]heptane-6-carboxamide

[0853] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide

[0854] (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide

[0855] (3aR,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrole-5-carboxamide

[0856] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxo-3-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide

[0857] (1S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-methyl-3,6-diazabicyclo[3.2.2]nonane-3-carboxamide

[0858] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-methyl-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide

[0859] (3aS,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-oxo-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolo-5-carboxamide

[0860] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxa-2-azaspiro[3,4]octane-2-carboxamide

[0861] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-7-oxa-2-azaspiro[3.5]nonane-2-carboxamide

[0862] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxo-2,7-diazaspiro[3,4]octane-2-carboxamide

[0863] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide

[0864] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-6-oxo-2,5,7-triazaspiro[3,4]octane-2-carboxamide

[0865] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxamide

[0866] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-5-oxo-2,6-diazaspiro[3,4]octane-2-carboxamide

[0867] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide

[0868] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-ethyl-piperazine-1-carboxamide

[0869] N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazo-2-yl]-4-(oxetane-3-yl)piperazine-1-carboxamide

[0870] 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]piperidine-4-carboxylic acid

[0871] (3S)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid

[0872] 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-(hydroxymethyl)azacyclobutane-1-carboxamide

[0873] (3R)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid

[0874] 4-Cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide

[0875] N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-3-methyl-azacyclobutane-1-carboxamide

[0876] 3-Cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-azacyclobutane-1-carboxamide

[0877] N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide

[0878] 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-azacyclobutane-1-carboxamide

[0879] 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]azacyclobutane-3-carboxylic acid

[0880] (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide

[0881] (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-methyl-azacyclobutane-1-carboxamide

[0882] (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)azacyclobutane-1-carboxamide

[0883] (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methylmorpholin-4-carboxamide

[0884] (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide

[0885] (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide

[0886] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide

[0887] (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-methyl-azacyclobutane-1-carboxamide

[0888] N-[4-(3-cyano-2-methyl-phenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0889] (3R)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]pyrrolidine-1,3-dicarboxamide

[0890] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-7-azaspiro[4.4]nonane-7-carboxamide

[0891] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-7-azaspiro[3,4]octane-7-carboxamide

[0892] (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azacyclobutane-1-carboxamide

[0893] (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azacyclobutane-1-carboxamide

[0894] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-morpholino-pyrrolidine-1-carboxamide

[0895] (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-5-oxo-piperazin-1-carboxamide

[0896] (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methylmorpholin-4-carboxamide

[0897] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxa-1-azaspiro[3.3]heptane-1-carboxamide

[0898] (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide

[0899] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1,3-dimethyl-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide

[0900] (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide

[0901] (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-5-oxo-piperazin-1-carboxamide

[0902] (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)azacyclobutane-1-carboxamide

[0903] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-methyl-5-oxo-2,6-diazaspiro[3,4]octane-2-carboxamide

[0904] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0905] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-methyl-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide

[0906] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-methylsulfonyl-piperidine-1-carboxamide

[0907] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-hydroxy-4-methylpiperidine-1-carboxamide

[0908] N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0909] (4aR,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide

[0910] N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0911] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperazine-1-carboxamide

[0912] (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-piperazin-1-carboxamide

[0913] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide

[0914] trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-dimethyl-piperazine-1-carboxamide

[0915] 4-Amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide

[0916] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide

[0917] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

[0918] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[0919] (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxamide

[0920] cis-(2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-dimethyl-piperazine-1-carboxamide

[0921] (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,6-dimethyl-piperazin-1-carboxamide

[0922] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,2-dimethyl-piperazin-1-carboxamide

[0923] 1-Acetylimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide

[0924] N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0925] N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazo-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide

[0926] (3R)-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide

[0927] N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazo-2-yl]-1-oxo-1,4-thiazinyl-4-carboxamide

[0928] N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-(oxetane-3-yl)piperazine-1-carboxamide

[0929] N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazo-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide

[0930] 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]piperidine-1-carboxamide

[0931] 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamide

[0932] 4,4-Dicyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]piperidine-1-carboxamide

[0933] 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methoxy-piperidine-1-carboxamide

[0934] N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinyl-4-carboxamide

[0935] 1-Cyanoimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide

[0936] 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide

[0937] N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-6-oxa-2-azaspiro[3,4]octane-2-carboxamide

[0938] N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0939] N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0940] Racemic-(3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,5-dimethyl-piperazine-1-carboxamide

[0941] (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(trifluoromethyl)piperazine-1-carboxamide

[0942] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-5-oxa-2,8-diazaspiro[3,5]nonane-2-carboxamide

[0943] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide

[0944] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide

[0945] (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-(trifluoromethyl)piperazine-1-carboxamide

[0946] (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperazine-1-carboxamide

[0947] (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperazine-1-carboxamide

[0948] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4,7-diazaspiro[2,5]octane-7-carboxamide

[0949] (3S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3,5-dimethyl-piperazin-1-carboxamide

[0950] (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-methylpiperazine-1-carboxamide

[0951] (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide

[0952] (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide

[0953] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide

[0954] (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-methyl-piperazin-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide

[0955] (3R)-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazolyl-2-yl]-3-methylpiperazine-1-carboxamide

[0956] (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide

[0957] (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide

[0958] Racemic-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide

[0959] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-cyclopropyl-piperazine-1-carboxamide

[0960] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide

[0961] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3,3-dimethyl-piperazin-1-carboxamide

[0962] N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl)thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide

[0963] N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide

[0964] N-[4-(3-cyanophenyl)-5-(2,6-dichloro-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0965] N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazo-2-yl]-1-oxo-1,4-thiazinyl-4-carboxamide

[0966] N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide

[0967] N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxecyclobutan-3-yl)-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0968] N-[5-(2-cyano-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide

[0969] N-[4-(3-cyanophenyl)-5-[2-(fluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0970] N-[4-(3-cyanophenyl)-5-(2-cyclopropyl-6-methyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0971] N-[4-(3-cyanophenyl)-5-(2-isopropyl-6-methyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0972] N-[4-(3-cyanophenyl)-5-(2-ethyl-6-methyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0973] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxonium-4-yl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0974] 4-Cyano-N-[4-(3-cyano-2-methyl-phenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methyl-piperidine-1-carboxamide

[0975] N-[5-(2-acetamido-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0976] N-[5-[2-(acetamidomethyl)-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0977] N-[4-(3-cyanophenyl)-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0978] N-[4-(3-cyanophenyl)-5-[2-(1-methoxyethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0979] N-[5-[2-chloro-6-(1-hydroxy-1-methyl-ethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0980] 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide

[0981] N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0982] 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-pyrrolidine-1-carboxamide

[0983] N-[5-[2,6-bis(trideuteratedmethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazolyl]-4-cyano-4-methylpiperidine-1-carboxamide

[0984] N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0985] N-[4-(3-cyanophenyl)-5-[2-[(1S)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0986] (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-pyrrolidine-1-carboxamide

[0987] (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-pyrrolidine-1-carboxamide.

[0988] Specific compounds of the present invention include any compound described in the Examples section of this application or a pharmaceutically acceptable salt or solvation thereof, and, in particular, any one of the following:

[0989] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]morpholine-4-carboxamide;

[0990] N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide;

[0991] (2R)-N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide;

[0992] N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]piperazine-1-carboxamide;

[0993] N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]pyrrolidine-1-carboxamide;

[0994] N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-2-(2-hydroxy-2-methyl-propyl)pyrrolidine-1-carboxamide;

[0995] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide;

[0996] (2S)-4-[[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]carbamoyl]piperazine-2-carboxylic acid;

[0997] N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-methyl-piperazin-1-carboxamide;

[0998] N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-hydroxy-4-methyl-piperidine-1-carboxamide;

[0999] N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-cyano-4-methyl-piperidine-1-carboxamide;

[1000] (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide carboxylate;

[1001] (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide carboxylate

[1002] N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-(oxetane-3-yl)piperazine-1-carboxamide;

[1003] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide;

[1004] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-methyl-piperazine-1-carboxamide;

[1005] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide;

[1006] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide;

[1007] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide;

[1008] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-(oxetane-3-yl)piperazine-1-carboxamide;

[1009] (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-pyrrolidine-1-carboxamide;

[1010] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(methoxymethyl)piperidine-1-carboxamide;

[1011] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-fluoro-piperidine-1-carboxamide;

[1012] (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazo-2-yl]pyrrolidine-1-carboxamide;

[1013] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-3-methyl-azacyclobutane-1-carboxamide;

[1014] (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazo-2-yl]pyrrolidine-1-carboxamide;

[1015] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxamide;

[1016] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[1017] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-oxo-piperazin-1-carboxamide

[1018] N4-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]morpholine-2,4-dicarboxamide

[1019] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-methyl-3-oxo-piperazin-1-carboxamide;

[1020] (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide;

[1021] 4-Acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperazine-1-carboxamide;

[1022] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-methylsulfonyl-piperazine-1-carboxamide;

[1023] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-aminosulfonyl-piperazine-1-carboxamide;

[1024] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide;

[1025] (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide;

[1026] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methoxy-piperidine-1-carboxamide;

[1027] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamide;

[1028] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide;

[1029] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(hydroxymethyl)azacyclobutane-1-carboxamide;

[1030] 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]azacyclobutane-1-carboxamide;

[1031] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1,1-dioxo-1,4-thiazinane-4-carboxamide

[1032] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide

[1033] N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperidine-1,4-dicarboxamide

[1034] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-azacyclobutane-1-carboxamide

[1035] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-(2-hydroxyethyl)-3-oxo-piperazine-1-carboxamide;

[1036] 4,4-Dicyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide;

[1037] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)azacyclobutane-1-carboxamide;

[1038] (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]carbamoyl]piperazine-2-carboxylic acid;

[1039] (2R)-4-[[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazolyl-2-yl]carbamoyl]piperazine-2-carboxylic acid methyl ester;

[1040] (3S)-N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide;

[1041] (3R)-N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide;

[1042] (3S)-N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-methyl-piperazin-1-carboxamide;

[1043] (3R)-N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-methyl-piperazin-1-carboxamide;

[1044] (1S,4S)-N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazolyl-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide;

[1045] (3R)-N1-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]piperazine-1,3-dicarboxamide;

[1046] (3S)-N1-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]piperazine-1,3-dicarboxamide;

[1047] 4-Amino-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]-4-methyl-piperidine-1-carboxamide;

[1048] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methyl-piperidine-1-carboxamide;

[1049] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperazine-1-carboxamide;

[1050] (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-piperazine-1-carboxamide;

[1051] 4-Amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide; and

[1052] 1-Acetylimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide.

[1053] Typically, various functional groups and substituents constituting a compound having formula (I) are selected such that the molecular weight of the compound having formula (I) does not exceed 1000. More generally, the molecular weight of the compound will be 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, and for example 550 or less.

[1054] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of sufficiently basic compounds of the present invention, such as acid addition salts with, for example, 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 sufficiently acidic compounds of the present invention are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations (e.g., salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine).

[1055] Compounds with the same molecular formula but different atomic bonding properties or sequences, or different spatial arrangements of atoms, are called "isomers." The term "stereoisomer" refers to isomers whose atoms differ in spatial arrangement. Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, that asymmetric center is bonded to four different groups, there may be a pair of enantiomers. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)- isomers, respectively) by the Cahn and Prelog R and S sequencing rules, or by the method of rotating the plane of polarized light. Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[1056] The compounds of this invention may have one or more asymmetric centers; therefore, such compounds may be generated as individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise stated, the description or naming of specific compounds in the specification and claims is intended to include individual enantiomers and their racemic mixtures or other mixtures. Methods for stereochemical determination and stereoisomer separation are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolving racemic forms. Some compounds of this invention may have geometric isomer centers (E and Z isomers). It should be understood that this invention covers all optical, diastereomers, and geometric isomers and mixtures thereof with antiproliferative activity.

[1057] This invention also covers compounds of the invention containing one or more isotopic substitutions as defined herein. For example, H may be in any isotopic form, including 1H, 2H(D), and 3H(T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 16O and 18O; and so on.

[1058] It should also be understood that some compounds having formula (I) can exist in both solvated and non-solvated forms, such as hydrated forms. It should be understood that this invention covers all such solvated forms exhibiting antiproliferative activity.

[1059] It should also be understood that some compounds having Formula I can exhibit polymorphism, and the present invention covers all such forms having antiproliferative activity.

[1060] Compounds having Formula I can exist in many different tautomer forms, and references to compounds having Formula I include all such forms. To avoid ambiguity, Formula I still includes all other forms even when a compound can exist in one of several tautomer forms, and only one is specifically described or shown. Examples of tautomer forms include ketone, enol, and enolate forms, for example, as in the following tautomer pairs: ketone / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[1061]

[1062] Compounds of Formula I containing amine functional groups can also form N-oxides. The compounds of Formula I containing amine functional groups mentioned herein also include 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 tertiary amines containing nitrogen heterocycles or N-oxides of nitrogen atoms. 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, *Advanced Organic Chemistry*, edited by Jerry March, 4th ed., Wiley Interscience, p. More specifically, N-oxides can be prepared by the procedure in LWDeady (Syn.Comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[1063] Compounds having formula (I) can be administered as prodrugs, which decompose in humans or animals to release the compounds of the present invention. Prodrugs can be used to modify 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 suitable groups or substituents to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxyl or hydroxyl group in compounds having formula (I) and in vivo cleavable amide derivatives that can be formed at the carboxyl or amino group in compounds having formula (I).

[1064] Therefore, the present invention includes those compounds having formula (I) as defined above, when they are obtainable by organic synthesis and when they are obtainable in humans or animals by cleaving their prodrugs. Thus, the present invention includes those compounds having formula I produced by organic synthesis, and also includes such compounds produced in humans or animals by metabolizing precursor compounds, i.e., compounds having formula (I) that are either synthetically produced or metabolically produced.

[1065] A suitable pharmaceutically acceptable prodrug of a compound having formula (I) is based on reasonable medical judgment as a pharmaceutically acceptable prodrug suitable for administration to humans or animals without undesirable pharmacological activity and without abnormal toxicity.

[1066] For example, various forms of prodrugs have been described in the following literature:

[1067] a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985);

[1068] b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985);

[1069] c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, edited by H. Bundgaard, pp. 113-191 (1991);

[1070] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[1071] e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

[1072] f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984);

[1073] g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems,” ACS Symposium Series, Volume 14; and

[1074] h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[1075] Suitable pharmaceutically acceptable prodrugs of compounds having Formula I (which have a carboxyl group) are, for example, esters that are cleavable in vivo. Cleavable esters of compounds having Formula I containing a carboxyl group are, for example, pharmaceutically acceptable esters that are cleaved in humans or animals to produce a parent acid. Suitable pharmaceutically acceptable esters with carboxyl groups include C1-6 alkyl esters (such as methyl, ethyl, and tert-butyl), C1-6 alkoxymethyl esters (such as methoxymethyl esters), C1-6 alkyloxymethyl esters (such as neopentyloxymethyl esters), 3-phthalyl esters, C3-8 cycloalkylcarbonyloxy-C1-6 alkyl esters (such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters), 2-oxo-1,3-dioxacyclopentenylmethyl esters (such as 5-methyl-2-oxo-1,3-dioxacyclopenten-4-ylmethyl esters), and C1-6 alkoxycarbonyloxy-C1-6 alkyl esters (such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters).

[1076] Suitable pharmaceutically acceptable prodrugs of compounds having formula (I) (which have a hydroxyl group) are, for example, esters or ethers that are cleavable in vivo. Cleavable esters or ethers of compounds of formula I containing a hydroxyl group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in a human or animal body to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include inorganic esters, such as phosphate esters (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include C1-10 alkyl acyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, C1-10 alkoxy carbonyl groups such as ethoxy carbonyl, N,N-(C1-6)2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include α-acyloxyalkyl groups such as acetoxymethyl and neopentyloxymethyl.

[1077] Suitable pharmaceutically acceptable prodrugs having a carboxyl group of a compound having formula (I) are, for example, amides that are cleavable in vivo, such as amides or esters thereof 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.

[1078] Suitable pharmaceutically acceptable prodrugs (having an amino group) of compounds having Formula I are, for example, amide derivatives of which are capable of in vivo cleavage. Suitable pharmaceutically acceptable amides derived from the amino group include, for example, amides formed with C1-10 alkyl acyl groups (such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups). Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-4 alkyl)piperazine-1-ylmethyl.

[1079] The in vivo effects of compounds having formula (I) can be exerted in part through one or more metabolites formed in humans or animals following administration of the compound having formula (I). As described above, the in vivo effects of compounds having formula (I) can also be exerted by metabolizing prodrugs (prodrugs).

[1080] While the invention may relate to any compound or particular group of compounds as defined herein by means of optional, preferred or suitable features or otherwise for particular embodiments, the invention may also relate to any compound or particular group of compounds that specifically excludes the optional, preferred or suitable features or particular embodiments.

[1081] Suitablely, the present invention excludes any single compound that does not have the biological activity defined herein.

[1082] synthesis

[1083] The compounds of the present invention can be prepared by any suitable technique known in the art. Specific methods for forming compounds having Formula I as defined herein are shown in the appended examples.

[1084] In the description of the synthetic methods described herein, and in any reference synthetic methods used to prepare the starting materials, it should be understood that those skilled in the art can choose all the proposed reaction conditions, including the selection of solvent, reaction atmosphere, reaction temperature, experimental duration, and post-treatment procedures.

[1085] Those skilled in the art of organic synthesis should understand that the functional groups present on each part of a molecule must be compatible with the reagents and reaction conditions used.

[1086] It should be understood that during the synthesis of the compounds of the present invention in the process defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituents to prevent undesirable reactions. Skilled chemists will understand when such protection is needed, and how such protecting groups can be placed in the appropriate positions and subsequently removed.

[1087] For examples of protecting groups, see one of the many general texts on the subject, such as Theodora Green’s “Protective Groups in Organic Synthesis” (John Wiley & Sons). Protecting groups can be removed by any convenient method suitable for removing the protecting groups in question, as described in the literature or known to a skilled chemist, chosen so as to achieve the removal of the protecting groups with minimal perturbation to groups elsewhere in the molecule.

[1088] Therefore, if the reactants include, for example, groups such as amino, carboxyl, or hydroxyl groups, it may be desirable to protect those groups in some of the reactions mentioned herein.

[1089] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups like acetyl groups, alkoxycarbonyl groups like methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl groups, arylmethoxycarbonyl groups like benzyloxycarbonyl groups, or aromatic acyl groups like benzoyl groups. The deprotection conditions for these protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups like alkanoyl, alkoxycarbonyl, or aromatic acyl 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 like tert-butoxycarbonyl groups can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups like benzyloxycarbonyl groups can be removed, for example, by hydrogenation with a catalyst such as palladium on carbon, or by treatment with a Lewis acid such as boron tris(trifluoroacetate). Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines (e.g., dimethylaminopropylamine) or with hydrazine.

[1090] Suitable protecting groups for the hydroxyl group are, for example, acyl groups (e.g., alkanoyl groups such as acetyl, aromatic acyl groups such as benzoyl) or arylmethyl groups (e.g., benzyl). The deprotection conditions for these protecting groups will necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or aromatic acyl groups can be removed by hydrolysis with a suitable base (e.g., an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or ammonia). Alternatively, arylmethyl groups such as benzyl can be removed, for example, by hydrogenation with a catalyst such as palladium on carbon.

[1091] Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl (which can be removed, for example, by hydrolysis with a base such as sodium hydroxide), or tert-butyl (which can be removed, for example, by treatment with an acid such as an organic acid such as trifluoroacetic acid), or benzyl (which can be removed, for example, by hydrogenation with a catalyst such as palladium on carbon).

[1092] Resins can also be used as protecting groups.

[1093] The methods used to synthesize compounds having formula (I) will vary depending on the nature of R1, R2, R3, R4, R5, and R6, as well as any substituents associated therewith. Suitable methods for their preparation are further described in the accompanying examples.

[1094] Once a compound having formula (I) has been synthesized using any of the methods defined herein, the method may further include one or more of the following additional steps:

[1095] (i) Remove any protecting groups present;

[1096] (ii) Converting a compound having formula (I) into another compound having formula (I);

[1097] (iii) Forming a pharmaceutically acceptable salt, hydrate, or solvate of a compound having formula I; and / or

[1098] (iv) Forming a prodrug of a compound having formula I.

[1099] The example of (ii) above is when a compound having formula (I) is synthesized and then one or more of groups R1, R2, R3, R4, R5 and R6 can be further reacted to change the properties of the groups and provide an alternative compound having formula (I).

[1100] The obtained compound having formula (I) can be separated and purified using techniques well known in the art.

[1101] Bioactivity

[1102] The bioassays described in the Examples section (Biological Examples 1 to 3) can be used to measure the pharmacological effects of the compounds of the present invention.

[1103] Although the pharmacological properties of compounds having Formula I vary with structural changes, as expected, the compounds of the present invention were found to be active in the assays described in biological Examples 1, 2 and 3.

[1104] Generally, regarding the antagonistic effect of adenosine A2a, the compounds of the present invention showed an IC50 of 1 μM or lower in the assay described in Biological Example 1. 50 The preferred compounds of the present invention exhibit IC50 values ​​of 200 nM or lower. 50 Furthermore, the most preferred compound of the present invention exhibits an IC50 concentration of 50 nM or lower. 50 .

[1105] Generally, regarding the antagonistic effect of adenosine A2b, the compounds of the present invention showed an IC50 of 1 μM or lower in the assay described in Biological Example 1. 50 The preferred compounds of the present invention exhibit IC50 values ​​of 200 nM or lower. 50 Furthermore, the most preferred compound of the present invention exhibits an IC50 concentration of 50 nM or lower. 50 .

[1106] Suitablely, the IC50 of the adenosine A1 or A3 receptor of the compounds of the present invention is determined in the manner described in Biological Example 1. 50 IC50 of adenosine A2a receptor 50 At least twice as high, and more appropriately, at least five times as high, and even more appropriately at least ten times as high.

[1107] Pharmaceutical Composition

[1108] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention as defined above, in combination with a pharmaceutically acceptable diluent or carrier, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1109] The compositions of the present invention may be in forms suitable for use in the following ways: oral administration (e.g., as tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical administration (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as fine powders or liquid aerosols), administration by blowing (e.g., as fine powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[1110] The compositions of the present invention can use conventional pharmaceutical excipients and are obtained through conventional procedures well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[1111] An effective amount of the compound of the invention used in a therapy is sufficient to treat or prevent the proliferative disease mentioned herein, slow its progression, and / or alleviate the symptoms associated with the disease.

[1112] The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual being treated and the specific route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, from 0.5 mg to 0.5 g of active ingredient (more preferably from 0.5 to 100 mg, e.g., from 1 to 30 mg), which is compounded with an appropriate and convenient amount of excipients, the amount of which can vary from about 5% by weight to about 98% by weight of the total composition.

[1113] Based on well-known medical principles, the dosage of a compound of formula I for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[1114] When using the compounds of the present invention for therapeutic or preventative purposes, they are typically administered such that, if fractionation is required, a daily dose ranging from, for example, 0.1 mg / kg to 75 mg / kg body weight is received. Generally, a lower dose is administered when administered via a parenteral route. Thus, for example, for intravenous or intraperitoneal administration, a dose ranging from, for example, 0.1 mg / kg body weight to 30 mg / kg body weight will typically be used. Similarly, for administration by inhalation, a dose ranging from, for example, 0.05 mg / kg body weight to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compounds of the present invention.

[1115] Therapeutic uses and applications

[1116] The present invention provides compounds that function as antagonists of adenosine A2 receptors, particularly adenosine A2a receptors.

[1117] According to another aspect of the invention, a method for antagonizing adenosine A2a receptors in vitro or in vivo is provided, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[1118] According to another aspect of the invention, a method for selectively antagonizing adenosine A2a receptors in vitro or in vivo is provided, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[1119] According to another aspect of the invention, a method for inhibiting cell proliferation in vitro or in vivo is provided, the method comprising contacting cells 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 antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1120] According to another aspect of the invention, a method is provided for treating a patient in need of such treatment with a disease or disorder related to adenosine A2a receptor activity, the method 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.

[1121] According to another aspect of the invention, a method for treating a patient requiring such treatment for a proliferative disorder is provided, the method 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1122] According to another aspect of the invention, a method for treating cancer in a patient requiring such treatment is provided, the method 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. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1123] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions thereof, are provided for use in therapy.

[1124] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, are provided for use in the treatment of proliferative disorders. Suitably, the compounds or pharmaceutical compositions are administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1125] According to another aspect of the invention, compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, are provided for use in the treatment of cancer. In a specific embodiment, the cancer is human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1126] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided for use as adenosine A2a antagonists. In examples, the compounds of the invention are selective adenosine A2a antagonists. In alternative examples, certain compounds of the invention are selective adenosine A2a and adenosine A2b antagonists.

[1127] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided for use in the treatment of diseases or disorders associated with adenosine A2a.

[1128] According to another aspect of the invention, use is provided in the manufacture of a medicament for treating proliferative disorders, in the form of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvation thereof. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1129] According to another aspect of the invention, use is provided in the manufacture of a medicament for treating cancer, as defined herein, of a compound or a pharmaceutically acceptable salt, hydrate, or solvation thereof. Suitably, the cancer is human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1130] According to another aspect of the invention, use is provided in the manufacture of a medicament for use as an adenosine A2a antagonist, in a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1131] According to another aspect of the invention, use is provided in the manufacture of a medicament for use as an adenosine A2a antagonist, in a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1132] According to another aspect of the invention, the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvation thereof, in the manufacture of a medicament for treating diseases or disorders associated with adenosine A2a receptor activity is provided.

[1133] The term "proliferative disorder" is used interchangeably throughout this document and refers to unwanted or uncontrolled cell proliferation (whether in vitro or in vivo) of an undesirable excess or abnormal number of cells, such as vesicular or proliferative growth. Examples of proliferative disorders include, but are not limited to, premalignant and malignant cell proliferation, including but not limited to malignant growths and tumors, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., fibroproliferative disorders of connective tissue), and atherosclerosis. Treatment can be administered to any type of cell, including but not limited to those in the lungs, colon, breast, ovaries, prostate, liver, pancreas, brain, and skin.

[1134] The antiproliferative effects of the compounds of the present invention are particularly suitable for the treatment of human cancers (due to their adenosine A2a antagonist activity).

[1135] More specifically, the use of compounds having general formula (I) in the treatment of cancer, particularly solid tumors such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma is provided.

[1136] More specifically, the use of compounds having the general formula (I) in the treatment of cancers, such as lung cancer, including small cell lung cancer or non-small cell lung cancer, is provided.

[1137] It also provides the use of compounds having general formula (I) in the manufacture of drugs for treating cancer, particularly solid tumors such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma.

[1138] The present invention further provides a method for treating cancer, particularly solid tumors such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma, the method comprising administering an effective amount of a compound having the general formula (I) to a patient in need of such treatment.

[1139] The patients to be treated are appropriately mammals, and even more so, humans.

[1140] Application route

[1141] The compounds of the present invention or pharmaceutical compositions comprising these compounds may be administered to a subject via any convenient route of administration, whether systemic, peripheral, or local (i.e., at the site of desired action).

[1142] Routes of administration include, but are not limited to, oral (e.g., by swallowing); buccal; sublingual; percutaneous (including, for example, by patches, plasters, etc.); mucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, via aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by a pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcorneal, intra-articular, subarachnoid, intrasternal, and intratumoral; and implantation into a reservoir or depository, such as subcutaneous or intramuscular.

[1143] The compounds of the present invention or pharmaceutical compositions comprising these compounds may be administered via intratumoral delivery.

[1144] Combination therapy

[1145] Compounds having Formula I can be used to treat and / or prevent proliferative disorders, such as cancer. Compounds having Formula I as defined herein can be used in combination with one or more other antiproliferative / anticancer therapies, such as chemotherapy with one or more other antiproliferative / anticancer agents, radiation therapy, and / or conventional surgery.

[1146] Additionally, antiproliferative / anticancer agents may be included in pharmaceutical compositions containing compounds having formula (I) as defined herein, or alternatively, may be administered alone, or simultaneously, earlier, or later with compounds having formula (I).

[1147] Therefore, in another aspect of the invention, a product is provided comprising a compound having general formula (I) and additional pharmaceutical agents for treating or preventing cancer, which is used as a combination formulation for simultaneous, sequential or individual use in the treatment of cancer.

[1148] The present invention also provides compounds having general formula (I) in combination with one or more other antiproliferative / anticancer agents for the treatment of cancer, wherein the combination formulation is used simultaneously, sequentially or alone in the treatment of cancer.

[1149] In particular, the combination therapies defined in this article are suitable for the treatment of solid tumors, such as non-small cell or small cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial carcinoma.

[1150] Suitable additional antiproliferative / anticancer agents that can be used in combination with compounds of formula I as defined herein [alone or as part of a combination pharmaceutical composition or a combination formulation with a compound of general formula (I)] include:

[1151] 1) Other forms of cancer immunotherapy and anticancer chemotherapy;

[1152] 2) Adenosine pathway regulators, including but not limited to A2b antagonists, CD73 inhibitors and CD39 inhibitors;

[1153] 3) Anti-PD-1 and PDL-1 antibodies, including but not limited to cilimatumab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab; and

[1154] 4) Anti-CTLA4 antibodies, including but not limited to ipilimumab.

[1155] Compounds of Formula I as defined herein are particularly suitable for use in combination with anti-PD-1 and PDL-1 antibodies, including but not limited to cilimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab.

[1156] Appropriately, anti-PD1 antibodies are those disclosed in U.S. Publication No. 2019 / 0225689 or U.S. Publication No. 2017 / 0121409 (incorporated herein by reference in its entirety), such as cilimab. Cilimab (JNJ-63723283, CET) is a fully human immunoglobulin (Ig) G4κ monoclonal antibody that binds to programmed death receptor-1 (PD-1) with high affinity and specificity. Cilimab has shown activity in solid tumors. Rutkowski P et al. Journal of Clinical Oncology. 2019; 37(8):31.

[1157] Compounds of Formula I as defined herein are particularly suitable for use in combination with adenosine pathway regulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors.

[1158] A2a antagonists with general formula (I) can also be used in combination with cell-based immunotherapies and cancer vaccines (including but not limited to CAR-T cell therapy).

[1159] Other examples of antiproliferative / anticancer chemotherapeutic agents include, but are not limited to, any one or more of the following:

[1160]

[1161] Interferon α-nl; Interferon α-n3; Interferon β-la; Interferon γ-lb; Isopropylplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprorelin acetate; Riazol hydrochloride; Lometraxo sodium; Lomustine; Loxoanthraquinone hydrochloride; Masrophenone; Maytansine; Nitrogen mustard hydrochloride; Medroxyprogesterone acetate; Meropenem; Minoril; Mercaptopurine; Methotrexate; Methotrexate sodium; Chlorpheniramine; Metotepamine; Mildolipid; Mitoxin; Mitoxin; Mitoxin; Mitoxin; Mitoxin; Mitoxin; Mitoxin Tan; Mitoxanthraquinone hydrochloride; Mycophenolic acid; Nocodazolate; Nopramine; Omaplatin; Oxysoxime; Pegaspargase; Peripromycin; Pentazolamide; Pyromycin sulfate; Pephosphatamide; Piperabromide; Piperabromide; Pyroanthraquinone hydrochloride; Procainamide; Promethene; Porphyrom sodium; Methylmitromycin; Prenimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazofuranoline; Lipoadenosine; Rogulam; Safungo; Safungo; Semustine; Citric acid; Sparfosate sodium sodium); Sparmycin; Germanium spiroamine hydrochloride; Spiromustin; Spiroplatin; Streptomycin; Streptozotocin; Sulfonamide; Tarimycin; Tecogallan sodium; Tegafur; Teloanthraquinone hydrochloride; Temopofen; Teniposide; Tiroxicon; Testrolide; Thiomipurine; Thioguanine; Thiotepa; Thiazofuranoline; Tirazamine; Toremifen citrate; Tritoprolone acetate; Tricerebroside phosphate; Trimethotraxa; Trimethotraxa glucuronide; Triptorelin; Tobradex hydrochloride; Uramustin; Uretepa; Vapotetide; Vertepofen; Vincristine sulfate; Sulfuric acid Vincristine; vindesine; vindesine sulfate; vinpidin sulfate; vinblastine sulfate; vinorelbine sulfate; vinorelbine tartrate; vinrodin sulfate; vinorelbine sulfate; vorticazole; zeniplatin; fentostatin; zorubicin hydrochloride; agents that arrest cells in the G2-M phase and / or regulate microtubule formation or stability (e.g., Taxol™ (paclitaxel), Taxotere™); compounds containing a taxane skeleton; irbuproazole (R-55104); sulphurin 10 (DLS-10 and NSC-376128); mivobulin ethanesulfonate. isethionate (i.e., CI-980); vincristine; NSC-639829; Discodermolide (i.e., NVP-XX-A-296); ABT-751 (Abbott, i.e., E-7010); Altorhyrtin (e.g., Altorhyrtin A and Altorhyrtin C); Spongistatin (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9);Cimadolicine hydrochloride (i.e., LU-103793 and NSC-D-669356); epothilones (such as epothilone A, epothilone B, epothilone C (i.e., deoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, and epothilone B). N-oxide, epothilone AN-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., deoxyepothilone F and dEpoF), 26-fluoroepothilone); auratestatin PE (i.e., NSC-654663); soblidotin (i.e., TZT-1027); vincristine sulfate; cyclopeptide 52 (e.g., LY-355703); vitilevuamide; tubulin inhibitor (tubulysin) A; canadensol; centaureidin (i.e., NSC-106969), oncocidin A1 (i.e., BTO-956 and DFE); Fijianolide B; Laulimalide; Nascapine (also known as NSC-5366); Nascapine; Hammetrine; Vanadyl acetylacetonate; Monsatrol; lnanocine (i.e., NSC-698666); Eleutherobin (such as desmethyleleutherobin, desaetyleleutherobin, isoeleutherobin A, and Z-eleutherobin)); Caribaeolin; Halichondrin B; Diazonamide A; arbutin A; Diozostatin; (-)-phenylalanine (i.e., NSCL-96F037); stromal protein B; Resverastatin sodium phosphate; Steroids (e.g., dexamethasone); Finasteride; Aromatase inhibitors; Gonadotropin-releasing hormone agonists (GnRH) (e.g., goserelin or leuprorelin); Adrenocortical steroids (e.g., prednisone); Progesterone (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate); Estrogens (e.g., diethylstilbestrol, ethinylestradiol); Antiestrogens (e.g., tamoxifen); Androgens (e.g., testosterone propionate, fluoxymesterone); Antiandrogens (e.g., flutamide);Immunostimulants (e.g., BCG, levamisole, interleukin-2, alpha-interferon, etc.); monoclonal antibodies (e.g., anti-CD20, anti-FLER2, anti-CD52, anti-ULA-DR, and anti-VEGF monoclonal antibodies); immunotoxins (e.g., anti-CD33 monoclonal antibody-cucurbitacin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.); radioimmunotherapy (e.g., anti-CD20 monoclonal antibody, conjugated to ln, 0Y or I, etc.); Tripterygium wilfordii; Homoharringtonine; Heparin; Doxorubicin; Epirubicin; Topotecan; Itraconazole; Vincristine; Cirivastatin; Vincristine; Deoxyadenosine; Sertraline; Pitavastatin; Irinotecan; Clofazimine; 5-Nonoxytryptamine; Vemurafenib; Dabrafenib; Erlotinib; Gefitinib; EGFR inhibitors; Epidermal growth factor receptor (EGFR) targeted therapy or therapeutic agents (e.g., Gefitinib (Iressa); TM ), Erlotinib (Tarceva) TM Cetuximab (Erbitux) TM Lapatinib (Tykerb) TM Panitumumab (Vectibix) TM ), Caprelsa TM (Afatinib / BIBW2992, CI-1033 / canenatinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, peritinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626); sorafenib; imatinib; sunitinib; dasatinib; hormone therapy, etc.

[1162] As indicated above, the combination therapies of the present invention can be achieved by administering the individual components of the treatment simultaneously, sequentially, or individually. Such combination products utilize compounds of the present invention within the dosage range described above, as well as other pharmaceutically active agents within their approved dosage ranges.

[1163] According to this aspect of the invention, a combination for treating cancer (e.g., cancer involving solid tumors) is provided, comprising a compound of the invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional antiproliferative / anticancer agents.

[1164] According to this aspect of the invention, a combination for treating proliferative conditions such as cancer (e.g., cancer involving solid tumors) is also provided, comprising the compounds of the invention as defined above, or pharmaceutically acceptable salts, hydrates or solvates thereof, and one or more additional antiproliferative / anticancer agents selected from those listed above.

[1165] In another aspect of the invention, the compounds of the invention or their pharmaceutically acceptable salts, hydrates or solvates are provided in combination with another antitumor agent for the treatment of cancer, the other antitumor agent optionally selected from one of the antitumor agents listed above.

[1166] In this document, the term "combination" is understood to mean simultaneous, individual, or sequential application. In one aspect of the invention, "combination" means simultaneous application. In another aspect of the invention, "combination" means individual application. In yet another aspect of the invention, "combination" means sequential application. In the case of sequential or individual application, delaying the application of the second component should not result in the loss of the beneficial effects of the combination.

[1167] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with an antitumor agent (optionally selected from one of the antitumor agents listed above), in conjunction with a pharmaceutically acceptable diluent or carrier.

[1168] Example

[1169] General conditions:

[1170] Mass spectrometry was performed on an LC-MS system using electrospray ionization. These were performed using 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) + ZQ mass spectrometer, or an Acquity i-Class (quaternary pump / PDA detector) + Quattro Micro mass spectrometer, a Waters Acquity LC system with Waters PDA and ELS detectors, or a Shimadzu LCMS-2010EV system. [M+H]+ refers to the molecular weight of the single isotope.

[1171] NMR spectra were run on a Bruker Ultrashield 500MHz NMR spectrometer, a Bruker Avance III HD 400MHz NMR spectrometer, or a Bruker Avance III HD 500MHz spectrometer. Spectra were recorded at 298K with the solvent peak used as a reference.

[1172] The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporation is carried out in a vacuum, preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods (e.g., trace analysis) and spectroscopic characteristics (e.g., MS, IR, and NMR). Abbreviations used are those conventional in the art. Unless otherwise defined, these terms have their generally accepted meanings.

[1173] abbreviation

[1174] app appearance

[1175] br wide peak

[1176] CDI 1,1′-carbonyldiimidazole

[1177] d double peak

[1178] dd double peak

[1179] DCM dichloromethane

[1180] DIPEA (diisopropylethylamine)

[1181] DMF N,N-dimethylformamide

[1182] DMA dimethylacetamide

[1183] EtOAc (ethyl acetate)

[1184] HPLC (High-Performance Liquid Chromatography)

[1185] LC-MS (Liquid Chromatography and Mass Spectrometry)

[1186] MeOH MeOH

[1187] MeCN Acetonitrile

[1188] MS mass spectrometry

[1189] m multiplet

[1190] mins

[1191] mL

[1192] m / z mass-to-charge ratio

[1193] NMR (Nuclear Magnetic Resonance)

[1194] ppm (parts per million)

[1195] Rt retention time

[1196] s single peak

[1197] t triple peak

[1198] TBAF tetra-n-butylammonium fluoride

[1199] TFA (trifluoroacetic acid)

[1200] THF Tetrahydrofuran

[1201] Referring to the following examples, the compounds of the preferred embodiments were synthesized using the methods described herein or other methods known in the art.

[1202] Various starting materials, intermediates, and compounds of the preferred embodiments can be separated and purified using conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, where appropriate. Unless otherwise stated, all starting materials are obtained from commercial suppliers and are ready for use without further purification. Salts can be prepared from the compounds using known salt-forming procedures.

[1203] Unless otherwise specified, the analytical HPLC conditions are as follows:

[1204] Method 2A

[1205] Pillar: Kinetex Core-Shell C18 2.1 x 50 mm 5μm

[1206] Column temperature 40℃

[1207] Eluent: A: H2O + 0.1% formic acid, B: MeCN + 0.1% formic acid

[1208] Flow rate: 1.2 mL / min

[1209] Gradient: 0-1.83min 5-100% B, 1.83-2.25min 100% B, 2.25-2.26min 100% - 5% B

[1210] Method 2.5B

[1211] Column: Phenomenex Gemini-NX C18 2 x 50mm 3μm

[1212] Column temperature: 40℃

[1213] Eluent: A: 2mM ammonium bicarbonate, buffered to pH 10; B: MeCN

[1214] Flow rate: 1 mL / min

[1215] Gradient: 0-1.80 min 1%-100% B, 1.80-2.10 min 100% B, 2.10- 2.30min 100%-1% B

[1216] Method 2B

[1217] Column: Acquity UPLC BEH C18 2.1x 50mm, 1.7μm

[1218] Column temperature: 50℃

[1219] Eluent: A: H2O, 0.1% formic acid; B: MeCN

[1220] Flow rate: 0.8 mL / min

[1221] Gradient: 0.0-1.8 min 2%-98% B, 1.8-2.1 min 98% B, 2.1-2.5 min 98% A

[1222] Method 3A

[1223] Column: Acquity LC BEH C18 2.1x 50mm 1.7μm

[1224] Column temperature: 50℃

[1225] Eluent: A: H2O, 0.1% formic acid, B: MeCN

[1226] Flow rate: 0.6 mL / min

[1227] Gradient: 0.2-2.5 min 2%-98% B, 2.5-3.3 min 98% B, 3.3-3.5 min 98% A

[1228] Method 3B

[1229] Column: Acquity LC BEH C18 2.1x 50mm 1.7μm

[1230] Column temperature: 50℃

[1231] Eluent: A: H2O, 0.1% ammonia, B: MeCN

[1232] Flow rate: 0.6 mL / min

[1233] Gradient: 0.2-2.5 min 2%-98% B, 2.5-3.3 min 98% B, 3.3-3.5 min 98% A

[1234] Method 5A

[1235] Column: YMC-Triart C18 2x 50mm, 5μm.

[1236] Flow rate: 0.8 mL / min.

[1237] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% Formic Acid

[1238] 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

[1239] Method 5B

[1240] Column: Waters Alliance ZQ MS, YMC-Triart C18 50x 2mm, 5μm

[1241] Column temperature: room temperature

[1242] Eluent: A: H2O, B: CH3CN, C: 50% H2O / 50% CH3CN + 1.0% ammonia (aqueous)

[1243] Flow rate: 0.8 mL / min.

[1244] 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

[1245] Method 7A

[1246] Column: Phenomenex Kinetix-XB C18 2.1 x 100 mm, 1.7 μm

[1247] Column temperature: 40℃

[1248] Eluent: A: H2O 0.1% formic acid, B: MeCN 0.1% formic acid

[1249] Flow rate: 0.6 mL / min

[1250] Gradient: 0-5.3 min 5%-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100%-5%B, 5.82-7.00min 5%B

[1251] Method 7B

[1252] Column: Waters BEH TM C18, 2.1mm x 100mm, 1.7μm

[1253] Column temperature: 40℃

[1254] Eluent: A: 2mM ammonium bicarbonate, buffered to pH 10; B: MeCN

[1255] Flow rate: 0.6 mL / min

[1256] Gradient: 0-5.3 min 5%-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100%-5%B, 5.82-7.00min 5%B

[1257] Method 8A

[1258] Column: Acquity UPLC BEH C18 2.1x 100mm, 1.7μm

[1259] Column temperature: 50℃

[1260] Eluent: A: H2O, 0.1% formic acid; B: MeCN

[1261] Flow rate: 0.6 mL / min

[1262] Gradient: 0.5-6.5 min 2%-98% B; 6.5-7.5 min 98% B

[1263] Method 8B

[1264] Column: Acquity UPLC BEH C18 2.1x 100mm, 1.7μm

[1265] Column temperature: 50℃

[1266] Eluent: A: H2O, 0.1% ammonia; B: MeCN

[1267] Flow rate: 0.6 mL / min

[1268] Gradient: 0.5-6.5 min 2%-98% B; 6.5-7.5 min 98% B

[1269] Method 15A

[1270] Column: YMC-Triart C18 2x 50mm, 5μm.

[1271] Flow rate: 0.8 mL / min.

[1272] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% Formic Acid

[1273] 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

[1274] Method 15B

[1275] Column: YMC-Triart C18 50x 2mm, 5μm.

[1276] Flow rate: 0.8 mL / min.

[1277] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% ammonia (aqueous)

[1278] 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

[1279] Preparative HPLC using acidic pH and early elution methods

[1280] 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 of 10%–95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in MeCN) for 14.44 min, followed by 95% B for 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.

[1281] Preparative HPLC using alkaline pH and early elution methods

[1282] Purification by preparative HPLC (alkaline pH, early elution method) was performed on a Gilson LC system using a Waters Xbridge C18 column (30 mm × 100 mm, 10 μM; temperature: room temperature) with a gradient of 10%–95% (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in MeCN) for 14.44 min, followed by 95% B for 2.11 min. The injection volume was 1500 μL and the flow rate was 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[1283] Example 1

[1284] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]morpholine-4-carboxamide

[1285]

[1286] Step 1 N-[4-(3-cyanophenyl)thiazolyl-2-yl]morpholine-4-carboxamide

[1287]

[1288] Sodium hydride (60% in mineral oil) (150 mg, 3.75 mmol) was added to a stirred solution of 3-(2-aminothiazolyl-4-yl)benzyl nitrile (intermediate A) (653 mg, 3.08 mmol) in 10 mL of THF. After stirring at room temperature for 20 min, morpholine-4-carbonyl chloride (520 μL, 4.55 mmol) was added and stirring was continued for 18 h. The resulting mixture was diluted with 10 mL of THF and then treated with sodium hydride (60% in mineral oil) (150 mg, 3.75 mmol). After stirring for 10 min, morpholine-4-carbonyl chloride (520 μL, 4.55 mmol) was added and stirring was continued for 4 h. 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 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and concentrated under vacuum. The resulting brown oil was purified by chromatography on silica using 0-100% EtOAc elution in heptane to give the title compound as a beige solid.

[1289] LC-MS (Method 2A): Rt 1.06 min; MS m / z 315.1 = [M + H] +

[1290] 1H NMR (400MHz, DMSO-d6) δ11.05(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).

[1291] Step 2 N-[5-bromo-4-(3-cyanophenyl)thiazo-2-yl]morpholine-4-carboxamide

[1292]

[1293] NBS (499 mg, 2.8 mmol) was added to a solution of N-[4-(3-cyanophenyl)thiazolyl]morpholine-4-carboxamide (step 1) (790 mg, 2.34 mmol) in THF (20 mL), 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 NaHCO3 solution (2 × 30 mL), and brine (30 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to give the title compound as a yellow solid.

[1294] LC-MS (Method 2A): Rt 1.18 min; MS m / z 393.0 / 395.0 = [M+H]+

[1295] 1 H NMR(500MHz,DMSO-d6)δ11.35(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).

[1296] Step 3 N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]morpholine-4-carboxamide

[1297] A stirred solution of N-[5-bromo-4-(3-cyanophenyl)thiazo-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 ethylene glycol dimethyl ether (3 mL) and water (0.5 mL) was degassed with nitrogen for 5 min. Bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.03 mmol) was added, and the reaction mixture was heated at 85 °C for 7.5 h. After cooling to room temperature, the mixture was diluted with DCM (5 mL) and water (5 mL). The organic layer was separated by passing it through a hydrophobic glass frit and concentrated under vacuum. The crude product was purified by elution with acetonitrile / water / 0.1% formic acid using C18 reversed-phase chromatography, and then further purified by elution with acetonitrile / water / 0.1% ammonia using C18 reversed-phase chromatography to obtain the title compound as a bright yellow powder.

[1298] LC-MS (Method 2.5B): Rt 3.58 min; MS m / z 440.1 / 442.1=[M+H]+

[1299] 1 H NMR(400MHz,DMSO-d6)δ11.40(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)

[1300] Example 2

[1301] N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide

[1302]

[1303] Step 1 N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]imidazol-1-carboxamide

[1304]

[1305] A solution of 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (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 h. Another portion of CDI (55 mg, 0.34 mmol) was added and stirring continued at room temperature for 2 h, followed by stirring at 50 °C for 1 h. After cooling to room temperature, the resulting precipitate was collected by vacuum filtration to give the title compound as a pale yellow solid.

[1306] LC-MS (Method 7B): Rt 3.76 min; MS m / z 385.1 = [M-(C3N2H5)+(OCH3)]+; Methyl carbamate was observed from the reaction of the title compound with MeOH.

[1307] 1 H NMR (400MHz, DMSO-d6) δ8.43(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).

[1308] Step 2 N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide

[1309] Add 2-pyrrolidine-3-ylprop-2-ol (22 mg, 0.17 mmol) to a stirred solution of N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazolyl-2-yl]imidazolium-1-carboxamide (step 1) (59 mg, 0.09 mmol) in DMA (0.5 mL), and stir the reaction mixture at room temperature for 30 min. Add another portion of 2-pyrrolidine-3-ylprop-2-ol (22 mg, 0.17 mmol) and continue stirring for 3 days. Add DIPEA (30 μL, 0.17 mmol), followed by further addition of 2-pyrrolidine-3-ylprop-2-ol (22 mg, 0.17 mmol), and heat the mixture to 50 °C for 18 h. Dilute the resulting mixture with water (3 mL) and extract with EtOAc (3 × 3 mL). Filter the combined organic extracts through a phase separation column and concentrate under vacuum. The crude product was purified by chromatography on silica using 0-100% EtOAc in DCM, followed by elution with 0-10% MeOH in EtOAc to give the title compound as a grayish-white solid.

[1310] LC-MS (Method 7B): Rt 3.23 min; MS m / z 482.3 / 484.2 = [M+H]+

[1311] 1 H NMR (400MHz, DMSO-d6) δ11.05(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,1H),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).

[1312] Example 3

[1313] (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide

[1314]

[1315] A solution of 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (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 allowed to cool to room temperature and then stirred with 2-[(2R)-pyrrolidine- [2-yl]prop-2-ol hydrochloride (40 mg, 0.24 mmol) and DIPEA (55 μL, 0.32 mmol). Stirring was continued for 1 h at room temperature and then at 50 °C for 1 h. After cooling to room temperature, the mixture was diluted with water (3 mL) and extracted with EtOAc (3 × 3 mL). The combined organic extracts were filtered through a phase separation column and concentrated under vacuum. The resulting orange solid was purified by chromatography on silica using 0–100% EtOAc in DCM, followed by a second purification by chromatography on silica using 0–100% EtOAc in heptane to give the title compound as a grayish-white solid.

[1316] LC-MS (Method 7B): Rt 3.62 min; MS m / z 482.3 / 484.3=[M+H]+

[1317] 1 H NMR (400MHz, DMSO-d6) δ12.00(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,1 H),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).

[1318] Similar to Example 3, compounds of the examples listed below (Table Ex3) are prepared from 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate D) and a suitable amine.

[1319] Table Ex3

[1320]

[1321]

[1322]

[1323] BY23IM02020FGPC-CN

[1324]

[1325]

[1326] Example 4

[1327] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-methylpiperazine-1-carboxamide

[1328]

[1329] A solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (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 stirred at 50 °C for another 1 h. After cooling to room temperature, the crude mixture was purified by preparative HPLC using an early elution under acidic conditions to give the title compound.

[1330] LC-MS (Method 7B): Rt 2.43 min; MS m / z 433.3 = [M + H] +

[1331] 1 H NMR(500MHz,DMSO-d6)δ11.27(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).

[1332] Example 4.1

[1333] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide

[1334]

[1335] A solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (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-carboxynitrile (36 mg, 0.33 mmol) and DIPEA (90 μL, 0.49 mmol) and stirred at 50 °C for 30 min. After cooling to room temperature, the crude material was purified by C18 reversed-phase chromatography by elution with 5–20% MeCN in water (+0.1% ammonium hydroxide modifier) ​​to obtain a solid, which was suspended in Et2O (2 mL), collected by filtration, washed with Et2O (2 × 1.5 mL), and dried to give the title compound as a yellow solid.

[1336] LC-MS (Method 8B): Rt 4.17 min; MS m / z 443.3 = [M + H] +

[1337] 1 H NMR (500MHz, DMSO-d6) δ11.28(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).

[1338] Similar to Example 4 or Example 4.1, compounds of the examples listed below (Table Ex4) are prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and a suitable amine.

[1339] TableEx4

[1340]

[1341]

[1342]

[1343]

[1344] BY23IM02020FGPC-CN

[1345]

[1346]

[1347]

[1348]

[1349]

[1350] BY23IM02020FGPC-CN

[1351]

[1352] BY23IM02020FGPC-CN

[1353]

[1354]

[1355] BY23IM02020FGPC-CN

[1356]

[1357]

[1358] Example 4.12

[1359] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1360]

[1361] 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)thiazolyl-4-yl]benzylnitrile (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 allowed to cool to room temperature, then diluted with EtOAc (150 mL), washed with 90% brine (100 mL), 50% brine (3 × 100 mL), dried over MgSO4, and concentrated under vacuum. The title compound was purified by chromatography on silica using a gradient elution of 0 to 4% MeOH in DCM to give a grayish-white solid.

[1362] LC-MS (Method 8B): Rt 2.82 min; MS m / z 432.0 = [M + H] +

[1363] 1H NMR (500MHz, DMSO-d6) δ11.35(s,1H),7.88(t,J=1.7Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7.70(d t,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).

[1364] Example 5: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]carbamoyl]piperazine-2-carboxylic acid

[1365]

[1366] Example 5.1: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]carbamoyl]piperazine-2-carboxylic acid methyl ester

[1367]

[1368] Step 1: (2R)-1-tert-butoxycarbonyl-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]carbamoyl]piperazine-2-carboxylic acid

[1369]

[1370] A solution of 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (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-butoxycarbonylpiperazin-2-carboxylic acid (106 mg, 0.46 mmol) and DIPEA (53 μL, 0.31 mmol) and stirred and heated at 50 °C for 1 h. 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 column and concentrated under vacuum. 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 under vacuum to give the title compound as a brown solid.

[1371] LC-MS (Method 2A): Rt 1.25 min; MS m / z 583.2 / 585.2=[M+H]+

[1372] 1 ¹H NMR (400MHz, 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.

[1373] Step 2: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]carbamoyl]piperazine-2-carboxylic acid and (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]carbamoyl]piperazine-2-carboxylic acid methyl ester

[1374] To a solution of (2R)-1-tert-butoxycarbonyl-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]carbamoyl]piperazin-2-carboxylic acid (step 1) (94 mg, 0.13 mmol) in DCM (2 mL) and MeOH (0.2 mL), 4 M HCl (322 μL, 1.29 mmol) in 1,4-dioxane was added, and the reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under vacuum, and the crude mixture was purified by HPLC using acidic conditions and early elution to give the following compounds:

[1375] Example 5: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazolyl]carbamoyl]piperazin-2-carboxylic acid is a grayish-white solid.

[1376] LC-MS (Method 7A): Rt 2.08 min; MS m / z 483.2 / 485.1 = [M + H] + (99%, at 215 nm)

[1377] 1¹H NMR (500MHz, 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). No 2x NH and COOH protons were observed. 2x CH signal was observed under H₂O signal.

[1378] Example 5.1: Methyl (2R)-4-[[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazolyl-2-yl]carbamoyl]piperazine-2-carboxylate is a grayish-white solid.

[1379] LC-MS (Method 7A): Rt 2.10 min; MS m / z 497.2 / 499.1 = [M + H] + (99%, at 215 nm)

[1380] 1 H NMR(500MHz,DMSO-d6)δ7.92(t,J=1.5Hz,1H),7.85(dt,J=7.7,1.3Hz,1H),7.7 2(dt,J=8.0,1.4Hz,1H),7.59(t,J=7.8Hz,1H),7.18(s,1H),7.06(s,1H),4.07– 4.00(m,1H),3.74(d,J=12.9Hz,1H),3.66(s,3H),3.46(dd,J=8.3,3.5Hz,1H),3 .22–3.17(m,1H),2.91(dt,J=11.9,3.3Hz,1H),2.62–2.58(m,1H),2.40(s,3H). No 2x NH protons were observed. A 1x CH signal was observed under H2O signal.

[1381] Similar to Example 5, compounds of the examples listed below (Table Ex5) were prepared from 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate D) and a suitable amine (step 1), followed by deprotection with 4M HCl in 1,4-dioxane (step 2).

[1382] Table Ex5

[1383]

[1384]

[1385]

[1386]

[1387]

[1388]

[1389]

[1390] Example 6

[1391] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methyl-piperidine-1-carboxamide

[1392]

[1393] A solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (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 4-methylpiperidin-4-carboxynitrile hydrochloride (52 mg, 0.33 mmol) and DIPEA (85 μL, 0.49 mmol) and stirred at 50 °C for 1 h. After cooling to room temperature, the crude mixture was purified by preparative HPLC using an early elution under acidic conditions to give the title compound as a colorless solid.

[1394] Example 6 was also prepared using the following procedure:

[1395] 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)thiazolyl-4-yl]benzylnitrile (intermediate C) (1.20 g, 3.92 mmol) in DMA (12 mL), and the solution was heated at 50 °C overnight. 4-Methylpiperidine-4-carboxynitrile 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, diluted with EtOAc (150 mL), washed with 90% brine (100 mL), 50% brine (3 × 100 mL), dried over MgSO4, and concentrated under vacuum. The yellow solid was purified by chromatography on silica using a gradient elution of 1% to 3% MeOH in DCM. The addition of MeOH (15 mL) yielded a white solid, which was collected by filtration, washed with MeOH (2 mL) and Et₂O (20 mL), and dried to give the title compound as a colorless solid.

[1396] LC-MS (Method 8B): Rt 3.24 min; MS m / z 457.2 = [M + H] +

[1397] 1H NMR (500MHz, DMSO-d6) δ11.31(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).

[1398] Similar to Example 6, compounds of the examples listed below (Table Ex 6) are prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzylnitrile (intermediate C) or a suitable starting intermediate and a suitable amine.

[1399] Table Ex6

[1400]

[1401] BY23IM02020FGPC-CN

[1402]

[1403] BY23IM02020FGPC-CN

[1404]

[1405]

[1406]

[1407]

[1408]

[1409]

[1410]

[1411]

[1412]

[1413]

[1414]

[1415]

[1416]

[1417]

[1418]

[1419]

[1420]

[1421]

[1422]

[1423]

[1424]

[1425]

[1426]

[1427]

[1428]

[1429]

[1430]

[1431]

[1432]

[1433]

[1434]

[1435]

[1436]

[1437]

[1438]

[1439]

[1440]

[1441]

[1442]

[1443]

[1444]

[1445]

[1446]

[1447]

[1448]

[1449]

[1450]

[1451]

[1452]

[1453]

[1454]

[1455]

[1456]

[1457]

[1458] Example 7

[1459] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperazine-1-carboxamide

[1460]

[1461] Step 1: 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]piperazine-1-carboxylic acid tert-butyl ester

[1462]

[1463] A solution of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (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 stirred 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 column, and concentrated under vacuum. The crude product was purified by chromatography on silica using 0–100% EtOAc elution in DCM to give the title compound.

[1464] LC-MS (Method 7A): Rt 2.16 min; MS m / z 519.3 = [M + H] +

[1465] 1 H NMR (500MHz, DMSO-d6) δ11.30(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).

[1466] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperazine-1-carboxamide

[1467] A solution of 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]piperazine-1-carboxylic acid tert-butyl ester (step 1) (70 mg, 0.14 mmol) in DCM (2 mL), MeOH (2 drops), and 4M HCl (338 μL, 1.35 mmol) in 1,4-dioxane was stirred at room temperature for 22 h. The resulting mixture was concentrated under vacuum, and the crude product was purified by preparative HPLC under acidic conditions with early elution to give the title compound.

[1468] LC-MS (Method 7A): Rt 0.94 min; MS m / z 419.2 = [M + H] +

[1469] 1 ¹H 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). No 2x NH protons were observed.

[1470] Example 7.1

[1471] (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-piperazin-1-carboxamide

[1472]

[1473] Step 1: (2R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

[1474]

[1475] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and (2R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester.

[1476] LC-MS (Method 2A): Rt 1.07 min; MS m / z 533.3 = [M + H] +

[1477] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),7.89(t,J=1.5Hz,1H),7.82(dt,J=7.7,1.7H z,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),3.0 9–3.00(m,1H),2.99–2.89(m,1H),2.36(s,6H),1.42(s,9H),1.07(d,J=6.7Hz,3H).

[1478] Step 2: (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-piperazin-1-carboxamide

[1479] Similar to step 2 of Example 7, the title compound was prepared from (2R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester and 4M HCl in 1,4-dioxane.

[1480] LC-MS (Method 7A): Rt 1.00 min; MS m / z 433.2 = [M + H] +

[1481] 1 ¹H NMR (400MHz, 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). No 2x NH protons were observed.

[1482] Example 7.2

[1483] 4-Amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide

[1484]

[1485] Step 1: N-[4-cyano-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-4-piperidinyl]tert-butyl carbamate

[1486]

[1487] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and N-(4-cyano-4-piperidinyl)carbamate tert-butyl ester.

[1488] LC-MS (Method 5B): Rt 2.95 min; MS m / z 558.2 = [M + H] +

[1489] 1 H NMR (500MHz, DMSO-d6) δ 11.34 (s, 1H), 7.88 (s, 1H), 7.82 (d, J = 7.9Hz, 1H), 7.77 (s, 1H), 7.70 (d, J = 7.9Hz, 1H), 7.56 (t, J = 7.9Hz, 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 1xCH2 signal was observed.

[1490] Step 2: 4-Amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide

[1491] Similar to step 2 of Example 7, the title compound was prepared from N-[4-cyano-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-4-piperidinyl] tert-butyl carbamate and 4M HCl in 1,4-dioxane.

[1492] LC-MS (Method 8B): Rt 3.30 min; MS m / z 458.3 = [M + H] +

[1493] 1H NMR (500MHz, DMSO-d6) δ11.31(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).

[1494] Example 7.3

[1495] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide

[1496]

[1497] Step 1: 9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylic acid tert-butyl ester

[1498]

[1499] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate.

[1500] LC-MS (Method 2A): Rt 0.77 min; MS m / z 589.3 = [M + H] +

[1501] 1H NMR (500MHz, DMSO-d6) δ11.22(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),3.28–3.1 6(m,4H),2.36(s,6H),1.75–1.69(m,2H),1.52–1.44(m,2H),1.41(s,9H).

[1502] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide

[1503] Similar to step 2 of Example 7, the title compound was prepared from 9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylic acid tert-butyl ester (step 1) and 4M HCl in 1,4-dioxane.

[1504] LC-MS (Method 7B): Rt 2.68 min; MS m / z 489.4 = [M + H] +

[1505] ¹H NMR (500MHz, DMSO-d⁶) 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). No 2x NH protons were observed.

[1506] Example 7.4

[1507] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

[1508]

[1509] Step 1: 8-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[1510]

[1511] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate.

[1512] LC-MS (Method 2A): Rt 0.77 min; MS m / z 545.3 = [M + H] +

[1513] 1H NMR (400MHz, DMSO-D6) δ11.37(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),4.60–4.49(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).

[1514] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

[1515] Similar to step 2 of Example 7, the title compound was prepared from 8-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (step 1) and 4M HCl in 1,4-dioxane.

[1516] LC-MS (Method 7B): Rt 2.57 min; MS m / z 445.4 = [M + H] +

[1517] ¹H NMR (500 MHz, methanol-d⁴) 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). No 2x NH protons were observed.

[1518] Example 7.5

[1519] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[1520]

[1521] Step 1: 6-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester

[1522]

[1523] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate.

[1524] LC-MS (Method 2A): Rt 0.70 min; MS m / z 531.3 = [M + H] +

[1525] 1H NMR (500MHz, DMSO-d6) δ11.59(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,2H),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).

[1526] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[1527] Similar to step 2 of Example 7, the title compound was prepared from 6-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (step 1) and 4M HCl in 1,4-dioxane.

[1528] LC-MS (Method 7A): Rt 0.98 min; MS m / z 431.3 = [M + H] +

[1529] ¹H NMR (500 MHz, methanol-d⁴) 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). No 2x NH protons were observed.

[1530] Example 7.6

[1531] (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxamide

[1532]

[1533] Step 1: (1R,4R)-5-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester

[1534]

[1535] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and (2R,5R)-5-ethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester.

[1536] LC-MS (Method 2A): Rt 0.76 min; MS m / z 545.3 = [M + H] +

[1537] 1H NMR (500MHz, DMSO-d6) δ11.07(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).

[1538] Step 2: (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxamide

[1539] Similar to step 2 of Example 7, the title compound was prepared from (1R,4R)-5-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (step 1) and 4M HCl in 1,4-dioxane.

[1540] LC-MS (Method 7A): Rt 0.99 min; MS m / z 445.3 = [M + H] +

[1541] 1H NMR (500MHz, methanol-d4) δ7.91(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 = 10.7Hz, 1H), 3.28–3.23(m, 1H), 3.22–3.18(m, 1H), 3.11(dd, J = 11.5, 1.9Hz, 1H), 2.43(s, 6H), 2.08–1.98(m, 2H), 1.97–1.89(m, 1H), 1.88–1.80(m, 1H). No 2x NH protons were observed.

[1542] Example 7.7

[1543] (2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,5-dimethyl-piperazin-1-carboxamide

[1544]

[1545] Step 1: (2S,5S)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

[1546]

[1547] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and cis-(2S,5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester.

[1548] LC-MS (Method 7A): Rt 0.80 min; MS m / z 547.4 = [M + H] +

[1549] 1H NMR (400MHz, DMSO-d6) δ11.19(s,1H),7.89(t,J=1.7Hz,1H),7.82(dt,J=7.8,1.4H z,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=14.2,1 0.7Hz, 1H), 2.36 (s, 6H), 1.39 (s, 9H), 1.10 (d, J = 6.1Hz, 3H), 1.06 (d, J = 6.1Hz, 3H).

[1550] Step 2: (2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,5-dimethyl-piperazin-1-carboxamide

[1551] Similar to step 2 of Example 7, the title compound was prepared from (2S,5S)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (step 1) and 4M HCl in 1,4-dioxane.

[1552] LC-MS (Method 7B): Rt 2.72 min; MS m / z 447.3 = [M + H] +

[1553] 1H NMR (500MHz, methanol-d4) δ7.91(t,J=1.7Hz,1H),7.71(dt,J=7.9,1.4Hz,1H),7.69( dt,J=7.8,1.4Hz,1H),7.49(dd,J=7.8,7.8Hz,1H),7.00(s,2H),4.37–4.29(m,1 H),3.98–3.90(m,1H),2.99(dd,J=12.9,4.2Hz,1H),2.90(dd,J=12.9,1.5Hz,1H ),2.78–2.69(m,2H),2.43(s,6H),1.31(d,J=6.9Hz,3H),1.16(d,J=5.8Hz,3H). No 2x NH protons were observed.

[1554] Example 7.8

[1555] (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,6-dimethyl-piperazin-1-carboxamide

[1556]

[1557] Step 1 (3R,5R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

[1558]

[1559] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and (3R,5R)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester.

[1560] LC-MS (Method 2A): Rt 0.81 min; MS m / z 547.3 = [M + H] +

[1561] 1H NMR (400MHz, DMSO-d6) δ11.16(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),7.5 6(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).

[1562] Step 2: (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,6-dimethyl-piperazin-1-carboxamide

[1563] Similar to step 2 of Example 7, the title compound was prepared from racemic-(3R,5R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3,5-dimethyl-piperazine-1-carboxylate (step 1) and 4M HCl in 1,4-dioxane.

[1564] LC-MS (Method 7B): Rt 2.73 min; MS m / z 447.4 = [M + H] +

[1565] ¹H NMR (400 MHz, methanol-d⁴) 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). - No 2x NH protons observed.

[1566] Example 7.9

[1567] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,2-dimethyl-piperazin-1-carboxamide

[1568]

[1569] Step 1:4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

[1570]

[1571] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and tert-butyl 3,3-dimethylpiperazine-1-carboxylate.

[1572] LC-MS (Method 2A): Rt 0.83 min; MS m / z 547.3 = [M + H] +

[1573] 1H NMR (500MHz, DMSO-d6) δ11.24(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).

[1574] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,2-dimethyl-piperazin-1-carboxamide

[1575] Similar to step 2 of Example 7, the title compound was prepared from 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (step 1) and 4M HCl in 1,4-dioxane.

[1576] LC-MS (Method 7B): Rt 2.88 min; MS m / z 447.4 = [M + H] +

[1577] ¹H NMR (400 MHz, methanol-d⁴) 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). No 2x NH protons were observed.

[1578] Example 7.10

[1579] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide

[1580]

[1581] Step 1: 5-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-5,8-diazaspiro[3,5]nonane-8-carboxylic acid tert-butyl ester

[1582]

[1583] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and tert-butyl 5,8-diazaspiro[3.5]nonane-8-carboxylate.

[1584] LC-MS (Method 2A): Rt 0.83 min; MS m / z 559.3 = [M + H] +

[1585] 1H NMR (400MHz, DMSO-d6) δ11.40(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,6 H),2.28–2.16(m,3H),2.04–1.97(m,2H),1.81–1.75(m,1H),1.42(s,9H).

[1586] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide

[1587] Similar to step 2 of Example 7, the title compound was prepared from 5-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-5,8-diazaspiro[3.5]nonane-8-carboxylic acid tert-butyl ester (step 1) and 4M HCl in 1,4-dioxane.

[1588] LC-MS (Method 7B): Rt 2.48 min; MS m / z 459.3 = [M+H]+

[1589] ¹H NMR (400 MHz, methanol-d⁴) 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). No 2x NH protons were observed.

[1590] Example 7.11

[1591] trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-dimethyl-piperazine-1-carboxamide

[1592]

[1593] Step 1: trans-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

[1594]

[1595] Similar to step 1 in Example 7, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and trans-2,5-dimethylpiperazine-1-carboxylate tert-butyl ester.

[1596] LC-MS (Method 2A): Rt 0.81 min; MS m / z 547.3 = [M + H] +

[1597] 1H NMR (400MHz, DMSO-d6) δ11.29(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),3.92–3.8 5(m,1H),3.65–3.56(m,1H),2.36(s,6H),1.42(s,9H),1.15–1.01(m,6H).

[1598] Step 2: trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-dimethyl-piperazine-1-carboxamide

[1599] Similar to step 2 of Example 7, the title compound was prepared from trans-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (step 1) and 4M HCl in 1,4-dioxane.

[1600] LC-MS (Method 7A): Rt 1.10 min; MS m / z 447.3 = [M + H] +

[1601] ¹H NMR (400 MHz, methanol-d⁴) 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). No 2x NH protons were observed.

[1602] Example 8

[1603] 1-Acetylimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide

[1604]

[1605] Triethylamine (37 μL, 0.27 mmol) was added to a suspension of N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide (Example 4.2) (50 mg, 0.11 mmol) in DCM (2.5 mL) at 0 °C, followed by the addition of acetyl chloride (10 μL, 0.14 mmol), and the mixture was stirred for 1 h. Another portion of acetyl chloride (10 μL, 0.14 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min, followed by the addition of additional acetyl chloride (4 μL, 0.05 mmol), and the reaction mixture was stirred at 0 °C for 15 min. The resulting mixture was concentrated under vacuum and then partitioned between 10% MeOH (20 mL) and water (20 mL) in EtOAc. The layers were separated, and the aqueous layer was further extracted with 10% MeOH (2 × 20 mL) in EtOAc. The combined organic extracts were concentrated under vacuum, and the crude material was purified by C18 reversed-phase chromatography with 5–15% MeCN elution in water (+0.1% ammonium hydroxide modifier) ​​to give the title compound as a grayish-white solid.

[1606] LC-MS (Method 8B): Rt 2.16 min; MS m / z 509.3 = [M + H] +

[1607] 1 H NMR (500MHz, DMSO-d6) δ11.58(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).

[1608] Example 9

[1609] N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1610]

[1611] A solution of 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate I) (60 mg, 0.13 mmol) and CDI (49 mg, 0.30 mmol) in DMA (0.5 mL) was stirred overnight at 50 °C. 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 stirred at 50 °C for 30 min. The reaction mixture was cooled to room temperature and 1 M TBAF (211 μL, 0.21 mmol) in THF was added. After stirring for 15 min, the resulting mixture was purified by C18 reversed-phase chromatography using a gradient elution of 5% to 15% MeCN in water (+0.1% ammonium hydroxide modifier). The product fractions were combined, concentrated, and loaded onto... SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH3 (30 mL) in MeOH. The solvent was removed under vacuum and the resulting material was ground in 2:1 hexane / diethyl ether (1 mL) to give a solid. The solid was further purified by chromatography on silica using a gradient elution of 0 to 4% MeOH in DCM to give the title compound as a yellow solid.

[1612] LC-MS (Method 8B): Rt 2.93 min; MS m / z 448.3 = [M + H] +

[1613] 1H NMR (500MHz, DMSO-d6) δ11.36(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).

[1614] Similar to Example 9, compounds of the examples listed below (Table Ex 9) are prepared from 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate I) and a suitable amine.

[1615] Table Ex9

[1616]

[1617]

[1618]

[1619]

[1620]

[1621] Example 10

[1622] N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinyl-4-carboxamide

[1623]

[1624] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate M) and 1,4-thiazine 1-oxide hydrochloride.

[1625] LC-MS (Method 8A): Rt 2.64 min; MS m / z 470.3 = [M + H] +

[1626] 1H NMR (500MHz, DMSO-d6) δ11.51(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).

[1627] Example 11

[1628] 1-Cyanoimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide

[1629]

[1630] DMAP (14 mg, 0.12 mmol) was added to a suspension of N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-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, followed by the addition of cyanogen bromide (23 mg, 0.21 mmol), and the mixture was stirred at 0 °C for 1 h 10 min. Additional cyanogen bromide (3 mg, 0.03 mmol) and DMAP (2 mg, 0.02 mmol) were added, and stirring continued at 0 °C for 1 h. Additional cyanogen bromide (6 mg, 0.05 mmol) and DMAP (3 mg, 0.03 mmol) were added, and after stirring for 45 min, the mixture was concentrated under vacuum. The crude product was purified by C18 reversed-phase chromatography with elution of 5% to 40% MeCN in water (containing 0.1% ammonium hydroxide modifier), and further purified by chromatographic gradient elution on silica with 0% to 5% MeOH in DCM, followed by chromatographic gradient elution on silica with 0% to 80% EtOAc in DCM to give the title compound as a yellow solid.

[1631] LC-MS (Method 8B): Rt 4.70 min; MS m / z 492.0 = [M + H] +

[1632] 1H NMR (500MHz, DMSO-d6) δ11.64(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,1H),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).

[1633] Example 12

[1634] 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide

[1635]

[1636] Step 1: 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidine-1-carboxamide

[1637]

[1638] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate J) and 4-methylpiperidine-4-carboxynitrile.

[1639] LC-MS (Method 3B): Rt 2.37 min; MS m / z 621.4 = [M + H] +

[1640] 1H NMR(500MHz,DMSO-d6)δ11.34(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),6.86–6.8 0(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).

[1641] Step 2: 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide

[1642] Trifluoroacetic acid (0.38 mL, 4.96 mmol) was added to a solution of 4-cyano-N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide (step 1) (77 mg, 0.12 mmol) in DCM (3.6 mL), and the mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with DCM (15 mL) and washed with a saturated NaHCO3 solution (2 × 20 mL), then dried over Na2SO4 and the solvent was removed under vacuum. The oil was purified by chromatography on silica by elution with 3% MeOH in DCM, which was then suspended in 10% Et2O / hexane, resulting in the formation of a precipitate, which was collected by filtration and dried to give the title compound as a grayish-white solid.

[1643] LC-MS (Method 8B): Rt 4.20 min; MS m / z 501.2 = [M + H] +

[1644] 1H NMR (500MHz, DMSO-d6) δ11.33(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).

[1645] Example 12.1

[1646] N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-6-oxa-2-azaspiro[3,4]octane-2-carboxamide

[1647]

[1648] Step 1: N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-6-oxa-2-azaspiro[3,4]octane-2-carboxamide

[1649]

[1650] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate J) and 6-oxa-2-azaspiro[3.4]octane.

[1651] LC-MS (Method 3B): Rt 2.17 min; MS m / z 610.3 = [M + H] +

[1652] 1H NMR (500MHz, methanol-d4) δ7.82(t,J=1.6Hz,1H),7.69(dt,J=7.8,1.6Hz,1H),7.51(dt, J=7.8,1.6Hz,1H),7.38(t,J=7.8Hz,1H),7.26(d,J=1.6Hz,1H),7.15(d,J=1.6Hz,1 (H), 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=7.0Hz,2H), 3.80(s,3H), 2.54(s,3H), 2.23(t,J=7.0Hz,2H), 1.54(s,6H). No 1x NH protons were observed.

[1653] Step 2: N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-6-oxa-2-azaspiro[3,4]octane-2-carboxamide

[1654] Similar to step 2 of Example 12, the title compound was prepared from N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide (step 1) and TFA.

[1655] LC-MS (Method 8B): Rt 3.18 min; MS m / z 490.1 = [M + H] +

[1656] 1H NMR(500MHz,DMSO-d6)δ11.36(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=1.6Hz,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).

[1657] Example 12.2

[1658] N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1659]

[1660] Step 1: N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1661]

[1662] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate J) and 2-oxa-6-azaspiro[3.3]heptane.

[1663] LC-MS (Method 3B): Rt 2.06 min; MS m / z 596.3 = [M + H] +

[1664] 1H NMR(500MHz,DMSO-d6)δ11.37(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).

[1665] Step 2: N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1666] Similar to step 2 of Example 12, the title compound was prepared from N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (step 1) and TFA.

[1667] LC-MS (Method 8B): Rt 3.68 min; MS m / z 476.2 = [M + H] +

[1668] 1H NMR (500MHz, DMSO-d6) δ11.35(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=1.6Hz,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).

[1669] Example 12.3

[1670] N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1671]

[1672] Step 1: N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]ethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1673]

[1674] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]ethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate PA) and 2-oxa-6-azaspiro[3.3]heptane.

[1675] LC-MS (Method 3B): Rt 1.81 min; MS m / z 580.4 = [MH]-

[1676] 1H NMR (500MHz, DMSO-d6) δ11.38(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(brd,J=1.6Hz,1H),6.88–6.84(m,2H),4.67(s,4H),4.42(q,J= 6.5Hz,1H),4.23–4.18(m,5H),4.16(d,J=11.5Hz,1H),3.75(s,3H),2.46(s,3H),1.27(d,J=6.5Hz,3H).

[1677] Step 2: N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1678] Similar to step 2 of Example 12, the title compound was prepared from N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)methoxy]ethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (step 1) and TFA.

[1679] LC-MS (Method 8B): Rt 3.67 min; MS m / z 462.2 = [M + H] +

[1680] 1H NMR (500MHz, DMSO-d6) δ11.36(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).

[1681] Examples 12.3a and 12.3b

[1682] Racemic N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (Example 12.3) was dissolved in EtOH / DCM (4:1) to 50 mg / mL and purified by SFC to obtain individual enantiomers:

[1683] Purification conditions;

[1684] Column details Lux iC5 (21.2mm × 250mm, 5µm)

[1685] Column temperature 40℃

[1686] Flow rate 50 mL / min

[1687] BPR 100BarG

[1688] Detector wavelength 218nm

[1689] Injection volume: 250 μL (2 mg)

[1690] Isotropic conditions 50:50 EtOH:CO2

[1691] Chiral purity analysis conditions;

[1692] Column details Lux iC5 (4.6mm × 250mm, 5µm)

[1693] Column temperature 40℃

[1694] Flow rate 4 mL / min

[1695] Detector wavelength 210-400nm

[1696] Injection volume 1.0 μL

[1697] BPR 125BarG

[1698] Isocratic conditions 50:50 EtOH:CO2 (0.2% v / v NH3)

[1699] Example 12.3a

[1700] N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazolyl-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]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1701]

[1702] First elution peak: Chiral LCMS retention time: = 3.12 min

[1703] LC-MS (Method 8B): Rt 2.56 min; MS m / z 462.1 = [M + H] +

[1704] 1H NMR (500MHz, DMSO-d6) δ11.36(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

[1705] (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).

[1706] Example 12.3b

[1707] N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazolyl-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]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1708]

[1709] The second elution peak: Chiral LCMS retention time: = 4.12 min

[1710] LC-MS (Method 8B): Rt 2.74 min; MS m / z 462.1 = [M + H] +

[1711] 1H NMR (500MHz, DMSO-d6) δ11.36(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),7.1 2(d,J=1.7Hz,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).

[1712] Example 13

[1713] (3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3,5-dimethyl-piperazin-1-carboxamide

[1714]

[1715] Step 1: Racemic-(2S,6R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

[1716] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and (2R,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester.

[1717] LC-MS (Method 2B): Rt 1.69 min; MS m / z 547.2 = [M + H] +

[1718] 1H NMR (500MHz, DMSO-d6) δ11.39(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=7.8 Hz,1H),6.94(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).

[1719] Step 2:(3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3,5-dimethyl-piperazin-1-carboxamide

[1720] Trimethylsilyl iodide (0.08 mL, 0.58 mmol) was added dropwise to a stirred solution of (2S,6R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (step 1) (100 mg, 0.14 mmol) in chloroform (2 mL), and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under a nitrogen stream, and chloroform (2 mL) was added and the mixture was concentrated again. The product was purified by C18 reversed-phase chromatography with a gradient elution of 15% to 40% MeCN in water (+0.1% ammonium hydroxide modifier), followed by freeze-drying to fractionate the product to give the title compound as a white solid.

[1721] LC-MS (Method 8B): Rt 3.04 min; MS m / z 447.2 = [M + H] +

[1722] ¹H NMR (500 MHz, DMSO-d⁶) 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 1x NH protons were observed.

[1723] Similar to Example 13, compounds of the examples listed below (Table Ex 13) were prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and a suitable amine (step 1), followed by deprotection with trimethylsilyl iodide (step 2).

[1724] Table Ex13

[1725]

[1726]

[1727]

[1728]

[1729]

[1730]

[1731]

[1732]

[1733]

[1734]

[1735]

[1736]

[1737] Example 14

[1738] (3R)-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazolyl-2-yl]-3-methylpiperazine-1-carboxamide

[1739]

[1740] Step 1: (2R)-4-[[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazolyl-2-yl]carbamoyl]-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[1741]

[1742] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate H) and (2R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester.

[1743] LC-MS (Method 5B): Rt 3.29 min; MS m / z 587.5 = [M + H] +

[1744] ¹H NMR (500MHz, DMSO-d⁶) δ 11.46 (s, ¹H), 7.92 (s, ¹H), 7.87 (d, J = 7.7Hz, ¹H), 7.75 (d, J = 7.9Hz, ¹H), 7.60 (t, J = 7.8Hz, 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 = 6.7Hz, 3H). No 1x CH₃ signal was observed.

[1745] Step 2: (3R)-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazolyl-2-yl]-3-methylpiperazine-1-carboxamide

[1746] TFA (0.71 mL, 9.27 mmol) was added to a solution of (2R)-4-[[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazolyl-2-yl]carbamoyl]-2-methyl-piperazin-1-carboxylic acid tert-butyl ester (step 1) (83 mg, 0.14 mmol) in DCM (3.6 mL), and the reaction mixture was stirred at room temperature for 1 h. EtOAc (20 mL) and 1 M NaOH (aqueous solution) (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 Na2SO4 and concentrated under vacuum to give a yellow oil. The crude product was purified by C18 reversed-phase chromatography with a gradient elution of 10% to 30% MeCN in water (+0.1% ammonium hydroxide modifier) ​​to give the title compound as a white solid.

[1747] LC-MS (Method 8B): Rt 4.37 min; MS m / z 487.2 = [M + H] +

[1748] ¹H NMR (500 MHz, methanol-d⁴) 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). No 2xNH protons were observed.

[1749] Example 14.1

[1750] Racemic-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate

[1751]

[1752] Step 1: Racemic-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester

[1753]

[1754] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate G) and racemic-(4aS,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester.

[1755] LC-MS (Method 2B): Rt 1.49 min; MS m / z 597.2 = [M + H] +

[1756] 1H NMR(500MHz,DMSO-d6)δ11.61(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,1H),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).

[1757] Step 2Racemic-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate

[1758] Similar to step 2 of Example 14, the title compound was prepared from racemic-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (step 1) and TFA.

[1759] LC-MS (Method 8B): Rt 2.35 min; MS m / z 497.1 = [M + H] +

[1760] ¹H NMR (500 MHz, DMSO-d⁶) 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.

[1761] Example 14.2

[1762] Racemic-(4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate

[1763]

[1764] Step 1: Racemic-(4aS,7aR)-6-[[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester

[1765]

[1766] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate G) and racemic-(4aS,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester.

[1767] LC-MS (Method 2B): Rt 1.48 min; MS m / z 597.2 = [M + H] +

[1768] 1H NMR(500MHz,DMSO-d6)δ11.23(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).

[1769] Step 2: Racemic-(4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate

[1770] Similar to step 2 of Example 14, the title compound was prepared from racemic-(4aS,7aR)-6-[[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (step 1) and TFA.

[1771] LC-MS (Method 8B): Rt 2.73 min; MS m / z 467.1 = [M + H] +

[1772] ¹H NMR (500 MHz, methanol-d⁴) 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 (dt, J = 12.6, 1.5 Hz, 1H), 2.55 (s, 3H). No exchangeable protons were observed.

[1773] Example 14.3

[1774] Racemic-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate

[1775]

[1776] Step 1: Racemic-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester

[1777]

[1778] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and racemic-(4aS,7aS)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester.

[1779] LC-MS (Method 3B): Rt 1.70 min; MS m / z 559.4 = [MH]+

[1780] 1H NMR (500MHz, DMSO-d6) δ11.51(s,1H),7.89(t,J=1.6Hz,1H),7.83(dt,J=7.8,1.6Hz,1 H),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).

[1781] Step 2: Racemic-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate

[1782] Similar to step 2 of Example 14, the title compound was prepared from racemic-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (step 1) and TFA.

[1783] LC-MS (Method 8A): Rt 1.76 min; MS m / z 461.1 = [M + H] +

[1784] ¹H NMR (500 MHz, methanol-d⁴) δ 7.96 (t, J = 1.7 Hz, ¹H), 7.83–7.78 (m, 2H), 7.59 (t, J = 7.8 Hz, ¹H), 7.46 (s, 2H), 4.30 (dd, J = 11.8, 7.1 Hz, 1H), 4.18 (ddd, J = 11.8, 3.7, 1.5 Hz, 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.

[1785] Example 14.4

[1786] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-cyclopropyl-piperazine-1-carboxamide

[1787]

[1788] Step 1: 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3-cyclopropyl-piperazine-1-carboxylic acid tert-butyl ester

[1789]

[1790] Similar to Example 4, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and tert-butyl 3-cyclopropylpiperazine-1-carboxylate.

[1791] LC-MS (Method 2.5A): Rt 0.80 min; MS m / z 559.3 = [M + H] +

[1792] 1H NMR (400MHz, DMSO-d6) δ11.21(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),6.9 2(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).

[1793] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-cyclopropyl-piperazine-1-carboxamide

[1794] Similar to step 2 of Example 14, the title compound was prepared from 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3-cyclopropyl-piperazine-1-carboxylic acid tert-butyl ester (step 1) and TFA.

[1795] LC-MS (Method 7B): Rt 2.80 min; MS m / z 459.4 = [M+H]+

[1796] 1H NMR (500MHz, methanol-d4) δ7.90(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(t d, J = 13.0, 3.2 Hz, 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). No 2x NH protons were observed.

[1797] Example 14.5

[1798] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide

[1799]

[1800] Step 1 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3-(cyclopropylmethyl)piperazine-1-carboxylic acid tert-butyl ester

[1801]

[1802] Similar to Example 4, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and tert-butyl 3-(cyclopropylmethyl)piperazine-1-carboxylate.

[1803] LC-MS (Method 2A): Rt 0.87 min; MS m / z 573.3 = [M + H] +

[1804] 1H NMR (400MHz, DMSO-d6) δ11.28(s,1H),7.88(t,J=1.7Hz,1H),7.82(dt,J=7.7,1.4H z,1H),7.71(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8Hz,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=6.6,2.4Hz,2H), 0.70–0.62(m,1H), 0.44–0.33(m,2H), 0.13–0.03(m,2H). No 1x CH protons were observed.

[1805] Step 2 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide

[1806] Similar to step 2 of Example 14, the title compound was prepared from 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-3-(cyclopropylmethyl)piperazine-1-carboxylic acid tert-butyl ester (step 1) and TFA.

[1807] LC-MS (Method 7B): Rt 3.14 min; MS m / z 473.4 = [M + H] +

[1808] ¹H NMR (400 MHz, 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), 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). - No 2x NH protons were observed.

[1809] Example 14.6

[1810] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3,3-dimethyl-piperazin-1-carboxamide

[1811]

[1812] Step 1: 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

[1813]

[1814] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and tert-butyl 2,2-dimethylpiperazine-1-carboxylate.

[1815] LC-MS (Method 2B): Rt 1.62 min; MS m / z 547.2 = [M + H] +

[1816] 1H NMR(500MHz,DMSO-d6)δ10.97(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).

[1817] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3,3-dimethyl-piperazin-1-carboxamide

[1818] Similar to step 2 of Example 14, the title compound was prepared from 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (step 1) and TFA.

[1819] LC-MS (Method 8B): Rt 2.82 min; MS m / z 447.1 = [M + H] +

[1820] ¹H 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). No 2x NH protons were observed.

[1821] Example 14.7

[1822] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide

[1823]

[1824] Step 1:9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-4-oxa-1,9-diazaspiro[5.5]undecane-1-carboxylic acid tert-butyl ester

[1825]

[1826] Similar to Example 4, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and tert-butyl 4-oxa-1,9-diazaspiro[5.5]undecane-1-carboxylate.

[1827] LC-MS (Method 2A): Rt 0.74 min; MS m / z 589.2 = [M + H] +

[1828] 1H NMR (500MHz, CDCl3) δ8.11(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,2 H), 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).

[1829] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide

[1830] Similar to step 2 of Example 14, the title compound was prepared from tert-butyl 9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]-4-oxa-1,9-diazaspiro[5.5]undecane-1-carboxylate (step 1) and TFA.

[1831] LC-MS (Method 7A): Rt 1.16 min; MS m / z 489.3 = [M + H] +

[1832] ¹H 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). No 2x NH protons were observed.

[1833] Example 16

[1834] N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl)thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide

[1835]

[1836] DIPEA (0.12 mL, 0.70 mmol) was added to a solution of 3-[2-amino-5-(2-methoxy-6-methyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate K) (75 mg, 0.23 mmol) and CDI (75 mg, 0.47 mmol) in DMA (1.2 mL), and the reaction mixture was stirred overnight at 50 °C. 1-Imine-1,4-thiazinane 1-oxide (47 mg, 0.35 mmol) was added, and stirring was continued at 50 °C for another 1 h. The resulting mixture was purified by C18 reversed-phase chromatography using a gradient elution of 5% to 20% MeCN in water (+0.1% ammonium hydroxide) to give the title compound as a white solid.

[1837] LC-MS (Method 8B): Rt 3.55 min; MS m / z 483.3 = [M + H] +

[1838] 1H NMR (500MHz, DMSO-d6) δ11.53(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).

[1839] The compounds in the examples listed below (Table Ex16) are prepared similarly to those in Example 16 from suitable starting compounds and amines, as shown in the table.

[1840] Table Ex16

[1841]

[1842]

[1843]

[1844]

[1845]

[1846] Example 17

[1847] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxonium-4-yl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1848]

[1849] Step 1: 3-[2-amino-5-(2,6-dimethyl-1-oxonium-pyridin-1-onthiazolyl-4-yl)thiazolyl]benzylnitrile

[1850]

[1851] At 0 °C, mCPBA (110 mg, 0.49 mmol) was added to a suspension of 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) (100 mg, 0.33 mmol) in DCM (2 mL). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Additional mCPBA (73 mg, 0.33 mmol) was added and stirring continued for 1 h. The resulting solution was diluted in DCM (10 mL) and washed with saturated NaHCO3 solution (2 × 20 mL). The organic matter was dried over Na2SO4 and concentrated under vacuum to give a red oil. The oil was dried, loaded onto silica, and purified by chromatography on silica using a gradient elution of 0–5% MeOH in DCM to give a solid, which was milled with Et2O, filtered, and washed with Et2O (3 × 2 mL) to give the title compound as a yellow solid.

[1852] LC-MS (Method 5A): Rt 1.86 min; MS m / z 323.1 = [M + H] +

[1853] 1H NMR(500MHz,DMSO-d6)δ7.86(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).

[1854] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxonium-4-yl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1855] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-1-oxano-pyridin-1-onthio-4-yl)thiazo-4-yl]benzylnitrile (step 1) and 2-oxa-6-azaspiro[3.3]heptane.

[1856] LC-MS (Method 8A): Rt 2.53 min; MS m / z 448.2 = [M + H] +

[1857] 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 1x NH protons were observed.

[1858] Example 18

[1859] 4-Cyano-N-[4-(3-cyano-2-methyl-phenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methyl-piperidine-1-carboxamide

[1860]

[1861] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]-2-methylbenzylnitrile (intermediate O) and 4-methylpiperidine-4-carboxynitrile hydrochloride.

[1862] LC-MS (Method 8B): Rt 4.25 min; MS m / z 471.3 = [M + H] +

[1863] 1H NMR (500MHz, DMSO-d6) δ11.36(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).

[1864] Example 19

[1865] N-[5-(2-acetamido-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1866]

[1867] Similar to Example 6, the title compound was prepared from N-[4-[2-amino-4-(3-cyanophenyl)thiazolyl-5-yl]-6-methyl-2-pyridyl]acetamide (intermediate KG) and 2-oxa-6-azaspiro[3.3]heptane.

[1868] LC-MS (Method 8B): Rt 2.89 min; MS m / z 475.3 = [M+H]+

[1869] 1H NMR (500MHz, DMSO-d6) δ11.35(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).

[1870] Example 20

[1871] N-[5-[2-(acetamidomethyl)-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1872]

[1873] Similar to Example 6, the title compound was prepared from N-[[4-[2-amino-4-(3-cyanophenyl)thiazolyl-5-yl]-6-methyl-2-pyridyl]methyl]acetamide (intermediate KH) and 2-oxa-6-azaspiro[3.3]heptane.

[1874] LC-MS (Method 8B: Rt 2.59 min; MS m / z 489.0 = [M + H] +

[1875] 1H NMR(500MHz,DMSO-d6)δ11.37(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,1H),7.04(s,1H),6.87(s,1H),4.68(s,4H),4.23–4.19(m,6H),2.40(s,3H),1.76(s,3H). Contains 1% Et2O

[1876] Example 21

[1877] N-[4-(3-cyanophenyl)-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1878]

[1879] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-(methoxyphenyl)-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate KI) and 2-oxa-6-azaspiro[3.3]heptane.

[1880] LC-MS (Method 8B): Rt 3.30 min; MS m / z 462.3 = [M + H] +

[1881] 1H NMR (500MHz, DMSO-d6) δ11.38(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=7.8Hz,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).

[1882] Example 22

[1883] N-[4-(3-cyanophenyl)-5-[2-(1-methoxyethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1884]

[1885] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate P) and 2-oxa-6-azaspiro[3.3]heptane.

[1886] LC-MS (Method 8B): Rt 3.92 min; MS m / z 476.3 = [M + H] +

[1887] 1H NMR (500MHz, DMSO-d6) δ11.45(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).

[1888] Example 23

[1889] N-[5-[2-chloro-6-(1-hydroxy-1-methyl-ethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1890]

[1891] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-chloro-6-(1-hydroxy-1-methyl-ethyl)-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate Q) and 2-oxa-6-azaspiro[3.3]heptane.

[1892] LC-MS (Method 8B): Rt 3.40 min; MS m / z 496.1 = [M+H]+

[1893] 1H NMR (500MHz, DMSO-d6) δ11.47(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).

[1894] Example 24

[1895] 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide

[1896]

[1897] Step 1: N-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazo-2-yl]-4-cyano-4-methylpiperidin-1-carboxamide

[1898]

[1899] Similar to Example 6, the title compound was prepared from 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate I) and 4-methylpiperidine-4-carboxynitrile hydrochloride.

[1900] LC-MS (Method 3B): Rt 2.34 min; MS m / z 587.3 = [M + H] +

[1901] 1H NMR(500MHz,DMSO-d6)δ11.35(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).

[1902] Step 2: 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide

[1903] To a solution of N-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazolyl-2-yl]-4-cyano-4-methyl-piperidin-1-carboxamide (step 1) (188 mg, 0.32 mmol) in THF (6.4 mL), TBAF (0.64 mL, 0.64 mmol) was added, 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 another 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 under vacuum. Purification was achieved by chromatography on silica using elution with 0% to 30% MeOH in EtOAc to give a yellow solid. The solid was further purified by C18 reversed-phase chromatography with a gradient elution of 10% to 35% MeCN in water (+0.1% ammonium hydroxide) to obtain a solid, which was then ground in Et2O and filtered to give the title compound as a white solid.

[1904] LC-MS (Method 8B): Rt 3.75 min; MS m / z 473.3 = [M + H] +

[1905] 1H NMR(500MHz,DMSO-d6)δ11.32(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).

[1906] Example 26

[1907] N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1908]

[1909] Similar to Example 9, the title compound was prepared from 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(trifluoromethyl)-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate IA) and 2-oxa-6-azaspiro[3.3]heptane.

[1910] LC-MS (Method 8B): Rt 3.49 min; MS m / z 502.2 = [M + H] +

[1911] 1H NMR (500MHz, DMSO-d6) δ11.52(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).

[1912] Example 27

[1913] 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-pyrrolidine-1-carboxamide

[1914]

[1915] 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)thiazolyl-4-yl]benzyl nitrile (intermediate C) (1.1 g, 3.59 mmol) in DMA (11 mL), and the solution was heated overnight at 50 °C. 3-methylpyrrolidine-3-carboxynitrile 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 allowed to cool to room temperature and diluted with EtOAc (150 mL). The mixture was washed with 90% brine (100 mL) and 50% brine (3 × 100 mL), dried over MgSO4, and concentrated under vacuum. The yellow solid was purified by chromatography on silica using a gradient elution of 1% to 2% MeOH in DCM. The addition of MeOH (10 mL) yielded a white solid, which was collected by filtration, washed with MeOH (2 mL) and Et₂O (20 mL), and dried to give the title compound as a white solid.

[1916] LC-MS (Method 8B): Rt 3.03 min; MS m / z 443.1 = [M + H] +

[1917] 1H NMR (500MHz, DMSO-d6) δ11.24(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=11.1H z,1H),2.43–2.38(m,1H),2.36(s,6H),2.14–2.02(m,1H),1.47(s,3H).

[1918] Examples 27a and 27b

[1919] Racemic 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-pyrrolidine-1-carboxamide (Example 27) was dissolved in EtOH / DCM (4:1) to 50 mg / mL and purified by SFC. The combined fractions of each enantiomer were evaporated to near dryness and then transferred to a final container with DCM (which was removed under a stream of compressed air at 35 °C) and stored in a vacuum oven at 35 °C and 5 mbar until constant weight was achieved.

[1920] Purification conditions;

[1921] Column details of Lux iA3 (21.2mm × 250mm, 5µm)

[1922] Column temperature 40℃

[1923] Flow rate 50 mL / min

[1924] BPR 100BarG

[1925] Detector wavelength 16nm

[1926] Injection volume: 250 μL (12.5 mg)

[1927] Isocratic conditions 35:65 EtOH:CO2 (0.2% v / v NH3)

[1928] Chiral purity analysis conditions;

[1929] Column details: Chiralpak IG (4.6mm x 250mm, 5µm)

[1930] Column temperature 40℃

[1931] Flow rate 4 mL / min

[1932] Detector wavelength 210-400nm

[1933] Injection volume 1.0 μL

[1934] BPR 125BarG

[1935] Isocratic conditions 25:75EtOH:CO2 (0.2% v / v NH3)

[1936] Example 27a

[1937] (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-pyrrolidine-1-carboxamide

[1938]

[1939] First elution peak: Chiral LCMS retention time: = 7.05 min

[1940] LC-MS (Method 8B): Rt 3.04 min; MS m / z 443.0 = [M + H] +

[1941] 1H NMR (500MHz, DMSO-d6) δ11.24(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).

[1942] Example 27b

[1943] (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-pyrrolidine-1-carboxamide

[1944]

[1945] The second elution peak: Chiral LCMS retention time: = 8.59 min

[1946] LC-MS (Method 8B): Rt 2.92 min; MS m / z 443.0 = [M + H] +

[1947] 1H NMR (500MHz, DMSO-d6) δ11.24(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).

[1948] Another sample of Example 27b was obtained under the following conditions:

[1949] Racemic 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-pyrrolidine-1-carboxamide (Example 27) was dissolved in EtOH / DCM (4:1) to 25 mg / mL and purified by SFC. The combined fractions of each enantiomer were evaporated to near dryness. The resulting solids were transferred to a final container with DCM (which was removed under a stream of compressed air at 35 °C) and stored in a vacuum oven at 35 °C and 5 mbar until constant weight was achieved. The material was ground in Et2O / MeOH under sonication and the resulting thick suspension was filtered. The solids were washed with Et2O / MeOH and vacuum dried on a sinter, followed by further drying overnight in a vacuum oven at 50 °C to give the title compound as a creamy solid.

[1950] Purification conditions;

[1951]

[1952]

[1953] Chiral purity analysis conditions;

[1954]

[1955] The second elution peak: Chiral LCMS retention time: = 9.73 min

[1956] LC-MS (Method 8A): Rt 2.37 min; MS m / z 443.3 = [M + H] +

[1957] 1H NMR (500MHz, DMSO-d6) δ11.23(br s,1H),7.89(br t,J=1.5Hz,1H),7.82(brdt,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).

[1958] Alternatively, similar to Example 6, Examples 27a and 27b were prepared from 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzyl nitrile (intermediate C) and (3R)-3-methylpyrrolidine-3-carboxynitrile hydroiodate (intermediate U) or (3S)-3-methylpyrrolidine-3-carboxynitrile hydroiodate (intermediate UA).

[1959] Example 28

[1960] N-[5-[2,6-bis(trideuteratedmethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazolyl]-4-cyano-4-methylpiperidine-1-carboxamide

[1961]

[1962] In a sealed tube under nitrogen atmosphere, 3-[2-amino-5-[2,6-bis(trideuteratedmethyl)-4-pyridyl]thiazolyl-4-yl]benzyl nitrile (intermediate N) (465 mg, 1.49 mmol) and CDI (483 mg, 2.98 mmol) were dissolved in anhydrous DMA (7.5 mL). DIPEA (778 μL, 4.47 mmol) was added and the resulting solution was stirred at 50 °C for 17 h. 4-Methylpiperidine-4-carboxynitrile 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 allowed to cool to room temperature, then diluted with EtOAc (80 mL) and washed successively with 80% saline (80 mL), 20% saline (2 × 80 mL), and 50% saline (80 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to obtain a crude material that was a pale yellow foam. Purification was performed by chromatography on silica using a gradient elution of 1% to 2% MeOH in DCM to obtain a clear, straw-colored glassy substance. This substance was ground and azeotropically reacted with Et2O to obtain the title compound as a cream-colored solid.

[1963] LC-MS (Method 8B): Rt 3.08 min; MS m / z 463.1 = [M + H] +

[1964] 1H NMR (500MHz, DMSO-d6) δ11.31(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).

[1965] Preparation of intermediates

[1966] Intermediate A

[1967] 3-(2-aminothiazolyl-4-yl)benzyl nitrile hydrobromide

[1968]

[1969] The following preparation is based on the procedure in step 2 of Example 15 on page 24 of patent WO 2012 / 100734 by Wang, Y. and Yang, T.

[1970] Thiourea (1.87 g, 24.55 mmol) was added to a flask containing 50 mL of EtOH and 3-(2-bromoacetyl)benzyl nitrile (5 g, 22.32 mmol), and the mixture was stirred at room temperature for 30 minutes. The volume of the solvent was reduced by approximately 50% under vacuum, resulting in the formation of a suspension. The suspension was sonicated, filtered, and dried to give the title compound as a colorless solid.

[1971] LC-MS (Method 3B): Rt 1.62 min; MS m / z 202.3 = [M + H] +

[1972] 1 ¹H NMR (500MHz, DMSO-d⁶) 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 NH₂ protons were observed.

[1973] 3-(2-aminothiazolyl-4-yl)benzyl nitrile can also be prepared as follows:

[1974] 3-(2-bromoacetyl)benzyl nitrile (3.0 g, 13.39 mmol) was added to a flask containing thiourea (2.04 g, 26.78 mmol) in pyridine (50 mL), 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 × 100 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, and concentrated under vacuum. The crude product was purified by chromatography on silica using 0–100% EtOAc in DCM. The resulting solid was recrystallized from EtOAc to give 3-(2-aminothiazolyl-4-yl)benzyl nitrile as a pale yellow solid.

[1975] LC-MS (Method 7A): Rt 1.75 min; MS m / z 202.1 = [M + H] +

[1976] 1 H NMR(400MHz,DMSO-d6)δ8.20(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).

[1977] Intermediate B

[1978] 3-(2-amino-5-bromo-thiazo-4-yl)benzylnitrile

[1979]

[1980] The following preparation is based on the procedure in step 3 of Example 15 on pages 24-25 of patent WO 2012 / 100734 by Wang, Y. and Yang, T.

[1981] NBS (1.97 g, 11.06 mmol) was added to a solution of 3-(2-aminothiazolyl-4-yl)benzyl nitrile hydrobromide (intermediate A) (2.6 g, 9.21 mmol) in THF (40 mL), 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 layer was further extracted with EtOAc (2 × 50 mL). The combined organics were dried over MgSO4 and concentrated under vacuum to give an orange solid. The solid was suspended in DCM (20 mL), filtered, washed with DCM, and dried to give the title compound as a grayish-white solid.

[1982] LC-MS (Method 3B): Rt 1.64 min; MS m / z 279.9 / 281.9=[M+H]+

[1983] 1 H NMR (500MHz, DMSO-d6) δ 8.16 (t, J = 1.7 Hz, 1H), 8.15 (dt, J = 7.9, 1.7 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.42 (s, 2H).

[1984] Intermediate C

[1985] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazolyl-4-yl]benzylnitrile

[1986]

[1987] 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-thiazo-4-yl)benzylnitrile (intermediate B) (35.0 g, 124.94 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (34.95 g, 149.93 mmol) in 1,4-dioxane (840 mL), and the mixture was deoxygenated by bubbling under nitrogen for 20 min. Bis(tri-tert-butylphosphine)palladium (0) (6.38 g, 12.49 mmol) was added, the flask was sealed, and the contents were evacuated and backfilled with nitrogen (3 × cycle). The reaction mixture was stirred at 80 °C for 1 h and then allowed to cool 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) and pure brine (200 mL), dried over Na2SO4, and then subjected to… The mixture was filtered through a filter plug and eluted with EtOAc (4 × 200 mL). The filtrate was concentrated under vacuum and the resulting material was sonicated and ground in DCM (150 mL). The solid was collected by filtration, washed with DCM (3 × 50 mL), and vacuum dried to give the title compound as a light brown solid.

[1988] LC-MS (Method 2B): Rt 1.26 min; MS m / z 307.0 = [M + H] +

[1989] 1H NMR (500MHz, DMSO-d6) δ7.81(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).

[1990] Intermediate D

[1991] 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazolyl-4-yl]benzylnitrile

[1992]

[1993] A solution of 3-(2-amino-5-bromo-thiazo-4-yl)benzylnitrile (intermediate B) (710 mg, 2.53 mmol), 2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (649 mg, 2.56 mmol) and cesium carbonate (1652 mg, 5.07 mmol) in ethylene glycol dimethyl ether (28.4 mL) and water (3.5 mL) was degassed with nitrogen for 5 min. Pd(dppf)Cl2·CH2Cl2 (517 mg, 0.63 mmol) was added, and the reaction mixture was heated at 80 °C under nitrogen for 1 h. 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 under vacuum. The crude product was purified by chromatography on silica using elution with 0-50% EtOAc in DCM to give the title compound as a brown solid.

[1994] LC-MS (Method 2A): Rt 1.12 min; MS m / z 327.0 / 329.0 = [M+H]+

[1995] 1 H NMR(400MHz,DMSO-d6)δ7.86–7.80(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).

[1996] Intermediate E

[1997] 4-(hydroxymethyl)piperidine-4-carboxynitrile hydrochloride

[1998]

[1999] To a solution of tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (100 mg, 0.42 mmol) in DCM (1 mL), 4 M HCl in 1,4-dioxane (2.08 mL, 8.32 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum to give the title compound as a colorless solid.

[2000] 1 H NMR (400MHz, DMSO-d6) δ9.11 (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).

[2001] intermediate F

[2002] Piperidine-4,4-dianitronic acid hydrochloride

[2003]

[2004] Step 1 1-Benzylpiperidine-4,4-dionitrile

[2005]

[2006] The following preparation is based on the procedure described by Zahler, R. and Vath, J. on pages 56 and 57 of patent WO 2017027684(A1).

[2007] K₂CO₃ (1132 mg, 8.19 mmol) was added to a solution of malononitrile (0.23 mL, 3.72 mmol) in DMF (5 mL), and the reaction mixture was stirred at 65 °C for 2 h. N-benzyl-2-chloro-N-(2-chloroethyl)ethylamine hydrochloride (1.0 g, 3.72 mmol) in DMF (5 mL) was added to the mixture, 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 under vacuum. The crude material was purified by chromatography on silica using elution with 10–40% EtOAc in petroleum ether to give the title compound as a colorless oil.

[2008] LC-MS (Method 8B): Rt 4.31 min; MS m / z 226.2 = [M + H] +

[2009] 1 H NMR (500MHz, CDCl3) δ7.37–7.25(m,5H),3.56(s,2H),2.64(s,4H),2.25(s,4H).

[2010] Step 2: Piperidine-4,4-dianitronic acid hydrochloride

[2011] 1-Chloroethyl chloroformate (0.36 mL, 3.31 mmol) was added dropwise to a stirred solution of 1-benzylpiperidine-4,4-dionitrile (step 1) (622 mg, 2.76 mmol) in DCE (5 mL) at 0 °C. The reaction mixture was heated under reflux for 24 h and then concentrated under vacuum to give a colorless oil. Methanol (5 mL) was then added, and the solution was heated under reflux for 3 h. The resulting mixture was concentrated under vacuum to give the title compound as a colorless solid.

[2012] 1 H NMR (500MHz, DMSO-d6) δ9.38(m,2H),3.21(s,4H),2.65–2.57(m,4H).

[2013] intermediate G

[2014] 3-[2-amino-5-(2-difluoromethyl-6-methyl-4-pyridyl)thiazolyl-4-yl]benzylnitrile

[2015]

[2016] Similar to intermediate C, the title compound was prepared from 3-(2-amino-5-bromo-thiazo-4-yl)benzylnitrile (intermediate B) and 2-(difluoromethyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine.

[2017] LC-MS (Method 5B): Rt 2.83 min; MS m / z 343.1 = [M + H] +

[2018] 1H NMR(500MHz,DMSO-d6)δ7.84(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).

[2019] intermediate H

[2020] 3-[2-amino-5-(2-trifluoromethyl-6-methyl-4-pyridyl)thiazolyl-4-yl]benzylnitrile

[2021]

[2022] Similar to intermediate C, the title compound was prepared from 3-(2-amino-5-bromo-thiazo-4-yl)benzylnitrile (intermediate B) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-6-(trifluoromethyl)pyridine.

[2023] LC-MS (Method 3B): Rt 1.86 min; MS m / z 359.3 = [MH]-

[2024] 1H NMR (500MHz, DMSO-d6) δ7.88–7.81(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).

[2025] Intermediate I

[2026] 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzylnitrile

[2027]

[2028] Step 1: (4-Bromo-6-methyl-2-pyridyl)methoxy-tert-butyl-dimethylsilane

[2029]

[2030] Imidazole (0.03 mL, 12.87 mmol) was added to a solution of (4-bromo-6-methyl-2-pyridyl)methanol (2.0 g, 9.9 mmol) in DMF (15 mL) at 0 °C, followed by the addition of 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 under vacuum to give the title compound as a yellow oil, which was then allowed to crystallize slowly to give a yellow solid.

[2031] 1H NMR (500MHz, DMSO-d6) δ7.45 (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).

[2032] Step 2:

[2033] 2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine

[2034]

[2035] A solution of (4-bromo-6-methyl-2-pyridyl)methoxy-tert-butyl-dimethyl-silane (step 1) (2.96 g, 9.35 mmol), bis(pinacol)diboron (3.56 g, 14.02 mmol), potassium acetate (5.16 g, 37.39 mmol), and Pd(dppf)Cl2 (889 mg, 1.22 mmol) in 1,4-dioxane (45 mL) was heated to 80 °C overnight. The resulting mixture was concentrated under vacuum, and the residue was dissolved in hexane (with a small volume of DCM added to aid dissolution). The mixture was then passed through... (Filter material) is filtered and vacuum concentrated to obtain the title compound as a brown solid.

[2036] 1H NMR (500MHz, DMSO-d6) δ7.46(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).

[2037] Step 3:3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzylnitrile

[2038] Bis(tert-butylphosphine)palladium (0) (182 mg, 0.36 mmol) was added to a degassed mixture of 3-(2-amino-5-bromo-thiazo-4-yl)benzylnitrile (intermediate B) (1.0 g, 3.57 mmol), 2-{[(tert-butyldimethylsilyl)oxy]methyl}-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-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). The reaction mixture was heated at 80 °C for 1 h and then allowed to cool to room temperature. The resulting mixture was diluted in EtOAc (100 mL) and water (100 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over MgSO4 and concentrated under vacuum. The solid was purified by chromatography on silica using a gradient elution of 10% to 40% EtOAc in petroleum ether. The solid was ground in diethyl ether (8 mL), collected by filtration, washed with diethyl ether (3 × 2 mL), and dried under vacuum overnight to give the title compound as a yellow solid.

[2039] LC-MS (Method 3B): Rt 2.28 min; MS m / z 435.4 = [MH]-

[2040] 1H NMR(500MHz,DMSO-d6)δ7.82–7.75(m,2H),7.68(dt,J=7.9,1.5Hz,1H),7.52(td,J=7.6,7.0,1.3 Hz, 1H), 7.48 (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).

[2041] Intermediate IA

[2042] 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(trifluoromethyl)-4-pyridyl]thiazolyl-4-yl]benzylnitrile

[2043]

[2044] Step 1: [4-Bromo-6-(trifluoromethyl)-2-pyridyl]methoxy-tert-butyl-dimethylsilane

[2045]

[2046] Similar to step 1 of intermediate I, the title compound was prepared from [4-bromo-6-(trifluoromethyl)-2-pyridyl]methanol and tert-butyldimethylsilyl chloride.

[2047] LC-MS (Method 3B): Rt 2.84 min; MS m / z 370.0 / 372.0 = [M+H]+

[2048] 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).

[2049] Step 2: tert-butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-6-(trifluoromethyl)-2-pyridyl]methoxy]silane

[2050]

[2051] Similar to step 2 of intermediate I, the title compound was prepared from [4-bromo-6-(trifluoromethyl)-2-pyridyl]methoxy-tert-butyl-dimethyl-silane (step 1) and bis(pinacol)diboron.

[2052] 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).

[2053] Step 3: 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(trifluoromethyl)-4-pyridyl]thiazolyl-4-yl]benzylnitrile

[2054] Similar to step 3 of intermediate I, the title compound is prepared from tert-butyl-dimethyl-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-6-(trifluoromethyl)-2-pyridinyl]methoxy]silane (step 2) and 3-(2-amino-5-bromo-thiazo-4-yl)benzylnitrile (intermediate B).

[2055] LC-MS (Method 3B): Rt 2.38 min; MS m / z 491.2 = [M + H] +

[2056] 1H NMR(500MHz,DMSO-d6)δ7.86(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).

[2057] Intermediate J

[2058] 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzylnitrile

[2059]

[2060] Step 1: 2-(4-bromo-6-methyl-2-pyridyl)prop-2-ol

[2061]

[2062] At 0 °C under nitrogen, a solution of ethyl 4-bromo-6-methylpyridine-2-carboxylate (1.04 g, 4.25 mmol) in anhydrous THF (20 mL) was added dropwise over 10 minutes to a stirred solution of methyl magnesium bromide (3.4 M, in 2-Me-THF) (2.75 mL, 9.36 mmol) 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 then cooled to 5 °C and the reaction was quenched by adding 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 adding saturated NaHCO3 solution. The layers were then shaken and separated. The aqueous layer was extracted with EtOAc (30 mL), and the combined organic extracts were dried over Na2SO4 and concentrated under vacuum to give the title compound as a pale yellow oil.

[2063] LC-MS (Method 3B): Rt 1.59 min; MS m / z 230.1 / 232.1=[M+H]+

[2064] 1H NMR (500MHz, CDCl3) δ7.33 (d, J = 1.0 Hz, 1H), 7.24 (d, J = 1.0 Hz, 1H), 5.08 (s, 1H), 2.54 (s, 3H), 1.51 (s, 6H).

[2065] Step 2:4-Bromo-2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-pyridine

[2066]

[2067] Under nitrogen atmosphere, NaH (60% in oil) (229 mg, 5.74 mmol) was added to a solution of 2-(4-bromo-6-methyl-2-pyridyl)prop-2-ol (step 1) (660 mg, 2.87 mmol) in anhydrous DMF (15 mL), 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 dropwise addition of water (1 mL), followed by dilution with EtOAc (75 mL). The mixture was washed with 90% brine (75 mL), 50% brine (3 × 75 mL), and brine (75 mL), dried over Na₂SO₄, and concentrated under vacuum. The title compound, which was obtained as a colorless oil, was purified by elution of silica with 5% EtOAc in n-hexane using chromatography.

[2068] LC-MS (Method 3B): Rt 2.46 min; MS m / z 350.1 / 352.1=[M+H]+

[2069] ¹H NMR (500 MHz, chloroform-d) δ 7.62 (apr dd, J = 1.7, 0.7 Hz, ¹H), 7.30–7.27 (m, 2H), 7.20 (d, J = 1.7 Hz, 1H), 6.91–6.88 (m, 2H), 4.29 (s, 2H), 3.81 (s, 3H), 2.52 (s, 3H), 1.61 (s, 6H).

[2070] Step 3: 2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine

[2071]

[2072] Similar to step 2 of intermediate I, the title compound was prepared from 4-bromo-2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-pyridine (step 2) and bis(pinacol)diboron.

[2073] LC-MS (Method 3B): Rt 1.19 min; MS m / z 316.2 = [M+H]+[NB-mass ion of parent boric acid].

[2074] 1H NMR(500MHz,DMSO-d6)δ7.62(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).

[2075] Step 4: 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazolyl-4-yl]benzylnitrile

[2076] 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-thiazo-4-yl)benzylnitrile (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-dioxaborhecyclopentan-2-yl)pyridine (step 3) (396 mg, 1.0 mmol) in 1,4-dioxane (6 mL), and the mixture was degassed by bubbling under nitrogen for 10 min. Pd(tBu₃P)₂ (39 mg, 0.08 mmol) was added and the mixture was heated at 50 °C for 1 h. The resulting mixture was allowed to cool to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification was achieved by chromatography on silica using elution with 1% MeOH in DCM to obtain a yellow gelatinous foam, which was dissolved in Et2O and concentrated to give the title compound as a yellow solid.

[2077] LC-MS (Method 3B): Rt 2.21 min; MS m / z 471.3 = [M + H] +

[2078] 1H NMR (500MHz, DMSO-d6) δ7.78(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).

[2079] intermediate K

[2080] 3-[2-amino-5-(2-methoxy-6-methyl-4-pyridyl)thiazolyl-4-yl]benzylnitrile

[2081]

[2082] Similar to intermediate C, the title compound was prepared from 3-(2-amino-5-bromo-thiazo-4-yl)benzyl nitrile (intermediate B) and 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine.

[2083] LC-MS (Method 3B): Rt 1.81 min; MS m / z 321.2 = [MH]-

[2084] 1H NMR (500MHz, DMSO-d6) δ7.82(s,1H),7.79(d,J=7.7Hz,1H),7.67(d,J=8.1Hz,1H),7. 54(t,J=7.8Hz,1H),7.46(s,2H),6.60(s,1H),6.29(s,1H),3.34(s,3H),2.29(s,3H).

[2085] intermediate KA

[2086] 3-[2-amino-5-(2-cyano-6-methyl-4-pyridyl)thiazolyl-4-yl]benzylnitrile

[2087]

[2088] Similar to intermediate C, the title compound was prepared from 3-(2-amino-5-bromo-thiazo-4-yl)benzyl nitrile (intermediate B) and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine-2-carboxynitrile.

[2089] LC-MS (Method 3B): Rt 1.53 min; MS m / z 318.0 = [MH]+

[2090] 1H NMR (500MHz, DMSO-d6) δ7.86(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).

[2091] intermediate KB

[2092] 3-[2-amino-5-[2-(fluoromethyl)-6-methyl-4-pyridyl]thiazolyl-4-yl]benzylnitrile

[2093]

[2094] Step 1: 4-Bromo-2-(fluoromethyl)-6-methylpyridine

[2095]

[2096] Diethylaminosulfur trifluoride (0.36 mL, 2.72 mmol) was added dropwise to a solution of (4-bromo-6-methyl-2-pyridyl)methanol (500 mg, 2.47 mmol) in DCM (5 mL) at -40 °C. The mixture was stirred at -40 °C for 30 h and then allowed to warm to room temperature. The mixture was diluted with DCM (5 mL), water (5 mL), and saturated NaHCO3 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 Na2SO4, and the solvent was removed under vacuum. The title compound was purified by chromatography on silica using a gradient elution of 1% to 20% EtOAc in petroleum ether to give a white solid.

[2097] LC-MS (Method 3B): Rt 1.66 min; MS m / z 204.0 / 205.9 = [M+H]+

[2098] 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).

[2099] Step 2: 2-(fluoromethyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine

[2100]

[2101] A mixture of 4-bromo-2-(fluoromethyl)-6-methylpyridine (step 1) (370 mg, 1.81 mmol), bis(pinacol)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 min. Pd(dppf)C was then added. l2 (133 mg, 0.18 mmol), and the flask was purged and backfilled with nitrogen (×3). The reaction mixture was heated to 95 °C for 16 h and then allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (50 mL) and passed through a purging tank. (Filter material) Filter and elute with EtOAc. Concentrate the filtrate under vacuum to obtain the title compound as a brown oil.

[2102] 1H NMR (500MHz, DMSO-d6) δ7.93 (s, 1H), 7.45 (d, J = 11.9 Hz, 1H), 5.44 (d, J = 47.1 Hz, 2H), 3.57 (s, 3H), 1.31 (s, 12H).

[2103] Step 3: 3-[2-amino-5-[2-(fluoromethyl)-6-methyl-4-pyridyl]thiazolyl-4-yl]benzylnitrile

[2104] Similar to intermediate C, the title compound was prepared from 3-(2-amino-5-bromo-thiazo-4-yl)benzyl nitrile (intermediate B) and 2-(fluoromethyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (step 2).

[2105] LC-MS (Method 3B): Rt 1.56 min; MS m / z 325.1 = [M + H] +

[2106] 1H NMR(500MHz,DMSO-d6)δ7.84–7.79(m,2H),7.68(dt,J=8.0,1.4Hz,1H),7.5 6–7.51(m,3H),6.98(d,J=15.9Hz,2H),5.32(d,J=46.9Hz,2H),2.38(s,3H).

[2107] intermediate KC

[2108] 3-[2-amino-5-(2-cyclopropyl-6-methyl-4-pyridyl)thiazolyl-4-yl]benzylnitrile

[2109]

[2110] Similar to intermediate C, the title compound was prepared from 3-(2-amino-5-bromo-thiazo-4-yl)benzylnitrile (intermediate B) and 2-cyclopropyl-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine.

[2111] LC-MS (Method 3B): Rt 1.33 min; MS m / z 333.0 = [M + H] +

[2112] 1H NMR (500MHz, DMSO-d6) δ7.81(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).

[2113] intermediate KD

[2114] 3-[2-amino-5-(2-isopropyl-6-methyl-4-pyridyl)thiazolyl-4-yl]benzylnitrile

[2115]

[2116] Similar to intermediate C, the title compound was prepared from 3-(2-amino-5-bromo-thiazo-4-yl)benzylnitrile (intermediate B) and 2-isopropyl-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine.

[2117] LC-MS (Method 5B): Rt 2.86 min; MS m / z 335.1 = [M + H] +

[2118] 1H NMR (500MHz, DMSO-d6) δ7.80(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).

[2119] intermediate KE

[2120] 3-[2-amino-5-(2-ethyl-6-methyl-4-pyridyl)thiazolyl-4-yl]benzylnitrile

[2121]

[2122] Similar to intermediate C, the title compound was prepared from 3-(2-amino-5-bromo-thiazo-4-yl)benzyl nitrile (intermediate B) and 2-ethyl-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine.

[2123] LC-MS (Method 5B): Rt 2.64 min; MS m / z 321.1 = [M + H] +

[2124] 1H NMR (500MHz, CDCl3) δ7.86(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).

[2125] intermediate KF

[2126] 3-[2-amino-5-(2,6-dichloro-4-pyridyl)thiazolyl-4-yl]benzylnitrile

[2127]

[2128] Similar to intermediate C, the title compound was prepared from 3-(2-amino-5-bromo-thiazo-4-yl)benzyl nitrile (intermediate B) and 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine.

[2129] LC-MS (Method 5B): Rt 3.10 min; MS m / z 346.9 = [M + H] +

[2130] 1H NMR (500MHz, DMSO-d6) δ7.91(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).

[2131] intermediate KG

[2132] N-[4-[2-amino-4-(3-cyanophenyl)thiazolyl-5-yl]-6-methyl-2-pyridyl]acetamide

[2133]

[2134] Step 1: N-(4-bromo-6-methyl-2-pyridyl)acetamide

[2135]

[2136] 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-methylpyridin-2-amine (550 mg, 2.94 mmol) in THF (20 mL) and heated to 50 °C for 22 h, followed by heating under reflux for 2 h. The resulting mixture was allowed to cool to room temperature and partitioned between EtOAc (100 mL) and saturated NaHCO3 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 MgSO4 and concentrated under vacuum to give a white solid. The solid was dried, loaded onto silica, and purified by chromatography on silica using a gradient elution of 0% to 8% MeOH to give the title compound as a white solid.

[2137] LC-MS (Method 5A): Rt 2.28 min; MS m / z 228.9 / 230.9=[M+H]+

[2138] 1H NMR (500MHz, DMSO-d6) δ10.66(s,1H),8.13(d,J=1.6Hz,1H),7.25(d,J=1.6Hz,1H),2.39(s,3H),2.07(s,3H).

[2139] Step 2:N-[6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-pyridyl]acetamide

[2140]

[2141] Similar to step 2 of intermediate KB, the title compound was prepared from N-(4-bromo-6-methyl-2-pyridyl)acetamide (step 1) and bis(pinacol)diboron.

[2142] 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).

[2143] Step 3: N-[4-[2-amino-4-(3-cyanophenyl)thiazolyl-5-yl]-6-methyl-2-pyridyl]acetamide

[2144] Similar to intermediate C, the title compound was prepared from 3-(2-amino-5-bromo-thiazo-4-yl)benzyl nitrile (intermediat...

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, having the following structural formula I: in: R x Selected from methyl, CD3, chlorine and CF3; R1 is selected from (1-3C)alkyl, halogen, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C) hydroxyalkyl, cyano, cyclopropyl, oxetane-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 、-(CR 1C R 1D ) q1 -SO2N(R 1B )R 1A or -(CR) 1C R 1D ) q1 -N(R 1B SO2R 1A Where p is 0, 1, or 2. Where q1 is 0, 1, or 2; and Where R 1A and R 1B Each is independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl; Where R 1C and R 1D Each is 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 fluorine, methyl or methoxy. The connection of R4 and R5 allows them, together with the attached nitrogen atom, to form a heterocycle selected from any of the following options: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 The asterisk (*) indicates the N atom attached to R4 and R5; 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-; Q3 is CH, CR 10C Or N; Ring A is a spirofused 4, 5, or 6-membered carbon ring or heterocycle; Ring B is a fused 4, 5, or 6-membered carbon ring or heterocycle; Where R e Selected from hydrogen, (1-3C)alkyl, or (2-3C)alkylyl; In each of the heterocyclic systems, one or more R atoms are optionally located on any available carbon atom. 10c Substituent substitution; Where R 10C Selected from oxo groups, halogen or cyano substituents, or groups having the following formula: –[CH2] n –L–Z in n is between 0 and 2; L does not exist or is selected from -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 It is hydrogen; and Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, 4-7-membered heterocyclic, or 5- or 6-membered heteroaryl; and wherein Z is optionally substituted by one or more substituents selected from: (1-2C)alkyl, halogen, (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 Or an oxy group, where y is 0, 1, or 2; Where R c and R d Each is independently selected from hydrogen or (1-2C) alkyl; In each heterocyclic system, any available N atom is optionally in the form of an N-oxide or optionally surrounded by one or more R atoms. 10N replace, Where R 10N It is -S(O)2NH2 or selected from: (i)–Z1; (ii)–L 1a –Z1; or (iii)–[CR 8a R 8b ] 1-2 –L 1b –Z1; in R 8a and R 8b They are all hydrogen; L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R) a1 )-, where R a1 It is hydrogen; L 1b It does not exist or is selected from -O-, -S-, -SO-, -SO 2- -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 It is hydrogen; and Z1 is selected from (1-4C) alkyl, phenyl, 4-7-membered heterocyclic, or 5- or 6-membered heteroaryl, provided that when Z1 is a heterocyclic group directly attached to the N atom, it is a carbon-linked heterocyclic group; and wherein Z1 is optionally substituted by one or more substituents selected from: (1-2C) alkyl, halogen, (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 , where y is 0, 1, or 2; and where R e and R f Each is independently selected from hydrogen or methyl; Furthermore, any S atom present in this heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). e ) exists, where R e Selected from hydrogen or methyl; and R6 is selected from hydrogen, halogen, methyl, methoxy, and trifluoromethyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R x Selected from methyl or CD3.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from (1-3C)alkyl, halogen, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxetane-3-yl, and -(CH2). q1 -OR 1A and -(CH2) q1 -C(O)R 1A ; Where q1 is 0 or 1; and Where R 1A Selected from hydrogen or (1-2C)alkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from methyl, CD3, isopropyl, halogen, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxetane-3-yl, -OMe, -CH2F, -CHF2 or -CF3.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R2 and R3 are both hydrogen, or one of R2 and R3 is hydrogen and the other is fluorine or methyl.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Both R2 and R3 are hydrogen.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The connection of R4 and R5 allows them, together with the attached nitrogen atom, to form a heterocycle selected from any of the following options: 、 、 、 、 、 、 、 、 、 、 、 The asterisk (*) indicates the N atom attached to R4 and R5; 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-; Q3 is CH, CR 10C Or N; Ring A is a spiro-fused 4, 5, or 6-membered carbon ring or heterocycle; Ring B is a fused 4, 5, or 6-membered carbon ring or heterocycle; Where R e Selected from hydrogen, (1-2C)alkyl, or (2C)alkanoyl; In each of the heterocyclic systems, one or more R atoms are optionally located on any available carbon atom. 10c Substituent substitution; and In each heterocyclic system, any available N atom is optionally in the form of an N-oxide or optionally surrounded by one or more R atoms. 10N replace, Where R 10c and R 10N It is as defined in claim 1.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The connection of R4 and R5 allows them, together with the attached nitrogen atom, to form a heterocycle selected from any of the following options: 、 、 、 、 、 、 The asterisk (*) indicates the N atom attached to R4 and R5; 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 Selected from hydrogen, (1-2C)alkyl, or (2C)alkanoyl; In each of the heterocyclic systems, one or more R atoms are optionally located on any available carbon atom. 10c Substituent substitution; and In each heterocyclic system, any available N atom is optionally in the form of an N-oxide or optionally surrounded by one or more R atoms. 10N replace, Where R 10c and R 10N It is as defined in claim 1.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, The R4 and R5 linkages allow them, together with the attached nitrogen atom, to form a heterocycle selected from any of the following options: 、 、 The asterisk (*) indicates the N atom attached to R4 and R5; 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 Selected from hydrogen, (1-2C)alkyl, or (2C)alkanoyl; In each of the heterocyclic systems, one or more R atoms are optionally located on any available carbon atom. 10c Substituent substitution; and In each heterocyclic system, any available N atom is optionally in the form of an N-oxide or optionally surrounded by one or more R atoms. 10N replace, Where R 10c and R 10N It is as defined in claim 1.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, The connection of R4 and R5 allows them, together with the attached nitrogen atom, to form a heterocycle selected from any of the following options: 、 、 The asterisk (*) indicates the N atom attached to R4 and R5; 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 Selected from hydrogen, methyl, or (2C) alkyl group; And R 10c and R 10N It is as defined in claim 1.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, The R4 and R5 linkages allow them, together with the attached nitrogen atom, to form a heterocycle selected from any of the following options: 、 The asterisk (*) indicates the N atom attached to R4 and R5; 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 Selected from hydrogen, methyl, or (2C) alkyl group; And R 10c Or R 10N It is as defined in claim 1.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, The connection of R4 and R5 allows them, together with the attached nitrogen atom, to form a heterocycle with the following structure: The asterisk (*) indicates the N atom attached to R4 and R5; And each R 10c The option is selected independently from the options defined in claim 1.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, R6 is selected from hydrogen, halogen, or methyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, R6 is hydrogen.

15. A compound having the formula IA, IB, or IC: Where R x R1, R2, R3, R4, R5 and R6 are each as defined in claim 1.

16. A compound, or a pharmaceutically acceptable salt thereof, selected from any of the following: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]morpholine-4-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]piperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-(oxetane-3-yl)piperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[5-(2-chloro-6-methyl-4-pyridinyl)-4-(3-cyanophenyl)thiazo-2-yl]pyrrolidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-2-(2-hydroxy-2-methyl-propyl)pyrrolidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide (2S)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]carbamoyl]piperazine-2-carboxylic acid N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-methylpiperazin-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-hydroxy-4-methylpiperidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-4-cyano-4-methyl-piperidin-1-carboxamide (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-methylpiperazine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-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)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-oxo-piperazin-1-carboxamide N4-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]morpholine-2,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-methyl-3-oxo-piperazin-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide 4-Acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methylsulfonyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-aminosulfonyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methoxy-piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(hydroxymethyl)azacyclobutane-1-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]azacyclobutane-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1,1-dioxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-azacyclobutane-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-(2-hydroxyethyl)-3-oxo-piperazin-1-carboxamide 4,4-Dicyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-(1-hydroxy-1-methyl-ethyl)azacyclobutane-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(2-hydroxy-2-methyl-propyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-methyl-1,7-diazaspiro[3,4]octane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(2-hydroxy-1,1-dimethyl-ethyl)piperazine-1-carboxamide (8aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-carboxamide (8aR)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-(oxetane-3-yl)piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-pyrrolidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(methoxymethyl)piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-fluoro-piperidine-1-carboxamide (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-3-methyl-azacyclobutane-1-carboxamide (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]carbamoyl]piperazine-2-carboxylic acid (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]carbamoyl]piperazine-2-carboxylic acid methyl ester (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-(hydroxymethyl)piperazine-1-carboxamide (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-methylpiperazin-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-3-methylpiperazine-1-carboxamide (1S,4S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (3R)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]piperazine-1,3-dicarboxamide (3S)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]piperazine-1,3-dicarboxamide 4-Amino-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methyl-piperidine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazolyl-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)thiazolyl-2-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (1S,4S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide N-[5-[2,6-bis(trideuteratedmethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-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]thiazolyl-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]thiazolyl-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]thiazolyl-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)thiazo-2-yl]-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxecyclobutan-3-yl)-4-pyridyl]thiazolyl-2-yl]-3-methyl-pyrrolidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxecyclobutane-3-yl)-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-morpholino-azacyclobutane-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-tetrahydropyran-4-yl-piperazin-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-3-pyrrolidine-1-yl-azacyclobutane-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(dimethylamino)azacyclobutane-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-(morpholinomethyl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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)thiazolyl-2-yl]-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1,4-diazabicyclo[3.2.1]octane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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-pyridinyl)thiazo-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-pyridinyl)thiazolyl-2-yl]-4-oxo-3,6,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-9-oxo-3,4,6,7,8,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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)thiazolyl-2-yl]-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazo-2-yl]-1-oxo-1,4-thiazinyl-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-aminosulfonyl-pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazo-2-yl]-4-pyrazol-1-yl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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)thiazolyl-2-yl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(1H-imidazol-2-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-10-oxo-3,9-diazaspiro[5.5]undecane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-N4-methylpiperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-8-oxa-2-azaspiro[4.5]decane-2-carboxamide (3S)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]pyrrolidine-1,3-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(2-oxoimidazolidine-1-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(1,2,4-oxadiazol-5-yl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-methylimino-1-oxo-1,4-thiazinane-4-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-N4-(2-hydroxyethyl)piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxo-7-oxa-2,5-diazaspiro[3,5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-6,9-dioxo-1,3,4,7,8,9a-hexahydropyrazino[1,2-a]pyrazin-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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)thiazolyl-2-yl]-2-methyl-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl)thiazolyl-2-yl]-8-methyl-6,9-dioxo-3,4,7,9a-tetrahydro-1H-pyrazino[1,2-a]pyrazin-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-oxo-2,9-diazaspiro[5.5]undecane-9-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-(1-hydroxy-1-methyl-ethyl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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-pyridinyl)thiazolyl-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-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)thiazolyl-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide (3aR,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1,3,3a,4,6,6a-hexahydrofurano[3,4-c]pyrrole-5-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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)thiazolyl-2-yl]-6-methyl-3,6-diazabicyclo[3.2.2]nonane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-methyl-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide (3aS,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-oxo-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolo-5-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxa-2-azaspiro[3,4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-7-oxa-2-azaspiro[3.5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxo-2,7-diazaspiro[3,4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-6-oxo-2,5,7-triazaspiro[3,4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-5-oxo-2,6-diazaspiro[3,4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-ethyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazo-2-yl]-4-(oxetane-3-yl)piperazine-1-carboxamide 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]piperidine-4-carboxylic acid (3S)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-(hydroxymethyl)azacyclobutane-1-carboxamide (3R)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid 4-Cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-hydroxy-3-methyl-azacyclobutane-1-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-azacyclobutane-1-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-azacyclobutane-1-carboxamide 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]carbamoyl]azacyclobutane-3-carboxylic acid (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-methyl-azacyclobutane-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)azacyclobutane-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methylmorpholin-4-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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)thiazo-2-yl]-2-methyl-azacyclobutane-1-carboxamide N-[4-(3-cyano-2-methyl-phenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (3R)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]pyrrolidine-1,3-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-7-azaspiro[4.4]nonane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-7-azaspiro[3,4]octane-7-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azacyclobutane-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azacyclobutane-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-morpholino-pyrrolidine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-5-oxo-piperazin-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methylmorpholin-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxa-1-azaspiro[3.3]heptane-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1,3-dimethyl-2-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-5-oxo-piperazin-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-(hydroxymethyl)azacyclobutane-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-methyl-5-oxo-2,6-diazaspiro[3,4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-methyl-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-methylsulfonyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-4-hydroxy-4-methylpiperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (4aR,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperazine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-piperazin-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-dimethyl-piperazine-1-carboxamide 4-Amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-diazabicyclo[2.2.2]octane-2-carboxamide cis-(2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2,5-dimethyl-piperazine-1-carboxamide (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,6-dimethyl-piperazin-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2,2-dimethyl-piperazin-1-carboxamide 1-Acetylimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazo-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazo-2-yl]-1-oxo-1,4-thiazinyl-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-(oxetane-3-yl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazo-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamide 4,4-Dicyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methoxy-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinyl-4-carboxamide 1-Cyanoimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl)-6-methyl-4-pyridyl]thiazolyl-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]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide Racemic-(3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,5-dimethyl-piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-(trifluoromethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-5-oxa-2,8-diazaspiro[3,5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-(trifluoromethyl)piperazine-1-carboxamide (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperazine-1-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4,7-diazaspiro[2,5]octane-7-carboxamide (3S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3,5-dimethyl-piperazin-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-methylpiperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-2-methylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazolyl-2-yl]-3-methylpiperazine-1-carboxamide (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazolyl-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]thiazolyl-2-yl]-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide Racemic-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-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)thiazolyl-2-yl]-2-cyclopropyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3,3-dimethyl-piperazin-1-carboxamide N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl)thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thiazo-2-yl]-1-imino-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dichloro-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl]thiazo-2-yl]-1-oxo-1,4-thiazinyl-4-carboxamide N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl)thiazo-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxecyclobutan-3-yl)-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[5-(2-cyano-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-1-oxo-1,4-thiazinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(fluoromethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2-cyclopropyl-6-methyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2-isopropyl-6-methyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2-ethyl-6-methyl-4-pyridyl)thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxonium-4-yl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide 4-Cyano-N-[4-(3-cyano-2-methyl-phenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-4-methyl-piperidine-1-carboxamide N-[5-(2-acetamido-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thiazo-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[5-[2-(acetamidomethyl)-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-methoxyethyl)-6-methyl-4-pyridyl]thiazolyl-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)thiazolyl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4-pyridyl]thiazolyl-2-yl]-4-methyl-piperidin-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-(trifluoromethyl)-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-pyrrolidine-1-carboxamide N-[5-[2,6-bis(trideuteratedmethyl)-4-pyridyl]-4-(3-cyanophenyl)thiazolyl]-4-cyano-4-methylpiperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-[(1S)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazolyl-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo-2-yl]-3-methyl-pyrrolidine-1-carboxamide (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazolyl-2-yl]-3-methyl-pyrrolidine-1-carboxamide.

17. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable diluent or carrier.

18. Use of the compound of claim 1 or 16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17, in the manufacture of a medicament for treating cancer.

19. The use according to claim 18, wherein the compound or pharmaceutical composition is administered in combination with one or more other anticancer agents.

20. The use according to claim 19, wherein the one or more additional anticancer agents are selected from: 1) Other forms of cancer immunotherapy and anticancer chemotherapy; 2) Adenosine pathway regulators; 3) Anti-PD-1 and PDL-1 antibodies; and 4) Anti-CTLA4 antibody.

21. The use according to claim 20, wherein: (A) The adenosine pathway regulators are selected from A2b antagonists, CD73 inhibitors and CD39 inhibitors; (B) The anti-PD-1 and PDL-1 antibodies are selected from cilimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab; and / or (C) The anti-CTLA4 antibody is selected from ipilimumab.

22. Use of the compound of claim 1 or 16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17, in the manufacture of a medicament for use as an adenosine A2a antagonist.

23. Use of the compound of claim 1 or 16, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17, in the manufacture of a medicament for treating diseases or disorders related to adenosine A2a receptor activity.

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