Antagonists of adenosine receptors

Abstract

The present invention relates to compounds of formula I as shown below: # imgabs0 # wherein R1, R4, R5 and R6 are each as defined herein. The invention also relates to processes for preparing these compounds, pharmaceutical compositions comprising them and their use in the treatment of diseases or conditions in which adenosine A2a and / or A2b receptor activity is implicated, such as, for example, cancer.

Description

[0001] introduction

[0002] The present invention relates to certain compounds that act as antagonists of adenosine A2a receptors. In addition, some of the compounds are also antagonists of both A2a and A2b receptors. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions containing them, and their use in treating diseases or conditions in which adenosine A2a and / or A2b receptor activity is implicated, such as, for example, cancer. Background Art

[0003] Many immunosuppressive pathways are active in the tumor microenvironment, which enables tumor cells to evade elimination by cytotoxic T cells and can reduce patients' clinical responses to immunotherapy using anti-checkpoint antibodies. The anti-PD-1 antibodies pembrolizumab and nivolumab, as well as the anti-PD-L1 antibodies durvalumab, avelumab, and atezolizumab are approved for the treatment of a variety of solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma. However, only 20-30% of patients respond to checkpoint blockade, and the side effects of such treatments are significant (Sukari et al., 2016). Therefore, other methods of enhancing the cytotoxic potential of the tumor microenvironment are being actively studied. This includes agents that can be used as monotherapy or, more likely, in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy.

[0004] One approach gaining attention is to interfere with the production and / or action of adenosine in the tumor microenvironment (Vijayan et al., 2017). Adenosine has immunosuppressive properties and is present at high concentrations in the tumor microenvironment. Recent studies estimate that adenosine concentrations in human tumors are approximately 10 μM, compared to <1 μM in normal tissue (Houthuys et al., 2017). Adenosine is formed at intracellular and extracellular sites via two distinct pathways involving two different substrates. Intracellular adenosine is derived from AMP and S-adenosylhomocysteine, while the high extracellular adenosine concentrations observed during metabolic stress are associated with the release and degradation of precursor adenine nucleotides (ATP, ADP, and AMP) through the coordinated action of CD39 and CD73 (Vijayan et al., 2017).

[0005] CD39 and CD73 are upregulated in the tumor microenvironment in response to hypoxia. CD73 represents a putative patient stratification approach for adenosine antagonists, as its expression on tumor cells is also associated with poor overall prognosis in many different cancer types, suggesting that adenosine production contributes to the undesirable immunosuppressive phenotype of the tumor microenvironment (Gao et al., 2014; Loi et al., 2013). CD73 expression by tumor-infiltrating immune cells is also important in promoting tumor immunosuppression, as CD73-negative Treg cells are unable to suppress effector T cell function (Deaglio et al., 2007; Reinhardt et al., 2017). In addition, patients resistant to anti-PD1 therapy have elevated levels of CD73 (Reinhardt et al., 2017).

[0006] Adenosine regulates cellular function through specific GPCRs on the cell surface that occupy the P1 purinergic receptor subtype. The P1 receptor family is further subdivided into A1, A2a, A2b, and A3.

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

[0008] Pharmacological blockade of A2a has been used to mimic the effects of A2a genetic deficiency in mouse models. A2a antagonists have been shown to enhance cytotoxic CD8+ T cells and increase the ability of NK cells to prevent metastasis of CD73-expressing tumors (Beavis et al., 2013). Importantly, A2a antagonists enhance the efficacy of anti-PD1 antibodies (Beavis et al., 2015).

[0009] These findings have prompted the development of selective A2a antagonists for use in tumor immunotherapy, and clinical trials are underway with CPI-444, the first selective A2a antagonist evaluated in cancer, used as a monotherapy and in combination with the anti-PD-1 antibody atezolizumab. Preliminary data indicate that the compound is well tolerated and shows early signs of reducing tumor size and enhancing CD8+ T cell infiltration into tumor tissue.

[0010] Adenosine A2b receptors also play a key role in cancer progression by regulating the tumor microenvironment. A2b is expressed by myeloid-derived cells, and high concentrations of adenosine found in the tumor microenvironment can alter the behavior of tumor-associated macrophages, myeloid-derived suppressor cells, and dendritic cells. Activation of A2b leads to the polarization of immunosuppressive M2 macrophages (Csoka et al., 2012), the formation of myeloid-derived suppressor cells (Rhyzov et al., 2011), and promotes the immunosuppressive and proangiogenic phenotype of dendritic cells (Novitskiy et al., 2008; Wilson et al., 2009). Blocking A2b has been shown to reduce tumor size in numerous mouse cancer models (Cekic et al., 2012; Sorrentino et al., 2015; Iannone et al., 2013), an effect that correlates with reduced MDSC infiltration and VEGF production (Sorrentino et al., 2015; Iannone et al., 2013).

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

[0012] 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.

[0013] According to another 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, and a pharmaceutically acceptable diluent or carrier.

[0014] According to another aspect of the present invention, there is provided a method of antagonizing adenosine A2a receptor 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.

[0015] According to another aspect of the present invention, there is provided a method for selectively antagonizing adenosine A2a receptor 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.

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

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

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

[0019] According to another aspect of the present invention, there is provided a method for treating cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0020] According to another aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

[0021] According to another 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 treating proliferative conditions. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

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

[0023] According to another aspect of the 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. In one embodiment, the compound of the invention is a selective adenosine A2a and A2b antagonist.

[0024] According to another 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 condition in which adenosine A2a and / or A2b is involved.

[0025] According to another 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 preparation of a medicament for treating a proliferative condition. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

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

[0027] According to another aspect of the present invention, there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the preparation of a medicament for use as an adenosine A2a and / or A2b antagonist.

[0028] According to another 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 preparation of a medicament for the treatment of a disease or condition in which adenosine A2a is involved.

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

[0030] According to another aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof, which can be obtained by a method for preparing a compound as defined herein, or obtained by a method for preparing a compound as defined herein, or directly obtained by a method for preparing a compound as defined herein.

[0031] According to another aspect of the present invention there is provided a novel intermediate as defined herein, suitable for use in any of the synthetic methods described herein.

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

[0033] definition

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

[0035] It should be understood that references to "treating" include prevention as well as alleviation of established symptoms of a condition. Thus, "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the development of the condition, disorder, or condition in a human who may have or be susceptible to the condition, disorder, or condition but who does not yet experience or display clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or (3) remitting or palliating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0036] A "therapeutically effective amount" refers to the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment of the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0037] In this specification, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups (such as "propyl") specifically refer only to the straight-chain form, and references to individual branched-chain alkyl groups (such as "isopropyl") specifically refer only to the branched form. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl. Similar conventions apply to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0038] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix refers to any group having from m to n carbon atoms.

[0039] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to link two other chemical groups. Thus, "(1-6C)alkylene" refers to a straight-chain saturated divalent hydrocarbon group of one to six carbon atoms or a branched-chain saturated divalent hydrocarbon group of three to six carbon atoms, such as methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

[0040] "(2-6C)alkenylene" refers to a straight-chain divalent hydrocarbon group of two to six carbon atoms or a branched-chain divalent hydrocarbon group of three to six carbon atoms containing at least one double bond, for example, vinylene, 2,4-pentadienylene, and the like.

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

[0042] "(3-8C)cycloalkyl" refers to a hydrocarbon ring containing 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

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

[0044] "(3-8C)cycloalkyl-(1-6C)alkylene" refers to a (3-8C)cycloalkyl group covalently linked to a (1-6C)alkylene group, both as defined herein.

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

[0046] The term "heterocyclyl", "heterocyclic" or "heterocycle" refers to a non-aromatic saturated or partially saturated monocyclic, fused, bridged or spiral bicyclic heterocyclic ring system. The monocyclic heterocyclic ring contains about 3 to 12 (suitably 3 to 7) ring atoms and has 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. The bicyclic heterocycle contains 7 to 17 member atoms in the ring, suitably 7 to 12 member atoms. The bicyclic heterocycle can be a fused, spiral or bridged ring system. The example of the heterocyclic group includes cyclic ethers, such as oxiranyl, oxetane, tetrahydrofuranyl, dioxanyl and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiophene. Other heterocycles include dihydrothioxazolyl, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxothiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include sulfoxide and sulfone forms of tetrahydrothiophene and thiomorpholinyl, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for heterocyclyl groups with 1 or 2 oxo (=O) or thio (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyl groups containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by those skilled in the art, any heterocycle can be connected to another group via any suitable atom (such as via a carbon or nitrogen atom). However, mention herein of piperidino or morpholino refers to a piperidin-1-yl or morpholino ring connected via a ring nitrogen.

[0047] "Bridged ring system" refers to a ring system in which two rings share more than two atoms, see, e.g., Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, pp. 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.

[0048] "Spiro bicyclic ring system" refers to two ring systems sharing a common spiro carbon atom, i.e., a heterocyclic ring is connected to another carbocyclic or heterocyclic ring via 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.

[0049] "Heterocyclyl(1-6C)alkyl" refers to a heterocyclyl group covalently linked to a (1-6C)alkylene group, both as defined herein.

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

[0051] Examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazene, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, Quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, 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, imidazo[1,2b]

[124] triazinyl. "Heteroaryl" also encompasses 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 rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or -sulfur-. Examples of some aromatic heteroaryl groups include, for example, tetrahydroisoquinolyl, tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothiophenyl, 4,5,6,7-tetrahydrobenzofuranyl, dihydroindole, 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.

[0052] Examples of five-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.

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

[0054] The bicyclic heteroaryl group may be, for example, a group selected from:

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

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

[0057] a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0058] a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

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

[0060] a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0061] an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0062] an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

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

[0064] a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

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

[0066] a thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

[0067] a furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms;

[0068] a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; and

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

[0070] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guanidinyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0071] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, thiochromenyl, chromanyl, thiochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0072] "Heteroaryl(1-6C)alkyl" refers to a heteroaryl group covalently linked to a (1-6C)alkylene group, both as defined herein. Examples of heteroarylalkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0073] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes 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.

[0074] The term "aryl(1-6C)alkyl" refers to 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.

[0075] This specification also uses several composite terms to describe groups that contain more than one functional group. Such terms will be understood by those skilled in the art. For example, heterocyclyl (m-nC) alkyl includes (m-nC) alkyl substituted with a heterocyclyl.

[0076] The term "optionally substituted" refers to both substituted and unsubstituted groups, structures or molecules. The term "wherein R 1 One / any CH, CH2, CH3 group or heteroatom (ie NH) within the group is optionally substituted" suitably means R 1 (Any) hydrogen radical in a group is replaced by the relevant specified group.

[0077] When optional substituents are 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.

[0078] The phrase "compounds of the present invention" refers to those compounds disclosed both generically and specifically herein.

[0079] Compounds of the present invention

[0080] In a first aspect, the present invention relates to a compound having structural formula I shown below or a pharmaceutically acceptable salt, hydrate or solvate thereof:

[0081]

[0082] in:

[0083] R1 is selected from:

[0084]

[0085]

[0086]

[0087] in:

[0088] Any available C atom in R1 is optionally substituted with one or more R2 substituent groups, and

[0089] Any available N atom in R1 is optionally in the form of an N-oxide or substituted by an R3 group;

[0090] in

[0091] Each R2 is independently selected from (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 (where p is 0, 1, or 2), -(CR 1C R 1D ) q1 -SO2N(R 1B )R 1A or -(CR 1C R 1D) q1 -N(R 1B )SO2R 1A ,

[0092] where q1 is 0, 1, or 2; and

[0093] where R 1A and R 1B each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl;

[0094] where R 1C and R 1D are each independently selected from hydrogen or (1-2C)alkyl; and

[0095] R3 is selected from hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, C-attached 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 3Aor -(CR 3C R 3D ) 1-2 -N(R 3B )SO2R 3A ,

[0096] where R 3A and R 3B each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl;

[0097] where R 3C and R 3D are each independently selected from hydrogen or (1-2C)alkyl; and

[0098] where q3 is 0, 1, or 2; and

[0099] R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substitution,

[0100] where R 10C is selected from oxo, thio, halo or cyano substituents, or a group of the formula:

[0101] -[CR 7a R 7b ] n -LZ

[0102] in

[0103] n is an integer from 0 to 6;

[0104] R 7a and R 7b are each independently selected from hydrogen, fluoro or (1-2C)alkyl;

[0105] L is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-N(R a )C(O)N(R b )-、-C(S)N(R a )-、-N(R a )C(S)-、-N(R a )C(S)N(R b )-、-S(O)2N(R a )-or-N(R a)SO2-, where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; and

[0106] 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; and wherein Z is optionally substituted with one or more substituents selected from the group consisting of (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), -SO2N(R c )R d 、-N(R c )SO2R d 、-(CH2) z NR c R d (wherein z is 1, 2 or 3) or oxo,

[0107] wherein any alkyl moiety in the substituent groups 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, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;

[0108] and wherein any available N atom in the ring formed by R4 and R5 is optionally in the form of an N-oxide or optionally replaced by one or more R 10N replace,

[0109] where R 10N is -S(O)2NH2 or is selected from:

[0110] (i)-Z1;

[0111] (ii)-L 1a -Z1; or

[0112] (iii)-[CR 8a R 8b ] 1-6 -L 1b -Z1;

[0113] in

[0114] R 8a and R 8b are each independently selected from hydrogen, fluoro or (1-2C)alkyl;

[0115] L 1a Selected from -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 )-、-S(O)2N(R a1 )-or-N(R a1 )-, where R a1 is selected from hydrogen or (1-2C)alkyl;

[0116] L 1b Not present or selected from -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)2N(R a2 )-or-N(R a2 )SO2, where R a2 and R b2 are each independently selected from hydrogen or (1-2C)alkyl; and

[0117] 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 attached to the N atom, it is a carbon-attached heterocyclyl; and wherein Z1 is optionally substituted with one or more substituents selected from: (1-6C) - Alkyl, halo, (1-6C) haloalkoxy, cyano, nitro, -NR eR 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), -SO2N(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 wherein R e and R f are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;

[0118] and wherein any S atom present in the heterocyclic ring may optionally be present as S(=O), S(=O)2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, (1-3C)alkyl or (2-3C)alkanoyl; and R6 is selected from hydrogen, halo, methyl, methoxy and trifluoromethyl.

[0119] In another aspect, the present invention relates to a compound having structural formula I shown below, or a pharmaceutically acceptable salt, hydrate or solvate thereof:

[0120]

[0121] in:

[0122] R1 is selected from:

[0123]

[0124]

[0125]

[0126] in:

[0127] Any available C atom in R1 is optionally substituted with one or more R2 substituent groups, and

[0128] Any available N atom in R1 is optionally in the form of an N-oxide or substituted by an R3 group;

[0129] in

[0130] Each R2 is independently selected from (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 (where p is 0, 1, or 2), -(CR 1C R 1D ) q1 -SO2N(R 1B )R 1A or -(CR 1C R 1D ) q1 -N(R 1B )SO2R 1A ,

[0131] where q1 is 0, 1, or 2; and

[0132] where R 1A and R 1Beach independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl;

[0133] where R 1C and R 1D are each independently selected from hydrogen or (1-2C)alkyl; and

[0134] R3 is selected from hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, C-attached 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 ,

[0135] where q3 is 0, 1, or 2; and

[0136] R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substitution,

[0137] where R 10C is selected from oxo, thio, halo or cyano substituents, or a group of the formula:

[0138] -[CR 7a R 7b ] n -LZ

[0139] in

[0140] n is an integer from 0 to 6;

[0141] R 7a and R 7b are each independently selected from hydrogen, fluoro or (1-2C)alkyl;

[0142] L is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-N(R a )C(O)N(R b )-、-C(S)N(R a )-、-N(R a )C(S)-、-N(R a )C(S)N(R b )-、-S(O)2N(R a )-or-N(R a )SO2-, where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; and

[0143] 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; and wherein Z is optionally substituted with one or more substituents selected from: (1-6C) - Alkyl, halo, (1-6C)haloalkyl, (1-6C)haloalkoxy, cyano, nitro, -NR c R d 、-OR c 、-C(O)Rc 、-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), -SO2N(R c )R d 、-N(R c )SO2R d 、-(CH2) z NR c R d (wherein z is 1, 2 or 3) or oxo,

[0144] wherein any alkyl moiety in the substituent groups 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, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;

[0145] and wherein any available N atom in the ring formed by R4 and R5 is optionally in the form of an N-oxide or optionally replaced by one or more R 10N replace,

[0146] where R 10N is -S(O)2NH2 or is selected from:

[0147] (i)-Z1;

[0148] (ii)-L 1a -Z1; or

[0149] (iii)-[CR 8a R 8b ] 1-6 -L 1b -Z1;

[0150] in

[0151] R 2a and R 2b are each independently selected from hydrogen, fluoro or (1-2C)alkyl;

[0152] L 1a Selected from -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 )-、-S(O)2N(Ra1 )-or-N(R a1 )-, where R a1 is selected from hydrogen or (1-2C)alkyl;

[0153] L 1b Not present or selected from -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)2N(R a2 )-or-N(R a2 )SO2, where R a2 and R b2 are each independently selected from hydrogen or (1-2C)alkyl; and

[0154] 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 attached to the N atom, it is a carbon-attached heterocyclyl; and wherein Z1 is optionally substituted with one or more substituents selected from: (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), -SO2N(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 wherein R e and R f are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl;

[0155] and wherein any S atom present in the heterocyclic ring may optionally be present as S(=O), S(=O)2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, (1-3C)alkyl or (2-3C)alkanoyl; and R6 is selected from hydrogen, halo, methyl, methoxy and trifluoromethyl.

[0156] Specific compounds of the present invention include, for example, compounds of Formula I, or pharmaceutically acceptable salts, hydrates, and / or solvates thereof, wherein, unless otherwise indicated, each of R1, R2, R3, R4, R5, R6, and any associated substituent groups has any meaning as defined above or in any of paragraphs (1) to (36) below:

[0157] (1) R1 is selected from the group consisting of:

[0158]

[0159]

[0160] wherein each R1 is optionally substituted on any available carbon atom with one or more R2, and R2 and R3 are as defined herein.

[0161] (2) R1 is selected from the group consisting of:

[0162]

[0163]

[0164] wherein R1 is optionally substituted on any available carbon atom with one or more R2 substituent groups; and R2 and R3 are as defined herein.

[0165] (3) R1 is selected from the group consisting of:

[0166]

[0167] wherein R1 is optionally substituted on any available carbon atom with one or more R2 substituent groups, and R2 is as defined herein.

[0168] (4) R1 is:

[0169]

[0170] wherein R1 is optionally substituted on any available carbon atom with one or more R2 substituent groups, and R2 is as defined herein.

[0171] (5) R1 is:

[0172]

[0173] wherein R2 is as defined herein.

[0174] (6) R1 is selected from the group consisting of:

[0175]

[0176]

[0177]

[0178] (7) R1 is:

[0179]

[0180] (8) If present, each R2 is independently selected from (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 ;

[0181] where q1 is 0 or 1; and

[0182] where R 1A and R 1B are each independently selected from hydrogen, (1-2C)alkyl;

[0183] where R 1C and R 1D are each independently selected from hydrogen or (1-2C)alkyl;

[0184] (9) If present, each R2 is 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 -OR1A ;

[0185] where q1 is 0 or 1; and

[0186] where R 1A and R 1B are each independently selected from hydrogen, (1-2C)alkyl;

[0187] (10) if present, each R2 is independently selected from methyl, ethyl or methoxy;

[0188] (11) if present, each R2 is methyl;

[0189] (11a) 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, (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 ;

[0190] where R 3A and R 3B are each independently selected from hydrogen or (1-2C)alkyl;

[0191] where R 3C and R 3D are each independently selected from hydrogen or (1-2C)alkyl; and wherein q3 is 0, 1 or 2;

[0192] (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;

[0193] (12) R3 is selected from hydrogen or (1-3C)alkyl;

[0194] (13) R3 is selected from fluoro or methyl;

[0195] (14) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substituted, where R 10C is selected from oxo, thio, halo or cyano substituents, or a group of the formula:

[0196] -[CH2] n -LZ

[0197] in

[0198] n is 0 to 4;

[0199] L is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-N(R a )C(O)N(R b )-、-S(O)2N(R a )-or-N(R a )SO2-, where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; and

[0200] Z is selected from hydrogen, (1-6C) - wherein Z is optionally substituted with one or more substituents selected from the group consisting of: (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), -SO2N(R c )R d 、-N(R c )SO2R d 、-(CH2) z NR c R d (wherein z is 1, 2 or 3) or oxo,

[0201] wherein any alkyl moiety in the substituent groups 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, (1-4C)alkyl, (1-4C)haloalkyl or (3-6C)cycloalkyl;

[0202] and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substituted, where R 10N is -S(O)2NH2 or is selected from:

[0203] (i)-Z1;

[0204] (ii)-L 1a -Z1; or

[0205] (iii)-[CR 8a R 8b ] 1-4 -L 1b-Z1;

[0206] in

[0207] R 8a and R 8b All are hydrogen;

[0208] L 1a Selected from -C(O)-, -S(O)2-, -C(O)O-, -C(O)N(R a1 )-or-S(O)2N(R a1 )-, where R a1 is hydrogen or methyl;

[0209] L 1b Not present or selected from -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)2N(R a2 )-or-N(R a2 )SO2, where R a2 and R b2 are each independently selected from hydrogen or methyl; and

[0210] 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 attached to the N atom, it is a carbon-attached heterocyclyl; and wherein Z1 is optionally substituted with one or more substituents selected from the group consisting of: (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), -SO2N(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 wherein R e and R f are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)haloalkyl or (3-6C)cycloalkyl;

[0211] and wherein any S atom present in the heterocyclic ring may optionally be present as S(=O), S(=O)2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, (1-3C)alkyl or (2-3C)alkanoyl;

[0212] (15) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substituted, where R 10C is selected from oxo, halo or cyano substituents, or a group of the formula:

[0213] -[CH2] n -LZ

[0214] in

[0215] n is 0 to 2 (i.e., n is 0, 1 or 2);

[0216] L is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-、-N(R a2 )C(O)-、-N(R a2 )C(O)N(R b2 )-、-S(O)2N(R a2 )-or-N(R a2 )SO2-, where R a2 and R b2 are each independently selected from hydrogen or methyl; and

[0217] 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; and wherein Z is optionally substituted with one or more substituents selected from: (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), -SO2N(R c )R d 、-N(R c )SO2R d 、-(CH2) z NR c R d (wherein z is 1 or 2) or oxo;

[0218] wherein any alkyl moiety in the substituent group on Z1 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;

[0219] and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substituted, where R 10N is -S(O)2NH2 or is selected from:

[0220] (i)-Z1;

[0221] (ii)-L 1a -Z1; or

[0222] (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1;

[0223] in

[0224] R8a and R 8b All are hydrogen;

[0225] L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 is hydrogen or methyl;

[0226] L 1b Not present or selected from -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)2N(R a2 )-or-N(R a2 )SO2, where R a2 and R b2 are each independently selected from hydrogen or methyl; and

[0227] 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 attached to the N atom, it is a carbon-attached heterocyclyl; and wherein Z1 is optionally substituted with one or more substituents selected from: (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), -SO2N(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 wherein R e and R f are each independently selected from hydrogen or (1-2C)alkyl;

[0228] and wherein any S atom present in the heterocyclic ring may optionally be present as S(=O), S(=O)2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, (1-3C)alkyl or (2-3C)alkanoyl;

[0229] (16) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substituted, where R 10C is selected from oxo, halo or cyano substituents, or a group of the formula:

[0230] -[CH2] n -LZ

[0231] in

[0232] n is 0 to 2 (i.e., n is 0, 1 or 2);

[0233] L is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-N(R a )C(O)N(R b )-、-S(O)2N(R a )-or-N(R a )SO2-, where R a and R b is hydrogen or methyl; and

[0234] 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; and wherein Z is optionally substituted with one or more substituents selected from: (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), -SO2N(R c )R d 、-N(R c )SO2R d 、-(CH2) z NR c R d (wherein z is 1 or 2) or oxo;

[0235] where R c and R d are each independently selected from hydrogen, (1-2C)alkyl or (1-2C)haloalkyl;

[0236] and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substituted, where R 10N is -S(O)2NH2 or is selected from:

[0237] (i)-Z1;

[0238] (ii)-L 1a -Z1; or

[0239] (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1;

[0240] in

[0241] R 8a and R 8b All are hydrogen;

[0242] L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 It is hydrogen;

[0243] L 1b Not present or selected from -O-, -S-, -SO-, -SO 2- 、-N(R a2 )-、-C(O)N(R a2 )-、-N(R a2 )C(O)-、-S(O)2N(R a2)-or-N(R a2 )SO2, where R a2 is hydrogen; and

[0244] Z1 is selected from (1-6C) - alkyl, (3-6C)cycloalkyl, aryl, heterocyclyl, heteroaryl, provided that when Z1 is a heterocyclyl group directly attached to the N atom, it is a carbon-attached heterocyclyl; and wherein Z1 is optionally substituted with one or more substituents selected from: (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), -SO2N(R e )R f 、-N(R e )SO2R f 、-(CH2) z NR c R d (where z is 1 or 2); and where R e and R f are each independently selected from hydrogen or methyl;

[0245] and wherein any S atom present in the heterocyclic ring may optionally be present as S(=O), S(=O)2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl;

[0246] (17) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substitution,

[0247] where R 10C is selected from oxo, halo or cyano, or a group of the formula:

[0248] -[CH2] n -LZ

[0249] in

[0250] n is 0 to 2 (i.e., n is 0, 1 or 2);

[0251] L is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-S(O)2N(R a )-or-N(R a )SO2-, where R a and R b are each independently selected from hydrogen or methyl; and

[0252] Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl, 4-7 membered heterocyclyl, 4-7 membered heterocyclyl(1-2C)alkyl, or 5 or 6 membered heteroaryl; and wherein Z is optionally substituted with one or more substituents selected from: (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), -SO2N(R c )R d 、-N(R c )SO2R d 、-(CH2) z NR c R d (wherein z is 1 or 2) or oxo;

[0253] where R c and R d are each independently selected from hydrogen or (1-2C)alkyl;

[0254] and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substituted, where R 10Nis -S(O)2NH2 or is selected from:

[0255] (i)-Z1;

[0256] (ii)-L 1a -Z1; or

[0257] (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1;

[0258] in

[0259] R 8a and R 8b All are hydrogen;

[0260] L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 It is hydrogen;

[0261] L 1b Not present or selected from -O-, -S-, -SO-, -SO 2- 、-N(R a2 )-、-C(O)N(R a2 )-、-N(R a2 )C(O)-、-S(O)2N(R a2 )-or-N(R a2 )SO2, where R a2 is hydrogen; and

[0262] Z1 is selected from (1-4C)alkyl, phenyl, 4-7 membered heterocyclyl or 5 or 6 membered heteroaryl, provided that when Z1 is a heterocyclyl group directly attached to the N atom, it is a carbon-attached heterocyclyl; and wherein Z1 is optionally substituted with one or more substituents selected from: (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), -SO2N(R e)R f 、-N(R e )SO2R f 、-(CH2) z NR c R d (where z is 1 or 2); and where R e and R f are each independently selected from hydrogen or methyl;

[0263] and wherein any S atom present in the heterocyclic ring may optionally be present as S(=O), S(=O)2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl;

[0264] (18) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substituted, where R 10C is selected from oxo, halo or cyano substituents, or a group of the formula:

[0265] -[CH2] n -LZ

[0266] in

[0267] n is 0 to 2 (i.e., n is 0, 1 or 2);

[0268] L is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-S(O)2N(R a )-or-N(R a )SO2-, where R a and R b are each independently selected from hydrogen or methyl; and

[0269] Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl, 4-7 membered heterocyclyl, 4-7 membered heterocyclyl(1-2C)alkyl, or 5 or 6 membered heteroaryl; and wherein Z is optionally substituted with one or more substituents selected from: (1-2C) - Alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, -NR c R d 、-ORc 、-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;

[0270] where R c and R d are each independently selected from hydrogen or (1-2C)alkyl;

[0271] and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substituted, where R 10N is -S(O)2NH2 or is selected from:

[0272] (i)-Z1;

[0273] (ii)-L 1a -Z1; or

[0274] (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1;

[0275] in

[0276] R 8a and R 8b All are hydrogen;

[0277] L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 It is hydrogen;

[0278] L 1b Not present or selected from -O-, -S-, -SO-, -SO 2- 、-N(R a2 )-、-C(O)N(R a2 )-、-N(R a2 )C(O)-、-S(O)2N(R a2 )-or-N(R a2 )SO2, where R a2 is hydrogen; and

[0279] Z1 is selected from (1-4C)alkyl, phenyl, 4-7 membered heterocyclyl or 5 or 6 membered heteroaryl, provided that when Z1 is a heterocyclyl group directly attached to the N atom, it is a carbon-attached heterocyclyl; and wherein Z1 is optionally substituted with one or more substituents selected from: (1-2C) - Alkyl, halo, (1-2C) haloalkoxy, cyano, -NR e R f 、-OR e 、-C(O)R e 、-C(O)N(R e )R f 、-N(R e )C(O)R f 、-S(O) y R e (where y is 0, 1 or 2); and where R e and R f are each independently selected from hydrogen or methyl;

[0280] and wherein any S atom present in the heterocyclic ring may optionally be present as S(=O), S(=O)2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, methyl or (2C)alkanoyl;

[0281] (19) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substituted, where R 10C is selected from oxo, halo or cyano substituents, or a group of the formula:

[0282] -[CH2] n -LZ

[0283] in

[0284] n is 0 to 2 (i.e., n is 0, 1 or 2);

[0285] L is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-S(O)2N(R a )-or-N(R a )SO2-, where R a and R b are each independently selected from hydrogen or methyl; and

[0286] Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, 4-7 membered heterocyclyl, 4-7 membered heterocyclyl(1-2C)alkyl, or 5 or 6 membered heteroaryl; and wherein Z is optionally substituted with one or more substituents selected from: (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;

[0287] where R c and R d are each independently selected from hydrogen or (1-2C)alkyl;

[0288] and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substituted, where R 10N is -S(O)2NH2 or is selected from:

[0289] (i)-Z1;

[0290] (ii)-L 1a -Z1; or

[0291] (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z1;

[0292] in

[0293] R 8a and R 8b All are hydrogen;

[0294] L 1a Selected from -C(O)-, -S(O)2- or -S(O)2N(R a1 )-, where R a1 It is hydrogen;

[0295] L 1b Not present or selected from -O-, -S-, -SO-, -SO 2- 、-N(R a2)-、-C(O)N(R a2 )-、-N(R a2 )C(O)-、-S(O)2N(R a2 )-or-N(R a2 )SO2, where R a2 is hydrogen; and

[0296] Z1 is selected from (1-4C)alkyl or 4-7 membered heterocyclyl, provided that when Z1 is a heterocyclyl group directly attached to the N atom, it is a carbon-attached heterocyclyl;

[0297] wherein Z1 is optionally substituted with one or more substituents selected from the group consisting of: (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 (where y is 0, 1 or 2); and where R e and R f are each independently selected from hydrogen or methyl;

[0298] and wherein any S atom present in the heterocyclic ring may optionally be present as S(=O), S(=O)2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, methyl or (2C)alkanoyl;

[0299] (20) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substituted, where R 10C is selected from oxo, halo or cyano substituents, or a group of the formula;

[0300] -LZ

[0301] in

[0302] L is absent or selected from -O-, -S-, -SO-, -SO2-, -N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-S(O)2N(Ra )-or-N(R a )SO2-, where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; and

[0303] Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, 4-7 membered heterocyclyl or heterocyclyl(1-2C)alkyl; and Z is optionally substituted with one or more substituents 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 alkyl moiety in the substituent groups 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, (1-6C)alkyl;

[0304] and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substituted, where R 10N is -S(O)2NH2 or (1-4C)alkyl,

[0305] and wherein any S atom present in the heterocyclic ring may optionally be present as S(=O), S(=O)2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, methyl or (2C)alkanoyl;

[0306] (21) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substituted, where R 10C A group selected from oxo, halo, cyano or the following formula:

[0307] -LZ

[0308] in

[0309] L does not exist, is -O or -N(R a )-, where R a is hydrogen or methyl;

[0310] Z is selected from (1-4C)alkyl, 4-7 membered heterocyclyl, (3-6C)cycloalkyl(1-2C)alkyl, wherein any (1-4C)alkyl, 4-7 membered heterocyclyl or (3-6C)cycloalkyl(1-2C)alkyl is optionally substituted with one or more substituents selected from cyano, -NR c R d OR c , where R c and R d are each independently selected from hydrogen or methyl;

[0311] and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substituted, where R 10N is (1-4C)alkyl,

[0312] and wherein any S atom present in the heterocyclic ring may optionally be present as S(=O);

[0313] (22) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substituted, wherein each R 10C are independently selected from (1-4C)alkyl or cyano, wherein (1-4C)alkyl is optionally substituted with cyano, -NR c R d OR c Substituted, where R c and R d are each independently selected from hydrogen or methyl;

[0314] and wherein any available N atom is optionally replaced by one or more R 10N Substituted, where R 10N It's methyl.

[0315] (23) R4 and R5 are linked such that together with the nitrogen atom to which they are attached they form a 4- to 12-membered heterocyclic ring, and wherein the heterocyclic ring is optionally replaced by one or more R 10C or R 10N Substituent group substituted, where R 10c and R 10N As defined in any of paragraphs (14) to (22) above;

[0316] (24) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a 4- to 8-membered monocyclic or bridged heterocyclic ring or a 7- to 12-membered bicyclic or spirobicyclic heterocyclic ring, and wherein the heterocyclic ring is optionally replaced by one or more R 10C or R 10NSubstituent group substituted, where R 10c and R 10N As defined in any of paragraphs (14) to (22) above;

[0317] (25) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a 4- to 7-membered monocyclic or bridged heterocyclic ring or a 7- to 11-membered bicyclic or spirobicyclic heterocyclic ring, and wherein the heterocyclic ring is optionally replaced by one or more R 10C or R 10N Substituent group substituted, where R 10c and R 10N As defined in any of paragraphs (14) to (22) above;

[0318] (26) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a 5- or 6-membered monocyclic heterocyclic ring or a 7- to 10-membered bicyclic or spirobicyclic heterocyclic ring, and wherein the heterocyclic ring is optionally replaced by one or more R 10C or R 10N Substituent group substituted, where R 10c and R 10N As defined in any of paragraphs (14) to (22) above;

[0319] (27) R4 and R5 are linked such that together with the nitrogen atom to which they are attached they form a heterocyclic ring selected from any one of the following options:

[0320]

[0321]

[0322] Wherein * represents the N atom to which R4 and R5 are attached;

[0323] Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0324] CHR 10C or C(R 10c )2;

[0325] Q2 is -CH2-, -CHR 10C -、-C(R 10c )2-、-CHR 10C -CH2-, -CH2-

[0326] CHR 10C -、-CHR 10C -CHR 10C -、-C(R 10c)2-CH2- or -CH2-C(R 10c )2-;

[0327] Q3 is CH, CR 10C or N;

[0328] Ring A is a spiro-fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring;

[0329] Ring B is a fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring;

[0330] where R e is selected from hydrogen or methyl;

[0331] and wherein each of the heterocyclic ring systems is optionally replaced by one or more R as defined in any of paragraphs (14) to (22) above 10c or R 10N Substituent group substitution;

[0332] (28) R4 and R5 are linked such that together with the nitrogen atom to which they are attached they form a heterocyclic ring selected from any one of the following options:

[0333]

[0334]

[0335] Wherein * represents the N atom to which R4 and R5 are attached;

[0336] Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0337] CHR 10C or C(R 10c )2;

[0338] Q2 is -CH2-, -CHR 10C -or-C(R 10c )2-;

[0339] Q3 is CH, CR 10C or N;

[0340] Ring A is a spiro-fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring;

[0341] Ring B is a fused 4-, 5-, or 6-membered carbocyclic or heterocyclic ring;

[0342] where R e is selected from hydrogen, (1-3C)alkyl or (2-3C)alkanoyl;

[0343] and wherein each of the heterocyclic ring systems is optionally replaced by one or more R as defined in any of paragraphs (14) to (22) above 10c or R 10N Substituent group substitution;

[0344] (29) R4 and R5 are linked such that together with the nitrogen atom to which they are attached they form a heterocyclic ring selected from any one of the following options:

[0345]

[0346]

[0347] Wherein * represents the N atom to which R4 and R5 are attached;

[0348] Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0349] CHR 10C or C(R 10c )2;

[0350] Q2 is -CH2-;

[0351] Q3 is CH, CR 10C or N;

[0352] Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0353] CHR 10C or C(R 10c )2;

[0354] Q5 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0355] CHR 10C or C(R 10c )2;

[0356] Q6 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0357] CHR 10C or C(R 10c )2;

[0358] Q7 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0359] CHR 10C or C(R 10c )2;

[0360] where R e is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl;

[0361] and wherein each of the heterocyclic ring systems is optionally replaced by one or more R as defined in any of paragraphs (14) to (22) above 10c or R 10N Substituent group substitution;

[0362] (30) R4 and R5 are linked such that together with the nitrogen atom to which they are attached they form a heterocyclic ring selected from any one of the following options:

[0363]

[0364] Wherein * represents the N atom to which R4 and R5 are attached;

[0365] Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0366] CHR 10C or C(R 10c )2;

[0367] Q2 is -CH2-;

[0368] Q3 is CH, CR 10C or N;

[0369] Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0370] CHR 10C or C(R 10c )2;

[0371] Q5 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0372] CHR 10C or C(R 10c )2;

[0373] Q6 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0374] CHR 10C or C(R 10c )2;

[0375] Q7 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0376] CHR 10C or C(R 10c )2;

[0377] where R e is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl;

[0378] and wherein each of the heterocyclic ring systems is optionally replaced by one or more R as defined in any of paragraphs (14) to (22) above 10c or R 10N Substituent group substitution;

[0379] (33) R4 and R5 are linked such that together with the nitrogen atom to which they are attached they form a heterocyclic ring selected from any one of the following options:

[0380]

[0381] Wherein * represents the N atom to which R4 and R5 are attached;

[0382] Q1 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0383] CHR 10C or C(R 10c )2;

[0384] Q4 is O, NH, S, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0385] CHR 10C or C(R 10c )2;

[0386] where R e is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl;

[0387] and wherein each of the heterocyclic ring systems is optionally replaced by one or more R as defined in any of paragraphs (14) to (22) above 10c or R 10N Substituent group substitution;

[0388] (34) R4 and R5 are linked such that together with the nitrogen atom to which they are attached they form a heterocyclic ring selected from any one of the following options:

[0389]

[0390] Wherein * represents the N atom to which R4 and R5 are attached;

[0391] Q1 is O, NH, NR 10N , CH2, CHR 10C or C(R 10c )2;

[0392] Q4 is O, NH, NR 10N , CH2, CHR 10C or C(R 10c )2;

[0393] where R e is selected from hydrogen, methyl or (2C)alkanoyl;

[0394] R 10c or R 10N As defined in any of paragraphs (14) to (22) above;

[0395] (35) R4 and R5 are linked such that together with the nitrogen atom to which they are attached they form a heterocyclic ring selected from any one of the following options:

[0396]

[0397] Wherein * represents the N atom to which R4 and R5 are attached;

[0398] Q1 is O, NH, S(O), S(O)2, S(O)(=NR e ),NR 10N 、CH2、

[0399] CHR 10C or C(R 10c )2;

[0400] where R e is selected from hydrogen, methyl or (2C)alkanoyl;

[0401] R 10c or R 10NAs defined in any of paragraphs (14) to (22) above;

[0402] (36) R4 and R5 are linked so that together with the nitrogen atom to which they are attached they form a heterocyclic ring of the following structure:

[0403]

[0404] Wherein * represents the N atom to which R4 and R5 are attached;

[0405] And each R 10c Independently selected from the options defined in any of paragraphs (14) to (22) above;

[0406] (37) R6 is selected from hydrogen, halo or methyl;

[0407] (38) R6 is selected from hydrogen or methyl;

[0408] (39) R6 is hydrogen.

[0409] Suitably, the heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl group containing one, two or three heteroatoms selected from N, O or S, or a monocyclic, bicyclic, spirobicyclic or bridged heterocyclyl group.

[0410] Suitably, the heteroaryl group is a 5 or 6 membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0411] Suitably, the heterocyclyl group is a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, the heterocyclyl group is a 5-, 6- or 7-membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g., morpholinyl (e.g., 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl or pyrrolidonyl] or a 7-, 8-, 9- or 10-membered spirobicyclic ring system comprising one, two or three heteroatoms selected from N, O or S.

[0412] Suitably, the aryl group is phenyl.

[0413] Suitably, R1 is as defined in any one of paragraphs (1) to (7) above. More suitably, R1 is as defined in paragraphs (3) to (7) above. Most suitably, R1 is as defined in paragraphs (5) or (7) above.

[0414] Suitably, R2 is as defined in any one of paragraphs (8) to (11) above. More suitably, R2 is as defined in any one of paragraphs (9) to (11) above. Most suitably, R2 is as defined in paragraphs (10) or (11) above.

[0415] Suitably, R3 is as defined in paragraphs (11a), (11b), (12) or (13) above. More suitably, R3 is as defined in paragraphs (12) or (13) above. Most suitably, R3 is as defined in paragraph (13) above.

[0416] Suitably, R4 and R5 are linked such that together with the nitrogen atom to which they are attached they form a heterocyclic ring which is optionally substituted as defined in any of paragraphs (14) to (22) above. More suitably, the heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (19) to (22) above. Most suitably, the heterocyclic ring formed by R4 and R5 is optionally substituted as defined in paragraphs (21) or (22) above.

[0417] Suitably, R4 and R5 are as defined in any of paragraphs (23) to (36) above. More suitably, R4 and R5 are as defined in any of paragraphs (27) to (36) above. Most suitably, R4 and R5 are as defined in paragraphs (35) or (36) above.

[0418] Suitably, R 10c and R 10N As defined in any of paragraphs (14) to (22) above. More suitably, R 10c and R 10N As defined in any of paragraphs (19) to (22) above. Even more suitably, R 10c and R 10N As defined in any of paragraphs (20), (21) or (22) above.

[0419] Suitably, R6 is as defined in any one of paragraphs (37) to (39) above. More suitably, R6 is as defined in paragraph (39) above, i.e. R6 is hydrogen.

[0420] In a specific group of compounds of Formula I above, R1 is as defined in any of paragraphs (1), (2), (3), (4), (5), (6) or (7), and R2, R3, R4, R5 and R6 each have any of the definitions described herein.

[0421] In a specific group of compounds of the above formula I, R1 is as defined in paragraph (4), i.e., the compound has the structural formula IA (a subformula of formula I) shown below:

[0422]

[0423] wherein R2, R4, R5 and R6 each have any of the definitions described herein.

[0424] In an embodiment of the compound having Formula IA:

[0425] R2 is as defined in any of paragraphs (8) to (11) above;

[0426] R4 and R5 are as defined in any of paragraphs (23) to (36) above;

[0427] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (14) to (22) above; and

[0428] R6 is as defined in any of paragraphs (37) to (39) above.

[0429] In an embodiment of the compound having Formula IA:

[0430] R2 is as defined in any of paragraphs (9) to (11) above;

[0431] R4 and R5 are as defined in any of paragraphs (27) to (36) above;

[0432] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (19) to (22) above; and

[0433] R6 is as defined in paragraph (38) or (39) above.

[0434] In an embodiment of the compound having Formula IA:

[0435] R2 is as defined in paragraph (10) or (11) above;

[0436] R4 and R5 are as defined in paragraph (35) or (36) above;

[0437] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in paragraph (21) or (22) above; and

[0438] R6 is as defined in paragraph (38) or (39) above.

[0439] In an embodiment of the compound having Formula IA:

[0440] R2 is as defined in paragraph (11) above;

[0441] R4 and R5 are as defined in paragraph (35) above;

[0442] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (19) to (22) above; and

[0443] R6 is as defined in paragraph (38) or (39) above.

[0444] In an embodiment of the compound having Formula IA:

[0445] R2 is as defined in paragraph (11) above;

[0446] R4 and R5 are as defined in any of paragraphs (27) to (36) above;

[0447] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in paragraph (21) or (22) above; and

[0448] R6 is as defined in paragraph (38) or (39) above.

[0449] In a specific 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:

[0450]

[0451] wherein R2, R4, R5 and R6 each have any of the definitions described herein.

[0452] In an embodiment of the compound having Formula IB:

[0453] R2 is as defined in any of paragraphs (8) to (11) above;

[0454] R4 and R5 are as defined in any of paragraphs (23) to (36) above;

[0455] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (14) to (22) above; and

[0456] R6 is as defined in any of paragraphs (37) to (39) above.

[0457] In an embodiment of the compound having Formula IB:

[0458] R2 is as defined in any of paragraphs (9) to (11) above;

[0459] R4 and R5 are as defined in any of paragraphs (27) to (36) above;

[0460] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (19) to (22) above; and

[0461] R6 is as defined in paragraph (38) or (39) above.

[0462] In an embodiment of the compound having Formula IB:

[0463] R2 is as defined in paragraph (10) or (11) above;

[0464] R4 and R5 are as defined in paragraph (35) or (36) above;

[0465] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in paragraph (21) or (22) above; and

[0466] R6 is as defined in paragraph (38) or (39) above.

[0467] In an embodiment of the compound having Formula IB:

[0468] R2 is as defined in paragraph (11) above;

[0469] R4 and R5 are as defined in paragraph (35) above;

[0470] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (19) to (22) above; and

[0471] R6 is as defined in paragraph (38) or (39) above.

[0472] In an embodiment of the compound having Formula IB:

[0473] R2 is as defined in paragraph (11) above;

[0474] R4 and R5 are as defined in any of paragraphs (27) to (36) above;

[0475] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in paragraph (21) or (22) above; and

[0476] R6 is as defined in paragraph (38) or (39) above.

[0477] In a specific group of compounds of formula I above, R1 is as defined in paragraph (7), i.e., the compound has the structural formula IC (a subformula of formula I) shown below:

[0478]

[0479] wherein R1, R4, R5 and R6 each have any of the definitions described herein.

[0480] In an embodiment of the compound having Formula IC:

[0481] R4 and R5 are as defined in any of paragraphs (23) to (36) above;

[0482] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (14) to (22) above; and

[0483] R6 is as defined in any of paragraphs (37) to (39) above.

[0484] In an embodiment of the compound having Formula IC:

[0485] R4 and R5 are as defined in any of paragraphs (27) to (36) above;

[0486] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (19) to (22) above; and

[0487] R6 is as defined in paragraph (38) or (39) above.

[0488] In an embodiment of the compound having Formula IC:

[0489] R4 and R5 are as defined in paragraph (35) or (36) above;

[0490] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in paragraph (21) or (22) above; and

[0491] R6 is as defined in paragraph (38) or (39) above.

[0492] In an embodiment of the compound having Formula IC:

[0493] R4 and R5 are as defined in paragraph (35) above;

[0494] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (19) to (22) above; and

[0495] R6 is as defined in paragraph (38) or (39) above.

[0496] In an embodiment of the compound having Formula IC:

[0497] R4 and R5 are as defined in any of paragraphs (27) to (36) above;

[0498] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in paragraph (21) or (22) above; and

[0499] R6 is as defined in paragraph (38) or (39) above.

[0500] In a specific group of compounds of the above formula I, R6 is hydrogen, ie the compound has the structural formula ID (subformula of formula I') shown below:

[0501]

[0502] wherein R1, R4 and R5 each have any of the definitions given herein.

[0503] In embodiments of compounds having Formula ID:

[0504] Suitably, R1 is as defined in any one of paragraphs (1) to (7) above;

[0505] R4 and R5 are as defined in any of paragraphs (23) to (36) above;

[0506] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (14) to (22) above; and

[0507] R6 is as defined in any of paragraphs (37) to (39) above.

[0508] In embodiments of compounds having Formula ID:

[0509] R1 is as defined in paragraphs (3) to (7) above;

[0510] R4 and R5 are as defined in any of paragraphs (27) to (36) above;

[0511] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (19) to (22) above; and

[0512] R6 is as defined in paragraph (38) or (39) above.

[0513] In embodiments of compounds having Formula ID:

[0514] R1 is as defined in paragraphs (3) to (7) above;

[0515] R4 and R5 are as defined in paragraph (35) or (36) above;

[0516] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in paragraph (21) or (22) above; and

[0517] R6 is as defined in paragraph (38) or (39) above.

[0518] In embodiments of compounds having Formula ID:

[0519] R1 is as defined in paragraph (5), (6) or (7) above;

[0520] R4 and R5 are as defined in paragraph (35) above;

[0521] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in any of paragraphs (19) to (22) above; and

[0522] R6 is as defined in paragraph (38) or (39) above.

[0523] In embodiments of compounds having Formula ID:

[0524] R1 is as defined in paragraphs (3) to (7) above;

[0525] R4 and R5 are as defined in any of paragraphs (27) to (36) above;

[0526] The heterocyclic ring formed by R4 and R5 is optionally substituted as defined in paragraph (21) or (22) above; and

[0527] R6 is as defined in paragraph (38) or (39) above.

[0528] In a specific group of compounds of the above formula I, R1 is as defined in paragraph (4), and R4 and R5 are as defined in paragraph (36), i.e., the compound has the structural formula IE or IF (a subformula of formula I) shown below:

[0529]

[0530]

[0531] Among them, R2, R6 and R 10c Each has any of the definitions described herein.

[0532] In embodiments of compounds having Formula IE or IF:

[0533] R2 is as defined in any of paragraphs (8) to (11) above;

[0534] R6 is as defined in any of paragraphs (37) to (39) above; and

[0535] R 10c As defined in any of paragraphs (14) to (22) above.

[0536] In embodiments of compounds having Formula IE or IF:

[0537] R2 is as defined in any of paragraphs (9) to (11) above;

[0538] R6 is as defined in paragraph (38) or (39) above; and

[0539] R 10c As defined in any of paragraphs (19) to (22) above.

[0540] In embodiments of compounds having Formula IE or IF:

[0541] R2 is as defined in paragraph (10) or (11) above;

[0542] R6 is as defined in paragraph (38) or (39) above; and

[0543] R 10c As defined in any of paragraphs (20), (21) or (22) above.

[0544] Specific compounds of the present invention include any of the compounds described in the Examples section of this application, or a pharmaceutically acceptable salt or solvate thereof, and in particular any of the following compounds:

[0545] (3S)-3-Cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide;

[0546] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxamide;

[0547] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine-1-carboxamide;

[0548] N-[4-(3-cyanophenyl)-5-(4-methyl-1H-indazol-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0549] N-[4-(3-cyanophenyl)-5-(7-methyl-3H-benzotriazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0550] 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;

[0551] 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;

[0552] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-piperazin-1-yl-piperidine-1-carboxamide;

[0553] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide;

[0554] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-oxa-2,9-diazaspiro[4.5]decane-2-carboxamide;

[0555] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxamide;

[0556] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-8-oxa-2,5-diazaspiro[3.5]nonane-2-carboxamide;

[0557] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxamide;

[0558] (3S)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide;

[0559] 4-Cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide;

[0560] (3R)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)pyrrolidine-1-carboxamide;

[0561] (3R)-3-Cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide;

[0562] 4-(1-cyano-1-methyl-ethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide;

[0563] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-carboxamide;

[0564] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-methyl-2,6-diazaspiro[3.3]heptane-2-carboxamide;

[0565] 4-(1-cyanoethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide;

[0566] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(dimethylamino)piperidine-1-carboxamide;

[0567] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide;

[0568] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-[(dimethylamino)methyl]morpholine-4-carboxamide;

[0569] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(2-pyrrolidin-1-ylethoxy)pyrrolidine-1-carboxamide;

[0570] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxamide;

[0571] 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;

[0572] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(4-methylpiperazin-1-yl)piperidine-1-carboxamide;

[0573] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(1-methyl-4-piperidinyl)piperazine-1-carboxamide;

[0574] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-morpholino-piperidine-1-carboxamide;

[0575] 4-(Cyanomethyl)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide;

[0576] (3S)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-carboxamide;

[0577] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxamide;

[0578] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1,4-diazepane-1-carboxamide;

[0579] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0580] (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;

[0581] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]piperazine-1-carboxamide;

[0582] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-piperazine-1-carboxamide;

[0583] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-oxo-1,8-diazaspiro[4.5]decane-8-carboxamide;

[0584] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxamide;

[0585] 3-Cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl-pyrrolidine-1-carboxamide;

[0586] 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;

[0587] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(2-hydroxyethyl)piperazine-1-carboxamide;

[0588] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-(oxetan-3-yl)piperazine-1-carboxamide;

[0589] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0590] (2S)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide;

[0591] (2R)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide;

[0592] (2S)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide;

[0593] (2R)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide;

[0594] N-[4-(3-cyanophenyl)-5-(2-methylquinazolin-7-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0595] N-[4-(3-cyanophenyl)-5-(2,4-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0596] N-[4-(3-Cyanophenyl)-5-quinazolin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0597] N-[4-(3-cyanophenyl)-5-(4-methyl-6-quinolyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0598] N-[4-(3-cyanophenyl)-5-(4-methoxyquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0599] N-[4-(3-cyanophenyl)-5-(4-ethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0600] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-4-methyl-piperidine-1-carboxamide;

[0601] N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0602] 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;

[0603] 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;

[0604] 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;

[0605] 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;

[0606] N-[4-(3-cyanophenyl)-5-(4,8-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0607] 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;

[0608] 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;

[0609] 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;

[0610] 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;

[0611] N-[4-(3-cyanophenyl)-5-(3-methylbenzimidazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0612] N-[4-(3-cyanophenyl)-5-imidazo[1,2-a]pyridin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0613] N-[4-(3-cyanophenyl)-5-(7-methyl-1H-indazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0614] N-[4-(3-cyanophenyl)-5-(2,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0615] 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;

[0616] N-[4-(3-cyanophenyl)-5-(1,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0617] N-[4-(3-cyanophenyl)-5-(6-methylpyridazin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0618] N-[4-(3-cyanophenyl)-5-[5-methyl-6-(triazol-2-yl)-3-pyridinyl]thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide;

[0619] N-[4-(3-cyanophenyl)-5-pyrazolo[1,5-a]pyridin-5-yl-thiazol-2-yl]morpholine-4-carboxamide;

[0620] 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

[0621] N-[5-(1,3-Benzoxazol-6-yl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide.

[0622] The various functional groups and substituents comprising the compounds of formula (I) are typically selected so that the molecular weight of the compounds of formula (I) does not exceed 1000. More typically, the molecular weight of the compound will be less than 900, e.g., less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, and for example, is 550 or less.

[0623] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, sufficiently basic acid addition salts of the compounds of the present invention, for example, salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate methanesulfonate or maleic acid. In addition, suitable pharmaceutically acceptable salts of sufficiently acidic compounds of the present invention are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts or salts with organic bases that provide pharmaceutically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

[0624] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or the spatial arrangement of their atoms are termed "isomers". Isomers that differ in the spatial arrangement of their atoms are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers", while stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers". When a compound has an asymmetric center, for example when it is bonded to four different groups, there may be a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S order of Cahn and Prelog or by the way in which the molecules rotate the plane of polarized light and are designated as right-handed or left-handed (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as their individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture".

[0625] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds can be prepared 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 its individual enantiomers and mixtures, whether racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of racemic forms. Some compounds of the present invention may have geometric isomerization centers (E and Z isomers). It should be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof having antiproliferative activity.

[0626] The present invention also encompasses compounds of the present invention as defined herein that contain one or more isotopic substitutions. For example, H can be in any isotopic form, including 1H, 2H (D), and 3H (T); C can be in any isotopic form, including 12C, 13C, and 14C; O can be in any isotopic form, including 16O and 18O; etc.

[0627] It will also be appreciated that certain compounds of formula (I) may exist in solvated as well as unsolvated forms, such as, for example, hydrated forms. It will be understood that the invention encompasses all such solvated forms which possess antiproliferative activity.

[0628] It will also be understood that certain compounds of Formula I may exhibit polymorphic forms and that the present invention encompasses all such forms that possess antiproliferative activity.

[0629] The compounds of Formula I may exist in a number of different tautomeric forms, and reference to compounds of Formula I includes all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are still included in Formula I. Examples of tautomeric forms include keto-, enol-, and enolate-forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acidic nitro.

[0630]

[0631] Compounds of formula I containing amine functional groups can also form N-oxides. Mention herein that compounds of formula I containing amine functional groups also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, p. 166. More specifically, N-oxides can be prepared by the procedure of LW Deany (Syn. Comm. 1977, 7, 509-514), wherein an amine compound is reacted with meta-chloroperbenzoic acid (mCPBA), for example, in an inert solvent (such as dichloromethane).

[0632] The compounds of formula (I) can be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the invention. Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain suitable groups or substituents to which property-modifying groups can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxyl or hydroxyl groups of the compounds of formula (I) and in vivo cleavable amide derivatives that can be formed at the carboxyl or amino groups of the compounds of formula (I).

[0633] Thus, the present invention includes those compounds of formula (I) as defined above when obtained by organic synthesis and when obtained in the human or animal body by cleavage of its prodrug. Thus, the present invention includes those compounds of formula I produced by organic synthesis means and such compounds produced in the human or animal body by metabolism of precursor compounds, i.e., the compounds of formula (I) may be synthetically produced compounds or metabolically produced compounds.

[0634] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) are prodrugs that are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity, based on sound medical judgment.

[0635] Various forms of prodrugs have been described, for example, in:

[0636] a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985);

[0637] b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985);

[0638] c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5, "Design and Application of Pro-drugs", H.Bundgaard, pages 113-191 (1991);

[0639] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[0640] e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

[0641] f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984);

[0642] g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Vol. 14; and

[0643] h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0644] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a carboxyl group are, for example, in vivo cleavable esters thereof. An in vivo cleavable ester of a compound of formula I containing a carboxyl group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for the carboxyl group 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-o-phenylenedimethyl ester, C3-8 cycloalkylcarbonyloxy-C1-6 alkyl esters (such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl ester), 2-oxo-1,3-dioxolmethyl esters (such as 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester) and C1-6 alkoxycarbonyloxy-C1-6 alkyl esters (such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl ester).

[0645] The suitable pharmaceutically acceptable prodrug of the compound of formula (I) with hydroxyl group is for example ester or ether that can be decomposed in its body.Ester or ether that can be decomposed in the body of the compound of formula I containing hydroxyl group are for example cracked in human or animal body to produce pharmaceutically acceptable ester or ether of parent hydroxy compound.The suitable pharmaceutically acceptable ester group of hydroxyl group comprises inorganic ester, such as phosphate (comprising phosphoramidate cyclic ester).Other suitable pharmaceutically acceptable ester groups of hydroxyl group comprise C1-10 alkanoyl group (such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl group), C1-10 alkoxycarbonyl group (such as ethoxycarbonyl, N, N-(C1-6)2 formamyl, 2-dialkylaminoacetyl and 2-carboxyacetyl group). Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0646] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having a carboxyl 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 their esters.

[0647] Suitable pharmaceutically acceptable prodrugs of compounds of formula I with amino groups are, for example, amide derivatives cleavable in vivo thereof. Suitable pharmaceutically acceptable amides from amino groups include, for example, amides formed with C1-10 alkanoyl groups (such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups). Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl and 4-(C1-4 alkyl)piperazine-1-ylmethyl.

[0648] The in vivo effects of the compounds of formula (I) may be exerted in part by one or more metabolites formed in the human or animal body after administration of the compounds of formula (I). As described above, the in vivo effects of the compounds of formula (I) may also be exerted by the metabolism of precursor compounds (prodrugs).

[0649] Although the present invention may relate to any compound or specific group of compounds defined herein by an optional, preferred or suitable feature or otherwise according to a particular embodiment, the present invention may also relate to any compound or specific group of compounds that specifically excludes that optional, preferred or suitable feature or particular embodiment.

[0650] Suitably, the present invention excludes any individual compound that does not possess the biological activity defined herein.

[0651] synthesis

[0652] The compounds of the present invention may be prepared by any suitable technique known in the art. Specific methods for forming compounds of formula I as defined herein are shown in the accompanying examples.

[0653] In the descriptions of synthetic methods described herein and in any referenced synthetic methods for preparing starting materials, it is understood that all suggested reaction conditions (including choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and work-up procedures) can be selected by one skilled in the art.

[0654] Those skilled in the art of organic synthesis will understand that the functionality present on various parts of the molecule must be compatible with the reagents and reaction conditions employed.

[0655] It will be appreciated that during the synthesis of the compounds of the invention in the methods defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesirable reactions. A skilled chemist will understand when such protection is necessary and how to place such protecting groups in the appropriate positions and then remove them.

[0656] For examples of protecting groups, see one of the many general texts on the subject, for example, "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist as suitable for removing the protecting group in question, such method being selected so as to remove the protecting group with minimal interference with other groups in the molecule.

[0657] Thus, if reactants include, for example, groups such as amino, carboxyl or hydroxy, it may be desirable to protect this group in some of the reactions mentioned herein.

[0658] For example, the suitable protecting group of amino or alkylamino group is for example acyl group, for example alkanoyl group (such as acetyl), alkoxycarbonyl group (such as methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl group (such as benzyloxycarbonyl) or aroyl group (such as benzoyl).The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.Therefore, for example, acyl group (such as alkanoyl) or alkoxycarbonyl group or aroyl group can be removed by for example hydrolysis with suitable alkali (such as alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide).Alternatively, acyl group (such as tert-butoxycarbonyl group) can be removed for example by processing with suitable acid (such as hydrochloric acid, sulfuric acid or phosphoric acid) or trifluoroacetic acid, and arylmethoxycarbonyl group (such as benzyloxycarbonyl group) can be removed for example by hydrogenation on catalyst (such as palladium carbon) or by processing with Lewis acid (for example tris (trifluoroacetic acid) boron). 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.

[0659] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, for example, alkanoyl groups (such as acetyl), aroyl groups (such as benzoyl) or arylmethyl groups (such as benzyl). The deprotection conditions of the above-mentioned protecting groups will inevitably vary with the selection of the protecting group. Thus, for example, acyl groups (such as alkanoyl) or aroyl groups can be removed, for example, by hydrolysis with a suitable base (such as an alkali metal hydroxide, for example lithium hydroxide, sodium hydroxide or ammonia). Alternatively, arylmethyl groups (such as benzyl) can be removed, for example, by hydrogenation over a catalyst (such as palladium on carbon).

[0660] A suitable protecting group for a carboxyl group is, for example, an esterifying group, such as a methyl or ethyl group, which can be removed, for example, by hydrolysis with a base, such as sodium hydroxide, or for example a tert-butyl group, which can be removed, for example, by treatment with an acid, such as an organic acid, such as trifluoroacetic acid, or for example a benzyl group, which can be removed, for example, by hydrogenation over a catalyst, such as palladium on carbon.

[0661] The resin can also serve as a protecting group.

[0662] The method for synthesizing the compounds of formula (I) will vary depending on the nature of R1, R2, R3, R4, R5 and R6 and any substituent groups associated therewith. Suitable methods for their preparation are further described in the accompanying examples.

[0663] Once a compound of formula (I) has been synthesized by any of the methods defined herein, the method may further comprise one or more additional steps:

[0664] (i) removing any protecting groups present;

[0665] (ii) converting a compound of formula (I) into another compound of formula (I);

[0666] (iii) forming a pharmaceutically acceptable salt, hydrate or solvate of the compound of Formula I; and / or

[0667] (iv) forming a prodrug of a compound of formula I.

[0668] An example of (ii) above is when a compound of formula (I) is synthesized, then one or more of R1, R2, R3, R4, R5 and R6 may be further reacted to change the nature of the group and provide an alternative compound of formula (I).

[0669] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0670] Biological activity

[0671] The biological assays described in the Examples section (Biological Example 1 to Biological Example 3) can be used to determine the pharmacological effects of the compounds of the invention.

[0672] Although the pharmacological properties of the compounds of Formula I vary with structure, as expected, the compounds of the invention were found to be active in the assays described in Biological Example 1, Biological Example 2, and Biological Example 3.

[0673] In general, with respect to adenosine A2a antagonism, the compounds of the present invention exhibited an IC of 1 μM or less in the assay described in Biological Example 1. 50, preferred compounds of the present invention show an IC of 200 nM or less 50 , and the most preferred compounds of the present invention showed an IC of 50 nM or less 50 .

[0674] In general, with respect to adenosine A2b antagonism, the compounds of the present invention exhibited an IC of 1 μM or less in the assay described in Biological Example 1. 50 , preferred compounds of the present invention show an IC of 200 nM or less 50 , and the most preferred compounds of the present invention showed an IC of 50 nM or less 50 .

[0675] Suitably, the compounds of the invention have an IC of 0.0001 for adenosine A1 or A3 receptors in the assay described in Biological Example 1. 50 Comparison of IC of adenosine A2a receptor 50 At least two times higher, more suitably at least five times higher, and even more suitably at least ten times higher.

[0676] Pharmaceutical composition

[0677] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0678] The compositions of the present invention may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for topical use (e.g., as creams, ointments, gels or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., as finely divided powders or liquid aerosols), in a form suitable for administration by insufflation (e.g., as finely divided powders), or in a form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as suppositories for rectal administration).

[0679] The compositions of the present 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.

[0680] 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 a proliferative condition referred to herein.

[0681] 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 being treated and the particular route of administration. For example, a formulation for oral administration to humans typically contains, for example, 0.5 mg to 0.5 g of active agent (more suitably 0.5 mg to 100 mg, e.g., 1 mg to 30 mg) mixed with an appropriate and convenient amount of excipients, which may comprise from about 5% to about 98% by weight of the total composition.

[0682] The size of the dose of the compound of formula I for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, in accordance with well-known medical principles.

[0683] When the compound of the present invention is used for treatment or prevention purposes, it is usually applied so as to accept a daily dose within the range of, for example, 0.1mg / kg to 75mg / kg body weight, if necessary given in divided doses. When parenteral route is adopted, lower doses are usually applied. Therefore, for example, for intravenous or intraperitoneal administration, a dosage within the range of, for example, 0.1mg / kg to 30mg / kg body weight is usually used. Similarly, for administration by inhalation, a dosage within the range of, for example, 0.05mg / kg to 25mg / kg body weight will be used. Oral administration can also be suitable, particularly in tablet form. Typically, a unit dosage form will contain about 0.5mg to 0.5g of the compound of this invention.

[0684] Therapeutic uses and applications

[0685] The present invention provides compounds that are useful as antagonists of adenosine A2 receptors, particularly adenosine A2a receptors.

[0686] According to another aspect of the present invention, there is provided a method for 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.

[0687] According to another aspect of the present invention, there is provided a method for 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.

[0688] According to another aspect of the present invention, there is provided a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the 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 antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0689] According to another aspect of the present invention, there is provided a method of treating a disease or condition in which adenosine A2a receptor activity is implicated in a patient in need of such treatment, said 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.

[0690] According to another aspect of the present invention, there is provided a method for treating a proliferative disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0691] According to another aspect of the present invention, there is provided a method for treating cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0692] According to another aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

[0693] According to another 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 treating proliferative conditions. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0694] According to another aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition for use in the treatment of cancer. In a specific embodiment, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0695] According to another 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 compounds of the present invention are selective adenosine A2a antagonists. In alternative embodiments, certain compounds of the present invention are selective adenosine A2a and adenosine A2b antagonists.

[0696] According to another 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 condition in which adenosine A2a is implicated.

[0697] According to another 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 preparation of a medicament for treating a proliferative condition. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0698] According to another 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 preparation of a medicament for the treatment of cancer. Suitably, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0699] According to another 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 preparation of a medicament for use as an adenosine A2a antagonist.

[0700] According to another 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 preparation of a medicament for use as an adenosine A2a antagonist.

[0701] According to another 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 preparation of a medicament for the treatment of a disease or condition in which adenosine A2a receptor activity is implicated.

[0702] The term "proliferative disorder" is used interchangeably herein and relates to cell proliferation of an unwanted or uncontrolled excess or abnormal cell, such as tumor growth or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cell proliferation, including but not limited to malignancies and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., fibroproliferative disorders 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.

[0703] 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).

[0704] More particularly, compounds of general formula (I) are provided for use in the treatment of cancer, in particular solid tumors, such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma.

[0705] More particularly, provided are compounds 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.

[0706] Also provided is the use of a compound of formula (I) in the preparation of a medicament for treating cancer, in particular solid tumors, such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma.

[0707] The present invention also provides a method for treating cancer, particularly solid tumors, such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I).

[0708] The patient to be treated is suitably a mammal, and more suitably a human.

[0709] Route of administration

[0710] The compounds of the invention, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (ie, at the desired site of action).

[0711] Routes of administration include, but are not limited to, oral (e.g., by ingestion); oral; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ophthalmic (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, using, for example, via an aerosol, such as through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by vaginal ring); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, intrasternal, and intratumoral; by implantation of a reservoir or depot, such as subcutaneous or intramuscular.

[0712] The compounds of the present invention or pharmaceutical compositions comprising these compounds can be administered by intratumoral delivery.

[0713] Combination therapy

[0714] The compounds of formula I can be used to treat and / or prevent proliferative disorders, such as, for example, cancer. The compounds of formula I as defined herein can be used in combination with one or more additional antiproliferative / anticancer therapies, such as, for example, chemotherapy with one or more additional antiproliferative / anticancer agents, radiotherapy and / or conventional surgery.

[0715] The additional antiproliferative / anticancer agent may be included in the pharmaceutical composition together with the compound of formula (I) as defined herein, or alternatively it may be administered separately, simultaneously with the compound of formula (I) or at an earlier or later time.

[0716] Thus, in another aspect of the present invention, there is provided a product comprising a compound of 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.

[0717] The present invention also provides combinations of a compound of general formula (I) and one or more additional antiproliferative / anticancer agents for use in the treatment of cancer as a combined preparation for simultaneous, sequential or separate use in the treatment of cancer.

[0718] In particular, the combination therapies defined herein are suitable for the treatment of solid tumours, such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma.

[0719] Suitable additional antiproliferative / anticancer agents that may be used in combination with the compounds of formula I as defined herein [either alone or as part of a pharmaceutical composition or combined preparation in combination with a compound of general formula (I)] include:

[0720] 1) Other forms of cancer immunotherapy and anticancer chemotherapy agents;

[0721] 2) adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors;

[0722] 3) anti-PD-1 and PDL-1 antibodies, including but not limited to cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab; and

[0723] 4) Anti-CTLA4 antibodies, including but not limited to ipilimumab.

[0724] 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, cilizumab, pembrolizumab, nivolumab, durvalumab, avelumab and atezolizumab.

[0725] Suitably, the anti-PD1 antibody is one of the antibodies disclosed in U.S. Publication No. 2019 / 0225689 or U.S. Publication No. 2017 / 0121409 (incorporated herein by reference in their entirety), such as silimab. Silimab (JNJ-63723283, CET) is a fully human immunoglobulin (Ig) G4κ monoclonal antibody that binds to programmed death receptor 1 (PD-1) with high affinity and specificity. Silimab has shown activity in solid tumors. Rutkowski P et al. Journal of Clinical Oncology. 2019; 37(8): 31.

[0726] 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.

[0727] The A2a antagonists of formula (I) may also be used in combination with cell-based immunotherapies and cancer vaccines, including but not limited to CAR-T cell therapy.

[0728] Examples of additional anti-proliferative / anti-cancer chemotherapeutic agents include, but are not limited to, any one or more of the following:

[0729] TM ), erlotinib (Tarceva TM ), cetuximab (Erbitux TM ), lapatinib (Tykerb TM ), panitumumab (Vectibix TM ), vandetanib (Caprelsa TM ), afatinib / BIBW2992, CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethyl erlotinib , AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, hormone therapy, etc.

[0730] As stated above, combination therapies of the present invention may be achieved by simultaneous, sequential or separate administration of the individual components of the treatment.Such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within its approved dosage range.

[0731] 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 hereinbefore defined, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional antiproliferative / anticancer agents.

[0732] 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 involving solid tumours), comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional antiproliferative / anticancer agents selected from those listed above.

[0733] In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer in combination with another anti-tumor agent, optionally selected from one listed above.

[0734] As used herein, when the term "combination" is used, it is understood that this refers to simultaneous, separate, or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In another aspect of the invention, "combination" refers to sequential administration. When administered sequentially or separately, the delay in administering the second component should not be such as to negate the beneficial effects of the combination.

[0735] According to another aspect of the present invention, a pharmaceutical composition is provided, comprising a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, an antitumor agent (optionally selected from one listed above), and a pharmaceutically acceptable diluent or carrier.

[0736] Example

[0737] General Conditions :

[0738] Mass spectra were run on an LC-MS system using electrospray ionization. These were run using a Waters Acquity H-Class UPLC with PDA and QDa mass detection, an Acquity UPLC (binary pump / PDA detector) + ZQ mass spectrometer, or an Acquityi-Class (quaternary pump / PDA detector) + Quattro micromass spectrometer, a Waters Acquity UPLC system with a Waters PDA and ELS detector, or a Shimadzu LC-MS-2010EV system. [M+H]+ refers to monoisotopic molecular weight.

[0739] NMR spectra were run on a Bruker Ultrashield 500 MHz NMR spectrometer or a Bruker Avance III HD 400 MHz NMR spectrometer. Spectra were recorded at 298 K using the solvent peak as a reference.

[0740] The following examples are intended to illustrate the present invention and should not be construed as limiting the invention. Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations were performed under vacuum, preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods, such as microanalysis and spectral characteristics, such as MS and NMR. The abbreviations used are those commonly used in the art. If not defined, these terms have their generally accepted meanings.

[0741] abbreviation

[0742] br broad peak

[0743] CDI 1,1'-Carbonyldiimidazole

[0744] d Twin Peaks

[0745] dd double peaks

[0746] DCM dichloromethane

[0747] DIPEA Diisopropylethylamine

[0748] DMA dimethylacetamide

[0749] DMAP 4-dimethylaminopyridine

[0750] DMF N,N-dimethylformamide

[0751] DMSO dimethyl sulfoxide

[0752] EtOAc

[0753] HPLC High-pressure liquid chromatography

[0754] LC-MS liquid chromatography and mass spectrometry

[0755] MeOH MeOH

[0756] MeCN Acetonitrile

[0757] MS

[0758] m multiplet

[0759] min

[0760] mL milliliters

[0761] m / z mass-to-charge ratio

[0762] NBS N-bromosuccinimide

[0763] NMP N-Methyl-2-pyrrolidone

[0764] NMR Nuclear Magnetic Resonance

[0765] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0766] Rt retention time

[0767] s single peak

[0768] t Triplet

[0769] TFAA trifluoroacetic anhydride

[0770] TFA trifluoroacetic acid

[0771] THF Tetrahydrofuran

[0772] Referring to the following examples, compounds of the preferred embodiments were synthesized using methods described herein or other methods known in the art.

[0773] Where appropriate, conventional techniques (such as precipitation, filtration, crystallization, evaporation, distillation and chromatography) can be used to separate and purify the various starting materials, intermediates and compounds of the preferred embodiments. Unless otherwise stated, all starting materials are obtained from commercial suppliers and used without further purification. Salts can be prepared from compounds by known salt-forming procedures.

[0774] Unless otherwise stated, analytical HPLC conditions were as follows:

[0775] Instrument: LC-MS-1:

[0776] Method 2A

[0777] Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm

[0778] Column temperature: 50°C

[0779] Flow rate: 0.8 mL / min.

[0780] Eluent: A: H2O, 0.1% formic acid, B: MeCN

[0781] Gradient: 0.0-1.8 min 2-98% B, 1.8-2.1 min 98% B, 2.1-2.5 min 98% A.

[0782] Method 2B

[0783] Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm

[0784] Column temperature: 50°C

[0785] Flow rate: 0.8 mL / min.

[0786] Eluent: A: H2O, 0.1% ammonia, B: MeCN

[0787] Gradient: 0.0-1.8 min 2-98% B, 1.8-2.1 min 98% B, 2.1-2.5 min 98% A.

[0788] Method 3A

[0789] Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm

[0790] Column temperature: 50°C

[0791] Eluent: A: H2O, 0.1% formic acid, B: MeCN

[0792] Flow rate: 0.6 mL / min

[0793] Gradient: 0.0-2.5 min 2-98% B, 2.5-3.3 min 98% B, 3.3-3.5 98% A.

[0794] Method 3B

[0795] Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm

[0796] Column temperature: 50°C

[0797] Eluent: A: H2O, 0.1% ammonia, B: MeCN

[0798] Flow rate: 0.6 mL / min

[0799] Gradient: 0.2-2.5 min 2-98% B, 2.5-3.3 min 98% B, 3.3-3.5 98% A.

[0800] Method 5A

[0801] Column: YMC-Triart C18 50×2mm, 5μm

[0802] Column temperature: room temperature

[0803] Flow rate: 0.8 mL / min.

[0804] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% formic acid

[0805] Gradient: 0.0-4.0 min 0-95% B, 5% C; 4.0-4.4 min 95% B, 5% C; 4.4-5.0 min 95% A, 5% B.

[0806] Method 8A

[0807] Column: Acquity UPLC BEH C18 2.1×50mm, 1.7μm

[0808] Column temperature: 50°C

[0809] Eluent: A: H2O, 0.1% formic acid, B: MeCN

[0810] Flow rate: 0.6 mL / min

[0811] Gradient: 0.5-6.5 min 2-98% B, 6.5-7.6 min 98% B, 7.6-8.0 98% A.

[0812] Method 8B

[0813] Column: Acquity UPLC BEH C18 2.1×50mm, 1.7μm

[0814] Column temperature: 50°C

[0815] Eluent: A: H2O, 0.1% ammonia, B: MeCN

[0816] Flow rate: 0.6 mL / min

[0817] Gradient: 0.5-6.5 min 2-98% B, 6.5-7.6 min 98% B, 7.6-8.0 98% A.

[0818] Instrument: LC-MS-2:

[0819] Method 2A

[0820] Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm

[0821] Column temperature: 50°C

[0822] Flow rate: 0.8 mL / min.

[0823] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 2.0% formic acid

[0824] Gradient: 0.0-1.7 min 0-95% B, 5% C; 1.7-2.1 min 95% B, 5% C; 2.1-2.5 min 95% A, 5% C.

[0825] Method 2B

[0826] Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm

[0827] Column temperature: 50°C

[0828] Flow rate: 0.8 mL / min.

[0829] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 2.0% ammonia (aqueous solution)

[0830] Gradient: 0.0-1.7 min 0-95% B, 5% D; 1.7-2.1 min 95% B, 5% D; 2.1-2.5 min 95% A, 5% D.

[0831] Method 8A

[0832] Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm

[0833] Column temperature: 50°C

[0834] Flow rate: 0.8 mL / min.

[0835] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 2.0% formic acid

[0836] Gradient: 0.0-0.5 min 95% A, 5% C; 0.5-6.5 min 0-95% B, 5% C; 6.6-7.5 min 95% B, 5% C; 7.5-7.6 min 0-95% A, 5% C; 7.6-8.0 min

[0837] 95%A, 5%C.

[0838] Method 8B

[0839] Column: Acquity UPLC BEH C18 2.1×50mm 1.7μm

[0840] Column temperature: 50°C

[0841] Flow rate: 0.8 mL / min.

[0842] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 2.0% ammonia (aqueous solution)

[0843] Gradient: 0.0-0.5min 95%A, 5%D; 0.5-6.5min 0-95%B, 5%D; 6.6-7.5min 95%B, 5%D; 7.5-7.6min 0-95%A, 5%D; 7.6-8.0min 95%A, 5%D.

[0844] Instrument: LC-MS

[0845] Method 7A

[0846] Column: Phenomenex Kinetix-XB C18 2.1×100 mm, 1.7 μm

[0847] Column temperature: 40°C

[0848] Eluent: A: H2O 0.1% formic acid, B: acetonitrile, 0.1% formic acid

[0849] Flow rate: 0.6 mL / min

[0850] Gradient: 0-5.3 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5%

[0851] B, 5.82-7.00min 5%B.

[0852] Method 7B

[0853] Column: Waters BEH TM C18, 2.1 mm × 100 mm, 1.7 μm column

[0854] Column temperature: 55°C

[0855] Eluent: A: 2 mM ammonium bicarbonate buffered to pH 10, B: acetonitrile

[0856] Flow rate: 0.6 mL / min

[0857] Gradient: 0-5.3 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5%

[0858] B, 5.82-7.00min 5%B.

[0859] Instrument: LCMS-W

[0860] Method 2A

[0861] Column: Waters UPLCTM BEHTM C18 2.1×50mm, 1.7μm

[0862] Column temperature: 40°C

[0863] Eluent: A: H2O 0.1% formic acid, B: acetonitrile, 0.1% formic acid

[0864] Flow rate: 0.9 mL / min

[0865] 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.

[0866] Instrument: LCMS-S

[0867] Method 2A

[0868] Column: Kinetex Core-Shell C18, 2.1 mm × 50 mm, 5 μm

[0869] Column temperature: 40°C

[0870] Eluent: A: H2O 0.1% formic acid, B: acetonitrile, 0.1% formic acid Flow rate: 1.2 mL / min

[0871] 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.

[0872] Example 1

[0873] (3S)-3-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-methyl- Pyrrolidine-1-carboxamide

[0874]

[0875] 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 hours. (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 minutes. The resulting mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and H O (20 mL). The organic portion was separated and the aqueous solution was extracted with EtOAc (2×20 mL). The combined organics were washed with brine (5×20 mL), dried over Na SO and the solvent removed in vacuo. Purify by silica gel chromatography eluting with a gradient of 85% EtOAc / DCM then 3% MeOH / DCM to afford a yellow glassy solid.Dry the solid in a vacuum oven at 50°C for 64 hours to afford the title compound as a yellow solid.

[0876] LC-MS-1 (Method 8A): Rt 3.27 min; MS m / z 480.4 = [M+H] +

[0877] 1H NMR (500MHz, DMSO-d6) δ11.25 (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).

[0878] Example 2

[0879] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-oxa-1,9-diazaspiro [5.5] Undecane-9-carboxamide

[0880]

[0881] Step 1: 9-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]- tert-Butyl 4-oxa-1,9-diazaspiro[5.5]undecane-1-carboxylate

[0882]

[0883] 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 hours. 4-Oxa-1,9-diazaspiro[5.5]undecane-1-carboxylic acid tert-butyl ester (373 mg, 1.46 mmol) was added, and the mixture was heated at 50° C. for 30 minutes. The resulting mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and H O (20 mL). The organic portion was separated, and the aqueous solution was extracted with EtOAc (2×20 mL). The combined organics were washed with brine (5×20 mL), dried over Na SO , and the solvent was removed in vacuo. Purify by silica gel chromatography eluting with 3% MeOH / DCM followed by a second purification by silica gel chromatography eluting with 80% EtOAc / DCM to give the title compound as a yellow solid.

[0884] LC-MS-1 (Method 2B): Rt 1.49 min; MS m / z 626.5 = [M+H] +

[0885] 1H NMR(500MHz,DMSO-d6)δ11.19(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=11.4,6.8Hz,2H),3.74–3.68(m,4H),3.48(t,J=5.4Hz,2H),3.18(t ,J=12.8Hz,2H),2.84(s,3H),1.64(dt,J=13.6,3.6Hz,2H),1.38(s,9H). No 1×CH2 signal was observed.

[0886] Step 2: N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-oxa-1,9-diol Azaspiro[5.5]undecane-9-carboxamide

[0887] 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 hours. The volatile solvents were removed under a stream of nitrogen and the resulting mixture was diluted with MeOH and charged to 2.5 g of 4-nitropropane-1,4-dihydro ... On SCX posts (pre-wetting with MeOH). The post is rinsed with 5 times of column volumes of MeOH, and the product is eluted with MeOH / MeOH (about 20 mL) containing 4: 1 7M NH. The solvent is removed in a vacuum and purified by C18 reverse phase chromatography, eluted with MeCN / water containing 0.1% NHOH, then subjected to silica chromatography, eluted with MeOH / DCM containing 5% 7M NH to give a yellow oil. EtO (2 mL) is added, and the yellow solid formed is collected by filtration, washed with EtO (1 mL) and dried in a vacuum oven at 60 ° C to give the title compound as a yellow solid.

[0888] LC-MS-1 (Method 8B): Rt 2.56 min; MS m / z 526.5 = [M+H] +

[0889] 1H NMR(500MHz,DMSO-d6)δ11.15(s,1H),9.12(s,1H),8.21(d,J=2.0Hz,1H),7.96 –7.90(m,2H),7.80(d,J=7.8Hz,1H),7.77(dd,J=8.8,2.0Hz,1H),7.71(d,J=7.8 Hz,1H),7.52(t,J=7.8Hz,1H),3.77–3.68(m,2H),3.52–3.45(m,2H),3.45–3.3 8(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 NH were not observed.

[0890] Example 2.1

[0891] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(cyclopropylmethyl)piperazine- 1-Formamide

[0892]

[0893] Step 1: 4-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]- tert-Butyl 3-(cyclopropylmethyl)piperazine-1-carboxylate

[0894]

[0895] The title compound was prepared in analogy to Example 2, Step 1, from 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) and tert-butyl 3-(cyclopropylmethyl)piperazine-1-carboxylate.

[0896] LC-MS-W (Method 2A): Rt 1.09 min; MS m / z 610.3 = [M+H] +

[0897] 1H NMR (400MHz, CDCl3) δ9.18(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, 2H), 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). No NH was observed.

[0898] Step 2: N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(cyclopropyl)thiazol- 1-Methyl-1-piperazine-1-carboxamide

[0899] The title compound was prepared in analogy to Example 2, Step 2, 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.

[0900] LC-MS (Method 7A): Rt 2.35 min; MS m / z 510.1 = [M+H] +

[0901] 1H NMR(400MHz,MeOD)δ9.07(s,1H),8.25(d,J=2.0Hz,1H),7.97–7.93(m,2H),7.86(dd,J=8.8,2.0Hz,1H),7.7 1(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.

[0902] Example 2.2

[0903] N-[4-(3-cyanophenyl)-5-(4-methyl-1H-indazol-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[0904]

[0905] 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

[0906]

[0907] The title compound was prepared in analogy to Example 2, Step 1, 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.

[0908] LC-MS-2 (Method 2B): Rt 1.99 min; MS m / z 697.3 = [MH]-

[0909] 1H NMR (500MHz, DMSO-d6) δ11.20(s,1H),8.05(s,1H),7.86(s,1H),7.75(dd,J=12.3,7.9Hz,2H),7.50(t,J=7.9 Hz,1H),7.42–7.36(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).

[0910] Step 2: N-[4-(3-cyanophenyl)-5-(4-methyl-1H-indazol-6-yl)thiazol-2-yl]-2-oxa-6-nitropropane Heterospiro[3.3]heptane-6-carboxamide

[0911] The title compound was prepared in analogy to Example 2, Step 2, 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.

[0912] LC-MS-2 (Method 8B): Rt 3.24 min; MS m / z 457.1 = [M+H] +

[0913] 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). CH3 was not observed.

[0914] Example 2.3

[0915] N-[4-(3-cyanophenyl)-5-(7-methyl-3H-benzotriazol-5-yl)thiazol-2-yl]-2-oxa-6-azepine Spiro[3.3]heptane-6-carboxamide

[0916]

[0917] Step 1: N-[4-(3-cyanophenyl)-5-(7-methyl-3-trityl-benzotriazol-5-yl)thiazole-2- 2-Oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0918]

[0919] The title compound was prepared in analogy to Example 2, Step 1, 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.

[0920] LC-MS-2 (Method 2B): Rt 1.85 min; MS m / z 698.3 = [MH]-.

[0921] 1H NMR (500MHz, DMSO) δ11.21(s,1H),7.69(dt,J=7.0,1.8Hz,1H),7.61(d,J=1.8Hz,1H),7.42–7.34(m,2H),7.3 6–7.27(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).

[0922] 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

[0923] The title compound was prepared in analogy to Example 2, Step 2, 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.

[0924] LC-MS-2 (Method 8B): Rt 2.33 min; MS m / z 458.0 = [M+H] +

[0925] 1H 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). 2×NH was not observed.

[0926] Example 2.4

[0927] N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxa-6-nitropropane Heterospiro[3.3]heptane-6-carboxamide

[0928]

[0929] Step 1: 4-[4-(3-cyanophenyl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonylamino)thiazole- tert-Butyl 5-yl]pyrrolo[2,3-b]pyridine-1-carboxylate

[0930]

[0931] The title compound was prepared in analogy to Example 2, Step 1, 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.

[0932] LC-MS-1 (Method 3B): Rt 1.78 min; MS m / z 543.2 = [M+H] +

[0933] 1H NMR (500MHz, DMSO) δ11.42(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).

[0934] Step 2: N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxo- 6-azaspiro[3.3]heptane-6-carboxamide

[0935] The title compound was prepared in analogy to Example 2, Step 2, 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.

[0936] LC-MS-1 (Method 8B): Rt 3.49 min; MS m / z 443.2 = [M+H] +

[0937] 1H NMR (500MHz, DMSO) δ11.83(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).

[0938] Example 2.5

[0939] N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazol-2-yl]-2-oxo 6-azaspiro[3.3]heptane-6-carboxamide

[0940]

[0941] 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

[0942]

[0943] The title compound was prepared in analogy to Example 2, Step 1, 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.

[0944] LC-MS-2 (Method 2B): Rt 1.93 min; MS m / z 700.3 = [M+H] +

[0945] 1H NMR (500MHz, DMSO) δ11.48(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,1 H),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).

[0946] Step 2: N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)thiazole-2-yl] 2-Oxa-6-azaspiro[3.3]heptane-6-carboxamide

[0947] The title compound was prepared in analogy to Example 2, Step 2, 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.

[0948] LC-MS-2 (Method 8B): Rt 2.62 min; MS m / z 458.0 = [M+H] +

[0949] 1H NMR (500MHz, DMSO) δ13.52(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).

[0950] Example 3

[0951] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-piperazin-1-yl-piperidin-1- Formamide

[0952]

[0953] Step 1: 4-[1-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl tert-Butyl]-4-piperidinyl]piperazine-1-carboxylate

[0954]

[0955] 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 in a sealed vial for 22 hours. To this mixture was added tert-butyl 4-(4-piperidinyl)piperazine-1-carboxylate (78 mg, 0.29 mmol) and heated at 50 ° C for 2 hours. The resulting mixture was cooled to room temperature and diluted with water (10 mL) and then sonicated. The precipitate formed was collected under vacuum filtration and dried in a vacuum oven to give the title compound as a beige solid.

[0956] LC-MS-W (Method 2A): Rt 0.72 min; MS m / z 639.2 = [M+H]+

[0957] 1H NMR (500MHz, CDCl3) δ9.18(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).

[0958] Step 2: N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-piperazin-1-yl- Piperidine-1-carboxamide

[0959] A solution of tert-butyl 4-[1-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-4-piperidinyl]piperazine-1-carboxylate (step 1) (88 mg, 0.13 mmol) in DCM (5 mL) and MeOH (0.5 mL) was treated with 4M HCl in 1,4-dioxane (319 μL, 1.28 mmol) and stirred for 24 hours. After standing at room temperature for an additional 24 hours, the mixture was concentrated in vacuo and then eluted using 2 g of HCl. The free base was treated on an SCX column and eluted with 7M NH3 / MeOH. The resulting yellow gum was dissolved in 3:1:1 DMSO:MeCN:H2O (1.4 mL) and purified using preparative HPLC under acidic conditions. Further purification was performed using C18 reverse phase chromatography, eluting with 0.1% NH4OH / MeCN / water to give the title compound as a yellow powder.

[0960] LC-MS (Method 7A): Rt 1.87 min; MS m / z 539.2 = [M+H] +

[0961] 1H 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). 2×NH was not observed.

[0962] Example 3.1

[0963] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-4,9-diazaspiro [5.5] Undecane-9-carboxamide

[0964]

[0965] Step 1: 9-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]- tert-Butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate

[0966]

[0967] The title compound was prepared in analogy to Example 3, Step 1, 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.

[0968] LC-MS-W (Method 2A): Rt 0.99 min; MS m / z 626.2 = [M+H] +

[0969] 1H NMR(500MHz,DMSO)δ11.23(s,1H),9.11(s,1H),8.20(s,1H),7.91(d,J=1.9Hz,1H) ,7.79(d,J=7.7Hz,1H),7.78–7.75(m,1H),7.71(dt,J=8.3,1.2Hz,1H),7.52(dd,J= 7.8,7.8 Hz,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). No 1×CH2 was observed.

[0970] Step 2: N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-1-oxa-4,9-diol Azaspiro[5.5]undecane-9-carboxamide

[0971] The title compound was prepared in analogy to Example 3, Step 2, 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.

[0972] LC-MS (Method 7A): Rt 2.18 min; MS m / z 526.1 = [M+H] +

[0973] 1H NMR(500MHz,MeOD)δ9.07(s,1H),8.24(d,J=2.0Hz,1H),7.97–7.93(m,2H),7.85(d d,J=8.7,1.9Hz,1H),7.71(dt,J=7.9,1.4Hz,1H),7.66(dt,J=7.7,1.4Hz,1H),7.4 3 (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.

[0974] Example 4

[0975] N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-oxa-2,9-diazaspiro [4.5]Decane-2-carboxamide

[0976]

[0977] Step 1: 2-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]- tert-Butyl 6-oxa-2,9-diazaspiro[4.5]decane-9-carboxylate

[0978]

[0979] 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 hours. 6-Oxa-2,9-diazaspiro[4.5]decane-9-carboxylic acid tert-butyl ester (106 mg, 0.44 mmol) was added and the mixture was stirred at 50 ° C for 1 hour. The resulting mixture was cooled to room temperature and partitioned between EtOAc (40 mL) and H2O (40 mL). The phases were separated and the aqueous portion was further extracted with EtOAc (2×40 mL). The organic matter is combined and 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 silica gel chromatography, eluting with a gradient of 50-100% EtOAc / petroleum ether, then 0-10% MeOH / EtOAc, gives the title compound as a light yellow solid.

[0980] LC-MS-1 (Method 2B): Rt 1.45 min; MS m / z 612.5 = [M+H] +

[0981] 1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),9.12(s,1H),8.21(d,J=2.0Hz,1H),8.1 4(s,1H),7.93–7.91(m,1H),7.79(dd,J=7.7,1.4Hz,1H),7.77(dd,J=8.8,2.1H z,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).

[0982] Step 2: N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-6-oxa-2,9-diol Azaspiro[4.5]decane-2-carboxamide

[0983] To a solution of 2-[[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]carbamoyl]-6-oxa-2,9-diazaspiro[4.5]decane-9-tert-butyl carboxylate (step 1) (90 mg, 0.093 mmol) in chloroform (3 mL) is added trimethylsilyl iodide (84 μL, 0.59 mmol), and the mixture is stirred at room temperature for 1 hour. The resulting mixture is concentrated under a stream of nitrogen, chloroform (2 mL) is added and the mixture is concentrated again. The crude mixture is absorbed in DMSO (10 mL) and purified by C18 reverse phase chromatography, eluted with 0.1% NH4OH / MeCN / water. The product is freeze-dried overnight and then ground with Et2O to give the title compound as a light yellow solid.

[0984] LC-MS-1 (Method 8B): Rt 2.76 min; MS m / z 512.5 = [M+H] +

[0985] 1H NMR (500 MHz, DMSO-d6) 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.

[0986] The compounds of the following examples (Table Ex4) were prepared in analogy 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.

[0987] TableEx4

[0988]

[0989]

[0990]

[0991] Example 5

[0992] (3S)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl)thiazol-2-yl (4-Methyl-1-(2-(2-amino-2-ethyl)pyrrolidine-1-carboxamide)

[0993]

[0994] 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 hours. 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 another 30 min. The resulting mixture was cooled to room temperature, diluted with EtOAc (200 mL), and washed with 80% brine (200 mL), 50% brine (3×200 mL). The organic portion was dried over Na 2 SO 4 and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 0 to 5% MeOH / DCM gave a light yellow foam / glass which was mechanically broken into a powder and dried in a vacuum oven at 50 °C overnight to give the title compound as a light yellow solid.

[0995] LC-MS-2 (Method 8A): Rt 3.33 min; MS m / z 499.2 = [M+H] +

[0996] 1H NMR (500MHz, DMSO) δ10.95(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(brs,1H),1.84(brs,2H),1.12(s,6H).

[0997] Example 6

[0998] 4-cyano-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-4-methyl-piperidin- 1-Formamide

[0999]

[1000] Under nitrogen, 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, and the resulting orange-brown solution was stirred at 50° C. for 18 hours. 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 another 3 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc (20 mL) and washed with 80% brine (20 mL) and then 50% brine (3×50 mL). The organic portion was dried over Na 2 SO 4 and concentrated in vacuo. The product of 4-nitro-2-oxo-4-oxo-6 ...6-oxo-4-oxo-6-oxo-6-oxo-4-oxo-6-oxo-6-oxo-4-oxo-6-oxo-6-oxo-4-oxo-6-oxo-6-oxo-4-oxo-6-oxo-6-oxo-4-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-oxo-6-

[1001] LC-MS-1 (Method 8A): Rt 3.49 min; MS m / z 494.4 = [M+H] +

[1002] 1H NMR (500MHz, DMSO) δ11.33(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(brdt,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).

[1003] Example 7

[1004] (3R)-N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-3-(1-hydroxy-1-methyl)thiazol-2-yl (4-Methyl-1-(2-(2-amino-2-ethyl)pyrrolidine-1-carboxamide)

[1005]

[1006] Under nitrogen, 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, 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 min. The resulting mixture was allowed to cool to room temperature and then partitioned between EtOAc (50 mL) and H O (50 mL). The organic portion was separated and the aqueous solution was extracted with EtOAc (2×30 mL). The combined organics were washed with brine (5×40 mL), dried over Na SO and the solvent removed in vacuo. Purification by silica gel chromatography eluting with 0 to 5% MeOH / DCM afforded a light yellow glassy solid.The solid was azeotroped and triturated with Et2O to afford the title compound as a light yellow solid.

[1007] LC-MS-1 (Method 8A): Rt 3.19 min; MS m / z 499.4 = [M+H] +

[1008] 1H NMR (500MHz, methanol-d4) δ9.07 (s, 1H), 8.24 (d, J = 2.0Hz, 1H), 7.98–7.91 (m, 2H), 7.85 ( dd,J=8.8,2.0Hz,1H),7.73–7.68(m,1H),7.68–7.63(m,1H),7.43(t,J=7.9Hz,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.

[1009] The compounds of the following examples (Table Ex7) were prepared in analogy to Examples 5-7 from 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile (Intermediate A) and the appropriate amine.

[1010] Table Ex7

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021] Examples 7.7a ​​and 7.7b

[1022] Chiral separation of racemic N-[4-(3-cyanophenyl)-5-(4-methylquinazolin-6-yl)thiazol-2-yl]-2-(1-hydroxy-1-methyl-ethyl)morpholine-4-carboxamide (Example 7.7) was performed using supercritical fluid chromatography using the following conditions to provide the individual enantiomers:

[1023] Purification conditions- Column details: Chiralpak IH (20 mm×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:CO 2 .

[1024] Chiral pure analysis conditions- Column details: Chiralpak 1H (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 2 (0.1% v / v NH 3 ).

[1025] 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

[1026]

[1027] First eluting peak : SFC retention time = 2.53 min

[1028] LC-MS-1 (Method 8A): Rt 3.20 min; MS m / z 515.5 = [M+H] +

[1029] 1H NMR (500MHz, DMSO) δ11.34(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).

[1030] 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

[1031]

[1032] Second elution peak : SFC retention time = 3.05 min

[1033] LC-MS-1 (Method 8A): Rt 3.20 min; MS m / z 515.5 = [M+H] +

[1034] 1H NMR (500MHz, DMSO) δ11.34(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).

[1035] Example 8

[1036] N-[4-(3-cyanophenyl)-5-(2-methylquinazolin-7-yl)thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[1037]

[1038] The title compound was prepared in analogy 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.

[1039] LC-MS-1 (Method 8A): Rt 2.62 min; MS m / z 469.4 = [M+H] +

[1040] 1H NMR (500MHz, DMSO-d6) δ11.32(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).

[1041] Example 9

[1042] N-[4-(3-cyanophenyl)-5-(2,4-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[1043]

[1044] The title compound was prepared in analogy 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.

[1045] LC-MS-1 (Method 8B): Rt 2.63 min; MS m / z 483.8 = [M+H] +

[1046] 1H NMR (500MHz, DMSO-d6) δ11.19(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=7.6,1.5Hz,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).

[1047] Example 10

[1048] N-[4-(3-cyanophenyl)-5-quinazolin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane- 6-Formamide

[1049]

[1050] The title compound was prepared in analogy 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.

[1051] LC-MS-1 (Method 8B): Rt 2.59 min; MS m / z 455.4 = [M+H] +

[1052] 1H NMR(500MHz,DMSO-d6)δ11.36(s,1H),9.61(s,1H),9.30(s,1H),8.22(s,1H),7.96(d,J=8.7Hz,1H),7.8 9(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).

[1053] Example 11

[1054] N-[4-(3-cyanophenyl)-5-(4-methyl-6-quinolyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3] Heptane-6-carboxamide

[1055]

[1056] The title compound was prepared in analogy to Example 7 from 3-[2-amino-5-(4-methyl-6-quinolinyl)thiazol-4-yl]benzonitrile (Intermediate AD) and 2-oxa-6-azaspiro[3.3]heptane.

[1057] LC-MS-1 (Method 8A): Rt 3.19 min; MS m / z 468.4 = [M+H] +

[1058] 1H NMR (500MHz, DMSO-d6) δ11.22(s,1H),8.76(d,J=4.3Hz,1H),8.02(d,J=2.0 Hz,1H),7.96(d,J=8.7Hz,1H),7.89(t,J=1.8Hz,1H),7.77(dt,J=7.6,1.5H z,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).

[1059] Example 12

[1060] N-[4-(3-cyanophenyl)-5-(4-methoxyquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[1061]

[1062] The title compound was prepared in analogy 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.

[1063] LC-MS-2 (Method 8A): Rt 3.28 min; MS m / z 485.1 = [M+H] +

[1064] 1H NMR(500MHz,DMSO-d6)δ11.34(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).

[1065] Example 13

[1066] N-[4-(3-cyanophenyl)-5-(4-ethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[1067]

[1068] The title compound was prepared in analogy 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.

[1069] LC-MS-2 (Method 8B): Rt 3.19 min; MS m / z 483.1 = [M+H] +

[1070] 1H NMR (500MHz, DMSO) δ11.30(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).

[1071] Example 14

[1072] 4-Cyano-N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-4-methyl-piperidin Pyridine-1-carboxamide

[1073]

[1074] The title compound was prepared in analogy 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.

[1075] LC-MS-2 (Method 8B): Rt 3.00 min; MS m / z 447.1 = [M+H] +

[1076] 1H NMR (500MHz, DMSO) δ11.36(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).

[1077] Example 15

[1078] N-[4-(3-cyanophenyl)-5-(2,4-dimethyloxazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[1079]

[1080] The title compound was prepared in analogy 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.

[1081] LC-MS-1 (Method 8B): Rt 2.69 min; MS m / z 422.1 = [M+H] +

[1082] 1H NMR (500MHz, DMSO) δ11.41(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).

[1083] Example 16

[1084] 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

[1085]

[1086] The title compound was prepared in analogy 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.

[1087] LC-MS-1 (Method 8B): Rt 3.01 min; MS m / z 457.3 = [M+H] +

[1088] 1H NMR (500MHz, DMSO-d6) δ11.17(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=7.8,1.5Hz,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).

[1089] Example 17

[1090] N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxa-6-nitropropane Heterospiro[3.3]heptane-6-carboxamide

[1091]

[1092] Step 1: tert-Butyl 3-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]pyrrolo[2,3-b]pyridine-1-carboxylate ester

[1093]

[1094] Bis(tri-tert-butylphosphine)palladium(0) (55 mg, 0.11 mmol) was added 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). The flask was evacuated, backfilled with nitrogen (3× cycles) and heated at 50° C. for 1 hour. 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 (2×40 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography eluting with a gradient of 20-70% EtOAc / petroleum ether gave the title compound as an orange solid.

[1095] LC-MS-2 (Method 2B): Rt 1.53 min; MS m / z 418.0 = [M+H] +

[1096] 1H NMR(500MHz,DMSO)δ8.40(dd,J=4.7,1.6Hz,1H),7.89(t,J=1.8Hz,1H),7.84(s,1H),7.67(ddt,J=7.5 ,5.7,1.4Hz,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).

[1097] Step 2: 3-[4-(3-cyanophenyl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonylamino)thiazole- tert-Butyl 5-yl]pyrrolo[2,3-b]pyridine-1-carboxylate

[1098]

[1099] The title compound was prepared in analogy 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.

[1100] LC-MS-1 (Method 2B): Rt 1.32 min; MS m / z 543.3 = [M+H] +

[1101] Step 3: N-[4-(3-cyanophenyl)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-yl]-2-oxo- 6-azaspiro[3.3]heptane-6-carboxamide

[1102] 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 of 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 hour. The resulting mixture was diluted in DCM (20 mL) and washed with saturated NaHCO3 aqueous solution (20 mL) and brine (20 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to give a yellow solid. Purified by silica gel chromatography eluting with a gradient of 2-5% MeOH / DCM to give the title compound as a beige solid.

[1103] LC-MS-2 (Method 8B): Rt 2.84 min; MS m / z 443.0 = [M+H] +

[1104] 1H NMR (500MHz, DMSO) δ12.06(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=2.6 Hz,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).

[1105] Example 18

[1106] N-[4-(3-cyanophenyl)-5-(3,8-dimethylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxo 6-azaspiro[3.3]heptane-6-carboxamide

[1107]

[1108] The title compound was prepared in analogy to Example 7 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.

[1109] LC-MS-2 (Method 8B): Rt 2.83 min; MS m / z 471.1 = [M+H] +

[1110] 1H NMR (500MHz, DMSO) δ11.24(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).

[1111] Example 19

[1112] 4-cyano-N-[4-(3-cyanophenyl)-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazole-2- 4-Methyl-piperidine-1-carboxamide

[1113]

[1114] The title compound was prepared in analogy 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.

[1115] LC-MS-1 (Method 8B): Rt 2.59 min; MS m / z 483.3 = [M+H] +

[1116] 1H NMR (500MHz, DMSO) δ12.87(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).

[1117] Example 20

[1118] N-[4-(3-cyanophenyl)-5-(4,8-dimethylquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azepine Spiro[3.3]heptane-6-carboxamide

[1119]

[1120] The title compound was prepared in analogy 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.

[1121] LC-MS-2 (Method 8B): Rt 3.12 min; MS m / z 483.1 = [M+H] +

[1122] 1H NMR (500MHz, DMSO) δ11.34(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,1H),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).

[1123] Example 21

[1124] 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

[1125]

[1126] The title compound was prepared in analogy 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.

[1127] LC-MS-2 (Method 8B): Rt 2.91 min; MS m / z 457.1 = [M+H] +

[1128] 1H NMR (500MHz, DMSO-d6) δ11.36(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).

[1129] Example 22

[1130] 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

[1131]

[1132] The title compound was prepared in analogy to Example 7 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.

[1133] LC-MS-2 (Method 8B): Rt 2.71 min; MS m / z 457.1 = [M+H] +

[1134] 1H NMR(500MHz,DMSO-d6)δ11.27(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).

[1135] Example 23

[1136] N-[4-(3-cyanophenyl)-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl)thiazol-2-yl]-2-oxo 6-azaspiro[3.3]heptane-6-carboxamide

[1137]

[1138] The title compound was prepared in analogy 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 2-oxa-6-azaspiro[3.3]heptane.

[1139] LC-MS-2 (Method 8B): Rt 2.45 min; MS m / z 458.1 = [M+H] +

[1140] 1H NMR (500MHz, DMSO) δ12.85(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).

[1141] Example 24

[1142] N-[4-(3-cyanophenyl)-5-(1,6-dimethylpyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxo 6-azaspiro[3.3]heptane-6-carboxamide

[1143]

[1144] The title compound was prepared in analogy 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.

[1145] LC-MS-2 (Method 8B): Rt 3.35 min; MS m / z 471.1 = [M+H] +

[1146] 1H NMR (500MHz, MeOD) δ7.87(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),7.20(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).

[1147] No NH was observed.

[1148] Example 25

[1149] N-[4-(3-cyanophenyl)-5-(3-methylbenzimidazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[1150]

[1151] The title compound was prepared in analogy 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.

[1152] LC-MS-2 (Method 8B): Rt 2.64 min; MS m / z 457.1 = [M+H] +

[1153] 1H NMR (500MHz, DMSO-d6) δ11.19(s,1H),8.23(s,1H),7.84(s,1H),7.71(d,J=7.8Hz,1H),7.67(d,J=7.8Hz,1 H),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).

[1154] Example 26

[1155] N-[4-(3-Cyanophenyl)-5-imidazo[1,2-a]pyridin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[1156]

[1157] The title compound was prepared in analogy 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.

[1158] LC-MS-1 (Method 8B): Rt 2.49 min; MS m / z 443.2 = [M+H] +

[1159] 1H NMR(500MHz,DMSO-d6)δ11.30(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).

[1160] Example 27

[1161] N-[4-(3-cyanophenyl)-5-(7-methyl-1H-indazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[1162]

[1163] The title compound was prepared in analogy to Example 7 from 5-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-7-methyl-indazole-1-carboxylic acid tert-butyl ester (Intermediate AU) and 2-oxa-6-azaspiro[3.3]heptane and after addition of the amine the mixture was heated for 16 hours.

[1164] LC-MS-1 (Method 8B): Rt 3.03 min; MS m / z 457.3 = [M+H] +

[1165] 1H NMR (500MHz, DMSO-d6) δ13.30(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).

[1166] Example 28

[1167] N-[4-(3-cyanophenyl)-5-(2,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[1168]

[1169] The title compound was prepared in analogy 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.

[1170] 1H NMR (500MHz, DMSO) δ11.16(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).

[1171] LC-MS-1 (Method 8B): Rt 3.82 min; MS m / z 471.2 = [M+H] +

[1172] Example 29

[1173] 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

[1174]

[1175] The title compound was prepared in analogy 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.

[1176] LC-MS-1 (Method 8B): Rt 3.72 min; MS m / z 457.2 = [M+H] +

[1177] 1H NMR (500MHz, DMSO-d6) δ11.26(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).

[1178] Example 30

[1179] N-[4-(3-cyanophenyl)-5-(1,7-dimethylindazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro [3.3] Heptane-6-carboxamide

[1180]

[1181] The title compound was prepared in analogy 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.

[1182] LC-MS-1 (Method 8B): Rt 4.22 min; MS m / z 471.2 = [M+H] +

[1183] 1H NMR (500MHz, DMSO) δ11.16(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).

[1184] Example 31

[1185] N-[4-(3-cyanophenyl)-5-(6-methylpyridazin-4-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3] Heptane-6-carboxamide

[1186]

[1187] The title compound was prepared in analogy 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.

[1188] LC-MS-1 (Method 8B): Rt 1.90 min; MS m / z 419.1 = [M+H] +

[1189] 1H NMR (500MHz, DMSO-d6) δ11.50(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 (dt, 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).

[1190] Example 32

[1191] N-[4-(3-cyanophenyl)-5-[5-methyl-6-(triazol-2-yl)-3-pyridinyl]thiazol-2-yl]-2-oxa- 6-Azaspiro[3.3]heptane-6-carboxamide

[1192]

[1193] The title compound was prepared in analogy to Example 7 from 3-[2-amino-5-[5-methyl-6-(triazol-2-yl)-3-pyridinyl]thiazol-4-yl]benzonitrile (Intermediate AN) and 2-oxa-6-azaspiro[3.3]heptane.

[1194] LC-MS-1 (Method 8A): Rt 3.27 min; MS m / z 485.1 = [M+H] +

[1195] 1H NMR(500MHz,DMSO-d6)δ10.97(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).

[1196] Example 33

[1197] N-[4-(3-Cyanophenyl)-5-pyrazolo[1,5-a]pyridin-5-yl-thiazol-2-yl]morpholine-4-carboxamide

[1198]

[1199] Step 1: N-[4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide

[1200]

[1201] At 0 ℃, sodium hydride (60% in mineral oil) (150 mg, 3.75 mmol) is added to a stirred solution of 3-(2-aminothiazole-4-yl)benzonitrile (intermediate P) (653 mg, 3.08 mmol) in THF (10 mL). After stirring at room temperature for 20 min, morpholine-4-carbonyl chloride (520 μ L, 4.55 mmol) is added and stirring is continued for 18 hours. The gained mixture is diluted with THF (10 mL), then treated with sodium hydride (60% in mineral oil) (150 mg, 3.75 mmol). After stirring for 10 min, morpholine-4-carbonyl chloride (520 μ L, 4.55 mmol) is added and stirring is continued for 4 hours. The reaction is quenched with water (20 mL) and extracted with EtOAc (2 × 40 mL). New water layer is slowly acidified to pH 5 using 1M HCl and extracted with EtOAc (2 × 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 gel chromatography eluting with 0-100% EtOAc / heptane to give the title compound as a beige solid.

[1202] LC-MS-S (Method 2A): Rt 1.06 min; MS m / z 315.1 = [M+H] +

[1203] 1H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.31(t,J=1.5Hz,1H),8.21(dt,J=7.9,1.3Hz,1H),7.76( dt,J=7.7,1.3Hz,1H),7.73(s,1H),7.63(t,J=7.8Hz,1H),3.67–3.58(m,4H),3.56–3.48(m,4H).

[1204] Step 2: N-[5-bromo-4-(3-cyanophenyl)thiazol-2-yl]morpholine-4-carboxamide

[1205]

[1206] 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 min. The resulting mixture was diluted with EtOAc (50 mL) and washed with water (30 mL), saturated aqueous NaHCO3 (2×30 mL) and brine (30 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow solid.

[1207] LC-MS-S (Method 2A): Rt 1.18 min; MS m / z 393.0 / 395.0 = [M+H] +

[1208] 1H NMR(500MHz,DMSO-d6)δ11.35(s,1H),8.25(t,J=1.5Hz,1H),8.21(dt,J=8.0,1.4Hz,1H), 7.88(dt,J=7.7,1.3Hz,1H), 7.71(t,J=7.9Hz,1H), 3.63–3.56(m,4H), 3.55–3.48(m,4H).

[1209] Step 3: N-[4-(3-cyanophenyl)-5-pyrazolo[1,5-a]pyridin-5-yl-thiazol-2-yl]morpholine-4-carboxylate Amide

[1210] 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 min. Bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.04 mmol) was added and a sealed container was heated to 85 ° C for 17 hours under nitrogen. The resulting mixture was cooled 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 column and concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with 0.1% formic acid / MeCN / water to give a solid which was triturated in MeCN, filtered and the filtrate concentrated in vacuo to give a yellow solid.

[1211] Purification by preparative HPLC (conditions below) gave the title compound as a yellow solid.

[1212] Purification conditions - column details: Waters XBridge C18 column (19 mm × 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 / acetonitrile), 2.0 min, then within 20 min, 5-55% B gradient, then within 0.5 min, 55-100% B gradient and hold for 2.0 min.

[1213] LC-MS (Method 7B): Rt 2.65 min; MS m / z 431.2 = [M+H] +

[1214] 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.

[1215] Example 34

[1216] N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl]-2-oxo 6-azaspiro[3.3]heptane-6-carboxamide

[1217]

[1218] Step 1: 4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-6-methyl-pyrrolo[2,3-b]pyridine-1- tert-Butyl formate

[1219]

[1220] The title compound was prepared in analogy to Example 17, Step 1, 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).

[1221] LC-MS-2 (Method 2B): Rt 1.64 min; MS m / z 432.1 = [M+H] +

[1222] 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). 1×CH3 was not observed.

[1223] Step 2: 4-[4-(3-cyanophenyl)-2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonylamino)thiazole- tert-Butyl 5-yl]-6-methyl-pyrrolo[2,3-b]pyridine-1-carboxylate

[1224]

[1225] The title compound was prepared in analogy to Example 7 from 4-[2-amino-4-(3-cyanophenyl)thiazol-5-yl]-6-methyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (step 1) and 2-oxa-6-azaspiro[3.3]heptane.

[1226] LC-MS-1 (Method 3B): Rt 1.83 min; MS m / z 557.3 = [M+H] +

[1227] 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). 1×CH3 was not observed.

[1228] Step 3: N-[4-(3-cyanophenyl)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazole-2- 2-Oxa-6-azaspiro[3.3]heptane-6-carboxamide

[1229] The title compound was prepared in analogy to Example 17, step 3, from 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-carboxylic acid tert-butyl ester (step 2) and TFA.

[1230] LC-MS-2 (Method 8B): Rt 2.89 min; MS m / z 457.1 = [M+H] +

[1231] 1H NMR (500 MHz, methanol-d4) 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). 2×NH was not observed.

[1232] Example 35

[1233] N-[5-(1,3-benzoxazol-6-yl)-4-(3-cyanophenyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3] Heptane-6-carboxamide

[1234]

[1235] The title compound was prepared in analogy 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.

[1236] LC-MS-2 (Method 2B): Rt 2.84 min; MS m / z 444.2 = [M+H] +

[1237] 1H NMR (500MHz, DMSO-d6) δ11.27(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).

[1238] Preparation of intermediates

[1239] Intermediate A

[1240] 3-[2-Amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile

[1241]

[1242] Step 1: 4-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline

[1243]

[1244] 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 for 10 min via nitrogen bubbling. Pd(dppf)Cl2 (1.64 g, 2.24 mmol) and KOAc (5.5 g, 56.04 mmol) were added, a reflux condenser was installed, and the system was evacuated and backfilled with nitrogen (3 × cycles). The reaction mixture was stirred at 80 ° C for 20 hours and then allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (100 mL) and filtered. (filter material) plug filtered, eluting with EtOAc. The filtrate was concentrated in vacuo to give the title compound as a dark brown residue.

[1245] LC-MS-1 (Method 2B): Rt 0.70 min; MS m / z 271.3 = [M+H] +

[1246] 1H NMR (500MHz, DMSO-d6) δ9.14 (s, 1H), 8.52 (t, J = 1.0 Hz, 1H), 8.16 (dd, J = 8.3, 1.0 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 2.96 (s, 3H), 1.17 (s, 12H).

[1247] Step 2: 3-[2-amino-5-(4-methylquinazolin-6-yl)thiazol-4-yl]benzonitrile

[1248] A solution of KCO (6.45 g, 46.67 mmol) in water (35 mL) was added to 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 via nitrogen bubbling 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 (3× cycles). The reaction mixture was stirred at 80° C. for 75 min and then allowed to cool to room temperature. The resulting mixture is diluted with EtOAc (400mL) and washed with water (400mL) and brine (2×200mL). The organic portion is dried over Na2SO4 and concentrated in vacuo to give a dark brown residue. This material is ground in DCM (50mL) containing 2% MeOH by ultrasound and the suspension is collected by filtration. The solid is washed with DCM (2×5mL) and dried in vacuo to give a tan solid. The material is ground with 10:1 MeOH / MeCN (30mL) under ultrasound and the suspension is filtered. The solid is washed with 10:1 MeOH / MeCN (10mL) and dried in vacuo to give the title compound as a tan solid.

[1249] LC-MS-2 (Method 2B): Rt 1.22 min; MS m / z 344.0 = [M+H] +

[1250] 1H NMR (500MHz, DMSO) δ9.08 (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).

[1251] The intermediates in the table below were prepared analogously to Intermediate A, Steps 1 and 2, from appropriate starting compounds.

[1252] Table Int AX

[1253]

[1254]

[1255]

[1256]

[1257]

[1258]

[1259]

[1260]

[1261]

[1262]

[1263]

[1264]

[1265]

[1266] Intermediate B

[1267] (3S)-3-Methylpyrrolidine-3-carbonitrile hydroiodide

[1268]

[1269] Step 1: (3S)-benzyl 3-carbamoyl-3-methylpyrrolidine-1-carboxylate

[1270]

[1271] Under nitrogen, 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. Ammonium hydroxide (35% in water) (43.21 mL, 379.81 mmol) was added and stirring continued for 30 min. THF was removed in a vacuum and the aqueous residue was extracted with EtOAc (100 mL). The organic fraction was washed with HCl aqueous solution (100 mL), saturated NaHCO aqueous solution (100 mL) and brine (100 mL), then dried over MgSO and concentrated in a vacuum to give the title compound as a white solid.

[1272] LC-MS-2 (Method 2B): Rt 1.17 min; MS m / z 263.0 = [M+H] +

[1273] 1H NMR (500MHz, DMSO) δ7.44–7.26(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).

[1274] Step 2: (3S)-benzyl 3-cyano-3-methylpyrrolidine-1-carboxylate

[1275]

[1276] To a solution of (3S)-3-carbamoyl-3-methyl-pyrrolidine-1-carboxylic acid benzyl ester (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 hours. 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 NaHCO3 aqueous solution (20 mL). The organic layer was separated and the aqueous solution was further extracted with EtOAc (2×20 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo to give the title compound as a yellow oil.

[1277] LC-MS-1 (Method 2B): Rt 1.30 min; MS m / z 267.2 = [M+Na]+

[1278] 1H NMR(500MHz,DMSO-d6)δ7.40–7.35(m,4H),7.35–7.29(m,1H),5.09(s,2H),3.78(dd,J=22.8,10.9Hz,1 H),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).

[1279] Step 3: (3S)-3-Methylpyrrolidine-3-carbonitrile hydroiodide

[1280] Under nitrogen at 0 ° C, trimethylsilyl iodide (0.42mL, 2.95mmol) was added dropwise to a stirred solution of (3S)-3-cyano-3-methyl-pyrrolidine-1-carboxylic acid benzyl ester (step 2) (300mg, 1.23mmol) in DCM (12mL) by syringe. The resulting solution was warmed to room temperature and stirred for 1 hour. MeOH (0.5mL, 12.28mmol) was added dropwise to precipitate a light-colored solid and the resulting mixture was stirred at room temperature for 30min, then at 0 ° C for 15min. The suspension was filtered, and the solid was washed with cold DCM (2×5mL) and dried in vacuo to give the title compound as a white solid.

[1281] 1H NMR(500MHz,DMSO-d6)δ9.10(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).

[1282] Intermediate BA

[1283] (3R)-3-Methylpyrrolidine-3-carbonitrile hydroiodide

[1284]

[1285] Step 1: (3R)-benzyl 3-carbamoyl-3-methylpyrrolidine-1-carboxylate

[1286]

[1287] The title compound was prepared in analogy to Intermediate B, Step 1, from (3R)-1-benzyloxycarbonyl-3-methyl-pyrrolidine-3-carboxylic acid.

[1288] LC-MS-2 (Method 2B): Rt 1.17 min; MS m / z 263.0 = [M+H] +

[1289] 1H NMR (500MHz, DMSO) δ7.40–7.28(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).

[1290] Step 2: (3R)-benzyl 3-cyano-3-methylpyrrolidine-1-carboxylate

[1291]

[1292] (3R)-3-Carbamoyl-3-methyl-pyrrolidine-1-carboxylic acid benzyl ester (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 and stirred at 35 ° C for 17 hours. The resulting mixture was cooled to room temperature, diluted with DCM (40 mL) and washed with 1M HCl (50 mL) and then brine (25 mL). The organic portion was dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography eluting with a gradient of 10-50% EtOAc / petroleum ether gave the title compound as a clear, colorless syrup.

[1293] LC-MS-2 (Method 2B): Rt 1.39 min; MS m / z 245.0 = [M+H] +

[1294] 1H NMR(500MHz,DMSO)δ7.40–7.28(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).

[1295] Step 3: (3R)-3-Methylpyrrolidine-3-carbonitrile hydroiodide

[1296] The title compound was prepared in analogy to Intermediate B, Step 3, from (3R)-3-cyano-3-methyl-pyrrolidine-1-carboxylic acid benzyl ester (Step 2) and trimethylsilyl iodide.

[1297] 1H NMR(500MHz,DMSO)δ9.10(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).

[1298] Intermediate C

[1299] 2-Methyl-2-piperazin-1-yl-propionitrile hydrochloride

[1300]

[1301] 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 1,4-dioxane (4.93 mL, 19.74 mmol) containing 4M HCl, and the mixture was stirred for 16 hours. The solvent was removed in vacuo to give a white solid, which was suspended in Et2O and collected by filtration. The solid was dried under high vacuum to give the title compound as a white solid.

[1302] 1H NMR (500MHz, DMSO-d6) δ9.16 (s, 2H), 3.10 (apr p, J = 4.8Hz, 4H), 2.78 (apr t, J = 5.0Hz, 4H), 1.46 (s, 6H).

[1303] Intermediate D

[1304] 2-[(2S)-Piperazin-2-yl]propan-2-ol dihydrochloride

[1305]

[1306] Step 1: (2S)-piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester

[1307]

[1308] 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 NaHCO aqueous solution (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.

[1309] 1H NMR (500MHz, DMSO-d6) δ4.56 (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).

[1310] Step 2: (2S)-di-tert-butyl 2-(1-hydroxy-1-methyl-ethyl)piperazine-1,4-dicarboxylate

[1311]

[1312] To a solution of (2S)-piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl 2-methyl ester (step 1) (712 mg, 2.07 mmol) in THF (20 mL) was added dropwise MeMgCl (3 M in THF) (1.72 mL, 5.17 mmol) at 0 ° C. The reactant was allowed to warm to room temperature and stirred at this temperature for 3 hours. The reactant was diluted with DCM (70 mL) and washed with saturated NH4Cl aqueous 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 gel chromatography eluting with a gradient of 1-2% MeOH / DCM gave the title compound as a clear oil.

[1313] 1H NMR (500MHz, DMSO-d6) δ4.39(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).

[1314] Step 3: 2-[(2S)-piperazin-2-yl]propan-2-ol dihydrochloride

[1315] 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 4N HCl in 1,4-dioxane (2.4 mL, 9.60 mmol) and the reaction mixture was stirred at room temperature for 6 hours and then concentrated in vacuo to give the title compound as a white solid.

[1316] 1H NMR(500MHz,DMSO-d6)δ9.67(s,2H),9.41(s,1H),9.07(s,1H),5.57(s,1H),3.62–3.53(m,1 H),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).

[1317] Intermediate E

[1318] 6-Bromo-4-ethyl-quinazoline

[1319]

[1320] Step 1: 1-(2-Amino-5-bromo-phenyl)propan-1-one

[1321]

[1322] The following materials were prepared according to the procedure of WO2018 / 130184, pages 74-75.

[1323] At 0 DEG C, ethylmagnesium bromide (3M in Et is added to the stirred flask of 2-amino-5-bromo-benzonitrile (5.0g, 25.38mmol) in THF (100mL) (25.38mL, 76.13mmol) and the solution is stirred at 0 DEG C for 15min.The mixture is allowed to warm to room temperature and stirred overnight.The resulting solution is cooled to 0 DEG C and treated with saturated NH4Cl aqueous solution (100mL).EtOAc (300mL) is added and the layers are separated.The water layer is extracted with EtOAc (300mL), and the combined organic extracts are washed with brine (300mL), through MgSO4, dried and concentrated in a vacuum.Purified by silica gel chromatography, eluted with the gradient of 0-40% EtOAc / petroleum ether, obtain the title compound as a yellow solid.

[1324] LC-MS-2 (Method 2B): Rt 1.54 min; MS m / z 227.9 / 229.9 = [M+H] +

[1325] 1H NMR (500MHz, DMSO) δ7.85 (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).

[1326] Step 2: 6-Bromo-4-ethyl-quinazoline

[1327] The following materials were prepared according to the procedure of WO2018 / 130184, pages 74-75.

[1328] A solution of 1-(2-amino-5-bromobenzene)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 hour. The resulting mixture was cooled to room temperature and distributed between EtOAc (50 mL) and saturated NaHCO3 aqueous solution (50 mL). The layers were separated and the aqueous layer was back extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 20-40% EtOAc / petroleum ether gave the title compound as a yellow solid.

[1329] LC-MS-1 (Method 2B): Rt 1.47 min; MS m / z 237.1 / 239.1 = [M+H] +

[1330] 1H NMR (500MHz, DMSO) δ9.21 (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).

[1331] Intermediate F

[1332] 5-Bromo-3-methyl-2-(triazol-2-yl)pyridine

[1333]

[1334] To a solution of 5-bromo-2-chloro-3-methyl-pyridine (2.0 g, 9.69 mmol) in DMF (15 mL) was added K CO (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 hours, then heated at 100° C. for another 2 hours. Additional 2H-triazole (0.84 mL, 14.53 mmol) and K CO (2.68 g, 19.37 mmol) were added and stirring was continued at 100° C. for 18 hours. 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 Na SO and concentrated in vacuo. Purification by silica gel chromatography eluting with a gradient of 0-20% EtOAc in petroleum ether gave the title compound as a clear oil.

[1335] LC-MS-1 (Method 5A): Rt 2.56 min; MS m / z 240.9 = [M+H] +

[1336] 1H NMR (500 MHz, CHLOROFORM-d) δ 8.54–8.49 (m, 1H), 7.95–7.87 (m, 3H), 2.51–2.45 (m, 3H).

[1337] Intermediate G

[1338] 6-Bromo-2,4-dimethyl-quinazoline

[1339]

[1340] The following materials were prepared according to the procedure of Raju et al., Chemistry Select, 2018, 3, 32, 9388-9392.

[1341] 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 hours. The mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The organic fraction was separated and the aqueous solution was further extracted with EtOAc (2 × 50 mL), then the combined organics were washed with brine (2 × 50 mL), dried over Na2SO4 and the solvent was removed in vacuo. Purification by silica gel chromatography, eluting with 70% EtOAc / DCM, gave a solid, which was suspended in Et2O, collected by filtration and dried to give the title compound as a paste solid.

[1342] LC-MS-1 (Method 2B): Rt 1.22 min; MS m / z 237.1 / 239.1 = [M+H] +

[1343] 1H NMR (500 MHz, CHLOROFORM-d) δ 8.20 (d, J = 2.1 Hz, 1H), 7.90 (dd, J = 9.0, 2.1 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 2.89 (s, 3H), 2.83 (s, 3H).

[1344] Intermediate H

[1345] 6-Bromo-3,8-dimethylimidazo[1,2-a]pyridine

[1346]

[1347] Step 1: N-(5-bromo-3-methyl-2-pyridyl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester

[1348]

[1349] To the solution of 5-bromo-6-methyl-pyridine-2-amine (2.0g, 10.69mmol) in DCM (50mL), add di-tert-butyl dicarbonate (2.8g, 12.83mmol), triethylamine (2.24mL, 16.04mmol) and DMAP (65mg, 0.53mmol), and the mixture is stirred at room temperature for 4 hours.Add other di-tert-butyl dicarbonate (2.8g, 12.83mmol), triethylamine (2.24mL, 16.04mmol) and DMAP (65.32mg, 0.53mmol) and continue to stir for other 16 hours at room temperature.Gained mixture is washed with water (50mL), and aqueous fraction is further extracted with DCM (2 × 30mL).By the organic matter merged through MgSO4Drying and removing solvent in a vacuum, obtain viscous brown oil, which is solidified to obtain the title compound as a brown solid.

[1350] LC-MS-1 (Method 2B): Rt 1.56 min; MS m / z 387.2 / 389.2 = [M+H] +

[1351] 1H NMR (500 MHz, CHLOROFORM-d) δ 8.35–8.31 (m, 1H), 7.67–7.64 (m, 1H), 2.15 (t, J=0.8 Hz, 3H), 1.34 (s, 18H).

[1352] Step 2: tert-Butyl N-(5-bromo-3-methyl-2-pyridyl)carbamate

[1353]

[1354] To a solution of crude N-(5-bromo-3-methyl-2-pyridyl)-N-tert-butoxycarbonyl-t-butyl carbamate (step 1) (1.0 g, 2.58 mmol) in DCM (10 mL) was added dropwise TFA (0.4 mL, 5.16 mmol), and the mixture was stirred at room temperature for 65 hours. Additional TFA (0.2 mL, 2.58 mmol) was added and continued to stir for 20 hours. Three more parts of TFA (0.2 mL, 2.58 mmol) were added at intervals of 20 hours, and the mixture was stirred for another 48 hours after the last addition. The resulting mixture was washed with saturated NaHCO aqueous solution (3 × 20 mL), dried over MgSO and the solvent was removed in a vacuum. Purified by silica gel chromatography, eluted with 0.5% MeOH / DCM, to give the title compound as a white solid.

[1355] LC-MS-2 (Method 2B): Rt 1.51 min; MS m / z 286.9 / 288.9 = [M+H] +

[1356] 1H NMR (500MHz, CDCl3) δ8.30 (d, J = 2.3Hz, 1H), 7.66–7.62 (m, 1H), 6.67 (s, 1H), 2.27 (s, 3H), 1.51 (s, 9H).

[1357] Step 3: N-(5-Bromo-3-methyl-2-pyridinyl)-N-prop-2-ynyl-carbamic acid tert-butyl ester

[1358]

[1359] 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 hours and 20 minutes. 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 x 20 mL), then dried over NaSO and concentrated in vacuo to give the title compound as a yellow slurry.

[1360] LC-MS-2 (Method 2B): Rt 1.72 min; MS m / z 324.9 / 326.9 = [M+H] +

[1361] 1H NMR (500MHz, CDCl3) δ8.37 (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).

[1362] Step 4: 5-Bromo-3-methyl-N-prop-2-ynyl-pyridin-2-amine

[1363]

[1364] TFA (2.0mL, 26.12mmol) is added to a solution of N-(5-bromo-3-methyl-2-pyridyl)-N-prop-2-ynyl-t-butyl carbamate (step 3) (260mg, 0.80mmol) in DCM (4mL), and the mixture is stirred at room temperature for 40min. The resulting mixture is diluted with DCM (25mL) and saturated NaHCO3 aqueous solution (50mL) is added, and the mixture is stirred until bubbling stops. Each layer is separated and the aqueous portion is further extracted with DCM (25mL). The combined organic extracts are dried over Na2SO4 and concentrated in vacuo to obtain the title compound as a turbid light brown oil.

[1365] LC-MS-2 (Method 2B): Rt 1.46 min; MS m / z 224.9 / 226.9 = [M+H] +

[1366] 1H NMR (500MHz, CDCl3) δ8.08 (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).

[1367] Step 5: 6-Bromo-3,8-dimethyl-imidazo[1,2-a]pyridine

[1368] The following materials were prepared according to the procedure of Adimurthy et al., J. Org. Chem. 2013, 78, 1266-1272.

[1369] Water (4mL) is added to 5-bromo-3-methyl-N-prop-2-ynyl-pyridine-2-amine (step 4) (177mg, 0.79mmol) in a sealed tube under nitrogen, and the mixture is stirred at 120°C for 1 hour. The resulting mixture is cooled to room temperature and then distributed between DCM (20mL) and a saturated aqueous solution. NaHCO aqueous solution (20mL) is washed. The organic fraction is separated and the aqueous solution is further extracted with DCM (2×20mL). The combined organic portion is dried over NaSO and concentrated in vacuo. Purified by silica gel chromatography, eluted with EtOAc, to obtain a light yellow slurry, which slowly crystallizes to obtain the title compound as a pale waxy solid.

[1370] LC-MS-2 (Method 2B): Rt 1.32 min; MS m / z 224.9 / 226.9 = [M+H] +

[1371] 1H NMR (500MHz, MeOD) δ8.28(s,1H),7.34(s,1H),7.20(s,1H),2.53(s,3H),2.48(s,3H).

[1372] Intermediate I

[1373] 6-Bromo-4,8-dimethyl-quinazoline

[1374]

[1375] Step 1: 1-(2-Amino-5-bromo-3-methyl-phenyl)ethanone

[1376]

[1377] The following materials were prepared according to the procedure of WO2020 / 011220, page 41.

[1378] Methylmagnesium bromide (3.4M in 2-Me-THF) (13.5mL, 0.05mmol) is added dropwise to a solution of 2-amino-5-bromo-3-methyl-benzonitrile (1.94g, 0.01mmol) in THF (92mL) at -10°C, and the mixture is stirred overnight while warming to room temperature. 10% HCl (92mL, 0.01mmol) is added dropwise, and the resulting mixture is stirred for 1 hour, then extracted with EtOAc (3 × 100mL). The combined organic extracts are washed with brine (90mL), through Na2SO4, and concentrated in vacuo. Purified by silica gel chromatography, eluted with the gradient of 0-50% EtOAc / petroleum ether, then ground with MeOH to obtain the title compound as a yellow solid.

[1379] LC-MS-2 (Method 2B): Rt 1.53 min; MS m / z 226.1 / 228.1 = [MH]-

[1380] 1H NMR (500MHz, DMSO-d6) δ7.76(s,1H),7.35(s,1H),7.18(s,2H),2.53(s,3H),2.10(s,3H).

[1381] Step 2: 6-Bromo-4,8-dimethyl-quinazoline

[1382] The following materials were prepared according to the procedure of WO2020 / 011220, page 42.

[1383] A mixture of 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) in triethyl orthoformate (0.91 mL, 5.47 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) and washed with brine (2 × 80 mL), dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by silica chromatography, eluting with a gradient of 0 to 50% EtOAc / petroleum ether, followed by a second silica gel chromatography, eluting with 0 to 40% EtOAc / DCM to give the title compound as a brown solid.

[1384] LC-MS-2 (Method 2B): Rt 1.46 min; MS m / z 236.9 / 238.9 = [M+H] +

[1385] 1H NMR (500MHz, DMSO) δ9.17 (s, 1H), 8.33 (d, J = 2.2Hz, 1H), 8.02 (s, 1H), 2.90 (s, 3H), 2.68 (s, 3H).

[1386] Intermediate J

[1387] 4-Bromo-1-methyl-pyrrolo[2,3-b]pyridine

[1388]

[1389] In an ice bath, NaH (60% dispersion in mineral oil) (122 mg, 3.05 mmol) is added to a cooled suspension of 4-bromo-1H-pyrrolo[2,3-b]pyridine (550 mg, 2.79 mmol) in DMF (3 mL). After 30 min, iodomethane (0.17 mL, 2.79 mmol) is added and stirring is continued for another 30 min. The reaction is quenched with water (30 mL) and dissolved in EtOAc (30 mL). The layers are separated and the aqueous solution is extracted with EtOAc (30 mL). The combined organic extracts are washed with 90% brine (30 mL), 50% brine (2 × 30 mL), dried over MgSO4 and concentrated in vacuo. Purified by silica gel chromatography, eluting with a gradient of 30-50% EtOAc / hexane, to give the title compound as an off-white solid.

[1390] LC-MS-2 (Method 2B): Rt 1.44 min; MS m / z 210.9 / 212.9 = [M+H] +

[1391] 1H NMR (500MHz, DMSO-d6) δ 8.13 (d, J = 5.2 Hz, 1H), 7.66 (d, J = 3.5 Hz, 1H), 7.36 (d, J = 5.1 Hz, 1H), 6.43 (d, J = 3.5 Hz, 1H), 3.83 (s, 3H).

[1392] Intermediate K

[1393] 6-Bromo-4-methyl-1-trityl-indazole

[1394]

[1395] To a stirred suspension of NaH (60% dispersion in mineral oil) (46 mg, 1.14 mmol) in DMF (4.74 mL) containing 6-bromo-4-methyl-1H-indazole (200 mg, 0.95 mmol) was added dropwise at 0°C and stirred for 1 hour. Triphenylmethane (291 mg, 1.04 mmol) was added and the solution was allowed to warm to room temperature and stirred for 1 hour. 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 x 50 mL), and the combined organic extracts were treated with 90% brine (50 mL), 50% brine (2 x 50 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography eluting with 20% EtOAc / hexane gave the title compound (and corresponding regioisomers).

[1396] Isomer 1: LC-MS-1 (Method 2B): Rt 1.93 min; MS m / z 451.1 / 453.1 = [MH]-

[1397] 1H NMR (500MHz, DMSO-d6) δ8.08(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).

[1398] Isomer 2: LC-MS-1 (Method 2B): Rt 1.90 min; MS m / z 209.1 / 211.1 = [MH-trityl]-

[1399] 1H NMR (500MHz, DMSO-d6) δ8.26(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).

[1400] Intermediate L

[1401] 6-Bromo-4-methyl-1-trityl-benzotriazole

[1402]

[1403] The title compound was prepared in analogy to intermediate K from 5-bromo-7-methyl-1H-benzotriazole and triphenylmethane.

[1404] LC-MS-2 (Method 2B): Rt 2.09 min; MS m / z 212.0 = [MH-trityl] +

[1405] 1H NMR (500MHz, DMSO) δ7.43–7.36 (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).

[1406] Intermediate M

[1407] 4-Bromo-1,6-dimethyl-pyrrolo[2,3-b]pyridine

[1408]

[1409] The title compound was prepared in analogy to intermediate J from 4-bromo-6-methyl-1H-pyrrolo[2,3-b]pyridine and iodomethane.

[1410] LC-MS-2 (Method 2B): Rt 1.57 min; MS m / z 224.9 / 226.9 = [M+H] +

[1411] 1H NMR (500MHz, DMSO) δ7.53 (d, J = 3.5 Hz, 1H), 7.26 (s, 1H), 6.36 (d, J = 3.5 Hz, 1H), 3.79 (s, 3H), 2.55 (s, 3H).

[1412] Intermediate N

[1413] tert-Butyl 5-bromo-7-methyl-indazole-1-carboxylate

[1414]

[1415] To the solution of tert-butyl dicarbonate (2.59g, 11.84mmol) and 5-bromo-7-methyl-1H-indazole (2.0g, 9.48mmol) in MeCN (20mL), triethylamine (1.52mL, 10.9mmol) and DMAP (0.12g, 0.95mmol) are added, and the mixture is stirred at room temperature overnight. The gained mixture is concentrated in a vacuum, and residue is dissolved in EtOAc: petroleum ether (7:3, 150mL). Water (75ml) washing solution is separated organic fraction, and with EtOAc:Pet (1:1,2×50mL) aqueous solution extraction. By the organic fraction water (100mL), saturated NH4Cl aqueous solution (50mL), water (2×50mL), saturated NaHCO3 aqueous solution (2×75mL), salt solution (50mL) washing, and through MgSO4 drying, then concentrate in a vacuum. Purification by silica gel chromatography eluting with a gradient of 1-30% EtOAc in petroleum ether gave the title compound as an orange solid.

[1416] LC-MS-1 (Method 3B): Rt 2.27 min; MS m / z 211.0 / 212.9 = [M+H-Boc] +

[1417] 1H NMR (500 MHz, CHLOROFORM-d) δ 8.49 (s, 1H), 7.63 (dd, J = 1.7, 0.8 Hz, 1H), 7.15 (p, J = 1.3 Hz, 1H), 2.62 (t, J = 1.0 Hz, 3H), 1.71 (s, 9H).

[1418] Intermediate O

[1419] 2,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole

[1420]

[1421] By bis (pinacolato) diboron (654mg, 2.57mmol), methoxy (cyclooctadiene) iridium (I) dimer (51mg, 0.08mmol) and 4,4 '-di-tert-butyl-2,2 '-bipyridine (41mg, 0.15mmol) are placed in a vial sealed with a polytetrafluoroethylene cap, and the contents are evacuated and backfilled with nitrogen (3 × circulation). Fresh deoxygenated anhydrous cyclohexane (10mL) is added, and the gained red-brown solution is vigorously stirred at room temperature for 20min. Then 2,4- dimethyloxazole (0.26mL, 2.57mmol) is added, and the gained mixture is stirred at room temperature overnight. The mixture is concentrated in a vacuum to obtain the title compound as a dark red-brown oil.

[1422] LC-MS-2 (Method 2B): Rt 0.74 min; MS m / z 224.1 = [M+H] +

[1423] 1H NMR (500MHz, DMSO) δ2.38 (s, 3H), 2.18 (s, 3H), 1.27 (s, 12H).

[1424] Intermediate P

[1425] 3-(2-Aminothiazol-4-yl)benzonitrile hydrobromide

[1426]

[1427] The following materials were prepared according to the procedure of WO 2012 / 100734, page 24, Example 15, step 2.

[1428] To the flask containing EtOH (50mL) containing 3-(2-bromoacetyl)benzonitrile (5g, 22.32mmol), thiourea (1.87g, 24.55mmol) was added, and the mixture was stirred at room temperature for 30min. The volume of the solvent was reduced by about 50% in a vacuum, resulting in the formation of a suspension. The ultrasonic treatment suspension was filtered and dried to obtain the title compound as a white solid.

[1429] LC-MS-1 (Method 3B): Rt 1.62 min; MS m / z 200.0 = [MH]

[1430] 1H NMR (500 MHz, DMSO-d6) δ 8.22 (t, J = 1.8 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.37 (s, 1H). No NH2 was observed. The HBr salt was assigned based on the mass of the obtained compound.

[1431] 3-(2-Aminothiazol-4-yl)benzonitrile can also be prepared as follows:

[1432] Under nitrogen, 3- (2- bromoacetyl) benzonitrile (3.0 g, 13.39 mmol) was added to a flask containing pyridine (50 mL) containing thiourea (2.04 g, 26.78 mmol), and the mixture was stirred at room temperature for 1 hour. 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 gel chromatography, eluting with 0-100% EtOAc / DCM. The resulting solid was recrystallized from EtOAc to obtain 3- (2- aminothiazole -4- bases) benzonitrile as a light yellow solid.

[1433] LC-MS (Method 7A): Rt 1.75 min; MS m / z 202.1 = [M+H] + , 243.3 = [M+H+MeCN] +

[1434] 1H NMR(400MHz,DMSO-d6)δ8.20(t,J=1.5Hz,1H),8.11(dt,J=7.9,1.4Hz,1H),7 .70(dt,J=7.7,1.3Hz,1H),7.58(t,J=7.6Hz,1H),7.26(s,1H),7.14(s,2H).

[1435] Intermediate Q

[1436] 3-(2-Amino-5-bromo-thiazol-4-yl)benzonitrile

[1437]

[1438] The following materials were prepared according to the procedure of WO 2012 / 100734, pages 24-25, Example 15, step 3.

[1439] 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 hour. The resulting mixture was diluted with EtOAc (60 mL) and washed with water (100 mL). The organic portion was separated and the aqueous solution was extracted with EtOAc (2 × 50 mL). The combined organics were dried over MgSO4 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.

[1440] LC-MS-1 (Method 3B): Rt 1.64 min; MS m / z 279.9 / 281.9 = [M+H] +

[1441] 1H NMR (500MHz, DMSO-d6) δ 8.16 (t, J = 1.7 Hz, 1H), 8.15 (dt, J = 7.9, 1.7 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.42 (s, 2H).

[1442] Intermediate R

[1443] 6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine- tert-Butyl 1-formate

[1444]

[1445] Step 1: 4-Bromo-6-methyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester

[1446]

[1447] The title compound was prepared in analogy to intermediate N from 4-bromo-6-methyl-1H-pyrrolo[2,3-b]pyridine and di-tert-butyl decarbonate.

[1448] LC-MS-2 (Method 2B): Rt 1.86 min; MS m / z 310.9 / 312.9 = [M+H] +

[1449] 1H NMR (500MHz, DMSO-d6) δ7.79 (d, J = 4.0 Hz, 1H), 7.49 (s, 1H), 6.59 (d, J = 4.0 Hz, 1H), 2.55 (s, 3H), 1.61 (s, 9H).

[1450] Step 2: 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3- b] tert-Butyl pyridine-1-carboxylate

[1451] The title compound was prepared in analogy to Intermediate A, Step 1, from 4-bromo-6-methyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (Step 1) and bis(pinacolato)diboron.

[1452] LC-MS-2 (Method 2B): Rt 1.72 min; MS m / z 359.1 = [M+H] +

[1453] 1H NMR (500MHz, DMSO-d6) δ7.72 (d, J = 4.0 Hz, 1H), 7.36 (s, 1H), 6.78 (d, J = 4.0 Hz, 1H), 2.56 (s, 3H), 1.61 (s, 9H), 1.34 (s, 12H).

[1454] Intermediate S

[1455] 3-[2-Amino-5-(6-methyl-1-trityl-pyrazolo[3,4-b]pyridin-4-yl)thiazol-4-yl]benzonitrile

[1456]

[1457] Step 1: 4-Bromo-6-methyl-1-trityl-pyrazolo[3,4-b]pyridine

[1458]

[1459] At 0 ° C, a solution of 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). The solution was stirred at 0 ° C for 45 min and triphenylmethane (723.08 mg, 2.59 mmol) was added. The solution was warmed to room temperature and stirred for 1 hour. The solution was cooled to 0 ° C again and water (10 mL) was slowly added. 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 Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography eluting with a gradient of 0-30% EtOAc in petrol gave the title compound as an orange solid.

[1460] LC-MS-2 (Method 2B): Rt 2.14 min; MS m / z 454.0 / 456.0 = [M+H] +

[1461] 1H NMR (500MHz, DMSO) δ8.16(s,1H),7.33(s,1H),7.34–7.18(m,9H),7.19–7.12(m,6H),2.19(s,3H).

[1462] Step 2: 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl- Pyrazolo[3,4-b]pyridine

[1463]

[1464] The title compound was prepared in analogy to Intermediate A, Step 1, from 4-bromo-6-methyl-1-trityl-pyrazolo[3,4-b]pyridine (Step 1) and bis(pinacolato)diboron.

[1465] LC-MS-2 (Method 2B): Rt 1.57 min; MS m / z 420.1 = [M-C6H 10 ]+

[1466] 1H NMR (500MHz, DMSO) δ8.17(s,1H),7.93(s,1H),7.25–7.16(m,15H),2.22(s,3H),1.34(s,12H).

[1467] Step 3: 3-[2-amino-5-(6-methyl-1-trityl-pyrazolo[3,4-b]pyridin-4-yl)thiazole-4-yl] [Methyl]benzonitrile

[1468] The title compound was prepared in analogy to Intermediate A, Step 2, 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).

[1469] LC-MS-2 (Method 2B): Rt 1.96 min; MS m / z 575.1 = [M+H] +

[1470] 1H NMR (500MHz, DMSO) δ7.73(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),7.46(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).

[1471] Biological Examples

[1472] Biological Example 1 - Adenosine Receptor Time-Resolved Fluorescence Resonance Energy Transfer (TRFRET) Binding Assay

[1473] 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 close proximity of the donor and acceptor during the binding event. To investigate 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.

[1474] Mosquito (TTP Labtech, UK) was used to perform serial dilutions of the test compounds in pure DMSO (1:3 dilutions) and 400 nL of the test compound samples were transferred to the assay plate. The compound samples were incubated for 2 hours at room temperature with a fixed concentration of CA200645 defined for each receptor (see above) 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 in 40 μL assay buffer. The total binding and nonspecific binding of CA200645 were measured in the absence and presence of 10 μM XAC, respectively. After incubation for 2 hours, the level of CA200645 binding was detected on a Pherastar FSX (BMG Labtech, Germany) using standard TR-FRET. Terbium donors were excited by three laser flashes at a wavelength of 337 nm, and donor and acceptor emissions were detected at 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. GraphPad Prism 7.0 (GraphPad, USA) was used to analyze compound IC50 curves, and the Ki affinity values ​​were determined based on the IC50 values ​​obtained using the method of Cheng and Prusoff. The results are shown in Table 1.

[1475] Table 1

[1476]

[1477]

[1478]

[1479] Biological Example - NECA Reversal Assay of CD3 / CD28-Stimulated IL-2 Release in Human PBMCs

[1480] Use sodium citrate as anticoagulant (0.3% final concentration) to draw blood from healthy volunteers. After centrifuging blood on Histopaque-1077, PBMC is collected from Histopaque / plasma interface, and washed twice in PBS (300g, 10min at room temperature). Cells are seeded in 150 μl RPMI / 10% FCS with 50,000 cells / well in 96-well cell culture plates pre-coated with 1ug / ml CD3 antibody. Add the compound mixture of 50 μl dilutions to cells to obtain a final concentration of 1ug / ml CD28 antibody, 1uM NECA and 0.003-10 μM adenosine receptor antagonist. Assay plate is hatched 24 hours at 37 ℃ in a humidified incubator. Use human IL-2 tissue culture kit (Meso Scale Discovery) to test the IL-2 level of culture supernatant. Data from dose-response curves were calculated as % inhibition, with 100% inhibition defined as the no agonist control wells (+CD3 / 28-NECA).

[1481] Table 2

[1482]

[1483]

[1484] Biological Example - Measurement of pCREB in CD8+ T cells in human whole blood

[1485] Heparinized human whole blood was preincubated with serially diluted A2a antagonists and the phosphodiesterase inhibitor rolipram for 20 minutes at 37°C to amplify the pCREB reaction. The adenosine receptor agonist NECA was then added at a final concentration of 3 μM. After a 60-minute incubation, the blood was fixed and the red blood cells lysed. Leukocytes were isolated, permeabilized, and stained with fluorescent antibodies directly conjugated to phospho-CREB (Alexa Fluor 488) and CD8 (Alexa Fluor 647). Phospho-CREB levels in CD8+ T cells were measured by FACS using a BD Accuri C6 flow cytometer.

[1486] Table 3

[1487] Example pCREB IC50 (μM) 2 0.02 2.1 0.05 3 0.07 3.1 0.01 4 0.01 4.1 0.008 5 0.015 6 0.011 7 0.01 7.4 0.06 7.17 0.004 7.23 0.03 7.24 0.012 7.25 0.007 7.26 0.015 7.28 0.022 7.29 0.005 19 0.216 20 0.105 33 0.219

[1488] MoDC pCREB assay

[1489] 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 in Mo-DC differentiation medium (Miltenyi Biotec 130-094-812) for 5 days. MoDCs were seeded in fresh culture medium in U-bottom 96-well culture plates and incubated at 37°C with serially diluted A 2A / B The cells were pre-incubated with the phosphodiesterase inhibitor rolipram (final concentration of 20 μM) for 15 minutes. At the same time, the cells were co-incubated with the phosphodiesterase inhibitor rolipram (final concentration of 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 incubation at 37°C for 45 minutes, the cells were fixed, permeabilized and stained with fluorescent antibodies directly conjugated to phospho-CREB (Alexa Fluor 488), CD209 (PerCP-Cy5.5) and CD86 (APC). The samples were analyzed by FACS to measure fluorescence in the corresponding channels, as well as forward scatter and side scatter. The CD209+ / CD86- low cell population corresponding to immature dendritic cells was gated to analyze pCREB levels. Based on the specific response to the highly selective antagonist PSB-603, the adenosine receptor response in this cell population was mainly to A 2B Be specific.

[1490] In the absence of agonist stimulation, approximately 5% of the analyzed cells were positive for pCREB, representing background signaling of all pathways upstream of CREB. After NECA stimulation, this increased to approximately 80% pCREB+ve, and this increase was enhanced by A 2B or Double A 2A / B Antagonists are essentially completely reversible.

[1491] IC50 is expressed as the inflection point of the sigmoidal curve.

[1492] Table 4

[1493] Example pCREB IC50 (μM) 2 0.003 2.1 0.003 3 0.006 4.1 0.002 5 0.003 6 0.002 7 0.003 7.4 0.004 7.17 0.002 7.23 0.003 7.24 0.002 7.25 0.002 7.26 0.002 7.28 0.005 20 0.003

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Claims

1. A compound having structural formula I shown below or a pharmaceutically acceptable salt thereof: in: R 1 Selected from: in: R 1 Any available C atom in is optionally replaced by one or more R 2 The substituent group is substituted, and R 1 Any available N atom in is optionally in the form of an N-oxide or replaced by R 3 group substitution; in Each R 2 is independently selected from (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 (where p is 0, 1 or 2), -(CR 1C R 1D ) q1 -SO 2 N(R 1B )R 1A or -(CR 1C R 1D ) q1 -N(R 1B )SO 2 R 1A , where q1 is 0, 1, or 2; and Where R 1A and R 1B 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; and R 3 is selected from hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, aryl, aryl(1-2C)alkyl, C-attached 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 -SO 2 N(R 3B )R 3A or -(CR 3C R 3D ) 1-2 -N(R 3B )SO 2 R 3A ; Where R 3A and R 3B 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; and where q3 is 0, 1, or 2; and R 4 and R 5 are linked so that they, together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substitution, Where R 10C is selected from oxo, thio, halo or cyano substituents, or a group of the formula: -[CR 7a R 7b ] n -L-Z in 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 selected from -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 )SO 2 -, where R a and R b are each independently selected from hydrogen or (1-2C)alkyl; and 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; and wherein Z is optionally substituted with one or more substituents selected from (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 (where y is 0, 1 or 2), -SO 2 N(R c )R d 、-N(R c )SO 2 R d 、-(CH 2 ) z NR c R d (wherein z is 1, 2 or 3) or oxo, wherein any alkyl moiety in the substituent groups 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, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl; And among them, R 4 and R 5 Any available N atom in the formed ring is optionally in the form of an N-oxide or optionally replaced by one or more R 10N replace, Where R 10N Yes-S(O) 2 NH 2 Or choose from: (i)-Z 1 ; (ii)-L 1a -Z 1 ;or (iii)-[CR 8a R 8b ] 1-6 -L 1b -Z 1 ; in R 8a and R 8b are each independently selected from hydrogen, fluoro or (1-2C)alkyl; L 1a Selected from -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 Not present or selected from -O-, -S-, -SO-, -SO 2- 、-N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-、-N(R a2 )C(O)-、-N(R a2 )C(O)N(R b2 )-、-C(S)N(R a2 )-、-N(R a2 )C(S)-、-N(R a2 )C(S)N(R b2 )-、-S(O) 2 N(R a2 )-or-N(R a2 )SO 2 , where R a2 and R b2 are each independently selected from hydrogen or (1-2C)alkyl; and 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 when Z 1 is a heterocyclyl group directly attached to a N atom, it is a carbon-attached heterocyclyl; and wherein Z 1 Optionally substituted with one or more substituents selected from the group consisting of: (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 (where y is 0, 1 or 2), -SO 2 N(R e )R f 、-N(R e )SO 2 R f 、-(CH 2 ) z NR e R f (wherein z is 1, 2 or 3) or oxo, and wherein R e and R f are each independently selected from hydrogen, (1-6C)alkyl, (1-6C)haloalkyl or (3-6C)cycloalkyl; and wherein any S atom present in the heterocyclic ring can optionally serve as S(=O), S(=O) 2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, (1-3C)alkyl or (2-3C)alkanoyl; and R 6 is selected from hydrogen, halo, methyl, methoxy and trifluoromethyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: Where R 1 Optionally, on any available carbon atom, one or more R 2 Substituent group substituted; and R 2 and R 3 As defined in claim 1.

3. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: Where R 1 Optionally, on any available carbon atom, one or more R 2 Replace, and R 2 As defined in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 yes: Where R 2 As defined in claim 1.

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R, if present, 2 are 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 ; where q1 is 0 or 1; and Where R 1A and R 1B Each is independently selected from hydrogen or (1-2C)alkyl.

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R, if present, 2 Independently selected from methyl, ethyl or methoxy.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen or (1-3C)alkyl.

8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are linked so that they, together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substitution, Where R 10C is selected from oxo, halo or cyano substituents, or a group of the formula: -[CH 2 ] n -LZ in n is 0 to 2; L is absent or selected from -O-, -S-, -SO-, -SO 2 -、-N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-、-N(R a2 )C(O)-、-N(R a2 )C(O)N(R b2 )-、-S(O) 2 N(R a2 )-or-N(R a2 )SO 2 -, where R a2 and R b2 are each independently selected from hydrogen or methyl; and 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; and wherein Z is optionally substituted by one or more substituents selected from the group consisting of (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, -NR c R d 、-OR c 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-C(O)N(R c )R d 、-N(R c )C(O)R d 、-S(O) y R c (where y is 0, 1 or 2), -SO 2 N(R c )R d 、-N(R c )SO 2 R d 、-(CH 2 ) z NR c R d (wherein z is 1 or 2) or oxo; Where Z 1 Any alkyl moiety in the substituent groups on R 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; and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substitution, where R 10N Yes-S(O) 2 NH 2 Or choose from: (i)-Z 1 ; (ii)-L 1a -Z 1 ;or (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z 1 ; in R 8a and R 8b All are hydrogen; L 1a Selected from -C(O)-, -S(O) 2 -or-S(O) 2 N(R a1 )-, where R a1 is hydrogen or methyl; L 1b Not present or selected from -O-, -S-, -SO-, -SO 2- 、-N(R a2 )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a2 )-、-N(R a2 )C(O)-、-N(R a2 )C(O)N(R b2 )-、-S(O) 2 N(R a2 )-or-N(R a2 )SO 2 , where R a2 and R b2 are each independently selected from hydrogen or methyl; and 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 when Z 1 is a heterocyclyl group directly attached to a N atom, it is a carbon-attached heterocyclyl; and wherein Z 1 is optionally substituted with one or more substituents selected from the group consisting of: (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 (where y is 0, 1 or 2), -SO 2 N(R e )R f 、-N(R e )SO 2 R f 、-(CH 2 ) z NR e R f (wherein z is 1, 2 or 3) or oxo, and wherein R e and R f are each independently selected from hydrogen or (1-2C)alkyl; and wherein any S atom present in the heterocyclic ring can optionally serve as S(=O), S(=O) 2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, (1-3C)alkyl or (2-3C)alkanoyl.

9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are linked so that they, together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substitution, Where R 10C is selected from oxo, halo or cyano substituents, or a group of the formula: -[CH 2 ] n -LZ in n is 0 to 2; L is absent or selected from -O-, -S-, -SO-, -SO 2 -、-N(R a )-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R a )-、-N(R a )C(O)-、-S(O) 2 N(R a )-or-N(R a )SO 2 -, where R a and R b are each independently selected from hydrogen or methyl; and Z is selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, phenyl, 4-7 membered heterocyclyl, 4-7 membered heterocyclyl(1-2C)alkyl or 5- or 6-membered heteroaryl; and wherein Z is optionally substituted by one or more substituents selected from the group consisting of: (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, -NR c R d 、-OR c 、-C(O)R c 、-C(O)OR c 、-OC(O)R c 、-C(O)N(R c )R d 、-N(R c )C(O)R d 、-S(O) y R c (where y is 0, 1 or 2), -SO 2 N(R c )R d 、-N(R c )SO 2 R d 、-(CH 2 ) z NR c R d (wherein z is 1 or 2) or oxo; Where R c and R d are each independently selected from hydrogen or (1-2C)alkyl; and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substitution, where R 10N Yes-S(O) 2 NH 2 Or choose from: (i)-Z 1 ; (ii)-L 1a -Z 1 ;or (iii)-[CR 8a R 8b ] 1-2 -L 1b -Z 1 ; in R 8a and R 8b All are hydrogen; L 1a Selected from -C(O)-, -S(O) 2 -or-S(O) 2 N(R a1 )-, where R a1 It is hydrogen; L 1b Not present or selected from -O-, -S-, -SO-, -SO 2- 、-N(R a2 )-、-C(O)N(R a2 )-、-N(R a2 )C(O)-、-S(O) 2 N(R a2 )-or-N(R a2 )SO 2 , where R a2 is hydrogen; and Z 1 is selected from (1-4C)alkyl, phenyl, 4-7 membered heterocyclyl or 5 or 6 membered heteroaryl, provided that when Z 1 is a heterocyclyl group directly attached to a N atom, it is a carbon-attached heterocyclyl; and wherein Z 1 Optionally substituted with one or more substituents selected from the group consisting of: (1-2C)alkyl, halo, (1-2C)haloalkoxy, cyano, -NR e R f 、-OR e 、-C(O)R e 、-C(O)OR e 、-OC(O)R e 、-C(O)N(R e )R f 、-N(R e )C(O)R f 、-S(O) y R e (where y is 0, 1 or 2), -SO 2 N(R e )R f 、-N(R e )SO 2 R f 、-(CH 2 ) z NR c R d (where z is 1 or 2); and where R e and R f are each independently selected from hydrogen or methyl; and wherein any S atom present in the heterocyclic ring can optionally serve as S(=O), S(=O) 2 or S(=O)(=NR e ) exists, where R e is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl.

10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are linked so that they, together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally substituted on any available carbon atom with one or more R 10C Substituent group substitution, R 10C A group selected from oxo, halo, cyano or the following formula: -LZ in L does not exist, is -O or -N(R a )-, where R a is hydrogen or methyl; and Z is selected from (1-4C)alkyl, 4-7 membered heterocyclyl or (3-6C)cycloalkyl(1-2C)alkyl, wherein any (1-4C)alkyl, 4-7 membered heterocyclyl or (3-6C)cycloalkyl(1-2C)alkyl is optionally substituted with one or more selected from cyano, -NR c R d OR c Substituents, where R c and R d are each independently selected from hydrogen or methyl; and wherein any available N atom is optionally in the form of an N-oxide or optionally replaced by one or more R 10N Substitution, where R 10N is (1-4C)alkyl, And any S atom present in the heterocyclic ring can optionally be present as S(=0).

11. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are connected such that they, together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from any one of the following options: Where * indicates R 4 and R 5 the attached N atom; Q 1 is O, NH, S, S(O), S(O) 2 、S(O)(=NR e ), NR 10N , CH 2 , CHR 10C or C(R 10c ) 2 ; 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 -; Q 3 It 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; and wherein each of the heterocyclic ring systems is optionally replaced by one or more R as defined in any one of claims 1, 8, 9 or 10 10c or R 10N Substituents are group substituted.

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are connected such that they, together with the nitrogen atom to which they are attached, form a heterocyclic ring selected from any one of the following options: Where * indicates R 4 and R 5 the attached N atom; Q 1 is O, NH, S, S(O), S(O) 2 、S(O)(=NR e ), NR 10N , CH 2 , CHR 10C or C(R 10c ) 2 ; Q 4 is O, NH, S, S(O), S(O) 2 、S(O)(=NR e ), NR 10N , CH 2 , CHR 10C or C(R 10c ) 2 ; Where R e is selected from hydrogen, (1-2C)alkyl or (2C)alkanoyl; and wherein each of the heterocyclic ring systems is optionally replaced by one or more R as defined in any one of claims 1, 8, 9 or 10 10c or R 10N Substituents are group substituted.

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are connected so that they, together with the nitrogen atom to which they are attached, form a heterocyclic ring of the following structure: Where * indicates R 4 and R 5 the attached N atom; And each R 10c Independently selected from the options defined in any one of claims 1, 8, 9 or 10.

14. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, halo or methyl.

15. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 6 It's hydrogen.

16. A compound of formula IA, IB, IC, ID, IE or IF: Where R 2 , R 4 , R 5 , R 6 and R 10c Each as defined in any one of claims 1 to 16.

17. A compound selected from any one of the following or a pharmaceutically acceptable salt thereof: (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-piperidinyl)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-pyridinyl]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.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

19. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 for use in therapy.

20. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 for use in: (i) treating proliferative conditions; (ii) treatment of cancer; (iii) treating cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents; (iv) treating cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents selected from the group consisting of: 1) Other forms of cancer immunotherapy and anticancer 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 (e.g., cilizumab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab); and 4) Anti-CTLA4 antibodies (eg, ipilimumab).

21. A method of treating a proliferative disorder in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18.

22. A method of treating cancer in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18.

23. A method of treating a proliferative disorder in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in combination with one or more additional anticancer agents.

24. The method of claim 23, wherein the one or more additional anticancer agents are selected from: 1) Other forms of cancer immunotherapy and anticancer 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 (e.g., cilizumab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab); and 4) Anti-CTLA4 antibodies (eg, ipilimumab).

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