Antagonist compound

Abstract

The present invention provides pharmaceutical compositions and methods for use in the treatment of diseases or conditions involving adenosine A2a and / or A2b receptor activity, such as cancer. [Solution] A compound of the following formula I is provided. Also provided are a process for preparing these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or conditions involving adenosine A2a and / or A2b receptor activity, such as cancer. JPEG2026086419000278.jpg69170

Description

[Technical Field]

[0001] This invention relates to specific compounds that function as antagonists for the adenosine A2a receptor. Furthermore, some of the compounds are antagonists of both A2a and A2b receptors. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions containing them, and adeno In the treatment of diseases or conditions involving syn-A2a and / or A2b receptor activity, such as cancer. Regarding their use in [location]. [Background technology]

[0002] In the tumor microenvironment, many tumor cells evade elimination by cytotoxic T cells. Furthermore, reducing patients' clinical response to immunotherapy with anti-checkpoint antibodies. The immunosuppressive pathway that enables this is active. Pembrolizumab and Nivolt are anti-PD-1 antibodies. Mab, as well as the anti-PD-L1 antibodies durvalumab, avelumab, and atezolizumab, It is used in the treatment of many solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma. However, only 20-30% of patients respond to checkpoint blockade. Yes, and this treatment has considerable side effects (Sukari et al, 2016). Therefore, other methods to enhance the cytotoxicity of the tumor microenvironment are being actively researched. This includes, or more likely to be, used as monotherapy, but checkpoints This includes drugs that can be used in combination with inhibitors and cytotoxic agents to enhance their efficacy. It can be done.

[0003] One method attracting attention is the production and / or action of adenosine in the tumor microenvironment. This is to inhibit (Vijayan et al, 2017). Adenosine is immunosuppressive. It possesses inhibitory properties and is present in the tumor microenvironment at high concentrations. Recent studies have shown that human adenosine The concentration is estimated to be <1 μM in normal tissue, compared to approximately 10 μM in tumors. (Houthuys et al 2017). Adenosine contains two different substrates. It is formed in both intracellular and extracellular locations by two separate pathways. Nosine is derived from AMP and S-adenosylhomocysteine, while during metabolic stress... The observed high concentrations of extracellular adenosine are due to the synergistic action of CD39 and CD73, which are precursors. Related to the release and degradation of adenine nucleotides (ATP, ADP, and AMP) (Vij ayan et al, 2017).

[0004] CD39 and CD73 are upregulated in the tumor microenvironment in response to hypoxia. D73 represents the estimated patient stratification method for adenosine antagonists. This is tumor cell Its expression in cells is also associated with a poor overall prognosis in many different types of cancer, and adeno This suggests that synth production is related to undesirable immunosuppressive phenotypes in the tumor microenvironment. This is because (Gao et al 2014; Loi et al, 2013). C D73-negative Treg cells cannot suppress effector T cell function, therefore tumor infiltration immunohistochemistry CD73 expression by cells is also important for promoting tumor immunosuppression (Deaglio et al, 2007; Reinhardt et al, (2017). Furthermore, anti Patients who are resistant to PD1 treatment have elevated CD73 levels (Reinhard (t et al, 2017).

[0005] Adenosine occupies specific GPCRs on the cell surface of the P1 purine receptor subtype. They regulate cellular functions. The P1 receptor family includes A1, A2a, A2b and It is further subdivided into A3.

[0006] A2 receptors are classified based on their high and low affinity for adenosine, respectively, as A2a It is further subdivided into A2b. A2a is expressed by lymphocytes, and activation of A2a is site This leads to the suppression of kine production and other effector functions. Tumor growth is observed in syngeneic mouse models. In this process, the A2a gene is inhibited by its removal, and this effect is associated with lymphocyte activation and cell regeneration. This has been demonstrated to be due to the enhancement of injury function (Ohta et al, 2006; Wa ickman et al 2012;Beavis et al,2013;Mitt al et al, 2014; Cekic et al, 2014). A2a- / - Mau The study showed an increased response to inhibition of checkpoint pathways such as PD-1, and tumor-free development. It improves both survival and overall survival. Adenosine-mediated A2a activation is also an anti-CTLA4 treatment. It limits the effectiveness of the treatment (Iannone et al, 2014).

[0007] The effect of A2a gene deficiency in mouse models is mimicked by pharmacological blockade of A2a. It is imitated. A2a antagonists enhance cytotoxic CD8+ T cells and NK cells. It has been shown to enhance the ability to prevent metastasis in D73-expressing tumors (Beavis e (t al, 2013). Importantly, A2a antagonists enhance the efficacy of anti-PD1 antibodies. Strengthen (Beavis et al, 2015).

[0008] These findings are relevant to the development of selective A2a antagonists for use in cancer immunotherapy. Clinical trials have shown that it can be used as monotherapy and in combination with the anti-PDL1 antibody atezolizumab. CPI-444, the first selective A2a antagonist to be evaluated in cancer, is used in [unspecified]. It is currently being used. Preliminary data suggests that this compound is well tolerated and reduces tumor size. This reduced the amount of CD8+T, showing early signs of enhanced CD8+T infiltration into tumor tissue.

[0009] Adenosine A2b receptors also play a crucial role in cancer progression through the regulation of the tumor microenvironment. A2b is expressed by cells of bone marrow origin and is found in high concentrations within the tumor microenvironment. Denosine alters the behavior of tumor-associated macrophages, bone marrow-derived suppressor cells, and dendritic cells. It can be modified. Activation of A2b leads to the polarization of immunosuppressive M2 macrophages (Cso Ka et al, 2012), formation of myeloid-derived suppressor cells (Rhyzov et al, (2011) This leads to immunosuppression and pro-angiogenic phenotypes in dendritic cells (Nov itskiy et al, 2008; Wilson et al, 2009). A2b Blocking has been shown to reduce tumor size in many mouse cancer models. (Cekic et al,2012;Sorrentino et al,2015; Iannone et al, 2013) reported that it reduces MDSC infiltration and VEGF This is an effect related to production (Sorrentino et al, 2015; Ianno (ne et al, 2013).

[0010] Therefore, dual inhibition of both A2a and A2b reduces immunosuppression within the tumor microenvironment. This is an attractive approach because it inhibits proliferation. [Overview of the project] [Means for solving the problem]

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

[0012] According to further aspects of the present invention, a compound as defined herein, or a pharmaceutically acceptable compound thereof. The salt, hydrate, or solvate is mixed with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition is provided.

[0013] According to a further aspect of the present invention, the adenosine A2a receptor, in vitro or in vivo, or a method of antagonizing A2a and A2b receptors, wherein cells are subjected to the chemicals defined herein. Contact with an effective amount of the compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. A method including the above is provided.

[0014] According to a further aspect of the present invention, the adenosine A2a receptor, in vitro or in vivo, or a method for selectively antagonizing A2a and A2b receptors, wherein cells are defined herein as Contact with an effective amount of the compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. A method is provided that includes causing this to happen.

[0015] According to a further aspect of the present invention, a method for inhibiting cell proliferation in vitro or in vivo. The cells are subjected to the compounds defined herein, or their pharmaceutically acceptable salts or hydrates. Alternatively, contact with an effective amount of a solvate or a pharmaceutical composition as defined herein. A method is provided that includes the compound or pharmaceutical composition, which may include one or more additional antiproliferative agents. Administered in combination with (for example, checkpoint inhibitors and / or cytotoxic agents) .

[0016] According to a further aspect of the present invention, the adenosine A2a and / or A2b receptor activity is related to A method of providing treatment for a disease or disorder to a patient who requires such treatment, the aforementioned To the patient, the compound as defined herein, or a pharmaceutically acceptable salt or hydrate thereof. A method comprising administering a therapeutically effective amount of a solvate or a pharmaceutical composition as defined herein. The law is provided.

[0017] According to a further aspect of the present invention, treatment of cell proliferation disorders is provided for those who require such treatment. A method for administering to a patient, wherein the patient is given a compound as defined herein, or a pharmaceutically acceptable compound thereof. Salts, hydrates, or solvates that are permissible, or the therapeutic agents of pharmaceutical compositions as defined herein A method is provided which includes administering a therapeutically effective dose. Preferably, the compound or pharmaceutical composition is One or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents) It is administered in combination with [another drug].

[0018] According to a further aspect of the present invention, cancer treatment is administered to patients who require such treatment. A method comprising administering to the patient a compound as defined herein, or a pharmaceutically acceptable compound thereof. A therapeutically effective amount of a salt, hydrate, or solvate, or a pharmaceutical composition as defined herein, is administered. A method is provided which includes giving. Preferably, the compound or pharmaceutical composition includes one or more additional Combined with additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents) It will be administered.

[0019] According to a further aspect of the present invention, a compound defined herein for use in treatment or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof is provided. It can be done.

[0020] According to a further aspect of the present invention, for use in the treatment of cell proliferation pathologies, The defined compound, or its pharmaceutically acceptable salt, hydrate, or solvate, or this A pharmaceutical composition as defined in the specification is provided. Preferably, the compound or pharmaceutical composition is one Combined with the above additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents) They are administered together.

[0021] According to a further aspect of the present invention, a chemical formula defined herein for use in the treatment of cancer Compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions are proposed. Provided. In certain embodiments, cancer is human cancer. Preferably, the compound or pharmaceutical composition one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents) It is administered in combination with [another drug].

[0022] According to a further aspect of the present invention, an adenosine A2a and / or A2b antagonist and Compounds as defined herein, or pharmaceutically acceptable salts thereof, water, for use in the specified manner. A dihydrate or solvate is provided. In one embodiment, the compound of the present invention is selectively adenosyl It is an A2a and A2b antagonist.

[0023] According to a further aspect of the present invention, diseases involving adenosine A2a and / or A2b or This refers to compounds as defined herein, or their pharmaceutically acceptable properties, for use in the treatment of disorders. A salt, hydrate, or solvate is provided.

[0024] According to further aspects of the present invention, a compound as defined herein, or a pharmaceutically acceptable compound thereof. In the manufacture of a pharmaceutical product for the treatment of a cell proliferation disorder, the salt, hydrate, or solvate thereof. Uses are provided. Preferably, the compound or pharmaceutical composition includes one or more additional antiproliferative agents. For example, it is administered in combination with checkpoint inhibitors and / or cytotoxic agents.

[0025] According to further aspects of the present invention, a compound as defined herein, or a pharmaceutically acceptable compound thereof. The use of the salt, hydrate, or solvate thereof in the manufacture of a pharmaceutical for the treatment of cancer is provided. Preferably, the cancer is human cancer. Preferably, the compound or pharmaceutical composition contains one or more Combined with additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents) It is administered.

[0026] According to a further aspect of the present invention, an adenosine A2a and / or A2b antagonist and In the manufacture of a pharmaceutical product for use as a pharmaceutical product, the compounds defined herein, or their pharmaceutically The use of acceptable salts, hydrates, or solvates is provided.

[0027] According to a further aspect of the present invention, for the treatment of diseases or disorders involving adenosine A2a Compounds as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals. The use of a hydrate or solvate is provided.

[0028] According to further aspects of the present invention, a compound as defined herein, or a pharmaceutically acceptable compound thereof. A method for preparing a salt, hydrate, or solvate is provided.

[0029] According to a further aspect of the present invention, the method for preparing the compounds defined herein is Compounds that can be obtained, or are obtained, or are directly obtained, or their pharmaceutically acceptable A salt, hydrate, or solvate is provided.

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

[0031] Features including any preferred and desirable features related to one aspect of the present invention are also part of the present invention. The features may include any preferred and desirable features related to any other embodiment. [Modes for carrying out the invention]

[0032] definition Unless otherwise stated, the following terms used in this specification and in the claims have the same meaning as: The following meanings are described below.

[0033] References to "treat" or "cure" include prevention and relief of established symptoms of a disease. It should be understood as follows: Therefore, "to treat" or "to treat" a condition, disorder, or pathology. (1) There is a possibility that the person is suffering from or has a predisposition to a condition, disorder, or illness. However, they have not yet experienced or exhibited any clinical or potential symptoms of a condition, disorder, or pathology. In humans, it is not possible to prevent or delay the appearance of clinical symptoms of a condition, disorder, or pathology that does not occur. (2) to suppress a condition, disorder or pathological state, that is, the onset or To prevent recurrence (in the case of maintenance therapy) or to prevent at least one clinical or potential symptom thereof, (3) To alleviate or delay the disease, that is, To regress a condition, disorder, or pathological state, or at least one of its clinical or potential symptoms. This includes [something].

[0034] "Therapeutic dose" refers to the effective dose of a substance administered to a mammal to treat a disease. This refers to the amount of a compound sufficient to produce such a therapeutic effect. "Therapeutic dose" means the amount of a compound sufficient to produce such a therapeutic effect. The composition of the disease and its severity, as well as the age and weight of the mammal being treated, will vary. ru.

[0035] In this specification, the term "alkyl" includes both linear and branched alkyl groups. The references to individual alkyl groups such as "propyl" are specific only to linear types, and References to individual branched alkyl groups such as "sopropyl" are specific only to branched alkyl groups. For example, "(1-6C) alkyl" is equivalent to (1-4C) alkyl, (1-3C) alkyl This includes propyl, isopropyl, and t-butyl. Similar rules apply to other groups, for example. For example, "phenyl(1-6C)alkyl" is phenyl(1-4C)alkyl, benzyl Contains 1-phenylethyl and 2-phenylethyl.

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

[0037] The "alkylene," "alkenylene," or "alkynylene" group is located between two other chemical groups. These are alkyl, alkenyl, or alkynyl groups located at the base and playing a role in connecting them. Therefore, "(1-6C)alkylene" is a divalent linear saturated alkylene with 1-6 carbon atoms. A hydrocarbon group or a divalent branched saturated hydrocarbon group with 3 to 6 carbon atoms, for example, methylene This refers to ethylene, propylene, 2-methylpropylene, pentylene, etc.

[0038] "(2-6C) alkenylenes" are, for example, ethenylene and 2,4-pentadienylene. How to form a divalent linear carbide of 2-6 carbon atoms containing at least one double bond This refers to a hydrogen group or a divalent branched hydrocarbon group consisting of 3 to 6 carbon atoms.

[0039] "(2-6C) Alkynylene" refers to, for example, ethynylene, propynylene, and butynylene. For example, a divalent linear carbon of 2 to 6 carbon atoms containing at least one triple bond. This refers to a hydrogenated group or a divalent branched hydrocarbon group consisting of 3 to 6 carbon atoms.

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

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

[0042] "(3-8C)cycloalkyl-(1-6C)alkylene" is equivalent to (1-6C)alkylene This refers to a (3-8C) cycloalkyl group covalently bonded to a base, and all of these are as defined herein. It is defined.

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

[0044] The terms "heterocyclyl," "heterocyclic," or "heterocyclic" refer to non-aromatic saturated compounds. Alternatively, it refers to a partially saturated monocyclic, condensed, bridged, or spironic heterocyclic system. The ring contains approximately 3 to 12 (preferably 3 to 7) ring atoms, and the ring contains nitrogen, oxygen, or sulfur. It contains 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from the following. Bicyclic heteroatoms The ring contains 7 to 17 member atoms, preferably 7 to 12 member atoms. The bicyclic heterocycle is It can be a fused ring system, a spiro ring system, or a bridging ring system. An example of a heterocyclic group is oxylanil. , cyclic ethers such as oxetanyl, tetrahydrofuranyl, dioxanyl and substituted cyclic ethers Examples include ethers. Examples of nitrogen-containing heterocycles include azetidinyl and pyro Ridinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyra Examples include zolyl. Typical heterocycles containing sulfur include tetrahydrothie Nyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydr Rotiepine is one example. Other heterocycles include dihydrooxathiolyl and tetrahydroxathiolyl. Looxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetra Hydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, molar Folinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahyde Lobenzofuranil, octahydrobenzimidazolyl, and octahydrobenzothiazolyl Examples include: For sulfur-containing heterocycles, sulfur oxide containing SO or SO2 groups. Yellow heterocycles are also included. Examples include tetrahydrothienyl and thiomorpholinyl sul. Phoxide and sulfone forms, for example, tetrahydrothiene 1,1-dioxide and thiomethyl One example is rufolinyl 1,1-dioxide. It contains one or two oxo (=O) or thioxo A proper meaning of a heterocyclyl group having a (=S) substituent is, for example, 2-oxopyrrolidine Nyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl Lidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxo The specific heterocyclyl group is either imidazolidinyl or 2,6-dioxopiperidinyl. , saturated monocyclic compound containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur 3-7 member heterocyclyl, e.g., azetidinil, tetrahydrofuranil, tetrahydro Pyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl , 1,1-dioxide, thiomorpholinyl, thiomorpholinyl, 1,1-dioxide, pi Peridinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. To understand this, the heterocycle is formed via any suitable atom, for example, a carbon or nitrogen atom. And can be linked to another group. However, piperidino or morpholino in this specification References to the piperidine-1-yl ring or morpholine-4 linked via a ring nitrogen - Refers to the Illusory ring.

[0045] A "bridged ring system" refers to a ring system in which two rings share three or more atoms, for example, Adv anced Organic Chemistry,by Jerry March,4 th Edition,Wiley Interscience,pages 131- See 133, 1992. An example of a bridged heterocyclyl ring system is aza-bisic. [2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, A Zarbicyclo[2.2.2]octane, azabicyclo[3.2.1]octane and quinu Cryzine is one example.

[0046] A "spiro-bicyclic system" is a system in which two ring systems share one common spirocarbon atom. The heterocycle is linked to a further carbocycle or heterocycle via a single common spirocarbon atom. This means that it is being done. An example of a spiro ring system is 6-azaspiro[3.4]octa n, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]hepta n, 2-oxa-6-azaspiro[3,3]heptane, 7-oxa-2-azaspiro[3 [5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azas Examples include spiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane. .

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

[0048] The terms "heteroaryl" or "heteroaromatic" are selected from nitrogen, oxygen, or sulfur. Aromatics incorporating one or more heteroatoms (e.g., 14, especially 1, 2, or 3) This refers to monocyclic, bicyclic, or polycyclic rings. The term "heteroaryl" refers to monovalent and bicyclic rings. It includes both valence species. Examples of heteroaryl groups have 5 to 12 ring members, more generally 5 to 1 These are monocyclic and bicyclic groups containing 0 ring members. Heteroaryl groups, for example, have 5 or 6 members. A single ring or a 9 or 10-membered biring ring, for example, a condensed 5-membered ring and a 6-membered ring, or two It can be a bicyclic structure formed from condensed six-membered rings. Each ring is generally composed of nitrogen, sulfur, and It may contain up to about four heteroatoms selected from oxygen. Generally, heteroatoms A ring can have up to three heteroatoms, or more generally, up to two heteroatoms, for example, a single ring. It contains one heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. It contains a child. The nitrogen atom in the heteroaryl ring is imidazole or pyridine. It is either basic, as in the case of nitrogen indole or pyrrole, or substantially It can be nonbasic. Generally, in heteroaryl groups containing any amino group substituent of the ring. The number of basic nitrogen atoms present is less than 5.

[0049] Examples of heteroaryls include furyl, pyrrolyl, thienyl, oxazolyl, isooxyl Sazolyl, Imidazolyl, Pyrazolyl, Thiazolyl, Isothiazolyl, Oxadiazolyl thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridadinil, pyrimidinil Lu, pyrazinyl, 1,3,5-triazenicyl, benzofuranyl, indolyl, isoindolind Lyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, Benzothiazolyl, indazolyl, prinyl, benzoflazanil, quinolyl, isoquinol Lu, quinazolinyl, quinoxalinyl, sinnolinyl, pteridinyl, naphthidinyl, ka Basolyl, phenazinil, benzoisoquinolinil, pyridopyrazinil, thieno[2,3b] ]-Furanyl-, 2H-Flo[3,2b]-Pyranyl-, 5H-Pyrido[2,3-d]- Oxazinyl-, 1H-pyrazolo[4,3-d]-oxazinyl, 4H-imidazo[4, 5d] Thiazolyl, pyrazino[2,3d]pyridazinyl, -imidazo[2,1b]thiazo Examples include ril and -imidazo[1,2b][1,2,4]-triazinyl. "Reel" also means that at least one ring is an aromatic ring and one or more of the other rings are non-aromatic. A saturated or partially saturated ring, wherein at least one ring is selected from nitrogen, oxygen, or sulfur. It includes a partially aromatic bicyclic or polycyclic ring system containing one or more heteroatoms. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl Trahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydro Robenzthienyl, dihydrobenzufranyl, 2,3-dihydro-benzo[1,4]diode Xynyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2- Benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2 ,3,4-tetrahydro-1,8-naphthilidinyl, 1,2,3,4-tetrahydropyridinyl do[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2b][1,4] Oxazinyl and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]p Rajnir is one example.

[0050] Examples of 5-membered heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, Flazanil, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl Examples include thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups. However, it is not limited to these.

[0051] Examples of 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyridadinyl, and pyrimidi. Examples include, but are not limited to, yl and triazinyl compounds.

[0052] A bicyclic heteroaryl group can be, for example, a group selected from the following: A benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; A pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; A pyrimidine ring condensed into a 5- or 6-membered ring containing one or two ring heteroatoms; A pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; A pyrazole ring condensed into a 5- or 6-membered ring containing one or two ring heteroatoms; A pyrazine ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; An imidazole ring condensed into a 5- or 6-membered ring containing one or two ring heteroatoms; An oxazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; An isoxazole ring condensed into a 5- or 6-membered ring containing one or two ring heteroatoms; A thiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; An isothiazole ring condensed into a 5- or 6-membered ring containing one or two ring heteroatoms; A thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; A furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; Cyclohexyl condensed on a 5 or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms The ring; and Cyclopentol condensed on a 5 or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms Ru-kan.

[0053] A specific example of a bicyclic heteroaryl group containing a six-membered ring fused to a five-membered ring is benzophthol. Ranyl, benzothiophenyl, benzimidazolyl, benzooxazolyl, benzoiso Xazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranil, indri Lu, isoindolyl, indolidinyl, indolinyl, isoindolinyl, prinyl (example) For example, adeninyl, guaninyl, indazolyl, benzodioxolyl and pyrazolopyriolyl Examples include, but are not limited to, the dinyl group.

[0054] A specific example of a bicyclic heteroaryl group containing two fused six-membered rings is quinolinyl, Soquinolinyl, Chromanil, Thiocromanil, Clomenil, Isoclomenil, Chromanil Isochromanil, benzodioxanil, quinolidinil, benzoxazinil, benzodi Azinyl, Pyridopyridinyl, Quinoxalinyl, Quinazolinyl, Synnolinyl, Phthalazi Examples include, but are not limited to, nyl, naphthilidinyl, and pteridinyl groups.

[0055] "Heteroaryl(1-6C)alkyl" is covalently bonded to a (1-6C)alkylene group. This refers to a heteroaryl group, both of which are defined herein. Examples of the groups include pyridine-3-ylmethyl and 3-(benzofuran-2-yl)propyl. These are some examples.

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

[0057] The term "aryl(1-6C)alkyl" refers to a group covalently bonded to a (1-6C)alkylene group. This refers to an aryl group, and both are defined herein. aryl-(1-6C) Examples of lukyl groups include benzyl and phenylethyl.

[0058] This specification also uses several compound terms to describe groups containing two or more functional groups. To use. Such terms will be understood by those skilled in the art. For example, heterocyclyl (m~nC)alkyl includes (m~nC)alkyl substituted with heterocyclyl. nothing.

[0059] The term "may be substituted" refers to the substituted group, structure, or molecule, and the substituted This refers to a group, structure, or molecule that is not present. "Here, R 1 One / any CH, CH2, C within the base The phrase "the H3 group or heteroatom (i.e., NH) may be substituted" is preferred. R 1 One of the hydrogen groups of the group is replaced by the specified group in question. It means that.

[0060] If an optional substituent is selected from "one or more" groups, this definition means that one of the groups This includes all substituents selected from one or more of a particular group, or substituents selected from two or more of a specific group. Please understand this.

[0061] The phrase "compounds of the present invention" is disclosed herein both in general and specifically. It means a compound.

[0062] The compound of the present invention In a first aspect, the present invention relates to a compound having the following structural formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof:

Chemical Formula

[0063] In a second aspect, the present invention relates to a compound having the following structural formula I' (sub-definition of formula I) , or relating to the pharmaceutically acceptable salts, hydrates, or solvates thereof: [ka] [In formula: R1 is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)halo Lucoxy, cyano, -(CH2) q1 -OR 1A ,-(CH2) q1 -C(O)R 1A , -(CH2) q1 -C(O)OR 1A ,-(CH2) q1 -OC(O)R 1A ,-(CH 2) q1 -C(O)N(R 1B )R 1A ,-(CH2) q1 -N(R 1B )C(O)R1 A,-(CH2) q1 -S(O) p R 1A (where p is 0, 1, or 2), -(C H2) q1 -SO2N(R 1B )R 1A , or -(CH2) q1 -N(R 1B )SO2R 1A Selected from (Here, q1 is 0, 1, or 2; R 1A and R 1B These are, independently, hydrogen, (1-2C) alkyl, and (3-4C) (Selected from cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl) ; R2 and R3 are both hydrogen, or one of R2 and R3 is hydrogen and the other is f Selected from ruo, methyl, or methoxy; R4 and R5, along with the nitrogen atom to which they are bonded, are one or more R 10C By substituent They are linked together to form a heterocycle which may be substituted on any available carbon atoms. It is (Here, R 10C is an oxo, thioxo, halo, or cyano substituent, or formula: -[CR 7a R 7b ] n -LZ Selected from the basis (In the formula, n is between 0 and 6; R 7a and R 7b Each of these is independently hydrogen, fluoro, or (1-2C)alkyl. Selected; L does not exist, or -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(Ra )-,-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 )-If is -N(R a ) Selected from SO2- (where R a and R b Each of them is independent of water. Selected from elemental or (1-2C) alkyl; Z represents hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, and (3-6C) cycloalkyl. hydroxyalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroalkyl Krill, heterocyclyl(1-2C)alkyl, heteroaryl, or heteroaryl(1 Selected from (1-6C) alkyl; Z is (1-6C) alkyl, halo, (1-6C) halo Alkyl, (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), -SO 2N(R c )R d , -N(R c )SO2R d ,-(CH2) z NR c R d (Here, z is Even if substituted with one or more substituents selected from , 1, 2 or 3 or oxo often; The alkyl portion of the substituent on Z can be cyano, halo, hydroxy, amino, oxo, (1-2 C) may be further substituted with alkyl or (1-2C)alkoxy, R c and R d Each is independently hydrogen, (1-6C) alkyl, (1-6C) haloalkyl or ( 3-6C) Selected from cycloalkyl groups); Furthermore, any available N atom in the formula may be one or more R atoms, even in the form of an N-oxide. 10N It may also be replaced by (Here, R 10N is either -S(O)2NH2 or (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~6 -L 1b -Z1 Selected from (In the ceremony R 2a and R 2b Each of these is independently hydrogen, fluoro, or (1-2C)alkyl. Selected; L 1a -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 ) -, -S(O)2N(R a1 )- or N(R a1 )-Selected from (where R a1 teeth, Selected from hydrogen or (1-2C) alkyl); L 1b It does not exist, or -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 a 2)-, -N(R a2 )C(S)-, -N(R a2 )C(S)N(R b2 )-,-S(O )2N(R a2 )-or-N(R a2 ) Selected from SO2 (here, R a2 and R b2 Each of these elements is independently selected from hydrogen or (1-2C) alkyl groups; Z1 is (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heteroalkyl Ryl, heteroaryl, (3-6C)cycloalkyl, (1-2C)alkyl, aryl 1-2C) alkyl, heterocyclyl(1-2C) alkyl or heteroaryl(1-2 C) Selected from alkyl groups (where Z1 is a heterocyclyl group directly linked to the N atom) In some cases, it is a heterocyclyl linked to carbon; Z1 is (1-6C)alkyl Lu, Halo, (1~6C) Haloalkoxy, Cyano, Nitro, -NR e R f , -OR e ,- C(O)R e , -C(O)OR e ,-OC(O)R e ,-C(O)N(R e )R f , -N (R e )C(O)R f , -S(O) y R e (where y is 0, 1, or 2), -S O2N(R e )R f , -N(Re )SO2R f ,-(CH2) z NR e R f (Here, z (is 1, 2, or 3) or even if substituted with one or more substituents selected from the oxo Often, R e and R f These are, independently, hydrogen, (1-6C) alkyl, and (1-6C) (Selected from haloalkyl or (3-6C)cycloalkyl); Furthermore, any S atom present in the heteroring in the formula is S(=O), S(=O)2, or S( =O)(=NR e )(Here, R e These are hydrogen, (1-3C) alkyl or (2-3C) alkyl It may exist as (selected from Lucanoil); R6 is selected from hydrogen, halo, methyl, methoxy, and trifluoromethyl.

[0064] Examples of specific compounds of the present invention include, for example, the compound of formula I, or a pharmaceutically acceptable compound thereof. Examples include salts, hydrates and / or solvates, and here, unless otherwise specified, R x , R 1, R2, R3, R4, R5, and R6 are each in the above or below paragraphs (1) to (32 It has one of the meanings defined in either of the following: (1) R1 is (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) Haloalkoxy, cyano, -(CH2) q1 -OR 1A and (CH2) q1 -C(O)R 1A Selected from (Here, q1 is either 0 or 1; R 1A (Selected from hydrogen or (1-2C) alkyl); (1a) R1 is (1-3C) alkyl, halo, (1-3C) haloalkyl, (1-3C ) Haloalkoxy, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxal Tan-3-yl, -(CH2) q1 -OR 1A and (CH2) q1 -C(O)R 1A from Selected (Here, q1 is either 0 or 1; R 1A (Selected from hydrogen or (1-2C) alkyl); (2) R1 is (1-2C)alkyl, halo, (1-2C)haloalkyl and C(O)R 1A Selected from; (Here, R 1A (Selected from hydrogen or methyl); (2a) R1 is (1-3C) alkyl, halo, (1-3C) haloalkyl, (1-3C ) Haloalkoxy, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxal Tan-3-yl and OR 1A Selected from; (3) R1 is selected from methyl, halo, and CF3; (3a) R1 is methyl, CD3, isopropyl, halo, (1-3C) hydroxyalkyl L, cyano, cyclopropyl, oxetane-3-yl, -OMe, -CH2F, -CHF Selected from 2 and CF3; (3b) R1 is methyl, CD3, isopropyl, halo, (1-3C) hydroxyalkyl L, cyano, cyclopropyl, oxetane-3-yl, -OMe, -CHF2 and CF3 Selected from; (4) R1 is selected from methyl and halo; (4a) R1 is methyl, CD3, isopropyl, hydroxymethyl, 2-hydroxy Selected from sopropyl, cyclopropyl, oxetane-3-yl, and halo; (5) R1 is selected from methyl, fluoro, or chloro; (6) R1 is selected from methyl or chloro; (7) R1 is methyl; (7a) R1 is methyl or CD3; (8) R1 is chloro; (8a) R1 is CD3; (8b) R1 is isopropyl; (8c)R1 is hydroxymethyl; (8d)R1 is 2-hydroxyisopropyl; (8e)R1 is cyclopropyl; (8f)R1 is oxetane-3-yl; (9) Both R2 and R3 are hydrogen, or one of R2 and R3 is hydrogen and the other is hydrogen. The compound is either fluoro or methyl; (10) Both R2 and R3 are hydrogen; (11) R4 and R5, together with the nitrogen atom to which they are bonded, one or more R 10C Place The substitution group forms a heterocycle which may be substituted on any available carbon atom. It is connected to (here, R 10C This refers to oxo, thioxo, halo, or cyano substitutions. Base, or formula: -[CH2] n -LZ Selected from the basis (In the ceremony n is between 0 and 4; L does not exist, or -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(Rb )-,-S(O)2N(R a )-or -N(R a ) Selected from SO2- (where R a and R b Each of them independently, hydrogen or selected from (1-2C) alkyl groups); Z represents hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, and (3-6C) cycloalkyl. hydroxyalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroalkyl Krill, heterocyclyl(1-2C)alkyl, heteroaryl, or heteroaryl(1 Selected from (1-4C) alkyl; Z is (1-4C) alkyl, halo, (1-4C) halo Alkyl, (1-4C)haloalkoxy, cyano, nitro, -NR c R d , -OR c ,- C(O)R c , -C(O)OR c ,-OC(O)R c ,-C(O)N(R c )R d , -N (R c )C(O)R d , -S(O) y R c (where y is 0, 1, or 2), -SO 2N(R c )R d , -N(R c )SO2R d ,-(CH2) z NR c R d (Here, z is Even if substituted with one or more substituents selected from , 1, 2 or 3 or oxo often; The alkyl portion of the substituent on Z can be cyano, halo, hydroxy, amino, oxo, (1~ R may be further substituted with 2C)alkyl or (1-2C)alkoxy, cand R d Each of these is independently hydrogen, (1-4C) alkyl, (1-6C) haloalkyl or (3-4C) Selected from cycloalkyl groups; Furthermore, any available N atom may be in the form of an N-oxide, or one or more R 10 N It may also be replaced by (where R 10N Is it -S(O)2NH2, or teeth: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~4 -L 1b -Z1 Selected from (In the formula, R 2a and R 2b Both are hydrogen; L 1a -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 ) -or S(O)2N(R a1 )-Selected from (where R a1 is hydrogen or methyl ru); L 1b It does not exist, or -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 a 2)-, -N(R a2 )C(S)-, -N(R a2 )C(S)N(R b2 )-,-S(O )2N(Ra2 )-or-N(R a2 ) Selected from SO2 (here, R a2 and R b2 Each is independently selected from hydrogen or methyl; Z1 is (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heteroalkyl Ryl, heteroaryl, (3-6C)cycloalkyl, (1-2C)alkyl, aryl 1-2C) alkyl, heterocyclyl(1-2C) alkyl or heteroaryl(1-2 C) Selected from alkyl groups (where Z1 is a heterocyclyl group directly linked to the N atom) In some cases, it is a heterocyclyl linked to carbon; Z1 is (1-4C)alkyl Lu, Halo, (1-4C) Haloalkoxy, Cyano, Nitro, -NR e R f , -OR e ,- C(O)R e , -C(O)OR e ,-OC(O)R e ,-C(O)N(R e )R f , -N (R e )C(O)R f , -S(O) y R e (where y is 0, 1, or 2), -S O2N(R e )R f , -N(R e )SO2R f ,-(CH2) z NR e R f (Here, z (is 1, 2, or 3) or even if substituted with one or more substituents selected from the oxo Often, R e and R f These are, independently, hydrogen, (1-4C) alkyl, and (1-4C) (Selected from haloalkyl or (3-6C)cycloalkyl); Furthermore, any S atom present in the heteroring in the formula is S(=O), S(=O)2, or S (=O)(=NR e )(Here, R e is hydrogen, (1-3C) alkyl or (2-3C) May exist as (selected from Alkanoyl); (12) R4 and R5, together with the nitrogen atom to which they are bonded, one or more R 10C Place The substitution group forms a heterocycle which may be substituted on any available carbon atom. It is connected to (here, R 10C is an oxo, halo, or cyano substituent, or formula : -[CH2] n -LZ Selected from the basis (In the formula, n is between 0 and 2; L does not exist, or -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 ) Selected from SO2 (here, R a2 and R b2 Each Independently selected from hydrogen or methyl); Z represents hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, and (3-6C) cycloalkyl. Roalkyl(1-2C)alkyl, aryl, heterocyclyl or heteroaryl(1- Selected from (2C) alkyl; Z is (1-2C) alkyl, halo, (1-2C) halo Lukil, (1-2C) Haloalkoxy, Cyano, -NRc 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 (Here, z is 1 or 2 It may be substituted with one or more substituents selected from the oxo; The alkyl portion of the substituent on Z1 can be cyano, halo, hydroxy, amino, oxo, (1 R may be further substituted with (~2C) alkyl or (1~2C) alkoxy, c and R d These are, independently, hydrogen, (1-2C) alkyl, (1-2C) haloalkyl or (Selected from (3-6C) cycloalkyl groups)); Furthermore, any available N atom may be in the form of an N-oxide, or one or more R 10 N It may also be replaced by (where R 10N Is it -S(O)2NH2, or teeth: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~2 -L 1b -Z1 Selected from (In the formula, R 2a and R 2b Both are hydrogen; L 1a These are -C(O)-, -S(O)2-, or S(O)2N(R a1 )- Selected from (Here, R a1 (It is hydrogen or methyl); L 1b It does not exist, or -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 ) Selected from SO2 (here, R a2 and R b2 That Each is independently selected from hydrogen or methyl; Z1 is (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heteroalkyl Lyle, heteroaryl, (3-6C)cycloalkyl, (1-2C)alkyl, or aryl Selected from (1-2C)alkyl groups (however, heteroalkyl groups where Z1 is directly linked to the N atom) If it is a lyl group, it is a heterocyclyl linked to carbon); Z1 is (1~2C )Alkyl, Halo, (1-2C) Haloalkoxy, Cyano, Nitro, -NR e R f , -O R 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 (child Here, z is 1, 2, or 3) or substituted with one or more substituents selected from oxo. It's fine to do so, R e and R f Each is independently derived from hydrogen or (1-2C)alkyl. (Selected)); Furthermore, any S atom present in the heteroring in the formula is S(=O), S(=O)2, or S (=O)(=NR e )(Here, R e is hydrogen, (1-3C) alkyl or (2-3C) May exist as (selected from Alkanoyl); (13) R4 and R5, together with the nitrogen atom to which they are bonded, one or more R 10C Place The substitution group forms a heterocycle which may be substituted on any available carbon atom. It is connected to (here, R 10C is an oxo, halo, or cyano substituent, or formula : -[CH2] n -LZ Selected from the basis (In the formula, n is between 0 and 2; L does not exist, or -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(Ra )-or -N(R a ) Selected from SO2 (here, R a and R b It is hydrogen; Z can be hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, aryl, or hetero. Selected from cyclyl or heteroaryl; Z is (1-2C)alkyl, halo, (1- 2C) Haloalkyl, (1-2C) Haloalkoxy, Cyano, -NR c R d , -OR c , -C(O)R c , -C(O)OR c ,-OC(O)R c ,-C(O)N(R c )R d ,- N(R c )C(O)R d , -S(O) y R c (where y is 0, 1, or 2), -S O2N(R c )R d , -N(R c )SO2R d ,-(CH2) z NR c R d (Here, z (is 1 or 2) or may be substituted with one or more substituents selected from oxo. Ku; R c and R d These are, independently, hydrogen, (1-2C)alkyl, or (1-2C)alkyl. (Selected from rhalkyl); Furthermore, any available N atom may be in the form of an N-oxide, or one or more R 10 N It may also be replaced by (where R 10N Is it -S(O)2NH2, or teeth: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~2 -L 1b -Z1 Selected from (In the formula, R 2a and R 2b Both are hydrogen; L 1a These are -C(O)-, -S(O)2-, or S(O)2N(R a1 )- Selected from (Here, R a1 It is hydrogen; L 1b It does not exist, or -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 ) Selected from SO2 (here, R a2 It is hydrogen; Z1 is (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heteroalkyl Selected from lyl and heteroaryl (however, Z1 is a heterocyclic compound directly bonded to the N atom) If it is a lyl group, it is a heterocyclyl linked to carbon); Z1 is (1~2C )Alkyl, Halo, (1-2C) Haloalkoxy, Cyano, -NR e R f , -OR e ,- C(O)R e , -C(O)OR e ,-OC(O)R e ,-C(O)N(R e )R f , -N (R e )C(O)R f , -S(O) y R e(where y is 0, 1, or 2), -S O2N(R e )R f , -N(R e )SO2R f ,-(CH2) z NR c R d (Here, z R may be substituted with one or more substituents selected from (1 or 2), e and R f (Each is independently selected from hydrogen or methyl.) Furthermore, any S atom present in the heteroring in the formula is S(=O), S(=O)2, or S (=O)(=NR e )(Here, R e This is hydrogen, (1-2C) alkyl or (2C) May exist as (selected from Kanoyle); (14) R4 and R5, together with the nitrogen atom to which they are bonded, one or more R 10C Place The substitution group forms a heterocycle which may be substituted on any available carbon atom. It is connected to the sea urchin. (Here, R 10C is an oxo, halo, or cyano substituent, or formula: -[CH2] n -LZ Selected from the basis (In the formula, n is between 0 and 2; L does not exist, or -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 ) Selected from SO2 (this Here, R a and R bIt is hydrogen; Z represents hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, phenyl, 4-7 Selected from a 5-membered heterocyclyl or a 5- or 6-membered heteroarylalkyl; Z is (1 ~2C)alkyl, halo, (1~2C)haloalkyl, (1~2C)haloalkoxy, cy Um, -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 (Here, y is 0, 1, or 2), -SO2N(R c )R d , -N(R c )SO2R d ,-(C H2) z NR c R d (where z is 1 or 2) or one selected from oxo It may also be substituted by the substituents listed above; R c and R d Each of these elements is independently selected from hydrogen or (1-2C) alkyl. ); Furthermore, any available N atom may be in the form of an N-oxide, or one or more R 10 N It may also be replaced by (where R 10N Is it -S(O)2NH2, or teeth: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ]1~2 -L 1b -Z1 Selected from (In the formula, R 2a and R 2b Both are hydrogen; L 1a These are -C(O)-, -S(O)2-, or S(O)2N(R a1 )- Selected from (Here, R a1 It is hydrogen; L 1b It does not exist, or -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 ) Selected from SO2 (here, R a2 It is hydrogen; Z1 is (1-4C) alkyl, phenyl, 4-7 membered heterocycline, or 5 or 6 Selected from heteroaryl groups (where Z1 is directly linked to the N atom). If it is a group, it is a heterocyclyl linked to carbon; Z1 is (1~2C) Lukil, Halo, (1-2C) Haloalkoxy, Cyano, -NR e R f , -OR e , -C( O)R e , -C(O)OR e ,-OC(O)R e ,-C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (where y is 0, 1, or 2), -SO2 N(R e )R f , -N(R e )SO2Rf ,-(CH2) z NR c R d (Here, z is 1 It may also be substituted with one or more substituents selected from (or 2); R e and R f (Each is independently selected from hydrogen or methyl.) Furthermore, any S atom present in the heteroring in the formula is S(=O), S(=O)2, or S (=O)(=NR e )(Here, R e This is hydrogen, (1-2C) alkyl or (2C) May exist as (selected from Kanoyle); (15) R4 and R5, together with the nitrogen atom to which they are bonded, one or more R 10C Place The substitution group forms a heterocycle which may be substituted on any available carbon atom. It is connected to (here, R 10C is an oxo, halo, or cyano substituent, or formula : -[CH2] n -LZ Selected from the basis (In the formula, n is between 0 and 2; L does not exist, or -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 ) Selected from SO2 (this Here, R a and R b It is hydrogen; Z represents hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, phenyl, 4-7 Selected from a 5-membered heterocyclyl or a 5- or 6-membered heteroarylalkyl; Z is (1 ~2C)alkyl, halo, (1~2C)haloalkyl, (1~2C)haloalkoxy, cy Um, -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 oxo They may be substituted with one or more substituents selected from; R c and R d Each of these elements is independently selected from hydrogen or (1-2C) alkyl. ); Furthermore, any available N atom may be in the form of an N-oxide, or one or more R 10 N It may also be replaced by (where R 10N Is it -S(O)2NH2, or teeth: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~6 -L 1b -Z1 Selected from (In the formula, R 2a and R 2b Both are hydrogen; L 1a These are -C(O)-, -S(O)2-, or S(O)2N(R a1 )- Selected from (Here, R a1 It is hydrogen; L 1bIt does not exist, or -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 ) Selected from SO2 (here, R a2 It is hydrogen; Z1 is (1-4C) alkyl, phenyl, 4-7 membered heterocycline, or 5 or 6 Selected from heteroaryl groups (where Z1 is directly linked to the N atom). If it is a group, it is a heterocyclyl linked to carbon; Z1 is (1~2C) Lukil, Halo, (1-2C) Haloalkoxy, Cyano, -NR e R f , -OR e , -C( O)R e ,-C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e ( Here, y is substituted with one or more substituents selected from 0, 1, or 2. Also; R e and R f (Each is independently selected from hydrogen or methyl.) Furthermore, any S atom present in the heteroring in the formula is S(=O), S(=O)2, or S (=O)(=NR e )(Here, R e This is selected from hydrogen, methyl, or (2C)alkanoyl. It may exist as (being selected); (15a) R4 and R5, together with the nitrogen atom to which they are bonded, one or more R 10C Forms a heterocycle which may be substituted on any available carbon atom by substituents. They are connected in this way (where R 10C is an oxo, halo, or cyano substituent, or formula: -[CH2] n -LZ Selected from the basis (In the formula, n is between 0 and 2; L does not exist, or -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 ) Selected from SO2 (this Here, R a and R b It is hydrogen; Z is selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; Z is , (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalcohydrate C, Cyan, -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 It may be substituted with one or more substituents selected from the oxo; R c and R d Each of these elements is independently selected from hydrogen or (1-2C) alkyl. ); Furthermore, any available N atom may be in the form of an N-oxide, or one or more R 10 NIt may also be replaced by (where R 10N Is it -S(O)2NH2, or teeth: (i)-Z1; (ii)-L 1a -Z1; or (iii)-[CR 8a R 8b ] 1~2 -L 1b -Z1 Selected from (In the formula, R 2a and R 2b Both are hydrogen; L 1a These are -C(O)-, -S(O)2-, or S(O)2N(R a1 )- Selected from (Here, R a1 It is hydrogen; L 1b It does not exist, or -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 ) Selected from SO2 (here, R a2 It is hydrogen; Z1 is selected from (1-4C) alkyl; Z1 is (1-2C) alkyl, halo, (1~2C) Haloalkoxy, Cyano, -NR e R f , -OR e , -C(O)R e , -C (O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (Here, y is, It may be substituted with one or more substituents selected from 0, 1, or 2; R e Reach biR f (Each is independently selected from hydrogen or methyl.) Furthermore, any S atom present in the heteroring in the formula is S(=O), S(=O)2, or S (=O)(=NR e )(Here, R e This is selected from hydrogen, methyl, or (2C)alkanoyl. It may exist as (being selected); (15b) R4 and R5, together with the nitrogen atom to which they are bonded, one or more R 10C Forms a heterocycle which may be substituted on any available carbon atom by substituents. They are connected in this way (where R 10C is an oxo, halo, or cyano substituent, or formula: -LZ Selected from the basis (In the formula, L does not exist, or -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 ) Selected from SO2 (this Here, R a and R b It is hydrogen; Z is selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl. ); Furthermore, any available N atom may be in the form of an N-oxide, or one or more R 10 N It may also be replaced by (where R 10N is -S(O)2NH2 or (1~ 4C) It is alkyl): Furthermore, any S atom present in the heteroring in the formula is S(=O), S(=O)2, or S (=O)(=NR e )(Here, R e This is selected from hydrogen, methyl, or (2C)alkanoyl. It may exist as (being selected); (15c) R4 and R5, together with the nitrogen atom to which they are bonded, one or more R 10C Forms a heterocycle which may be substituted on any available carbon atom by substituents. They are connected in this way (where R 10C These are oxo, halo, cyano, (1-4C)al Selected from cycloalkyl or (3-6C)cycloalkyl): Furthermore, any available N atom may be in the form of an N-oxide, or one or more R 10 N It may also be replaced by (where R 10N is -S(O)2NH2 or (1~ 4C) It is alkyl): Furthermore, any S atom present in the heteroring is S(=O), S(=O)2, or S(=O) )(=NR e )(Here, R e is selected from hydrogen, methyl, or (2C)alkanoyl. It may exist as (ru); (16) R4 and R5, together with the nitrogen atom to which they are bonded, form a 4-12 member heterocycle. They are linked to form a heterocycle, and one or more R 10C or R 10N substituent It may be replaced with (where R 10C and R 10N This refers to the above paragraph (11) As defined in any one of (15c); (17) R4 and R5, together with the nitrogen atom to which they are bonded, form a 4- to 8-membered monocyclic heteropolyte A rib ring or a bridged heterocycle, or a 7-12 membered bicyclic heterocycle or spirodicycle. They are linked to form a heterocycle, and the heterocycle consists of one or more R 10C or R 10N It may be substituted with a substituent (where R 10C and R 10N The above parag As defined in any one of Rough (11) to (15c); (18) R4 and R5, together with the nitrogen atom to which they are bonded, form a 4-7 member monocyclic heteropolyte A rib ring or a bridged heterocycle, or a bicyclic heterocycle or spirodicycle with 7 to 11 members. They are linked to form a heterocycle, and the heterocycle consists of one or more R 10C or R 10N It may be substituted with a substituent (where R 10C and R 10N The above parag As defined in any one of Rough (11) to (15c); (19) R4 and R5, together with the nitrogen atom to which they are bonded, form a monoring of 5 or 6 members. Forming a heterocyclic ring, or a bicyclic heterocyclic ring or spiro-bicyclic heterocyclic ring with 7 to 10 members. They are linked in such a way that the heterocycle has one or more R 10C or R 10N Substituting with substituents It is fine to be (here, R 10C and R 10N This refers to the above paragraphs (11) to (15) c) as defined in any one of the following ways); (20) R4 and R5, along with the nitrogen atom to which they are bonded, are one of the following: They are linked to form a heterocycle selected from one of the following: [ka] (In the formula,* This indicates the N atom to which R4 and R5 are bonded; 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 -CH 2-, -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-condensed 4, 5, or 6-membered carbon ring or heteroring; Ring B is a condensed 4, 5, or 6-membered carbon ring or heteroring; Here, R e is selected from hydrogen or methyl; Each heterocyclic system is defined in one of the following ways: One or more R 10C or R 10N They may be substituted with substituents; (20a) R4 and R5, along with the nitrogen atom to which they are bonded, are of the following options They are linked to form a heterocycle selected from one of the following: [ka] (In the formula, * This indicates the N atom to which R4 and R5 are bonded; Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR10C or C(R 10C )2; Q2 is -CH2-, -CHR 10C -, -C(R 10C )2-, -CHR 10C -CH 2-, -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-condensed 4, 5, or 6-membered carbon ring or heteroring; Ring B is a condensed 4, 5, or 6-membered carbon ring or heteroring; Here, R e is selected from hydrogen or methyl; Each heterocyclic system is defined in one of the following ways: One or more R 10C or R 10N They may be substituted with substituents; (21) R4 and R5, along with the nitrogen atom to which they are bonded, are one of the following: They are linked to form a heterocycle selected from one of the following: [ka] (In the formula, * This indicates the N atom to which R4 and R5 are bonded; 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 10Cor N; Ring A is a spiro-condensed 4, 5, or 6-membered carbon ring or heteroring; Ring B is a condensed 4, 5, or 6-membered carbon ring or heteroring; Here, R e This is selected from hydrogen, (1-3C) alkyl, or (2-3C) alkanoyl. re; Each heterocyclic system is defined in one of the following ways: One or more R 10C or R 10N They may be substituted with substituents; (21a) R4 and R5, along with the nitrogen atom to which they are bonded, are of the following options They are linked to form a heterocycle selected from one of the following: [ka] (In the formula, * This indicates the N atom to which R4 and R5 are bonded; 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 spiro-condensed 4, 5, or 6-membered carbon ring or heteroring; Ring B is a condensed 4, 5, or 6-membered carbon ring or heteroring; Here, R e This is selected from hydrogen, (1-3C) alkyl, or (2-3C) alkanoyl. re; Each heterocyclic system is defined in one of the following ways: One or more R 10C or R10N They may be substituted with substituents; (21b) R4 and R5, along with the nitrogen atom to which they are bonded, are one of the following options They are linked to form a heterocycle selected from one of the following: [ka] (In the formula, * This indicates the N atom to which R4 and R5 are bonded; 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; Here, R eis selected from hydrogen, (1-2C) alkyl, or (2C) alkanoyl; Each heterocyclic system is defined in one of the following ways: One or more R 10C or R 10N They may be substituted with substituents; (22) R4 and R5, along with the nitrogen atom to which they are bonded, are one of the following: They are linked to form a heterocycle selected from one of the following: [ka] (In the formula, * This indicates the N atom to which R4 and R5 are bonded; 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; Here, R e is selected from hydrogen, (1-2C) alkyl, or (2C) alkanoyl; Each heterocyclic system is defined in one of the following ways: One or more R 10C or R 10N They may be substituted with substituents; (22a) R4 and R5, along with the nitrogen atom to which they are bonded, are of the following options They are linked to form a heterocycle selected from one of the following: [ka] (In the formula, * This indicates the N atom to which R4 and R5 are bonded; 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; Here, R e is selected from hydrogen, (1-2C) alkyl, or (2C) alkanoyl; Each heterocyclic system is defined in one of the following ways: One or more R 10C or R 10N They may be substituted with substituents; (22b) R4 and R5, along with the nitrogen atom to which they are bonded, are one of the following options They are linked to form a heterocycle selected from one of the following: [ka] (In the formula, * This indicates the N atom to which R4 and R5 are bonded; 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; Here, R e is selected from hydrogen, methyl, or (2C)alkanoyl; R 10c or R 10N This is defined in any one of the above paragraphs (11) to (15c). That is correct; (23) R4 and R5, along with the nitrogen atom to which they are bonded, are one of the following: They are linked to form a heterocycle selected from one of the following: [ka] (In the formula, * This indicates the N atom to which R4 and R5 are bonded; 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-; Here, R e is selected from hydrogen, methyl, or (2C)alkanoyl; R 10c or R 10NThis is defined in any one of the above paragraphs (11) to (15c). That is correct; (24) R4 and R5, together with the nitrogen atom to which they are bonded, form a heteroring with the following structure. They are connected to form: [ka] (In the formula, * This indicates the N atom to which R4 and R5 are bonded; Each R 10c This is defined independently in any one of the above paragraphs (11) to (15c). Selected from the available options); (25) R6 is selected from hydrogen, halo, or methyl; (26) R6 is selected from hydrogen or methyl; (27) R6 is hydrogen; (28)R x This is selected from methyl, CD3, or chloro; (29)R x This is selected from methyl or CD3; (30)R x It is methyl; (31)R x It is CD3. (32)R x It is chloro;

[0065] Preferably, the heteroaryl or heterocyclyl group as defined herein is N, O or A monocyclic heteroaryl or monocyclic heteroaryl compound containing one, two, or three heteroatoms selected from S. It is a bicyclic, spiro-bicyclic, or bridging heterocyclyl group.

[0066] Preferably, the heteroaryl is composed of one, two, or three heteroatoms selected from N, O, or S. It is a 5- or 6-membered heteroaryl ring containing a child.

[0067] Preferably, the heterocyclyl group consists of 1, 2, or 3 heterocyclyl groups selected from N, O, or S. It is a 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered heterocyclyl ring containing atoms. Preferably, the heterocyclyl group consists of 1, 2, or 3 selected from N, O, or S. A 5, 6, or 7-membered ring containing a heteroatom [e.g., morpholinyl (e.g., 4-morpholinyl)] Linyl, pyridinyl, piperazinyl, homopiperazinyl, or pyrrolidinonyl, also It contains 7, 8, or 9 heteroatoms selected from N, O, or S. Alternatively, it is a 10-membered spirodicyclic ring system.

[0068] Preferably, the aryl group is phenyl.

[0069] Preferably, R1 is as defined in paragraphs (1) to (8) above. In the application configuration, R1 is as defined in paragraph (6) above.

[0070] Preferably, R1 is as defined in paragraphs (1) to (8f) above. Preferably, R1 is in the above paragraphs (1a), (2a), (3a), (3b), (4 a), (7a), (8a), (8b), (8c), (8d), (8e), or (8f) are determined as follows: As is understood. In one embodiment, R1 is as described in paragraph (4a) or (7a) above. As defined below.

[0071] Preferably, R2 and R3 are defined in either paragraph (9) or (10) above. As defined above. Most preferably, R2 and R3 are defined in paragraph (10) above. It is as correct.

[0072] Preferably, R4 and R5 are defined in any one of the above paragraphs (11) to (24). As is understood. More preferably, R4 and R5 are as described in paragraph (15) above, ( 15a), (15b) or (15c), (20a), (21a), (21b), (22a As defined in (22b) or (22b). In a particular group of compounds of the present invention, R Sections 4 and R5 refer to the above paragraphs (16), (17), (18), (20), (21), (22), (23), (24), (20a), (21a), (21b), (22a) or As defined in (22b).

[0073] Preferably, R4 and R5 are defined in any one of the above paragraphs (11) to (24). As defined above. More preferably, R4 and R5 are defined in paragraph (15) above. As is understood. More preferably, R4 and R5 are as described in paragraph (16) above. As defined in (17) or (18). In a particular group of compounds of the present invention Therefore, R4 and R5 refer to the above paragraphs (20), (21), (22), (23) or As defined in (24).

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

[0075] Preferably, R 10c and R 10N This refers to any of the above paragraphs (11) to (15c). It is defined as one of the following. More preferably, R 10c and R 10N The above paragraph As defined in any one of graphs (15) to (15c). More preferably R 10c and R 10N This refers to the above paragraphs (15a), (15b), or (15c As defined in one of the following:

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

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

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

[0079] In the specific group of compounds of formula I described above, R2 and R3 are hydrogen, i.e., The compound has the following structural formula IA (a sub-formula of formula I): [ka] (In the formula, R x , R1, R4, R5, R6 and R xEach of these terms is defined as described herein. (Having either one or the other).

[0080] In embodiments of the compound of formula IA, R x This is defined in any one of the above paragraphs (28) to (31): the law of nature; R1 is defined as in any one of the above paragraphs (1) to (8f): ; R4 and R5 are defined in any one of the above paragraphs (11) to (24). It is a cage; R6 is defined as in any one of the above paragraphs (25) to (27). ru;

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

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

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

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

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

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

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

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

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

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

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

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

[0093] In a particular group of the compounds of formula I above, R6 is hydrogen, i.e., the compound has the following structural formula IB (sub-formula of formula I'):

Chemical formula

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

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

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

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

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

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

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

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

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

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

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

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

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

[0107] In the specific group of compounds of formula I described above, R2, R3, and R6 are hydrogen, that is, The compound has the following structural formula IC (subordinate formula of formula I): [ka] (In the formula, R x R1, R4, and R5 each have one of the definitions set forth herein. (to possess).

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

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

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

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

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

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

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

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

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

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

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

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

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

[0121] In the specific group of compounds of formula I described above, R2 and R3 are hydrogen, i.e., The compound has the following structural formula IA' (a sub-formula of formula I): [ka] (In the formula, R1, R4, R5, and R6 each represent one of the definitions set forth herein.) (to possess).

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

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

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

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

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

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

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

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

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

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

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

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

[0134] In a specific group of compounds of formula I above, R6 is hydrogen, that is, the compound is It has the following structural formula IB' (a sub-formula of formula I): [ka] (In the formula, R1, R2, R3, R4, and R5 are each one of the definitions described herein.) (Having one).

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

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

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

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

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

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

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

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

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

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

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

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

[0147] In the specific group of compounds of formula I described above, R2, R3, and R6 are hydrogen, that is, The compound has the following structural formula IC' (a sub-formula of formula I): [ka] (In the formula, R1, R4, and R5 each have one of the definitions described herein) ).

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

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

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

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

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

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

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

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

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

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

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

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

[0160] The specific compounds of the present invention include any of the compounds described in the Examples section of this application, or the same Pharmacopoeia-acceptable salts or solvates, in particular, including any of the following: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]morpholine-4-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1- Carboxamide (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph Helicobacter pylori (Henyl)thiazole-2-yl)-2-(1-hydroxy-1-methyl-ethyl) Zin-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl piperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piper Zin-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-1-imino-1-oxo-1,4-thiadinane-4-carboxa Mido N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]pyrroridine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-2-(2-hydroxy-2-methylpropyl)pyrrolidine-1 -Carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)morpholine-4- Carboxamide (2S)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]carbamoyl]piperazine-2-carbonsan N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-4-methylpiperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl)-4-hydroxy-4-methylpiperidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-4-cyano-4-methylpiperidine-1-carboxamide (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piper Zin-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-methylpiperazine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]piperidine-1-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]pyrroridine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-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)thiazo [Lu-2-yl]-2-oxa-6-azaspiro[3,3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-oxopiperazine-1-carboxamide N4-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [L-2-yl]morpholine-2,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-methyl-3-oxopiperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide 4-acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyri [Dil)thiazole-2-yl]piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-methylsulfonylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-sulfamoyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-Il]-1-imino-1-oxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8 -Carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]-4-methoxypiperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu)thiazole-2-yl]-4-(hydroxymethyl)piperidine-1-carboxami Do N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-oxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-(hydroxymethyl)azetidine-1-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1,1-dioxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazospiro[ 4.5] Decane-8-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Il-2-yl]piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-hydroxyazetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo (Lu-2-yl)-4-(2-hydroxyethyl)-3-oxopiperazine-1-carb Xamide 4,4-Dicyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4- Pyridyl)thiazole-2-yl]piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-(1-hydroxy-1-methyl-ethyl)azetidine-1-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(2-hydroxy-2-methylpropyl)piperazine-1-cal Boxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-1-methyl-1,7-diazaspiro[3.4]octane-7-carbocyanide Thamid N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-(2-hydroxy-1,1-dimethylethyl)piperazine-1- Carboxamide (8aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]-3,4,6,7,8,8a-Hexahydro-1H-pyrrolo [1,2-a]pyrazine-2-carboxamide (8aR)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]-3,4,6,7,8,8a-Hexahydro-1H-pyrrolo [1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-hydroxy-pyrrolidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu)thiazole-2-yl]-4-(methoxymethyl)piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]-4-fluoropiperidine-1-carboxamide (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]pyrroridine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-3-hydroxy-3-methylazetidine-1-carboxamide (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]carbamoyl]piperazine-2-carbonsan Methyl(2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3- [Cyanophenyl)thiazole-2-yl]carbamoyl]piperazine-2-carboxylate te (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-3-(hydroxymethyl)piperazine-1-carb Thamid (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-3-(hydroxymethyl)piperazine-1-carb Thamid (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [enyl)thiazole-2-yl]-3-methylpiperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [enyl)thiazole-2-yl]-3-methylpiperazine-1-carboxamide (1S,4S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyan Anophenyl)thiazole-2-yl]-2,5-diazabicyclo[2.2.1]hepta n-2-carboxamide (3R)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]piperazine-1,3-dicarboxamide (3S)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]piperazine-1,3-dicarboxamide 4-amino-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]-4-methylpiperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl Thiazol-2-yl-4-methylpiperidine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]2-oxa-6-azaspiro[3.3]heptane-6-carbocyanate Thamid (1R,4R)-5-acetyl-N-[4-(3-cyanophenyl)-5-(2,6-di Methyl-4-pyridyl)thiazole-2-yl]-2,5-diazabicyclo[2.2.1 Heptane-2-carboxamide (1S,4S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-5-methyl-2,5-diazabicyclo[2.2.1] Heptane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-methyl-2-oxo-1,3,8-triazospiro[4.5]deca n-8-carboxamide N-[5-[2,6-bis(triduteriomethyl)-4-pyridyl]-4-(3-cy Anophenyl)thiazole-2-yl]-2-oxa-6-azaspiro[3.3]hepta n-6-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyri [Dil)thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane-6- Carboxamide (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethicone)] [Lu)-6-methyl-4-pyridyl]thiazole-2-yl]-4-methyl-2,3,4a ,5,7,7a-Hexahydropyrrolo[3,4-b][1,4]oxazine-6-carb Xamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4 -Pyridyl]thiazole-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]thiazole-2-yl]-6-oxa-2,9-diazaspiro[4.5]de Can-2-carboxamide (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethicone)] [Lu)-6-methyl-4-pyridyl]thiazole-2-yl]-4-methyl-2,3,4a ,5,7,7a-Hexahydropyrrolo[3,4-b][1,4]oxazine-6-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxo-1,3,8-triazospiro[4.5]decane-8-cal Boxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetane) -3-yl)-4-pyridyl]thiazole-2-yl]-3-methylpyrrolidine-1- Carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetane) -3-yl)-4-pyridyl]thiazole-2-yl]-4-methyl-piperidine-1- Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-morpholino-azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-tetrahydropyran-4-yl-piperazine-1-carboxamide ; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-3-pyrroridine-1-ylazetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-(dimethylamino)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(morpholinomethyl)piperidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [4.5]-3-methyl-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]-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-ca Ruboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1,4-diazabicyclo[3.2.1]octane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3 ,4-a]pyrazine-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-2,2-dioxo-3,4,6,7,9,9a-hexahydro-1H- Pyrazino[2,1-c][1,4]thiadin-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-oxo-3,6,7,8,9,9a-hexahydro-1H-pyridone [1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-9-oxo-3,4,6,7,8,9a-hexahydro-1H-pyrazi no[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-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)thiazo Ru-2-yl]-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2 -a] Pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboc Thamid N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-3-sulfamoyl-pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-il]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxa Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-4-pyrazole-1-yl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-(1,2,4-oxazole-3-yl)piperidine-1-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-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)thiazo [Lu-2-yl]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxa Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(1H-imidazole-2-yl)piperidine-1-carboxami Do N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-10-oxo-3,9-diazaspiro[5.5]undecane-3-cal Boxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-cal Boxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [-2-yl]-N4-methyl-piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-8-oxa-2-azaspiro[4.5]decane-2-carboxamide (3S)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]pyrroridine-1,3-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-(2-oxoimidazolidine-1-yl)piperidine-1-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(1,2,4-oxazol-5-yl)piperidine-1-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-methylimino-1-oxo-1,4-thiadinane-4-carboxa Mido N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-N4-(2-hydroxyethyl)piperidine-1,4-dicarbocyanate Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-il]-6-oxo-7-oxa-2,5-diazaspiro[3.5]nonan-2 -Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6,9-dioxo-1,3,4,7,8,9a-hexahydropyrazino [1,2-a]pyrazine-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) )Thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine- 1-Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-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)thiazo Ru-2-yl)-2-methyl-3-oxo-2,8-diazaspiro[4.5]decane-8 -Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl]-8-methyl-6,9-dioxo-3,4,7,9a-tetrahydro-1 H-pyrazino[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo (Lu-2-yl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxa Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-oxo-2,9-diazaspiro[5.5]undecane-9-carb Xamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu)thiazol-2-yl]-4-(1-hydroxy-1-methyl-ethyl)piperidine -1-Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrazi no[1,2-c]pyrimidine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyridone [1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2 -Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxa Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-il]-2,2-dioxo-2-lambda^{6}-thia-6-azaspiro[3.3 Heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carb Xamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) )Thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine- 1-Carboxamide (3aR,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-1,3,3a,4,6,6a-hexahydrofloxacin [3,4-c]pyrrole-5-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-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-p Lysyl)thiazole-2-yl]-6-methyl-3,6-diazabicyclo[3.2.2] Nonane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-methyl-2-oxo-1,3,8-triazospiro[4.5]deca n-8-carboxamide (3aS,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-3-oxo-1,2,3a,4,6,6a-hex Sahydropyrrolo[3,4-c]pyrrole-5-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-7-oxa-2-azaspiro[3.5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-Il]-6-oxo-2,7-diazaspiro[3.4]octane-2-carbocyanide Thamid N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-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 [Lu-2-yl]-6-oxo-2,5,7-triazospiro[3.4]octane-2-ca Ruboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxo-1,9-diazaspiro[5.5]undecane-9-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-Il]-5-oxo-2,6-diazaspiro[3.4]octane-2-carbocyanide Thamid N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [4.5]-2-yl-3-methyl-2,4-dioxo-1,3,8-triazospiro[4.5 Decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl]-4-ethyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)- 4-Pyridyl]thiazole-2-yl]-4-(oxetan-3-yl)piperazine-1 -Carboxamide 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Il-2-yl]carbamoyl]piperidine-4-carboxylic acid (3S)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl [Lu)thiazole-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu)thiazole-2-yl]-3-(hydroxymethyl)azetidine-1-carboxamine Do (3R)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl [Lu)thiazole-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid 4-Cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl Lu-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carbox Mido N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyri [Dyl)thiazole-2-yl]-3-hydroxy-3-methylazetidine-1-carb Xamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl [Lu-4-pyridyl)thiazole-2-yl]-3-methylazetidine-1-carbox Mido N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyri [Dil)thiazole-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane- 7-Carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl Thiazol-2-yl-3-methylazetidine-1-carboxamide 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Il-2-yl]carbamoyl]azetidine-3-carboxylic acid (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-methylazetidine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) )Thiazol-2-yl]-2-(hydroxymethyl)azetidine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methylmorpholine-4-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) )Thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine- 1-Carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8 -Carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-methylazetidine-1-carboxamide N-[4-(3-cyano-2-methylphenyl)-5-(2,6-dimethyl-4-pyri) [Dil)thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane-6- Carboxamide (3R)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]pyrroridine-1,3-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxa-7-azaspiro[4.4]nonane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxa-7-azaspiro[3.4]octane-7-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) )Thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azetidine- 1-Carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) )Thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azetidine- 1-Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-morpholino-pyrrolidine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methyl-5-oxopiperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methylmorpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxa-1-azaspiro[3.3]heptan-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-1,3-dimethyl-2-oxo-1,3,8-triazospiro[4.5 Decane-8-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methyl-5-oxopiperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) )Thiazol-2-yl]-2-(hydroxymethyl)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-6-methyl-5-oxo-2,6-diazaspiro[3.4]octane 2-Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-oxa-6-azaspiro[3,3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-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 [Lu-2-yl]-4-methylsulfonyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-hydroxy-4-methylpiperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]2-oxa-6-azapiro[3,3]heptane -6-Carboxamide (4aR,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-4-methyl-2,3,4a,5,7,7a-hexyl Sahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)- 4-Pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3.3]hepta n-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]piperazine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide 4-amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-2,5-diazabicyclo[2.2.2]octane-2 -Carboxamide cis-(2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]-2,5-dimethylpiperazine-1-carb Xamide (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-2,6-dimethyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2,2-dimethylpiperazine-1-carboxamide 1-Acetylamino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboc Thamid N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]2-oxa-6-azapiro[3,3]heptane -6-Carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]-3-oxo-2,7-diazaspiro[3.5]no Nan-7-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6- [methyl-4-pyridyl]thiazole-2-yl]-3-(1-hydroxy-1-methyl- Ethyl)pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboc Thamid N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]-4-(oxetan-3-yl)piperazine-1- Carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]-1,3-dimethyl-2,4-dioxo-1,3, 8-Triazospiro[4.5]decane-8-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6 -methyl-4-pyridyl]thiazole-2-yl]piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6 -methyl-4-pyridyl]thiazole-2-yl]-4-(hydroxymethyl)piperidi n-1-carboxamide 4,4-Dicyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl )-6-methyl-4-pyridyl]thiazole-2-yl]piperidine-1-carboxami Do 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6 -methyl-4-pyridyl]thiazole-2-yl]-4-methoxypiperidine-1-ca Ruboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyri [Dil)thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboxamide 1-Cyanoimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4- Pyridyl)thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboxa Mido 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl [Tyl-ethyl)-6-methyl-4-pyridyl]thiazole-2-yl]-4-methyl-pyridyl Peridine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl) )-6-methyl-4-pyridyl]thiazole-2-yl]-6-oxa-2-azaspirol [3.4] Octane-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl) )-6-methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspirol [3.3] Heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl -4-pyridyl]thiazole-2-yl]2-oxa-6-azaspiro[3.3]hept Tan-6-carboxamide rac-(3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]-3,5-dimethylpiperazine-1-carb Xamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) )Thiazol-2-yl]-3-(trifluoromethyl)piperazine-1-carboxami Do N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxa Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxa Mido (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) )Thiazol-2-yl]-3-(trifluoromethyl)piperazine-1-carboxami Do (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]piperazine-1-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4,7-diazaspiro[2.5]octane-7-carboxamide (3S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-3,5-dimethyl-piperazine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-methylpiperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-methylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxa Mido (3R)-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoro [methyl)-4-pyridyl]thiazole-2-yl]-3-methylpiperazine-1-cal Boxamide (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethicone)] [Lu)-6-methyl-4-pyridyl]thiazole-2-yl]-3,4,4a,5,7,7 α-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carbox Mido (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethicone)] [Lu)-6-methyl-4-pyridyl]thiazole-2-yl]-3,4,4a,5,7,7 α-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carbox Mido rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl [Thi-4-pyridyl)thiazole-2-yl]-3,4,4a,5,7,7a-hexa-yl Dro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-2-cyclopropyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,3-dimethylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl) [thiazole-2-yl]-1-imino-1-oxo-1,4-thiadinane-4-carboxy Thamid N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]-1-imino-1-oxo-1,4-thiadinane- 4-Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dichloro-4-pyridyl)thiazo [Lu-2-yl]-2-oxa-6-azaspiro[3,3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)- 4-Pyridyl]thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carb Xamide N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl) Thiazol-2-yl]-1-oxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetan-3-yl) -4-pyridyl]thiazole-2-yl]2-oxa-6-azaspiro[3.3]hept Tan-6-carboxamide N-[5-(2-cyano-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-1-oxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(fluoromethyl)-6-methyl-4- Pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane- 6-Carboxamide N-[4-(3-cyanophenyl)-5-(2-cyclopropyl-6-methyl-4-pyriol) [Dil)thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane-6- Carboxamide N-[4-(3-cyanophenyl)-5-(2-isopropyl-6-methyl-4-pyridyl [3.3]thiazole-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-ca Ruboxamide N-[4-(3-cyanophenyl)-5-(2-ethyl-6-methyl-4-pyridyl) Azole-2-yl]2-oxa-6-azaspiro[3.3]heptane-6-carbocyanate Thamid N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxide-pyridine] -1-ium-4-yl)thiazole-2-yl]-2-oxa-6-azaspiro[3. 3] Heptane-6-carboxamide 4-Cyano-N-[4-(3-cyano-2-methylphenyl)-5-(2,6-dimethylphenyl) Lu-4-pyridyl)thiazol-2-yl]-4-methyl-piperidine-1-carbox Mido N-[5-(2-acetamido-6-methyl-4-pyridyl)-4-(3-cyanophenic acid [3.3]thiazole-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-ca Ruboxamide N-[5-[2-(acetamidomethyl)-6-methyl-4-pyridyl]-4-(3-Cylamidemethyl) Anophenyl)thiazole-2-yl]-2-oxa-6-azaspiro[3.3]hepta n-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(methoxymethyl)-6-methyl-4- Pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane- 6-Carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-methoxyethyl)-6-methyl- 4-Pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3.3]hepta n-6-carboxamide N-[5-[2-chloro-6-(1-hydroxy-1-methylethyl)-4-pyridyl ]-4-(3-cyanophenyl)thiazole-2-yl]-2-oxa-6-azaspirol [3.3] Heptane-6-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6 -methyl-4-pyridyl]thiazole-2-yl]-4-methyl-piperidine-1-cal Boxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-(triflu Oromethyl)-4-pyridyl]thiazole-2-yl]-2-oxa-6-azapiro[ 3.3] Heptane-6-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl Thiazol-2-yl-3-methylpyrrolidine-1-carboxamide N-[5-[2,6-bis(triduteriomethyl)-4-pyridyl]-4-(3-cy Anophenyl)thiazole-2-yl]-4-cyano-4-methylpiperidine-1-ca Ruboxamide N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]- 6-methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3 .3] Heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-[(1S)-1-hydroxyethyl]- 6-methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3 .3] Heptane-6-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]-3-methylpyrrolidine-1-carboxamide (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]-3-methylpyrrolidine-1-carboxamide .

[0161] The specific compounds of the present invention include any of the compounds described in the Examples section of this application, or the same Pharmacopoeia-acceptable salts or solvates, in particular, including any of the following: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]morpholine-4-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1- Carboxamide; (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pylori Zin-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]piperazine-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]pyrroridine-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-2-(2-hydroxy-2-methylpropyl)pyrrolidine-1 -Carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)morpholine-4- Carboxamide; (2S)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]carbamoyl]piperazine-2-carboxylic acid; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-4-methylpiperazine-1-carboxamide; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-4-hydroxy-4-methylpiperidine-1-carboxamide ; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-4-cyano-4-methylpiperidine-1-carboxamide; (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piper Zin-1-carboxamide forate; (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piper Zin-1-carboxamide forate N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide ; N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-1-imino-1-oxo-1,4-thiadinane-4-carboxa Mido; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-methylpiperazine-1-carboxamide; 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]piperidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-imino-1-oxo-1,4-thiadinane-4-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide; (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-hydroxy-pyrrolidine-1-carboxamide; 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu)thiazole-2-yl]-4-(methoxymethyl)piperidine-1-carboxamide ; 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]-4-fluoropiperidine-1-carboxamide; (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]pyrroridine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-hydroxy-3-methylazetidine-1-carboxamide; (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]pyrroridine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-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)thiazo [Lu-2-yl]-2-oxa-6-azaspiro[3,3]heptane-6-carboxamide ; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-oxopiperazine-1-carboxamide N4-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [L-2-yl]morpholine-2,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl]-4-methyl-3-oxopiperazine-1-carboxamide; (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide ; 4-acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyri [Dil)thiazole-2-yl]piperazine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl]-4-methylsulfonylpiperazine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-4-sulfamoyl-piperazine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8 -Carboxamide; (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide ; 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl Thiazol-2-yl]-4-methoxypiperidine-1-carboxamide; 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu)thiazole-2-yl]-4-(hydroxymethyl)piperidine-1-carboxami Do; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-1-oxo-1,4-thiadinane-4-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-(hydroxymethyl)azetidine-1-carboxamide; 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]azetidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1,1-dioxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazospiro[ 4.5] Decane-8-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Il-2-yl]piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-hydroxyazetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(2-hydroxyethyl)-3-oxopiperazine-1-carb Xamide; 4,4-Dicyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4- Pyridyl)thiazole-2-yl]piperidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-(1-hydroxy-1-methyl-ethyl)azetidine-1-carb Xamide; (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]carbamoyl]piperazine-2-carboxylic acid; Methyl(2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3- [Cyanophenyl)thiazole-2-yl]carbamoyl]piperazine-2-carboxylate rt; (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-3-(hydroxymethyl)piperazine-1-carb Samido; (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-3-(hydroxymethyl)piperazine-1-carb Samido; (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [enyl)thiazole-2-yl]-3-methylpiperazine-1-carboxamide; (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [enyl)thiazole-2-yl]-3-methylpiperazine-1-carboxamide; (1S,4S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyan Anophenyl)thiazole-2-yl]-2,5-diazabicyclo[2.2.1]hepta n-2-carboxamide; (3R)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]piperazine-1,3-dicarboxamide; (3S)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]piperazine-1,3-dicarboxamide; 4-amino-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]-4-methylpiperidine-1-carboxamide; 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl Thiazol-2-yl]-4-methylpiperidine-1-carboxamide; N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]piperazine-1-carboxamide; (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methylpiperazine-1-carboxamide; 4-amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl [-4-pyridyl)thiazole-2-yl]piperidine-1-carboxamide; 1-Acetylamino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboc Samido.

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

[0163] A suitable pharmaceutically acceptable salt of the compound of the present invention is, for example, a sufficiently basic salt of the present invention. Acid addition salts of compounds, for example, inorganic acids or organic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, etc. Acid addition with nic acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. It is a salt. Furthermore, a suitable pharmaceutically acceptable salt of the compound of the present invention that is sufficiently acidic is: Alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example , calcium or magnesium salts, ammonium salts, or pharmaceutically acceptable cathodic acid Salts with organic bases that give a compound, for example, methylamine, dimethylamine, trimethylamine It is a salt of piperidine, morpholine, or tris(2-hydroxyethyl)amine. .

[0164] They have the same molecular formula, but the properties or arrangement of the bonds between their atoms, or their spatial relationship Compounds with different arrangements of atoms are called "isomers." Isomers with different arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called stereoisomers. Diastereomers are mirror images of each other that cannot be superimposed. The body is called an "enantiomer." When a compound has a chiral center, for example, four different bodies When bonded to a certain group, a pair of enantiomers is possible. Enantiomers are It can be characterized by the absolute configuration of the asymmetric center, and the R and S of Kahn and Prelogue. According to the ordering rules, or by the rotation of the plane of polarization, the molecules become dextrorotatory or levorotatory (i.e., These are described in a format referred to as (+) or (-) isomers, respectively. Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0165] The compounds of the present invention may have one or more chiral centers, and such compounds may have Therefore, they are produced as individual (R) or (S) stereoisomers, or as mixtures thereof. It is possible. Unless otherwise indicated, the specifics in this specification and the claims The description or naming of the compounds refers to the individual enantiomers and their mixtures, racemates, or so It is intended to include both of the others, for example, by synthesis from optically active starting materials. The method for determining stereochemistry and separating stereoisomers by dividing a racemic mixture, or by the said technique, Well known in the field of Advanced Organic Chemistry try”,4th edition J.March,John Wiley and See Chapter 4 of Sons, New York, 2001 for further discussion. Some substances may have geometric isomer centers (E and Z isomers). The present invention provides antiproliferative activity. All optical isomers, diastereoisomers, and geometric isomers, as well as mixtures thereof. Please understand that this means inclusion.

[0166] The present invention also includes compounds of the present invention as defined herein, comprising one or more isotopic substitutions. It includes any isotopic form, including 1H, 2H(D), and 3H(T). Often, C may be any isotopic form including 12C, 13C, and 14C, O This may be any isotopic form containing 16O and 18O.

[0167] Furthermore, the specific compound of formula (I) exists in both solvated and non-solvated forms, such as hydrated forms. It should also be understood that all such solvations having antiproliferative activity may exist. Please understand that this encompasses form.

[0168] Furthermore, the specific compound of formula I may exhibit polymorphism, and the present invention may not be limited to all compounds that have antiproliferative activity. It should also be understood that this includes such forms.

[0169] Compounds of formula I can exist in many different tautomers, and the expression for compounds of formula I The term includes all such forms. To avoid doubt, the compound exhibits several tautomerisms. It can exist in one of its forms, and only one is specifically described or indicated. Nevertheless, all others are encompassed in formula I. Examples of tautomers include, for example, Examples of tautomers include the keto form, enol form, and enolate form, as shown below. Re: Keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, A Midine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acid - nitro. [ka]

[0170] Compounds of formula I containing an amine functional group may also form N-oxides. References herein to compounds of formula I containing the group also include N-oxides. If it contains several amine functional groups, one or more nitrogen atoms are oxidized to form an N-oxide. It is possible. Specific examples of N-oxides are tertiary amines or nitrogen-containing heterocycles. It is an N-oxide of an elementary atom. The N-oxide is converted into hydrogen peroxide or peracid ( For example, it can be formed by treatment with an oxidizing agent such as peroxycarboxylic acid. For example, Advanced Organic Ch by Jerry March emistry,4th Edition,Wiley Interscience,p See ages. More specifically, N-oxide is LWDeady(Sy It can be prepared by following the procedure in n.Comm.1977,7,509-514), In this case, the amine compound is subjected to m-chloropeptide in an inert solvent such as dichloromethane. It is reacted with ruoxybenzoic acid (mCPBA).

[0171] The compound of formula (I) is broken down in the body of a human or animal to release the compound of the present invention. It can be administered in drug form. Prodrugs are the physical properties of the compounds of the present invention. and / or can be used to alter pharmacokinetic properties. Prodrugs are a form of invention. Formation occurs when the compound contains suitable groups or substituents to which characteristic modifying groups can be attached. This can be done. Examples of prodrugs include the carboxyl group or hydro in the compound of formula (I). In vivo cleavable ester derivatives that can be formed at the xy group, and compounds of formula (I). In vivo cleavable amide derivatives that can be formed at the carboxyl group or amino group within are It can be listed.

[0172] Therefore, the present invention is made available by organic synthesis, and its prodrug cleavage Therefore, when made available in the body of a human or animal, the compound of formula (I) as defined above This includes. Therefore, the present invention relates to a compound of formula I produced by an organic synthesis means, and also to the preceding This includes compounds that are produced in the body of a human or animal by the metabolism of the precursor compound. In other words, the compound of formula (I) is either a compound produced synthetically or a compound produced metabolically. could be.

[0173] A suitable pharmaceutically acceptable prodrug of the compound of formula (I) is an undesirable pharmacological It is inactive, does not have excessive toxicity, and is suitable for administration to the body of humans or animals. It is based on rational medical judgment.

[0174] Various forms of prodrugs are described in the following literature, for example: a)Methods in Enzymology,Vol.42,p.309-396 , edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Else vier, 1985); c)A Textbook of Drug Design and Development ent, Krogsgaard-Larsen and H. Bundgaard, eds., C. hapter 5“Design and Application of Pro-d rugs”, H. Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Rev. iews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmace Utical Sciences, 77, 285 (1988); f) N.Kakeya,et al.,Chem.Pharm.Bull.,32,69 2 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as N ovel Delivery Systems”,ACSSymposium S series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0175] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a carboxyl group include, for example, It is an ester that can be cleaved in vivo. A compound of formula I containing a carboxyl group. Esters that can be cleaved in vivo are, for example, cleaved in the body of a human or animal to produce a hydrophilic acid. It is a pharmaceutically acceptable ester. A suitable pharmaceutically acceptable ester for carboxyl Examples of esters include C1-6 alkyl esters such as methyl, ethyl, and tert-butyl. methoxymethyl esters and other C1-6 alkoxymethyl esters, pivaloyl oxy C1-6 alkanoyloxymethyl esters such as methyl esters, for example, pivaloyl methyl esters Xymethyl ester, 3-phthalidyl ester, cyclopentylcarbonyloxymethyl and C3-8 cycloalkyl esters such as 1-cyclohexylcarbonyloxyethyl esters. Carbonyloxy-C1~6 alkyl esters, 5-methyl-2-oxo-1,3-diode Xollen-4-ylmethyl esters and other 2-oxo-1,3-dioxolenylmethyl esters Stel, as well as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl Examples include C1-6 alkoxycarbonyloxy C1-6 alkyl esters such as esters. It is possible.

[0176] A suitable pharmaceutically acceptable prodrug of a compound of formula (I) having a hydroxyl group is: For example, its ester or ether which is cleavable in vivo. It contains a hydroxyl group. Esters or ethers of compounds of formula I that can be cleaved in vivo include, for example, human or animal compounds. pharmaceutically acceptable esters or ethers that cleave in the body to produce hydroxyl-parent compounds It is a suitable pharmaceutically acceptable ester-forming group for the hydroxyl group. Examples include inorganic esters such as nitrate esters (including phosphoramide cyclic esters). Further preferred pharmaceutically acceptable ester-forming groups for the hydroxyl group include acetone. Tyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups Which C1-10 alkanoyl group, ethoxycarbonyl, N,N-(C1-6)2 carbomol C1-10 groups such as yl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups Examples include the lucoxycarbonyl group. Phenylacetyl and benzoyl ring substituents Examples include aminomethyl, N-alkylaminomethyl, and N,N-dialkylaminomethyl L, morpholinomethyl, piperazine-1-ylmethyl and 4-(C1-4 alkyl) pipe Radin-1-ylmethyl is an example. Suitable pharmaceutically acceptable for the hydroxyl group. Examples of ether-forming groups include acetoxymethyl and pivaloyloxymethyl groups, which are α-ether-forming groups. Examples include siloxyalkyl groups.

[0177] A suitable pharmaceutically acceptable prodrug of a compound of formula (I) having a carboxyl group is: For example, amides that can be cleaved in vivo, such as amines like ammonia, methyl amides C1-4 alkylamines such as mine, dimethylamine, N-ethyl-N-methylamine, or These include (C1-4 alkyl) 2-amines such as diethylamine, and 2-methoxyethylamine. Phenylen-C1 such as C1-C4 alkoxy-C2-C4 alkylamines and benzylamines amides formed from ~4 alkylamines and amino acids such as glycine or its esters. That is the case.

[0178] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having an amino group include, for example, It is an amide derivative that can be cleaved in vivo. A suitable pharmaceutically acceptable derivative from the amino group. Examples of amides include acetyl, benzoyl, phenylacetyl, and substituted benzyl. Examples include amides formed with C1-10 alkanoyl groups such as zoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl , N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, pi Perazine-1-ylmethyl and 4-(C1~4 alkyl)piperazine-1-ylmethyl It can be listed.

[0179] The in vivo effect of the compound of formula (I) is partially observed in humans or animals after administration of the compound of formula (I). It can be exerted by one or more metabolites formed in the body. As mentioned above, formula The in vivo effect of compound (I) is also exerted through the metabolism of its precursor compound (prodrug). It is possible.

[0180] The present invention relates to any, preferred, or suitable features, or to a particular embodiment. The invention may relate to any compound or a specific group of compounds as defined herein, but the present invention also Any, any preferred or suitable feature, or any particular embodiment that excludes any of the above-mentioned features, preferences, or suitable features, or any other features that exclude any particular embodiment. It may also refer to the compound or a specific group of compounds.

[0181] Preferably, the present invention relates to any individual compound that does not have biological activity as defined herein. To remove an item.

[0182] synthesis The compounds of the present invention can be prepared by any preferred method known in the art. Yes, it is possible. A specific method for forming a compound of formula I as defined herein is an example of the attached method. For example.

[0183] This specification describes the synthesis methods and any optional materials used to prepare the starting materials. In the reference synthesis method, the solvent, reaction atmosphere, reaction temperature, duration of the experiment, and post-processing procedure are specified. It is understood that all proposed reaction conditions, including the selection of [specific condition], can be selected by those skilled in the art. I want to.

[0184] Those skilled in organic synthesis will know that the functional groups present in various parts of a molecule are used in reagents and reagents. It is understood that the conditions must be met.

[0185] During the synthesis of the compounds of the present invention in the processes defined herein, or in certain starting materials During the synthesis, it is desirable to protect specific substituents to prevent their undesirable reactions. It will be understood that there are times when such protection is necessary. A skilled chemist will know when such protection is needed. To understand how such protecting groups are positioned and how they can be removed later. It is likely.

[0186] For an example of a protecting group, see one of the many general texts on the subject, for example, The "Protective Groups in Orga" by odora Green See "nic Synthesis" (Publisher: John Wiley & Sons). Please ensure that the protecting group is described in the literature in a manner appropriate for the removal of the protecting group in question. To remove by any convenient method known to or familiar to a skilled chemist. This method allows for protecting a protective group while minimizing interference with other groups in the molecule. Selected to remove.

[0187] Therefore, if the reactants contain groups such as amino, carboxy, or hydroxyl, In addition, in some of the reactions described herein, it may be desirable to protect the group. .

[0188] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, Alkanoyl groups such as acetyl, alkoxycarbonyl groups, for example, methoxycarbonyl , ethoxycarbonyl or butoxycarbonyl group, arylmethoxycarbonyl group For example, benzyloxycarbonyl, or an alloyl group, for example, benzoyl. The deprotection conditions for the protecting group inevitably change depending on the choice of protecting group. Therefore, for example, Acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups are, for example, Suitable salts such as alkali metal hydroxides, for example, lithium hydroxide or sodium hydroxide. It can be removed by hydrolysis with a group such as a tert-butoxycarbonyl group. The acyl group can be, for example, hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, which are suitable. It can be removed by acid treatment, and aryl groups such as benzyloxycarbonyl groups can be removed. The toxiccarbonyl group can be obtained, for example, by hydrogenation using a catalyst such as palladium carbon, or It can be removed by treatment with a Lewis acid, such as borontris (trifluoroacetate). This is possible. Suitable alternative protecting groups for primary amino groups include, for example, alkylamines. For example, the f can be removed by treatment with dimethylaminopropylamine or hydrazine. It is a taloyl group.

[0189] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, and for example, alkano groups such as acetyl. Iyl group, alloyl group, for example benzoyl, or arylmethyl group, for example benzyl Yes. The deprotection conditions for the above protecting group will inevitably change depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or aroyl groups are, for example, alkali metals. Suitable salts such as hydroxides, for example, lithium hydroxide, sodium hydroxide, or ammobia. It can be removed by hydrolysis with a group such as a benzyl group or an arylmethyl group. This can be removed, for example, by hydrogenation using a catalyst such as palladium-carbon.

[0190] Suitable protecting groups for carboxyl groups include, for example, esterifying groups such as sodium hydroxide. Which methyl or ethyl group can be removed by hydrolysis with any base, or, for example, t-butyl groups that can be removed by treatment with an acid, such as an organic acid such as trifluoroacetic acid. Alternatively, the benzyl group can be removed by hydrogenation using a catalyst such as palladium-carbon. be.

[0191] Resin can also be used as a protective group.

[0192] The methodology used to synthesize the compound of formula (I) is R1, R2, R3, R4, R The properties of 5 and R6, and any substituents associated with them, vary. A suitable process for manufacturing is further described in the attached examples.

[0193] The compound of formula (I) was synthesized by any one of the processes defined herein. Then the process may further include one or more of the following additional steps: (i) A step of removing any existing protecting groups; (ii) The process of converting compound formula (I) to another compound of formula (I); (iii) A step of forming a pharmaceutically acceptable salt, hydrate, or solvate of the compound of formula I; and / or (iv) A step of forming a prodrug of the compound of formula I.

[0194] The example in (ii) above involves synthesizing the compound of formula (I), and then R1, R2, R3, R4, Further reactions of one or more of the R5 and R6 groups alter the properties of the groups and substitute for formula (I). This is the case when providing a compound.

[0195] The resulting compound of formula (I) was isolated and purified using techniques well known in the art. It is possible.

[0196] biological activity Using the biological assays described in the Examples section (Biological Examples 1-3), the present invention was formulated. The pharmacological effects of the compound can be measured.

[0197] The pharmacological properties of the compound of formula I change with structural changes, as expected, but The compound of the invention is active in the assays described in Biological Examples 1, 2, and 3. That's what I found out.

[0198] In general, regarding adenosine A2a antagonistic activity, the compound of the present invention is shown in Biological Example 1. In the assay described, IC of 1 μM or less 50 The preferred compound of the present invention is 20 ICs with a minimum impedance of 0 nM 50 The most preferred compound of the present invention is IC50 nM or less. 50 of show.

[0199] In general, with respect to adenosine A2b antagonistism, the compounds of the present invention are biologically implemented. In the assay described in Example 1, IC50 is 1 μM or less. 50 The preferred compound of the present invention is shown. ICs with a impedance of 200 nM or less 50 The most preferred compound of the present invention is IC50 nM or less. 50 This indicates.

[0200] Preferably, in the assay described in Biological Example 1, the compound of the present invention is used in adenosine IC at A1 or A3 receptors 50 IC at the adenosine A2a receptor 50 twist It is at least twice as high, more preferably at least five times higher, and even more preferably less Both are 10 times more expensive.

[0201] Pharmaceutical composition According to further aspects of the present invention, the compound of the present invention as defined above, or its pharmaceutical A pharmaceutically acceptable salt, hydrate, or solvate is combined with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition containing the above is provided.

[0202] The compositions of the present invention are for oral use (for example, tablets, lozenges, hard or soft capsules, water) Oily or soluble suspensions, emulsions, dispersible powders or granules, syrups or other liquids. (As a Lixyl agent), for topical use (e.g., cream, ointment, gel, or aqueous or oily) Administration by inhalation (for example, as a solution or suspension of a liquid aerosol) Administration by airflow (for example, as a finely powdered substance), or parenteral administration (for example, Aqueous or oily sterile solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration. It may be in a form suitable as a suppository for rectal administration.

[0203] The composition of the present invention uses conventional pharmaceutical excipients that are well known in the art, It can be obtained by procedure. Therefore, compositions intended for oral use are, for example, It may contain one or more coloring agents, sweeteners, flavoring agents, and / or preservatives.

[0204] The effective amount of the compound of the present invention for use in treatment is the proliferative pathology referred to herein. To treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the condition. That's a sufficient amount.

[0205] The amount of active ingredient combined with one or more excipients to produce a single dosage form is the amount of active ingredient used for treatment. It will inevitably change depending on the individual and the specific route of administration. For example, oral administration to humans The illustrated formulation generally contains, for example, 0.5 mg to 0.5 g of active agent (more preferably 0. 5-100 mg (for example, 1-30 mg) varies in weight from approximately 5-98% of the total composition. It is contained in a mixture with an appropriate and convenient amount of excipients.

[0206] The size of the dose of the compound of formula I for therapeutic or prophylactic purposes is, of course, determined by well-known medical knowledge. According to the established principles, the nature and severity of the disease, the age and sex of the animal or patient, and the administration period are considered. It changes depending on the road.

[0207] The compounds of the present invention are generally used for therapeutic or preventive purposes, for example, in a concentration of 0.1 If a daily dose in the range of mg / kg to 75 mg / kg body weight is required, it can be administered in divided doses. It is administered in this manner. Generally, when parenteral routes are used, a smaller dose is administered. Therefore, for example, in intravenous or intraperitoneal administration, for example, 0.1 mg / kg to 30 mg Doses in the range of g / kg body weight are commonly used. Similarly, for inhalation administration, for example, Doses ranging from 0.05 mg / kg to 25 mg / kg body weight are used. Oral administration, especially tablets. The dosage form may also be preferable. Typically, the unit dosage form contains about 0.5 mg to 0 mg of the compound of the present invention. Contains 0.5g.

[0208] Therapeutic use and application The present invention relates to an antagonist of the adenosine A2 receptor, particularly the adenosine A2a receptor. To provide compounds that function in this way.

[0209] According to a further aspect of the present invention, the adenosine A2a receptor can be activated in vitro or in vivo. A method of antagonizing cells with a compound defined herein, or a pharmaceutically acceptable compound thereof. A method is provided which involves contacting with an effective amount of a salt, hydrate, or solvate.

[0210] According to a further aspect of the present invention, the adenosine A2a receptor can be activated in vitro or in vivo. A method for selectively antagonizing cells with a compound defined herein, or pharmaceutically thereof A method is provided which includes contacting with an effective amount of an acceptable salt, hydrate, or solvate. ru.

[0211] A further aspect of the present invention is a method for inhibiting cell proliferation in vitro or in vivo. and the cells are subjected to the compounds defined herein, or their pharmaceutically acceptable salts, hydrates Alternatively, contact with an effective amount of a solvate or a pharmaceutical composition as defined herein. A method is provided that includes the compound or pharmaceutical composition, which may include one or more additional antiproliferative agents. Administered in combination with (for example, checkpoint inhibitors and / or cytotoxic agents) .

[0212] According to a further aspect of the present invention, diseases or disorders related to adenosine A2a receptor activity A method for administering the treatment of the specified to a patient in need of such treatment, wherein the patient is specified Compounds defined as, or their pharmaceutically acceptable salts, hydrates, or solvates, A method is provided which includes administering a therapeutically effective amount of a pharmaceutical composition as defined herein.

[0213] According to a further aspect of the present invention, treatment of cell proliferation disorders is provided for those who require such treatment. A method for administering to a patient, wherein the patient is given a compound as defined herein, or a pharmaceutically acceptable compound thereof. Salts, hydrates, or solvates that are permissible, or the therapeutic agents of pharmaceutical compositions as defined herein A method is provided which includes administering a therapeutically effective dose. Preferably, the compound or pharmaceutical composition is One or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents) It is administered in combination with [another drug].

[0214] According to a further aspect of the present invention, cancer treatment is administered to patients who require such treatment. A method comprising administering to the patient a compound as defined herein, or a pharmaceutically acceptable compound thereof. A therapeutically effective amount of a salt, hydrate, or solvate, or a pharmaceutical composition as defined herein, is administered. A method is provided which includes giving. Preferably, the compound or pharmaceutical composition includes one or more additional Combined with additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents) It will be administered.

[0215] According to a further aspect of the present invention, a compound defined herein for use in treatment or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof is provided. It can be done.

[0216] According to a further aspect of the present invention, for use in the treatment of cell proliferation pathologies, The defined compound, or its pharmaceutically acceptable salt, hydrate, or solvate, or this A pharmaceutical composition as defined in the specification is provided. Preferably, the compound or pharmaceutical composition is one Combined with the above additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents) They are administered together.

[0217] According to a further aspect of the present invention, a chemical formula defined herein for use in the treatment of cancer Compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions are proposed. Provided. In certain embodiments, cancer is human cancer. Preferably, the compound or pharmaceutical composition one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents) It is administered in combination with [another drug].

[0218] According to a further aspect of the present invention, to be used as an adenosine A2a antagonist The compounds as defined herein, or their pharmaceutically acceptable salts, hydrates, or solvents. A compound is provided. In one embodiment, the compound of the present invention is a selective adenosine A2α antagonist. It is a gonist. In alternative embodiments, certain compounds of the present invention are selective adenosine A2 It is both an α antagonist and an adenosine A2b antagonist.

[0219] According to a further aspect of the present invention, adenosine A2a can be used to treat diseases or disorders in which adenosine A2a is involved. Compounds as defined herein, or pharmaceutically acceptable salts, hydrates thereof, for use in this invention. Alternatively, a solvate is provided.

[0220] According to further aspects of the present invention, a compound as defined herein, or a pharmaceutically acceptable compound thereof. In the manufacture of a pharmaceutical product for the treatment of a cell proliferation disorder, the salt, hydrate, or solvate thereof. Uses are provided. Preferably, the compound or pharmaceutical composition includes one or more additional antiproliferative agents. For example, it is administered in combination with checkpoint inhibitors and / or cytotoxic agents.

[0221] According to further aspects of the present invention, a compound as defined herein, or a pharmaceutically acceptable compound thereof. The use of the salt, hydrate, or solvate thereof in the manufacture of a pharmaceutical for the treatment of cancer is provided. Preferably, the cancer is human cancer. Preferably, the compound or pharmaceutical composition contains one or more Combined with additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents) It is administered.

[0222] According to further aspects of the present invention, a compound as defined herein, or a pharmaceutically acceptable compound thereof. The salt, hydrate, or solvate used as an adenosine A2α antagonist. Use in the manufacture of pharmaceuticals for this purpose is provided.

[0223] According to further aspects of the present invention, a compound as defined herein, or a pharmaceutically acceptable compound thereof. The salt, hydrate, or solvate used as an adenosine A2α antagonist. Use in the manufacture of pharmaceuticals for this purpose is provided.

[0224] According to further aspects of the present invention, a compound as defined herein, or a pharmaceutically acceptable compound thereof. The salt, hydrate, or solvate of the salt, hydrate, or solvate is used in diseases involving adenosine A2a receptor activity or It is provided for use in the manufacture of pharmaceuticals for the treatment of disorders.

[0225] The term "proliferative disorder" is used interchangeably in this specification and applies to in vitro or in vivo Therefore, undesirable excess or abnormal cells such as neoplastic or hyperplastic proliferation It is related to uncontrolled cell proliferation. Examples of proliferative conditions include malignant neoplasms and tumors. , cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., connective tissue), and atheroma This includes, but is not limited to, pre-malignant and malignant cell proliferation, including, atherosclerosis. These include, but are not limited to, the lungs, colon, breasts, ovaries, prostate, liver, pancreas, brain, and skin. It is possible to treat any type of cell, not limited to these.

[0226] The antiproliferative effect of the compounds of the present invention is due to their adenosine A2α antagonist activity. It is particularly applicable to the treatment of human cancer.

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

[0228] More specifically, it is used in the treatment of cancer, such as lung cancer, including small cell lung cancer or non-small cell lung cancer. A compound of general formula (I) is provided for this purpose.

[0229] Cancer, in particular solid tumors, such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urinary tract cancer. The use of compounds of general formula (I) in the manufacture of pharmaceuticals for the treatment of urothelial carcinoma is also It will be provided.

[0230] The present invention further relates to cancer, particularly solid tumors, such as non-small cell lung cancer or small cell lung cancer, head and neck. A method for treating squamous cell carcinoma and urothelial carcinoma, which is effective for patients requiring such treatment. The present invention provides a method comprising administering a certain amount of a compound of general formula (I).

[0231] The patients to be treated are preferably mammals, and more preferably humans.

[0232] Route of administration The compounds of the present invention or pharmaceutical compositions containing these compounds may be used systemically / peripherally or topically. Regardless of the desired site of action, the drug can be administered to the target via any convenient route of administration. It is possible.

[0233] The routes of administration include oral (e.g., by ingestion by mouth), cheek, sublingual, and transdermal (e.g., Examples include, but are not limited to, transmucosal (e.g., by patch, plaster, etc.) (e.g., by patches, plasters, etc.), intranasal cavity (e.g., by nasal spray), intraocular (For example, by eye drops), lungs (for example, aerosols, for example, inhalation through the mouth or nose) (by blown-in therapy), rectal (e.g., by suppositories or enemas), vaginal (e.g., by pessaries) (by the skin), parenteral (e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, subarachnoid) Intramedullary cavity, intracapsular cavity, subcapsular cavity, intraorbital cavity, intratracheal cavity, subepidermal cavity, intraarticular cavity, subarachnoid cavity, substernal cavity and by injection, including into the tumor, and by depot or reservoir, for example, subcutaneous or intramuscular. Examples include, but are not limited to, implants.

[0234] The compounds of the present invention or pharmaceutical compositions containing these compounds are administered by intratumor delivery. It is possible.

[0235] Combination therapy Compounds of formula I are useful, for example, in the treatment and / or prevention of cell proliferation disorders such as cancer. Compounds of formula I as defined herein are used in conjunction with one or more additional antiproliferative / anticancer therapies, e.g. If so, chemotherapy with one or more additional antiproliferative / anticancer agents, radiotherapy and / or conventional methods It can be used in combination with techniques and other methods.

[0236] Additional antiproliferative / anticancer agents, together with the compound of formula (I) as defined herein, in the pharmaceutical composition It may be contained within, or separately, simultaneously with, or earlier than, the compound of formula (I) It may be administered at a later time.

[0237] Therefore, in a further aspect of the present invention, simultaneous, sequential, or individual use in the treatment of cancer. Compounds of general formula (I) as combination formulations for the treatment or prevention of cancer Products containing additional medications are offered.

[0238] The present invention also provides combination formulations for simultaneous, sequential, or individual use in the treatment of cancer. For use in the treatment of cancer, in combination with one or more additional antiproliferative / anticancer agents. The present invention provides a compound of the general formula (I).

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

[0240] Suitable additional antiproliferative agents that may be used in combination with compounds of formula I as defined herein. / Anticancer [separately, or as part of a pharmaceutical composition in combination with a compound of general formula (I)] Examples of preparations that may include, or combine with, the following: 1) Other forms of cancer immunotherapy and anticancer chemotherapy agents; 2) Adenosine pathway modulators (A2b antagonists, CD73 inhibitors and CD3 This includes, but is not limited to, 9 inhibitors; 3) Anti-PD-1 and PDL-1 antibodies (cetrerimab, pembrolizumab, nivolumab, d This includes, but is not limited to, ulvalumab, avelumab, and atezolizumab; and to 4) Anti-CTLA4 antibodies (including, but not limited to, ipilimumab).

[0241] The compounds of formula I as defined herein are anti-PD-1 antibodies and anti-PDL-1 antibodies (Setre Limab, pembrolizumab, nivolumab, durvalumab, avelumab and atezolizumab It is particularly suitable for use in combination with (including, but not limited to) . Preferably The anti-PD1 antibody is described in U.S. Patent Application Publication No. 2019 / 0225689 or U.S. Patent Approved Patent Application Publication No. 2017 / 0121409 (the entire specification is incorporated herein by reference) One of the antibodies disclosed in (included) is, for example, cetrelimab. Cetrelimab ( JNJ-63723283 (CET) is a programmed death receptor with high affinity and specificity. Fully human immunoglobulin (Ig) G4 kappa monoclonal antibody that binds to PD-1 It is a solid tumor. Cetrelimab has shown activity in solid tumors. Rutkowski P,et al.Journal of Clinical Oncology.201 9;37(8):31.

[0242] Compounds of formula I as defined herein are, in particular, adenosine pathway modulators, for example , but not limited to, A2b antagonists, CD73 inhibitors and CD39 inhibitors It is suitable for use in combination with other items.

[0243] A2a antagonists of general formula (I) are also, but are not limited to, CAR-T cells. It can be used in combination with cell-based immunotherapy and cancer vaccines, including therapeutics. .

[0244] Examples of additional antiproliferative / anticancer chemotherapy agents include, but are not limited to, the following: One or more of the following can be listed: MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., X L518, CI-1040, PD035901, selmetinib / AZD6244, GSK 1 120212 / Trametinib, GDC-0973, ARRY-162, ARRY-3 00, AZD8330, PD0325901, U0126, PD98059, TAK-7 33, PD3 18088, AS703026, BAY 869766), alkylating agent (For example, cyclophosphamide, ifosfamide, chlorambucil, busulfan, mel Phalan, Mechloretamine, Uramustine, Thiotepa, Nitrosourea, Nitrogen Mustard (for example, mechloroetamine, cyclophosphamide, chlorambucil, mayf (Alane), ethyleneimine and methylmelamine (e.g., hexamethylmelamine, thiotene) P), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., caramel) (Sutine, Lomustine, Semustine, Streptozocin), Triazene (Dacarbazine) antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludaravin) Gemcitabine, pemetrexed, larcitrexed, folic acid analogs (e.g., methotrexed) Lexate, or pyrimidine analogs (e.g., fluorouracil, floxouridine) , cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentos) Plant alkaloids (e.g., vincristine, vinblastine, vinole) Rubin, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topo Isomerase inhibitors (e.g., irinotecan, topotecan, amsacrin, etoposide) VP16), etoposide phosphate, teniposide, etc., anticancer antibiotics (e.g., doxol) Bicin, Adriamycin, Daunorubicin, Epirubicin, Actinomycin, Bleo Mycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds or This includes platinum-containing agents (e.g., cisplatin, oxaloplatin, arboplatin), and anthracite. Cerdione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), meth Ruhydrazine derivatives (e.g., procarbazine), adrenocortical inhibitors (e.g., mitotane, (aminoglutethimide), epipodophyllotoxin (e.g., etoposide), antibiotics (e.g.) For example, daunorubicin, doxorubicin, bleomycin), enzymes (for example, L-aspirin) Laginase), mitogen-activated protein kinase signaling inhibitors (e.g., U 0126, PD98059, PD184352, PD0325901, ARRY-142 886, SB239063, SP600125, BAY 43-9006, Waltman Nin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., Rituxamic acid) (, gossyphol, genacence, polyphenol E, chlorophyll) Syn, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor related Apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all Trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine Imatinib (Gleevec RTM), geldanamycin, 17-N-allylamine No-17-demethoxygeldanamycin (17-AAG), flavopyridol, LY29 4002, Bortezomib, Trastuzumab, BAY 11-7082, PKC412, P D184352, 20-epi-1,25-dihydroxyvitamin D3; 5-ethinylura Sil; Abiraterone; Acralubicin; Achillfluben; Adecipenolon; Adzelesin Aldesleukin; ALL-TK antagonist; Altrethamine; Ambamastine; Amidox; Amiphostin; Aminolevulinic acid; Amrubicin; Amsacrin; Anag Lerid; Anastrozole; Andrographolide; Angiogenesis inhibitors; Antagonists D; Antagonist G; Antarelix; Anti-adsorption morphogenetic protein-1; Anti-and Rogen (prostate cancer); anti-estrogen; antineoplaster; antisense oligonucleotide Reotide; aphydicolinglycinate; apoptosis gene modulator; apot Cis-regulator; aprinic acid; ara-CDP-DL-PTBA; arginine deamix Nase; Asuraculin; Atamestan; Atrimastin; Axinastatin 1; Axi Nastatin 2; Axinastatin 3; Azasetron; Azatoxin; Azatyrosine; B Catin III derivatives; varanol; batimassat; BCR / ABL antagonists; ba Nzochlorin; benzoyl staurosporine; beta-lactam derivatives; beta-aretin Betacramycin B; Betulinic acid; bFGF inhibitor; Bicalutamide; Bisanthren; B Suaziridinylspermine; Visnafid; Bistratin A; Bizeresin; Blefrate Bropyrimine; Budotitan; Butionine sulfoximine; Calcipotriol; Carfo Sutene C; Camptothecin derivatives; Canalipox IL-2; Capecitabine; Carboxa Mid-amino-triazole; Carboxamide triazole; CaRest M3; C ARN 700; cartilage-derived inhibitors; carzelesin; casein kinase inhibitors (ICOS) Castanospermine; Cecropine B; Cetrorelix; Chlorine; Chloroquinoxa Phosphatesulfonamide; cicaprost; cis-porphyrin; cladribine; clomife Clotrimazole analog; Clotrimazole; Corismycin A; Corismycin B; Combretasta Tin A4; Combretastatin analog; Conagenin; Crambesidine 816; Crisna Toll; Cryptophycin 8; Cryptophycin A derivative; Crasin A; Cyclopenta Intraquinone; cycloplatam; cypemycin; cytarabine octophosphate; cell lysis Factors; Sitostatin; Dacliximab; Decitabine; Dehydrodidemine B; Deslorerin Dexamethasone; Dexphosphamide; Dexrazoxane; Dexverapamil; Dia Dicon; Didemnin B; Zidox; Diethylnorspermine; Dihydro-5-azacit Zin; 9-dioxamycin; diphenylspiromustine; docosanol; drasetron ;Doxifluridine;Doroxifen;Dronabinol;Duocalmycin SA;E Buserene; Ecomustine; Edelfosine; Edrecolomab; Eflornithine; Elemen Emitefour; Epirubicin; Epristeride; Estramustine analog; Estro Estrogen agonist; estrogen antagonist; etanidazole; etoposide phosphate; e Xemestane; Fadrozol; Fazarabine; Fenretinide; Filgrastim; F Inasteride; Flavopyridol; Frezelastine; Fluasterone; Fludarabine; F Luorodaunornicine hydrochloride; Forphenimex; Formestan; Fostoliesin ;Hotemustine;Gadolinium texapyrin;Gallium nitrate;Gallocitabine;Ganirelli Kus; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfame; hele Grin; Hexamethylenebisacetamide; Hypericin; Ibandronic acid; Idarbi Syn; Idoxifen; Idramanton; Irmofosin; Irmostat; Imidazoa Cridone; Imiquimod; Immunostimulant peptides; Insulin-like growth factor-1 receptor inhibitors; Interferon agonist; interferon; interleukin; iobenguan; Iododoxorubicin; Ipomeanol, 4-; Iropract; Ilsogladine; Isobe Ngazole; Isohomohalichondrin B; Itasetron; Jasplakinolide; Kaharali D F; Lamelalin-N Triacetate; Lanreotide; Reinamycin; Renograstim Lentinan sulfate; leptolstatin; letrozole; leukemia inhibitor; leukocyte alpha Interferon; leuprolide + estrogen + progesterone; leuprorelin; Lebamisol; Rialozol; Linear polyamine analog; Lipophilic disaccharide peptide; Lipophilic Platinum compounds; lissoclinamide; rovaplatin; Lombrisin; Lomethelexol; Ronidamin; Losoxantrone; Lovastatin; Lox Solibine; Lulutotecan; Lutetium Texaphylline; Lysophylline; Cellulosic Peptide Do; Mytansin; Mannostatin A; Marimast; Masoprocol; Maspin; Ma Trilysine inhibitors; matrix metalloproteinase inhibitors; menogalil; melbaron; Meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; mi Lutefosine; Millimostim; Inappropriate double-stranded RNA; Mitoguazone; Mitractol; My Tomycin analog; Mitonafide; Mitotoxin fibroblast growth factor-saporin; Mi Toxantrone; Mofalotene; Morglamostim; Monoclonal antibody, Human chorionic gonad Nadotrophins; monophosphoryl lipid A + myobacteria Cell wall SK; Mopidamole; Multidrug resistance gene inhibitors; Therapeutic drugs based on multiple tumor suppressor factors. Mustard anticancer agent; Micapeloxide B; Mycobacterium cell wall extract; Myriapol N-acetyldinalin; N-substituted benzamide; Nafarelin; Naglestipp; Naloxone + Pentazocine; Napavin; Naphtharpine; Naltograstim; Nedaplatin Nemorubicin; Nelidronic acid; Neutral endopeptidase; Niltamide; Nisamycin; Nitric oxide modulator; nitroxide antioxidant; nitrulline; 06-benzylguami Octreotide; oxenon; oligonucleotide; onapristone; ondancet Ron; Ondansetron; Oracin; Oral cytokine inducer; Ormaplatin; Osateron; Oxaliplatin; Oxaunomycin; Paraamine; Palmitoyl Lyso Xin; Pamidronic acid; Panoxytriol; Panomiphene; Parabactin; Pazelipit n; pegaspar gauze; perdecine; pentosan sodium polysulfate; pentostatin; pe Ntozole; Perflubron; Perphosphamide; Periryl alcohol; Phenazino Mycin; Phenylate; Phosphatase inhibitors; Picibanil; Pilocarpine hydrochloride; Pirarubicin; Pyritrexime; Placetin A; Placetin B; Plasminogen activation Factor inhibitors; platinum complexes; platinum compounds; platinum triamine complexes; sodium porfimer Porphyromycin; Prednisone; Propylbis-acridone; Prostaglandin J2; proteasome inhibitors; protein A system immunomodulators; protein kinases C inhibitors; protein kinase C inhibitors, microalgae; tyrosine phosphatase proteins Inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoloacrylidine; Pyridoxylated hemoglobin polyoxyethylene Synjugation; RAF antagonist; L'artitrexed; Ramosetron; RAS farnesyl Protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylation Reteriptin; Rhenium-Re186 etidronate; Rhizoxin; Ribozyme; RII Retinamide; Logretimid; Rohitzkin; Lomultide; Lokinimex; Rubidinone B 1; Ruboxyl; Safingol; Saintpin; SarCNU; Sarcophytol A; Sa Lugramostim; Sdi 1 mimetic; Semustine; Senessense-derived inhibitor 1; Se Signaling oligonucleotide; signaling inhibitor; signaling modulator; single-chain antigen Binding proteins; schizophyllan; sobuzoxane; borocaptate sodium; phenyl vinegar Sodium acid; sorbol; somatomedin-binding protein; sonelmin; sparfosic acid Spicamycin D; Spiromustine; Suprenopentin; Spongestatin 1; Squa Lamin; stem cell inhibitors; stem cell division inhibitors; stipiamide; stromelicin inhibitors; s Rufinosin; hyperactive vasoactive enteric peptide antagonist; Suradista; Suramin Swansonin; Synthetic glycosaminoglycans; Talimustin; Tamoxifen methiozide ; Tauromustine; Tazarotene; Tecogalan sodium; Tegafur; Tellapyrium; Telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecao Xydo; Tetrazomine; Talibrasticin; Thiocoralin; Thrombopoietin; Thrombo Poietin mimetic; thymalfazine; thymopoietin receptor agonist; thymotri Nan; Thyroid-stimulating hormone; Tin ethyl ethiopropyl purine; Tillapazamin; Titanocene 2 Chloride; Topsentin; Toremifene; Pluripotent stem cell factor; Translation inhibitors; Tretinoin; Triacetyluridine; trisirivine; trimethrexate; triptrelin; tropice Thoron; turosteride; tyrosine kinase inhibitor; thilphostine; UBC inhibitor; ube Nimex; a growth inhibitor derived from the urogenital sinus; a urokinase receptor antagonist; vapleo Tide; Variolin B; Vector system, red blood cell gene therapy; Veraresol; Veramine Bardine; Verteporfin; Vinorelbine; Binxaltin; Vitaxin; Borozol Al; Zanoterone; Zeniplatin; Zirascorb; Zinostatin stimulamer, Adri amycin, dactinomycin, bleomycin, vinblastine, cisplatin, A Cibicin; Acralubicin; Acodazole hydrochloride; Acronin; Adzelesin; Aldes Leukin; Altoretamine; Ambomycin; Amethantrone acetate; Aminoglutethimide Amsacrin; Anastrozole; Anthramycin; Asparaginase; Aspergillin Azacitidine; Azetape; Azotomycin; Batymast; Benzodepa; Bical Tamide; Bisanthren hydrochloride; Bisnafid dimesylate; Bizeresin; Bleomycetin sulfate Syn; Brekiner sodium; Bropyrimine; Busulfan; Cactinomycin; Callus Terone; Calasemide; Carbetimer; Carboplatin; Carmustine; Carbicin hydrochloride Salt; Calzersin; Sedefingol; Chlorambucil; Cyloremycin; Cladribine; Cristinator mesylate; cyclophosphamide; cytarabine; dacarbazine; daunol Bicin hydrochloride; decitabine; dexolomaplatin; desaguamine; desaguamine mesylates To; Diadicon; Doxorubicin; Doxorubicin hydrochloride; Doroxifen; Citric acid Droloxifen; Dromostanolone propionate; Duazomycin; Edatrexate To; Eflornithine hydrochloride; Elsamitolcine; Enloplatin; Empromate; E Pipropidine; Epirubicin hydrochloride; Elbrozol; Esolubicin hydrochloride; Estram Stearustine; Estramustine sodium phosphate; Ethanidazole; Etoposide; Eto phosphate Poside; Etoprine; Fadrozol hydrochloride; Fazarabine; Fenretinide; Phlox Uridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; Fostriesin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; salt Idarubicin acid; Ifosfamide; Imofosin; Interleukin II (recombinant I) Interleukin-2 or rlL.sub.2 (containing interleukin-2 or rlL.sub.2), interferon alpha-2a; Interferon alpha-2b; Interferon alpha-n1; Interferon Alpha-n3; interferon beta-la; interferon gamma-lb; type Loplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate ;Rialozol hydrochloride;Lometrexol sodium;Lomustine;Losoxantrone salt Salts; Masopropyl alcohol; Maytansine; Mechloretamine hydrochloride; Megestrol acetate; Vinegar Melengestrol acid; melphalan; menogalyl; mercaptopurine; methotrexate Methotrexate sodium; Metoprine; Metsuredepa; Mitindomide; Mitocalci Mitochromin; Mitogiline; Mitomarcin; Mitospel; Mitotan Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazoie Nogaramycin; Ormaplatin; Oxythran; Pegaspargaze; Periomycin Pentamustine; Peplomycin sulfate; Perphosphamide; Pipobroman; Piposul Fan; Pyroxantrone hydrochloride; Plicamycin; Promethane; Porfimanatri Um; Porphyromycin; Prednimustine; Procarbazine hydrochloride; Promycin; Promycin hydrochloride; pyrazofulin; ribopurine; logretimide; safingol; safi Ngol hydrochloride; Semustine; Simtrazene; Sparfosate sodium; Sparsomy Syn; Spirogermanium hydrochloride; Spiromustin; Spiroplatin; Streptonigrin Streptozocin; Slophenur; Talisomycin; Tecogalan sodium; Tega Fool; teroxantrone hydrochloride; temoporfin; teniposide; teroxylon; test Lactone; Thiamipurine; Thioguanine; Thiotepa; Thiazofulin; Tirapazamine; Quercus Toremifene acid; Trestron acetate; Trisibilin phosphate; Trimethrexate; Glucose Trimethrexate curonate; Triptorelin; Tubrozol hydrochloride; Uracil Master Do; Uredepa; Bupreotide; Verteporfin; Vinblastine sulfate; Vincris sulfate Vindesine; Vindesine sulfate; Vinepidine sulfate; Vindesine sulfate; Vindesine sulfate Leulosin; Vinorelbine tartrate; Vinrosidine sulfate; Vinzokidine sulfate; Borozol; Zeniplatin; dinostatin; zolubicin hydrochloride, which arrest cells in the G2-M phase and / or agents that modulate microtubule formation or stability (for example, Taxol (trademark) (in other words) Paclitaxel, Taxotere (trademark) (compound containing a taxane skeleton), Lubrozol (i.e., R-55104), Dorastatin 10 (i.e., DLS-1) (0 and NSC-376128), isethionate mybobrin (i.e., CI-980) (, vincristine, NSC-639829, discodermolide (i.e., NV) (as P-XX-A-296), ABT-751 (Abbott, i.e., E-701) 0) Altriltine (e.g., Altriltine A and Altriltine C), Sponge Star Chin (for example, Sponge Statin 1, Sponge Statin 2, Sponge Statin 3, Sponge Distatin 4, Sponge statin 5, Sponge statin 6, Sponge statin 7, Sponge Distatin 8 and spongistatin 9), semadine hydrochloride (i.e., LU-1037) 93 and NSC-D-669356), Epotilon (e.g., Epotilon A, Epotilon) B, Epothyron C (i.e., desoxyepothyron A or dEpoA), Epothyron D ( That is, KOS-862, dEpoB and desoxyepotilone B), epotilone E, Epotilon F, Epotilon B N-oxide, Epotilon A N-oxide, 16-Aza - Epothyron B, 21-aminoepothyron B (i.e., BMS-3-10705), 2 1-Hydroxyepotyron D (i.e., desoxyepotyron F and dEpoF), 2 6-Fluoroepothyron, Auristatin PE (i.e., NSC-654663), So Bridotin (i.e., TZT-1027), vincristine sulfate, cryptophycin 5 2 (i.e., LY-355703), bitilebuamide, tubulcin A, canadensol , Sendaureidine (i.e., NSC-106969), Oncosidine Al (i.e., , BTO-956 and DF E), Fizianolido B, Laurimalid, Narcosine (NS Also known as C-5366), nascapine, hemiasterine, vanadocephalic acid Setanate, Monsatrol, Inanosine (i.e., NSC-698666), Eleuth Desaetyle leutherobin), leutherobin A and Z leutherobin, carib Oside, Caribaeolin, Halichondrin B, Diazonamide A, Taccaronolide A, Geo Zostatin, (-)-phenylahistine (i.e., NSCL-96F037), Myo Severin B, resverastatin sodium phosphate, steroid (e.g., dexamethasone) ), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (G nRH), for example, goserelin or leuprolide, adrenocorticosteroids (for example) (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, acetate) Megestrol, medroxyprogesterone acetate), estrogen (e.g., diethyl acetate) Chilbestrol, ethinylestradiol), anti-estrogens (e.g., tamoxifen) (androgens), androgens (e.g., testosterone propionate, fluoxymesterone) , antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus calmet) Guerlain (BCG), Levamysol, Interleukin-2, Alpha-Interferon (etc.), monoclonal antibodies (e.g., anti-CD20, anti-F£ER2, anti-CD52, anti-UL) A-DR and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibodies), Monoclonal antibody - calicheamicin conjugate, anti-CD22 monoclonal antibody - sho Domonas exotoxin conjugate, etc.), radioimmunotherapy drugs (e.g., ln, 0Y or I) (e.g., denjugated anti-CD20 monoclonal antibodies), triptolides, homoharing Tonin, Dactinomycin, Doxorubicin, Epirubicin, Topotecan, Itraconazol Servol, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline N, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, Vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epithelium Growth factor receptor (EGFR) targeted therapy or therapeutic agent (e.g., gefitinib (Iressa) (Trademark), Erlotinib (Tarceva (Trademark)), Cetuximab (Erbitux (Trademark), lapatinib (Tykerb(Trademark)), panitumumab (Vectibix( (Trademark), Vandetanib (Caprelsa (Trademark)), Afatinib / BIBW299 2. CI-1033 / Canertinib, Neratinib / HKI-272, CP-724714 , TAK-285, AST-1306, ARRY334543, ARRY-380, AG -1478, Dacomitinib / PF299804, OSI-420 / Desmethylerlotinib Bu, AZD8931, AEE788, Peritinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD1530 35, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, Or hormone therapy, etc.

[0245] As described above, the combination therapy of the present invention involves the simultaneous, sequential, or individual treatment of the individual components of the treatment. This can be achieved by administration. Such combination products are within the dosage range described above. Use the compound of the invention and other pharmaceutically active agents within the approved dosage range.

[0246] According to this aspect of the present invention, the compounds of the present invention as defined above, or their pharmaceutically acceptable properties A salt, hydrate, or solvate of which is included, and one or more further antiproliferative agents / anticancer agents, for cancer ( For example, combinations are provided for use in the treatment of cancers, including solid tumors.

[0247] According to this aspect of the present invention, cell proliferation pathologies such as cancer (for example, cancer including solid tumors) A combination for use in treatment, comprising the previously defined compounds of the present invention, or the drug thereof. Scientifically acceptable salts, hydrates, or solvates, and selected from those listed above. Combinations including one or more additional antiproliferative / anticancer agents are also provided.

[0248] In further aspects of the present invention, other options may be optionally selected from those listed above herein. The compound of the present invention, or its pharmaceutically acceptable properties, for use in combination with antitumor agents for the treatment of cancer. A salt, hydrate, or solvate that is permissible is provided.

[0249] In this specification, when the term “combination” is used, it means simultaneously, individually, or consecutively. Please understand that this refers to subsequent administration. In one aspect of the present invention, "combination" refers to simultaneous administration. In another aspect of the present invention, “combination” refers to individual administration. In a further aspect of the present invention In this case, "combination" refers to continuous administration. When administration is continuous or individual, the second component Delays in administration should not result in the loss of the beneficial effects of the combination.

[0250] According to a further aspect of the present invention, the compound of the present invention, or a pharmaceutically acceptable salt thereof, water The dilution or solvate is combined with a pharmaceutically acceptable diluent or carrier (as specified herein). Pharmaceuticals containing an antitumor agent (arbitrarily selected from those listed above) in combination with the above-mentioned pharmaceuticals. A composition is provided. [Examples]

[0251] General conditions: The mass spectrum was obtained using electrospray ionization and performed on an LC-MS system. These were Waters Acquity HC with PDA and QDa mass detection. Waters Acquity C with lass UPLC, PDA and SQ mass detection Classic UPLC, Acquity LC (Binary Pump / PDA Detector) + Z Q Mass Spectrometer or Acquity i-Class (Quaternary Pump / PDA Spectrometer) output device) + Quattro Micro mass Spectrometer, Wate Waters Acquity LC system with rs PDA and ELS detectors, or performed using either the Shimadzu LCMS-2010EV system. [M+H]+ refers to the monoisotopic molecular weight.

[0252] The NMR spectrum was obtained using a Bruker Ultrashield 500MHz NMR spectrum analyzer. Spectrometer, Bruker Avance III HD 400MHz NMR spectrometer, The analysis was performed using a Bruker Avance III HD 500MHz. The spectrum was obtained from 2 The data was recorded at 98K, and the solvent peak was used as the reference.

[0253] The following examples illustrate the present invention, but the present invention is not limited thereto. Temperatures are expressed in Celsius. Unless otherwise specified, all evaporation is performed under vacuum, preferably at about 1°C. The procedure is carried out at a pressure of 5 mmHg to 100 mmHg (= 20 to 133 mbar). Final product, intermediate product. The structure of the body and starting materials can be determined by standard analytical methods, such as trace analysis and spectroscopic properties, for example, Confirmation is made by MS, IR, and NMR. The abbreviations used are common in the relevant field. These terms are of origin. Unless otherwise defined, these terms are generally accepted. It has a taste.

[0254] Abbreviation App appearance br broad CDI 1,1'-Carbonyldiimidazole d double line dd compound double line DCM Dichloromethane DIPEA Diisopropylethylamine DMF (N,N-dimethylformamide) DMA (dimethylacetamide) HCl ethyl acetate HPLC (High-Performance Liquid Chromatography) LC-MS Liquid Chromatography-Mass Spectrometry MeOH MeOH MeCN acetonitrile MS mass spectrometry m multiplet mins minutes mL (milliliter) m / z mass-to-charge ratio NMR nuclear magnetic resonance ppm parts per million Rt retention time s single line t multiplet TBAF Tetra-n-butylammonium fluoride TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran)

[0255] With respect to the following examples, the compounds of the preferred embodiments are described by the method specified herein, or It was synthesized using other methods known in the art.

[0256] Various starting materials, intermediates, and compounds of the preferred embodiment may be precipitated and filtered as needed. Isolation and purification are performed using conventional techniques such as crystallization, evaporation, distillation, and chromatography. It is possible. Unless otherwise specified, all starting materials are obtained from commercial suppliers. It is used without further purification. The salt is prepared from the compound by known salt formation procedures. It is possible.

[0257] Unless otherwise specified, the analytical HPLC conditions are as follows:

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

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

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

[0261] Method 3A Column: Acquity LC BEH C18 2.1×50mm 1.7μm Column temperature: 50℃ Eluent: A: H2O, 0.1% formic acid, B: MeCN Flow rate: 0.6mL / min Gradient: 0.2-2.5 min 2-98%B, 2.5-3.3 min 98%B, 3.3-3.5 98% A

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

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

[0264] Method 5B Column: Waters Alliance ZQ MS, YMC-Triart C18 50 x 2 mm, 5 μm Column temperature: Room temperature Eluent: A: H2O, B: CH3CN, C: 50%H2O / 50%CH3CN+1.0% Ammonia (water-based) Flow rate: 0.8mL / min Gradient: 0.0-4.0 min 0-95%B, 5%C; 4.0-4.4 min 95%B, 5%C ;4.4~4.5 minutes 95%A, 5%B

[0265] Method 7A Column: Phenomenex Kinetix-XB C18 2.1×100mm, 1.7 μm Column temperature: 40℃ Eluents: A: H2O + 0.1% formic acid, B: MeCN + 0.1% formic acid Flow rate: 0.6mL / min Gradient: 0-5.3.0 min 5-100%B, 5.3-5.8 min 100%B, 5.8-5 .82 minutes 100~5%B, 5.82~7.00 minutes 5%B

[0266] Method 7B Column: Waters LC(registered trademark) BEH(trademark) C18, 2.1mm x 100m m, 1.7μm Column temperature: 40℃ Eluent: A: 2 mM ammonium bicarbonate buffered to pH 10, B: MeCN Flow rate: 0.6mL / min Gradient: 0-5.3.0 min 5-100%B, 5.3-5.8 min 100%B, 5.8-5 .82 minutes 100~5%B, 5.82~7.00 minutes 5%B

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

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

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

[0270] Method 15B Column: YMC-Triart C18 50×2mm, 5μm Flow rate: 0.8mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% A Monia (water-based) Gradient: 0.0~12.0 min 0~95%B, 5%C; 12.0~14.0 min 95%B, 5%C; 14.0~14.2 minutes 95%A, 5%B

[0271] Preparative HPLC using acidic pH, early elution method Purification is performed using a Gilson LC system with a Waters Sunfire C18 carburetor. (30mm x 100mm, 10μM; temperature: room temperature), and 10-95%B (A=0 in water) 0.1% formic acid (B = 0.1% formic acid in MeCN) for 14.44 minutes, then 95% B for 2 minutes. The procedure was performed using an 11-minute gradient with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV Spectrum The data was recorded at 215 nm using a Gilson detector.

[0272] Preparative HPLC using alkaline pH, early elution method Purification by preparative HPLC (alkaline pH, early elution method) is performed using a Gilson LC system. Waters Xbridge C18 column (30mm x 100mm, 10 μM; temperature: room temperature), and 10-95% B (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in MeCN for 14.44 minutes, then 95% B for 2.1 The procedure was performed using a 1-minute gradient with an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectrum This was recorded at 215 nm using a Gilson detector.

[0273] Example 1 N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]morpholine-4-carboxamide [ka] Step 1: N-[4-(3-cyanophenyl)thiazole-2-yl]morpholine-4-ca Ruboxamide [ka] 3-(2-aminothiazole-4-yl)benzonitrile in THF (10 mL) In a stirred solution of interstitial substance A) (653 mg, 3.08 mmol), sodium hydride (at 0°C) 60% (150 mg, 3.75 mmol) of mineral oil was added. After stirring at room temperature for 20 minutes, Add morpholine-4-carbonyl chloride (520 μL, 4.55 mmol) and stir. This was continued for 18 hours. The resulting mixture was diluted with THF (10 mL), and then sodium hydride was added. The sample was retreated with lium (60% in mineral oil) (150 mg, 3.75 mmol). The mixture was stirred for 10 minutes. Then, add morpholine-4-carbonyl chloride (520 μL, 4.55 mmol). The mixture was stirred for 4 hours. The reaction was quenched with water (20 mL) and toluene (2 x 40 mL). Extraction was performed using ) and the aqueous layer was acidified to pH 5 with 1M HCl, and ethyl acetate (2 × 30 m Extraction was performed using L). The combined organic extracts were washed with brine (30 mL) and dried with MgSO4. The mixture was dried and concentrated under vacuum. The resulting brown oily substance was then mixed with 0-100% toluene / heptane. The title compound was purified by silica chromatography to obtain a beige solid. I obtained it by doing so. LC-MS (Method 2A): Rt1.06 min; MS m / z315.1=[M+H]+ 11 H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.3 1(t,J=1.5Hz,1H),8.21(dt,J=7.9,1.3Hz,1H), 7.76(dt,J=7.7,1.3Hz,1H),7.73(s,1H),7.63( t,J=7.8Hz,1H),3.67-3.58(m,4H),3.56-3.48( m,4H).

[0274] Step 2: N-[5-bromo-4-(3-cyanophenyl)thiazole-2-yl]morpho Phosphorus-4-carboxamide [ka] N-[4-(3-cyanophenyl)thiazole-2-yl]mol in THF (20 mL) In a solution of ruforin-4-carboxamide (step 1) (790 mg, 2.34 mmol), NBS (499 mg, 2.8 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture is diluted with toluene (50 mL), water (30 mL), and saturated NaHCO3. The samples were washed with solution (2 × 30 mL) and brine (30 mL). The organic layer was dried over MgSO4. The compound was then concentrated under vacuum to obtain the title compound as a yellow solid. LC-MS (Method 2A): Rt1.18 min; MS m / z393.0 / 395.0=[M +H]+ 1 H NMR(500MHz,DMSO-d6)δ 11.35(s,1H),8.25 (t,J=1.5Hz,1H),8.21(dt,J=8.0,1.4Hz,1H),7 .88(dt,J=7.7,1.3Hz,1H),7.71(t,J=7.9Hz,1H ),3.63-3.56(m,4H),3.55-3.48(m,4H).

[0275] Step 3: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophen [Nyl)thiazole-2-yl]morpholine-4-carboxamide N-[5-bromo-4-(3-cyano Phenyl)thiazole-2-yl]morpholine-4-carboxamide (Step 2) (50ml) g, 0.13 mmol), (2-chloro-6-methyl-4-pyridyl)boronic acid (87 ml) A stirred solution of (g, 0.51 mmol) and cesium carbonate (124 mg, 0.38 mmol). The mixture was degassed with nitrogen for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride Add 18 mg (0.03 mmol) and heat the reaction mixture at 85°C for 7.5 hours. After cooling to room temperature, the mixture was diluted with DCM (5 mL) and water (5 mL). The organic layer was divided. The mixture was separated, passed through hydrophobic frit, and concentrated under vacuum. The crude product was divided into acetonitrile / water / 0. Purified by C18 reverse-phase chromatography eluting with 0.1% formic acid, followed by acetonite Further analysis can be performed by C18 reverse-phase chromatography using lyl / water / 0.1% ammonia. The title compound was obtained by purification as a bright yellow powder. LC-MS (Method 2.5B): Rt3.58 min; MS m / z440.1 / 442.1= [M+H]+ 1 H NMR(400MHz,DMSO-d6)δ 11.40(br s,1H),7 .90(t,J=1.4Hz,1H),7.84(dt,J=7.7,1.3Hz,1H ),7.72(dt,J=7.9,1.3Hz,1H),7.58(t,J=7.9Hz ,1H),7.14(s,1H),7.01(s,1H),3.62-3.57(m,4 H), 3.54-3.49 (m, 4H), 2.39 (s, 3H)

[0276] Example 2 N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1- Carboxamide [ka] Step 1: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophen [Nyl]thiazole-2-yl]imidazole-1-carboxamide [ka] 3-[2-amino-5-(2-chloro-6-methyl-4-p-2p-2- Lysyl)thiazole-4-yl]benzonitrile (intermediate D) (73 mg, 0.17 mm The solutions of (1 ol) and CDI (55 mg, 0.34 mmol) were stirred at room temperature for 24 hours. Add the remaining portion of DI (55 mg, 0.34 mmol), leave at room temperature for 2 hours, then 5 The mixture was stirred at 0°C for 1 hour. After cooling to room temperature, the resulting precipitate was collected by vacuum filtration. The title compound was obtained as a pale yellow solid. LC-MS (Method 7B): Rt3.76 min; MS M / z385.1=[M-(C3N2 (H5) + (OCH3)] +; Methyl carbamate was observed from the reaction of the title compound with MeOH. They figured it out. 1 H NMR(400MHz,DMSO-d6)δ 8.43(s,1H),8.11( d,J=3.6Hz,1H),7.90(d,J=1.5Hz,1H),7.84(d, J=1.4Hz,1H),7.83-7.79(m,1H),7.76-7.72(m, 1H),7.69(dt,J=7.9,1.4Hz,1H),7.56(t,J=7.8 Hz,1H),7.01(s,1H),6.91(s,1H),2.35(s,3H).

[0277] Step 2: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophen [Nyl)thiazole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine n-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4 in DMA (0.5 mL) -(3-cyanophenyl)thiazole-2-yl]imidazole-1-carboxamide ( Step 1) Add 2-pyrrolidine-3-ylpro to the stirred solution of (59 mg, 0.09 mmol) Add pan-2-ol (22 mg, 0.17 mmol) and allow the reaction mixture to stand at room temperature for 30 minutes. Stirring was performed. 2-Pyrrolidine-3-ylpropan-2-ol (22 mg, 0.17 mm) Further portions of DIPEA (30 μL, 0.17 m) were added, and stirring continued for 3 days. Add (mol), then add 2-pyrrolidine-3-ylpropane-2-ol (22m (g, 0.17 mmol) was added, and the mixture was heated at 50°C for 18 hours. The resulting mixture The solution was diluted with water (3 mL) and extracted with ethyl acetate (3 × 3 mL). The combined organic extract was then mixed with The solution was filtered through a separation cartridge and concentrated under vacuum. 0-100% siRNA / DCM Next, a silica chromatography assay using 0-10% MeOH / siRNA was performed to extract the crude The product was purified to obtain the title compound as an off-white solid. LC-MS (Method 7B): Rt3.23 min; MS m / z482.3 / 484.2=[M +H]+ 1 H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),7.92 (t,J=1.5Hz,1H),7.85(dt,J=7.7,1.4Hz,1H),7 .73(dt,J=7.9,1.3Hz,1H),7.59(t,J=7.9Hz,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).

[0278] Example 3 (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pylori Zin-1-carboxamide [ka] 3-[2-amino-5-(2-chloro-6-methyl-4-p-2p-2- Lysyl)thiazole-4-yl]benzonitrile (intermediate D (52 mg, 0.16 mmol) The solution of l) and CDI (31 mg, 0.19 mmol) was stirred at 50°C for 22 hours. Then, CDI (31 mg, 0.19 mmol) was added, and stirring was continued at 50°C for a total of 46 hours. After the resulting mixture is cooled to room temperature, 2-[(2R)-pyrrolidine-2-yl]propane N-2-ol hydrochloride (40 mg, 0.24 mmol) and DIPEA (55 μL, 0. The sample was treated with 32 mmol. The mixture was stirred at room temperature for 1 hour, followed by 1 hour at 50°C. After cooling, the mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 × 3 mL). The combined organic extracts were filtered through a phase separation cartridge and concentrated under vacuum. The orange solid is eluted by silica chromatography using 0-100% acetone / DCM. The sample is purified and then eluted with 0-100% dimethylheptane using silica chromatography. A second purification was performed using the method described above, yielding the title compound as an off-white solid. LC-MS (Method 7B): Rt3.62 min; MS m / z482.3 / 484.3=[M +H]+ 1 H NMR(400MHz,DMSO-d6)δ 12.00(s,1H),7.88 (t,J=1.5Hz,1H),7.85(dt,J=7.7,1.4Hz,1H),7 .69(dt,J=8.0,1.2Hz,1H),7.58(t,J=7.8Hz,1H ),7.21-7.16(m,1H),7.08-7.03(m,1H),4.01-3 .82(m,3H),2.40(s,3H),2.11-2.00(m,1H),1.9 0-1.60(m,4H),1.19(s,3H),1.10(s,3H).

[0279] The compounds of the examples shown in the table below (Table Ex3) were converted to 3-[2-amino-5-(2-chloro [6-methyl-4-pyridyl)thiazole-4-yl]benzonitrile (intermediate D) and A suitable amine was prepared in the same manner as in Example 3.

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[0283] Example 4 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-methylpiperazine-1-carboxamide [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl] in DMA (0.5 mL) ) Thiazol-4-yl]benzonitrile (intermediate C) (50 mg, 0.16 mmol) The solution of CDI (40 mg, 0.24 mmol) was stirred at 50°C for 18 hours. The mixture was treated with 1-methylpiperazine (36 μL, 0.33 mmol) and heated at 50°C for 1 Stirring was continued for a specified time. After cooling to room temperature, the crude mixture was subjected to acidic conditions and an early elution method. The title compound was obtained by purification using preparative HPLC. LC-MS (Method 7B): Rt2.43 min; MS m / z433.3=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 11.27(br s,1H),7 .89(t,J=1.5Hz,1H),7.82(dt,J=7.7,1.4Hz,1H ),7.70(dt,J=8.0,1.2Hz,1H),7.56(t,J=7.8Hz ,1H),6.93(s,2H),3.55-3.50(m,4H),2.36(s,6 H),2.34-2.30(m,4H),2.20(s,3H).

[0284] Example 4.1 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]piperidine-1-carboxamide [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl] in DMA (0.5 mL) ) Thiazol-4-yl]benzonitrile (intermediate C) (50 mg, 0.16 mmol) The solution of CDI (53 mg, 0.33 mmol) was stirred at 50°C for 18 hours. The mixture was treated with piperidine-4-carbonitride (36 mg, 0.33 mmol) and DIP. The sample was treated with EA (90 μL, 0.49 mmol) and stirred at 50°C for 30 minutes. After cooling, elute with 5-20% MeCN / water (+0.1% ammonium hydroxide regulator). The crude substance is purified by C18 reverse-phase chromatography to obtain a solid, which is then converted to Et2O(2 Suspend in (mL), recover by filtration, wash with Et2O (2 × 1.5 mL), and dry. The title compound was obtained as a yellow solid. LC-MS (Method 8B): Rt4.17 min; MS m / z443.3=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 11.28(s,1H),7.88 (s,1H),7.81(d,J=7.9Hz,1H),7.70(d,J=7.9Hz ,1H),7.56(t,J=7.9Hz,1H),6.92(s,2H),3.83- 3.76(m,2H),3.45-3.38(m,2H),3.14-3.08(m,1 H),2.36(s,6H),1.95-1.86(m,2H),1.75-1.65( m, 2H).

[0285] The compounds of the examples shown in the table below (Table Ex4) are 3-[2-amino-5-(2,6- Dimethyl-4-pyridyl)thiazole-4-yl]benzonitrile (intermediate C) and preferred It was prepared from the amine in the same manner as in Example 4 or Example 4.1.

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[0296] Example 4.12 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxa-6-azaspiro[3,3]heptane-6-carboxamide [ka] CDI (1.27 g, 7.83 mmol) and DIPEA (2.05 mL, 11.75 mmol) in DMA (12 mL) 3-[2-amino-5-(2,6-dimethyl-4 -Pyridyl)thiazole-4-yl]benzonitrile (intermediate C) (1.2g, 3.92 The mixture was added to the stirred solution of mmol, and the solution was heated overnight at 50°C. [3.3]Heptane (0.73 mL, 7.83 mmol) and additional DIPEA (2. Add 0.5 mL (11.75 mmol) and stir the solution at 50°C for 40 minutes. The resulting mixture After cooling the mixture to room temperature, dilute with ا(150mL) and 90% brine (100 Wash with 50% brine (3 x 100 mL), dry with MgSO4, and under vacuum. The solution was concentrated. Elution was obtained by silica chromatography using a gradient of 0-4% MeOH / DCM. The title compound was purified to obtain an off-white solid. LC-MS (Method 8B): Rt2.82 min; MS m / z432.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.35(s,1H),7.88 (t,J=1.7Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7 .70(dt,J=8.0,1.5Hz,1H),7.56(t,J=7.8Hz,1H ),6.93(s,2H),4.68(s,4H),4.21(s,4H),2.36( s,6H).

[0297] Example 5: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-( 3-Cyanophenyl)thiazole-2-yl]carbamoyl]piperazine-2-carbone acid [ka] Example 5.1: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4 -(3-cyanophenyl)thiazole-2-yl]carbamoyl]piperazine-2-yl Methyl phosphate [ka] Step 1: (2R)-1-tert-butoxycarbonyl-4-[[5-(2-chloro-6 [methyl-4-pyridyl)-4-(3-cyanophenyl)thiazole-2-yl]carb [Moyl]piperazine-2-carboxylic acid [ka] 3-[2-amino-5-(2-chloro-6-methyl-4-p-2p-2- Lysyl)thiazole-4-yl]benzonitrile (intermediate D) (50 mg, 0.15 mm Solutions of 0.31 mmol) and CDI (50 mg, 0.31 mmol) were stirred at 50°C for 20 hours. Reaction mixture (2R)-1-tert-butoxycarbonylpiperazine-2-carboxylic acid (106 mg, 0.46 mmol) and DIPEA (53 μL, 0.31 mmol) The mixture was then heated at 50°C and stirred for 1 hour. After cooling to room temperature, the resulting mixture was... The solution was diluted with water (2 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic extracts were then mixed. The product was filtered through a separation cartridge and concentrated under vacuum. The crude product was dissolved in DCM (4 mL). The mixture was dissolved, and heptane (10 mL) was added to form a precipitate. The solid was collected by vacuum filtration. The title compound was obtained as a brown solid. LC-MS (Method 2A): Rt1.25 min; MS m / z583.2 / 585.2=[M +H]+ 1 H NMR(400MHz,DMSO-d6)δ 7.91(t,J=1.5Hz,1 H),7.86(dt,J=7.7,1.3Hz,1H),7.72(dt,J=7.9 ,1.3Hz,1H),7.59(t,J=7.8Hz,1H),7.18(s,1H) ,7.06(s,1H),4.68-4.57(m,1H),4.51(d,J=30. 0Hz,2H),4.17-4.08(m,2H),3.77-3.69(m,2H), 2.40 (s, 3H), 1.39 (d, J=7.0Hz, 9H). NH and OH protons It was not observed.

[0298] Step 2: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3 -Cyanophenyl)thiazole-2-yl]carbamoyl]piperazine-2-carboxylic acid and (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cy [Anophenyl)thiazole-2-yl]carbamoyl]piperazine-2-carboxylic acid methyl Ru (2R)-1-tert-butoxy in DCM (2 mL) and MeOH (0.2 mL) Carbonyl-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-shea Nophenyl)thiazole-2-yl]carbamoyl]piperazine-2-carboxylic acid (process 1) Add 1,4-dioxane (322 μL, 1.5L) to a solution of (94 mg, 0.13 mmol). Add 4M HCl to 29 mmol and stir the reaction mixture at room temperature for 16 hours. The mixture was concentrated under vacuum, and the crude mixture was extracted using HPLC under acidic conditions and an early elution method. After purification, the following compounds were obtained: Example 5: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-( 3-Cyanophenyl)thiazole-2-yl]carbamoyl]piperazine-2-carbone Acid (as an off-white solid). LC-MS (Method 7A): Rt2.08 min; MS m / z483.2 / 485.1=[M +H]+(99%@215nm) 1 H NMR(500MHz,DMSO-d6)δ 7.91(t,J=1.5Hz,1 H),7.85(dt,J=7.7,1.3Hz,1H),7.72(dt,J=7.9 ,1.3Hz,1H),7.59(t,J=7.8Hz,1H),7.17(s,1H) ,7.05(s,1H),4.37(dd,J=10.9,3.2Hz,2H),4.0 2(d,J=13.0Hz,1H),3.11(dd,J=9.5,6.1Hz,1H) ,2.92-2.85(m,1H),2.40(s,3H).2×NH and COOH pro No tons were observed. 2×CH signal under H2O signal.

[0299] Example 5.1: (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4 -(3-cyanophenyl)thiazole-2-yl]carbamoyl]piperazine-2-yl Methyl phosphate (as an off-white solid). LC-MS (Method 7A): Rt2.10 min; MS m / z497.2 / 499.1=[M +H]+(99%@215nm) 1 H NMR(500MHz,DMSO-d6)δ 7.92(t,J=1.5Hz,1 H),7.85(dt,J=7.7,1.3Hz,1H),7.72(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,1 H),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). 2×NH protons Not observed. 1×CH signal under H2O signal.

[0300] The compounds of the examples shown in the table below (Table Ex5) are 3-[2-amino-5-(2-chloro [6-methyl-4-pyridyl)thiazole-4-yl]benzonitrile (intermediate D) and From a suitable amine, prepare in the same manner as in Example 5 (Step 1), followed by a 4M HCl-containing Deprotection was performed using 1,4-dioxane (Step 2).

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[0305] Example 6 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl Thiazol-2-yl-4-methylpiperidine-1-carboxamide [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl] in DMA (0.5 mL) ) Thiazol-4-yl]benzonitrile (intermediate C) (50 mg, 0.16 mmol) The solution of CDI (40 mg, 0.24 mmol) was stirred at 50°C for 18 hours. The mixture contains 4-methylpiperidine-4-carbonitrile hydrochloride (52 mg, 0.33 mg). Treat with (ol) and DIPEA (85 μL, 0.49 mmol), and stir at 50°C for 1 hour. Continued. After cooling to room temperature, the crude mixture was subjected to preparative HPL using acidic conditions and an early elution method. The title compound was obtained as a colorless solid by purification with C. Example 6 was also obtained using the following procedure. Prepared:

[0306] CDI (1.27 g, 7.83 mmol) and DIPEA (2.05 mL, 11.75 mmol) in DMA (12 mL) 3-[2-amino-5-(2,6-dimethyl-4 -Pyridyl)thiazole-4-yl]benzonitrile (intermediate C) (1.20g, 3.9 Add 2 mmol of the stirred solution and heat the solution overnight at 50°C. 4-Methylpiperidine- 4-Carbonitrile hydrochloride (1.26 g, 7.83 mmol) and additional DIPEA (2 (0.05 mL, 11.75 mmol) was added, and the solution was stirred at 50°C for 30 minutes. After cooling the mixture to room temperature, dilute it with ethyl acetate (150 mL) to make a 90% brine aqueous solution. Wash with (100 mL), 50% brine aqueous solution (3 × 100 mL), and dry with MgSO4. The silica chromatograph was then concentrated under vacuum. Elution was performed using a 1-3% MeOH / DCM gradient. Purification by roughing yielded a yellow solid. Adding MeOH (15 mL) yielded a white solid. The obtained solution is collected by filtration, washed with MeOH (2 mL) and Et2O (20 mL), and dried. The compound was dried and obtained as a colorless solid. LC-MS (Method 8B): Rt3.24 min; MS m / z457.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.31(s,1H),7.89 (t,J=1.8Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7 .70(dt,J=8.0,1.5Hz,1H),7.56(t,J=7.9Hz,1H ),6.93(s,2H),4.22(d,J=14.0Hz,2H),3.03(t, J=12.6Hz,2H),2.36(s,6H),1.92(d,J=13.4Hz, 2H),1.53(td,J=13.2,4.0Hz,2H),1.37(s,3H).

[0307] The compounds of the examples shown in the table below (Table Ex6) are 3-[2-amino-5-(2,6- Dimethyl-4-pyridyl)thiazole-4-yl]benzonitrile (intermediate C) or preferred A suitable starting intermediate and a suitable amine were prepared in the same manner as in Example 6.

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[0342] Example 7 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]piperazine-1-carboxamide [ka] Step 1: 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl )Thiazol-2-yl]carbamoyl]piperazine-1-carboxylate tert-butyl [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl] in DMA (0.5 mL) ) Thiazol-4-yl]benzonitrile (intermediate C) (50 mg, 0.16 mmol) The solution of CDI (40 mg, 0.24 mmol) was stirred at 50°C for 18 hours. The mixture contains piperazine-1-carboxylate tert-butyl (61 mg, 0.33 mmol). The mixture was treated with ) and stirred at 50°C for 1 hour. After cooling to room temperature, the crude mixture was treated with water (10 mL). The solution was diluted with ) and the precipitate was recovered by vacuum filtration. The solid was dissolved in DCM and phase separation cartridges were used. The sample was filtered through a filter and concentrated under vacuum. It eluted in 0-100% acetone / DCM. The crude product was purified by silica chromatography to obtain the title compound. LC-MS (Method 7A): Rt2.16 min; MS m / z519.3=[M+H]+ H NMR(500MHz,DMSO-d6)δ 11.30(s,1H),7.89( t,J=1.4Hz,1H),7.82(d,J=7.7Hz,1H),7.71(dt ,J=8.0,1.2Hz,1H),7.56(t,J=7.8Hz,1H),6.93 (s,2H),3.55-3.49(m,4H),3.39-3.34(m,4H),2 .36 (s, 6H), 1.42 (s, 9H).

[0343] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) [Thiazol-2-yl]piperazine-1-carboxamide DCM (2 mL), MeOH (2 drops), and 1,4-dioxane (33) containing 4M HCl 4-[[4-(3-cyanophenyl)-5-(2,6- [Dimethyl-4-pyridyl)thiazole-2-yl]carbamoyl]piperazine-1-cal A solution of tert-butyl vonate (step 1) (70 mg, 0.14 mmol) was heated at room temperature for 22 minutes. The mixture was stirred for a certain amount of time. The resulting mixture was concentrated under vacuum and then extracted using basic conditions and an early elution method. The crude product was purified by HPLC to obtain the title compound. LC-MS (Method 7A): Rt0.94 min; MS m / z419.2=[M+H]+ 1 H NMR(400MHz,DMSO-d6)δ 7.88(s,1H),7.81( d,J=7.7Hz,1H),7.71(d,J=8.0Hz,1H),7.56(t, J=7.8Hz,1H),6.92(s,2H),3.50-3.43(m,4H),2 .74-2.68(m,4H),2.36(s,6H).2×NH protons were not observed. It was.

[0344] Example 7.1 (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methylpiperazine-1-carboxamide [ka] Step 1: (2R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]carbamoyl]-2-methylpiperazine-1-carbamoyl] tert-butyl benzoate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and (2R)-2-methylpiperazine-1-carboxylic acid te The title compound was prepared from rt-butyl in the same manner as in step 1 of Example 7. LC-MS (Method 2A): Rt1.07 min; MS m / z533.3=[M+H]+ 1 H NMR(400MHz,DMSO-d6)δ 11.30(s,1H),7.89 (t,J=1.5Hz,1H),7.82(dt,J=7.7,1.7Hz,1H),7 .71(dt,J=8.0,1.3Hz,1H),7.56(t,J=7.8Hz,1H ),6.93(s,2H),4.20-4.09(m,2H),4.02(d,J=13 .7Hz,1H),3.78-3.69(m,1H),3.14(dd,J=13.7, 4.1Hz,1H),3.09-3.00(m,1H),2.99-2.89(m,1H ),2.36(s,6H),1.42(s,9H),1.07(d,J=6.7Hz,3 H).

[0345] Step 2: (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4- Pyridyl)thiazole-2-yl]-3-methylpiperazine-1-carboxamide (2R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyriol) [Dil)thiazole-2-yl]carbamoyl]-2-methylpiperazine-1-carbone From tert-butyl acid and 1,4-dioxane containing 4M HCl, step 2 of Example 7 and The title compound was prepared in the same manner. LC-MS (Method 7A): Rt1.00 min; MS m / z433.2=[M+H]+ 1 H NMR(400MHz,DMSO-d6)δ 7.89(t,J=1.5Hz,1 H),7.82(dt,J=7.7,1.3Hz,1H),7.73-7.69(m,1 H),7.56(t,J=7.8Hz,1H),6.93(s,2H),4.18-4. 08(m,2H),3.06(d,J=11.6Hz,1H),3.02-2.91(m ,2H),2.88(s,1H),2.82-2.73(m,1H),2.36(s,6 H), 1.08(d, J=6.3Hz, 3H). No 2×NH protons were observed.

[0346] Example 7.2 4-amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]piperidine-1-carboxamide [ka] Step 1: N-[4-cyano-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl [Thiyl-4-pyridyl]thiazole-2-yl]carbamoyl]-4-piperidyl]carba tert-butyl methyl phosphate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and N-(4-cyano-4-piperidyl)carbamate te The title compound was prepared from rt-butyl in the same manner as in step 1 of Example 7. LC-MS (Method 5B): Rt2.95 min; MS m / z558.2=[M+H]+ 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),7.7 0(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).1×CH No 2 signals were observed.

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

[0348] Example 7.3 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carb Xamide [ka] Step 1: 9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl ) Thiazol-2-yl]carbamoyl]-1-oxa-4,9-diazaspiro[5.5 tert-butyl undecane-4-carboxylate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and 1-oxa-4,9-diazaspiro[5.5]undeca From tert-butyl n-4-carboxylate, the title compound was obtained in the same manner as in step 1 of Example 7. We prepared it. LC-MS (Method 2A): Rt0.77 min; MS m / z589.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.22(s,1H),7.89 (t,J=1.5Hz,1H),7.82(dt,J=7.7,1.3Hz,1H),7 .70(dt,J=8.0,1.3Hz,1H),7.56(t,J=7.9Hz,1H ),6.92(s,2H),3.86-3.78(m,2H),3.64-3.59(m ,2H),3.36-3.32(m,2H),3.28-3.16(m,4H),2.3 6(s,6H),1.75-1.69(m,2H),1.52-1.44(m,2H), 1.41 (s, 9H).

[0349] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) [thiazole-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9 -Carboxamide 9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thia [Zol-2-yl]carbamoyl]-1-oxa-4,9-diazaspiro[5.5]un Decane-4-carboxylate tert-butyl (Step 1) and 1,4-dioxide containing 4M HCl The title compound was prepared from xane in the same manner as in step 2 of Example 7. LC-MS (Method 7B): Rt2.68 min; MS m / z489.4=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.88(t,J=1.7Hz,1 H),7.81(dt,J=7.9,1.4Hz,1H),7.70(dt,J=8.2 ,1.4Hz,1H),7.55(dd,J=7.8,7.8Hz,1H),6.91( s,2H),3.83(dt,J=13.2,4.1Hz,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 2×NH protons were observed.

[0350] Example 7.4 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide [ka] Step 1: 8-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl ) Thiazol-2-yl]carbamoyl]-3,8-diazabicyclo[3.2.1]oc tert-butyl tan-3-carboxylate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and 3,8-diazabicyclo[3.2.1]octane-3- The title compound was prepared from tert-butyl carboxylate in the same manner as in step 1 of Example 7. Ta. LC-MS (Method 2A): Rt0.77 min; MS m / z545.3=[M+H]+ 1H NMR(400MHz,DMSO-D6)δ 11.37(s,1H),7.88 (d,J=1.7Hz,1H),7.82(dt,J=7.8,1.4Hz,1H),7 .70(dt,J=8.1,1.4Hz,1H),7.56(dd,J=7.8,7.8 Hz,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).

[0351] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) [Thiazol-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carb Xamide 8-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thia [Zol-2-yl]carbamoyl]-3,8-diazabicyclo[3.2.1]octane- 3-Tert-butyl carboxylate (Step 1) and 1,4-dioxane containing 4M HCl Then, the title compound was prepared in the same manner as in step 2 of Example 7. LC-MS (Method 7B): Rt2.57 min; MS m / z445.4=[M+H]+ ¹H NMR (500 MHz, methanol-d4) δ 7.91 (t, J=1.7 Hz, 1H),7.72(dt,J=7.9,1.4Hz,1H),7.68(dt,J=7. 8,1.4Hz,1H),7.48(dd,J=7.8,7.8Hz,1H),7.01 (s,2H),4.43-4.37(m,2H),2.98(dd,J=13.1,2. 0Hz,2H),2.74(dd,J=13.1,2.1Hz,2H),2.44(s, No 6H, 2.05-1.98(m,4H) 2×NH protons were observed.

[0352] Example 7.5 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide [ka] Step 1: 6-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl )Thiazol-2-yl]carbamoyl]-3,6-diazabicyclo[3.1.1]hept tert-butyl tan-3-carboxylate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and 3,6-diazabicyclo[3.1.1]heptane-3- The title compound was prepared from tert-butyl carboxylate in the same manner as in step 1 of Example 7. Ta. LC-MS (Method 2A): Rt0.70 min; MS m / z531.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.59(s,1H),7.87 (t,J=1.7Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7 .69(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8 Hz,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).

[0353] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) [Thiazol-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carb Xamide 6-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thia [Zol-2-yl]carbamoyl]-3,6-diazabicyclo[3.1.1]heptane- 3-Tert-butyl carboxylate (Step 1) and 1,4-dioxane containing 4M HCl Then, the title compound was prepared in the same manner as in step 2 of Example 7. LC-MS (Method 7A): Rt0.98 min; MS m / z431.3=[M+H]+ ¹H NMR (500 MHz, methanol-d4) δ 7.90 (t, J=1.7 Hz, 1H),7.71(dt,J=8.0,1.4Hz,1H),7.68(dt,J=7. 8,1.4Hz,1H),7.51-7.45(m,1H),7.01(s,2H),4 .43-4.38(m,2H),3.48(d,J=13.2Hz,2H),2.99( dd,J=13.0,1.9Hz,2H),2.76-2.70(m,1H),2.44 (s,6H),1.84(d,J=8.8Hz,1H).2×NH protons were not observed. It was.

[0354] Example 7.6 (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-2,5-diazabicyclo[2.2.2]octane-2 -Carboxamide [ka] Step 1: (1R,4R)-5-[[4-(3-cyanophenyl)-5-(2,6-dimethic Lu-4-pyridyl)thiazol-2-yl]carbamoyl]-2,5-diazabicyclo[ 2.2.2] Octane-2-carboxylate tert-butyl [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and (2R,5R)-5-ethyl-2-methylpiperazine From tert-butyl-1-carboxylate, the title compound was obtained in the same manner as in step 1 of Example 7. Prepared. LC-MS (Method 2A): Rt0.76 min; MS m / z545.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.07(s,1H),7.88 (d,J=1.8Hz,1H),7.82(dt,J=7.8,1.5Hz,1H),7 .71(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8 Hz,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),1.9 1-1.73(m,4H),1.41(d,J=3.3Hz,9H).

[0355] Step 2: (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]-2,5-diazabicyclo[2.2.2]oc Tan-2-carboxamide (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4- Pyridyl)thiazole-2-yl]-2,5-diazabicyclo[2.2.2]octane- 2-Tert-butyl carboxylate (Step 1) and 1,4-dioxane containing 4M HCl Then, the title compound was prepared in the same manner as in step 2 of Example 7. LC-MS (Method 7A): Rt0.99 min; MS m / z445.3=[M+H]+ ¹H NMR (500 MHz, methanol-d4) δ 7.91 (t, J=1.7 Hz, 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. No 88-1.80(m,1H).2×NH protons were observed.

[0356] Example 7.7 (2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-2,5-dimethylpiperazine-1-carboxamide [ka] Step 1: (2S,5S)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl Ru-4-pyridyl)thiazole-2-yl]carbamoyl]-2,5-dimethylpipera tert-butyl din-1-carboxylate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and cis-(2S,5S)-2,5-dimethylpiperazine From tert-butyl-1-carboxylate, the title compound was obtained in the same manner as in step 1 of Example 7. Prepared. LC-MS (Method 7A): Rt0.80 min; MS m / z547.4=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.19(s,1H),7.89 (t,J=1.7Hz,1H),7.82(dt,J=7.8,1.4Hz,1H),7 .70(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8 Hz,1H),6.93(s,2H),4.20-4.08(m,2H),3.95-3 .84(m,2H),2.96(dd,J=14.6,11.2Hz,1H),2.88 (dd,J=14.2,10.7Hz,1H),2.36(s,6H),1.39(s, 9H),1.10(d,J=6.1Hz,3H),1.06(d,J=6.1Hz,3H ).

[0357] Step 2: (2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]-2,5-dimethylpiperazine-1-carb Xamide (2S,5S)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]carbamoyl]-2,5-dimethyl-piperazine- 1-Tert-butyl carboxylate (Step 1) and 1,4-dioxane containing 4M HCl Then, the title compound was prepared in the same manner as in step 2 of Example 7. LC-MS (Method 7B): Rt2.72 min; MS m / z447.3=[M+H]+ ¹H NMR (500 MHz, methanol-d4) δ 7.91 (t, J=1.7 Hz, 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,1H),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).2×NH Pro No tons were observed.

[0358] Example 7.8 (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-2,6-dimethyl-piperazine-1-carboxamide [ka] Step 1: (3R,5R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethic Ru-4-pyridyl)thiazole-2-yl]carbamoyl]-3,5-dimethylpipera tert-butyl din-1-carboxylate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and (3R,5R)-3,5-dimethylpiperazine-1- The title compound was prepared from tert-butyl rubonate in the same manner as in step 1 of Example 7. . LC-MS (Method 2A): Rt0.81 min; MS m / z547.3=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.16(s,1H),7.90 (t,J=1.7Hz,1H),7.82(dt,J=7.8,1.2Hz,1H),7 .71(dt,J=8.3,1.2Hz,1H),7.56(dd,J=7.8,7.8 Hz,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),1.23-1.1 7(m,6H).

[0359] Step 2: (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]-2,6-dimethylpiperazine-1-carb Xamide rac-(3R,5R)-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl [Tyl-4-pyridyl)thiazole-2-yl]carbamoyl]-3,5-dimethylpipe 1,4-dioxide containing tert-butyl radin-1-carboxylate (Step 1) and 4M HCl The title compound was prepared from xane in the same manner as in step 2 of Example 7. LC-MS (Method 7B): Rt2.73 min; MS m / z447.4=[M+H]+ ¹H NMR (400 MHz, methanol-d4) δ 7.91 (t, J=1.7 Hz, 1H),7.72(dt,J=8.0,1.5Hz,1H),7.69(dt,J=7. 8,1.4Hz,1H),7.49(t,J=7.8Hz,1H),7.01(s,2H ),4.02-3.95(m,2H),3.21(dd,J=13.0,3.9Hz,2 H),2.78(dd,J=13.1,4.5Hz,2H),2.44(s,6H),1 .34(d,J=6.5Hz,6H).2×NH protons were not observed.

[0360] Example 7.9 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2,2-dimethylpiperazine-1-carboxamide [ka] Step 1: 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl )Thiazol-2-yl]carbamoyl]-3,3-dimethyl-piperazine-1-carb tert-butyl phosphate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and 3,3-dimethylpiperazine-1-carboxylic acid tert -The title compound was prepared from butyl in the same manner as in step 1 of Example 7. LC-MS (Method 2A): Rt0.83 min; MS m / z547.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.24(s,1H),7.87 (t,J=1.7Hz,1H),7.82(dt,J=7.7,1.5Hz,1H),7 .70(dt,J=8.1,1.4Hz,1H),7.56(dd,J=7.8,7.8 Hz,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,6 H).

[0361] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) Thiazol-2-yl]-2,2-dimethylpiperazine-1-carboxamide 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thia [Zol-2-yl]carbamoyl]-3,3-dimethylpiperazine-1-carboxylic acid From ert-butyl (Step 1) and 1,4-dioxane containing 4M HCl, the process of Example 7 The title compound was prepared in the same manner as in Step 2. LC-MS (Method 7B): Rt2.88 min; MS m / z447.4=[M+H]+ 11H NMR (400 MHz, methanol-d4) δ 7.89 (t, J=1.5 Hz) ,1H),7.72-7.67(m,2H),7.49(dd,J=7.8,7.8Hz ,1H),7.00(s,2H),3.50-3.45(m,2H),2.99-2.9 3(m,2H),2.69(s,2H),2.44(s,6H),1.47(s,6H) No .2×NH protons were observed.

[0362] Example 7.10 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide [ka] Step 1: 5-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl ) Thiazol-2-yl]carbamoyl]-5,8-diazaspiro[3.5]nonane-8 -Tert-butyl carboxylate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and 5,8-diazaspiro[3.5]nonane-8-carbone The title compound was prepared from tert-butyl acid in the same manner as in step 1 of Example 7. LC-MS (Method 2A): Rt0.83 min; MS m / z559.3=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.40(s,1H),7.87 (t,J=1.7Hz,1H),7.82(dt,J=7.8,1.5Hz,1H),7 .70(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8 Hz,1H),6.93(s,2H),3.53(s,2H),3.50-3.44(m ,2H),3.29-3.25(m,2H),2.35(s,6H),2.28-2.1 6(m,3H),2.04-1.97(m,2H),1.81-1.75(m,1H), 1.42 (s, 9H).

[0363] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) Thiazol-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide 5-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thia [Zol-2-yl]carbamoyl]-5,8-diazaspiro[3.5]nonane-8-cal The process is carried out using tert-butyl benzoate (step 1) and 1,4-dioxane containing 4M HCl. The title compound was prepared in the same manner as in step 2 of Example 7. LC-MS (Method 7B): Rt2.48 min; MS m / z459.3=[M+H]+ 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=7.8,0.6Hz, 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 2×NH protons were observed.

[0364] Example 7.11 trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide [ka] Step 1: trans-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]carbamoyl]-2,5-dimethylpiperazine -1-Tert-butyl carboxylate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and trans-2,5-dimethylpiperazine-1-carb The title compound was prepared from tert-butyl phosphate in the same manner as in step 1 of Example 7. LC-MS (Method 2A): Rt0.81 min; MS m / z547.3=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.29(s,1H),7.89 (t,J=1.7Hz,1H),7.85-7.78(m,1H),7.70(dt,J =8.2,1.6Hz,1H),7.56(dd,J=7.8,7.8Hz,1H),6 .92(s,2H),4.44(d,J=21.6Hz,2H),4.31-4.21( m,1H),4.21-4.11(m,1H),3.92-3.85(m,1H),3. 65-3.56(m,1H),2.36(s,6H),1.42(s,9H),1.15 -1.01 (m, 6H).

[0365] Step 2: trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-2,5-dimethylpiperazine-1-carboxa Mido trans-4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]carbamoyl]-2,5-dimethyl-piperazine-1- From tert-butyl carboxylate (step 1) and 1,4-dioxane containing 4M HCl, The title compound was prepared in the same manner as in step 2 of Example 7. LC-MS (Method 7A): Rt1.10 min; MS m / z447.3=[M+H]+ 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=7.8,7.8Hz, 1H),7.00(s,2H),4.33-4.26(m,1H),3.74(dd,J =14.0,2.2Hz,1H),3.40(dd,J=13.6,4.0Hz,1H) ,3.26-3.17(m,2H),2.60(dd,J=13.5,2.9Hz,1H ),2.43(s,6H),1.33(d,J=6.8Hz,3H),1.22(d,J (=6.8Hz, 3H). No 2×NH protons were observed.

[0366] Example 8 1-Acetylimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboc Thamid [ka] N-[4-(3-cyanophenyl)-5-(2,6-dimethicone] in DCM (2.5 mL) Ru-4-pyridyl)thiazole-2-yl]-1-imino-1-oxo-1,4-thiadi In a suspension of Nan-4-carboxamide (Example 4.2) (50 mg, 0.11 mmol) At 0°C, add triethylamine (37 μL, 0.27 mmol), followed by acetyl chloride (1 Add 0 μL (0.14 mmol) and stir the mixture for 1 hour. Acetyl chloride (10 Add (μL, 0.14 mmol) and stir the reaction mixture at 0°C for 30 minutes, then... Add acetyl chloride (4 μL, 0.05 mmol) and allow the reaction mixture to stand at 0°C for 15 minutes. The mixture was stirred. The resulting mixture was concentrated under vacuum, and then Et containing 10% MeOH was added. The mixture was partitioned between 20 mL of OAc and 20 mL of water. The layers were separated, and the aqueous layer was treated with 10% Me. Further extraction was performed using OH-containing ال(2 × 20 mL). The combined organic extracts were then subjected to vacuum. Concentrate and elute with 5-15% MeCN / water (+0.1% ammonium hydroxide modifier). 18. The crude substance was purified by reverse-phase chromatography, and the title compound was obtained as an off-white solid. I acquired it physically. LC-MS (Method 8B): Rt2.16 min; MS m / z509.3=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 11.58(s,1H),7.88 (s,1H),7.83(d,J=7.8Hz,1H),7.70(d,J=7.8Hz ,1H),7.56(t,J=7.8Hz,1H),6.92(s,2H),4.26- 4.18(m,2H),3.77-3.65(m,4H),3.53-3.47(m,2 H), 2.36 (s, 6H), 1.99 (s, 3H).

[0367] Example 9 N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]2-oxa-6-azapiro[3,3]heptane -6-Carboxamide [ka] 3-[2-amino-5-[2-[[tert-butyl(dimethyl [Thiyl]silyl]oxymethyl]-6-methyl-4-pyridyl]thiazole-4-yl]be Nzonitrile (intermediate I) (60 mg, 0.13 mmol) and CDI (49 mg, 0. A 30 mmol solution was stirred overnight at 50°C. The resulting mixture was then mixed with DMA (0.1 mL). ) and 2-oxa-6-azaspiro[3] in DIPEA (78 μL, 0.45 mmol) .3] Treat with heptane (30 mg, 0.30 mmol) and continue stirring at 50°C for 30 minutes. The reaction mixture was cooled to room temperature, and 1M TBAF-containing THF (211 μL, 0.21 mm) was added. (ol) was added. After stirring for 15 minutes, the resulting mixture was mixed with 5-15% MeCN / water (+ C18 reverse-phase chromatography eluting with a gradient of 0.1% ammonium hydroxide (modifier) Further purification was performed. The product fractions were combined and concentrated, and the Isolute® SCX cartridge was used. The ridge was loaded. The column was flushed with MeOH (30 mL), and the product was collected in a 0.7 M solution. The substance was eluted with NH3-containing MeOH (30 mL). The solvent was removed under vacuum, and the obtained substance was extracted. The solid was obtained by trituration with 2:1 hexane / diethyl ether (1 mL). Further refinement is achieved by silica chromatography using a 0-4% MeOH / DCM gradient. The compound was prepared and obtained as a yellow solid. LC-MS (Method 8B): Rt2.93 min; MS m / z448.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),7.87 (d,J=1.5Hz,1H),7.81(d,J=7.8Hz,1H),7.71(d t,J=7.8,1.5Hz,1H),7.55(t,J=7.8Hz,1H),7.1 3(s,1H),6.96(s,1H),5.32(t,J=5.8Hz,1H),4. 67(s,4H),4.46(d,J=5.8Hz,2H),4.19(s,4H),2 .36 (s, 3H).

[0368] The compounds of the examples shown in the table below (Table Ex9) are 3-[2-amino-5-[2-[[ tert-butyl(dimethyl)silyl]oxymethyl]-6-methyl-4-pyridyl]thio From azole-4-yl]benzonitrile (intermediate I) and a suitable amine, the same method as in Example 9 is used. It was prepared in the following manner.

[0369] JPEG2026086419000110.jpg241170

[0370] JPEG2026086419000111.jpg186170

[0371] JPEG2026086419000112.jpg128170

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

[0373] Example 11 1-Cyanoimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4- Pyridyl)thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboxa Mido [ka] N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]-1-imino-1-oxo-1,4-thiadinane -4-Carboxamide (Example 4.2) (50 mg, 0.11 mmol) suspension, At °C, DMAP (14 mg, 0.12 mmol), followed by cyanogen bromide (23 mg, 0.2 Add 1 mmol of cyanogen bromide and stir the mixture at 0°C for 1 hour and 10 minutes. (0.03 mmol) and DMAP (2 mg, 0.02 mmol) were further added, and the mixture was incubated at 0°C for 1 hour. Stirring was continued. Additional cyanide bromide (6 mg, 0.05 mmol) and DMAP (3 mg) were added. (0.03 mmol) was added, and the mixture was stirred for 45 minutes, after which it was concentrated under vacuum. Dissolve the crude product in 5-40% MeCN / water (containing 0.1% ammonium hydroxide adjusting agent). The resulting solution is purified by C18 reverse-phase chromatography and then subjected to a 0-5% MeOH / DCM gradient. Further purification is performed by eluting silica chromatography, followed by 0-80% ammonium phosphate. The title compound was purified by silica chromatography eluting with a gradient of / DCM, and the resulting yellow color was obtained. It was obtained as a solid. LC-MS (Method 8B): Rt4.70 min; MS m / z492.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.64(s,1H),7.89 (s,1H),7.84(d,J=7.8Hz,1H),7.70(d,J=7.8Hz ,1H),7.57(t,J=7.8Hz,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).

[0374] Example 12 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl [Tyl-ethyl)-6-methyl-4-pyridyl]thiazole-2-yl]-4-methyl-pyridyl Peridine-1-carboxamide [ka] Step 1: 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-[1-[(4-Me Toxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thia Zole-2-yl]-4-methylpiperidine-1-carboxamide [ka] 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-me [Tyl-ethyl]-6-methyl-4-pyridyl]thiazole-4-yl]benzonitrile ( From intermediate J) and 4-methylpiperidine-4-carbonitride, in the same manner as in Example 6 The title compound was prepared. LC-MS (Method 3B): Rt2.37 min; MS m / z621.4=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.34(s,1H),7.84 (t,J=1.8Hz,1H),7.75-7.69(m,2H),7.52(t,J= 7.9Hz,1H),7.18-7.13(m,2H),7.00-6.95(m,2H) ),6.86-6.80(m,2H),4.25-4.18(m,2H),4.11(s ,2H),3.75(s,3H),3.08-2.99(m,2H),2.48(s,3 H),1.95-1.88(m,2H),1.57-1.50(m,2H),1.45( s,6H), 1.37(s,3H).

[0375] Step 2: 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy -1-methyl-ethyl)-6-methyl-4-pyridyl]thiazole-2-yl]-4-methyl Chil-piperidine-1-carboxamide 4-cyano-N-[4-(3-cyanophenyl)-5-[2 -[1-[(4-methoxyphenyl)methoxy]-1-methyl-ethyl]-6-methyl- 4-Pyridyl]thiazole-2-yl]-4-methylpiperidine-1-carboxamide (Step 1) Add trifluoroacetic acid (0.38 mL) to the solution of (77 mg, 0.12 mmol). Add 4.96 mmol of the reaction mixture and stir the mixture at room temperature for 45 minutes. Dilute with M (15 mL), wash with saturated NaHCO3 solution (2 × 20 mL), then Na2 The silica was dried on SO4 and the solvent was removed under vacuum. The oily substance was purified by chromatography and suspended in 10% Et2O / hexane. This process allows a precipitate to form, which is then collected by filtration and dried to obtain the title compound. It was obtained as a white solid. LC-MS (Method 8B): Rt4.20 min; MS m / z501.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.33(s,1H),7.85 (s,1H),7.83(d,J=7.8Hz,1H),7.77(d,J=7.8Hz ,1H),7.59(t,J=7.8Hz,1H),7.29(s,1H),7.03( s,1H),5.09(s,1H),4.23(apr d,J=14.1Hz,2H) ,3.04(apr t,J=13.1Hz,2H),2.43(s,3H),1.93 (apr d,J=13.6Hz,2H),1.58-1.50(m,2H),1.38 (s,3H), 1.36(s,6H).

[0376] Example 12.1 N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl) )-6-methyl-4-pyridyl]thiazole-2-yl]-6-oxa-2-azaspirol [3.4] Octane-2-carboxamide [ka] Step 1: N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl [Methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazole-2- Il-6-oxa-2-azaspiro[3,4]octane-2-carboxamide [ka] 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-me [Tyl-ethyl]-6-methyl-4-pyridyl]thiazole-4-yl]benzonitrile ( From intermediate J) and 6-oxa-2-azaspiro[3.4]octane, in the same manner as in Example 6 The title compound was then prepared. LC-MS (Method 3B): Rt2.17 min; MS m / z610.3=[M+H]+ ¹H NMR (500 MHz, methanol-d4) δ 7.82 (t, J=1.6 Hz, 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,1H),7.05-7.01(m ,2H),6.86-6.80(m,2H),4.16(s,2H),4.11(s,4 H),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).1×NH protons were not observed.

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

[0378] Example 12.2 N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl) )-6-methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspirol [3.3] Heptane-6-carboxamide [ka] Step 1: N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl [Methoxy]-1-methyl-ethyl]-6-methyl-4-pyridyl]thiazole-2- Il-2-oxa-6-azaspiro[3,3]heptane-6-carboxamide [ka] 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]-1-me [Tyl-ethyl]-6-methyl-4-pyridyl]thiazole-4-yl]benzonitrile ( From intermediate J) and 2-oxa-6-azaspiro[3.3]heptane, in the same manner as in Example 6 The title compound was then prepared. LC-MS (Method 3B): Rt2.06 min; MS m / z596.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.37(br s,1H),7 .83(br t,J=1.7Hz,1H),7.74-7.71(m,1H),7.7 3-7.68(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),3.7 5(s,3H),2.48(s,3H),1.45(s,6H).

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

[0380] Example 12.3 N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl -4-pyridyl]thiazole-2-yl]2-oxa-6-azaspiro[3.3]hept Tan-6-carboxamide [ka] Step 1: N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl [Methoxyethyl]-6-methyl-4-pyridyl]thiazole-2-yl]-2-ol Xa-6-azaspiro[3,3]heptan-6-carboxamide [ka] 3-[2-amino-5-[2-[1-[(4-methoxyphenyl)methoxy]ethyl] -6-methyl-4-pyridyl]thiazole-4-yl]benzonitrile (intermediate PA) and From 2-oxa-6-azaspiro[3.3]heptane, in the same manner as in Example 6, the title was obtained. A mixture was prepared. LC-MS (Method 3B): Rt1.81 min; MS m / z580.4=[MH]- 1H NMR(500MHz,DMSO-d6)δ 11.38(br s,1H),7 .85(t,J=1.7Hz,1H),7.75-7.71(m,2H),7.53(a pr t,J=7.8Hz,1H),7.16(br d,J=1.6Hz,1H),7 .06-7.02(m,2H),6.98(br d,J=1.6Hz,1H),6.8 8-6.84(m,2H),4.67(s,4H),4.42(q,J=6.5Hz,1 H),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).

[0381] Step 2: N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6 -methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azapiro[3. 3] Heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-[1-[(4-methoxyphenyl)me Toxyethyl-6-methyl-4-pyridylthiazol-2-yl-2-oxa- From 6-azaspiro[3.3]heptane-6-carboxamide (step 1) and TFA, The title compound was prepared in the same manner as in step 2 of Example 12. LC-MS (Method 8B): Rt3.67 min; MS m / z462.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),7.84 (br t,J=1.5Hz,1H),7.82(br dt,J=7.7,1.5Hz ,1H),7.74(br dt,J=8.0,1.5Hz,1H),7.57(apr t,J=7.8Hz,1H),7.12(s,1H),7.01(s,1H),5.2 3(d,J=4.5Hz,1H),4.67(s,4H),4.65-4.56(m,1 H),4.21(s,4H),2.40(s,3H),1.26(d,J=6.6Hz, 3H).

[0382] Examples 12.3a and 12.3b Racemic N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6 -methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azapiro[3. 3] Heptane-6-carboxamide (Example 12.3) in EtOH / DCM (4:1) Dissolved in 50 mg / mL of solution and purified by SFC to obtain individual enantiomers:

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

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

[0385] Example 12.3a N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]- 6-methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3 .3]heptan-6-carboxamide or N-[4-(3-cyanophenyl)-5-[2 -[(1S)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazole-2- Il-2-oxa-6-azaspiro[3,3]heptane-6-carboxamide [ka] First elution peak: Chiral LC-MS retention time: = 3.12 mins LC-MS (Method 8B): Rt2.56 min; MS m / z462.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),7.84 (t,J=1.6Hz,1H),7.82(dt,J=7.8,1.6Hz,1H),7 .74(dt,J=7.8,1.6Hz,1H),7.57(t,J=7.8Hz,1H ), 7.12(d,J=1.7Hz,1H),7.01 (d,J=1.7Hz,1H),5.23(d,J=4.5Hz,1H),4.67(s ,4H),4.60(td,J=6.5,4.5Hz,1H),4.21(s,4H), 2.40(s,3H),1.26(d,J=6.5Hz,3H).

[0386] Example 12.3b N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]- 6-methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[ 3.3]Heptan-6-carboxamide or N-[4-(3-cyanophenyl)-5-[ 2-[(1S)-1-hydroxyethyl]-6-methyl-4-pyridyl]thiazole-2 -yl]-2-oxa-6-azaaspiro[3,3]heptane-6-carboxamide [ka] Second elution peak: Chiral LC-MS retention time: = 4.12 mins LC-MS (Method 8B): Rt2.74 min; MS m / z462.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),7.84 (t,J=1.6Hz,1H),7.82(dt,J=7.8,1.6Hz,1H),7 .74(dt,J=7.8,1.6Hz,1H),7.57(t,J=7.8Hz,1H ),7.12(d,J=1.7Hz,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=6.5 Hz, 3H).

[0387] Example 13 (3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-3,5-dimethyl-piperazine-1-carboxamide [ka] Step 1: rac-(2S,6R)-4-[[4-(3-cyanophenyl)-5-(2,6 -dimethyl-4-pyridyl)thiazole-2-yl]carbamoyl]-2,6-dimethyl -Piperazine-1-carboxylate tert-butyl 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and (2R,6S)-2,6-dimethylpiperazine-1- The title compound was prepared from tert-butyl rubonate in the same manner as in Example 6. LC-MS (Method 2B): Rt1.69 min; MS m / z547.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.39(s,1H),7.90 (d,J=1.8Hz,1H),7.83(dt,J=7.8,1.5Hz,1H),7 .72(dt,J=8.0,1.5Hz,1H),7.57(t,J=7.8Hz,1H ),6.94(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).

[0388] Step 2: (3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]-3,5-dimethylpiperazine-1-carb Xamide (2S,6R)-4-[[4-(3-cyanophenyl)- in chloroform (2 mL) 5-(2,6-dimethyl-4-pyridyl)thiazole-2-yl]carbamoyl]-2, 6-dimethylpiperazine-1-carboxylate tert-butyl (Step 1) (100 mg, In a stirred solution of 0.14 mmol, add trimethylsilyl iodide (0.08 mL, 0.58 mL) The mixture was added dropwise, and the reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was then subjected to a nitrogen flow filter. The solution was concentrated below, chloroform (2 mL) was added, and then concentrated again. 15-40% MeCN / C18 reversed-phase chromatography eluting with a water (+0.1% ammonium hydroxide modifier) ​​gradient. After purification using a solvent, the product fraction was freeze-dried to obtain the title compound as a white solid. LC-MS (Method 8B): Rt3.04 min; MS m / z447.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.16(s,1H),7.90 (t,J=1.8Hz,1H),7.82(dt,J=7.7,1.5Hz,1H),7 .71(dt,J=8.0,1.5Hz,1H),7.56(t,J=7.8Hz,1H ),6.93(s,2H),4.10(d,J=12.5Hz,2H),2.74-2. 57(m,2H),2.37(s,6H),2.35-2.27(m,2H),0.99 (d, J=6.2Hz, 6H). No 1×NH protons were observed.

[0389] The compounds of the examples shown in the table below (Table Ex13) are 3-[2-amino-5-(2,6 -dimethyl-4-pyridyl)thiazole-4-yl]benzonitrile (intermediate C) and Prepare a suitable amine in the same manner as in Example 13 (Step 1), followed by trimethyl iodide. Deprotection was performed using silyl (step 2).

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[0400] Example 14 (3R)N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl [Thiyl)-4-pyridyl]thiazole-2-yl]-3-methylpiperazine-1-carb Xamide [ka] Step 1: (2R)-4-[[4-(3-cyanophenyl)-5-[2-methyl-6-( [Lifluoromethyl)-4-pyridyl]thiazole-2-yl]carbamoyl]-2-methyl tert-butyl ru-piperazine-1-carboxylate [ka] 3-[2-amino-5-[2-methyl-6-(trifluoromethyl)-4-pyridyl] Thiazol-4-yl]benzonitrile (intermediate H) and (2R)-2-methylpiperazi The title compound was prepared from tert-butyl n-1-carboxylate in the same manner as in Example 6. Ta. LC-MS (Method 5B): Rt3.29 min; MS m / z587.5=[M+H]+ 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 1×CH3 signal was observed.

[0401] Step 2: (3R)N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trif Luoromethyl)-4-pyridyl]thiazol-2-yl]-3-methylpiperazine-1 -Carboxamide (2R)-4-[[4-(3-cyanophenyl)-5-[2 -methyl-6-(trifluoromethyl)-4-pyridyl]thiazole-2-yl]carb [Moyl]-2-methylpiperazine-1-carboxylate tert-butyl (Step 1) (83 Add TFA (0.71 mL, 9.27 mmol) to a solution of (mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 1 hour. HCl (20 mL) and 1 M NaOH were added. (Aqueous solution) (20 mL) was added, and the layers were separated. The aqueous layer was extracted with phosphate (4 × 15 mL). The combined organic extracts were then dried with Na2SO4 and concentrated under vacuum to obtain a yellow oily substance. The crude product is mixed with 10-30% MeCN / water (+0.1% ammonium hydroxide regulator). The title compound was purified by C18 reverse-phase chromatography, yielding a white solid. I obtained it. LC-MS (Method 8B): Rt4.37 min; MS m / z487.2=[M+H]+ ¹H NMR (500 MHz, methanol-d4) δ 7.92 (s, ¹H), 7.72 (t,J=9.1Hz,2H),7.52(t,J=7.8Hz,1H),7.44(s ,1H),7.36(s,1H),4.14(d,J=12.9Hz,2H),3.07 -2.95(m,2H),2.84-2.76(m,2H),2.64(t,J=11. 9Hz,1H),2.55(s,3H),1.14(d,J=6.4Hz,3H).2× No NH protons were observed.

[0402] Example 14.1 rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(diflu Oromethyl)-6-methyl-4-pyridyl]thiazole-2-yl]-3,4,4a,5 ,7,7a-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-ca Ruboxamide 2,2,2-trifluoroacetate [ka] Step 1: rac-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-[2 -(difluoromethyl)-6-methyl-4-pyridyl]thiazole-2-yl]carbamate [Il]-2,3,4a,5,7,7a-Hexahydropyrrolo[3,4-b][1,4]o tert-butyl xazine-4-carboxylate [ka] 3-[2-amino-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thio Azole-4-yl]benzonitrile (intermediate G) and rac-(4aS,7aS)-3 ,4a,5,6,7,7a-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxy The title compound was prepared from tert-butyl sazin-4-carboxylate in the same manner as in Example 6. It was made. LC-MS (Method 2B): Rt1.49 min; MS m / z597.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.61(s,1H),7.91 (s,1H),7.87(d,J=7.8Hz,1H),7.78-7.72(m,1H ),7.60(t,J=7.8Hz,1H),7.41(s,1H),7.22(s,1 H),6.84(t,J=54.9Hz,1H),4.21(p,J=7.1,6.6H z,1H),4.14(d,J=12.7Hz,1H),4.08-3.97(m,1H ),3.78-3.60(m,2H),3.55(ddd,J=9.3,7.2,3.7 Hz,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).

[0403] Step 2: rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2- (Difluoromethyl)-6-methyl-4-pyridyl]thiazole-2-yl]-3,4, 4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine -6-Carboxamide 2,2,2-trifluoroacetate rac-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-[2-(di Fluoromethyl)-6-methyl-4-pyridyl]thiazole-2-yl]carbamoyl] -2,3,4a,5,7,7a-Hexahydropyrrolo[3,4-b][1,4]oxadi From tern-4-carboxylate tert-butyl (Step 1) and TFA, Step 2 of Example 14 and The title compound was prepared in the same manner. LC-MS (Method 8B): Rt2.35 min; MS m / z497.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.72(s,1H),9.00 (s,2H),7.93-7.86(m,2H),7.74(d,J=7.9Hz,1H ),7.60(t,J=7.8Hz,1H),7.38(s,1H),7.22(s,1 H),6.85(t,J=54.9Hz,1H),4.23-3.97(m,3H),3 .80-3.59(m,2H),3.46(dd,J=10.9,7.3Hz,1H), 3.27-3.12(m,3H),2.97(t,J=11.0Hz,1H).Replaceable No protons were observed.

[0404] Example 14.2 rac-(4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(diflu Oromethyl)-6-methyl-4-pyridyl]thiazole-2-yl]-3,4,4a,5 ,7,7a-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-ca Ruboxamide 2,2,2-trifluoroacetate [ka] Step 1: rac-(4aS,7aR)-6-[[4-(3-cyanophenyl)-5-[2 -(difluoromethyl)-6-methyl-4-pyridyl]thiazole-2-yl]carbamate [Il]-2,3,4a,5,7,7a-Hexahydropyrrolo[3,4-b][1,4]o tert-butyl xazine-4-carboxylate [ka] 3-[2-amino-5-[2-(difluoromethyl)-6-methyl-4-pyridyl]thio Azole-4-yl]benzonitrile (intermediate G) and rac-(4aS,7aR)-3 ,4a,5,6,7,7a-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxy The title compound was prepared from tert-butyl sazin-4-carboxylate in the same manner as in Example 6. It was made. LC-MS (Method 2B): Rt1.48 min; MS m / z597.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.23(s,1H),7.91 (d,J=1.7Hz,1H),7.86(dt,J=7.7,1.4Hz,1H),7 .74(dt,J=7.9,1.5Hz,1H),7.59(t,J=7.8Hz,1H ),7.39(s,1H),7.22(d,J=1.6Hz,1H),6.85(t,J =54.9Hz,1H),4.44(s,1H),3.99(s,1H),3.86(s ,2H),3.75-3.41(m,5H),3.05(d,J=59.6Hz,1H) ,2.49(s,3H),1.44(s,9H).

[0405] Step 2: rac-(4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2- (Difluoromethyl)-6-methyl-4-pyridyl]thiazole-2-yl]-3,4, 4a,5,7,7a-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine -6-Carboxamide 2,2,2-trifluoroacetate rac-(4aS,7aR)-6-[[4-(3-cyanophenyl)-5-[2-(di Fluoromethyl)-6-methyl-4-pyridyl]thiazole-2-yl]carbamoyl] -2,3,4a,5,7,7a-Hexahydropyrrolo[3,4-b][1,4]oxadi From tern-4-carboxylate tert-butyl (Step 1) and TFA, Step 2 of Example 14 and The title compound was prepared in the same manner. LC-MS (Method 8B): Rt2.73 min; MS m / z467.1=[M+H]+ ¹H NMR (500 MHz, methanol-d4) δ 7.94 (t, J=1.7 Hz, 1H),7.74(ddt,J=8.2,6.9,1.4Hz,2H),7.53(t, J=7.8Hz,1H),7.37(s,1H),7.33(s,1H),6.63(t ,J=55.2Hz,1H),4.45(s,1H),4.15-4.04(m,2H) ,4.00(t,J=9.4Hz,1H),3.95-3.80(m,2H),3.78 (s,2H),3.51-3.42(m,1H),3.24(dt,J=12.6,1. (5Hz, 1H), 2.55(s, 3H). No exchangeable protons were observed.

[0406] Example 14.3 rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl [Thi-4-pyridyl)thiazole-2-yl]-3,4,4a,5,7,7a-hexa-yl Dro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2, 2-trifluoroacetate [ka] Step 1: rac-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-(2 ,6-dimethyl-4-pyridyl)thiazole-2-yl]carbamoyl]-2,3,4a ,5,7,7a-Hexahydropyrrolo[3,4-b][1,4]oxazine-4-carb tert-butyl phosphate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and rac-(4aS,7aS)-3,4a,5,6,7, 7a-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carbone The title compound was prepared from tert-butyl acid in the same manner as in Example 6. LC-MS (Method 3B): Rt1.70 min; MS m / z559.4=[MH]+ 1H NMR(500MHz,DMSO-d6)δ 11.51(s,1H),7.89 (t,J=1.6Hz,1H),7.83(dt,J=7.8,1.6Hz,1H),7 .73-7.69(m,1H),7.57(t,J=7.8Hz,1H),6.94(s ,2H),4.20(dd,J=10.1,6.5Hz,1H),4.13(d,J=1 2.7Hz, 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),1.4 6-1.37 (m, 9H).

[0407] Step 2: rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2, 6-dimethyl-4-pyridyl)thiazole-2-yl]-3,4,4a,5,7,7a- Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide 2,2,2-trifluoroacetate rac-(4aS,7aS)-6-[[4-(3-cyanophenyl)-5-(2,6- Dimethyl-4-pyridyl)thiazole-2-yl]carbamoyl]-2,3,4a,5, 7,7a-Hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylic acid t From ert-butyl (Step 1) and TFA, the title compound was prepared in the same manner as in Step 2 of Example 14. I prepared the item. LC-MS (Method 8A): Rt1.76 min; MS m / z461.1=[M+H]+ 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=7.8Hz,1H),7 .46(s,2H),4.30(dd,J=11.8,7.1Hz,1H),4.18( ddd,J=11.8,3.7,1.5Hz,1H),4.06(br d,J=12. 9Hz,1H),3.87(td,J=11.8,3.2Hz,1H),3.79(dd d,J=11.2,9.6,7.4Hz,1H),3.57(dd,J=11.2,7. 4Hz,1H),3.46(t,J=11.8Hz,1H),3.29-3.21(m, 2H),3.13(t,J=11.2Hz,1H),2.61(s,6H).Replaceable No protons were observed.

[0408] Example 14.4 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-2-cyclopropyl-piperazine-1-carboxamide [ka] Step 1: 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl )Thiazol-2-yl]carbamoyl]-3-cyclopropyl-piperazine-1-cal tert-butyl benzoate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and 3-cyclopropyl-piperazine-1-carboxylic acid te The title compound was prepared from rt-butyl in the same manner as in Example 4. LC-MS (Method 2.5A): Rt0.80 min; MS m / z559.3=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.21(s,1H),7.88 (t,J=1.8Hz,1H),7.82(dt,J=7.7,1.5Hz,1H),7 .70(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8 Hz,1H),6.92(s,2H),4.10-3.92(m,3H),3.71-3 .61(m,1H),3.25-3.15(m,1H),3.07-2.80(m,2H ),2.36(s,6H),1.42(s,9H),1.25-1.19(m,1H), 0.54-0.38 (m, 4H).

[0409] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) Thiazol-2-yl]-2-cyclopropyl-piperazine-1-carboxamide 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thia [Zol-2-yl]carbamoyl]-3-cyclopropyl-piperazine-1-carboxylic acid From tert-butyl (Step 1) and TFA, the title was formed in the same manner as in Step 2 of Example 14. A mixture was prepared. LC-MS (Method 7B): Rt2.80 min; MS m / z459.4=[M+H]+ ¹H NMR (500 MHz, methanol-d4) δ 7.90 (t, J=1.7 Hz, 1H),7.71(dt,J=8.0,1.5Hz,1H),7.69(dt,J=7. 8,1.4Hz,1H),7.49(dd,J=7.8,7.8Hz,1H),7.00 (s,2H),4.00-3.94(m,1H),3.49(dd,J=10.3,3. 8Hz,1H),3.38(td,J=13.0,3.2Hz,1H),3.13-3. 09(m,1H),3.08-3.02(m,1H),2.93-2.88(m,1H) ,2.73(td,J=12.6,3.6Hz,1H),2.43(s,6H),1.6 8-1.60(m,1H),0.67-0.60(m,1H),0.56-0.49(m ,2H),0.40-0.34(m,1H). No 2×NH protons were observed.

[0410] Example 14.5 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide [ka] Step 1: 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl )Thiazol-2-yl]carbamoyl]-3-(cyclopropylmethyl)piperazine- 1-Tert-butyl carboxylate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and 3-(cyclopropylmethyl)piperazine-1-carb The title compound was prepared from tert-butyl phosphate in the same manner as in Example 4. LC-MS (Method 2A): Rt0.87 min; MS m / z573.3=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.28(s,1H),7.88 (t,J=1.7Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7 .71(dt,J=8.0,1.4Hz,1H),7.56(dd,J=7.8,7.8 Hz,1H),6.92(s,2H),4.44-4.36(m,1H),4.03-3 .82(m,3H),3.08-2.95(m,2H),2.35(s,6H),1.4 2(s,9H),0.84(dd,J=6.6,2.4Hz,2H),0.70-0.6 2(m,1H),0.44-0.33(m,2H),0.13-0.03(m,2H). No 1×CH protons were observed.

[0411] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) [Thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxami Do 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thia [Zol-2-yl]carbamoyl]-3-(cyclopropylmethyl)piperazine-1- From tert-butyl rubonate (Step 1) and TFA, in the same manner as in Step 2 of Example 14 The title compound was prepared. LC-MS (Method 7B): Rt3.14 min; MS m / z473.4=[M+H]+ 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=7.8,7.8Hz,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=13.0,4.2Hz,1H), 2.71(td,J=12.6,3.7Hz,1H),2.43(s,6H),1.79 -1.62(m,2H),0.74-0.65(m,1H),0.48-0.42(m, No 2×NH protons were observed (2H), 0.17-0.10(m,2H).

[0412] Example 14.6 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,3-dimethylpiperazine-1-carboxamide [ka] Step 1: 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl )Thiazol-2-yl]carbamoyl]-2,2-dimethyl-piperazine-1-carb tert-butyl phosphate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and 2,2-dimethylpiperazine-1-carboxylic acid tert -The title compound was prepared from butyl in the same manner as in Example 6. LC-MS (Method 2B): Rt1.62 min; MS m / z547.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 10.97(v br s,1H) ,7.89(t,J=1.8Hz,1H),7.82(dt,J=7.7,1.5Hz, 1H),7.71(dt,J=7.9,1.5Hz,1H),7.56(t,J=7.8 Hz,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),1.4 2(d,J=2.9Hz,9H), 1.34(s,6H).

[0413] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) Thiazol-2-yl]-2,2-dimethylpiperazine-1-carboxamide 4-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thia [Zol-2-yl]carbamoyl]-2,2-dimethyl-piperazine-1-carboxylic acid From ert-butyl (Step 1) and TFA, the title compound was prepared in the same manner as in Step 2 of Example 14. I prepared the item. LC-MS (Method 8B): Rt2.82 min; MS m / z447.1=[M+H]+ ¹H NMR (500MHz, methanol-d4) δ 7.92 (t, J=1.7Hz, 1 H),7.73(dt,J=8.0,1.5Hz,1H),7.70(dt,J=7.7 ,1.4Hz,1H),7.51(t,J=7.8Hz,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). 2×NH protons were not observed. It was.

[0414] Example 14.7 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carb Xamide [ka] Step 1: 9-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl ) Thiazol-2-yl]carbamoyl]-4-oxa-1,9-diazaspiro[5.5 tert-butyl undecane-1-carboxylate [ka] 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl] Benzonitrile (intermediate C) and 4-oxa-1,9-diazaspiro[5.5]undeca The title compound was prepared from tert-butyl n-1-carboxylate in the same manner as in Example 4. Ta. LC-MS (Method 2A): Rt0.74 min; MS m / z589.2=[M+H]+ 1H NMR(500MHz,CDCl3)δ 8.11(s,1H),7.76(t, J=1.6Hz,1H),7.69(dt,J=7.6,1.4Hz,1H),7.55 (dt,J=7.9,1.5Hz,1H),7.48(t,J=7.8Hz,1H),6 .90(s,2H),3.91(dt,J=11.6,5.1Hz,2H),3.77( t,J=5.3Hz,2H),3.60(s,2H),3.54(t,J=5.3Hz, 2H),3.49-3.41(m,2H),2.60(ddd,J=14.0,9.6, 4.5Hz,2H),2.54(s,6H),1.84-1.74(m,2H),1.4 5(s,9H).

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

[0416] Example 16 N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl) [thiazole-2-yl]-1-imino-1-oxo-1,4-thiadinane-4-carboxy Thamid [ka] 3-[2-amino-5-(2-methoxy-6-methyl-4- Pyridyl)thiazole-4-yl]benzonitrile (intermediate K) (75 mg, 0.23 mg) A solution of (mol) and CDI (75 mg, 0.47 mmol) with DIPEA (0.12 mL) Add 0.70 mmol of 1-imino-1 and stir the reaction mixture overnight at 50°C. Add 4-thiadinane 1-oxide (47 mg, 0.35 mmol) and further incubate at 50°C. Stirring continued for 1 hour. The resulting mixture was then mixed with 5-20% MeCN / water (+0.1% hydroxide). Purified by C18 reverse-phase chromatography using a gradient of ammonium compounds, and then presented. The compound in question was obtained as a white solid. LC-MS (Method 8B): Rt3.55 min; MS m / z483.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.53(s,1H),7.91 (s,1H),7.84(d,J=7.7Hz,1H),7.72(d,J=8.0Hz ,1H),7.58(t,J=7.8Hz,1H),6.74(s,1H),6.42( s,1H),4.11(d,J=14.4Hz,2H),3.84(s,1H),3.8 1(s,3H),3.78-3.68(m,2H),3.08(d,J=5.4Hz,4 H), 2.34(s,3H).

[0417] The compounds of the examples shown in the table below (Table Ex16) are used as appropriate starting compounds as shown in the table. The following was prepared from the amine in the same manner as in Example 16.

[0418] JPEG2026086419000153.jpg240170

[0419] JPEG2026086419000154.jpg166170

[0420] JPEG2026086419000155.jpg225170

[0421] JPEG2026086419000156.jpg141170

[0422] Example 17 N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxide-pyridine] -1-ium-4-yl)thiazole-2-yl]-2-oxa-6-azaspiro[3. 3] Heptane-6-carboxamide [ka] Step 1: 3-[2-amino-5-(2,6-dimethyl-1-oxide-pyridine-1-I [Um-4-yl)thiazole-4-yl]benzonitrile [ka] mCPBA (110 mg, 0.49 mmol) in DCM (2 mL) 3-[2-A Mino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl]benzonitrile (Intermediate C) (100 mg, 0.33 mmol) was added to a suspension at 0°C. This reaction mixture The mixture was heated to room temperature and stirred for 16 hours. Furthermore, mCPBA (73 mg, 0.33 mmol) was added. Add the following and continue stirring for 1 hour. Dilute the resulting solution with DCM (10 mL) and add saturated NaH The material was washed with CO3 solution (2 × 20 mL). The organic material was dried with Na2SO4 and concentrated under vacuum. It was reduced to obtain a red oily substance. The oily substance was dry-loaded onto silica and 0-5% MeOH / D The solid is obtained by purifying silica chromatography using a CM gradient, and this is then converted to Et2 Tritulate with O, filter, and wash with Et2O (3 × 2 mL) to obtain the title compound in yellow. It was obtained as a solid. LC-MS (Method 5A): Rt1.86 min; MS m / z323.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.86(d,J=1.9Hz,1 H),7.77(d,J=7.7Hz,1H),7.69(d,J=7.9Hz,1H) ,7.55-7.49(m,1H),7.46-7.39(m,2H),7.14(s, 2H), 2.27(s,6H).

[0423] Step 2: N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxide- Pyridine-1-ium-4-yl)thiazole-2-yl]-2-oxa-6-azaspir [3.3]heptan-6-carboxamide 3-[2-amino-5-(2,6-dimethyl-1-oxide-pyridine-1-ium- 4-yl)thiazole-4-yl]benzonitrile (Step 1) and 2-oxa-6-aza The title compound was prepared from spiro[3.3]heptane in the same manner as in Example 6. LC-MS (Method 8A): Rt2.53 min; MS m / z448.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.92(s,1H),7.78( d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.53(t, J=7.8Hz,1H),7.20(s,2H),4.67(s,4H),4.13(s ,4H),2.29(s,6H).1×NH protons were not observed.

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

[0425] Example 19 N-[5-(2-acetamido-6-methyl-4-pyridyl)-4-(3-cyanophenic acid [3.3]thiazole-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-ca Ruboxamide [ka] N-[4-[2-amino-4-(3-cyanophenyl)thiazole-5-yl]-6- Methyl-2-pyridyl]acetamide (intermediate KG) and 2-oxa-6-azaspiro[ 3.3] The title compound was prepared from heptane in the same manner as in Example 6. LC-MS (Method 8B): Rt2.89 min; MS m / z475.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.35(s,1H),10.4 9(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=7.8,1.5H z,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),2.0 2(s,3H).

[0426] Example 20 N-[5-[2-(acetamidomethyl)-6-methyl-4-pyridyl]-4-(3-Cylamidemethyl) Anophenyl)thiazole-2-yl]-2-oxa-6-azaspiro[3.3]hepta n-6-carboxamide [ka] N-[[4-[2-amino-4-(3-cyanophenyl)thiazole-5-yl]-6 -methyl-2-pyridyl]methyl]acetamide (intermediate KH) and 2-oxa-6-acetamide The title compound was prepared from zaspiro[3.3]heptane in the same manner as in Example 6. LC-MS (Method 8B: Rt2.59 min; MS m / z489.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.37(s,1H),8.30 (t,J=6.0Hz,1H),7.88-7.81(m,2H),7.68(dt,J =8.0,1.5Hz,1H),7.55(t,J=7.8Hz,1H),7.04(s ,1H),6.87(s,1H),4.68(s,4H),4.23-4.19(m,6 Contains H), 2.40(s,3H), 1.76(s,3H), and 1% Et2O.

[0427] Example 21 N-[4-(3-cyanophenyl)-5-[2-(methoxymethyl)-6-methyl-4- Pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane- 6-Carboxamide [ka] 3-[2-amino-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thia Zole-4-yl]benzonitrile (intermediate KI) and 2-oxa-6-azaspiro[3 .3] The title compound was prepared from heptane in the same manner as in Example 6. LC-MS (Method 8B): Rt3.30 min; MS m / z462.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.38(s,1H),7.87 (s,1H),7.83(dt,J=7.7,1.5Hz,1H),7.73(dt,J =8.0,1.5Hz,1H),7.58(t,J=7.8Hz,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).

[0428] Example 22 N-[4-(3-cyanophenyl)-5-[2-(1-methoxyethyl)-6-methyl- 4-Pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3.3]hepta n-6-carboxamide [ka] 3-[2-amino-5-[2-(methoxymethyl)-6-methyl-4-pyridyl]thia Zole-4-yl]benzonitrile (intermediate P) and 2-oxa-6-azaspiro[3. 3] The title compound was prepared from heptane in the same manner as in Example 6. LC-MS (Method 8B): Rt3.92 min; MS m / z476.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.45(s,1H),7.91 -7.87(m,2H),7.83(dt,J=7.9,1.5Hz,1H),7.67 -7.63(m,1H),7.21(d,J=1.6Hz,1H),6.95(d,J= 1.6Hz,1H),4.74(s,4H),4.33-4.20(m,5H),3.1 0(s,3H),2.51(s,3H),1.28(d,J=6.5Hz,3H).

[0429] Example 23 N-[5-[2-chloro-6-(1-hydroxy-1-methylethyl)-4-pyridyl ]-4-(3-cyanophenyl)thiazole-2-yl]-2-oxa-6-azaspirol [3.3] Heptane-6-carboxamide [ka] 3-[2-amino-5-[2-chloro-6-(1-hydroxy-1-methyl-ethyl) -4-pyridyl]thiazole-4-yl]benzonitrile (intermediate Q) and 2-oxa- The title compound was prepared from 6-azaspiro[3.3]heptane in the same manner as in Example 6. . LC-MS (Method 8B): Rt3.40 min; MS m / z496.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.47(s,1H),7.88 (t,J=1.6Hz,1H),7.86(dt,J=7.8,1.6Hz,1H),7 .76(dt,J=7.9,1.6Hz,1H),7.61(apr t,J=7.8H z,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),1.3 6(s,6H).

[0430] Example 24 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6 -methyl-4-pyridyl]thiazole-2-yl]-4-methyl-piperidine-1-cal Boxamide [ka] Step 1: N-[5-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]- [6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazole-2-yl]-4 -Cyano-4-methyl-piperidine-1-carboxamide [ka] 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymeth [L]-6-methyl-4-pyridyl]thiazole-4-yl]benzonitrile (intermediate I) And from 4-methylpiperidine-4-carbonitride hydrochloride, in the same manner as in Example 6, Table The compound in question was prepared. LC-MS (Method 3B): Rt2.34 min; MS m / z587.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.35(s,1H),7.85 (s,1H),7.82(d,J=7.8Hz,1H),7.72(d,J=7.9Hz ,1H),7.56(t,J=7.8Hz,1H),7.12(s,1H),7.01( s,1H),4.62(s,2H),4.22(d,J=14.0Hz,2H),3.0 3(t,J=12.9Hz,2H),2.42(s,3H),1.92(d,J=13. 6Hz,2H),1.58-1.49(m,2H),1.37(s,3H),0.77( s,9H),-0.02(s,6H).

[0431] Step 2: 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymeth [Lu)-6-methyl-4-pyridyl]thiazole-2-yl]-4-methyl-piperidine- 1-Carboxamide N-[5-[2-[[tert-butyl(dimethyl)silyl in THF (6.4mL) ]oxymethyl]-6-methyl-4-pyridyl]-4-(3-cyanophenyl)thiazo [Lu-2-yl]-4-cyano-4-methylpiperidine-1-carboxamide (Step 1) (188 mg, 0.32 mmol) solution with TBAF (0.64 mL, 0.64 mmol) ) was added and the reaction mixture was stirred at room temperature for 90 minutes. Additional TBAF (0.64 mL, Add 0.64 mmol of EtOA and continue stirring for another 2.5 hours. The resulting mixture was then mixed with EtOA. The mixture was diluted with c (50 mL) and water (50 mL). The layers were separated, and the aqueous phase was divided into alkyl (40 mL). Further extraction was performed using L). The combined organic extracts were washed with brine and dried with MgSO4. The solution was concentrated under vacuum. Silica chromatography was used to elute the solution with 0-30% MeOH / Depositphotos. The solid was purified using a fertilizer to obtain a yellow solid. The solid was then treated with 10-35% MeCN / water (+0.1%) Further purification is performed by C18 reverse-phase chromatography, which elutes the ammonium hydroxide at a gradient. The compound was prepared to obtain a solid, which was triturated with Et2O and filtered to obtain the title compound as a white solid. It was obtained as such. LC-MS (Method 8B): Rt3.75 min; MS m / z473.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.32(s,1H),7.89 (s,1H),7.82(d,J=7.7Hz,1H),7.72(d,J=7.8Hz ,1H),7.56(t,J=7.8Hz,1H),7.14(s,1H),6.98( s,1H),5.33(t,J=5.9Hz,1H),4.46(d,J=5.9Hz, 2H),4.23(d,J=14.0Hz,2H),3.02(t,J=13.1Hz, 2H),2.37(s,3H),1.92(d,J=13.6Hz,2H),1.52( dt,J=13.4,7.1Hz,2H),1.37(s,3H).

[0432] Example 26 N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-(triflu Oromethyl)-4-pyridyl]thiazole-2-yl]-2-oxa-6-azapiro[ 3.3] Heptane-6-carboxamide [ka] 3-[2-amino-5-[2-[[tert-butyl(dimethyl)silyl]oxymeth [L]-6-(trifluoromethyl)-4-pyridyl]thiazole-4-yl]benzonitrate From lyl (intermediate IA) and 2-oxa-6-azaspiro[3.3]heptane, Example 9 The title compound was prepared in the same manner. LC-MS (Method 8B): Rt3.49 min; MS m / z502.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.52(s,1H),7.92 (t,J=1.8Hz,1H),7.88(dt,J=7.8,1.4Hz,1H),7 .76(dt,J=8.0,1.4Hz,1H),7.65(d,J=1.5Hz,1H ),7.61(t,J=7.8Hz,1H),7.39(d,J=1.6Hz,1H), 5.63(t,J=5.9Hz,1H),4.68(s,4H),4.60(d,J=5 0.9Hz, 2H), 4.23(s, 4H).

[0433] Example 27 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl Thiazol-2-yl-3-methylpyrrolidine-1-carboxamide [ka] CDI (1.16 g, 7.18 mmol) and DIPEA (1.88 mL, 10.77 mmol) in DMA (11 mL) 3-[2-amino-5-(2,6-dimethyl-4 -Pyridyl)thiazole-4-yl]benzonitrile (intermediate C) (1.1g, 3.5g) The mixture of mmol was added to the stirred solution, and this solution was heated overnight at 50°C. 3-methylpyrrolidine -3-Carbonitrile hydrochloride (1.00g, 6.82 mmol) and additional DIPEA ( Add 1.88 mL (10.77 mmol) and stir the solution at 50°C for 30 minutes. The mixture was cooled to room temperature and diluted with alkyl (150 mL). The mixture was then diluted to 90%. Wash with an aqueous solution of 100 mL and a 50% brine aqueous solution (3 × 100 mL), then MgS The silica was dried with O4 and concentrated under vacuum. It eluted with a 1-2% MeOH / DCM gradient. Purification by chromatography yielded a yellow solid. MeOH (10 mL) was added. A white solid was obtained, which was recovered by filtration, and MeOH (2 mL) and Et2O (20 mL) were added. The compound was washed and dried to obtain the title compound as a white solid. LC-MS (Method 8B): Rt3.03 min; MS m / z443.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.24(s,1H),7.89 (t,J=1.8Hz,1H),7.82(dt,J=7.7,1.4Hz,1H),7 .71(dt,J=8.0,1.5Hz,1H),7.56(t,J=7.8Hz,1H ),6.94(s,2H),3.96-3.86(m,1H),3.64(d,J=34 .3Hz,2H),3.42(d,J=11.1Hz,1H),2.43-2.38(m ,1H),2.36(s,6H),2.14-2.02(m,1H),1.47(s,3 H).

[0434] Examples 27a and 27b Racemic 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-3-methylpyrrolidine-1-carboxamide ( Example 27) was dissolved in EtOH / DCM (4:1) at a concentration of 50 mg / mL and prepared by SFC. The fractions of each enantiomer were combined and evaporated until almost dry, then processed using DCM. Then transfer to the final container, remove DCM under compressed air flow at 35°C, and then 35°C and 5mb It was stored in a vacuum oven until it reached a certain weight.

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

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

[0437] Example 27a (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]-3-methylpyrrolidine-1-carboxamide [ka] First elution peak: Chiral LC-MS retention time: = 7.05 min LC-MS (Method 8B): Rt3.04 min; MS m / z443.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.24(s,1H),7.89 (t,J=1.6Hz,1H),7.82(dt,J=7.7,1.6Hz,1H),7 .71(dt,J=8.0,1.6Hz,1H),7.56(apr t,J=7.8H z,1H),6.93(s,2H),3.98-3.86(m,1H),3.72-3. 63(m,1H),3.64-3.55(m,1H),3.46-3.38(m,1H) ,2.43-2.36(m,1H),2.36(s,6H),2.12-2.03(m, 1H), 1.47(s,3H).

[0438] Example 27b (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]-3-methylpyrrolidine-1-carboxamide [ka] Second elution peak: Chiral LC-MS retention time: = 8.59 min LC-MS (Method 8B): Rt2.92 min; MS m / z443.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.24(s,1H),7.89 (t,J=1.6Hz,1H),7.82(dt,J=7.7,1.6Hz,1H),7 .71(dt,J=8.0,1.6Hz,1H),7.56(apr t,J=7.8H z,1H),6.93(s,2H),3.98-3.87(m,1H),3.71-3. 63(m,1H),3.64-3.55(m,1H),3.46-3.37(m,1H) ,2.43-2.38(m,1H),2.36(s,6H),2.13-2.02(m, 1H), 1.47(s,3H).

[0439] Further samples of Example 27b were obtained under the following conditions: Racemic 3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-3-methylpyrrolidine-1-carboxamide ( Example 27) was dissolved in EtOH / DCM (4:1) at a concentration of 25 mg / mL and prepared by SFC. The solution was purified. The fractions of each enantiomer were combined and evaporated until almost dry. The solid is transferred to the final container using DCM, the DCM is removed under a stream of compressed air at 35°C, and then 35 The material was stored in a vacuum oven at °C and 5 mbar until it reached a certain weight. The material was ultrasonically treated. The solid was tritulate in Et2O / MeOH below, and the resulting concentrated suspension was filtered. Wash with Et2O / MeOH, vacuum dry on the sintered material, then bake overnight in a vacuum furnace at 50°C. Further drying yielded the title compound as a cream-colored solid.

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

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

[0442] Second elution peak: Chiral LC-MS retention time: = 9.73 min LC-MS (Method 8A): Rt2.37 min; MS m / z443.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.23(br s,1H),7 .89(br t,J=1.5Hz,1H),7.82(br dt,J=7.7,1. 5Hz,1H),7.71(br dt,J=8.0,1.5Hz,1H),7.56( apr t,J=7.8Hz,1H),6.93(s,2H),3.92(br s,1 H),3.67(br s,1H),3.60(br s,1H),3.41(br d ,J=11.2Hz,1H),2.39(s,1H),2.36(s,6H),2.12 -2.03 (m, 1H), 1.47 (s, 3H).

[0443] Alternatively, Examples 27a and 27b are 3-[2-amino-5-(2,6-dimethyl-4 -Pyridyl)thiazole-4-yl]benzonitrile (intermediate C), and (3R)-3- Methylpyrrolidine-3-carbonitrili hydroiodide (intermediate U) or (3S)-3- From methylpyrrolidine-3-carbonitride hydroiodide (intermediate UA), Example 6 and It was prepared in the same manner.

[0444] Example 28 N-[5-[2,6-bis(triduteriomethyl)-4-pyridyl]-4 -(3-cyanophenyl)thiazole-2-yl]-4-cyano-4-methyl-piperidi n-1-carboxamide [ka] 3-[2-amino-5-[2,6-bis(triduteriomethyl)-4-pyridyl] [Thiazol-4-yl]benzonitrile (intermediate N) (465 mg, 1.49 mmol) And CDI (483 mg, 2.98 mmol) was administered under nitrogen in a sealed tube using anhydrous DMA (7. It was dissolved in 5 mL. DIPEA (778 μL, 4.47 mmol) was added, and the resulting solution was dissolved. The solution was stirred at 50°C for 17 hours. 4-Methylpiperidine-4-Carbonitrile hydrochloride (4 78 mg (2.98 mmol) and additional DIPEA (778 μL, 4.47 mmol) Add and stir the mixture at 50°C for 1 hour. After the mixture has cooled to room temperature, dimethyl Dilute with (80 mL) to make 80% brine (80 mL) and 20% brine (2 x 80 mL). The layers were then washed continuously with 50% brine (80 mL). The organic layer was dried with Na2SO4. The solution was filtered and concentrated under vacuum to obtain the crude substance as a pale yellow foam. 1-2% MeOH / DC The glass was purified by silica chromatography using a gradient of M to obtain a clear, straw-colored glass. This is then tritulated with Et2O and azeotrope-dilated to obtain the title compound as a cream-colored solid. I obtained it. LC-MS (Method 8B): Rt3.08 min; MS m / z463.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.31(s,1H),7.89 (t,J=1.6Hz,1H),7.82(dt,J=7.8,1.6Hz,1H),7 .70(dt,J=8.0,1.6Hz,1H),7.56(apr t,J=7.8H z,1H),6.93(s,2H),4.22(d,J=13.9Hz,2H),3.0 3(t,J=13.3Hz,2H),1.92(d,J=13.9Hz,2H),1.5 3(td,J=13.3,4.0Hz,2H),1.37(s,3H).

[0445] Preparation of intermediates Intermediate A 3-(2-aminothiazole-4-yl)benzonitrile hydrobromide [ka] See below for example 15 in the International Patent Publication No. 2012 / 100734, brochure, page 24. It was prepared according to the procedure of Wang, Y. and Yang, T. described in Step 2.

[0446] 3-(2-bromoacetyl)benzonitrile (5g, 22g) in EtOH (50mL). Add thiourea (1.87 g, 24.55 mmol) to a flask containing 32 mmol. In addition, this mixture was stirred at room temperature for 30 minutes. The volume of the solvent was reduced by approximately 50% under reduced pressure. A suspension was formed. The suspension was sonicated, filtered, and dried to obtain the title compound as a colorless solid. I obtained something. LC-MS (Method 3B): Rt1.62 min; MS m / z202.3=[M+H]+ 11 H NMR(500MHz,DMSO-d6)δ 8.22(t,J=1.8Hz, 1H),8.08(d,J=8.1Hz,1H),7.82(d,J=7.7Hz,1H ), 7.65(t,J=7.9Hz,1H),7.37(s,1H).NH2 protons are Not observed.

[0447] 3-(2-aminothiazole-4-yl)benzonitrile is also prepared as follows: Re: Under nitrogen, pyridine (50 mL) contains thiourea (2.04 g, 26.78 mmol). In a flask containing 3-(2-bromoacetyl)benzonitrile (3.0 g, 13.3g) mmol was added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was then mixed with water (100 ml). Diluted in mL and extracted with ethyl acetate (2 × 100 mL). The combined organic extract was then mixed. Washed with 50 mL of water, dried with MgSO4, and concentrated under vacuum. The crude product was 0 Purified by silica chromatography using ~100% ethyl acetate / dimethyl chloride. The resulting solid was recrystallized from SiO2, and 3-(2-aminothiazole-4-yl)be Nzonitrile was obtained as a pale yellow solid. LC-MS (Method 7A): Rt1.75 min; MS m / z202.1=[M+H]+ 1 H NMR(400MHz,DMSO-d6)δ 8.20(t,J=1.5Hz,1 H),8.11(dt,J=7.9,1.4Hz,1H),7.70(dt,J=7.7 ,1.3Hz,1H),7.58(t,J=7.6Hz,1H),7.26(s,1H) ,7.14(s,2H).

[0448] Intermediate B 3-(2-amino-5-bromo-thiazole-4-yl)benzonitrile [ka] The following is from the International Patent Publication No. 2012 / 100734, brochure, pages 24-25, implementation. It was prepared according to the procedure of Wang, Y. and Yang, T. described in Step 3 of Example 15.

[0449] 3-(2-aminothiazole-4-yl)benzonitrile bromide in THF (40 mL) NBS (1.97g, 1) in a solution of hydrochloride (intermediate A) (2.6g, 9.21mmol) Add 1.06 mmol of the solution and stir the reaction mixture at room temperature for 1 hour. The resulting mixture Diluted with HCl (60 mL) and washed with water (100 mL). The organic layer was separated and aqueous solution was used. The substance was further extracted with ethyl acetate (2 x 50 mL). The combined organic matter was dried with MgSO4. The mixture was then concentrated under vacuum to obtain an orange solid. This solid was suspended in DCM (20 mL) and filtered. The compound was then washed with DCM, dried, and obtained as an off-white solid. LC-MS (Method 3B): Rt1.64 min; MS m / z279.9 / 281.9=[M +H]+ 1 H NMR(500MHz,DMSO-d6)δ 8.16(t,J=1.7Hz,1 H),8.15(dt,J=7.9,1.7Hz,1H),7.83(d,J=7.9H z,1H),7.66(t,J=7.9Hz,1H),7.42(s,2H).

[0450] Intermediate C 3-[2-amino-5-(2,6-dimethyl-4-pyridyl)thiazole-4-yl]be Nzonitrile [ka] A solution of potassium carbonate (43.1 g, 312.34 mmol) in water (210 mL) 3-(2-amino-5-bromo-thiazole-4) in 1,4-dioxane (840 mL) -Il)benzonitrile (intermediate B) (35.0 g, 124.94 mmol) and 2,6 -dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) Add the solution of -yl)pyridine (34.95 g, 149.93 mmol) to this mixture. Deoxygenation was performed for 20 minutes by nitrogen sparging. Bis(tri-tert-butylphosphine) Add palladium(0) (6.38g, 12.49 mmol), seal the flask, and The inside of the LASCO was evacuated and filled with nitrogen (3 cycles). The reaction mixture was stirred at 80°C for 1 hour. Then, it was cooled to room temperature. The mixture was then mixed with acetylene (500 mL) and water (200 mL). The layers were separated by diluting with 20% brine (500 mL) and pure brine (2 Wash with 00 mL, dry with Na2SO4, and filter with Celite® (registered trademark). The material was filtered through a plug and eluted with siRNA (4 x 200 mL). The filtrate was then vacuum-sealed. The substance is concentrated below, and the resulting material is triturated in DCM (150 mL) by sonication. The solid was recovered by filtration, washed with DCM (3 x 50 mL), and vacuum-dried. The compound was obtained as a pale yellow solid. LC-MS (Method 2B): Rt1.26 min; MS m / z307.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 7.81(br t,J=1.5H z,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,1 H),7.50-7.36(m,2H),6.80(s,2H),2.32(s,6H) .

[0451] Intermediate D 3-[2-amino-5-(2-chloro-6-methyl-4-pyridyl)thiazole-4-I [Lu] Benzonitrile [ka] 3-(2-amino-5-bromo in monoglycerides (28.4 mL) and water (3.5 mL) -Thiazol-4-yl)benzonitrile (intermediate B) (710 mg, 2.53 mmol) ), 2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-diode Xaborolan-2-yl)pyridine (649 mg, 2.56 mmol) and cesium carbonate A solution of (1652 mg, 5.07 mmol) was degassed with nitrogen for 5 minutes. Pd(dppf) Add Cl2·CH2Cl2 (517 mg, 0.63 mmol), and the reaction mixture is prepared under nitrogen. The mixture was heated at 80°C for 1 hour. After cooling to room temperature, the resulting mixture was filtered, and the precipitate was EtO Washed with Ac (50 mL). The filtrate was divided into water (20 mL) and brine (20 mL). The organic layer was separated, dried over MgSO4, and concentrated under vacuum. The crude product was then divided into 0-50%. The title compound was purified by silica chromatography eluting with ammonium / DCM. It was obtained as a brown solid. LC-MS (Method 2A): Rt1.12 min; MS m / z327.0 / 329.0=[M +H]+ 1 H NMR(400MHz,DMSO-d6)δ 7.86-7.80(m,2H), 7.69(dt,J=7.9,1.4Hz,1H),7.60(s,2H),7.59- 7.54(m,1H),7.03-6.99(m,1H),6.92-6.89(m,1 H), 2.35 (s, 3H).

[0452] Intermediate E 4-(hydroxymethyl)piperidine-4-carbonitrile hydrochloride [ka] 4-cyano-4-(hydroxymethyl)piperidine-1-carbone in DCM (1 mL) A solution of tert-butyl phosphate (100 mg, 0.42 mmol) containing 4M HCl Add 4-dioxane (2.08 mL, 8.32 mmol) and leave this reaction mixture at room temperature. The mixture was stirred overnight. The resulting mixture was concentrated under vacuum to obtain the title compound as a colorless solid. . 1 H NMR(400MHz,DMSO-d6)δ 9.11(s,2H),5.66( t,J=5.8Hz,1H),3.52(d,J=5.8Hz,2H),3.41-3. 34(m,2H),2.90(td,J=13.1,3.0Hz,2H),2.04(d ,J=14.2Hz,2H),1.85-1.73(m,2H).

[0453] Intermediate F Piperidine-4,4-dicarbonitrile hydrochloride [ka] Step 1: 1-Benzylpiperidine-4,4-Dicarbonitrile [ka] See below for the following: Patent International Publication No. 2017 / 027684(A1), pamphlets, 56 and 5 It was prepared according to the procedures of Zahler, R. and Vath, J., as described on page 7.

[0454] K2CO3 (1132 mg, 8.19 mmol) in propanedin in DMF (5 mL) Add to a solution of Toll (0.23 mL, 3.72 mmol), and this reaction mixture is heated at 65°C. Stirred for 2 hours. Add N-benzyl-2-chloro-N- from DMF (5 mL) to this mixture. (2-chloroethyl)ethanamine hydrochloride (1.0 g, 3.72 mmol) was added, and 6 The mixture was stirred at 5°C for 16 hours. After cooling to room temperature, the reaction was quenched with ice water. The mixture was extracted with toluene (3 × 10 mL), dried with Na₂SO₄, and concentrated under vacuum. It shrunk. Silica chromatography that elutes with 10-40% HCl / petroleum ether The cruder substance was further purified to obtain the title compound as a colorless oily substance. LC-MS (Method 8B): Rt4.31 min; MS m / z226.2=[M+H]+ 1 H NMR(500MHz,CDCl3)δ 7.37-7.25(m,5H),3. 56(s,2H),2.64(s,4H),2.25(s,4H)....

Claims

1. Compounds having structural formula I shown below, or pharmaceutically acceptable salts thereof: 【Chemistry 1】 [In the formula, R ｘ methyl, CD ３ , chloro and CF ３ Selected from; R １ (1-3C)alkyl, halo, (1-3C)haloalkyl, (1-3C)haloa Lucoxy, (1-3C) Hydroxyalkyl, Cyano, Cyclopropyl, Oxetane-3 -イル、-(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 -SO ２ N(R) １Ｂ ) R １Ａ , or - (CR １Ｃ R １Ｄ ) ｑ１ -N(R) １Ｂ ) SO ２ R １Ａ Selected from (Here, q1 is 0, 1, or 2; R １Ａ and R １Ｂ These are, independently, hydrogen, (1-2C)alkyl, and (3-4C) Selected from cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl; R １Ｃ and R １Ｄ Each is independently selected from hydrogen or (1-2C) alkyl. (ru); R ２ and R ３ Both are hydrogen, or R ２ and R ３ One of them is hydrogen, and the other is f Selected from ruo, methyl, or methoxy; R ４ and R ５ Along with the nitrogen atom to which they are bonded, one or more R １０Ｃ By substituent They are linked together to form a heterocycle which may be substituted on any available carbon atoms. It is (Here, R １０Ｃ is an oxo, thioxo, halo, or cyano substituent, or formula: -[CR ７ａ R ７ｂ ] ｎ -L-Z Selected from the basis (In the formula, n is between 0 and 6; R ７ａ and R ７ｂ Each of these is independently hydrogen, fluoro, or (1-2C) alkyl. Selected from; L does not exist, or -O-, -S-, -SO-, -SO ２ -, -N(R ａ ) - -C(O)-、-C(O)O-、-OC(O)-、-C(O)N(R ａ )-、-N(R ａ )C(O)-、-N(R ａ )C(O)N(R ｂ )-、-C(S)N(R ａ )-、-N(R ａ )C(S)-,-N(R ａ ) C(S)N(R ｂ )-,-S(O) ２ N(R) ａ ) - if ha-N(R ａ ) SO ２ - is selected from (where R ａ and R ｂ Each of them is independent of water. (Selected from elemental or (1-2C) alkyl); Z is hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl Roalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heteroalkyl Krill, heterocyclyl(1-2C) alkyl, heteroaryl or heteroaryl(1 Selected from (1-6C) alkyl; Z is (1-6C) alkyl, halo, (1-6C) halo Alkyl, (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), -SO ２ N(R ｃ )R ｄ , -N(R ｃ )SO ２ R ｄ , -(CH ２ ) ｚ NR ｃ R ｄ (where z is Even if substituted with one or more substituents selected from 1, 2 or 3 or oxo often; The alkyl portion of the substituent on Z can be cyano, halo, hydroxy, amino, oxo, (1-2 C) May be further substituted with alkyl or (1-2C)alkoxy, R ｃ and R ｄ Each is independently hydrogen, (1-6C) alkyl, (1-6C) haloalkyl or ( 3-6C) Selected from cycloalkyl; Furthermore, any available N atom in the formula may be in the form of one or more R atoms, even if they are N-oxides. １０Ｎ It may also be replaced by (Here, R １０Ｎ is -S(O) ２ NH ２ is or (i)-Z １ ; (ii)-L １ａ -Z １ ; or (iii)-[CR ８ａ R ８ｂ ] １～６ -L １ｂ -Z １ Selected from (In the formula, R ２ａ and R ２ｂ Each of these is independently hydrogen, fluoro, or (1-2C) alkyl. Selected from; L １ａ は、-C(O)-、-S(O) ２ -、-C(O)O-、-C(O)N(R ａ１ ) -, -S(O) ２ N(R) ａ１ ) - or N (R ａ１ ) - Selected from (where R ａ１ teeth, (Selected from hydrogen or (1-2C) alkyl); L １ｂ It does not exist, or -O-, -S-, -SO-, -SO ２ -, -N(R ａ２ )-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)N(R ａ２ )-、- N(R ａ２ )C(O)-、-N(R ａ２ )C(O)N(R ｂ２ )-、-C(S)N(R ａ ２ )-、-N(R ａ２ )C(S)-、-N(R ａ２ )C(S)N(R ｂ２ )-、-S(O ) ２ N(R) ａ２ ) - or - N (R ａ２ ) SO ２ Selected from (where R ａ２ and R ｂ２ Each of these elements is independently selected from hydrogen or (1-2C) alkyl groups; Z １ (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heteroalkyl Ryl, heteroaryl, (3-6C)cycloalkyl, (1-2C)alkyl, aryl 1-2C) alkyl, heterocyclyl (1-2C) alkyl or heteroaryl (1-2 C) Selected from alkyl (however, Z １ This is a heterocyclyl group that is directly linked to the N atom. In some cases, it is a heterocycline linked to carbon; Z １ (1st to 6th century) Archi Lu, Halo, (1-6C) Haloalkoxy, Cyano, Nitro, -NR ｅ R ｆ , -OR ｅ , - C(O)R ｅ 、-C(O)OR ｅ 、-OC(O)R ｅ 、-C(O)N(R ｅ )R ｆ 、-N (R ｅ ) C(O)R ｆ , -S(O) ｙ R ｅ (where y is 0, 1, or 2), -S O ２ N(R) ｅ ) R ｆ , -N(R ｅ ) SO ２ R ｆ ,-(CH ２ ) ｚ NR ｅ R ｆ (Here, z Even if it is substituted with one or more substituents selected from 1, 2, or 3 or oxo) Often, R ｅ and R ｆ These are, independently, hydrogen, (1-6C) alkyl, and (1-6C) (selected from haloalkyl or (3-6C) cycloalkyl); Furthermore, any S atom present in the heteroring in the formula is S(=O), S(=O) ２ or S ( =O)(=NR ｅ ) (Here, R ｅ These are hydrogen, (1-3C) alkyl or (2-3C) alkyl It may exist as (selected from Lucanoil); R ６ [Selected from hydrogen, halo, methyl, methoxy, and trifluoromethyl.]

2. R ｘ is methyl or CD ３ A compound selected from, according to claim 1, or pharmaceutically thereof Allowable salt.

3. R １ (1-3C)alkyl, halo, (1-3C)haloalkyl, (1-3C)halo Alkoxy, (1-3C)hydroxyalkyl, cyano, cyclopropyl, oxetane - 3-Il, -(CH ２ ) ｑ１ -OR １Ａ and - (CH ２ ) ｑ１ -C(O)R １Ａ Select from And; q1 is either 0 or 1; R １Ａ is selected from hydrogen or (1-2C) alkyl, The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R １ methyl, CD ３ Isopropyl, halo, (1-3C) hydroxyalkyl, cy Ano, cyclopropyl, oxetane-3-yl, -OMe, -CH ２ F, -CHF ２ or CF ３ A compound selected from any one of claims 1 to 3, or a compound thereof that is pharmaceutically acceptable Salt is acceptable.

5. R ２ and R ３ Both are hydrogen, or R ２ and R ３ One of them is hydrogen, and the other is A compound or agent according to any one of claims 1 to 4, which is fluoro or methyl A scientifically acceptable salt.

6. R ２ and R ３ The compound according to any one of claims 1 to 5, wherein all of the compounds are hydrogen. The pharmaceutically acceptable salt.

7. R ４ and R ５ Along with the nitrogen atom to which they are bonded, one or more R １０Ｃ substituents Therefore, they are linked to form a heterocycle which may be substituted on any available carbon atom. It is tied, Here, R １０Ｃ is an oxo, halo, or cyano substituent, or formula: -[CH ２ ] ｎ -L-Z Selected from the basis (In the ceremony n is between 0 and 2; L does not exist, or -O-, -S-, -SO-, -SO ２ -, -N(R ａ２ ) - 、-C(O)-、-C(O)O-、-OC(O)-、-C(O)N(R ａ２ )-、-N( R ａ２ )C(O)-、-N(R ａ２ )C(O)N(R ｂ２ )-、-S(O) ２ N(R ａ２ ) - or - N (R ａ２ ) SO ２ - is selected from (where R ａ２ and R ｂ２ That (Each is independently selected from hydrogen or methyl); Z is hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl From ralkyl(1-2C)alkyl, aryl, heterocyclyl, or heteroaryl Selected; Z is (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C ) Haloalkoxy, cyano, -NR ｃ R ｄ , -OR ｃ , -C(O)R ｃ , -C(O)OR ｃ 、-OC(O)R ｃ 、-C(O)N(R ｃ )R ｄ 、-N(R ｃ )C(O)R ｄ 、-S( O) ｙ R ｃ (where y is 0, 1, or 2), -SO ２ N(R) ｃ ) R ｄ , -N(R ｃ ) SO ２ R ｄ ,-(CH ２ ) ｚ NR ｃ R ｄ (Here, z is 1 or 2) or oxo They may be substituted with one or more substituents selected from; Z １ Any alkyl portion of the above substituent can be cyano, halo, hydroxy, amino, or oxo. , may be further substituted with (1-2C)alkyl or (1-2C)alkoxy, R ｃ and R ｄ These are, independently, hydrogen, (1-2C)alkyl, and (1-2C)haloalkyl. (Selected from cycloalkyl or (3-6C) cycloalkyl); Furthermore, any available N atom may be in the form of an N-oxide, or one or more R １０ Ｎ It may also be replaced by (where R １０Ｎ ha-S(O) ２ NH ２ Is it, or teeth: (i)-Z １ ; (ii)-L １ａ -Z １ ; or (iii)-[CR ８ａ R ８ｂ ] １～２ -L １ｂ -Z １ Selected from (In the formula, R ２ａ and R ２ｂ They are all hydrogen; L １ａ is -C(O)-, -S(O) ２ - or S(O) ２ N(R) ａ１ ) - Selected from (Here, R ａ１ (is hydrogen or methyl); L １ｂ It does not exist, or -O-, -S-, -SO-, -SO ２ -, -N(R ａ２ )-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)N(R ａ２ )-、- N(R ａ２ )C(O)-、-N(R ａ２ )C(O)N(R ｂ２ )-、-S(O) ２ N(R ａ２ ) - or - N (R ａ２ ) SO ２ Selected from (where R ａ２ and R ｂ２ That (Each independently selected from hydrogen or methyl); Z １ (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heteroalkyl Lyle, heteroaryl, (3-6C)cycloalkyl, (1-2C)alkyl, or aryl Selected from (1-2C) alkyl groups (however, Z １ A heterocyclic compound that is directly linked to the N atom. If it is a lyl group, it is a heterocyclyl linked to carbon; Z １ (1-2C) ) Alkyl, halo, (1-2C) haloalkoxy, cyano, nitro, -NR ｅ R ｆ , -O R 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 (Here, y is 0, 1, or 2) )、-SO ２ () ｅ ) ｆ 、-N(R ｅ ))SO ２ - ｆ 、-(CH ２ ) ｚ NR ｅ - ｆ (こ Here, z is 1, 2, or 3) or substituted with one or more substituents selected from oxo. It's fine to do so, R ｅ and R ｆ Each is independently derived from hydrogen or (1-2C) alkyl. (to be selected); Furthermore, any S atom present in the heteroring is S(=O), S(=O) ２ or S (= O ) (=NR ｅ ) (Here, R ｅ is hydrogen, (1-2C) alkyl or (2C) alkanoid (Selected from) may exist as A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. R ４ and R ５ Along with the nitrogen atom to which they are bonded, one or more R １０Ｃ substituents Therefore, they are linked to form a heterocycle which may be substituted on any available carbon atom. It is tied, Here, R １０Ｃ is an oxo, halo, or cyano substituent, or formula: -[CH ２ ] ｎ -L-Z Selected from the basis (In the ceremony n is between 0 and 2; L does not exist, or -O-, -S-, -SO-, -SO ２ -, -N(R ａ ) - -C(O)-、-C(O)O-、-OC(O)-、-C(O)N(R ａ )-、-N(R ａ )C(O)-,-S(O) ２ N(R) ａ ) - or - N (R ａ ) SO ２ Selected from ( Here, R ａ and R ｂ (is hydrogen); Z is hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, phenyl, 4-7 Selected from a 5-membered heterocyclyl or a 5- or 6-membered heteroarylalkyl; Z is (1 ~2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cy アノ、-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 oxo They may be substituted with one or more substituents selected from; R ｃ and R ｄ Each of these elements is independently selected from hydrogen or (1-2C) alkyl. ）； Furthermore, any available N atom may be in the form of an N-oxide, or one or more R １０ Ｎ It may also be replaced by (where R １０Ｎ ha-S(O) ２ NH ２ Is it, or teeth: (i)-Z １ ; (ii)-L １ａ -Z １ ; or (iii)-[CR ８ａ R ８ｂ ] １～２ -L １ｂ -Z １ Selected from (In the formula, R ２ａ and R ２ｂ They are all hydrogen; L １ａ is -C(O)-, -S(O) ２ - or S(O) ２ N(R) ａ１ ) - Selected from (Here, R ａ１ (is hydrogen); L １ｂ It does not exist, or -O-, -S-, -SO-, -SO ２ -, -N(R ａ２ )-、-C(O)N(R ａ２ )-、-N(R ａ２ )C(O)-、-S(O) ２ N(R ａ２ ) - or - N (R ａ２ ) SO ２ Selected from (where R ａ２ (is hydrogen); Z １ (1-4C) alkyl, phenyl, 4-7 member heterocyclyl or 5 or 6 Selected from member heteroaryls (however, Z １ A heterocycline in which the N atom is directly bonded. If it is a group, it is a heterocyclyl linked to carbon); Z １ (1-2C) A Lukil, Halo, (1-2C) Haloalkoxy, Cyano, -NR ｅ R ｆ , -OR ｅ , -C( O)R ｅ 、-C(O)N(R ｅ )R ｆ 、-N(R ｅ )C(O)R ｆ 、-S(O) ｙ R ｅ ( Here, y is substituted with one or more substituents selected from 0, 1, or 2. Also; R ｅ and R ｆ Each of these is independently selected from hydrogen or methyl); Furthermore, any S atom present in the heteroring is S(=O), S(=O) ２ or S (= O ) (=NR ｅ ) (Here, R ｅ is hydrogen, (1-2C) alkyl or (2C) alkanoid (Selected from) may exist as A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. R ４ and R ５ Along with the nitrogen atom to which they are bonded, one or more R １０Ｃ substituents Therefore, they are linked to form a heterocycle which may be substituted on any available carbon atom. It is connected (here, R １０Ｃ These are oxo, halo, cyano, (1-4C) alkyl or (Selected from 3-6C cycloalkyl groups); Furthermore, any available N atom may be in the form of an N-oxide, or one or more R １０Ｎ It may also be replaced by (where R １０Ｎ is -S(O) ２ NH ２ or (1-4 C) It is alkyl): Furthermore, any S atom present in the heteroring is S(=O), S(=O) ２ or S (= O ) (=NR ｅ ) (Here, R ｅ is selected from hydrogen, methyl, or (2C)alkanoyl. It may exist as (ru), A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. R ４ and R ５ Along with the nitrogen atom to which they are bonded, one of the following options They are linked to form a heterocycle selected from: 【Chemistry 2】 (In the formula, ＊ R ４ and R ５ This indicates the N atom to which it is bonded; Q １ It is, O, NH, S, S(O), S(O) ２ 、S(O)(=NR) ｅ ), N-R １０Ｎ ,CH ２ _CHR １０Ｃ or C(R １０Ｃ ) ２ And; Q ２ is, -CH ２ -----CHR １０Ｃ -, -C(R １０Ｃ ) ２ -----CHR １０Ｃ -C H ２ -、-CH ２ -CHR １０Ｃ -、-CHR １０Ｃ -CHR １０Ｃ -、-C(R １０Ｃ ) ２ -CH ２ - or -CH ２ -C(R １０Ｃ ) ２ - and; Q ３ CH, CR １０Ｃ or N; Ring A is a spiro-condensed 4, 5, or 6-membered carbon ring or heteroring; Ring B is a condensed 4, 5, or 6-membered carbon ring or heteroring; Here, R ｅ is selected from hydrogen, (1-2C) alkyl, or (2C) alkanoyl. ； Each of the heterocyclic systems is defined as one or more of the following: Upper R １０Ｃ or R １０Ｎ (May be substituted with substituents) A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

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

12. R ４ and R ５ The structure is as follows, along with the nitrogen atom to which they are bonded: 【Chemistry 4】 (In the formula, ＊ R ４ and R ５ This indicates the N atom to which it is bonded; each R １０Ｃ The above claim 1 (Selected independently from any one of the options defined in 6, 7, or 8) The chemical according to any one of claims 1 to 11, which is linked to form a heterocycle. Compounds or pharmaceutically acceptable salts thereof.

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

14. R ６ is hydrogen, the compound according to any one of claims 1 to 13 or the pharmaceutically equivalent thereof Allowable salt.

15. Compounds of formula IA, IB, or IC: 【Transformation 5】 (In the formula, R ｘ , R １ , R ２ , R ３ , R ４ , R ５ and R ６ Each of claims 1 to 12 (As defined in any one of the terms).

16. A compound selected from any one of the following, or a pharmaceutically acceptable salt thereof: N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-ylmorpholine-4-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1- Carboxamide (2R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-2-(1-hydroxy-1-methyl-ethyl)pylli Zin-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl piperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [enyl)thiazole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piper Zin-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-1-imino-1-oxo-1,4-thiadinane-4-carboxa Mido N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]pyrroridine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-2-(2-hydroxy-2-methyl-propyl)pyrrolidine-1 - Carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)morpholine-4- Carboxamide (2S)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]carbamoyl]piperazine-2-carboxylic acid N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-4-methylpiperazine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl-4-hydroxy-4-methylpiperidine-1-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-4-cyano-4-methylpiperidine-1-carboxamide (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [enyl)thiazole-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piper Zin-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 [Lu) Thiazol-2-yl]piperidine-1-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]pyrroridine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-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)thiazo [Lu-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-oxopiperazine-1-carboxamide N4-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [L-2-yl]morpholine-2,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-methyl-3-oxopiperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide 4-acetyl-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyriol] [Dil)thiazole-2-yl]piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl-4-methylsulfonylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-sulfamoylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-Il]-1-imino-1-oxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2,4-dioxo-1,3,8-triazospiro[4.5]decane-8 - Carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)morpholine-4-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl Thiazol-2-yl-4-methoxypiperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu)thiazole-2-yl]-4-(hydroxymethyl)piperidine-1-carboxamine Do N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-oxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-3-(hydroxymethyl)azetidine-1-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridin [Lu) Thiazol-2-yl]azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1,1-dioxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-1,3-dimethyl-2,4-dioxo-1,3,8-triazospiro[ 4.5] Decane-8-carboxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [I-2-yl]piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl-4-(2-hydroxyethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-3-hydroxyazetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-(2-hydroxyethyl)-3-oxopiperazine-1-carb Xamide 4,4-dicyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4- Pyridyl)thiazole-2-yl]piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-(1-hydroxy-1-methyl-ethyl)azetidine-1-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-(2-hydroxy-2-methyl-propyl)piperazine-1-cal Boxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-methyl-1,7-diazaspiro[3.4]octane-7-carboxy Thamid N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-(2-hydroxy-1,1-dimethyl-ethyl)piperazine-1- Carboxamide (8aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridin [Lu) Thiazol-2-yl]-3,4,6,7,8,8a-Hexahydro-1H-pyrrolo [1,2-a]pyrazine-2-carboxamide (8aR)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl [Lu) Thiazol-2-yl]-3,4,6,7,8,8a-Hexahydro-1H-pyrrolo [1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl] ) Thiazol-2-yl]-3-hydroxypyrrolidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu)thiazole-2-yl]-4-(methoxymethyl)piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl Thiazol-2-yl-4-fluoropiperidine-1-carboxamide (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]pyrroridine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-hydroxy-3-methylazetidine-1-carboxamide (2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]carbamoyl]piperazine-2-carboxylic acid Methyl(2R)-4-[[5-(2-chloro-6-methyl-4-pyridyl)-4-(3- [Cyanophenyl)thiazole-2-yl]carbamoyl]piperazine-2-carboxylate te (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-3-(hydroxymethyl)piperazine-1-carbbox Thamid (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Henyl)thiazole-2-yl]-3-(hydroxymethyl)piperazine-1-carbbox Thamid (3S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Thiazol-2-yl]-3-methylpiperazine-1-carboxamide (3R)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanoph [Thiazol-2-yl]-3-methylpiperazine-1-carboxamide (1S,4S)-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cy Anophenyl)thiazole-2-yl]-2,5-diazabicyclo[2.2.1]hepta n-2-carboxamide (3R)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]piperazine-1,3-dicarboxamide (3S)-N1-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]piperazine-1,3-dicarboxamide 4-amino-N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyano Phenyl)thiazole-2-yl]-4-methylpiperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl Thiazol-2-yl-4-methylpiperidine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl] ) Thiazol-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxa-7-azaspiro[3.5]nonane-7-carboxamide N-[5-(2-chloro-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]2-oxa-6-azaspiro[3.3]heptane-6-carbocyanate Thamid (1R,4R)-5-acetyl-N-[4-(3-cyanophenyl)-5-(2,6-di Methyl-4-pyridyl)thiazole-2-yl]-2,5-diazabicyclo[2.2.1 ]Heptan-2-carboxamide (1S,4S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-5-methyl-2,5-diazabicyclo[2.2.1] Heptane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-methyl-2-oxo-1,3,8-triazospiro[4.5]deca n-8-carboxamide N-[5-[2,6-bis(triduteriomethyl)-4-pyridyl]-4-(3-cy Anophenyl)thiazole-2-yl]-2-oxa-6-azaspiro[3.3]hepta n-6-carboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyri [Dil)thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane-6- Carboxamide (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethicone)] [Lu)-6-methyl-4-pyridyl]thiazole-2-yl]-4-methyl-2,3,4a ,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carb Xamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4 -pyridyl]thiazole-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]thiazole-2-yl]-6-oxa-2,9-diazaspiro[4.5]de Can-2-carboxamide (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethicone)] [Lu)-6-methyl-4-pyridyl]thiazole-2-yl]-4-methyl-2,3,4a ,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxo-1,3,8-triazospiro[4.5]decan-8-cal Boxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetane] -3-yl)-4-pyridyl]thiazole-2-yl]-3-methylpyrrolidine-1- Carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetane] -3-yl)-4-pyridyl]thiazole-2-yl]-4-methyl-piperidine-1- Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-3-morpholino-azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl-4-tetrahydropyran-4-yl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl-3-pyrrolidine-1-ylazetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3-(dimethylamino)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(morpholinomethyl)piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [4.5]-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)thiazo [2-yl]-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-ca Ruboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1,4-diazabicyclo[3.2.1]octane-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3 ,4-a]pyrazine-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2,2-dioxo-3,4,6,7,9,9a-hexahydro-1H- Pyrazino[2,1-c][1,4]thiadin-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-oxo-3,6,7,8,9,9a-hexahydro-1H-pyridone [1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-9-oxo-3,4,6,7,8,9a-hexahydro-1H-pyrazi no[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-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)thiazo [Lu-2-yl]-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2 -a] Pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carbox Thamid N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-3-sulfamoyl-pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-Il]-3-oxo-2,7-diazaspiro[3.5]nonane-7-carboxa Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl-4-pyrazole-1-yl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(1,2,4-oxazole-3-yl)piperidine-1-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-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)thiazo [2-Il]-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxa Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-(1H-imidazole-2-yl)piperidine-1-carboxami Do N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lou-2-yl]-10-oxo-3,9-diazaspiro[5.5]undecane-3-cal Boxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-cal Boxamide N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [-2-yl]-N4-methyl-piperidine-1,4-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-8-oxa-2-azaspiro[4.5]decane-2-carboxamide (3S)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridinyl [Lu) Thiazol-2-yl]pyrroridine-1,3-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4-(2-oxoimidazolidine-1-yl)piperidine-1-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-4-(1,2,4-oxazole-5-yl)piperidine-1-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-methylimino-1-oxo-1,4-thiadinane-4-carboxa Mido N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-N4-(2-hydroxyethyl)piperidine-1,4-dicarbocate Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxo-7-oxa-2,5-diazaspiro[3.5]nonane-2 - Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6,9-dioxo-1,3,4,7,8,9a-hexahydropyrazino [1,2-a]pyrazine-2-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine- 1-Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [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)thiazo [Lu-2-yl]-2-methyl-3-oxo-2,8-diazaspiro[4.5]decane-8 - Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl]-8-methyl-6,9-dioxo-3,4,7,9a-tetrahydro-1 H-pyrazino[1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-Il]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxa Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-Il]-3-oxo-2,9-diazaspiro[5.5]undecane-9-carb Xamide 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu)thiazol-2-yl]-4-(1-hydroxy-1-methyl-ethyl)piperidine -1-Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrazi no[1,2-c]pyrimidine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyridone [1,2-a]pyrazine-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2 - Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxa Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Ru-2-Il]-2,2-Dioxo-2λ^{6}-Tia-6-Azaspiro[3.3]he Butan-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carb Xamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl] ) Thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine- 1-Carboxamide (3aR,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-1,3,3a,4,6,6a-hexahydrofloxacin [3,4-c]pyrrole-5-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-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-p Lysyl)thiazole-2-yl]-6-methyl-3,6-diazabicyclo[3.2.2] Nonane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-methyl-2-oxo-1,3,8-triazospiro[4.5]deca n-8-carboxamide (3aS,6aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-3-oxo-1,2,3a,4,6,6a-hex Sahydropyrrolo[3,4-c]pyrrole-5-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxa-2-azaspiro[3.4]octane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-7-oxa-2-azaspiro[3.5]nonane-2-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-Il]-6-oxo-2,7-diazaspiro[3.4]octane-2-carbocyanine Thamid N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-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-triazospiro[3.4]octane-2-ca Ruboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxo-1,9-diazaspiro[5.5]undecane-9-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-Il]-5-oxo-2,6-diazaspiro[3.4]octane-2-carbocyanine Thamid N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [4.5]-2-yl-3-methyl-2,4-dioxo-1,3,8-triazospiro[4.5 Decane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl-4-ethyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)- 4-Pyridyl]thiazole-2-yl]-4-(oxetan-3-yl)piperazine-1 - Carboxamide 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Il-2-yl]carbamoyl]piperidine-4-carboxylic acid (3S)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridin [Lu]thiazole-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridin [Lu)thiazole-2-yl]-3-(hydroxymethyl)azetidine-1-carboxamine Do (3R)-1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridin [Lu]thiazole-2-yl]carbamoyl]pyrrolidine-3-carboxylic acid 4-Cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl Lu-4-pyridyl)thiazole-2-yl]-4-methylpiperidine-1-carbox Mido N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyri [Dil)thiazole-2-yl]-3-hydroxy-3-methylazetidine-1-carb Xamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl Lu-4-pyridyl)thiazole-2-yl]-3-methylazetidine-1-carbox Mido N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyri [Dil)thiazole-2-yl]-3-oxo-2,7-diazaspiro[3.5]nonane- 7-Carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridin Thiazol-2-yl-3-methylazetidine-1-carboxamide 1-[[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Il-2-yl]carbamoyl]azetidine-3-carboxylic acid (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)pyrrolidine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-methylazetidine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)azetidine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methylmorpholine-4-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl] ) Thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine- 1-Carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl] ) Thiazol-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl]-2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8 - Carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-methylazetidine-1-carboxamide N-[4-(3-cyano-2-methylphenyl)-5-(2,6-dimethyl-4-pyri) [Dil)thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane-6- Carboxamide (3R)-N1-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridin [Lu) Thiazol-2-yl]pyrroridine-1,3-dicarboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-oxa-7-azaspiro[4.4]nonane-7-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-2-yl-2-oxa-7-azaspiro[3.4]octane-7-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azetidine- 1-Carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)azetidine- 1-Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-3-morpholino-pyrrolidine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methyl-5-oxopiperazine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl] ) Thiazol-2-yl]-3-methylmorpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxa-1-azaspiro[3.3]heptan-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-(hydroxymethyl)morpholine-4-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1,3-dimethyl-2-oxo-1,3,8-triazospiro[4.5 Decane-8-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methylsulfonyl-pyrrolidine-1-carboxamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl] ) Thiazol-2-yl]-3-methyl-5-oxopiperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)azetidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-6-methyl-5-oxo-2,6-diazaspiro[3.4]octane- 2-Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Ru-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 Lu-2-yl-4-methylsulfonyl-piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl-4-hydroxy-4-methylpiperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4 -pyridyl]thiazole-2-yl]2-oxa-6-azaspiro[3,3]heptane -6-Carboxamide (4aR,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-4-methyl-2,3,4a,5,7,7a-hex Sahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)- 4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3.3]hepta n-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]piperazine-1-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-methylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-5,8-diazaspiro[3.5]nonane-5-carboxamide trans-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl [Lu) Thiazol-2-yl]-2,5-dimethyl-piperazine-1-carboxamide 4-amino-4-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]piperidine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carb Xamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (1R,4R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-2,5-diazabicyclo[2.2.2]octane-2 - Carboxamide cis-(2S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]-2,5-dimethylpiperazine-1-carb Xamide (2R,6R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-2,6-dimethylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl-2,2-dimethylpiperazine-1-carboxamide 1-Acetylamino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4 -Pyridyl)thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboc Thamid N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -pyridyl]thiazole-2-yl]2-oxa-6-azaspiro[3,3]heptane -6-Carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -pyridyl]thiazole-2-yl]-3-oxo-2,7-diazaspiro[3.5]no Nan-7-carboxamide (3R)-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6- [methyl-4-pyridyl]thiazole-2-yl]-3-(1-hydroxy-1-methyl- Ethyl)pyrrolidine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carbox Thamid N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]-4-(oxetan-3-yl)piperazine-1- Carboxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-methyl-4 -pyridyl]thiazole-2-yl]-1,3-dimethyl-2,4-dioxo-1,3, 8-Triazospiro[4.5]decane-8-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6 -Methyl-4-pyridyl]thiazole-2-yl]piperidine-1-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6 -methyl-4-pyridyl]thiazole-2-yl]-4-(hydroxymethyl)piperidi n-1-carboxamide 4,4-dicyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl )-6-methyl-4-pyridyl]thiazole-2-yl]piperidine-1-carboxami Do 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6 -methyl-4-pyridyl]thiazole-2-yl]-4-methoxy-piperidine-1-ca Ruboxamide N-[4-(3-cyanophenyl)-5-(3-fluoro-2,6-dimethyl-4-pyri [Dil)thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboxamide 1-Cyanoimino-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4- Pyridyl)thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carboxa Mido 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl [Tyl-ethyl)-6-methyl-4-pyridyl]thiazole-2-yl]-4-methyl-pyridyl Peridine-1-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl )-6-methyl-4-pyridyl]thiazole-2-yl]-6-oxa-2-azaspirol [3.4] Octane-2-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxy-1-methyl-ethyl )-6-methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspirol [3.3] Heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-hydroxyethyl)-6-methyl -4-pyridyl]thiazole-2-yl]2-oxa-6-azaspiro[3.3]hept Tan-6-carboxamide rac-(3S,5R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl -4-pyridyl)thiazole-2-yl]-3,5-dimethylpiperazine-1-carb Xamide (3S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl] ) Thiazol-2-yl]-3-(trifluoromethyl)piperazine-1-carboxami Do N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxa Mido N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxa Mido (3R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-3-(trifluoromethyl)piperazine-1-carboxami Do (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]piperazine-1-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [2-yl]-4,7-diazaspiro[2.5]octane-7-carboxamide (3S,5S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-p Lysyl)thiazole-2-yl]-3,5-dimethylpiperazine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-methylpiperazine-1-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide (2S)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-(hydroxymethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxamide (2R)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl) ) Thiazol-2-yl]-2-methylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxa Mido (3R)-N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoro [methyl)-4-pyridyl]thiazole-2-yl]-3-methylpiperazine-1-cal Boxamide (4aS,7aS)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethicone)] [Lu)-6-methyl-4-pyridyl]thiazole-2-yl]-3,4,4a,5,7,7 α-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxa Mido (4aS,7aR)-N-[4-(3-cyanophenyl)-5-[2-(difluoromethicone)] [Lu)-6-methyl-4-pyridyl]thiazole-2-yl]-3,4,4a,5,7,7 α-Hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxa Mido rac-(4aS,7aS)-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl [Thi-4-pyridyl)thiazole-2-yl]-3,4,4a,5,7,7a-hexa-yl Dro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-cyclopropyl-piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo [Lu-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridyl)thiazo Lu-2-yl-3,3-dimethylpiperazine-1-carboxamide N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl) Thiazol-2-yl]-1-imino-1-oxo-1,4-thiadinane-4-carbox Thamid N-[4-(3-cyanophenyl)-5-[2-(difluoromethyl)-6-methyl-4 -Pyridyl]thiazole-2-yl]-1-imino-1-oxo-1,4-thiadinane- 4-Carboxamide N-[4-(3-cyanophenyl)-5-(2,6-dichloro-4-pyridyl)thiazo [Lu-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(trifluoromethyl)- 4-Pyridyl]thiazole-2-yl]-1-oxo-1,4-thiadinane-4-carb Xamide N-[4-(3-cyanophenyl)-5-(2-methoxy-6-methyl-4-pyridyl) Thiazol-2-yl]-1-oxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-methyl-6-(oxetan-3-yl) -4-pyridyl]thiazole-2-yl]2-oxa-6-azaspiro[3.3]hept Tan-6-carboxamide N-[5-(2-cyano-6-methyl-4-pyridyl)-4-(3-cyanophenyl)thio Azole-2-yl]-1-oxo-1,4-thiadinane-4-carboxamide N-[4-(3-cyanophenyl)-5-[2-(fluoromethyl)-6-methyl-4- Pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane- 6-Carboxamide N-[4-(3-cyanophenyl)-5-(2-cyclopropyl-6-methyl-4-pyriol [Dil)thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane-6- Carboxamide N-[4-(3-cyanophenyl)-5-(2-isopropyl-6-methyl-4-pyridyl [3.3]thiazole-2-yl]-2-oxa-6-azaspiro[3.3]heptan-6-ca Ruboxamide N-[4-(3-cyanophenyl)-5-(2-ethyl-6-methyl-4-pyridyl) Azole-2-yl]2-oxa-6-azaspiro[3.3]heptane-6-carbocyanate Thamid N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-1-oxidepyridine] -1-ium-4-yl)thiazole-2-yl]-2-oxa-6-azaspiro[3. 3) Heptane-6-carboxamide 4-Cyano-N-[4-(3-cyano-2-methylphenyl)-5-(2,6-dimethylphenyl) Lu-4-pyridyl)thiazole-2-yl]-4-methylpiperidine-1-carbox Mido N-[5-(2-acetamido-6-methyl-4-pyridyl)-4-(3-cyanophenic [3.3]thiazole-2-yl]-2-oxa-6-azaspiro[3.3]heptan-6-ca Ruboxamide N-[5-[2-(acetamidomethyl)-6-methyl-4-pyridyl]-4-(3-C Anophenyl)thiazole-2-yl]-2-oxa-6-azaspiro[3.3]hepta n-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-(methoxymethyl)-6-methyl-4- Pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3,3]heptane- 6-Carboxamide N-[4-(3-cyanophenyl)-5-[2-(1-methoxyethyl)-6-methyl- 4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3.3]hepta n-6-carboxamide N-[5-[2-chloro-6-(1-hydroxy-1-methyl-ethyl)-4-pyridyl ]-4-(3-cyanophenyl)thiazole-2-yl]-2-oxa-6-azaspirol [3.3] Heptane-6-carboxamide 4-Cyano-N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6 -methyl-4-pyridyl]thiazole-2-yl]-4-methyl-piperidine-1-cal Boxamide N-[4-(3-cyanophenyl)-5-[2-(hydroxymethyl)-6-(triflu Oromethyl)-4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[ 3.3] Heptane-6-carboxamide 3-Cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl-4-pyridin Thiazol-2-yl-3-methylpyrrolidine-1-carboxamide N-[5-[2,6-bis(triduteriomethyl)-4-pyridyl]-4-(3-cy Anophenyl)thiazole-2-yl]-4-cyano-4-methylpiperidine-1-ca Ruboxamide N-[4-(3-cyanophenyl)-5-[2-[(1R)-1-hydroxyethyl]- 6-methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3 3) Heptane-6-carboxamide N-[4-(3-cyanophenyl)-5-[2-[(1S)-1-hydroxyethyl]- 6-methyl-4-pyridyl]thiazole-2-yl]-2-oxa-6-azaspiro[3 3) Heptane-6-carboxamide (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]-3-methylpyrrolidine-1-carboxamide (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(2,6-dimethyl- 4-Pyridyl)thiazole-2-yl]-3-methylpyrrolidine-1-carboxamide 。

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

18. A compound or drug according to any one of claims 1 to 16 for use in treatment. A scientifically acceptable salt, or the pharmaceutical composition according to claim 17.

19. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, The pharmaceutical composition is as described in claim 17, (i) Treatment of cell proliferation disorders; (ii) Treatment of cancer; (iii) Treatment of cancer (wherein the compound or pharmaceutical composition is one or more additional anticancer agents) (Administered in combination with other drugs); (iv) Treatment of cancer (wherein the compound or pharmaceutical composition, 1) Other forms of cancer immunotherapy and anticancer chemotherapy agents; 2) Adenosine pathway modulators (for example, but not limited to, A2b antagonists) (Stol, CD73 inhibitors and CD39 inhibitors); 3) Anti-PD-1 and PDL-1 antibodies (e.g., cetrerimab, pembrolizumab, nivol) Mab, durvalumab, avelumab, and atezolizumab); and 4) Anti-CTLA4 antibody (e.g., ipilimumab) (Administered in combination with one or more additional anticancer agents selected from the group consisting of the following.) A compound or pharmaceutical composition for use in the pharmaceutical industry.

20. A method for administering treatment for cell proliferation disorders to patients in need of such treatment, A compound described in any one of paragraphs 1 to 16 or a pharmaceutically acceptable salt thereof, or claim A method comprising administering a therapeutically effective amount of the pharmaceutical composition described in item 17.

21. A method for administering cancer treatment to a patient in need of such treatment, the method according to claims 1 to 16. A compound described in any one of the claims or a pharmaceutically acceptable salt thereof, or the compound described in claim 17. A method comprising administering a therapeutically effective amount of a pharmaceutical composition.

22. A method for administering treatment for cell proliferation disorders to patients in need of such treatment, A compound described in any one of paragraphs 1 to 16 or a pharmaceutically acceptable salt thereof, or claim A therapeutically effective dose of the pharmaceutical composition described in item 17 is administered in combination with one or more additional anticancer agents. A method that includes doing something.

23. The one or more additional anticancer agents are: 1) Other forms of cancer immunotherapy and anticancer chemotherapy agents; 2) Adenosine pathway modulators (for example, but not limited to, A2b antagonists) (Stol, CD73 inhibitors and CD39 inhibitors); 3) Anti-PD-1 and PDL-1 antibodies (e.g., cetrerimab, pembrolizumab, nivol) Mab, durvalumab, avelumab, and atezolizumab); and 4) Anti-CTLA4 antibody (e.g., ipilimumab) The method according to claim 21, selected from the following.

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