Adenosine receptor antagonists

Abstract

The present invention relates to compounds of formula I, as shown below. [Formula 1] TIFF2025504966000181.tif54128 formula, R 1 , R 4 , R 5 and R 6 and each are as defined in the present application. The present invention also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or conditions in which adenosine A2a and / or A2b receptor activity is implicated, such as cancer.

Description

[Technical Field]

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

[0002] Several immunosuppressive pathways are active in the tumor microenvironment, allowing tumor cells to evade cytotoxic T cell elimination and potentially reducing patients' clinical responses to anti-checkpoint antibody immunotherapy. The anti-PD-1 antibodies pembrolizumab and nivolumab, as well as the anti-PD-L1 antibodies durvalumab, avelumab, and atezolizumab, have been approved for the treatment of many solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma. However, only 20–30% of patients respond to checkpoint blockade, and the side effects of such treatments are significant (Sukari et al., 2016). As a result, other approaches to enhance the cytotoxic potential of the tumor microenvironment are actively being investigated. These include drugs that can be used as monotherapies or in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0033] References to "treating" or "treatment" should be understood to include prevention and alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition in a person who may be suffering from or predisposed to the condition, disorder, or condition, but who has not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (3) relieving or attenuating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0052] The bicyclic heteroaryl group can be, for example, a group selected from the following:

[0053] a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; and A cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms.

[0054] Particular examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0055] Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromanyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0056] "Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently linked to a (1-6C)alkylene group, both as defined herein. Examples of heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0057] The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In certain embodiments, aryl is phenyl.

[0058] The term "aryl(1-6C)alkyl" means an aryl group covalently linked to a (1-6C)alkylene group, both as defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.

[0059] This specification also uses some compound terms to describe groups containing multiple functions. Such terms will be understood by those skilled in the art. For example, heterocyclyl(m-nC)alkyl includes (m-nC)alkyl substituted with heterocyclyl.

[0060] The term "optionally substituted" refers to groups, structures, or molecules that are substituted and groups, structures, or molecules that are not substituted. 1 One / all CH, CH, CH groups or heteroatoms (i.e., NH) within a group are optionally substituted,” suitably refers to R 1 It means that (any) one of the hydrogen radicals of the group is replaced by the associated defined group.

[0061] Where any substituent is selected from "one or more" groups, it is understood that this definition includes all substituents selected from one of the specified groups, or substituents selected from two or more of the specified groups.

[0062] The phrase "compounds of the invention" refers to both the compounds generally and specifically disclosed herein.

[0063] Compounds of the Invention In a first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, having structural formula I shown below:

[0064] [ka] where: R1 is

[0065] [ka]

[0066] [ka] is selected from where: any available C atom in R1 is optionally substituted by one or more R2 substituents, any available N atom in R1 is optionally in the form of an N-oxide or substituted with an R3 group; where: Each R2 is independently selected from the group consisting of (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl (e.g., 5-membered heteroaryl), heteroaryl(1-2C)alkyl, halo, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl, cyano, -(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 R1D ) q1 -S(O) p R 1A (wherein p is 0, 1 or 2), -(CR 1C R 1D ) q1 -SO2N(R 1B )R 1A , or -(CR 1C R 1D ) q1 -N(R 1B )SO2R 1A Selected from where q1 is 0, 1, or 2; where R 1A and R 1B are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; where R 1C and R 1D are each independently selected from hydrogen or (1-2C)alkyl; R3 is hydrogen, (1-3C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, C-linked heterocyclyl, heterocyclyl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl, (1-3C) haloalkyl, (1-3C) haloalkoxy, (1-3C) hydroxyalkyl, -(CR 3C R 3D ) 1-2 -OR 3A , -(CR 3C R 3D ) q3 -C(O)R 3A , -(CR 3C R 3D ) q3 -C(O)OR 3A , -(CR 3C R 3D ) 1-2 -OC(O)R 3A , -(CR 3C R 3D ) q3 -C(O)N(R 3B )R q3, -(CR 1C R 1D ) 1-2 -N(R 3B )C(O)R 3A , -(CR 3C R 3D )-S(O) p3 R 3A (where p3 is 0, 1 or 2), -(CR 3C R 3D ) 1-2 -SO2N(R 3B )R 3A , or -(CR 3C R 3D ) 1-2 -N(R 3B )SO2R 3A is selected from where R 3A and R 3B are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; where R 3C and R 3D are each independently selected from hydrogen or (1-2C)alkyl; where q3 is 0, 1, or 2; R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted by a substituent, where R 10C is an oxo, thioxo, halo, or cyano substituent, or a group of the formula: -[CR 7a R 7b ] n -LZ is selected from the group where: n is an integer from 0 to 6, R 7a and R 7b are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L is absent or is -O-, -S-, -SO-, -SO2-, -N(Ra )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)N(R b )-, -C(S)N(R a )-, -N(R a )C(S)-, -N(R a )C(S)N(R b )-, -S(O)2N(R a )- or -N(R a )SO2-, where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl or heteroaryl(1-2C)alkyl, where Z is optionally (1-6C)-alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, nitro, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1, 2 or 3) or oxo; wherein any alkyl moiety in the Z substituent is optionally further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl, or (1-2C)alkoxy; and R c and R d are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl; wherein any available N atom in the ring formed by R4 and R5 is optionally in the form of an N-oxide or optionally substituted with one or more R 10N is replaced by where R 10N is —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R 8b ] 1-6 -L 1b -Z1 is selected from where: R 8a and R 8b are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L 1a -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 )-, -S(O)2N(R a1 )- or -N(R a1 )-, where R a1 is selected from hydrogen or (1-2C) alkyl; L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -C(S)N(R a2 )-, -N(R a2 )C(S)-, -N(Ra2 )C(S)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 and R b2 are each independently selected from hydrogen or (1-2C)alkyl; Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclyl(1-2C)alkyl or heteroaryl(1-2C)alkyl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-linked heterocyclyl, wherein Z1 is optionally (1-6C)-alkyl, halo, (1-6C)haloalkoxy, cyano, nitro, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR e R f (wherein z is 1, 2, or 3) or oxo; and R e and R f are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl; Any S atom present in the heterocycle may optionally be S(=O), S(=O) or S(=O)(=NR e ), where R eis selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl, R6 is selected from hydrogen, halo, methyl, methoxy and trifluoromethyl; The present invention relates to a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0067] In another aspect, the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, having structural formula I shown below:

[0068] [ka] where: R1 is

[0069] [ka]

[0070] [ka] is selected from where: any available C atom in R1 is optionally substituted by one or more R2 substituents, any available N atom in R1 is optionally in the form of an N-oxide or substituted with an R3 group; where: Each R2 is independently selected from the group consisting of (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl (e.g., 5-membered heteroaryl), heteroaryl(1-2C)alkyl, halo, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl, cyano, -(CR 1C R 1D ) q1 -OR 1A , -(CR1C R 1D ) q1 -C(O)R 1A , -(CR 1C R 1D ) q1 -C(O)OR 1A , -(CR 1C R 1D ) q1 -OC(O)R 1A , -(CR 1C R 1D ) q1 -C(O)N(R 1B )R 1A , -(CR 1C R 1D ) q1 -N(R 1B )C(O)R 1A , -(CR 1C R 1D ) q1 -S(O) p R 1A (wherein p is 0, 1 or 2), -(CR 1C R 1D ) q1 -SO2N(R 1B )R 1A , or -(CR 1C R 1D ) q1 -N(R 1B )SO2R 1A Selected from where q1 is 0, 1, or 2; where R 1A and R 1B are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; where R 1C and R 1D are each independently selected from hydrogen or (1-2C)alkyl; R3 is hydrogen, (1-3C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, C-linked heterocyclyl, heterocyclyl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl, (1-3C) haloalkyl, (1-3C) haloalkoxy, (1-3C) hydroxyalkyl, -(CR 3C R 3D ) 1-2 -OR 3A , -(CR 3C R 3D ) q3 -C(O)R 3A , -(CR 3C R 3D ) q3 -C(O)OR 3A , -(CR 3C R 3D ) 1-2 -OC(O)R 3A , -(CR 3C R 3D ) q3 -C(O)N(R 3B )R q3 , -(CR 1C R 1D ) 1-2 -N(R 3B )C(O)R 3A , -(CR 3C R 3D )-S(O) p3 R 3A (where p3 is 0, 1 or 2), -(CR 3C R 3D ) 1-2 -SO2N(R 3B )R 3A , or -(CR 3C R 3D ) 1-2 -N(R 3B )SO2R 3A is selected from where q3 is 0, 1, or 2; R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted by a substituent, where R 10C is an oxo, thioxo, halo, or cyano substituent, or a group of the formula: -[CR 7a R 7b ] n -LZ is selected from the group where: n is an integer from 0 to 6, R 7a and R 7b are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)N(R b )-, -C(S)N(R a )-, -N(R a )C(S)-, -N(R a )C(S)N(R b )-, -S(O)2N(R a )- or -N(R a )SO2-, where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl or heteroaryl(1-2C)alkyl, where Z is optionally (1-6C)-alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, nitro, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )Rd , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1, 2 or 3) or oxo; wherein any alkyl moiety in the Z substituent is optionally further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl, or (1-2C)alkoxy; and R c and R d are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl; wherein any available N atom in the ring formed by R4 and R5 is optionally in the form of an N-oxide or optionally substituted with one or more R 10N is replaced by where R 10N is —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R 8b ] 1-6 -L 1b -Z1 is selected from where: R 2a and R 2b are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L 1a -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 )-, -S(O)2N(R a1 )- or -N(R a1 )-, where Ra1 is selected from hydrogen or (1-2C) alkyl; L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -C(S)N(R a2 )-, -N(R a2 )C(S)-, -N(R a2 )C(S)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 and R b2 are each independently selected from hydrogen or (1-2C)alkyl; Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclyl(1-2C)alkyl or heteroaryl(1-2C)alkyl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-linked heterocyclyl, wherein Z1 is optionally (1-6C)-alkyl, halo, (1-6C)haloalkoxy, cyano, nitro, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2)z NR e R f (wherein z is 1, 2, or 3) or oxo; and R e and R f are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl; Any S atom present in the heterocycle may optionally be S(=O), S(=O) or S(=O)(=NR e ), where R e is selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl, R6 is selected from hydrogen, halo, methyl, methoxy and trifluoromethyl; The present invention relates to a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0071] Particular compounds of the invention include, for example, compounds of Formula I, or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise specified, each of R1, R2, R3, R4, R5, R6 and any associated substituents has any of the meanings defined in any of paragraphs (1) through (36) below. (1) R1 is

[0072] [ka]

[0073] [ka] is selected from wherein each R1 is optionally substituted on any available carbon atom with one or more R2, and R2 and R3 are as defined herein. (2) R1 is

[0074] [ka]

[0075] [ka] is selected from R1 is optionally substituted on any available carbon atom with one or more R2 substituents, where R2 and R3 are as defined herein. (3) R1 is

[0076] [ka] is selected from R1 is optionally substituted on any available carbon atom with one or more R2 substituents, where R2 is as defined herein. (4) R1 is

[0077] [ka] and R1 is optionally substituted on any available carbon atom with one or more R2 substituents, where R2 is as defined herein. (5) R1 is

[0078] [ka] where R2 is as defined herein. (6) R1 is

[0079] [ka]

[0080] [ka]

[0081] [ka] is selected from. (7) R1 is

[0082] [ka] is. (8) each R, if present, is independently (1-3C) alkyl, (3-6C) cycloalkyl, 4- or 5-membered heterocyclyl, 5-membered heteroaryl, halo, (1-3C) haloalkyl, (1-3C) haloalkoxy, (1-3C) hydroxyalkyl, cyano, -(CR 1C R 1D ) q1 -OR 1A , -(CR 1C R 1D ) q1 -C(O)R 1A is selected from where q1 is 0 or 1, R 1A and R 1B are each independently selected from hydrogen, (1-2C)alkyl; where R 1C and R 1D are each independently selected from hydrogen or (1-2C)alkyl. (9) each R, if present, is independently (1-2C) alkyl, 5-membered heteroaryl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) hydroxyalkyl, cyano, —(CR 1C R 1D ) q1 -OR 1A is selected from where q1 is 0 or 1, R 1A and R 1B are each independently selected from hydrogen, (1-2C)alkyl. (10) Each R2, if present, is independently selected from methyl, ethyl, or methoxy. (11) Each R2, if present, is methyl. (11a) R3 is hydrogen, (1-3C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, C-linked heterocyclyl, heterocyclyl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl, (1-3C) haloalkyl, (1-3C) haloalkoxy, (1-3C) hydroxyalkyl, -(CR 3C R 3D ) 1-2 -OR 3A , -(CR 3C R 3D ) q3 -C(O)R 3A , -(CR 3C R 3D ) q3 -C(O)OR 3A , -(CR 3C R 3D ) 1-2 -OC(O)R 3A , -(CR 3C R 3D ) q3 -C(O)N(R 3B )R q3 , -(CR 1C R 1D ) 1-2 -N(R 3B )C(O)R 3A , -(CR 3C R 3D )-S(O) p3 R 3A (where p3 is 0, 1 or 2), -(CR 3C R 3D ) 1-2 -SO2N(R 3B )R 3A , or -(CR 3C R 3D ) 1-2 -N(R 3B )SO2R 3A is selected from where R 3A and R 3B are each independently selected from hydrogen or (1-2C)alkyl; where R3C and R 3D are each independently selected from hydrogen or (1-2C)alkyl; and q3 is 0, 1, or 2. (11b) R3 is selected from hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, C-linked heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (1-3C)haloalkyl, (1-3C)haloalkoxy or (1-3C)hydroxyalkyl. (12) R3 is selected from hydrogen or (1-3C) alkyl. (13) R3 is selected from hydrogen or methyl. (14) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted on any available carbon atom by a substituent, where R 10C is an oxo, thioxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group where: n is 0 to 4; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)N(R b )-, -S(O)2N(R a )- or -N(R a )SO2-, where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl, or heteroaryl(1-2C)alkyl, where Z is optionally (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, nitro, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1, 2 or 3) or oxo; wherein any alkyl moiety in the Z substituent is optionally further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl, or (1-2C)alkoxy; and R c and R d are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)haloalkyl, or (3-6C)cycloalkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10N is —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R8b ] 1-4 -L 1b -Z1 is selected from where: R 8a and R 8b are both hydrogen, L 1a -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 )- or -S(O)N(R a1 )-, where R a1 is hydrogen or methyl, L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -C(S)N(R a2 )-, -N(R a2 )C(S)-, -N(R a2 )C(S)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 and R b2 are each independently selected from hydrogen or methyl; Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclyl(1-2C)alkyl or heteroaryl(1-2C)alkyl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-linked heterocyclyl, wherein Z1 is optionally (1-4C)-alkyl, halo, (1-4C)haloalkoxy, cyano, nitro, -NR e R f , -OR e , -C(O)R e , -C(O)OR e, -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR e R f (wherein z is 1, 2, or 3) or oxo; and R e and R f are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)haloalkyl, or (3-6C)cycloalkyl; Any S atom present in the heterocycle may optionally be S(=O), S(=O) or S(=O)(=NR e ), where R e is selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl. (15) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted on any available carbon atom by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group where: n is 0 to 2 (i.e., n is 0, 1, or 2); L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2)-, -S(O)2N(R a2 )- or -N(R a2 )SO2-, where R a2 and R b2 are each independently selected from hydrogen or methyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, heterocyclyl, heterocyclyl(1-2C)alkyl or heteroaryl, where Z is optionally (1-2C)-alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1 or 2) or oxo; wherein any alkyl moiety in the substituent on Z is optionally further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl, or (1-2C)alkoxy; and R c and R d are each independently selected from hydrogen, (1-2C)alkyl, (1-2C)haloalkyl, or (3-6C)cycloalkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10Nis —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1 is selected from where: R 8a and R 8b are both hydrogen, L 1a is -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 is hydrogen or methyl, L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 and R b2 are each independently selected from hydrogen or methyl; Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl or aryl(1-2C)alkyl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-linked heterocyclyl, and Z1 is optionally (1-2C)alkyl, halo, (1-2C)haloalkoxy, cyano, nitro, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )Rf , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR e R f (wherein z is 1, 2, or 3) or oxo, wherein R e and R f are each independently selected from hydrogen or (1-2C)alkyl; Any S atom present in the heterocycle may optionally be S(=O), S(=O) or S(=O)(=NR e ), where R e is selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl. (16) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted on any available carbon atom by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group where: n is 0 to 2 (i.e., n is 0, 1, or 2); L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)N(R b )-, -S(O)2N(R a )- or -N(R a )SO2-, where R aand R b is hydrogen or methyl, Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, heterocyclyl, heterocyclyl(1-2C)alkyl or heteroaryl, where Z is optionally (1-2C)-alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1 or 2) or oxo; where R c and R d are each independently selected from hydrogen, (1-2C)alkyl, or (1-2C)haloalkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10N is —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1 is selected from where: R 8a and R 8b are both hydrogen, L 1a is -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 is hydrogen, L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 is hydrogen, Z1 is selected from (1-6C) alkyl, (3-6C) cycloalkyl, aryl, heterocyclyl, heteroaryl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-linked heterocyclyl, wherein Z1 is optionally (1-2C) alkyl, halo, (1-2C) haloalkoxy, cyano, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR c R d (wherein z is 1 or 2), wherein R e and R f are each independently selected from hydrogen or methyl; Any S atom present in the heterocycle may optionally be S(=O), S(=O) or S(=O)(=NR e ), where R e is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl. (17) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted by a substituent, where R 10C is oxo, halo or cyano, or of the formula: -[CH2] n -LZ is selected from the group where: n is 0 to 2 (i.e., n is 0, 1, or 2); L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -S(O)2N(R a )- or -N(R a )SO2-, where R a and R b are each independently selected from hydrogen or methyl; Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclyl(1-2C)alkyl, or 5- or 6-membered heteroaryl, where Z is optionally (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(Rc )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1 or 2) or oxo; where R c and R d are each independently selected from hydrogen or (1-2C)alkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10N is —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1 is selected from where: R 8a and R 8b are both hydrogen, L 1a is -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 is hydrogen, L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 is hydrogen, Z1 is selected from (1-4C)alkyl, phenyl, 4- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-linked heterocyclyl, wherein Z1 is optionally (1-2C)alkyl, halo, (1-2C)haloalkoxy, cyano, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR c R d (wherein z is 1 or 2), wherein R e and R f are each independently selected from hydrogen or methyl; Any S atom present in the heterocycle may optionally be S(=O), S(=O) or S(=O)(=NR e ), where R e is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl. (18) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted on any available carbon atom by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group where: n is 0 to 2 (i.e., n is 0, 1, or 2); L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -S(O)2N(R a )- or -N(R a )SO2-, where R a and R b are each independently selected from hydrogen or methyl; Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclyl(1-2C)alkyl, or 5- or 6-membered heteroaryl, where Z is optionally (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, —NR c R d , -OR c , -C(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d or -S(O) y R c wherein y is 0, 1 or 2, or oxo; where R c and R d are each independently selected from hydrogen or (1-2C)alkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10N is —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R 8b ]1-2 -L 1b -Z1 is selected from where: R 8a and R 8b are both hydrogen, L 1a is -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 is hydrogen, L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 is hydrogen, Z1 is selected from (1-4C)alkyl, phenyl, 4- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-linked heterocyclyl, wherein Z1 is optionally (1-2C)alkyl, halo, (1-2C)haloalkoxy, cyano, -NR e R f , -OR e , -C(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1, or 2), wherein R e and R f are each independently selected from hydrogen or methyl; Any S atom present in the heterocycle may optionally be S(=O), S(=O) or S(=O)(=NR e ), where R eis selected from hydrogen, methyl or (2C)alkanoyl. (19) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted on any available carbon atom by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group where: n is 0 to 2 (i.e., n is 0, 1, or 2); L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -S(O)2N(R a )- or -N(R a )SO2-, where R a and R b are each independently selected from hydrogen or methyl; Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclyl(1-2C)alkyl, or 5- or 6-membered heteroaryl, where Z is optionally (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, —NR c R d , -OR c , -C(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d or -S(O) y R c wherein y is 0, 1 or 2, or oxo; where R c and Rd are each independently selected from hydrogen or (1-2C)alkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10N is —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1 is selected from where: R 8a and R 8b are both hydrogen, L 1a is -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 is hydrogen, L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 is hydrogen, Z1 is selected from (1-4C) alkyl or 4- to 7-membered heterocyclyl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-bonded heterocyclyl; wherein Z1 is optionally (1-2C)alkyl, halo, (1-2C)haloalkoxy, cyano, -NR e R f , -OR e , -C(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f, -S(O) y R e (wherein y is 0, 1, or 2), wherein R e and R f are each independently selected from hydrogen or methyl; Any S atom present in the heterocycle may optionally be S(=O), S(=O) or S(=O)(=NR e ), where R e is selected from hydrogen, methyl or (2C)alkanoyl. (20) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted on any available carbon atom by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -LZ is selected from the group where: L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -S(O)2N(R a )- or -N(R a )SO2-, where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, 4- to 7-membered heterocyclyl or heterocyclyl(1-2C)alkyl; Z is optionally cyano, —NR c R d -OR c and R c and R dare each independently selected from hydrogen or methyl, any alkyl moiety in a substituent on Z is optionally substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy, and R c and R d are each independently selected from hydrogen and (1-6C)alkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10N is —S(O)2NH2 or (1-4C)-alkyl, Any S atom present in the heterocycle may optionally be S(=O), S(=O) or S(=O)(=NR e ), where R e is selected from hydrogen, methyl or (2C)alkanoyl. (21) R4 and R5, together with the nitrogen atom to which they are attached, optionally represent one or more R 10C are linked to form a heterocycle substituted on any available carbon atom by a substituent, where R 10C is oxo, halo, cyano, or a group of the formula: -LZ is selected from the group where: L is absent, -O- or -N(R a )-, where R a is hydrogen or methyl, Z is selected from (1-4C)alkyl, 4- to 7-membered heterocyclyl, (3-6C)cycloalkyl(1-2C)alkyl; wherein any (1-4C)alkyl, 4- to 7-membered heterocyclyl, or (3-6C)cycloalkyl(1-2C)alkyl is optionally substituted with cyano, —NR c R d -OR c and wherein R c and R d are each independently selected from hydrogen or methyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10N is (1-4C) alkyl, Any S atom present in the above heterocycle may optionally be present as S(=O). (22) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted on any available carbon atom by a substituent, wherein each R 10C is independently selected from (1-4C)alkyl or cyano, where (1-4C)alkyl is optionally selected from cyano, —NR c R d -OR c where R c and R d are each independently selected from hydrogen or methyl; wherein any available N atom is optionally substituted with one or more R 10N where R 10N is methyl. (23) R4 and R5 together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocycle, which may optionally contain one or more R 10C or R 10N substituted with a substituent, where R 10c and R 10N is as defined in any one of paragraphs (14) to (22) above. (24) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a 4- to 8-membered monocyclic or bridged heterocycle, or a 7- to 12-membered bicyclic or spiro-bicyclic heterocycle, which heterocycle may optionally contain one or more R 10C or R 10N substituted with a substituent, where R 10c and R 10N is as defined in any one of paragraphs (14) to (22) above. (25) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a 4- to 7-membered monocyclic or bridged heterocycle, or a 7- to 11-membered bicyclic or spiro-bicyclic heterocycle, which heterocycle may optionally contain one or more R 10C or R 10N substituted with a substituent, where R 10c and R 10N is as defined in any one of paragraphs (14) to (22) above. (26) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a 5- or 6-membered monocyclic heterocycle, or a 7- to 10-membered bicyclic or spiro-bicyclic heterocycle, which heterocycle may optionally contain one or more R 10C or R 10N substituted with a substituent, where R 10c and R 10N is as defined in any one of paragraphs (14) to (22) above. (27) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options:

[0083] [ka] where: * represents 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 -CH2-, -CH2-CHR 10C -, -CHR 10C -CHR 10C -, -C(R 10c )2-CH2-, or -CH2-C(R 10c )2- and Q3 is CH, CR 10C or N, Ring A is a spiro-fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; Ring B is a fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; where R e is selected from hydrogen or methyl; Each of the heterocyclic ring systems may optionally contain one or more R as defined in any one of paragraphs (14) to (22) above. 10c or R 10N It is substituted with a substituent. (28) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options:

[0084] [ka] where: * represents the N atom to which R4 and R5 are attached, Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10c )2, Q2 is -CH2-, -CHR 10C -or-C(R 10c )2- and Q3 is CH, CR 10C or N, Ring A is a spiro-fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; Ring B is a fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; where R e is selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl, Each of the heterocyclic ring systems may optionally contain one or more R as defined in any one of paragraphs (14) to (22) above. 10c or R 10N It is substituted with a substituent. (29) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options:

[0085] [ka] where: * represents 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, where R e is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; Each of the heterocyclic ring systems may optionally contain one or more R as defined in any one of paragraphs (14) to (22) above.10c or R 10N It is substituted with a substituent. (30) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options:

[0086] [ka] where: * represents the N atom to which R4 and R5 are attached, Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10c )2, Q2 is -CH2-, Q3 is CH, CR 10C or N, Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10c )2, Q5 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10c )2, Q6 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10c )2, Q7 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10c )2, where R e is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; Each of the heterocyclic ring systems may optionally contain one or more R as defined in any one of paragraphs (14) to (22) above. 10c or R 10N It is substituted with a substituent. (33) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options:

[0087] [ka] where: * represents the N atom to which R4 and R5 are attached, Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10c )2, Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10c )2, where R e is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; Each of the heterocyclic ring systems may optionally contain one or more R as defined in any one of paragraphs (14) to (22) above. 10c or R 10N It is substituted with a substituent. (34) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options:

[0088] [ka] where: * represents the N atom to which R4 and R5 are attached, Q1 is O, NH, NR 10N , CH2, CHR 10Cor C(R 10c )2, Q4 is O, NH, NR 10N , CH2, CHR 10C or C(R 10c )2, where R e is selected from hydrogen, methyl or (2C)alkanoyl; R 10c or R 10N is as defined in any of the preceding paragraphs (14) to (22). (35) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options:

[0089] [ka] where: * represents the N atom to which R4 and R5 are attached, Q1 is O, NH, S(O), S(O)2, S(O)(=NR e ), NR 10N , CH2, CHR 10C or C(R 10c )2, where R e is selected from hydrogen, methyl or (2C)alkanoyl; R 10c or R 10N is as defined in any of the preceding paragraphs (14) to (22). (36) R4 and R5, together with the nitrogen atom to which they are attached, form the structure:

[0090] [ka] are linked to form a heterocycle of where: * represents the N atom to which R4 and R5 are attached, Each R 10c are independently selected from the alternatives defined in any one of paragraphs (14) to (22) above. (37) R6 is selected from hydrogen, halo, or methyl. (38) R6 is selected from hydrogen or methyl. (39) R6 is hydrogen.

[0091] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or a monocyclic, bicyclic, spiro bicyclic or bridged heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0092] Suitably, the heteroaryl is a 5 or 6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0093] Preferably, the heterocyclyl group is a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, O, or S. Most preferably, the heterocyclyl group is a 5-, 6-, or 7-membered ring containing 1, 2, or 3 heteroatoms selected from N, O, or S [e.g., morpholinyl (e.g., 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl, or pyrrolidinonyl] or a 7-, 8-, 9-, or 10-membered spiro bicyclic ring system containing 1, 2, or 3 heteroatoms selected from N, O, or S.

[0094] Preferably, the aryl group is phenyl.

[0095] Preferably, R1 is as defined in any one of paragraphs (1) to (7) above. More preferably, R1 is as defined in paragraphs (3) to (7) above. Most preferably, R1 is as defined in paragraphs (5) or (7) above.

[0096] Preferably, R2 is as defined in any one of paragraphs (8) to (11) above. More preferably, R2 is as defined in any one of paragraphs (9) to (11). Most preferably, R2 is as defined in paragraphs (10) or (11) above.

[0097] Preferably, R3 is as defined in paragraphs (11a), (11b), (12), or (13) above. More preferably, R3 is as defined in paragraphs (12) or (13) above. Most preferably, R3 is as defined in paragraph (13) above.

[0098] Preferably, R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle, optionally substituted as defined in any one of paragraphs (14) to (22) above. More preferably, the heterocycle formed by R4 and R5 is optionally substituted as defined in any one of paragraphs (19) to (22) above. Most preferably, the heterocycle formed by R4 and R5 is optionally substituted as defined in paragraphs (21) or (22) above.

[0099] Preferably, R4 and R5 are as defined in any one of paragraphs (23) to (36) above. More preferably, R4 and R5 are as defined in any one of paragraphs (27) to (36) above. Most preferably, R4 and R5 are as defined in paragraphs (35) or (36) above.

[0100] Preferably, R 10c and R 10N is as defined in any one of paragraphs (14) to (22) above. More preferably, R 10c and R 10N is as defined in any one of paragraphs (19) to (22) above. Even more preferably, R 10c and R 10N is as defined in any one of paragraphs (20), (21) or (22) above.

[0101] Preferably, R6 is as defined in any one of paragraphs (37) to (39) above. More preferably, R6 is as defined in paragraph (39) above, i.e., R6 is hydrogen.

[0102] In certain groups of compounds of formula I above, R1 is as defined in any one of paragraphs (1), (2), (3), (4), (5), (6) or (7), and R2, R3, R4, R5 and R6 each have any one of the definitions described herein.

[0103] In a particular group of compounds of formula I above, R1 is as defined in paragraph (4), i.e., the compounds have the structural formula IA (a subformula of formula I) shown below:

[0104] [ka] wherein R2, R4, R5 and R6 each have one of the definitions described herein.

[0105] In one embodiment of the compound of formula IA, R2 is as defined in any one of paragraphs (8) to (11) above; R4 and R5 are as defined in any one of paragraphs (23) to (36) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (14) to (22); R6 is as defined in any one of paragraphs (37) to (39) above.

[0106] In one embodiment of the compound of formula IA, R2 is as defined in any one of paragraphs (9) to (11) above; R4 and R5 are as defined in any one of paragraphs (27) to (36) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (19) to (22); R6 is as defined in paragraph (38) or (39) above.

[0107] In one embodiment of the compound of formula IA, R2 is as defined in paragraph (10) or (11) above; R4 and R5 are as defined in paragraphs (35) or (36) above; the heterocycle formed by R4 and R5 is optionally substituted as defined in paragraphs (21) or (22) above; R6 is as defined in paragraph (38) or (39) above.

[0108] In one embodiment of the compound of formula IA, R2 is as defined in paragraph (11) above; R4 and R5 are as defined in paragraph (35) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (19) to (22); R6 is as defined in paragraph (38) or (39) above.

[0109] In one embodiment of the compound of formula IA, R2 is as defined in paragraph (11) above; R4 and R5 are as defined in any one of paragraphs (27) to (36) above; the heterocycle formed by R4 and R5 is optionally substituted as defined in paragraphs (21) or (22) above; R6 is as defined in paragraph (38) or (39) above.

[0110] In a particular group of compounds of formula I above, R1 is as defined in paragraph (5), i.e., the compound has the structural formula IB (a subformula of formula I) shown below:

[0111] [ka] wherein R2, R4, R5 and R6 each have one of the definitions described herein.

[0112] In one embodiment of the compound of formula IB, R2 is as defined in any one of paragraphs (8) to (11) above; R4 and R5 are as defined in any one of paragraphs (23) to (36) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (14) to (22); R6 is as defined in any one of paragraphs (37) to (39) above.

[0113] In one embodiment of the compound of formula IB, R2 is as defined in any one of paragraphs (9) to (11) above; R4 and R5 are as defined in any one of paragraphs (27) to (36) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (19) to (22); R6 is as defined in paragraph (38) or (39) above.

[0114] In one embodiment of the compound of formula IB, R2 is as defined in paragraph (10) or (11) above; R4 and R5 are as defined in paragraphs (35) or (36) above; the heterocycle formed by R4 and R5 is optionally substituted as defined in paragraphs (21) or (22) above; R6 is as defined in paragraph (38) or (39) above.

[0115] In one embodiment of the compound of formula IB, R2 is as defined in paragraph (11) above; R4 and R5 are as defined in paragraph (35) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (19) to (22); R6 is as defined in paragraph (38) or (39) above.

[0116] In one embodiment of the compound of formula IB, R2 is as defined in paragraph (11) above; R4 and R5 are as defined in any one of paragraphs (27) to (36) above; the heterocycle formed by R4 and R5 is optionally substituted as defined in paragraphs (21) or (22) above; R6 is as defined in paragraph (38) or (39) above.

[0117] In a particular group of compounds of formula I above, R1 is as defined in paragraph (7), i.e., the compounds have the structural formula IC (a subformula of formula I) shown below:

[0118] [ka] wherein R1, R4, R5 and R6 each have one of the definitions described herein.

[0119] In one embodiment of the compound of formula IC, R4 and R5 are as defined in any one of paragraphs (23) to (36) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (14) to (22); R6 is as defined in any one of paragraphs (37) to (39) above.

[0120] In one embodiment of the compound of formula IC, R4 and R5 are as defined in any one of paragraphs (27) to (36) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (19) to (22); R6 is as defined in paragraph (38) or (39) above.

[0121] In one embodiment of the compound of formula IC, R4 and R5 are as defined in paragraphs (35) or (36) above; the heterocycle formed by R4 and R5 is optionally substituted as defined in paragraphs (21) or (22) above; R6 is as defined in paragraph (38) or (39) above.

[0122] In one embodiment of the compound of formula IC, R4 and R5 are as defined in paragraph (35) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (19) to (22); R6 is as defined in paragraph (38) or (39) above.

[0123] In one embodiment of the compound of formula IC, R4 and R5 are as defined in any one of paragraphs (27) to (36) above; the heterocycle formed by R4 and R5 is optionally substituted as defined in paragraphs (21) or (22) above; R6 is as defined in paragraph (38) or (39) above.

[0124] In a particular group of compounds of formula I above, R6 is hydrogen, i.e., the compound has the structural formula ID (a subformula of formula I) shown below:

[0125] [ka] wherein R1, R4, and R5 each have one of the definitions described herein.

[0126] In one embodiment of the compound of formula ID, Preferably, R1 is as defined in any one of paragraphs (1) to (7) above; R4 and R5 are as defined in any one of paragraphs (23) to (36) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (14) to (22); R6 is as defined in any one of paragraphs (37) to (39) above.

[0127] In one embodiment of the compound of formula ID, R1 is as defined in paragraphs (3) through (7) above; R4 and R5 are as defined in any one of paragraphs (27) to (36) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (19) to (22); R6 is as defined in paragraph (38) or (39) above.

[0128] In one embodiment of the compound of formula ID, R1 is as defined in paragraphs (3) through (7) above; R4 and R5 are as defined in paragraphs (35) or (36) above; the heterocycle formed by R4 and R5 is optionally substituted as defined in paragraphs (21) or (22) above; R6 is as defined in paragraph (38) or (39) above.

[0129] In one embodiment of the compound of formula ID, R1 is as defined in paragraph (5), (6), or (7) above; R4 and R5 are as defined in paragraph (35) above; The heterocycle formed by R4 and R5 is optionally substituted with a substituent described in any one of the preceding paragraphs (19) to (22); R6 is as defined in paragraph (38) or (39) above.

[0130] In one embodiment of the compound of formula ID, R1 is as defined in paragraphs (3) through (7) above; R4 and R5 are as defined in any one of paragraphs (27) to (36) above; the heterocycle formed by R4 and R5 is optionally substituted as defined in paragraphs (21) or (22) above; R6 is as defined in paragraph (38) or (39) above.

[0131] In a particular group of compounds of formula I above, R1 is as defined in paragraph (4), and R4 and R5 are as defined in paragraph (36), i.e., the compounds have the structural formula IE or IF (subformula of formula I) shown below:

[0132] [ka] In the formula, R2, R6 and R 10c each have one of the definitions described herein.

[0133] In one embodiment of the compound of formula IE or IF, R2 is as defined in any one of paragraphs (8) to (11) above; R6 is as defined in any one of paragraphs (37) to (39) above; R 10c is as defined in any one of paragraphs (14) to (22) above.

[0134] In one embodiment of the compound of formula IE or IF, R2 is as defined in any one of paragraphs (9) to (11) above; R6 is as defined in paragraph (38) or (39) above; R 10c is as defined in any one of paragraphs (19) to (22) above.

[0135] In one embodiment of the compound of formula IE or IF, R2 is as defined in paragraph (10) or (11) above; R6 is as defined in paragraph (38) or (39) above; R 10c is as defined in any one of paragraphs (20), (21) or (22) above.

[0136] Particular compounds of the invention include any of the compounds described in the Examples section of this application, or a pharmaceutically acceptable salt or solvate thereof, particularly any of the following:

[0137] (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methyl-1H-indazol-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(7-methyl-3H-benzotriazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-piperazin-1-yl-piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-8-oxa-2,5-diazaspiro[3.5]nonane-2-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide, (3S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide, 4-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide, (3R)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide, (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide, 4-(1-cyano-1-methyl-ethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxamide, 4-(1-cyanoethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(dimethylamino)piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-[(dimethylamino)methyl]morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(2-pyrrolidin-1-ylethoxy)pyrrolidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-methyl-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridine-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(1-methyl-4-piperidyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-morpholino-piperidine-1-carboxamide, 4-(cyanomethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, (3S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1,4-diazepane-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide, (4aR,7aS)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxamide, 3-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, (2S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, (2R)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, (2S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, (2R)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(2-methylquinazolin-7-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(2,4-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-quinazolin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methyl-6-quinolyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methoxyquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-ethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, 4-cyano-N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1-methylpyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(3,8-dimethylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, 4-cyano-N-[4-(3-cyanophenyl)-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4,8-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1-methylpyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(3-methylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1,6-dimethylpyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(3-methylbenzimidazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-imidazo[1,2-a]pyridin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(7-methyl-1H-indazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(2,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(8-methylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(6-methylpyridazin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-[5-methyl-6-(triazol-2-yl)-3-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-pyrazolo[1,5-a]pyridin-5-yl-thiazol-2-yl]morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, or N-[5-(1,3-Benzoxazol-6-yl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide.

[0138] The various functional groups and substituents comprising the compound of formula (I) are typically selected so that the molecular weight of the compound of formula (I) does not exceed 1000. More usually, the molecular weight of the compound is less than 900, for example, less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, for example, 550 or less.

[0139] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of compounds of the present invention that are sufficiently basic, for example, acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid methanesulfonate, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris(2hydroxyethyl)amine.

[0140] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0141] The compounds of the present invention may have one or more asymmetric centers, and therefore, such compounds can be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both its individual enantiomers and mixtures, racemic or otherwise. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or resolution of racemates (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomeric centers (E and Z isomers). It should be understood that the present invention encompasses all optical, diastereomeric, and geometric isomers, and mixtures thereof, that possess antiproliferative activity.

[0142] The present invention also encompasses compounds of the present invention as defined herein that contain one or more isotopic substitutions. For example, H can be in any isotopic form, such as 1H, 2H (D), and 3H (T). C can be in any isotopic form, such as 12C, 13C, and 14C; O can be in any isotopic form, such as 16O and 18O, and so on.

[0143] It should also be understood that certain compounds of formula (I) can exist in unsolvated as well as solvated forms, such as, for example, hydrated forms, and it should be understood that the present invention encompasses all such solvated forms that possess antiproliferative activity.

[0144] It is also to be understood that certain compounds of formula I may exhibit polymorphism, and that the invention encompasses all such forms which possess antiproliferative activity.

[0145] Compounds of Formula I may exist in several different tautomeric forms, and references to compounds of Formula I include all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms but only one is specifically described or shown, all others are nevertheless encompassed by Formula I. Examples of tautomers include keto-, enol-, and enolate-forms, as found, for example, in the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0146] [ka]

[0147] Compounds of Formula I containing an amine functional group can also form N-oxides. Reference herein to compounds of Formula I containing an amine functional group also includes N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 1977. More specifically, N-oxides can be generated by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which, for example, an amine compound is reacted with m-chloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0148] The compounds of formula (I) may be administered in the form of prodrugs, which are broken down in the human or animal body to release the compounds of the present invention. Prodrugs may be used to alter the physical properties and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs may be formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives, which may be formed at a carboxy or hydroxy group in the compounds of formula (I), and in vivo cleavable amide derivatives, which may be formed at a carboxy or amino group in the compounds of formula (I).

[0149] The present invention therefore includes compounds of formula (I) as defined hereinbefore when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present invention includes compounds of formula I produced by organic synthetic means, and also includes compounds as produced in the human or animal body by metabolism of precursor compounds, i.e., compounds of formula (I) can be synthetically produced compounds or metabolically produced compounds.

[0150] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) are those that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity.

[0151] Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985), b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985), c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5 "Design and Application of Pro-drugs", by H.Bundgaard p.113-191(1991), d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988), f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984), g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14, and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0152] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a carboxy group are, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula I containing a carboxy group are, for example, pharmaceutically acceptable esters which are cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C1-6 alkyl esters such as methyl, ethyl and tert-butyl; C1-6 alkoxymethyl esters such as methoxymethyl ester; C1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl ester, 3-phthalidyl ester; C3-8 cycloalkylcarbonyloxy-C1-6 alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl ester; 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester; and C1-6 alkoxycarbonyloxy-C1-6 alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl ester.

[0153] Suitable pharmaceutically acceptable prodrugs of a compound of formula (I) having a hydroxy group are, for example, its in vivo cleavable esters or ethers. The in vivo cleavable esters or ethers of a compound of formula (I) containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the original hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include inorganic esters such as phosphate esters (e.g., phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include C1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, and C1-10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-6)2carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0154] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having a carboxy group are, for example, their in vivo cleavable amides, for example amides formed with amines such as ammonia, C1-4 alkylamines such as methylamine, (C1-4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-4 alkoxy-C2-4 alkylamines such as 2-methoxyethylamine, phenyl-C1-4 alkylamines such as benzylamine and amino acids such as glycine or its esters.

[0155] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, amides formed with C1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-4 alkyl)piperazin-1-ylmethyl.

[0156] The in vivo effects of the compounds of formula (I) may be exerted, in part, by one or more metabolic products formed in the human or animal body after administration of the compounds of formula (I). As noted hereinbefore, the in vivo effects of the compounds of formula (I) may also be exerted by metabolism of precursor compounds (prodrugs).

[0157] While the present invention may relate to any compound or particular group of compounds defined herein by any preferred or suitable feature or in any other way with respect to a particular embodiment, the present invention may also relate to any compound or particular group of compounds that explicitly excludes that any preferred or suitable feature or particular embodiment.

[0158] Preferably, the present invention excludes individual compounds that do not have biological activity as defined herein.

[0159] synthesis The compounds of the present invention may be prepared by any suitable technique known in the art. Particular methods for forming compounds of formula I as defined herein are illustrated in the accompanying Examples.

[0160] In describing the synthetic methods described herein and any referenced synthetic methods used to prepare starting materials, it should be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedure, can be selected by one of ordinary skill in the art.

[0161] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0162] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their undesired reactions. The skilled chemist will understand when such protection is necessary and how such protecting groups can be put in place and subsequently removed.

[0163] For examples of protecting groups, see one of the many general texts on the subject, such as "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to the skilled scientist as being suitable for the removal of the protecting group in question, such method being chosen to accomplish removal of the protecting group with minimal interference with groups elsewhere in the molecule.

[0164] Thus, if reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0165] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, e.g., alkanoyl groups such as acetyl; alkoxycarbonyl groups, e.g., methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl; arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl; or aroyl groups, e.g., benzoyl. The deprotection conditions for the above-mentioned protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, e.g., alkanoyl or alkoxycarbonyl groups, or aroyl groups, can be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium or sodium hydroxide. Alternatively, acyl groups, e.g., tert-butoxycarbonyl groups, can be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl groups, can be removed by hydrogenation over a catalyst, e.g., palladium on carbon, or by treatment with a Lewis acid, e.g., boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0166] Suitable protecting groups for hydroxy groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl), aroyl groups (e.g., benzoyl), or arylmethyl groups (e.g., benzyl). The deprotection conditions for the above protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups (e.g., alkanoyl or aroyl groups) can be removed by hydrolysis using a suitable base (e.g., alkali metal hydroxide, e.g., lithium, sodium hydroxide, or ammonia). Alternatively, arylmethyl groups (e.g., benzyl groups) can be removed by hydrogenation over a catalyst (e.g., palladium on carbon).

[0167] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group which may be removed by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed by treatment with an acid, for example an organic acid, such as trifluoroacetic acid, or for example a benzyl group which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0168] Resins can also be used as protecting groups.

[0169] The methods used to synthesize compounds of formula (I) will vary depending on the nature of R1, R2, R3, R4, R5 and R6 and any substituents associated therewith. Suitable processes for their preparation are further described in the accompanying Examples.

[0170] After a compound of formula (I) has been synthesised by any one of the methods defined herein, the method may further comprise one or more of the following additional steps: (i) removal of any protecting groups present; (ii) converting a compound of formula (I) into another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate of a compound of formula I; and / or (iv) forming a prodrug of a compound of formula I.

[0171] An example of (ii) above is when a compound of formula (I) is synthesized and then one or more of the groups R1, R2, R3, R4, R5 and R6 are further reacted to change the nature of the group to produce an alternative compound of formula (I).

[0172] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0173] biological activity The biological assays described in the Examples section (Biological Examples 1 to 3) can be used to measure the pharmacological effects of the compounds of the invention.

[0174] Although the pharmacological properties of compounds of formula I vary with structural changes, as expected, the compounds of the present invention were found to be active in the assays described in Biological Examples 1, 2 and 3.

[0175] Generally, with respect to adenosine A2a antagonism, compounds of the present invention have an IC2A activity of 1 μM or less in the assay described in Biological Example 1. 50 and preferred compounds of the present invention have an IC 50 and the most preferred compounds of the present invention have an IC of 50 nM or less. 50 Shows.

[0176] Generally, with respect to adenosine A2b antagonism, compounds of the present invention have an IC2b of 1 μM or less in the assay described in Biological Example 1. 50 and preferred compounds of the present invention have an IC 50 and the most preferred compounds of the present invention have an IC of 50 nM or less. 50 Shows.

[0177] Suitably, the IC50 of the compounds of the invention at adenosine A1 or A3 receptors in the assay described in Biological Example 1 50 is the IC at the adenosine A2a receptor 50 is at least two times higher, more preferably at least five times higher, and even more preferably at least ten times higher.

[0178] Pharmaceutical Composition According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present invention as defined hereinbefore or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0179] The compositions of the invention may be in a form suitable for oral use (e.g., in the form of tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., in the form of a finely divided powder or liquid aerosol), administration by insufflation (e.g., in the form of a finely divided powder) or parenteral administration (e.g., in the form of a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or in the form of a suppository for rectal administration).

[0180] The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0181] An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the proliferative conditions referred to herein.

[0182] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g of active agent (more preferably 0.5 to 100 mg, e.g., 1 to 30 mg), compounded with an appropriate and convenient amount of excipient, which may vary from about 5 to about 98% by weight of the total composition.

[0183] The size of a therapeutic or prophylactic dose of a compound of formula I will naturally vary according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0184] When using the compound of the present invention for therapeutic or prophylactic purposes, it is generally administered so that a daily dose of, for example, 0.1 mg / kg to 75 mg / kg body weight is administered, and if necessary, it is given in divided doses.Generally, when parenteral route is used, a lower dose is administered.Therefore, for example, when intravenously or intraperitoneally administered, a dose of, for example, 0.1 mg / kg to 30 mg / kg body weight is generally used.Similarly, when administered by inhalation, a dose of, for example, 0.05 mg / kg to 25 mg / kg body weight is used.Oral administration can also be suitable, especially in tablet form.Typically, a unit dosage form contains about 0.5 mg to 0.5 g of the compound of the present invention.

[0185] Therapeutic Uses and Applications The present invention provides compounds that function as antagonists of adenosine A2 receptors, particularly adenosine A2a receptors.

[0186] According to a further aspect of the present invention there is provided a method of antagonizing adenosine A2a receptors in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0187] According to a further aspect of the present invention there is provided a method of selectively antagonizing adenosine A2a receptors in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0188] According to a further aspect of the present invention there is provided a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0189] According to a further aspect of the present invention there is provided a method of treating a disease or disorder in which adenosine A2a receptor activity is implicated in a patient in need of such treatment, the method comprising administering to said patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0190] According to a further aspect of the present invention there is provided a method of treating a proliferative disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0191] According to a further aspect of the present invention there is provided a method of treating cancer in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0192] According to a further aspect of the invention there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0193] According to a further aspect of the present invention there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0194] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer. In certain embodiments, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0195] According to a further aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof for use as an adenosine A2a antagonist. In one embodiment, the compound of the present invention is a selective adenosine A2a antagonist. In an alternative embodiment, certain compounds of the present invention are selective adenosine A2a and adenosine A2b antagonists.

[0196] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which adenosine A2a is involved.

[0197] According to a further aspect of the present invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative condition. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0198] According to a further aspect of the present invention, there is provided the use of a compound defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the manufacture of a medicament for treating cancer. Preferably, the cancer is a human cancer. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0199] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use as an adenosine A2a antagonist.

[0200] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use as an adenosine A2a antagonist.

[0201] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which adenosine A2a receptor activity is implicated.

[0202] The term "proliferative disorder" is used interchangeably herein and refers to unwanted or uncontrolled cell proliferation of unwanted, excessive, or abnormal cells, e.g., neoplastic or hyperplastic proliferation, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, malignant neoplasms and tumors, including premalignant and malignant cell proliferation, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis. Any type of cell can be treated, including, but not limited to, lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

[0203] The antiproliferative effects of the compounds of the invention have particular application in the treatment of human cancers (due to their adenosine A2a antagonist activity).

[0204] More particularly, there is provided compounds of general formula (I) for use in the treatment of cancer, in particular solid tumors, such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma.

[0205] More particularly, there is provided a compound of general formula (I) for use in the treatment of cancer, for example lung cancer, such as small cell lung cancer or non-small cell lung cancer.

[0206] There is also provided the use of a compound of general formula (I) in the manufacture of a medicament for the treatment of cancer, in particular solid tumors, such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma and urothelial cancer.

[0207] The present invention further provides a method for treating cancer, in particular solid tumors such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma, which comprises administering to a patient in need of such treatment an effective amount of a compound of general formula (I).

[0208] The patient to be treated is preferably a mammal, more preferably a human.

[0209] Administration route The compounds of the present invention or pharmaceutical compositions containing these compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, at the desired site of action).

[0210] Routes of administration include, but are not limited to, oral (e.g., by ingestion), buccal, sublingual, transdermal (including, e.g., patches, bandages, etc.), transmucosal (including, e.g., patches, bandages, etc.), intranasal (e.g., by nasal spray), ophthalmic (e.g., by eye drops), pulmonary (e.g., via aerosol, e.g., used through the mouth or nose, e.g., by inhalation or insufflation therapy), rectal (e.g., by suppository or enema), vaginal (e.g., by pessary), parenteral by injection, such as, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, and intratumoral, e.g., by implantation of a depot or reservoir subcutaneously or intramuscularly.

[0211] The compounds of the present invention or pharmaceutical compositions containing these compounds may be administered by intratumoral delivery.

[0212] Combination therapy The compounds of formula I are useful for the treatment and / or prevention of proliferative disorders, such as cancer. The compounds of formula I as defined herein may be used in combination with one or more additional antiproliferative / anticancer therapies, such as chemotherapy with one or more additional antiproliferative / anticancer agents, radiation therapy, and / or conventional surgery.

[0213] The additional anti-proliferative / anti-cancer agent may be included in a pharmaceutical composition together with a compound of formula (I) as defined herein or may be administered simultaneously with the compound of formula (I), or separately at an earlier or later time point.

[0214] Thus, in a further aspect of the present invention there is provided a product comprising a compound of general formula (I) and an additional agent useful in the treatment or prevention of cancer as a combined preparation for simultaneous, sequential or separate use in the treatment of cancer.

[0215] The present invention also provides compounds of general formula (I) in combination with one or more additional anti-proliferative / anti-cancer agents for use in the treatment of cancer as a combined preparation for simultaneous, sequential or separate use in the treatment of cancer.

[0216] In particular, the combination therapy defined herein is suitable for the treatment of solid tumors, such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma.

[0217] Suitable additional anti-proliferative / anti-cancer agents that may be used in combination with compounds of formula I as defined herein (either separately or as part of a pharmaceutical composition or combined formulation in combination with a compound of general formula (I)) include: 1) other forms of cancer immunotherapy and anti-cancer chemotherapy agents; 2) adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors; 3) anti-PD-1 and PDL-1 antibodies, including but not limited to cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab; and 4) Anti-CTLA4 antibodies, including but not limited to ipilimumab.

[0218] The compounds of formula I as defined herein are particularly suitable for use in combination with anti-PD-1 and PDL-1 antibodies, including, but not limited to, cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab and atezolizumab.

[0219] Preferably, the anti-PD1 antibody is one of the antibodies disclosed in U.S. Patent Application Publication No. 2019 / 0225689 or U.S. Patent Application Publication No. 2017 / 0121409 (incorporated herein by reference in their entireties), such as cetrelimab. Cetrelimab (JNJ-63723283, CET) is a fully human immunoglobulin (Ig) G4 kappa monoclonal antibody that binds to programmed death receptor-1 (PD-1) with high affinity and specificity. Cetrelimab has demonstrated activity in solid tumors. Rutkowski P, et al. Journal of Clinical Oncology. 2019;37(8):31.

[0220] The compounds of formula I as defined herein are particularly suitable for use in combination with adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors and CD39 inhibitors.

[0221] The A2a antagonists of general formula (I) can also be used in combination with cell-based immunotherapies, including but not limited to CAR-T cell therapy, and cancer vaccines.

[0222] Examples of additional antiproliferative / anticancer chemotherapeutic agents include:Lastin; Thiocoraline; Thrombopoietin; Thrombopoietin mimetics; Thymalfasin; Thymopoietin receptor agonists; Thymotrin; Thyroid-stimulating hormone; Ethyl etiopurinse; Tirapazamine; Titanocene dichloride; Topsentin; Toremifene; Totipotent stem cell factor; Translation inhibitors; Tretinoin; Triacetyluridine; Triciribine; Trimetrexate; Triptorelin; Tropisetron; Turosteride; Tyrosine kinase inhibitors; Tyrphostins; UBC inhibitors; Ubenimex; Urogenital sinus-derived growth inhibitor; Urokinase receptor Antagonists; Vapreotide; Variolin B; Vector systems, red blood cell gene therapy; Veraresol; Veramine; Verdine; Verteporfin; Vinorelbine; Vinoxartin; Vitaxin; Vorozole; Zanoterone; Zeniplatin; Dilascorb; Zinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, Acivicin; Aclarubicin; Acodazole hydrochloride; Acronine; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Amethantrone acetate; Aminoglutethimide; Am Sacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene hydrochloride; Visnafide dimesylate; Biceresin; Bleomycin sulfate; Brequinar sodium; Bropirimine; Busulfan; Cactinomycin; Calsterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelcin; Cedefingol; Chlorambucil; Cilolemycin; Cladribine; Crisnatol mesylate ;Cyclophosphamide;Cytarabine;Dacarbazine;Daunorubicin hydrochloride;Decitabine;Dexorumaplatin;Dezaguanine;Dezaguanine mesylate;Diaziquone;Doxorubicin;Doxorubicin hydrochloride;Droloxifene;Droloxifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;Elsamitrucin;Enloplatin;Empromate;Epipropizin;Epirubicin hydrochloride;Elbrozole;Esorubicin hydrochloride;Estramustine;Estramustine phosphate sodium;Etanidazole; etoposide; etoposide phosphate; etopurine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine, foskidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin 2 (including recombinant interleukin 2, or rlL.sub.2), interferon alpha-2a; interferon alpha-2b; Interferon alfa-nl; interferon alfa-n3; interferon beta-la; interferon gamma-lb; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole; Lometerexol sodium hydrochloride; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcin; Mitochromin; Mitogillin; Mitomarcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazoie; Nogalamycin; Ormaplatin; Oxisuran; Pegaspargase; Periomycin; Pentamustine; Peplomycin sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone hydrochloride; Plicamycin; Promestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pirazofurin; Ribopurin; Rogletimide; Safingol; Safingol salts acid salt, semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride, spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; tallysomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxylon; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestron acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate phosphate; triptorelin; tuburozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phase and / or modulate the formation or stability of microtubules (e.g., Taxol™ (i.e., paclitaxel), taxanes, etc.) Sotere™, compounds containing a taxane skeleton, elbrozole (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobrine isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), orthrins (e.g., orthritol A and orthritol C), spongistatins (e.g., spongistatin 1, spongistatin 2,spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, spongistatin 9), cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilones (e.g., epothilone A, epothilone B, epothilone C (i.e., desoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16 aza-epothilone B, 21 amino epothilone B (i.e., BMS-3 10705), 21-hydroxyepothilone D (i.e., desoxyepothilone F and dEpoF), 26-fluoroepothilone, apristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), vincristine sulfate, cryptophycin 52 (i.e., LY-355703), bitilebamide, tubulysin A, canadensol, centauresin (i.e., NSC-106969), oncocidin A1 (i.e., BTO-956 and DF E), physianolide B, laulimalide, narcosine (also known as NSC-5366), nascapine, hemiasterlin, vanadocene acetylacetonate, monsatrol, lunanocin (i.e., NSC-698666), eleutherobin (such as desmethyleleutherobin, desaethyleleutherobin, isoeleutherobin A, and ZEeleutherobin), caribeoside, caribeolin, halichondrin B, diazonamide A, takalonolide A, diozostatin, (-)-phenylhistine (i.e., NSCL-96F037), myocerin B, Resbellastatin sodium phosphate, steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenal corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g.,testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, alpha interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-FER2, anti-CD52, anti-ULA-DR, anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas aeruginosa), exotoxin conjugates, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibodies conjugated to ln, 0Y, I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306 , ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, hormone therapy, and the like, but are not limited to one or more of the following.

[0223] As noted above, the combination therapies of the present invention may be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products utilize the compounds of this invention within the dosage ranges set forth hereinabove and the other pharmaceutically active agent within its approved dosage range.

[0224] According to this aspect of the invention there is provided a combination for use in the treatment of cancer (e.g. cancer involving solid tumours) comprising a compound of the invention as defined herein above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-proliferative / anti-cancer agents.

[0225] According to this aspect of the invention there is also provided a combination for use in the treatment of a proliferative condition, such as cancer (e.g. a cancer associated with a solid tumour), comprising a compound of the invention as defined herein above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional antiproliferative / anticancer agents selected from those listed above.

[0226] In a further aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer, optionally in combination with another anti-tumour agent selected from those listed herein above.

[0227] In this specification, when the term "combination" is used, it should be understood that it refers to simultaneous administration, separate administration, or sequential administration. In one aspect of the present invention, "combination" refers to simultaneous administration. In another aspect of the present invention, "combination" refers to separate administration. In a further aspect of the present invention, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such that the beneficial effect of the combination is lost.

[0228] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumor agent (optionally selected from those listed hereinabove), in association with a pharmaceutically acceptable diluent or carrier. [Example]

[0229] General conditions: Mass spectra were performed on an LC-MS system using electrospray ionization. These were performed using either a Waters Acquity H-Class UPLC equipped with PDA and QDa mass detection, an Acquity UPLC (binary pump / PDA detector) + ZQ mass spectrometer, or an Acquity i-Class (quaternary pump / PDA detector) + Quattro micro mass spectrometer, a Waters Acquity UPLC system equipped with Waters PDA and ELS detectors, or a Shimadzu LC-MS-2010EV system. [M+H]+ refers to the monoisotopic molecular weight.

[0230] NMR spectra were performed on either a Bruker Ultrashield 500 MHz NMR spectrometer or a Bruker Avance III HD 400 MHz NMR spectrometer. Spectra were recorded at 298 K and referenced using the solvent peak.

[0231] The following examples are intended to illustrate the present invention and should not be construed as limitations thereon. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporations are carried out in vacuo, preferably at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characterization, e.g., MS and NMR. Abbreviations used are conventional in the art. Unless defined, terms have their generally accepted meanings.

[0232] [Table 1]

[0233] With reference to the following examples, compounds of preferred embodiments were synthesized using methods described herein or other methods known in the art.

[0234] The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified, if necessary, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purification. Salts can be prepared from compounds by known salt-forming procedures.

[0235] Unless otherwise indicated, analytical HPLC conditions are as follows:

[0236] Equipment:LC-MS-1: Method 2A Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Flow rate: 0.8mL / min Eluent: A: HO, 0.1% formic acid, B: MeCN Gradient: 0.0–1.8 min 2–98% B, 1.8–2.1 min 98% B, 2.1–2.5 min 98% A.

[0237] Method 2B Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Flow rate: 0.8mL / min Eluent: A: H2O, 0.1% ammonia B: MeCN Gradient: 0.0–1.8 min 2–98% B, 1.8–2.1 min 98% B, 2.1–2.5 min 98% A.

[0238] Method 3A Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Eluent: A: HO, 0.1% formic acid, B: MeCN Flow rate: 0.6mL / min Gradient: 0.0–2.5 min 2–98% B, 2.5–3.3 min 98% B, 3.3–3.5 98% A.

[0239] Method 3B Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Eluent: A: H2O, 0.1% ammonia B: MeCN Flow rate: 0.6mL / min Gradient: 0.2–2.5 min 2–98% B, 2.5–3.3 min 98% B, 3.3–3.5 98% A.

[0240] Method 5A Column: YMC-Triart C18 50 x 2 mm, 5 μm. Column temperature: room temperature 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 4.4~5.0 minutes 95%A, 5%B.

[0241] Method 8A Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Eluent: A: HO, 0.1% formic acid, B: MeCN Flow rate: 0.6mL / min Gradient: 0.5–6.5 min 2–98% B, 6.5–7.6 min 98% B, 7.6–8.0 min 98% A.

[0242] Method 8B Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Eluent: A: H2O, 0.1% ammonia, B: MeCN Flow rate: 0.6mL / min Gradient: 0.5–6.5 min 2–98% B, 6.5–7.6 min 98% B, 7.6–8.0 min 98% A.

[0243] Equipment: LC-MS-2: Method 2A Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Flow rate: 0.8mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 2.0% formic acid Gradient: 0.0–1.7 min 0–95% B, 5% C; 1.7–2.1 min 95% B, 5% C 95%A, 5%C for 2.1~2.5 minutes.

[0244] Method 2B Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Flow rate: 0.8mL / min Eluent: A: HO, B: MeCN, C: 50% HO / 50% MeCN + 2.0% ammonia (aqueous solution) Gradient: 0.0–1.7 min 0–95% B, 5% D; 1.7–2.1 min 95% B, 5% D 2.1~2.5 minutes 95%A, 5%D.

[0245] Method 8A Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Flow rate: 0.8mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 2.0% formic acid Gradient: 0.0–0.5 min 95% A, 5% C; 0.5–6.5 min 0–95% B, 5% C; 6.6~7.5 minutes 95%B, 5%C; 7.5~7.6 minutes 0~95%A, 5%C; 7.6~8.0 minutes 95%A, 5%C.

[0246] Method 8B Column: Acquity UPLC BEH C18 2.1 x 50 mm 1.7 μm Column temperature: 50℃ Flow rate: 0.8mL / min Eluent: A: HO, B: MeCN, C: 50% HO / 50% MeCN + 2.0% ammonia (aqueous solution) Gradient: 0.0–0.5 min 95% A, 5% D; 0.5–6.5 min 0–95% B, 5% D; 6.6~7.5 minutes 95%B, 5%D; 7.5~7.6 minutes 0~95%A, 5%D; 7.6~8.0 minutes 95%A, 5%D.

[0247] Equipment:LC-MS Method 7A Column: Phenomenex Kinetix-XB C18 2.1 x 100 mm, 1.7 μm Column temperature: 40°C Eluent: A: H2O 0.1% formic acid, B: Acetonitrile 0.1% formic acid Flow rate: 0.6mL / min Gradient: 0–5.3 min 5–100% B, 5.3–5.8 min 100% B, 5.8–5.82 min 100–5% B, 5.82–7.00 min 5% B

[0248] Method 7B Column: Waters UPLC® BEH™ C18, 2.1 mm x 100 mm, 1.7 μm column Column temperature: 55℃ Eluent: A: 2 mM ammonium bicarbonate buffered to pH 10, B: acetonitrile Flow rate: 0.6mL / min Gradient: 0–5.3 min 5–100% B, 5.3–5.8 min 100% B, 5.8–5.82 min 100–5% B, 5.82–7.00 min 5% B

[0249] Equipment:LCMS-W Method 2A Column: Waters UPLC™ BEH™ C18 2.1 x 50 mm, 1.7 μm Column temperature: 40°C Eluent: A: H2O 0.1% formic acid, B: Acetonitrile 0.1% formic acid Flow rate: 0.9mL / min Gradient: 0–1.10 min 5–100% B, 1.10–1.35 min 100% B, 1.35–1.40 min 100–5% B, 1.40–1.50 min 5% B

[0250] Equipment:LCMS-S Method 2A Column: Kinetex Core-Shell C18, 2.1 mm x 50 mm, 5 μm Column temperature: 40°C Eluent: A: H2O 0.1% formic acid, B: Acetonitrile 0.1% formic acid Flow rate: 1.2mL / min Gradient: 0–1.20 min 5–100% B, 1.20–1.30 min 100% B, 1.30–1.31 min 100–5% B, 1.31–1.70 min 5% B

[0251] Example 1 (3S)-3-Cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide

[0252] [ka]

[0253] A mixture of 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) (100 mg, 0.29 mmol), CDI (94 mg, 0.58 mmol), and DIPEA (152 μL, 0.87 mmol) in DMA (1 mL) was stirred at 50 °C for 4 h. (3S)-3-Methylpyrrolidine-3-carbonitrile hydroiodide (Intermediate B) (139 mg, 0.58 mmol) and additional DIPEA (152 μL, 0.87 mmol) were added, and the mixture was heated for 15 min. The resulting mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and HO (20 mL). The organic portion was separated, and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (5 x 20 mL), dried over NaSO, and the solvent was removed in vacuo. Purification by chromatography on silica eluting with a gradient from 85% EtOAc in DCM to 3% MeOH in DCM gave a yellow glassy solid. The solid was dried in a vacuum oven at 50°C for 64 hours to give the title compound as a yellow solid. LC-MS-1 (Method 8A): 3.27 min at room temperature; MS m / z 480.4=[M+H]+ 1H NMR (500MHz, DMSO-d6) δ 11.25(s,1H),9.12(s,1H),8.22(d,J=2.0Hz,1H),7.96-7.89(m,2H),7.80(d ,J=7.8Hz,1H),7.77(dd,J=8.7,2.0Hz,1H),7.71(d,J=7.8Hz,1H),7.52(t,J =7.8Hz,1H),4.00-3.88(m,1H),3.75-3.66(m,1H),3.66-3.58(m,1H),3.47- 3.40(m,1H),2.84(s,3H),2.45-2.39(m,1H),2.12-2.04(m,1H),1.48(s,3H).

[0254] Example 2 N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide

[0255] [ka]

[0256] Step 1: tert-butyl 9-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-4-oxa-1,9-diazaspiro[5.5]undecane-1-carboxylate

[0257] [ka]

[0258] A mixture of 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) (250 mg, 0.73 mmol), CDI (236 mg, 1.46 mmol), and DIPEA (380 μL, 2.18 mmol) in DMA (2.5 mL) was stirred at 50° C. for 5.5 h. tert-Butyl 4-oxa-1,9-diazaspiro[5.5]undecane-1-carboxylate (373 mg, 1.46 mmol) was added, and the mixture was heated at 50° C. for 30 min. The resulting mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and HO (20 mL). The organic portion was separated, and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (5 × 20 mL), dried over NaSO, and the solvent was removed in vacuo. Purification by chromatography on silica eluting with 3% MeOH in DCM followed by a second purification by chromatography on silica eluting with 80% EtOAc in DCM gave the title compound as a yellow solid. LC-MS-1 (Method 2B): 1.49 min at room temperature; MS m / z 626.5=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.19(s,1H),9.11(s,1H),8.21(d,J=2.0Hz,1H),7.95-7.90(m,2H),7.81 -7.75(m,2H),7.71(dt,J=7.9,1.4Hz,1H),7.52(t,J=7.9Hz,1H),3.97(apr dt, J = 11.4, 6.8 Hz, 2H), 3.74-3.68 (m, 4H), 3.48 (t, J = 5.4 Hz, 2H), 3.18 (t, J = 12.8 Hz, 2H), 2.84 (s, 3H), 1.64 (dt, J = 13.6, 3.6 Hz, 2H), 1.38 (s, 9H). No CH2 signal was observed.

[0259] Step 2: N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide To a solution of tert-butyl 9-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-4-oxa-1,9-diazaspiro[5.5]undecane-1-carboxylate (Step 1) (216 mg, 0.35 mmol) in DCM (5 mL) was added TFA (0.53 mL, 6.9 mmol) dropwise, and the mixture was stirred at room temperature for 3 h. Volatile solvents were removed under a stream of nitrogen, and the resulting mixture was diluted with MeOH and loaded onto a 2.5 g Isolute® SCX cartridge (pre-wet with MeOH). The column was flushed with 5 column volumes of MeOH, and the product was eluted with 7 M NH3 in MeOH (4:1) (approximately 20 mL). The solvent was removed in vacuo and purified by C18 reverse phase chromatography eluting with 0.1% NH4OH in MeCN / water followed by silica chromatography eluting with 5% 7M NH3 in MeOH / DCM to give a yellow oil. Upon addition of Et2O (2 mL), a yellow solid formed which was collected by filtration, washed with Et2O (1 mL) and dried in a vacuum oven at 60 °C to give the title compound as a yellow solid. LC-MS-1 (Method 8B): 2.56 min at room temperature; MS m / z 526.5=[M+H]+ 1H NMR (500MHz, DMSO-d6) δ 11.15 (s, 1H), 9.12 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.96-7.90 (m, 2H), 7.80 (d, J = 7.8 Hz, 1H), 7.77 (dd, J = 8.8, 2.0 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 3.77-3.68 (m, 2H), 3.52-3.45 (m, 2H), 3.45-3.38 (m, 2H), 2.84 (s, 3H), 2.75-2.70 (m, 2H), 1.66-1.58 (m, 2H), 1.45-1.37 (m, 2H). 1×CH₂ and morpholine NH₂ were not observed.

[0260] Example 2.1 N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide

[0261] [ka]

[0262] Step 1: tert-butyl 4-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-3-(cyclopropylmethyl)piperazine-1-carboxylate

[0263] [ka]

[0264] The title compound was prepared analogously to Step 1 of Example 2 from 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) and tert-butyl 3-(cyclopropylmethyl)piperazine-1-carboxylate. LC-MS-W (Method 2A): 1.09 min at room temperature; MS m / z 610.3=[M+H]+ 1H NMR(400MHz,CDCl3)δ 9.18(s,1H),8.09(d,J=2.0Hz,1H),7.93(d,J=8.8Hz,1H),7.88(t,J=1.7Hz,1H),7.68(dd,J=8.7, 2.0Hz,1H),7.63-7.56(m,2H),7.35(dd,J=7.8,7.8Hz,1H),4.14(d,J=13.3Hz,3H),4.08-3.96(m,2 H), 3.90-3.77 (m, 1H), 3.18 (t, J = 12.5 Hz, 1H), 3.09 (d, J = 13.1 Hz, 1H), 2.97-2.89 (m, 1H), 2.87 (s, 3H), 1.45 (d, J = 1.2 Hz, 9H), 0.79-0.69 (m, 1H), 0.62-0.50 (m, 2H), 0.24-0.12 (m, 2H). NH was not observed.

[0265] Step 2: N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide The title compound was prepared from tert-butyl 4-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-3-(cyclopropylmethyl)piperazine-1-carboxylate (Step 1) and TFA in analogy to Step 2 of Example 2. LC-MS (Method 7A): 2.35 min at room temperature; MS m / z 510.1=[M+H]+ 1H NMR(400MHz,MeOD)δ 9.07(s,1H),8.25(d,J=2.0Hz,1H),7.97-7.93(m,2H),7.86(dd,J=8.8,2.0Hz,1H),7.71(dt,J=8.0,1.4Hz ,1H),7.66(dt,J=7.7,1.3Hz,1H),7.44(dd,J=7.8,7.8Hz,1H),4.38-4.31(m,1H),3.98-3.91(m,1H),3.08 (d, J = 13.1 Hz, 1H), 3.04-2.98 (m, 1H), 2.93 (dd, J = 13.1, 4.2 Hz, 1H), 2.88 (s, 3H), 2.73 (td, J = 12.6, 3.7 Hz, 2H), 1.76-1.64 (m, 2H), 0.75-0.68 (m, 1H), 0.49-0.44 (m, 2H), 0.16 (dd, J = 5.0, 1.8 Hz, 2H). 2 × NH was not observed.

[0266] Example 2.2 N-[4-(3-cyanophenyl)-5-(4-methyl-1H-indazol-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0267] [ka]

[0268] Step 1: N-[4-(3-cyanophenyl)-5-(4-methyl-1-trityl-indazol-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0269] [ka]

[0270] The title compound was prepared from 3-[2-amino-5-(4-methyl-1-trityl-indazol-6-yl)thiazol-4-yl]benzonitrile (Intermediate AO) and 2-oxa-6-azaspiro[3.3]heptane in analogy to Step 1 of Example 2. LC-MS-2 (Method 2B): 1.99 min at room temperature; MS m / z 697.3=[MH]- 1H NMR(500MHz,DMSO-d6)δ 11.20(s,1H),8.05(s,1H),7.86(s,1H),7.75(dd,J=12.3,7.9Hz,2H),7.50(t,J=7.9Hz,1H),7.4 2-7.36(m,10H),7.11(dd,J=7.2,2.6Hz,6H),6.69(s,1H),4.67(s,4H),4.20(s,4H),2.34(s,3H).

[0271] Step 2: N-[4-(3-cyanophenyl)-5-(4-methyl-1H-indazol-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide The title compound was prepared from N-[4-(3-cyanophenyl)-5-(4-methyl-1-trityl-indazol-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (Step 1) and TFA in analogy to Step 2 of Example 2. LC-MS-2 (Method 8B): 3.24 min at room temperature; MS m / z 457.1=[M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 13.03 (d, J = 1.6 Hz, 1H), 11.22 (s, 1H), 8.13 (d, J = 1.3 Hz, 1H), 7.88 (t, J = 1.8 Hz, 1H), 7.73 (dt, J = 7.6, 1.4 Hz, 1H), 7.67 (dt, J = 8.0, 1.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.24 (s, 1H), 6.82 (s, 1H), 4.68 (s, 4H), 4.20 (s, 4H). No CH3 was observed.

[0272] Example 2.3 N-[4-(3-cyanophenyl)-5-(7-methyl-3H-benzotriazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0273] [ka]

[0274] Step 1: N-[4-(3-cyanophenyl)-5-(7-methyl-3-trityl-benzotriazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0275] [ka]

[0276] The title compound was prepared from 3-[2-amino-5-(7-methyl-3-trityl-benzotriazol-5-yl)thiazol-4-yl]benzonitrile (Intermediate AP) and 2-oxa-6-azaspiro[3.3]heptane in analogy to Step 1 of Example 2. LC-MS-2 (Method 2B): 1.85 min at room temperature; MS m / z 698.3=[MH]-. 1H NMR(500MHz,DMSO)δ 11.21(s,1H),7.69(dt,J=7.0,1.8Hz,1H),7.61(d,J=1.8Hz,1H),7.42-7.34(m,2H),7.36-7.27(m, 9H),7.11(d,J=1.3Hz,1H),7.06-6.98(m,6H),5.92(s,1H),4.67(s,4H),4.18(s,4H),2.67(s,3H).

[0277] Step 2: N-[4-(3-cyanophenyl)-5-(7-methyl-3H-benzotriazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide The title compound was prepared from N-[4-(3-cyanophenyl)-5-(7-methyl-3-trityl-benzotriazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (Step 1) and TFA in analogy to Step 2 of Example 2. LC-MS-2 (Method 8B): 2.33 min at room temperature; MS m / z 458.0=[M+H]+ H NMR (500 MHz, MeOD) δ 7.92 (t, J = 1.7 Hz, 1H), 7.67 (dt, J = 8.0, 1.5 Hz, 1H), 7.63 (s, 1H), 7.61 (dt, J = 7.8, 1.4 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.18 (s, 1H), 4.84 (s, 4H), 4.33 (s, 4H), 2.66 (s, 3H). No 2×NH was observed.

[0278] Example 2.4 N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0279] [ka]

[0280] Step 1: tert-butyl 4-[4-(3-cyanophenyl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonylamino)thiazol-5-yl]pyrrolo[2,3-b]pyridine-1-carboxylate

[0281] [ka]

[0282] The title compound was prepared from tert-butyl 4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate AQ) and 2-oxa-6-azaspiro[3.3]heptane in analogy to Step 1 of Example 2. LC-MS-1 (Method 3B): 1.78 min at room temperature; MS m / z 543.2=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.42(s,1H),8.39(d,J=4.9Hz,1H),7.86(t,J=1.8Hz,1H),7.77-7.69(m,1H),7.55(dt,J=8.0,1.5Hz,1H), 7.44(t,J=7.9Hz,2H),7.21(d,J=5.0Hz,1H),6.24(d,J=4.1Hz,1H),4.69(s,4H),4.22(s,4H),1.61(s,9H).

[0283] Step 2: N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide The title compound was prepared from tert-butyl 4-[4-(3-cyanophenyl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonylamino)thiazol-5-yl]pyrrolo[2,3-b]pyridine-1-carboxylate (Step 1) and TFA in analogy to Step 2 of Example 2. LC-MS-1 (Method 8B): 3.49 min at room temperature; MS m / z 443.2=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.83(s,1H),11.36(s,1H),8.20(d,J=5.0Hz,1H),7.81(t,J=1.8Hz,1H),7.72(dt,J=7.7,1.5Hz,1H),7.62(dt,J =8.0,1.5Hz,1H),7.47-7.41(m,2H),6.97(d,J=5.0Hz,1H),6.05(dd,J=3.5,1.7Hz,1H),4.69(s,4H),4.22(s,4H).

[0284] Example 2.5 N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0285] [ka]

[0286] Step 1: N-[4-(3-cyanophenyl)-5-(6-methyl-1-trityl-pyrazolo[3,4-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0287] [ka]

[0288] The title compound was prepared from 3-[2-amino-5-(6-methyl-1-trityl-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl]benzonitrile (Intermediate S) and 2-oxa-6-azaspiro[3.3]heptane in analogy to Step 1 of Example 2. LC-MS-2 (Method 2B): 1.93 min at room temperature; MS m / z 700.3=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.48(s,1H),7.77(dt,J=7.7,1.4Hz,1H),7.66(dd,J=7.3,1.4Hz,2H),7.55-7.40(m,1H),7.33( s,1H),7.30-7.17(m,9H),7.14-7.06(m,6H),7.03(s,1H),4.68(s,4H),4.23(s,4H),2.20(s,3H).

[0289] Step 2: N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide The title compound was prepared from N-[4-(3-cyanophenyl)-5-(6-methyl-1-trityl-pyrazolo[3,4-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide (Step 1) and TFA in analogy to Step 2 of Example 2. LC-MS-2 (Method 8B): 2.62 min at room temperature; MS m / z 458.0=[M+H]+ 1H NMR(500MHz,DMSO)δ 13.52(s,1H),11.46(s,1H),7.85(t,J=1.7Hz,1H),7.76(dt,J=7.7,1.4Hz,1H),7.62(dt,J=8.0,1 .5Hz,1H),7.46(t,J=7.9Hz,1H),7.36(s,1H),7.06(s,1H),4.69(s,4H),4.23(s,4H),2.56(s,3H).

[0290] Example 3 N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-piperazin-1-yl-piperidine-1-carboxamide

[0291] [ka]

[0292] Step 1: tert-butyl 4-[1-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-4-piperidyl]piperazine-1-carboxylate

[0293] [ka]

[0294] A solution of 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) (50 mg, 0.15 mmol) and CDI (59 mg, 0.36 mmol) in DMA (0.5 mL) was stirred at 50° C. for 22 hours in a sealed vial. To this mixture was added tert-butyl 4-(4-piperidyl)piperazine-1-carboxylate (78 mg, 0.29 mmol), and heating was continued at 50° C. for 2 hours. The resulting mixture was allowed to cool to room temperature, diluted with water (10 mL), and then sonicated. A precipitate formed, which was collected under vacuum filtration and dried in a vacuum oven to give the title compound as a beige solid. LC-MS-W (Method 2A): 0.72 min at room temperature; MS m / z 639.2=[M+H]+ 1H NMR (500MHz, CDCl3) δ 9.18(s,1H),8.49(s,1H),8.09(d,J=2.0Hz,1H),7.93(d,J=8.8Hz,1H),7.91 -7.85(m,1H),7.69(dd,J=8.7,2.0Hz,1H),7.62-7.56(m,2H),7.35(dd,J=7.8 ,7.8Hz,1H),4.28-4.15(m,2H),3.65-3.44(m,4H),3.05-2.97(m,2H),2.87(s ,3H),2.73-2.53(m,4H),2.07-1.97(m,2H),1.67-1.60(m,2H),1.46(s,10H).

[0295] Step 2: N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-piperazin-1-yl-piperidine-1-carboxamide A solution of tert-butyl 4-[1-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-4-piperidyl]piperazine-1-carboxylate (Step 1) (88 mg, 0.13 mmol) in DCM (5 mL) and MeOH (0.5 mL) was treated with 4 M HCl in 1,4-dioxane (319 μL, 1.28 mmol) and stirred for 24 h. After standing at room temperature for an additional 24 h, the mixture was concentrated in vacuo and then purified using a 2 g Isolute® SCX cartridge and eluted with 7 M NH in MeOH. The resulting yellow gum was dissolved in 3:1:1 DMSO:MeCN:HO (1.4 mL) and purified using preparative HPLC under acidic conditions. Further purification using C18 reverse phase chromatography eluting with 0.1% NH4OH in MeCN / water gave the title compound as a yellow powder. LC-MS (Method 7A): 1.87 min at room temperature; MS m / z 539.2=[M+H]+ H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.95-7.89 (m, 2H), 7.81-7.73 (m, 2H), 7.70 (dt, J = 8.1, 1.4 Hz, 1H), 7.51 (dd, J = 7.8, 7.8 Hz, 1H), 4.29-4.21 (m, 2H), 2.90-2.79 (m, 5H), 2.75-2.69 (m, 4H), 2.47-2.40 (m, 5H), 1.81-1.73 (m, 2H), 1.40-1.27 (m, 2H). No 2×NH was observed.

[0296] Example 3.1 N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide

[0297] [ka]

[0298] Step 1: tert-butyl 9-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate

[0299] [ka]

[0300] The title compound was prepared from 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate in analogy to Step 1 of Example 3. LC-MS-W (Method 2A): 0.99 min at room temperature; MS m / z 626.2=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.23(s,1H),9.11(s,1H),8.20(s,1H),7.91(d,J=1.9Hz,1H),7.79(d,J=7.7Hz,1 H),7.78-7.75(m,1H),7.71(dt,J=8.3,1.2Hz,1H),7.52(dd,J=7.8,7.8Hz,1H),3. 87-3.80 (m, 2H), 3.62 (t, J = 5.0 Hz, 2H), 3.30-3.20 (m, 4H), 2.83 (s, 2H), 1.76-1.71 (m, 2H), 1.49 (t, J = 11.4 Hz, 2H), 1.41 (s, 9H), 1.26-1.21 (m, 2H). 1 × CH2 was not observed.

[0301] Step 2: N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide The title compound was prepared from tert-butyl 9-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (Step 1) and 4 M HCl in 1,4-dioxane in analogy to Step 2 of Example 3. LC-MS (Method 7A): 2.18 min at room temperature; MS m / z 526.1=[M+H]+ 1H NMR (500MHz, MeOD) δ 9.07 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.97-7.93 (m, 2H), 7.85 (dd, J = 8.7, 1.9 Hz, 1H), 7.71 (dt, J = 7.9, 1.4 Hz, 1H), 7.66 (dt, J = 7.7, 1.4 Hz, 1H), 7.43 (dd, J = 7.9, 7.9 Hz, 1H), 3.98-3.92 (m, 2H), 3.73-3.68 (m, 2H), 3.36-3.34 (m, 2H), 2.88 (s, 3H), 2.84-2.77 (m, 2H), 2.69 (s, 2H), 2.10-2.04 (m, 2H), 1.56-1.49 (m, 2H). 2 × NH was not observed.

[0302] Example 4 N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide

[0303] [ka]

[0304] Step 1: tert-butyl 2-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate

[0305] [ka]

[0306] To a solution of 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) (75 mg, 0.22 mmol) and CDI (107 mg, 0.66 mmol) in DMA (1 mL) was added DIPEA (0.12 mL, 0.69 mmol), and the reaction mixture was stirred at 50 °C for 3.5 h. tert-Butyl 6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (106 mg, 0.44 mmol) was added, and the mixture was stirred at 50 °C for 1 h. The resulting mixture was cooled to room temperature and partitioned between EtOAc (40 mL) and HO (40 mL). The phases were separated, and the aqueous portion was further extracted with EtOAc (2 × 40 mL). The organics were combined, washed with 90% brine (80 mL), 50% brine (80 mL), and brine (50 mL), dried over MgSO4, and concentrated in vacuo to give a yellow oil. Purification by chromatography on silica eluting with a gradient of 50 to 100% EtOAc in petroleum ether to 0 to 10% MeOH in EtOAc gave the title compound as a pale yellow solid. LC-MS-1 (Method 2B): 1.45 min at room temperature; MS m / z 612.5=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.10(s,1H),9.12(s,1H),8.21(d,J=2.0Hz,1H),8.14(s,1H),7.93-7. 91(m,1H),7.79(dd,J=7.7,1.4Hz,1H),7.77(dd,J=8.8,2.1Hz,1H),7.71 (dt,J=8.1,1.5Hz,1H),7.52(t,J=7.8Hz,1H),3.68-3.61(m,6H),3.57(d ,J=10.1Hz,4H),2.84(s,3H),2.09(dt,J=12.4,5.9Hz,2H),1.42(s,9H).

[0307] Step 2: N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide To a solution of tert-butyl 2-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate (Step 1) (90 mg, 0.093 mmol) in chloroform (3 mL) was added trimethylsilyl iodide (84 μL, 0.59 mmol), and the mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under a stream of nitrogen, chloroform (2 mL) was added, and the mixture was concentrated again. The crude mixture was dissolved in DMSO (1 mL) and purified by C18 reverse-phase chromatography eluting with 0.1% NH4OH in MeCN / water. The product was lyophilized overnight and then triturated with Et2O to give the title compound as a pale yellow solid. LC-MS-1 (Method 8B): 2.76 min at room temperature; MS m / z 512.5=[M+H]+ H NMR (500 MHz, DMSO-d) δ 11.06 (s, 1H), 9.12 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 9.6 Hz, 2H), 7.81-7.75 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 3.70-3.56 (m, 4H), 3.50 (s, 2H), 2.84 (s, 3H), 2.78 (d, J = 16.0 Hz, 2H), 2.72 (q, J = 5.2, 4.4 Hz, 2H), 2.09 (s, 1H), 1.91 (s, 1H). No morpholine NH was observed.

[0308] The compounds of the following examples (Table Ex4) were prepared analogously to steps 1 and 2 of Example 4 from 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) and the appropriate amine.

[0309] [Table 2-1]

[0310] [Table 2-2]

[0311] Example 5 (3S)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide

[0312] [ka]

[0313] Anhydrous DMA (15 mL) and DIPEA (2.28 mL, 13.1 mmol) were added to a mixture of 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) (1.5 g, 4.37 mmol) and CDI (1.42 g, 8.74 mmol) in a sealed flask, and the mixture was stirred at 50 °C for 18 h. A solution of 2-[(3S)-pyrrolidin-3-yl]propan-2-ol (1.13 g, 8.74 mmol) in anhydrous DMA (3 mL) was added, and the mixture was stirred at 50 °C for an additional 30 min. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (200 mL), and washed with 80% brine (200 mL) and 50% brine (3 × 200 mL). The organic portion was dried over Na SO and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0 to 5% MeOH in DCM gave a pale yellow foam / glass which was mechanically crushed to powder and dried in a vacuum oven at 50° C. overnight to give the title compound as a pale yellow solid. LC-MS-2 (Method 8A): 3.33 min at room temperature; MS m / z 499.2=[M+H]+ 1H NMR(500MHz,DMSO)δ 10.95(s,1H),9.11(s,1H),8.20(d,J=2.0Hz,1H),7.95-7.90(m,2H),7.81-7.75(m,2H),7.71(br dt,J=8.0,1.5Hz,1H),7.51(apr t,J=7.8Hz,1H),4.38(s,1H),3.65(br s,1H),3.57(br s,1H),3.27(br s,2H),2.83(s,3H),2.22(br s,1H),1.84(br s,2H),1.12(s,6H).

[0314] Example 6 4-Cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide

[0315] [ka]

[0316] Anhydrous DMA (2 mL) and DIPEA (228 μL, 1.31 mmol) were added to a mixture of 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) (150 mg, 0.44 mmol) and CDI (14 mg, 0.87 mmol) in a sealed tube under nitrogen, and the resulting orange-brown solution was stirred at 50° C. for 18 h. 4-Methylpiperidine-4-carbonitrile hydrochloride (140 mg, 0.87 mmol) and additional DIPEA (0.23 mL, 1.31 mmol) were added, and the mixture was stirred at 50° C. for an additional 3 h. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (20 mL), and washed with 80% brine (20 mL) followed by 50% brine (3×50 mL). The organic portion was dried over NaSO and concentrated in vacuo. Purification by silica chromatography, eluting with a gradient of 0 to 3% MeOH in DCM, gave a pale yellow solid. This material was azeotroped twice with MeCN, and the glassy residue was redissolved in DMSO (2 mL) and two drops of water were added. This mixture was repurified by C18 reverse-phase chromatography, eluting with MeCN / 0.1% NH4OH in water. Product fractions were combined and concentrated in vacuo to give a damp residue, which was azeotroped in a 1:1 mixture of MeCN and MeOH to give a clear yellow glass. This material was mechanically crushed to a powder and then dried under vacuum to give the title compound as a yellow solid. LC-MS-1 (Method 8A): 3.49 min at room temperature; MS m / z 494.4=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.33(br s,1H),9.11(s,1H),8.20(d,J=2.0Hz,1H),7.94-7.90(m,2H),7.79(br dt,J=7.6,1.5Hz,1H),7.76(dd,J=8.7,2.0Hz,1H),7.71(br dt,J=8.2,1.5Hz,1H),7.52(apr t,J=7.8Hz,1H),4.25(d,J=14.1Hz,2H),3.05(t,J=13.1Hz,2H),2.83(s,3H),1.93(d,J=13.6Hz,2H),1.54(td,J=13.1,4.0Hz,2H),1.38(s,3H).

[0317] Example 7 (3R)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide

[0318] [ka]

[0319] Anhydrous DMA (5.8 mL) and DIPEA (609 μL, 3.49 mmol) were added to a mixture of 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) (400 mg, 1.16 mmol) and CDI (378 mg, 2.33 mmol) in a sealed tube under nitrogen, and the mixture was stirred at 50° C. overnight. 2-[(3R)-Pyrrolidin-3-yl]propan-2-ol (301 mg, 2.33 mmol) was added, and the mixture was stirred at 50° C. for an additional 90 minutes. The resulting mixture was cooled to room temperature and then partitioned between EtOAc (50 mL) and HO (50 mL). The organic portion was separated, and the aqueous layer was further extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (5 × 40 mL), dried over NaSO, and the solvent was removed in vacuo. Purification by silica chromatography eluting with 0 to 5% MeOH in DCM gave a pale yellow glassy solid which was azeotroped and triturated with Et2O to give the title compound as a pale yellow solid. LC-MS-1 (Method 8A): 3.19 min at room temperature; MS m / z 499.4=[M+H]+ 1H NMR (500MHz, Methanol-d4) δ 9.07 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.98-7.91 (m, 2H), 7.85 (dd, J = 8.8, 2.0 Hz, 1H), 7.73-7.68 (m, 1H), 7.68-7.63 (m, 1H), 7.43 (t, J = 7.9 Hz, 1H), 3.73 (t, J = 9.4 Hz, 1H), 3.66 (dd, J = 10.2, 8.1 Hz, 1H), 3.45 (s, 1H), 3.39 (t, J = 10.1 Hz, 1H), 2.88 (s, 3H), 2.40 (s, 1H), 2.04 (s, 1H), 1.94 (s, 1H), 1.27 (d, J = 2.1 Hz, 6H). NH and OH protons were not observed.

[0320] The compounds of the following examples (Table Ex7) were prepared from 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) and the appropriate amine in the same manner as in Examples 5 to 7.

[0321] Table 3-1

[0322] Table 3-2

[0323] Table 3-3

[0324] Table 3-4

[0325] Table 3-5

[0326] Table 3-6

[0327] Table 3-7

[0328] Table 3-8

[0329] Table 3-9

[0330] Example 7.7a ​​and Example 7.7b Chiral separation of racemic N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methylethyl)morpholine-4-carboxamide (Example 7.7) using supercritical fluid chromatography was carried out to give the individual enantiomers using the following conditions: Purification conditions - Column details: Chiralpak IH (20 mm x 250 mm, 5 μm); column temperature: 40 °C, flow rate: 50 mL / min, BPR: 100 BarG, detector wavelength: 210 nm, injection volume: 500 μL (15.5 mg), isocratic conditions: 30:70 EtOH, CO2. Chiral purity analysis conditions - Column details: Chiralpak IH (4.6 mm × 250 mm, 5 μm); column temperature: 40 °C, flow rate: 4 mL / min, detector wavelength: 210–400 nm, injection volume: 1.0 μL, BPR: 125 BarG, isocratic conditions: 30:70 EtOH, CO (0.1% v / v NH).

[0331] Example 7.7a: (2S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide or (2R)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide

[0332] [ka]

[0333] First eluting peak: SFC retention time = 2.53 min LC-MS-1 (Method 8A): 3.20 min at room temperature; MS m / z 515.5=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.34(br s,1H),9.12(s,1H),8.21(br s,1H),7.95-7.90(m,2H),7.80(br d,J=7.7Hz,1H),7.77(br dd,J=8.6,2.0Hz,1H),7.71(br d,J=8.6Hz,1H),7.52(apr t,J=7.8Hz,1H),4.50(s,1H),4.26(br d,J=13.1Hz,1H),4.07(br d,J=13.1Hz,1H),3.94(dd,J=11.3,3.3Hz,1H),3.45(td,J=11.7,2.7Hz,1H),3.11(dd,J=10.9,2.4Hz,1H),2.99-2.92(m,1H),2.83(s,3H),2.80(br t,J=12.0Hz,1H),1.14(s,3H),1.10(s,3H).

[0334] Example 7.7b: (2S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide or (2R)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide

[0335] [ka]

[0336] Second eluting peak: SFC retention time = 3.05 min LC-MS-1 (Method 8A): 3.20 min at room temperature; MS m / z 515.5=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.34(br s,1H),9.12(s,1H),8.21(br s,1H),7.95-7.90(m,2H),7.80(br d,J=7.8Hz,1H),7.77(br dd,J=8.8,2.0Hz,1H),7.71(br d,J=8.1Hz,1H),7.52(apr t,J=7.8Hz,1H),4.50(s,1H),4.26(br d,J=13.1Hz,1H),4.07(br d,J=13.1Hz,1H),3.94(dd,J=11.3,3.3Hz,1H),3.45(td,J=11.7,2.8Hz,1H),3.11(dd,J=10.9,2.4Hz,1H),2.99-2.92(m,1H),2.83(s,3H),2.80(br t,J=11.9Hz,1H),1.14(s,3H),1.10(s,3H)

[0337] Example 8 N-[4-(3-cyanophenyl)-5-(2-methylquinazolin-7-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0338] [ka]

[0339] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(2-methylquinazolin-7-yl)thiazol-4-yl]benzonitrile (Intermediate AA) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8A): 2.62 min at room temperature; MS m / z 469.4=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.32(s,1H),9.50(s,1H),8.15(d,J=2.2Hz,1H),7.86(d,J=2.0Hz,1H),7.85(d,J=8.6Hz,1H),7.77(dd,J=7.8,1.5Hz,1H ),7.72(dd,J=8.7,2.1Hz,1H),7.67(dt,J=8.0,1.5Hz,1H),7.50(t,J=7.8Hz,1H),4.68(s,4H),4.21(s,4H),2.78(s,3H).

[0340] Example 9 N-[4-(3-cyanophenyl)-5-(2,4-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0341] [ka]

[0342] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(2,4-dimethylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate AB) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8B): 2.63 min at room temperature; MS m / z 483.8=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.19(s,1H),8.14(d,J=2.0Hz,1H),7.87(t,J=1.8Hz,1H),7.82(d,J=8.7Hz,1H),7.78(dt,J=7.6,1.5 Hz,1H),7.72-7.66(m,2H),7.50(t,J=7.9Hz,1H),4.68(s,4H),4.21(s,4H),2.78(s,3H),2.70(s,3H).

[0343] Example 10 N-[4-(3-cyanophenyl)-5-quinazolin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0344] [ka]

[0345] The title compound was prepared analogously to Example 7 from 3-(2-amino-5-quinazolin-6-yl-thiazol-4-yl)benzonitrile (Intermediate AC) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8B): 2.59 min at room temperature; MS m / z 455.4=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),9.61(s,1H),9.30(s,1H),8.22(s,1H),7.96(d,J=8.7Hz,1H),7.89(s,1H),7. 79(d,J=8.1Hz,2H),7.68(d,J=8.1Hz,1H),7.51(t,J=8.1Hz,1H),4.68(s,4H),4.22(s,4H).

[0346] Example 11 N-[4-(3-cyanophenyl)-5-(4-methyl-6-quinolyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0347] [ka]

[0348] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(4-methyl-6-quinolyl)thiazol-4-yl]benzonitrile (intermediate AD) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8A): 3.19 min at room temperature; MS m / z 468.4=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.22(s,1H),8.76(d,J=4.3Hz,1H),8.02(d,J=2.0Hz,1H),7.96(d,J=8.7Hz,1H),7.89(t,J=1.8Hz,1H),7.77(dt,J=7.6,1.5Hz,1H),7.71 (dt,J=8.1,1.4Hz,1H),7.56(dd,J=8.7,2.0Hz,1H),7.51(t,J=7.9Hz,1H),7.42-7.38(m,1H),4.68(s,4H),4.21(s,4H),2.59-2.56(m,3H).

[0349] Example 12 N-[4-(3-cyanophenyl)-5-(4-methoxyquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0350] [ka]

[0351] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(4-methoxyquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate AE) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-2 (Method 8A): 3.28 min at room temperature; MS m / z 485.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.34(s,1H),8.81(s,1H),8.07(d,J=2.1Hz,1H),7.90-7.84(m,2H),7.78(d,J=7.7Hz ,1H),7.73-7.67(m,2H),7.51(t,J=7.8Hz,1H),4.68(s,4H),4.20(s,4H),4.12(s,3H).

[0352] Example 13 N-[4-(3-cyanophenyl)-5-(4-ethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0353] [ka]

[0354] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(4-ethylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate AF) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-2 (Method 8B): 3.19 min at room temperature; MS m / z 483.1=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.30(br s,1H),9.17(s,1H),8.19(d,J=2.1Hz,1H),7.95(d,J=8.7Hz,1H),7.89(br t,J=1.5Hz,1H),7.82-7.76(m,2H),7.70(br dt,J=8.0,1.5Hz,1H),7.51(apr t,J=7.8Hz,1H),4.68(s,4H),4.22(s,4H),3.20(q,J=7.5Hz,2H),1.24(t,J=7.5Hz,3H).

[0355] Example 14 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide

[0356] [ka]

[0357] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(2,4-dimethyloxazol-5-yl)thiazol-4-yl]benzonitrile (Intermediate AG) and 4-methylpiperidine-4-carbonitrile hydrochloride. LC-MS-2 (Method 8B): 3.00 min at room temperature; MS m / z 447.1=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.36(s,1H),7.92(t,J=1.5Hz,1H),7.81(dt,J=7.6,1.5Hz,1H),7.76(dt,J=8.1,1.5Hz,1H),7.60(apr t,J=7.8Hz,1H),4.22(d,J=14.1Hz,2H),3.03(t,J=13.1Hz,2H),2.38(s,3H),1 .92(d,J=13.5Hz,2H),1.79(s,3H),1.53(td,J=13.5,4.1Hz,2H),1.37(s,3H).

[0358] Example 15 N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0359] [ka]

[0360] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(2,4-dimethyloxazol-5-yl)thiazol-4-yl]benzonitrile (Intermediate AG) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8B): 2.69 min at room temperature; MS m / z 422.1=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.41(s,1H),7.90(t,J=1.5Hz,1H),7.81(dt,J=7.7,1.5Hz,1H),7.75(dt,J=8.1,1.5Hz,1H),7.59(apr t,J=7.8Hz,1H),4.67(s,4H),4.20(s,4H),2.38(s,3H),1.76(s,3H).

[0361] Example 16 N-[4-(3-cyanophenyl)-5-(1-methylpyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0362] [ka]

[0363] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(1-methylpyrrolo[2,3-b]pyridin-3-yl)thiazol-4-yl]benzonitrile (intermediate AK) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8B): 3.01 min at room temperature; MS m / z 457.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.17(s,1H),8.29(dd,J=4.6,1.6Hz,1H),7.92(d,J=1.8Hz,1H),7.78(s,1H),7.73(dt,J=8.0,1.5Hz,1H),7.67(dt,J=7.8,1.5 Hz,1H),7.41(t,J=7.9Hz,1H),7.30(dd,J=7.9,1.6Hz,1H),6.99(dd,J=7.9,4.6Hz,1H),4.68(s,4H),4.20(s,4H),3.87(s,3H).

[0364] Example 17 N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0365] [ka]

[0366] Step 1: tert-butyl 3-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]pyrrolo[2,3-b]pyridine-1-carboxylate

[0367] [ka]

[0368] To a degassed solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (442 mg, 1.29 mmol), 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate Q) (300 mg, 1.07 mmol), and KCO (592 mg, 4.28 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added bis(tri-tert-butylphosphine)palladium(0) (55 mg, 0.11 mmol). The flask was evacuated and backfilled with nitrogen (three cycles) and heated at 50 °C for 1 h. The resulting mixture was cooled to room temperature and partitioned between EtOAc (40 mL) and water (40 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over MgSO and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 20 to 70% EtOAc in petroleum ether afforded the title compound as an orange solid. LC-MS-2 (Method 2B): 1.53 min at room temperature; MS m / z 418.0=[M+H]+ 1H NMR(500MHz,DMSO)δ 8.40(dd,J=4.7,1.6Hz,1H),7.89(t,J=1.8Hz,1H),7.84(s,1H),7.67(ddt,J=7.5,5.7,1.4 Hz,2H),7.42-7.35(m,2H),7.32(d,J=4.3Hz,2H),7.16(dd,J=7.9,4.7Hz,1H),1.62(s,9H).

[0369] Step 2.32: tert-butyl 3-[4-(3-cyanophenyl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonylamino)thiazol-5-yl]pyrrolo[2,3-b]pyridine-1-carboxylate

[0370] [ka]

[0371] The title compound was prepared analogously to Example 7 from tert-butyl 3-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]pyrrolo[2,3-b]pyridine-1-carboxylate (Step 1) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 2B): 1.32 min at room temperature; MS m / z 543.3=[M+H]+

[0372] Step 3: N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide To a stirred solution of tert-butyl 3-[4-(3-cyanophenyl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonylamino)thiazol-5-yl]pyrrolo[2,3-b]pyridine-1-carboxylate (crude product from Step 2) (134 mg, 0.25 mmol) in DCM (5 mL) was added TFA (0.63 mL, 8.17 mmol), and the solution was stirred at room temperature for 1 h. The resulting mixture was diluted with DCM (20 mL) and washed with aqueous NaHCO (20 mL) and brine (20 mL). The organic layer was dried over MgSO and concentrated in vacuo to give a yellow solid. Purification by chromatography on silica eluting with a gradient of 2 to 5% MeOH in DCM afforded the title compound as a beige solid. LC-MS-2 (Method 8B): 2.84 min at room temperature; MS m / z 443.0=[M+H]+ 1H NMR(500MHz,DMSO)δ 12.06(s,1H),11.16(s,1H),8.24(dd,J=4.7,1.6Hz,1H),7.89(t,J=1.7Hz,1H),7.74(dt,J=8.0,1.5Hz,1H),7.68(d,J=2.6Hz,1H),7 .66(dt,J=7.7,1.4Hz,1H),7.42(t,J=7.9Hz,1H),7.35(dd,J=8.0,1.6Hz,1H),6.97(dd,J=7.9,4.6Hz,1H),4.68(s,4H),4.20(s,4H).

[0373] Example 18 N-[4-(3-cyanophenyl)-5-(3,8-dimethylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0374] [ka]

[0375] The title compound was prepared from 3-[2-amino-5-(3,8-dimethylimidazo[1,2-a]pyridin-6-yl)thiazol-4-yl]benzonitrile (Intermediate AH) and 2-oxa-6-azaspiro[3.3]heptane in analogy to Example 7. LC-MS-2 (Method 8B): 2.83 min at room temperature; MS m / z 471.1=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.24(s,1H),8.15(s,1H),7.95(t,J=1.6Hz,1H),7.77-7.72(m,2H),7.50(apr t,J=7.9Hz,1H),7.36(d,J=1.1Hz,1H),6.83(t,J=1.6Hz,1H),4.68(s,4H),4.21(s,4H),2.44-2.37(m,6H).

[0376] Example 19 4-Cyano-N-[4-(3-cyanophenyl)-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide

[0377] [ka]

[0378] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-4-yl]benzonitrile (Intermediate AI) and 4-methylpiperidine-4-carbonitrile hydrochloride. LC-MS-1 (Method 8B): 2.59 min at room temperature; MS m / z 483.3=[M+H]+ 1H NMR(500MHz,DMSO)δ 12.87(s,1H),11.39(s,1H),8.17(s,1H),7.85(s,1H),7.69(d,J=7.7Hz,1H),7.49(d,J=8.0Hz,1H),7.36(t,J=7.9Hz,1H),7.30(s, 1H),4.24(d,J=14.0Hz,2H),3.06(t,J=13.0Hz,2H),2.60(s,3H),1.94(d,J=13.6Hz,2H),1.54(td,J=13.6,3.8Hz,2H),1.39(s,3H).

[0379] Example 20 N-[4-(3-cyanophenyl)-5-(4,8-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0380] [ka]

[0381] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(4,8-dimethylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate AJ) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-2 (Method 8B): 3.12 min at room temperature; MS m / z 483.1=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.34(s,1H),9.14(s,1H),8.00(d,J=2.0Hz,1H),7.93(t,J=1.8Hz,1H),7.80(dt,J=7.7,1.5Hz,1 H),7.75-7.65(m,2H),7.51(t,J=7.9Hz,1H),4.69(s,4H),4.23(s,4H),2.78(s,3H),2.61(s,3H).

[0382] Example 21 N-[4-(3-cyanophenyl)-5-(1-methylpyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0383] [ka]

[0384] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(1-methylpyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl]benzonitrile (intermediate AL) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-2 (Method 8B): 2.91 min at room temperature; MS m / z 457.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.36(s,1H),8.24(d,J=4.9Hz,1H),7.83(t,J=1.8Hz,1H),7.71(dt,J=7.6,1.4Hz,1H),7.58(dt,J=8.0,1.4Hz,1H),7.50( d,J=3.5Hz,1H),7.43(t,J=7.8Hz,1H),6.99(d,J=5.0Hz,1H),6.08(d,J=3.5Hz,1H),4.68(s,4H),4.21(s,4H),3.83(s,3H).

[0385] Example 22 N-[4-(3-cyanophenyl)-5-(3-methylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0386] [ka]

[0387] The title compound was prepared from m-{2-amino-5-(9-methyl-1,7-diazabicyclo[4.3.0]nona-2,4,6,8-tetraen-3-yl)-1,3-thiazol-4-yl}benzonitrile (intermediate AM) and 2-oxa-6-azaspiro[3.3]heptane in analogy to Example 7. LC-MS-2 (Method 8B): 2.71 min at room temperature; MS m / z 457.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.27(s,1H),8.32(s,1H),7.93-7.91(m,1H),7.78-7.73(m,2H),7.54-7.49(m,2H) ),7.41(s,1H),6.94(dd,J=9.2,1.8Hz,1H),4.68(s,4H),4.20(s,4H),2.44(s,3H).

[0388] Example 23 N-[4-(3-cyanophenyl)-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0389] [ka]

[0390] The title compound was prepared from 3-[2-amino-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-4-yl]benzonitrile (Intermediate AI) and 2-oxa-6-azaspiro[3.3]heptane in analogy to Example 7. LC-MS-2 (Method 8B): 2.45 min at room temperature; MS m / z 458.1=[M+H]+ 1H NMR(500MHz,DMSO)δ 12.85(s,1H),11.42(s,1H),8.16(s,1H),7.83(s,1H),7.68(d,J=7.7Hz,1H),7.48(d,J=8.0Hz,1H),7.36(apr t,J=7.8Hz,1H),7.30(s,1H),4.69(s,4H),4.23(s,4H),2.60(s,3H).

[0391] Example 24 N-[4-(3-cyanophenyl)-5-(1,6-dimethylpyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0392] [ka]

[0393] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(1,6-dimethylpyrrolo[2,3-b]pyridin-4-yl)thiazol-4-yl]benzonitrile (Intermediate AR) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-2 (Method 8B): 3.35 min at room temperature; MS m / z 471.1=[M+H]+ 1H NMR(500MHz,MeOD)δ 7.87(d,J=1.8Hz,1H),7.63(dt,J=8.1,1.5Hz,1H),7.57(dt,J=7.8,1.4Hz,1H),7.34(t,J=7.9Hz,1H),7.2 0(d,J=3.5Hz,1H),6.96(s,1H),6.04(d,J=3.5Hz,1H),4.60(s,4H),4.33(s,4H),3.87(s,3H),2.61(s,3H). No NH was observed.

[0394] Example 25 N-[4-(3-cyanophenyl)-5-(3-methylbenzimidazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0395] [ka]

[0396] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(3-methylbenzimidazol-5-yl)thiazol-4-yl]benzonitrile (Intermediate AS) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-2 (Method 8B): 2.64 min at room temperature; MS m / z 457.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.19(s,1H),8.23(s,1H),7.84(s,1H),7.71(d,J=7.8Hz,1H),7.67(d,J=7.8Hz,1H),7.64-7. 58(m,2H),7.46(t,J=7.8Hz,1H),7.06(d,J=8.5Hz,1H),4.68(s,4H),4.20(s,4H),3.81(s,3H).

[0397] Example 26 N-[4-(3-cyanophenyl)-5-imidazo[1,2-a]pyridin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0398] [ka]

[0399] The title compound was prepared analogously to Example 7 from 3-(2-amino-5-imidazo[1,2-a]pyridin-6-yl-thiazol-4-yl)benzonitrile (intermediate AT) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8B): 2.49 min at room temperature; MS m / z 443.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.30(s,1H),8.70(s,1H),7.95(s,1H),7.92(t,J=1.7Hz,1H),7.78-7.71(m,2H),7.60(d ,J=1.2Hz,1H),7.57-7.49(m,2H),6.97(dd,J=9.4,1.8Hz,1H),4.68(s,4H),4.19(s,4H).

[0400] Example 27 N-[4-(3-cyanophenyl)-5-(7-methyl-1H-indazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0401] [ka]

[0402] The title compound was prepared from tert-butyl 5-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-7-methyl-indazole-1-carboxylate (Intermediate AU) and 2-oxa-6-azaspiro[3.3]heptane in analogy to Example 7, and the mixture was heated for 16 hours after addition of the amine. LC-MS-1 (Method 8B): 3.03 min at room temperature; MS m / z 457.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 13.30(s,1H),11.16(s,1H),8.06(d,J=1.5Hz,1H),7.86(t,J=1.7Hz,1H),7.70(dt,J=7.7,1.4Hz,1H),7.65(dt,J= 8.1,1.5Hz,1H),7.55(d,J=1.5Hz,1H),7.44(t,J=7.9Hz,1H),7.04(s,1H),4.68(s,4H),4.20(s,4H),2.47(s,3H).

[0403] Example 28 N-[4-(3-cyanophenyl)-5-(2,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0404] [ka]

[0405] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(2,7-dimethylindazol-5-yl)thiazol-4-yl]benzonitrile (Intermediate AV) and 2-oxa-6-azaspiro[3.3]heptane. 1H NMR(500MHz,DMSO)δ 11.16(s,1H),8.32(s,1H),7.87(t,J=1.8Hz,1H),7.70(tt,J=7.7,1.4Hz,2H),7.52(d,J=1.6Hz,1H ),7.47(t,J=7.9Hz,1H),6.88(d,J=1.5Hz,1H),4.68(s,4H),4.20(s,4H),4.18(s,3H),2.44(s,3H). LC-MS-1 (Method 8B): 3.82 min at room temperature; MS m / z 471.2=[M+H]+

[0406] Example 29 N-[4-(3-cyanophenyl)-5-(8-methylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0407] [ka]

[0408] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(8-methylimidazo[1,2-a]pyridin-6-yl)thiazol-4-yl]benzonitrile (Intermediate AW) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8B): 3.72 min at room temperature; MS m / z 457.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.26(s,1H),8.54-8.52(m,1H),7.95(t,J=1.6Hz,1H),7.92(d,J=1.2Hz,1H),7.76(dt,J=7.8,1.6Hz,1H),7.73(dt,J=7. 8,1.6Hz,1H),7.56(d,J=1.2Hz,1H),7.51(t,J=7.8Hz,1H),6.86(t,J=1.5Hz,1H),4.68(s,4H),4.21(s,4H),2.42(s,3H).

[0409] Example 30 N-[4-(3-cyanophenyl)-5-(1,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0410] [ka]

[0411] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(1,7-dimethylindazol-5-yl)thiazol-4-yl]benzonitrile (intermediate AX) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8B): 4.22 min at room temperature; MS m / z 471.2=[M+H]+ 1H NMR(500MHz,DMSO)δ 11.16(br s,1H),7.96(s,1H),7.87(t,J=1.5Hz,1H),7.71(dt,J=7.7,1.5Hz,1H),7.65(dt,J=8.1,1.5Hz,1H),7.52(br s,1H),7.45(apr t,J=7.8Hz,1H),7.03(br s,1H),4.68(s,4H),4.27(s,3H),4.19(s,4H),2.69(s,3H).

[0412] Example 31 N-[4-(3-cyanophenyl)-5-(6-methylpyridazin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0413] [ka]

[0414] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(6-methylpyridazin-4-yl)thiazol-4-yl]benzonitrile (intermediate AY) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8B): 1.90 min at room temperature; MS m / z 419.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.50(s,1H),8.74(d,J=2.3Hz,1H),7.89(t,J=1.8Hz,1H),7.87(dt,J=7.8,1.5Hz,1H),7.71(d t,J=7.9,1.4Hz,1H),7.59(t,J=7.8Hz,1H),7.51(s,1H),4.67(s,4H),4.20(s,4H),2.59(s,3H).

[0415] Example 32 N-[4-(3-cyanophenyl)-5-[5-methyl-6-(triazol-2-yl)-3-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0416] [ka]

[0417] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-[5-methyl-6-(triazol-2-yl)-3-pyridyl]thiazol-4-yl]benzonitrile (Intermediate AN) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 8A): 3.27 min at room temperature; MS m / z 485.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 10.97(br s,1H),8.24(d,J=2.3Hz,1H),8.15(s,2H),7.94-7.91(m,2H),7.80(dd,J=7.8,1.5Hz,1H), 7.73(dt,J=7.8,1.5Hz,1H),7.56(t,J=7.8Hz,1H),4.68(s,4H),4.18(s,4H),2.25(s,3H).

[0418] Example 33 N-[4-(3-cyanophenyl)-5-pyrazolo[1,5-a]pyridin-5-yl-thiazol-2-yl]morpholine-4-carboxamide

[0419] [ka]

[0420] Step 1: N-[4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide

[0421] [ka]

[0422] To a stirred solution of 3-(2-aminothiazol-4-yl)benzonitrile (Intermediate P) (653 mg, 3.08 mmol) in THF (10 mL) was added sodium hydride (60% in mineral oil) (150 mg, 3.75 mmol) at 0 °C. After stirring at room temperature for 20 min, morpholine-4-carbonyl chloride (520 μL, 4.55 mmol) was added and stirring was continued for 18 h. The resulting mixture was diluted with THF (10 mL) and then re-treated with sodium hydride (60% in mineral oil) (150 mg, 3.75 mmol). After stirring for 10 min, morpholine-4-carbonyl chloride (520 μL, 4.55 mmol) was added and stirring was continued for 4 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (2 × 40 mL). The aqueous layer was acidified to pH 5 with 1 M HCl and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, and concentrated in vacuo. The resulting brown oil was purified by silica chromatography eluting with 0-100% EtOAc in heptane to afford the title compound as a beige solid. LC-MS-S (Method 2A): 1.06 min at room temperature; MS m / z 315.1=[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.31(t,J=1.5Hz,1H),8.21(dt,J=7.9,1.3Hz,1H),7.76(dt,J=7.7,1 .3Hz,1H),7.73(s,1H),7.63(t,J=7.8Hz,1H),3.67-3.58(m,4H),3.56-3.48(m,4H).

[0423] Step 2: N-[5-bromo-4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide

[0424] [ka]

[0425] To a solution of N-[4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide (Step 1) (790 mg, 2.34 mmol) in THF (20 mL) was added NBS (499 mg, 2.80 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with EtOAc (50 mL) and washed with water (30 mL), aqueous NaHCO (2 × 30 mL), and brine (30 mL). The organic layer was dried over MgSO and concentrated in vacuo to give the title compound as a yellow solid. LC-MS-S (Method 2A): 1.18 min at room temperature; MS m / z 393.0 / 395.0=[M+H]+ 1H 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).

[0426] Step 3: N-[4-(3-cyanophenyl)-5-pyrazolo[1,5-a]pyridin-5-yl-thiazol-2-yl]morpholine-4-carboxamide A stirred solution of N-[5-bromo-4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide (Step 2) (75 mg, 0.19 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (186 mg, 0.76 mmol), and cesium carbonate (186 mg, 0.57 mmol) in monoglyme (4 mL) and water (0.5 mL) was degassed with nitrogen for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.04 mmol) was added, and the sealed vessel was heated to 85 °C under nitrogen for 17 hours. The resulting mixture was allowed to cool to room temperature, diluted with water (2 mL), and extracted with EtOAc (4 × 3 mL). The combined organic extracts were filtered through a phase separation cartridge and concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with MeCN / 0.1% formic acid in water to give a solid which was triturated in MeCN, filtered and the filtrate concentrated in vacuo to give a yellow solid.

[0427] Purification by preparative HPLC (conditions below) gave the title compound as a yellow solid.

[0428] Purification conditions - column details: Waters XBridge C18 column (19 mm x 100 mm, 5 μm), column temperature: room temperature, flow rate: 20 mL / min, detector wavelength: 215 nm, solvent gradient: 5% B (A = 0.2% ammonium hydroxide in water, B = 0.2% ammonium hydroxide in acetonitrile) for 2.0 min, then a gradient of 5 to 55% B over 20 min, then a gradient of 55 to 100% B over 0.5 min, and hold for 2.0 min. LC-MS (Method 7B): 2.65 min at room temperature; MS m / z 431.2=[M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.91 (t, J = 1.4 Hz, 1H), 7.77-7.71 (m, 2H), 7.59 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 6.57 (s, 1H), 6.54 (dd, J = 7.1, 1.7 Hz, 1H), 3.61-3.54 (m, 4H), 3.53-3.47 (m, 4H). No NH was observed.

[0429] Example 34 N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0430] [ka]

[0431] Step 1: tert-butyl 4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-6-methylpyrrolo[2,3-b]pyridine-1-carboxylate

[0432] [ka]

[0433] The title compound was prepared from tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate R) and 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate Q) in analogy to Step 1 of Example 17. LC-MS-2 (Method 2B): 1.64 min at room temperature; MS m / z 432.1=[M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 7.79 (t, J = 1.5 Hz, 1H), 7.69 (dt, J = 7.7, 1.4 Hz, 1H), 7.56 (d, J = 4.1 Hz, 1H), 7.50 (dt, J = 8.0, 1.5 Hz, 1H), 7.49-7.43 (m, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.05 (s, 1H), 6.07 (d, J = 4.1 Hz, 1H), 1.59 (s, 9H). No 1×CH3 was observed.

[0434] Step 2: tert-butyl 4-[4-(3-cyanophenyl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonylamino)thiazol-5-yl]-6-methylpyrrolo[2,3-b]pyridine-1-carboxylate

[0435] [ka]

[0436] The title compound was prepared analogously to Example 7 from tert-butyl 4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-6-methyl-pyrrolo[2,3-b]pyridine-1-carboxylate (Step 1) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-1 (Method 3B): 1.83 min at room temperature; MS m / z 557.3=[M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 11.40 (s, 1H), 7.87 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.15 (s, 1H), 6.09-6.04 (m, 1H), 4.68 (s, 4H), 4.22 (s, 4H), 1.60 (s, 9H). No 1×CH3 was observed.

[0437] Step 3: N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide The title compound was prepared from tert-butyl 4-[4-(3-cyanophenyl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonylamino)thiazol-5-yl]-6-methyl-pyrrolo[2,3-b]pyridine-1-carboxylate (Step 2) and TFA in analogy to Step 3 of Example 17. LC-MS-2 (Method 8B): 2.89 min at room temperature; MS m / z 457.1=[M+H]+ H NMR (500 MHz, methanol-d) δ 7.86 (t, J = 1.5 Hz, 1H), 7.63 (dt, J = 7.8, 1.5 Hz, 1H), 7.55 (dt, J = 7.8, 1.5 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 3.5 Hz, 1H), 6.95 (s, 1H), 6.03 (d, J = 3.5 Hz, 1H), 4.83 (s, 4H), 4.31 (s, 4H), 2.55 (s, 3H). No 2×NH was observed.

[0438] Example 35 N-[5-(1,3-benzoxazol-6-yl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0439] [ka]

[0440] The title compound was prepared analogously to Example 7 from 3-[2-amino-5-(1,3-benzoxazol-6-yl)thiazol-4-yl]benzonitrile (intermediate AZ) and 2-oxa-6-azaspiro[3.3]heptane. LC-MS-2 (Method 2B): 2.84 min at room temperature; MS m / z 444.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 11.27(s,1H),8.79(s,1H),7.83(t,J=1.7Hz,1H),7.80(d,J=8.2Hz,1H),7.76(d,J=1.6Hz,1H),7.75-7.73(m, 1H),7.64(dt,J=8.0,1.4Hz,1H),7.48(t,J=7.8Hz,1H),7.30(dd,J=8.3,1.7Hz,1H),4.68(s,4H),4.20(s,4H).

[0441] Preparation of intermediate products intermediate product A 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile

[0442] [ka]

[0443] Step 1: 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline

[0444] [ka]

[0445] A solution of 6-bromo-4-methyl-quinazoline (5.0 g, 22.41 mmol) and bis(pinacolato)diboron (6.83 g, 26.9 mmol) in 1,4-dioxane (100 mL) was deoxygenated by nitrogen sparging for 10 minutes. Pd(dppf)Cl (1.64 g, 2.24 mmol) and KOAc (5.5 g, 56.04 mmol) were added, a reflux condenser was attached, and the system was evacuated and filled with nitrogen (3 cycles). The reaction mixture was stirred at 80 °C for 20 hours and then cooled to room temperature. The resulting mixture was diluted with EtOAc (100 mL) and filtered through a plug of Celite® (filter material), eluting with EtOAc. The filtrate was concentrated in vacuo to give the title compound as a dark brown residue. LC-MS-1 (Method 2B): 0.70 min at room temperature; MS m / z 271.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 9.14(s,1H),8.52(t,J=1.0Hz,1H),8.16(dd,J=8.3,1.0Hz,1H),7.96(d,J=8.3Hz,1H),2.96(s,3H),1.17(s,12H).

[0446] Step 2: 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile A solution of KCO (6.45 g, 46.67 mmol) in water (35 mL) was added to a solution of 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate Q) (5.23 g, 18.67 mmol) and crude 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (Step 1) (6.05 g, 22.4 mmol) in 1,4-dioxane (140 mL), and the mixture was deoxygenated by nitrogen sparging for 10 min. Bis(tri-tert-butylphosphine)palladium(0) (954 mg, 1.87 mmol) was added, the flask was sealed, and the contents were evacuated and backfilled with nitrogen (three cycles). The reaction mixture was stirred at 80 °C for 75 min and then cooled to room temperature. The resulting mixture was diluted with EtOAc (400 mL) and washed with water (400 mL) and brine (2 x 200 mL). The organic portion was dried over Na2SO4 and concentrated in vacuo to give a dark brown residue. This material was triturated in 2% MeOH in DCM (50 mL) with sonication, and the suspension was collected by filtration. The solid was washed with DCM (2 x 5 mL) and dried in vacuo to give a tan solid. This material was triturated with 10:1 MeOH / MeCN (30 mL) under sonication, and the suspension was filtered. The solid was washed with 10:1 MeOH / MeCN (10 mL) and dried in vacuo to give the title compound as a tan solid. LC-MS-2 (Method 2B): 1.22 min at room temperature; MS m / z 344.0=[M+H]+ 1H NMR(500MHz,DMSO)δ 9.08(s,1H),8.06(d,J=2.0Hz,1H),7.88(d,J=8.7Hz,1H),7.83(br t,J=1.5Hz,1H),7.76(br dt,J=7.7,1.5Hz,1H),7.71(dd,J=8.7,2.0Hz,1H),7.66(br dt,J=8.0,1.5Hz,1H),7.48(apr t,J=7.8Hz,1H),7.43(s,2H),2.78(s,3H).

[0447] The intermediates in the table below were prepared analogously to steps 1 and 2 of Intermediate A from the appropriate starting compounds.

[0448] [Table 4-1]

[0449] [Table 4-2]

[0450] [Table 4-3]

[0451] [Table 4-4]

[0452] [Table 4-5]

[0453] [Table 4-6]

[0454] [Table 4-7]

[0455] [Table 4-8]

[0456] [Table 4-9]

[0457] [Table 4-10]

[0458] [Table 4-11]

[0459] [Table 4-12]

[0460] [Table 4-13]

[0461] intermediate product B (3S)-3-Methylpyrrolidine-3-carbonitrile hydroiodide

[0462] [ka]

[0463] Step 1: Benzyl (3S)-3-carbamoyl-3-methyl-pyrrolidine-1-carboxylate

[0464] [ka]

[0465] A mixture of (3S)-1-benzyloxycarbonyl-3-methyl-pyrrolidine-3-carboxylic acid (5.0 g, 18.99 mmol) and CDI (3.39 g, 20.89 mmol) in anhydrous THF (100 mL) was stirred at room temperature for 2 hours under nitrogen. Ammonium hydroxide (35% in water) (43.21 mL, 379.81 mmol) was added and stirring was continued for 30 minutes. The THF was removed in vacuo, and the aqueous residue was extracted with EtOAc (100 mL). The organic fraction was washed with aqueous HCl (100 mL), saturated aqueous NaHCO (100 mL), and brine (100 mL), then dried over MgSO and concentrated in vacuo to give the title compound as a white solid. LC-MS-2 (Method 2B): 1.17 min at room temperature; MS m / z 263.0=[M+H]+ 1H NMR(500MHz,DMSO)δ 7.44-7.26(m,6H),6.97(s,1H),5.06(s,2H),3.69(dd,J=25.8,10.6Hz,1H),3.46-3.34(m,1H),3. 31-3.28(m,1H),3.11(dd,J=13.3,10.6Hz,1H),2.31-2.12(m,1H),1.78-1.61(m,1H),1.23(s,3H).

[0466] Step 2: Benzyl (3S)-3-cyano-3-methyl-pyrrolidine-1-carboxylate

[0467] [ka]

[0468] To a solution of benzyl (3S)-3-carbamoyl-3-methyl-pyrrolidine-1-carboxylate (Step 1) (1.0 g, 3.81 mmol) in DCE (15 mL) was added thionyl chloride (1.38 mL, 19.06 mmol), and the mixture was heated at 60° C. for 4 h. The resulting mixture was cooled to room temperature, and the solvent was removed in vacuo. The crude product was dissolved in EtOAc (20 mL) and washed with saturated aqueous NaHCO (20 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give the title compound as a yellow oil. LC-MS-1 (Method 2B): 1.30 min at room temperature; MS m / z 267.2=[M+Na]+ 1H NMR(500MHz,DMSO-d6)δ 7.40-7.35(m,4H),7.35-7.29(m,1H),5.09(s,2H),3.78(dd,J=22.8,10.9Hz,1H),3.58-3. 39(m,2H),3.31-3.24(m,1H),2.35-2.26(m,1H),2.06-1.94(m,1H),1.43(d,J=3.1Hz,3H).

[0469] Step 3: (3S)-3-Methylpyrrolidine-3-carbonitrile hydroiodide To a stirred solution of benzyl (3S)-3-cyano-3-methyl-pyrrolidine-1-carboxylate (Step 2) (300 mg, 1.23 mmol) in DCM (12 mL) under nitrogen at 0° C., trimethylsilyl iodide (0.42 mL, 2.95 mmol) was added dropwise via syringe. The resulting solution was warmed to room temperature and stirred for 1 h. MeOH (0.5 mL, 12.28 mmol) was added dropwise, precipitating a pale solid, and the resulting mixture was stirred at room temperature for 30 min and then at 0° C. for 15 min. The suspension was filtered, and the solid was washed with cold DCM (2×5 mL) and dried in vacuo to give the title compound as a white solid. 1H NMR(500MHz,DMSO-d6)δ 9.10(s,2H),3.66(d,J=12.2Hz,1H),3.40(ddd,J=12.0,8.0,5.4Hz,1H),3.35-3.28(m,1H),3.18 (d,J=12.3Hz,1H),2.44(ddd,J=13.1,7.6,5.4Hz,1H),2.06(dt,J=13.3,8.1Hz,1H),1.50(s,3H).

[0470] Intermediate product BA (3R)-3-Methylpyrrolidine-3-carbonitrile hydroiodide

[0471] [ka]

[0472] Step 1: Benzyl (3R)-3-carbamoyl-3-methyl-pyrrolidine-1-carboxylate

[0473] [ka]

[0474] The title compound was prepared from (3R)-1-benzyloxycarbonyl-3-methyl-pyrrolidine-3-carboxylic acid analogously to Intermediate B, Step 1. LC-MS-2 (Method 2B): 1.17 min at room temperature; MS m / z 263.0=[M+H]+ 1H NMR(500MHz,DMSO)δ 7.40-7.28(m,6H),6.97(s,1H),5.05(s,2H),3.68(dd,J=25.8,10.6Hz,1H),3.42-3.33(m,1H),3. 31-3.25(m,1H),3.11(dd,J=13.2,10.6Hz,1H),2.24-2.15(m,1H),1.75-1.66(m,1H),1.22(s,3H).

[0475] Step 2: Benzyl (3R)-3-cyano-3-methyl-pyrrolidine-1-carboxylate

[0476] [ka]

[0477] Benzyl (3R)-3-carbamoyl-3-methyl-pyrrolidine-1-carboxylate (Step 1) (996 mg, 3.8 mmol) and Burgess reagent (1.36 g, 5.7 mmol) were dissolved in DCM (9.5 mL) in a sealed tube under nitrogen and stirred at 35° C. for 17 h. The resulting mixture was allowed to cool to room temperature, diluted with DCM (40 mL), and washed with 1 M HCl (50 mL) followed by brine (25 mL). The organic portion was dried over NaSO and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 10 to 50% EtOAc in petroleum ether afforded the title compound as a clear, colorless syrup. LC-MS-2 (Method 2B): 1.39 min at room temperature; MS m / z 245.0=[M+H]+ 1H NMR(500MHz,DMSO)δ 7.40-7.28(m,5H),5.09(s,2H),3.78(dd,J=22.9,10.9Hz,1H),3.57-3.39(m,2H) ,3.30-3.25(m,1H),2.35-2.27(m,1H),2.05-1.94(m,1H),1.43(d,J=3.1Hz,3H).

[0478] Step 3: (3R)-3-Methylpyrrolidine-3-carbonitrile hydroiodide The title compound was prepared from benzyl (3R)-3-cyano-3-methyl-pyrrolidine-1-carboxylate (Step 2) and trimethylsilyl iodide in analogy to Step 3 of Intermediate B. 1H NMR(500MHz,DMSO)δ 9.10(br s,2H),3.66(d,J=12.2Hz,1H),3.40(ddd,J=11.9,8.0,5.4Hz,1H),3.35-3.29(m,1H),3.19(d, J=12.2Hz,1H), 2.43(ddd,J=13.2,7.6,5.4Hz,1H),2.06(dt,J=13.2,8.1Hz,1H),1.50(s,3H).

[0479] intermediate product C 2-Methyl-2-piperazin-1-yl-propanenitrile hydrochloride

[0480] [ka]

[0481] To a solution of tert-butyl 4-(1-cyano-1-methyl-ethyl)piperazine-1-carboxylate (250 mg, 0.99 mmol) in DCM (7.5 mL) was added 4 M HCl in 1,4-dioxane (4.93 mL, 19.74 mmol), and the mixture was stirred for 16 h. The solvent was removed in vacuo to give a white solid, which was suspended in EtO and collected by filtration. The solid was dried under high vacuum to give the title compound as a white solid. 1H NMR (500MHz, DMSO-d6) δ 9.16 (s, 2H), 3.10 (apr p, J=4.8Hz, 4H), 2.78 (apr t, J=5.0Hz, 4H), 1.46 (s, 6H).

[0482] intermediate product D 2-[(2S)-Piperazin-2-yl]propan-2-ol dihydrochloride

[0483] [ka]

[0484] Step 1: 1,4-Di-tert-butyl 2-methyl(2S)-piperazine-1,2,4-tricarboxylate

[0485] [ka]

[0486] A mixture of di-tert-butyl dicarbonate (479 mg, 2.19 mmol), 1-tert-butyl 2-methyl(2S)-piperazine-1,2-dicarboxylate (487 mg, 1.99 mmol), and triethylamine (0.39 mL, 2.79 mmol) in DCM (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (40 mL) and washed with saturated aqueous NaHCO (20 mL). The organic phase was dried over MgSO and concentrated in vacuo to give the title compound as a clear oil that solidified upon standing. 1H NMR(500MHz,DMSO-d6)δ 4.56(d,J=37.3Hz,1H),4.28(dd,J=31.7,13.8Hz,1H),3.83(s,1H),3.68(s,3H),3.23-2.72(m,4H),1.44-1.31(m,18H).

[0487] Step 2: Di-tert-butyl (2S)-2-(1-hydroxy-1-methyl-ethyl)piperazine-1,4-dicarboxylate

[0488] [ka]

[0489] To a solution of 1,4-di-tert-butyl 2-methyl(2S)-piperazine-1,2,4-tricarboxylate (Step 1) (712 mg, 2.07 mmol) in THF (20 mL) at 0 °C was added MeMgCl (3 M in THF) (1.72 mL, 5.17 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred at this temperature for 3 h. The reaction was diluted with DCM (70 mL) and washed with saturated NH4Cl solution (20 mL). The aqueous layer was extracted with DCM (20 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 1 to 2% MeOH in DCM afforded the title compound as a clear oil. 1H NMR(500MHz,DMSO-d6)δ 4.39(s,1H),4.03-3.43(m,4H),3.17-3.04(m,2H),3.01-2.82(m,1H),1.39(s,18H),1.17-1.01(m,6H)

[0490] Step 3: 2-[(2S)-piperazin-2-yl]propan-2-ol dihydrochloride To a solution of di-tert-butyl (2S)-2-(1-hydroxy-1-methyl-ethyl)piperazine-1,4-dicarboxylate (step 2) (331 mg, 0.96 mmol) in MeOH (8 mL) was added 4 N HCl in 1,4-dioxane (2.4 mL, 9.60 mmol) and the reaction mixture was stirred at room temperature for 6 h before being concentrated in vacuo to give the title compound as a white solid. 1H NMR(500MHz,DMSO-d6)δ 9.67(s,2H),9.41(s,1H),9.07(s,1H),5.57(s,1H),3.62-3.53(m,1H),3.49-3. 38(m,3H),3.29-3.21(m,2H),2.98(t,J=12.8Hz,1H),1.26(s,3H),1.19(s,3H).

[0491] intermediate product E 6-Bromo-4-ethyl-quinazoline

[0492] [ka]

[0493] Step 1: 1-(2-amino-5-bromo-phenyl)propan-1-one

[0494] [ka]

[0495] The following was prepared according to the procedure on pages 74-75 of WO 2018 / 130184:

[0496] To a stirred flask containing 2-amino-5-bromo-benzonitrile (5.0 g, 25.38 mmol) in THF (100 mL) at 0 °C was added ethylmagnesium bromide (3 M in EtO) (25.38 mL, 76.13 mmol) and the solution was stirred at 0 °C for 15 min. The mixture was allowed to warm to room temperature and stirred overnight. The resulting solution was recooled to 0 °C and treated with saturated aqueous NH Cl (100 mL). EtOAc (300 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (300 mL) and the combined organic extracts were washed with brine (300 mL), dried over MgSO and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 0 to 40% EtOAc in petroleum ether afforded the title compound as a yellow solid. LC-MS-2 (Method 2B): 1.54 min at room temperature; MS m / z 227.9 / 229.9=[M+H]+ 1H NMR(500MHz,DMSO)δ 7.85(d,J=2.4Hz,1H),7.35(dd,J=8.9,2.4Hz,1H),7.30(s,2H),6.74(d,J=8.9Hz,1H),2.96(q,J=7.2Hz,2H),1.04(t,J=7.2Hz,3H).

[0497] Step 2: 6-Bromo-4-ethyl-quinazoline The following was prepared according to the procedure on pages 74-75 of WO 2018 / 130184:

[0498] A solution of 1-(2-amino-5-bromo-phenyl)propan-1-one (Step 1) (1.3 g, 5.7 mmol) and ammonium acetate (1.32 g, 17.1 mmol) in triethyl orthoformate (2.84 mL, 17.1 mmol) was stirred at 110 °C for 1 h. The resulting mixture was allowed to cool to room temperature and partitioned between EtOAc (50 mL) and saturated aqueous NaHCO (50 mL). The layers were separated and the aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over MgSO and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 20 to 40% EtOAc in petroleum ether afforded the title compound as a yellow solid. LC-MS-1 (Method 2B): 1.47 min at room temperature; MS m / z 237.1 / 239.1=[M+H]+ 1H NMR(500MHz,DMSO)δ 9.21(s,1H),8.54(d,J=2.2Hz,1H),8.11(dd,J=8.9,2.2Hz,1H),7.94(d,J=8.9Hz,1H),3.42-3.24(m,2H),1.34(t,J=7.4Hz,3H).

[0499] intermediate product F 5-Bromo-3-methyl-2-(triazol-2-yl)pyridine

[0500] [ka]

[0501] To a solution of 5-bromo-2-chloro-3-methyl-pyridine (2.0 g, 9.69 mmol) in DMF (15 mL) was added K2CO3 (2.68 g, 19.37 mmol) and 2H-triazole (0.84 mL, 14.53 mmol), and the mixture was heated to 90 °C for 17 h, then at 100 °C for an additional 2 h. Additional 2H-triazole (0.84 mL, 14.53 mmol) and K2CO3 (2.68 g, 19.37 mmol) were added, and stirring was continued at 100 °C for 18 h. The resulting mixture was diluted with 90% brine (100 mL) and EtOAc (100 mL), and the layers were separated. The organics were washed with 50% brine (3 × 100 mL), dried over Na2SO4, and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 0 to 20% EtOAc in petroleum ether afforded the title compound as a clear oil. LC-MS-1 (Method 5A): 2.56 min at room temperature; MS m / z 240.9=[M+H]+ 1H NMR (500MHz, Chloroform-d) δ 8.54-8.49 (m, 1H), 7.95-7.87 (m, 3H), 2.51-2.45 (m, 3H).

[0502] intermediate product G 6-Bromo-2,4-dimethyl-quinazoline

[0503] [ka]

[0504] The following was prepared according to the procedure of Raju et al, Chemistry Select, 2018, 3, 32, 9388-9392:

[0505] A mixture of 1-(2-amino-5-bromo-phenyl)ethanone (2.5 g, 11.68 mmol), acetylacetone (1.44 mL, 14.01 mmol), and ammonium acetate (2.7 g, 35.04 mmol) was heated at 100 °C for 3.5 h. The mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and HO (100 mL). The organic fraction was separated and the aqueous layer was further extracted with EtOAc (2 × 50 mL), then the combined organic layers were washed with brine (2 × 50 mL), dried over NaSO, and the solvent removed in vacuo. Purification by silica chromatography eluting with 70% EtOAc in DCM gave a solid that was suspended in EtO, collected by filtration, and dried to give the title compound as a cream-colored solid. LC-MS-1 (Method 2B): 1.22 min at room temperature; MS m / z 237.1 / 239.1=[M+H]+ 1H NMR (500MHz, Chloroform-d) δ 8.20(d,J=2.1Hz,1H),7.90(dd,J=9.0,2.1Hz,1H),7.80(d,J=9.0Hz,1H),2.89(s,3H),2.83(s,3H).

[0506] intermediate product H 6-Bromo-3,8-dimethyl-imidazo[1,2-a]pyridine

[0507] [ka]

[0508] Step 1: tert-butyl N-(5-bromo-3-methyl-2-pyridyl)-N-tert-butoxycarbonyl-carbamate

[0509] [ka]

[0510] To a solution of 5-bromo-6-methyl-pyridin-2-amine (2.0 g, 10.69 mmol) in DCM (50 mL) was added di-tert-butyl dicarbonate (2.8 g, 12.83 mmol), triethylamine (2.24 mL, 16.04 mmol), and DMAP (65 mg, 0.53 mmol), and the mixture was stirred at room temperature for 4 h. Additional di-tert-butyl dicarbonate (2.8 g, 12.83 mmol), triethylamine (2.24 mL, 16.04 mmol), and DMAP (65.32 mg, 0.53 mmol) were added, and stirring was continued at room temperature for an additional 16 h. The resulting mixture was washed with water (50 mL), and the aqueous fraction was further extracted with DCM (2 × 30 mL). The combined organic layers were dried over MgSO4 and the solvent removed in vacuo to give a viscous brown oil which solidified to give the title compound as a brown solid. LC-MS-1 (Method 2B): 1.56 min at room temperature; MS m / z 387.2 / 389.2=[M+H]+ 1H NMR (500MHz, Chloroform-d) δ 8.35-8.31 (m, 1H), 7.67-7.64 (m, 1H), 2.15 (t, J = 0.8Hz, 3H), 1.34 (s, 18H).

[0511] Step 2: tert-butyl N-(5-bromo-3-methyl-2-pyridyl)carbamate

[0512] [ka]

[0513] To a solution of crude tert-butyl N-(5-bromo-3-methyl-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (Step 1) (1.0 g, 2.58 mmol) in DCM (10 mL) was added TFA (0.4 mL, 5.16 mmol) dropwise, and the mixture was stirred at room temperature for 65 h. Additional TFA (0.2 mL, 2.58 mmol) was added, and stirring was continued for 20 h. Three additional portions of TFA (0.2 mL, 2.58 mmol) were added at 20-h intervals, and the mixture was stirred for an additional 48 h after the final addition. The resulting mixture was washed with saturated aqueous NaHCO3 (3 x 20 mL), dried over MgSO4, and the solvent removed in vacuo. Purification by silica chromatography, eluting with 0.5% MeOH in DCM, afforded the title compound as a white solid. LC-MS-2 (Method 2B): 1.51 min at room temperature; MS m / z 286.9 / 288.9=[M+H]+ 1H NMR (500MHz, CDCl3) δ 8.30 (d, J = 2.3 Hz, 1 H), 7.66-7.62 (m, 1 H), 6.67 (s, 1 H), 2.27 (s, 3 H), 1.51 (s, 9 H).

[0514] Step 3: tert-butyl N-(5-bromo-3-methyl-2-pyridyl)-N-prop-2-ynyl-carbamate

[0515] [ka]

[0516] A cooled (0 °C) solution of tert-butyl N-(5-bromo-3-methyl-2-pyridyl)carbamate (Step 2) (257 mg, 0.90 mmol) in anhydrous DMF (3.6 mL) was treated with NaH (60% dispersion in mineral oil) (43 mg, 1.07 mmol) in one portion, and the mixture was stirred at 0 °C for 15 min. Propargyl bromide (80 wt % in toluene) (120 μL, 1.07 mmol) was added dropwise, and stirring was continued at 0 °C for 10 min, then at room temperature for an additional 2 h 20 min. The reaction was quenched by the careful addition of water (1 mL). The resulting mixture was diluted with EtOAc (40 mL), and the organic fraction was washed with 90% brine (20 mL) and 50% brine (3 × 20 mL), then dried over Na SO and concentrated in vacuo to afford the title compound as a yellow syrup. LC-MS-2 (Method 2B): 1.72 min at room temperature; MS m / z 324.9 / 326.9=[M+H]+ 1H NMR(500MHz, CDCl3)δ 8.37(d,J=2.4Hz,1H),7.71(dd,J=2.4,0.8Hz,1H),4.82-4.25(m,2H),2.29(s,3H),2.12(br t,J=2.5Hz,1H),1.43(s,9H).

[0517] Step 4: 5-Bromo-3-methyl-N-prop-2-ynyl-pyridin-2-amine

[0518] [ka]

[0519] To a solution of tert-butyl N-(5-bromo-3-methyl-2-pyridyl)-N-prop-2-ynylcarbamate (Step 3) (260 mg, 0.80 mmol) in DCM (4 mL) was added TFA (2.0 mL, 26.12 mmol), and the mixture was stirred at room temperature for 40 min. The resulting mixture was diluted with DCM (25 mL) and saturated aqueous NaHCO (50 mL), and the mixture was stirred until effervescence ceased. The layers were separated, and the aqueous portion was further extracted with DCM (25 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo to give the title compound as a cloudy, light brown oil. LC-MS-2 (Method 2B): 1.46 min at room temperature; MS m / z 224.9 / 226.9=[M+H]+ 1H NMR(500MHz,CDCl3)δ 8.08(d,J=2.4Hz,1H),7.36(dd,J=2.4,1.0Hz,1H),4.29(br s,1H),4.24(dd,J=5.0,2.5Hz,2H),2.23(t,J=2.5Hz,1H),2.10(s,3H).

[0520] Step 5: 6-Bromo-3,8-dimethyl-imidazo[1,2-a]pyridine The following was prepared according to the procedure of Adimurthy et al, J. Org. Chem. 2013, 78, 1266-1272:

[0521] Under nitrogen, water (4 mL) was added to 5-bromo-3-methyl-N-prop-2-ynyl-pyridin-2-amine (Step 4) (177 mg, 0.79 mmol) in a sealed tube, and the mixture was stirred at 120° C. for 1 h. The resulting mixture was cooled to room temperature and then partitioned between DCM (20 mL) and saturated NaHCO solution (20 mL). The organic fraction was separated, and the aqueous layer was further extracted with DCM (2×20 mL). The combined organic portions were dried over NaSO and concentrated in vacuo. Purification by chromatography on silica eluting with EtOAc gave a pale yellow syrup that slowly crystallized to give the title compound as an off-white waxy solid. LC-MS-2 (Method 2B): 1.32 min at room temperature; MS m / z 224.9 / 226.9=[M+H]+ 1H NMR (500MHz, MeOD) δ 8.28 (s, 1H), 7.34 (s, 1H), 7.20 (s, 1H), 2.53 (s, 3H), 2.48 (s, 3H).

[0522] Intermediate product I 6-Bromo-4,8-dimethyl-quinazoline

[0523] [ka]

[0524] Step 1: 1-(2-amino-5-bromo-3-methyl-phenyl)ethanone

[0525] [ka]

[0526] The following was prepared according to the procedure on page 41 of WO 2020 / 011220:

[0527] To a solution of 2-amino-5-bromo-3-methyl-benzonitrile (1.94 g, 0.01 mmol) in THF (92 mL) at −10° C. was added methylmagnesium bromide (3.4 M in 2-Me-THF) (13.5 mL, 0.05 mmol) dropwise, and the mixture was stirred overnight while warming to room temperature. 10% HCl (92 mL, 0.01 mmol) was added dropwise, and the resulting mixture was stirred for 1 h before being extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (90 mL), dried over NaSO, and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 0 to 50% EtOAc in petroleum ether, followed by trituration of the product with MeOH, afforded the title compound as a yellow solid. LC-MS-2 (Method 2B): 1.53 min at room temperature; MS m / z 226.1 / 228.1=[MH]- 1H NMR (500MHz, DMSO-d6) δ 7.76 (s, 1H), 7.35 (s, 1H), 7.18 (s, 2H), 2.53 (s, 3H), 2.10 (s, 3H).

[0528] Step 2: 6-Bromo-4,8-dimethyl-quinazoline The following was prepared according to the procedure on page 42 of WO 2020 / 011220:

[0529] A mixture of triethyl orthoformate (0.91 mL, 5.47 mmol) with 1-(2-amino-5-bromo-3-methyl-phenyl)ethanone (Step 1) (1.25 g, 5.47 mmol) and ammonium acetate (2.53 g, 32.8 mmol) was heated to 130 °C overnight. The resulting mixture was cooled to room temperature and then concentrated in vacuo. The residue was dissolved in EtOAc (150 mL), washed with brine (2 × 80 mL), dried over MgSO and concentrated in vacuo. The crude mixture was purified by chromatography on silica eluting with a gradient of 0 to 50% EtOAc in petroleum ether, followed by a second chromatographic purification on silica eluting with 0 to 40% EtOAc in DCM to give the title compound as a brown solid. LC-MS-2 (Method 2B): 1.46 min at room temperature; MS m / z 236.9 / 238.9=[M+H]+ 1H NMR (500MHz, DMSO) δ 9.17 (s, 1H), 8.33 (d, J = 2.2Hz, 1H), 8.02 (s, 1H), 2.90 (s, 3H), 2.68 (s, 3H).

[0530] intermediate product J 4-Bromo-1-methyl-pyrrolo[2,3-b]pyridine

[0531] [ka]

[0532] NaH (60% dispersion in mineral oil) (122 mg, 3.05 mmol) was added to a cooled suspension of 4-bromo-1H-pyrrolo[2,3-b]pyridine (550 mg, 2.79 mmol) in DMF (3 mL) in an ice bath. After 30 min, iodomethane (0.17 mL, 2.79 mmol) was added and stirring was continued for an additional 30 min. The reaction was quenched with water (30 mL) and dissolved in EtOAc (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were washed with 90% brine (30 mL), 50% brine (2 × 30 mL), dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 30 to 50% EtOAc in hexanes afforded the title compound as an off-white solid. LC-MS-2 (Method 2B): 1.44 min at room temperature; MS m / z 210.9 / 212.9=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 8.13(d,J=5.2Hz,1H),7.66(d,J=3.5Hz,1H),7.36(d,J=5.1Hz,1H),6.43(d,J=3.5Hz,1H),3.83(s,3H).

[0533] intermediate product K 6-Bromo-4-methyl-1-trityl-indazole

[0534] [ka]

[0535] 6-Bromo-4-methyl-1H-indazole (200 mg, 0.95 mmol) in DMF (4.74 mL) was added dropwise to a stirred suspension of NaH (60% dispersion in mineral oil) (46 mg, 1.14 mmol) in DMF (4.74 mL) at 0 °C and stirred for 1 h. Triphenylmethyl chloride (291 mg, 1.04 mmol) was added, and the solution was warmed to room temperature and stirred for 1 h. The reaction was quenched by the careful addition of water (10 mL). The resulting mixture was diluted with EtOAc (50 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 50 mL), and the combined organic extracts were washed with 90% brine (50 mL), 50% brine (2 × 50 mL), dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica eluting with 20% EtOAc in hexanes afforded the title compound (and the corresponding regioisomer). Isomer 1: LC-MS-1 (Method 2B): RT 1.93 min; MS m / z 451.1 / 453.1=[MH]- 1H NMR(500MHz,DMSO-d6)δ 8.08(d,J=1.0Hz,1H),7.71(s,1H),7.40-7.36(m,9H),7.11-7.08(m,6H),6.96(t,J=1.4Hz,1H),2.40(s,3H). Isomer 2: LC-MS-1 (Method 2B): 1.90 min at room temperature; MS m / z 209.1 / 211.1=[MH-trityl]- 1H NMR (500MHz, DMSO-d6) δ 8.26 (s, 1H), 7.37-7.28 (m, 9H), 7.22-7.19 (m, 1H), 7.14-7.10 (m, 6H), 7.04-7.02 (m, 1H), 2.54 (s, 3H).

[0536] intermediate product L 6-Bromo-4-methyl-1-trityl-benzotriazole

[0537] [ka]

[0538] The title compound was prepared similarly to intermediate K from 5-bromo-7-methyl-1H-benzotriazole and triphenylmethyl chloride. LC-MS-2 (Method 2B): 2.09 min at room temperature; MS m / z 212.0=[MH-trityl]+ 1H NMR (500MHz, DMSO) δ 7.43-7.36 (m, 9H), 7.33 (t, J=1.4Hz, 1H), 7.23-7.17 (m, 1H), 7.14-7.08 (m, 6H), 2.70 (s, 3H).

[0539] intermediate product M 4-Bromo-1,6-dimethyl-pyrrolo[2,3-b]pyridine

[0540] [ka]

[0541] The title compound was prepared similarly to intermediate J from 4-bromo-6-methyl-1H-pyrrolo[2,3-b]pyridine and iodomethane. LC-MS-2 (Method 2B): 1.57 min at room temperature; MS m / z 224.9 / 226.9=[M+H]+ 1H NMR (500MHz, DMSO) δ 7.53 (d, J = 3.5 Hz, 1 H), 7.26 (s, 1 H), 6.36 (d, J = 3.5 Hz, 1 H), 3.79 (s, 3 H), 2.55 (s, 3 H).

[0542] intermediate product N tert-Butyl 5-bromo-7-methyl-indazole-1-carboxylate

[0543] [ka]

[0544] To a solution of di-tert-butyl dicarbonate (2.59 g, 11.84 mmol) and 5-bromo-7-methyl-1H-indazole (2.0 g, 9.48 mmol) in MeCN (20 mL) was added triethylamine (1.52 mL, 10.9 mmol) and DMAP (0.12 g, 0.95 mmol), and the mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, and the residue was dissolved in EtOAc:petroleum ether (7:3, 150 mL). This solution was washed with water (75 mL), the organic fraction was separated, and the water was extracted with EtOAc:Pet (1:1, 2 × 50 mL). The combined organic fractions were washed with water (100 mL), saturated aqueous NH4Cl (50 mL), water (2 × 50 mL), saturated aqueous NaHCO3 (2 × 75 mL), brine (50 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 1 to 30% EtOAc in petroleum ether afforded the title compound as an orange solid. LC-MS-1 (Method 3B): 2.27 min at room temperature; MS m / z 211.0 / 212.9=[M+H-Boc]+ 1H NMR (500MHz, Chloroform-d) δ 8.49(s,1H),7.63(dd,J=1.7,0.8Hz,1H),7.15(p,J=1.3Hz,1H),2.62(t,J=1.0Hz,3H),1.71(s,9H).

[0545] intermediate product O 2,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole

[0546] [ka]

[0547] Bis(pinacolato)diboron (654 mg, 2.57 mmol), methoxy(cyclooctadiene)iridium(I) dimer (51 mg, 0.08 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridyl (41 mg, 0.15 mmol) were placed in a sealed vial with a Teflon cap, and the contents were evacuated and backfilled with nitrogen (three cycles). Freshly deoxygenated anhydrous cyclohexane (10 mL) was added, and the resulting reddish-brown solution was stirred vigorously at room temperature for 20 minutes. 2,4-Dimethyloxazole (0.26 mL, 2.57 mmol) was then added, and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the title compound as a dark reddish-brown oil. LC-MS-2 (Method 2B): 0.74 min at room temperature; MS m / z 224.1=[M+H]+ 1H NMR (500MHz, DMSO) δ 2.38 (s, 3H), 2.18 (s, 3H), 1.27 (s, 12H).

[0548] intermediate product P 3-(2-aminothiazol-4-yl)benzonitrile hydrobromide

[0549] [ka]

[0550] The following was prepared according to the procedure of WO 2012 / 100734, page 24, Example 15, step 2:

[0551] To a flask containing 3-(2-bromoacetyl)benzonitrile (5 g, 22.32 mmol) in EtOH (50 mL), thiourea (1.87 g, 24.55 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The volume of the solvent was reduced by approximately 50% in vacuo, forming a suspension. The suspension was sonicated, filtered, and dried to give the title compound as a white solid. LC-MS-1 (Method 3B): 1.62 min at room temperature; MS m / z 200.0=[MH] H NMR (500 MHz, DMSO-d) δ 8.22 (t, J = 1.8 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H). No NH was observed. HBr salt assigned based on the mass of the resulting compound.

[0552] 3-(2-aminothiazol-4-yl)benzonitrile can also be prepared as follows.

[0553] Under nitrogen, 3-(2-bromoacetyl)benzonitrile (3.0 g, 13.39 mmol) was added to a flask containing thiourea (2.04 g, 26.78 mmol) in pyridine (50 mL), and the mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo. The crude product was purified by silica chromatography eluting with 0–100% EtOAc in DCM. The resulting solid was recrystallized from EtOAc to give 3-(2-aminothiazol-4-yl)benzonitrile as a pale yellow solid. LC-MS (Method 7A): 1.75 min at room temperature; MS m / z 202.1=[M+H]+,243.3=[M+H+MeCN]+ 1H NMR(400MHz,DMSO-d6)δ 8.20(t,J=1.5Hz,1H),8.11(dt,J=7.9,1.4Hz,1H),7.70(dt,J=7.7,1.3Hz,1H),7.58(t,J=7.6Hz,1H),7.26(s,1H),7.14(s,2H).

[0554] intermediate product Q 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile

[0555] [ka]

[0556] The following was prepared according to the procedure of WO 2012 / 100734, pages 24-25, Example 15, step 3.

[0557] To a solution of 3-(2-aminothiazol-4-yl)benzonitrile hydrobromide (Intermediate P) (2.6 g, 9.21 mmol) in THF (40 mL) was added NBS (1.97 g, 11.06 mmol), and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with EtOAc (60 mL) and washed with water (100 mL). The organic portion was separated, and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organics were dried over MgSO and concentrated in vacuo to give an orange solid. The solid was suspended in DCM (20 mL), filtered, washed with DCM, and dried to give the title compound as an off-white solid. LC-MS-1 (Method 3B): 1.64 min at room temperature; MS m / z 279.9 / 281.9=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 8.16(t,J=1.7Hz,1H),8.15(dt,J=7.9,1.7Hz,1H),7.83(d,J=7.9Hz,1H),7.66(t,J=7.9Hz,1H),7.42(s,2H).

[0558] intermediate product R tert-Butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate

[0559] [ka]

[0560] Step 1: tert-butyl 4-bromo-6-methyl-pyrrolo[2,3-b]pyridine-1-carboxylate

[0561] [ka]

[0562] The title compound was prepared similarly to intermediate N from 4-bromo-6-methyl-1H-pyrrolo[2,3-b]pyridine and di-tert-butyl decarbonate. LC-MS-2 (Method 2B): 1.86 min at room temperature; MS m / z 310.9 / 312.9=[M+H]+ 1H NMR (500MHz, DMSO-d6) δ 7.79 (d, J = 4.0 Hz, 1 H), 7.49 (s, 1 H), 6.59 (d, J = 4.0 Hz, 1 H), 2.55 (s, 3 H), 1.61 (s, 9 H).

[0563] Step 2: tert-butyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine-1-carboxylate The title compound was prepared from tert-butyl 4-bromo-6-methyl-pyrrolo[2,3-b]pyridine-1-carboxylate (Step 1) and bis(pinacolato)diboron in analogy to Step 1 of Intermediate A. LC-MS-2 (Method 2B): 1.72 min at room temperature; MS m / z 359.1=[M+H]+ 1H NMR (500MHz, DMSO-d6) δ 7.72 (d, J = 4.0 Hz, 1 H), 7.36 (s, 1 H), 6.78 (d, J = 4.0 Hz, 1 H), 2.56 (s, 3 H), 1.61 (s, 9 H), 1.34 (s, 12 H).

[0564] intermediate product S 3-[2-amino-5-(6-methyl-1-trityl-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl]benzonitrile

[0565] [ka]

[0566] Step 1: 4-Bromo-6-methyl-1-trityl-pyrazolo[3,4-b]pyridine

[0567] [ka]

[0568] 4-Bromo-6-methyl-1H-pyrazolo[3,4-b]pyridine (500 mg, 2.36 mmol) in DMF (10 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil) (113 mg, 2.83 mmol) in DMF (10 mL) at 0 °C. The solution was stirred at 0 °C for 45 min, and triphenylmethyl chloride (723.08 mg, 2.59 mmol) was added. The solution was warmed to room temperature and stirred for 1 h. The solution was recooled to 0 °C, and water (10 mL) was added slowly. The solution was diluted with EtOAc (50 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 50 mL), and the combined organic extracts were washed with 90% brine (50 mL), 50% brine (2 × 50 mL), dried over Na SO , and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 0-30% EtOAc in petrol gave the title compound as an orange solid. LC-MS-2 (Method 2B): 2.14 min at room temperature; MS m / z 454.0 / 456.0=[M+H]+ 1H NMR (500MHz, DMSO) δ 8.16 (s, 1H), 7.33 (s, 1H), 7.34-7.18 (m, 9H), 7.19-7.12 (m, 6H), 2.19 (s, 3H).

[0569] Step 2: 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine

[0570] [ka]

[0571] The title compound was prepared from 4-bromo-6-methyl-1-trityl-pyrazolo[3,4-b]pyridine (Step 1) and bis(pinacolato)diboron in analogy to Step 1 of Intermediate A. LC-MS-2 (Method 2B): 1.57 min at room temperature; MS m / z 420.1=[M-C6H10 ]+ 1H NMR (500MHz, DMSO) δ 8.17 (s, 1H), 7.93 (s, 1H), 7.25-7.16 (m, 15H), 2.22 (s, 3H), 1.34 (s, 12H).

[0572] Step 3: 3-[2-amino-5-(6-methyl-1-trityl-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl]benzonitrile The title compound was prepared from 3-(2-amino-5-bromo-thiazol-4-yl)benzonitrile (Intermediate Q) and crude 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine (Step 2) in analogy to Step 2 of Intermediate A. LC-MS-2 (Method 2B): 1.96 min at room temperature; MS m / z 575.1=[M+H]+ 1H NMR(500MHz,DMSO)δ 7.73(dt,J=7.7,1.4Hz,1H),7.64(dt,J=8.0,1.5Hz,1H),7.61(t,J=1.7Hz,1H),7.57(s,2H),7.4 6(t,J=7.8Hz,1H),7.32(s,1H),7.31-7.19(m,9H),7.15-7.02(m,6H),6.90(s,1H),2.16(s,3H).

[0573] Biological Examples Biological Example 1 - Adenosine Receptor Time-Resolved Fluorescence Resonance Energy Transfer (TRFRET) Binding Assay All FRET binding experiments were performed at room temperature in white 384-well plates in assay binding buffer containing 1x LabMed (Cisbio, France), 100 μg / mL saponin, 1% DMSO, and 0.02% pluronic acid. Binding of the fluorescently labeled adenosine receptor antagonist XAC (CA200645, FRET acceptor) to terbium-labeled A1, A2a, A2b, and A3 adenosine receptors (FRET donor) was detected by time-resolved FRET due to the proximity of the donor and acceptor in the binding event. To examine the ability of unlabeled test compounds to bind to adenosine A1, A2a, A2b, and A3 receptors, dose-response curves were constructed to determine the ability of a range of concentrations to inhibit the binding of 30 nM CA200645 to the A2b receptor and 100 nM CA200645 to the A1, A2a, and A3 receptors.

[0574] A Mosquito (TTP Labtech, UK) was used to serially dilute test compounds (1:3 dilutions) from the stock solution in DMSO and transfer 400 nL samples of test compounds to the assay plate. Compound samples were incubated with CA200645 (see above) in 40 μL of assay buffer at a fixed concentration defined for each receptor and CHO cell membranes containing human adenosine A1 (0.5 μg / well), A2a (0.3 μg / well), A2b (1 μg / well), or A3 (1 μg / well) receptors for 2 h at room temperature. Total and nonspecific binding of CA200645 was measured in the absence and presence of 10 μM XAC, respectively. After 2 h of incubation, the level of CA200645 binding was detected using standard TR-FRET settings on a Pherastar FSX (BMG Labtech, Germany). The terbium donor was excited with three laser flashes at a wavelength of 337 nm, and donor and acceptor emissions were detected at wavelengths of 620 nm and 665 nm, respectively. FRET ratios were obtained by multiplying the acceptor / donor ratio by 10,000. Specific binding was determined by subtracting the nonspecific binding FRET ratio from the total binding FRET ratio. Compound IC50 curves were analyzed using GraphPad Prism 7.0 (GraphPad, USA), and Ki affinity values ​​were calculated from the IC50 values ​​obtained using the method of Cheng and Prusoff. The results are shown in Table 1.

[0575] [Table 5-1]

[0576] [Table 5-2]

[0577] Biological Example - CD3 / CD28 stimulated IL-2 release in human PBMCs NECA reversal assay Blood was collected from healthy volunteers using sodium citrate (final concentration 0.3%) as an anticoagulant. After centrifugation of the blood through Histopaque-1077, PBMCs were collected from the Histopaque / plasma interface and washed twice with PBS (300g, 10 minutes at room temperature). Cells were seeded at 50,000 cells / well in 150µl RPMI / 10% FCS in 96-well cell culture plates precoated with 1µg / mL CD3 antibody. 50µl of diluted compound mixture was added to the cells to obtain final concentrations of 1µg / mL CD28 antibody, 1µM NECA, and 0.003-10µM adenosine receptor antagonist. The assay plate was incubated at 37°C for 24 hours in a humidified incubator. IL-2 levels were assayed in the culture supernatant using a human IL-2 tissue culture kit (Meso Scale Discovery). Dose-response curve data are calculated as % inhibition, with 100% inhibition defined as no agonist control wells (+CD3 / 28-NECA).

[0578] [Table 6]

[0579] Biological Example - Measurement of pCREB in CD8+ T cells in human whole blood Heparinized human whole blood was preincubated with serial dilutions of an A2a antagonist and the phosphodiesterase inhibitor rolipram for 20 minutes at 37°C to amplify the pCREB response. The adenosine receptor agonist NECA was then added at a final concentration of 3 μM. After 60 minutes of incubation, the blood was fixed and red blood cells were lysed. Leukocytes were isolated, permeabilized, and stained with fluorescent antibodies directly conjugated to phospho-CREB (Alexa Fluor 488) and CD8 (Alexa Fluor 647). The levels of phospho-CREB in CD8+ T cells were measured by FACS using a BD Accuri C6 Flow Cytometer.

[0580] [Table 7]

[0581] MoDC pCREB assay Monocytes were isolated from human whole blood using CD14 microbeads (Miltenyi Biotec 130-050-201) and differentiated into immature monocyte-derived dendritic cells (MoDCs) by culturing them in Mo-DC differentiation medium (Miltenyi Biotec 130-094-812) for 5 days. MoDCs were seeded in fresh medium in U-bottom 96-well culture plates and incubated for 1 hour. 2A / B Cells were preincubated with serial dilutions of antagonist for 15 minutes at 37°C. At the same time, cells were co-incubated with the phosphodiesterase inhibitor rolipram (final concentration 20 μM) to amplify the subsequent pCREB response. The adenosine receptor agonist NECA was then added at a final concentration of 1 μM, resulting in increased CREB phosphorylation. After 45 minutes of incubation at 37°C, cells were fixed, permeabilized, and stained with directly conjugated fluorescent antibodies against phospho-CREB (Alexa Fluor 488), CD209 (PerCP-Cy5.5), and CD86 (APC). Samples were analyzed by FACS to measure the fluorescence in the corresponding channels, as well as forward and side scatter. The CD209+ / CD86-low cell population, corresponding to immature dendritic cells, was gated for analysis of pCREB levels. Adenosine receptor responses in this cell population were primarily A-dependent, based on their specific response to the highly selective antagonist PSB-603. 2B It is specific to

[0582] Approximately 5% of the analyzed cells were positive for pCREB detection in the absence of agonist stimulation, representing background signaling of all pathways upstream of CREB. After NECA stimulation, this increased to approximately 80% pCREB+ve, and this increase was consistent with A 2B or double A 2A / B It is essentially completely reversible by antagonists.

[0583] IC50 is represented as the inflection point of the sigmoid curve.

[0584]

Table 8

[0585] References 1. Sukari A, Nagasaka M, Al-Hadidi A, and Lum LG (2016). Anticancer Res. 36(11):5593 - 5606. 2. Vijayan D, Young A, Teng MWL, and Smyth MJ (2017), Nat Rev Cancer. 17(12):709 - 724. 3. Houthuys, E, Marillier R, Deregnaucourt, T, Brouwer, M, Pirson, R, Marchante, J, et al (2016). SITC 2017 Conference, Maryland. 4. Gao ZW, Dong K, Zhang HZ (2014). "The roles of CD73 in cancer". Biomed Res Int:2014:460654. 5. Loi S, Pommey S, Haibe-Kains B, Beavis PA, Darcy PK, Smyth MJ, et al. (2013), "CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer" Proc Natl Acad Sci U S A.;110(27):11091 - 6. 6. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A et al (2007). J.Exp Med..204, No.6, June 11, 2007 1257 - 1265. 7.Csoka B,Selmeczy Z,Koscso B,Nemeth ZH,Pacher P,Murray PJ,Kepka-Lenhart D,Morris SM Jr,Gause WC,Leibovich SJ,Hasko G(2012).Adenosine promotes alternative macrophage activation via A2A and A2B receptors.FASEB J 26:376-86。 8.Ryzhov S,Novitskiy SV,Goldstein AE,Biktasova A,Blackburn MR,Biaggioni I,Dikov MM,Feoktistov I(2011).Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+cells.J Immunol.187(11):6120-9。 9.Novitskiy SV,Ryzhov S,Zaynagetdinov R,Goldstein AE,Huang Y,Tikhomirov OY,Blackburn MR,Biaggioni I,Carbone DP,Feoktistov I,Dikov MM(2008).Adenosine receptors in regulation of dendritic cell differentiation and function.Blood 2008 112:1822-31 10.Wilson JM,Ross WG,Agbai ON,Frazier R,Figler RA,Rieger J,Linden J,Ernst PB(2009).The A2B adenosine receptor impairs the maturation and immunogenicity of dendritic cells.J.Immunol.18:4616-23。 11. Cekic C, Sag D, Li Y, Theodorescu D, Strieter RM, Linden JJ (2012). Adenosine A2B receptor blockade slows growth of bladder and breast tumors. J Immunol. 188:198-205. 12. Sorrentino C, Miele L, Porta A, Pinto A, Morello S (2015). Myeloid-derived suppressor cells contribute to A2B adenosine receptor-induced VEGF production and angiogenesis in a mouse melanoma model. Oncotarget.6:27478-89. 13. Iannone R, Miele L, Maiolino P, Pinto A, Morello S (2013). Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma.Neoplasia.2013 15(12):1400-9.

[0586] [Embodiment] (1) A compound or a pharmaceutically acceptable salt thereof, having structural formula I shown below: [ka] During the ceremony, R1 is [ka] [ka] is selected from where: any available C atom in R1 is optionally substituted by one or more R2 substituents, any available N atom in R1 is optionally in the form of an N-oxide or substituted with an R3 group; where: Each R2 is independently selected from the group consisting of (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl (e.g., 5-membered heteroaryl), heteroaryl(1-2C)alkyl, halo, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl, cyano, -(CR 1C R 1D ) q1 -OR 1A , -(CR 1C R 1D ) q1 -C(O)R 1A , -(CR 1C R 1D ) q1 -C(O)OR 1A , -(CR 1C R 1D ) q1 -OC(O)R 1A , -(CR 1C R 1D ) q1 -C(O)N(R 1B )R 1A , -(CR 1C R 1D ) q1 -N(R 1B )C(O)R 1A , -(CR 1C R 1D ) q1 -S(O) p R 1A (wherein p is 0, 1 or 2), -(CR 1C R 1D ) q1 -SO2N(R 1B )R 1A , or -(CR 1C R 1D ) q1 -N(R 1B)SO2R 1A is selected from where q1 is 0, 1, or 2; where R 1A and R 1B are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; where R 1C and R 1D are each independently selected from hydrogen or (1-2C)alkyl; R3 is hydrogen, (1-3C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl(1-2C) alkyl, aryl, aryl(1-2C) alkyl, C-linked heterocyclyl, heterocyclyl(1-2C) alkyl, heteroaryl, heteroaryl(1-2C) alkyl, (1-3C) haloalkyl, (1-3C) haloalkoxy, (1-3C) hydroxyalkyl, -(CR 3C R 3D ) 1-2 -OR 3A , -(CR 3C R 3D ) q3 -C(O)R 3A , -(CR 3C R 3D ) q3 -C(O)OR 3A , -(CR 3C R 3D ) 1-2 -OC(O)R 3A , -(CR 3C R 3D ) q3 -C(O)N(R 3B )R q3 , -(CR 1C R 1D ) 1-2 -N(R 3B )C(O)R 3A , -(CR 3C R 3D )-S(O) p3 R 3A (where p3 is 0, 1 or 2), -(CR 3C R 3D ) 1-2 -SO2N(R3B )R 3A , or -(CR 3C R 3D ) 1-2 -N(R 3B )SO2R 3A is selected from where R 3A and R 3B are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; where R 3C and R 3D are each independently selected from hydrogen or (1-2C)alkyl; where q3 is 0, 1, or 2; R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocycle substituted by a substituent, where R 10C is an oxo, thioxo, halo, or cyano substituent, or a group of the formula: -[CR 7a R 7b ] n -LZ is selected from the group During the ceremony, n is an integer from 0 to 6, R 7a and R 7b are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -N(R a )C(O)N(R b )-, -C(S)N(R a )-, -N(R a )C(S)-, -N(R a )C(S)N(R b )-, -S(O)2N(Ra )- or -N(R a )SO2-, where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl, or heteroaryl(1-2C)alkyl, where Z is optionally (1-6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, nitro, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1, 2 or 3) or oxo; wherein any alkyl moiety in the Z substituent is optionally further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl, or (1-2C)alkoxy; and R c and R d are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl; wherein any available N atom in the ring formed by R4 and R5 is optionally in the form of an N-oxide or optionally substituted with one or more R10N is replaced by where R 10N is —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R 8b ] 1-6 -L 1b -Z1 is selected from where: R 8a and R 8b are each independently selected from hydrogen, fluoro, or (1-2C)alkyl; L 1a -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 )-, -S(O)2N(R a1 )- or -N(R a1 )-, where R a1 is selected from hydrogen or (1-2C) alkyl; L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -C(S)N(R a2 )-, -N(R a2 )C(S)-, -N(R a2 )C(S)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 and R b2 are each independently selected from hydrogen or (1-2C)alkyl; Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclyl(1-2C)alkyl or heteroaryl(1-2C)alkyl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-linked heterocyclyl, wherein Z1 is optionally (1-6C)alkyl, halo, (1-6C)haloalkoxy, cyano, nitro, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR e R f (wherein z is 1, 2, or 3) or oxo; and R e and R f are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl, or (3-6C)cycloalkyl; Any S atom present in said heterocycle is optionally S(=O), S(=O) or S(=O)(=NR e ), where R e is selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl, R6 is selected from hydrogen, halo, methyl, methoxy and trifluoromethyl; The compound or a pharmaceutically acceptable salt thereof. (2) R1 is [ka] [ka] is selected from A compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted on any available carbon atom by one or more R2 substituents, and R2 and R3 are as defined in embodiment 1. (3) R1 is [ka] is selected from A compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted on any available carbon atom with one or more R2, and R2 is as defined in embodiment 1. (4) R1 is [ka] and 2. The compound according to embodiment 1, wherein R2 is as defined in embodiment 1, or a pharmaceutically acceptable salt thereof. (5) each R2, if present, independently represents (1-2C) alkyl, 5-membered heteroaryl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) hydroxyalkyl, cyano, -(CR 1C R 1D ) q1 -OR 1A is selected from where q1 is 0 or 1, R 1A and R 1B is each independently selected from hydrogen or (1-2C)alkyl; or a pharmaceutically acceptable salt thereof.

[0587] (6) The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein each R2, if present, is independently selected from methyl, ethyl, or methoxy. (7) The compound according to any one of embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from hydrogen or (1-3C)alkyl. (8) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R on any available carbon atom. 10C are linked to form a heterocycle substituted by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group During the ceremony, n is 0 to 2, L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -N(R a2 )C(O)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )SO2-, where R a2 and R b2 are each independently selected from hydrogen or methyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, heterocyclyl, heterocyclyl(1-2C)alkyl or heteroaryl, where Z is optionally (1-2C)-alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, -NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O)y R c (wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1 or 2) or oxo; wherein any alkyl moiety in the substituent on Z is optionally further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl, or (1-2C)alkoxy; and R c and R d are each independently selected from hydrogen, (1-2C)alkyl, (1-2C)haloalkyl, or (3-6C)cycloalkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10N is —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1 is selected from where: R 8a and R 8b are both hydrogen, L 1a is -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 is hydrogen or methyl, L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-, -N(R a2)C(O)-, -N(R a2 )C(O)N(R b2 )-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 and R b2 are each independently selected from hydrogen or methyl; Z1 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl or aryl(1-2C)alkyl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-linked heterocyclyl, and Z1 is optionally (1-2C)alkyl, halo, (1-2C)haloalkoxy, cyano, nitro, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR e R f (wherein z is 1, 2, or 3) or oxo, wherein R e and R f are each independently selected from hydrogen or (1-2C)alkyl; Any S atom present in said heterocycle is optionally S(=O), S(=O) or S(=O)(=NR e ), where R eis selected from hydrogen, (1-3C)alkyl, or (2-3C)alkanoyl; or a pharmaceutically acceptable salt thereof. (9) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R on any available carbon atom. 10C are linked to form a heterocycle substituted by a substituent, where R 10C is an oxo, halo, or cyano substituent, or a group of the formula: -[CH2] n -LZ is selected from the group During the ceremony, n is 0 to 2, L is absent or is -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-, -N(R a )C(O)-, -S(O)2N(R a )- or -N(R a )SO2-, where R a and R b are each independently selected from hydrogen or methyl; Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclyl(1-2C)alkyl, or 5- or 6-membered heteroaryl, where Z is optionally (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, —NR c R d , -OR c , -C(O)R c , -C(O)OR c , -OC(O)R c , -C(O)N(R c )R d , -N(R c )C(O)R d , -S(O) y R c(wherein y is 0, 1 or 2), -SON(R c )R d , -N(R c )SO2R d , -(CH2) z NR c R d (wherein z is 1 or 2) or oxo; where R c and R d are each independently selected from hydrogen or (1-2C)alkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10N is —S(O)2NH2, or (i)-Z1, (ii)-L 1a -Z1, or (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1 is selected from where: R 8a and R 8b are both hydrogen, L 1a is -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 is hydrogen, L 1b is absent or is -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)N(R a2 )-, -N(R a2 )C(O)-, -S(O)2N(R a2 )- or -N(R a2 )SO2, where R a2 is hydrogen, Z1 is selected from (1-4C)alkyl, phenyl, 4- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl, provided that when Z1 is a heterocyclyl group directly bonded to an N atom, it is a carbon-linked heterocyclyl, wherein Z1 is optionally (1-2C)alkyl, halo, (1-2C)haloalkoxy, cyano, -NR e R f , -OR e , -C(O)R e , -C(O)OR e , -OC(O)R e , -C(O)N(R e )R f , -N(R e )C(O)R f , -S(O) y R e (wherein y is 0, 1 or 2), -SON(R e )R f , -N(R e )SO2R f , -(CH2) z NR c R d (wherein z is 1 or 2), wherein R e and R f are each independently selected from hydrogen or methyl; Any S atom present in said heterocycle is optionally S(=O), S(=O) or S(=O)(=NR e ), where R e is selected from hydrogen, (1-2C)alkyl, or (2C)alkanoyl; or a pharmaceutically acceptable salt thereof. (10) R4 and R5, together with the nitrogen atom to which they are attached, optionally form one or more R 10C are linked to form a heterocyclic ring substituted by a substituent, and R 10C is oxo, halo, cyano or of the formula: -LZ is selected from the group During the ceremony, L is absent, -O- or -N(R a )-, where R a is hydrogen or methyl, Z is selected from (1-4C)alkyl, 4- to 7-membered heterocyclyl, or (3-6C)cycloalkyl(1-2C)alkyl; wherein any (1-4C)alkyl, 4- to 7-membered heterocyclyl, or (3-6C)cycloalkyl(1-2C)alkyl is optionally substituted with cyano, —NR c R d -OR c and wherein R c and R d are each independently selected from hydrogen or methyl; wherein any available N atom is optionally in the form of an N-oxide or optionally one or more R 10N where R 10N is (1-4C) alkyl, Embodiment 10. The compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein any S atom present in said heterocycle may optionally be present as S(=O).

[0588] (11) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] where: * represents 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 -CH2-, -CH2-CHR 10C-, -CHR 10C -CHR 10C -, -C(R 10c )2-CH2-, or -CH2-C(R 10c )2- and Q3 is CH, CR 10C or N, Ring A is a spiro-fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; Ring B is a fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring; where R e is selected from hydrogen or methyl; Each of said heterocyclic ring systems may optionally be one or more R as defined in any of embodiments 1, 8, 9 or 10. 10c or R 10N 11. The compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent. (12) R4 and R5, together with the nitrogen atom to which they are attached, are linked to form a heterocycle selected from any one of the following options: [ka] where: * represents 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, where R e is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; Each of said heterocyclic ring systems may optionally be one or more R as defined in any of embodiments 1, 8, 9 or 10. 10c or R 10N12. The compound according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, which is substituted with a substituent. (13) R4 and R5, together with the nitrogen atom to which they are attached, form the structure [ka] are linked to form a heterocycle of where: * represents the N atom to which R4 and R5 are bonded, Each R 10c are independently selected from the options defined in any of embodiments 1, 8, 9, or 10, or a pharmaceutically acceptable salt thereof. (14) The compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from hydrogen, halo, or methyl. (15) The compound according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen.

[0589] (16) Compounds of formula IA, IB, IC, ID, IE or IF, [ka] [ka] In the formula, R2, R4, R5, R6 and R 10c are each as defined in any one of embodiments 1 to 16. compound. (17) A compound or a pharmaceutically acceptable salt thereof, below, (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methyl-1H-indazol-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(7-methyl-3H-benzotriazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-piperazin-1-yl-piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-8-oxa-2,5-diazaspiro[3.5]nonane-2-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide, (3S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide, 4-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide, (3R)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide, (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide, 4-(1-cyano-1-methyl-ethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxamide, 4-(1-cyanoethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(dimethylamino)piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-[(dimethylamino)methyl]morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(2-pyrrolidin-1-ylethoxy)pyrrolidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-methyl-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridine-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(1-methyl-4-piperidyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-morpholino-piperidine-1-carboxamide, 4-(cyanomethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, (3S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1,4-diazepane-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide, (4aR,7aS)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxamide, 3-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, (2S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, (2R)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, (2S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, (2R)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(2-methylquinazolin-7-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(2,4-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-quinazolin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methyl-6-quinolyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methoxyquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-ethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, 4-cyano-N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1-methylpyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(3,8-dimethylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, 4-cyano-N-[4-(3-cyanophenyl)-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4,8-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1-methylpyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(3-methylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1,6-dimethylpyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(3-methylbenzimidazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-imidazo[1,2-a]pyridin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(7-methyl-1H-indazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(2,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(8-methylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(6-methylpyridazin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-[5-methyl-6-(triazol-2-yl)-3-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-pyrazolo[1,5-a]pyridin-5-yl-thiazol-2-yl]morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, or N-[5-(1,3-benzoxazol-6-yl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide or a pharmaceutically acceptable salt thereof, selected from any one of: (18) A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 17 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier. (19) A compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 18, for use in therapy. (20) (i) Use in the treatment of a proliferative condition; (ii) use in the treatment of cancer; (iii) Use in the treatment of cancer, wherein said compound or said pharmaceutical composition is administered in combination with one or more additional anti-cancer agents; (iv) the compound or the pharmaceutical composition is 1) other forms of cancer immunotherapy and anti-cancer chemotherapy agents; 2) adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors; 3) anti-PD-1 antibodies and anti-PDL-1 antibodies (e.g., cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab), and 4) Anti-CTLA4 antibodies (e.g., ipilimumab) 19. The compound of any of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 18, for use in the treatment of cancer, administered in combination with one or more additional anticancer agents selected from the group consisting of:

[0590] (21) A method for treating a proliferative disorder in a patient in need thereof, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 18. (22) A method for treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 18. (23) A method for treating a proliferative disorder in a patient in need thereof, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 18, in combination with one or more additional anticancer agents. (24) The one or more additional anticancer drugs are 1) other forms of cancer immunotherapy and anti-cancer chemotherapy agents; 2) adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors; 3) anti-PD-1 antibodies and anti-PDL-1 antibodies (e.g., cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab), and 4) The method of embodiment 23, wherein the antibody is selected from an anti-CTLA4 antibody (e.g., ipilimumab).

Claims

1. or a pharma- ceutically acceptable salt thereof, It has the structural formula I shown below: 【Chemistry 1】 During the ceremony, R １ teeth, 【Chemistry 2】 【Chemistry 3】 is selected from Where: R １ Any available C atom in the ２ is substituted by a substituent; R １ Any available N atom in is optionally in the form of an N-oxide or R ３ is substituted with a group, Where: Each R ２ are independently (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl (e.g., 5-membered heteroaryl), heteroaryl(1-2C)alkyl, halo, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl, cyano, -(CR １Ｃ R １Ｄ ) ｑ１ -OR １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -C(O)R １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -C(O)OR １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -OC(O)R １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -C(O)N(R １Ｂ ) R １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -N(R １Ｂ ) C(O)R １Ａ , -(CR １Ｃ R １Ｄ ) ｑ１ -S (O) ｐ R １Ａ (wherein p is 0, 1 or 2), -(CR １Ｃ R １Ｄ ) ｑ１ -SO ２ N (R １Ｂ ) R １Ａ , or -(CR １Ｃ R １Ｄ ) ｑ１ -N(R １Ｂ ) S.O. ２ R １Ａ is selected from where q1 is 0, 1, or 2; Here, R １Ａ and R １Ｂ are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl; Here, R １Ｃ and R １Ｄ are each independently selected from hydrogen or (1-2C)alkyl; R ３ is hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, C-linked heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, (1-3C)haloalkyl, (1-3C)haloalkoxy, (1-3C)hydroxyalkyl, -(CR ３Ｃ R ３Ｄ ) １－２ -OR ３Ａ , -(CR ３Ｃ R ３Ｄ ) ｑ３ -C(O)R ３Ａ , -(CR ３Ｃ R ３Ｄ ) ｑ３ -C(O)OR ３Ａ , -(CR ３Ｃ R ３Ｄ ) １－２ -OC(O)R ３Ａ , -(CR ３Ｃ R ３Ｄ ) ｑ３ -C(O)N(R ３Ｂ ) R ｑ３ , -(CR １Ｃ R １Ｄ ) １－２ -N(R ３Ｂ ) C(O)R ３Ａ , -(CR ３Ｃ R ３Ｄ ) -S(O) ｐ３ R ３Ａ (wherein p3 is 0, 1 or 2), -(CR ３Ｃ R ３Ｄ ) １－２ -SO ２ N (R ３Ｂ ) R ３Ａ , or -(CR ３Ｃ R ３Ｄ ) １－２ -N(R ３Ｂ ) S.O. ２ R ３Ａ is selected from Here, R ３Ａ and R ３Ｂ are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl; Here, R ３Ｃ and R ３Ｄ are each independently selected from hydrogen or (1-2C)alkyl; where q3 is 0, 1, or 2; R ４ and R ５ together with the nitrogen atom to which they are attached, optionally have one or more R １０Ｃ are linked to form a heterocycle substituted by a substituent; Here, R １０Ｃ is an oxo, thioxo, halo or cyano substituent, or a group of the formula: -[CR ７ａ R ７ｂ ] ｎ -L-Z is selected from the group During the ceremony, n is an integer from 0 to 6, R ７ａ and R ７ｂ are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L is absent or is -O-, -S-, -SO-, -SO ２ -, -N(R ａ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ ) -, -N(R ａ )C(O)-,-N(R ａ ) C(O)N(R ｂ )-, -C(S)N(R ａ ) -, -N(R ａ )C(S)-,-N(R ａ ) C(S)N(R ｂ ) -, -S(O) ２ N (R ａ )- or -N(R ａ ) S.O. ２ -, where R ａ and R ｂ are each independently selected from hydrogen or (1-2C)alkyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, heteroaryl or heteroaryl(1-2C)alkyl, where Z is optionally (1-6C)alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, nitro, -NR ｃ R ｄ , -OR ｃ , -C(O)R ｃ , -C(O)OR ｃ , -OC(O)R ｃ , -C(O)N(R ｃ ) R ｄ , -N(R ｃ ) C(O)R ｄ , -S(O) ｙ R ｃ (wherein y is 0, 1 or 2), -SO ２ N (R ｃ ) R ｄ , -N(R ｃ ) S.O. ２ R ｄ , -(CH ２ ) ｚ N.R. ｃ R ｄ (wherein z is 1, 2 or 3) or oxo; wherein any alkyl moiety in the Z substituent is optionally further substituted with cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy; R ｃ and R ｄ are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl; Here, R ４ and R ５ Any available N atom in the ring formed by is optionally in the form of an N-oxide or is optionally substituted with one or more R １０Ｎ is replaced by Here, R １０Ｎ is -S(O) ２ N.H. ２ or (i)-Z １ 、 (ii) -L １ａ -Z １ or (iii)-[CR ８ａ R ８ｂ ] １－６ -L １ｂ -Z １ is selected from Where: R ８ａ and R ８ｂ are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L １ａ is -C(O)-, -S(O) ２ -, -C(O)O-, -C(O)N(R ａ１ ) -, -S(O) ２ N (R ａ１ )-or-N(R ａ１ )-, where R ａ１ is selected from hydrogen or (1-2C)alkyl; L １ｂ is absent or is -O-, -S-, -SO-, -SO ２ -, -N(R ａ２ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ２ ) -, -N(R ａ２ )C(O)-,-N(R ａ２ ) C(O)N(R ｂ２ )-, -C(S)N(R ａ２ ) -, -N(R ａ２ )C(S)-,-N(R ａ２ ) C(S)N(R ｂ２ ) -, -S(O) ２ N (R ａ２ )- or -N(R ａ２ ) S.O. ２ where R ａ２ and R ｂ２ are each independently selected from hydrogen or (1-2C)alkyl; Z １ is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl, aryl(1-2C)alkyl, heterocyclyl(1-2C)alkyl or heteroaryl(1-2C)alkyl, provided that Z １ When Z is a heterocyclyl group directly bonded to an N atom, it is a carbon-bonded heterocyclyl, where Z １ is optionally (1-6C)alkyl, halo, (1-6C)haloalkoxy, cyano, nitro, -NR ｅ R ｆ , -OR ｅ , -C(O)R ｅ , -C(O)OR ｅ , -OC(O)R ｅ , -C(O)N(R ｅ ) R ｆ , -N(R ｅ ) C(O)R ｆ , -S(O) ｙ R ｅ (wherein y is 0, 1 or 2), -SO ２ N (R ｅ ) R ｆ , -N(R ｅ ) S.O. ２ R ｆ , -(CH ２ ) ｚ N.R. ｅ R ｆ (wherein z is 1, 2 or 3) or oxo; ｅ and R ｆ are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl; Any S atom present in the heterocycle is optionally represented by S(=O), S(=O) ２ Or S(=O)(=NR ｅ ), where R ｅ is selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl, R ６ is selected from hydrogen, halo, methyl, methoxy and trifluoromethyl; A compound or a pharma- ceutically acceptable salt thereof.

2. R １ but, 【Chemistry 4】 【Chemistry 5】 is selected from R １ optionally, one or more R ２ is substituted by a substituent, R ２ and R ３ 2. The compound of claim 1, wherein:

3. R １ but, 【Chemistry 6】 is selected from R １ optionally, one or more R ２ and R ２ 3. The compound according to claim 1 or 2, wherein:

4. R １ but, 【Chemistry 7】 and R ２ 2. The compound of claim 1, wherein:

5. Each R ２ is, if present, independently selected from (1-2C)alkyl, 5-membered heteroaryl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, cyano, -(CR １Ｃ R １Ｄ ) ｑ１ -OR １Ａ is selected from where q1 is 0 or 1; R １Ａ and R １Ｂ or a pharma- ceutically acceptable salt thereof, according to claim 1, wherein each is independently selected from hydrogen or (1-2C)alkyl.

6. Each R ２ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein, if present, is independently selected from methyl, ethyl or methoxy.

7. R ３ or a pharma- ceutically acceptable salt thereof, according to claim 1, wherein is selected from hydrogen or (1-3C)alkyl.

8. R ４ and R ５ together with the nitrogen atom to which they are attached, optionally have one or more R １０Ｃ are linked to form a heterocycle substituted by a substituent; Here, R １０Ｃ is an oxo, halo or cyano substituent, or of the formula: -[CH ２ ] ｎ -L-Z is selected from the group During the ceremony, n is 0 to 2; L is absent or is -O-, -S-, -SO-, -SO ２ -, -N(R ａ２ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ２ ) -, -N(R ａ２ )C(O)-,-N(R ａ２ ) C(O)N(R ｂ２ ) -, -S(O) ２ N (R ａ２ )- or -N(R ａ２ ) S.O. ２ -, where R ａ２ and R ｂ２ are each independently selected from hydrogen or methyl; Z is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, heterocyclyl, heterocyclyl(1-2C)alkyl or heteroaryl, where Z is optionally (1-2C)-alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, -NR ｃ R ｄ , -OR ｃ , -C(O)R ｃ , -C(O)OR ｃ , -OC(O)R ｃ , -C(O)N(R ｃ ) R ｄ , -N(R ｃ ) C(O)R ｄ , -S(O) ｙ R ｃ (wherein y is 0, 1 or 2), -SO ２ N (R ｃ ) R ｄ , -N(R ｃ ) S.O. ２ R ｄ , -(CH ２ ) ｚ N.R. ｃ R ｄ (wherein z is 1 or 2) or oxo; Here, Z １ Any alkyl moiety in the above substituents is optionally further substituted by cyano, halo, hydroxy, amino, oxo, (1-2C)alkyl or (1-2C)alkoxy; R ｃ and R ｄ are each independently selected from hydrogen, (1-2C)alkyl, (1-2C)haloalkyl, or (3-6C)cycloalkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally has one or more R １０Ｎ where R １０Ｎ is -S(O) ２ N.H. ２ or (i)-Z １ 、 (ii) -L １ａ -Z １ or (iii)-[CR ８ａ R ８ｂ ] １－２ -L １ｂ -Z １ is selected from Where: R ８ａ and R ８ｂ are both hydrogen, L １ａ is -C(O)-, -S(O) ２ -or-S(O) ２ N (R ａ１ )-, where R ａ１ is hydrogen or methyl; L １ｂ is absent or is -O-, -S-, -SO-, -SO ２ -, -N(R ａ２ )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ａ２ ) -, -N(R ａ２ )C(O)-,-N(R ａ２ ) C(O)N(R ｂ２ ) -, -S(O) ２ N (R ａ２ )- or -N(R ａ２ ) S.O. ２ where R ａ２ and R ｂ２ are each independently selected from hydrogen or methyl; Z １ is selected from (1-6C)alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, (3-6C)cycloalkyl(1-2C)alkyl or aryl(1-2C)alkyl, provided that Z １ When Z is a heterocyclyl group bonded directly to an N atom, it is a carbon-bonded heterocyclyl; １ is optionally (1-2C)alkyl, halo, (1-2C)haloalkoxy, cyano, nitro, -NR ｅ R ｆ , -OR ｅ , -C(O)R ｅ , -C(O)OR ｅ , -OC(O)R ｅ , -C(O)N(R ｅ ) R ｆ , -N(R ｅ ) C(O)R ｆ , -S(O) ｙ R ｅ (wherein y is 0, 1 or 2), -SO ２ N (R ｅ ) R ｆ , -N(R ｅ ) S.O. ２ R ｆ , -(CH ２ ) ｚ N.R. ｅ R ｆ (wherein z is 1, 2 or 3) or oxo, where R ｅ and R ｆ are each independently selected from hydrogen or (1-2C)alkyl; Any S atom present in the heterocycle is optionally represented by S(=O), S(=O) ２ Or S(=O)(=NR ｅ ), where R ｅ or a pharma- ceutically acceptable salt thereof, according to claim 1, wherein: is selected from hydrogen, (1-3C) alkyl or (2-3C) alkanoyl.

9. R ４ and R ５ together with the nitrogen atom to which they are attached, optionally have one or more R １０Ｃ are linked to form a heterocycle substituted by a substituent; Here, R １０Ｃ is an oxo, halo or cyano substituent, or of the formula: -[CH ２ ] ｎ -L-Z is selected from the group During the ceremony, n is 0 to 2; L is absent or is -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 ) S.O. ２ -, where R ａ and R ｂ are each independently selected from hydrogen or methyl; Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclyl(1-2C)alkyl or 5- or 6-membered heteroaryl, where Z is optionally (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, -NR ｃ R ｄ , -OR ｃ , -C(O)R ｃ , -C(O)OR ｃ , -OC(O)R ｃ , -C(O)N(R ｃ ) R ｄ , -N(R ｃ ) C(O)R ｄ , -S(O) ｙ R ｃ (wherein y is 0, 1 or 2), -SO ２ N (R ｃ ) R ｄ , -N(R ｃ ) S.O. ２ R ｄ , -(CH ２ ) ｚ N.R. ｃ R ｄ (wherein z is 1 or 2) or oxo; Here, R ｃ and R ｄ are each independently selected from hydrogen or (1-2C)alkyl; wherein any available N atom is optionally in the form of an N-oxide or optionally has one or more R １０Ｎ where R １０Ｎ is -S(O) ２ N.H. ２ or (i)-Z １ 、 (ii) -L １ａ -Z １ or (iii)-[CR ８ａ R ８ｂ ] １－２ -L １ｂ -Z １ is selected from Where: R ８ａ and R ８ｂ are both hydrogen, L １ａ is -C(O)-, -S(O) ２ -or-S(O) ２ N (R ａ１ )-, where R ａ１ is hydrogen, L １ｂ is absent or is -O-, -S-, -SO-, -SO ２ -, -N(R ａ２ )-, -C(O)N(R ａ２ ) -, -N(R ａ２ )C(O)-,-S(O) ２ N (R ａ２ )- or -N(R ａ２ ) S.O. ２ where R ａ２ is hydrogen, Z １ is selected from (1-4C)alkyl, phenyl, 4- to 7-membered heterocyclyl, or 5- or 6-membered heteroaryl, with the proviso that Z １ When Z is a heterocyclyl group directly bonded to an N atom, it is a carbon-bonded heterocyclyl, where Z １ is optionally (1-2C)alkyl, halo, (1-2C)haloalkoxy, cyano, -NR ｅ R ｆ , -OR ｅ , -C(O)R ｅ , -C(O)OR ｅ , -OC(O)R ｅ , -C(O)N(R ｅ ) R ｆ , -N(R ｅ ) C(O)R ｆ , -S(O) ｙ R ｅ (wherein y is 0, 1 or 2), -SO ２ N (R ｅ ) R ｆ , -N(R ｅ ) S.O. ２ R ｆ , -(CH ２ ) ｚ N.R. ｃ R ｄ (wherein z is 1 or 2), wherein R ｅ and R ｆ are each independently selected from hydrogen or methyl; Any S atom present in the heterocycle is optionally represented by S(=O), S(=O) ２ Or S(=O)(=NR ｅ ), where R ｅ or a pharma- ceutically acceptable salt thereof, according to claim 1, wherein: is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl.

10. R ４ and R ５ together with the nitrogen atom to which they are attached, optionally have one or more R １０Ｃ are linked to form a heterocyclic ring substituted by a substituent, R １０Ｃ is oxo, halo, cyano or the formula: -L-Z is selected from the group During the ceremony, L is absent, -O- or -N(R ａ )-, where R ａ is hydrogen or methyl; Z is selected from (1-4C)alkyl, 4- to 7-membered heterocyclyl or (3-6C)cycloalkyl(1-2C)alkyl; wherein any (1-4C)alkyl, 4- to 7-membered heterocyclyl or (3-6C)cycloalkyl(1-2C)alkyl is optionally selected from cyano, —NR ｃ R ｄ Or -OR ｃ wherein R ｃ and R ｄ are each independently selected from hydrogen or methyl; wherein any available N atom is optionally in the form of an N-oxide or optionally has one or more R １０Ｎ where R １０Ｎ is (1-4C)alkyl; 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein any S atom present in the heterocycle may optionally be present as S(=O).

11. R ４ and R ５ are linked together with the nitrogen atom to which they are attached to form a heterocycle selected from any one of the following options: 【Chemistry 8】 Where: ＊ is R ４ and R ５ represents the bonded N atom, Q １ is O, NH, S, S(O), S(O) ２ , S(O)(=NR ｅ ), N-R １０Ｎ , C.H. ２ , CHR １０Ｃ Or C(R １０ｃ ) ２ and Q ２ is -CH ２ --, --CHR １０Ｃ -, -C(R １０ｃ ) ２ --, --CHR １０Ｃ -CH ２ --, --CH ２ -CHR １０Ｃ --, --CHR １０Ｃ -CHR １０Ｃ -, -C(R １０ｃ ) ２ -CH ２ - or -CH ２ -C(R １０ｃ ) ２ - and Q ３ , CH, CR １０Ｃ or N, Ring A is a spiro-fused 4-, 5- or 6-membered carbocyclic or heterocyclic ring; Ring B is a fused 4-, 5- or 6-membered carbocyclic or heterocyclic ring; Here, R ｅ is selected from hydrogen or methyl; Each of said heterocyclic ring systems may optionally be one or more R １０ｃ Or R １０Ｎ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is substituted with a substituent.

12. R ４ and R ５ are linked together with the nitrogen atom to which they are attached to form a heterocycle selected from any one of the following options: 【Chemistry 9】 Where: ＊ is R ４ and R ５ represents the bonded N atom, Q １ is O, NH, S, S(O), S(O) ２ , S(O)(=NR ｅ ), N-R １０Ｎ , C.H. ２ , CHR １０Ｃ Or C(R １０ｃ ) ２ and Q ４ is O, NH, S, S(O), S(O) ２ , S(O)(=NR ｅ ), N-R １０Ｎ , C.H. ２ , CHR １０Ｃ Or C(R １０ｃ ) ２ and Here, R ｅ is selected from hydrogen, (1-2C) alkyl or (2C) alkanoyl; Each of said heterocyclic ring systems may optionally be one or more R １０ｃ Or R １０Ｎ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is substituted with a substituent.

13. R ４ and R ５ together with the nitrogen atom to which they are attached, form the structure 【Chemistry 10】 are linked to form a heterocycle of Where: ＊ is R ４ and R ５ represents the bonded N atom, Each R １０ｃ is independently selected from the options defined in any one of claims 1, 8, 9 or 10, or a pharma- ceutically acceptable salt thereof.

14. R ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is selected from hydrogen, halo, or methyl.

15. R ６ or a pharma- ceutically acceptable salt thereof, according to claim 1, wherein is hydrogen.

16. A compound of formula IA, IB, IC, ID, IE or IF, 【Chemistry 11】 【Chemistry 12】 In the formula, R ２ , R ４ , R ５ , R ６ and R １０ｃ are each as defined in claim 1, compound.

17. or a pharma- ceutically acceptable salt thereof, below, (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methyl-1H-indazol-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(7-methyl-3H-benzotriazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-piperazin-1-yl-piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-8-oxa-2,5-diazaspiro[3.5]nonane-2-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide, (3S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide, 4-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide, (3R)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide, (3R)-3-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide, 4-(1-cyano-1-methyl-ethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxamide, 4-(1-cyanoethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(dimethylamino)piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-[(dimethylamino)methyl]morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(2-pyrrolidin-1-ylethoxy)pyrrolidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-methyl-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b]pyridine-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(1-methyl-4-piperidyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-morpholino-piperidine-1-carboxamide, 4-(cyanomethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, (3S)—N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1,4-diazepane-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide, (4aR,7aS)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxamide, 3-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, (2S)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, (2R)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, (2S)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, (2R)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(2-methylquinazolin-7-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(2,4-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-quinazolin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methyl-6-quinolyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-methoxyquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(4-ethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, 4-cyano-N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1-methylpyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(3,8-dimethylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, 4-cyano-N-[4-(3-cyanophenyl)-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide, N-[4-(3-cyanophenyl)-5-(4,8-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1-methylpyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(3-methylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1,6-dimethylpyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(3-methylbenzimidazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-imidazo[1,2-a]pyridin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(7-methyl-1H-indazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(2,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(8-methylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(1,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-(6-methylpyridazin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-[5-methyl-6-(triazol-2-yl)-3-pyridyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, N-[4-(3-cyanophenyl)-5-pyrazolo[1,5-a]pyridin-5-yl-thiazol-2-yl]morpholine-4-carboxamide, N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide, or N-[5-(1,3-benzoxazol-6-yl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide or a pharma- ceutically acceptable salt thereof, selected from any one of:

18. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharma- ceutically acceptable salt thereof, in admixture with a pharma- ceutically acceptable diluent or carrier.

19. 20. A compound according to claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in therapy.

20. (i) use in the treatment of proliferative conditions; (ii) use in the treatment of cancer; (iii) use in the treatment of cancer, wherein said compound or said pharmaceutical composition is administered in combination with one or more additional anti-cancer agents; (iv) the compound or the pharmaceutical composition is 1) other forms of cancer immunotherapy and anti-cancer chemotherapy; 2) Adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors; 3) anti-PD-1 and anti-PDL-1 antibodies (e.g., cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab); and 4) Anti-CTLA4 antibodies (e.g., ipilimumab) 20. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition of claim 18, for use in the treatment of cancer, administered in combination with one or more additional anti-cancer agents selected from the group consisting of:

21. 19. A method of treating a proliferative disorder in a patient in need of such treatment, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 18.

22. 20. A method of treating cancer in a patient in need of such treatment, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition of claim 18.

23. 20. A method of treating a proliferative disorder in a patient in need of such treatment, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of claim 18, in combination with one or more additional anti-cancer agents.

24. the one or more additional anti-cancer agents 1) other forms of cancer immunotherapy and anti-cancer chemotherapy; 2) Adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors; 3) anti-PD-1 and anti-PDL-1 antibodies (e.g., cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab); and 4) an anti-CTLA4 antibody (e.g., ipilimumab), according to claim 23.

Images