Adenosine A2A receptor antagonist

Abstract

The present invention relates to compounds of formula I, as shown below: wherein R, R, R, R, R, and A are each defined in the present application. The present invention also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of diseases or conditions in which adenosine A receptor activity is implicated, such as cancer. [Formula 1] JPEG2023525762000449.jpg51170

Description

[Technical Field]

[0001] The present invention relates to certain compounds that function as antagonists of the adenosine A2a receptor. In addition, some of the compounds are also antagonists of the A2b receptor. 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 receptor activity is involved, such as cancer. [Background technology]

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

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

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

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

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

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

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

[0009] However, there remains a need for second-generation compounds that are potent adenosine A2a antagonists. In particular, there is a need for compounds that are potent and selective adenosine A2a antagonists, and in some cases, potent and selective adenosine A2a and A2b antagonists. There is also a need for potent adenosine A2a antagonists or adenosine A2a and A2b antagonists that retain their activity in the presence of high concentrations of adenosine present in the tumor microenvironment. [Means for solving the problem]

[0010] 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.

[0011] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0012] According to a further aspect of the present invention there is provided a method of antagonising adenosine A2a receptors (and optionally 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.

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

[0014] According to a further aspect of the present invention there is provided a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0015] According to a further aspect of the present invention there is provided a method of treating a disease or disorder associated with adenosine A2a receptor activity in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0016] According to a further aspect of the present invention there is provided a method of treating a cell proliferative disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

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

[0018] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

[0019] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a cell proliferative condition. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

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

[0021] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use as an adenosine A2a antagonist. In one embodiment, the compound of the present invention is a selective adenosine A2a antagonist. In an alternative embodiment, certain compounds of the present invention are selective adenosine A2a antagonists and adenosine A2b antagonists.

[0022] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which adenosine A2a is involved.

[0023] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a cell proliferative condition. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

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

[0025] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use as an adenosine A2a antagonist.

[0026] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which adenosine A2a is involved.

[0027] According to a further aspect of the present invention there is provided a process for preparing a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

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

[0029] According to a further aspect of the present invention, there is provided a novel intermediate as defined herein, which is suitable for use in any one of the synthetic methods described herein.

[0030] Features, including any suitable and preferred features, associated with one aspect of the invention may also be features, including any suitable and preferred features, associated with any other aspect of the invention.

[0031] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0032] References to "treating" or "treatment" should be understood to include prophylaxis, as well as the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition that occurs in humans who may be afflicted with or predisposed to the condition, disorder, or condition, but who have not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition; (2) arresting the condition, disorder, or condition, i.e., preventing, alleviating, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0033] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0034] As used herein, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups, such as "propyl," are specific to the straight-chain version only, and references to individual branched-chain alkyl groups, such as "isopropyl," are specific to the branched-chain version only. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl. Similar rules apply to other groups, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0035] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0036] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynyl group that is positioned between and serves to connect two other chemical groups. Thus, "(1-6C)alkylene" means a divalent linear saturated hydrocarbon group of 1 to 6 carbon atoms or a divalent branched saturated hydrocarbon group of 3 to 6 carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc.

[0037] "(2-6C)alkenylene" means a divalent linear hydrocarbon group of 2 to 6 carbon atoms or a divalent branched hydrocarbon group of 3 to 6 carbon atoms containing at least one double bond, such as ethenylene and 2,4-pentadienylene.

[0038] "(2-6C)alkynylene" means a divalent linear hydrocarbon group of 2 to 6 carbon atoms or a divalent branched hydrocarbon group of 3 to 6 carbon atoms containing at least one triple bond, such as, for example, ethynylene, propynylene, and butynylene.

[0039] The term "(m-nC)cycloalkyl" means a hydrocarbon ring containing m to n carbon atoms, for example, "(3-6C)cycloalkyl" means a hydrocarbon ring containing 3 to 6 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term "(m-nC)cycloalkyl" also encompasses non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbocyclic ring systems. The term "(m-nC)cycloalkyl" includes both monovalent and divalent species. Monocyclic "(m-nC)cycloalkyl" rings contain about 3 to 12 (preferably 3 to 8, most preferably 5 to 6) ring carbon atoms. Bicyclic "(m-nC)cycloalkyl" contains 7 to 17 ring carbon atoms, preferably 7 to 12 ring carbon atoms. Bicyclic "C m~n The "cycloalkyl" rings can be fused, spiro or bridged ring systems.

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

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

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

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

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

[0045] "Carbon-linked heterocyclyl" means a heterocyclic group, as defined above, that is linked via a carbon atom, rather than a heteroatom such as nitrogen.

[0046] "Spirocyclic ring system" means a compound having at least two rings that have only one atom in common and that are not joined by a bridge.

[0047] "Fused ring system" means a compound in which two rings share two adjacent atoms, in other words, the rings share one covalent bond.

[0048] "Bridged ring system" means a ring system in which two rings share three or more atoms, e.g., Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0049] "Spirobicyclic ring system" means that two ring systems share one common spiro carbon atom, i.e., a heterocycle is linked to an additional carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0050] "Heterocyclyl(1-6C)alkyl" means a heterocyclyl group covalently linked to a (1-6C)alkylene group, both of which are defined herein.

[0051] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic ring incorporating one or more (e.g., 14, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term "heteroaryl" includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more typically 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, e.g., a fused 5-membered and 6-membered ring, or a bicyclic structure formed from two fused 6-membered rings. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring contains up to three heteroatoms, more typically up to two heteroatoms, e.g., a single heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of an indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents on the ring, will be fewer than five.

[0052] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, and isoxazolyl. Examples include noryl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthidinyl, carbazolyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3b]-furanyl-, 2H-furo[3,2b]-pyranyl-, 5H-pyrido[2,3-d]-oxazinyl-, 1H-pyrazolo[4,3-d]-oxazinyl, 4H-imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, -imidazo[2,1b]thiazolyl, and -imidazo[1,2b][1,2,4]-triazinyl. "Heteroaryl" also includes partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other rings is non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2b][1,4]oxazinyl, and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl.

[0053] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0054] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0055] The bicyclic heteroaryl group can be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms; and A cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 ring heteroatoms.

[0056] Particular examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0057] Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0058] "Heteroaryl(1-6C)alkyl" means a heteroaryl group covalently linked to a (1-6C)alkylene group, both of which are defined herein. Examples of heteroaralkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0059] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In certain embodiments, aryl is phenyl.

[0060] The term "aryl(1-6C)alkyl" means an aryl group covalently linked to a (1-6C)alkylene group, both of which are defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, and the like.

[0061] This specification also uses some compound terms to describe groups containing two or more functional groups. Such terms will be understood by those skilled in the art. For example, heterocyclyl(m-nC)alkyl includes (m-nC)alkyl substituted with heterocyclyl.

[0062] The term "optionally substituted" refers to groups, structures, or molecules that are substituted and to groups, structures, or molecules that are not substituted. 1 The term "one / any CH, CH, CH group or heteroatom (i.e., NH) within the group may be substituted" preferably refers to R 1 It means that (any) one of the hydrogen radicals of the group is replaced by the associated defined group.

[0063] Where optional substituents are selected from "one or more" groups, this definition is understood to include all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

[0064] The phrase "compounds of the invention" refers both generically and specifically to the compounds disclosed herein.

[0065] Compounds of the Invention In a first aspect, the present invention relates to a compound having structural formula I, as shown below, or a pharmaceutically acceptable salt, hydrate, or solvate thereof: [ka] [In the formula, R0 is hydrogen or deuterium; R1 is selected from aryl or heteroaryl; (wherein R1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , (CH2) q1 OR 1B , (CH2) q1 C(O)R 1B , (CH2)q1C(O)OR 1B , (CH2) q1 OC(O)R 1B , (CH2) q1 C(O)N(R 1C )R 1B , (CH2) q1 N(R 1C )C(O)R 1B , (CH2) q1 S(O) p R 1B (wherein p is 0, 1 or 2), (CH2) q1 SO2N(R 1C )R 1B or (CH2) q1 N(R 1C )SO2R 1B one or more R independently selected from 1z may be substituted with a substituent, q1 is 0, 1, 2 or 3, and R 1B and R 1C are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl; R2 is hydrogen, cyano, halo, (1-4C) alkyl, (1-4C) haloalkyl, C(O)OR 2A , C(O)NR 2A R 2B aryl, heteroaryl, (2-6C)alkenyl, (2-6C)alkynyl or (1-4C)alkanoyl (where R 2A and R 2B are each independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or CONR 2A R 2B In the group, R 2A and R 2B are linked together to form a heterocycle with the nitrogen atom to which they are attached, alkyl, alkenyl, alkynyl, alkanoyl, aryl, heteroaryl or heterocyclyl group (R 2A and R 2B is formed by (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, amino, (1-4C) aminoalkyl, cyano, (CH2) q2 NR 2D R 2E , (CH2) q2 OR 2D , (CH2) q2 C(O)R 2D , (CH2) q2 C(O)OR 2D , (CH2) q2 OC(O)R 2D , (CH2)q 2C (O)N(R 2E )R 2D , (CH2) q2 N(R 2E )C(O)R 2D , (CH2) q2 S(O)pR 2D (wherein p is 0, 1 or 2), (CH2) q2 SO2N(R 2E )R 2D or (CH2) q2 N(R 2E )SO2R 2D and q2 is 0, 1, 2, or 3; and R 2D and R 2E are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C); R3 is hydrogen, halo, cyano or a group of the formula: -LYL q -Q (In the formula, L is absent or (1-4C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; Y is absent or is O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), C(O)N(R a )O,N(R a )C(O),N(R a )C(O)N(R b ), N(R a )C(O)O,OC(O)N(R a ), C(=NR y )N(R a ), N(R a )C(=NRy), N(R a )C(=NR y )N(R b ), S(O)2N(R a ), N(Ra)SO2, N(R a )SO2N(R b ) or C(O)N(R a )SO2 (where R a and R b are each independently selected from hydrogen or (1-4C) alkyl; R y is selected from hydrogen, (1-4C) alkyl, nitro or cyano, L q is absent or is a (1-4C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino or oxo, Q is hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-8) cycloalkyl, (3-8C) cycloalkenyl, heteroaryl, or heterocyclyl (wherein Q is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, NR c R d , OR c , C(O)Rc , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3), and may be further substituted with one or more substituents independently selected from c , R d and R e are each independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or R c and R d are linked together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy), and / or Q is a group having the formula: -L1-L Q1 -W1 (In the formula, L1 is absent or is a (1-3C)alkylene optionally substituted with one or more substituents selected from a (1-2C)alkyl or an oxo; L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O),N(R f )C(O)N(Rg ), N(R f )C(O)O,OC(O)N(R f ), S(O)2N(R f ), N(R f )SO2 (where R f and R g are each independently selected from hydrogen or (1-2C) alkyl, W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl, or heterocyclyl, where W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1 or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h (where s is 1, 2, or 3), and R h and R i are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl; The alkyl, alkoxy, aryl, heteroaryl, heterocyclyl or cycloalkyl moieties in the substituents present in W1 may be further substituted by one or more halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano or hydroxy groups; or R h and R i are linked together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle optionally substituted with one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy. and optionally substituted with one or more groups of is selected from the group A is selected from CR4 and N (wherein R4 is hydrogen, halo, or halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (CH2) qa NR 4A R 4B , (CH2) qa OR 4A , (CH2) qa C(O)Rc 4A , (CH2) qa C(O)OR 4A , (CH2) qa OC(O)R 4A , (CH2) qa C(O)N(R 4B )R 4A , (CH2) qa N(R 4B )C(O)R 4A , (CH2) qa S(O)pR 4A (wherein p is 0, 1 or 2), (CH2) qa SO2N(R 4B )R 4A or (CH2) qa N(R4B )SO2R 4A and qa is 0, 1, 2, or 3; and R 4A and R 4B are each independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl; The tertiary amine in the compound of formula I may be in the form of an N-oxide, and the nitrogen atom in the pyridine ring may be in the form of an N-oxide; Any S atom present in the heterocycle may be S(=O), S(=O)2 or S(=O)(=NR z ) (where R z may be present as hydrogen, (1-3C) alkyl or (2-3C) alkanoyl).

[0066] Particular compounds of the invention include, for example, compounds of Formula I, or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise specified, each of R, R, R, R, and A has any of the meanings defined above or in any of paragraphs (1) to (55) below: (1) R0 is hydrogen; (2) R0 is deuterium; (3) R1 is selected from aryl or heteroaryl (wherein R1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , (CH2) q1 OR 1B , (CH2) q1 C(O)R 1B , (CH2) q1 C(O)OR 1B , (CH2) q1 OC(O)R 1B , (CH2) q1 C(O)N(R 1C )R 1B , (CH2) q1N(R 1C )C(O)R 1B , (CH2) q1 S(O) p R 1B (wherein p is 0, 1 or 2), (CH2) q1 SO2N(R 1C )R 1B or (CH2) q1 N(R 1C )SO2R 1B one or more R independently selected from 1z may be substituted with a substituent, q1 is 0, 1, 2 or 3, and R 1B and R 1C are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; (4) R1 is selected from aryl or heteroaryl (wherein R1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , OR 1B , C(O)R 1B , C(O)OR 1B ,OC(O)R 1B , C(O)N(R 1C )R 1B , N(R 1C )C(O)R 1B , S(O) p R 1B (wherein p is 0, 1 or 2), SO2N(R 1C )R 1B or N(R 1C )SO2R 1B one or more R independently selected from 1z may be substituted with a substituent, q1 is 0, 1 or 2; R 1B and R 1C are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl; (5) R1 is selected from aryl or heteroaryl (wherein R1 is (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , OR 1B , C(O)R 1B , C(O)OR 1B ,OC(O)R 1B , C(O)N(R 1C )R 1B , N(R 1C )C(O)R 1B , S(O) p R 1B (wherein p is 0, 1 or 2), SO2N(R 1C )R 1B or N(R 1C )SO2R 1B one or more R independently selected from 1z may be substituted with a substituent, q1 is 0, 1 or 2; R 1B and R 1C are each independently selected from hydrogen, (1-2C) alkyl, or (3-4C) cycloalkyl; (5) R1 is selected from aryl or heteroaryl (wherein R1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , (CH2) q1 OR 1B , (CH2) q1 C(O)R 1B , (CH2) q1 C(O)OR 1B , (CH2) q1 OC(O)R 1B , (CH2) q1 C(O)N(R 1C )R 1B , (CH2) q1 N(R 1C )C(O)R 1B , (CH2)q1 S(O) p R 1B (wherein p is 0, 1 or 2), (CH2) q1 SO2N(R 1C )R 1B or (CH2) q1 N(R 1C )SO2R 1B one or more R independently selected from 1z may be substituted with a substituent, q1 is 0, 1 or 2; R 1B and R 1C are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl; (6) R1 is selected from phenyl or 5- or 6-membered heteroaryl (wherein R1 is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , OR 1B , C(O)R 1B , C(O)OR 1B ,OC(O)R 1B , C(O)N(R 1C )R 1B , N(R 1C )C(O)R 1B , S(O) p R 1B (wherein p is 0, 1 or 2), SO2N(R 1C )R 1B or N(R 1C )SO2R 1B one or more R independently selected from 1z may be substituted with a substituent, q1 is 0, 1 or 2; R 1B and R 1C are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl; (7) R1 is selected from aryl or heteroaryl (wherein R1 is (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , OR 1B , C(O)R 1B , C(O)OR 1B ,OC(O)R 1B , C(O)N(R 1C )R 1B , N(R 1C )C(O)R 1B , S(O) p R 1B (wherein p is 0, 1 or 2), SO2N(R 1C )R 1B or N(R 1C )SO2R 1B one or more R independently selected from 1z may be substituted with a substituent, q1 is 0, 1 or 2; R 1B and R 1C are each independently selected from hydrogen, (1-2C) alkyl, or (3-4C) cycloalkyl; (8) R1 is selected from aryl or heteroaryl (wherein R1 is (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , (CH2) q1 OR 1B , (CH2) q1 C(O)R 1B , (CH2) q1 C(O)OR 1B , (CH2) q1 OC(O)R 1B , (CH2) q1 C(O)N(R 1C )R 1B , or (CH2) q1 N(R 1C )C(O)R 1B one or more R independently selected from1z may be substituted with a substituent, q1 is 0, 1, 2 or 3, and R 1B and R 1C are each independently selected from hydrogen or (1-2C); (9) R1 is selected from aryl or heteroaryl (wherein R1 is (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , (CH2) q1 OR 1B or (CH2) q1 C(O)R 1B one or more R independently selected from 1z may be substituted with a substituent, q1 is 0, 1, 2 or 3, and R 1B and R 1C are each independently selected from hydrogen or (1-2C)alkyl; (10) R1 is selected from phenyl or 5- or 6-membered heteroaryl (wherein R1 is (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , OR 1B , C(O)R 1B , C(O)OR 1B ,OC(O)R 1B , C(O)N(R 1C )R 1B , N(R 1C )C(O)R 1B , S(O) p R 1B (wherein p is 0, 1 or 2), SO2N(R 1C )R 1B or N(R 1C )SO2R 1B one or more R independently selected from 1z may be substituted with a substituent, q1 is 0, 1 or 2; R1B and R 1C are each independently selected from hydrogen or (1-2C)alkyl; (11) R1 is one or more R1 as defined in any one of paragraphs (1) to (10) above. 1z It is an optionally substituted phenyl. (12) R1 is one or more R1s defined in any one of paragraphs (1) to (10) above. 1z It is an optionally substituted 5- or 6-membered heteroaryl. (13) R1 is selected from phenyl, furyl, pyridyl, oxazolyl, thiazolyl, isoxazolyl, or oxazolin-2-yl, wherein the phenyl, furyl, pyridyl, or oxazolyl ring is optionally substituted by halo, (1-2C)alkyl, (1-2C)alkoxy, or cyano. (14) R1 is selected from phenyl, furyl, pyridyl, or oxazolyl, wherein the phenyl, furyl, pyridyl, or oxazolyl ring is selected from halo, C 1~2 and optionally substituted by one or more of alkoxy or cyano. (15) R1 is selected from phenyl, furyl, pyridyl, or oxazolyl, wherein the phenyl, furyl, pyridyl, or oxazolyl ring is optionally substituted by halo or cyano. (16) R1 is selected from 3-cyanophenyl, furyl or oxazolyl, thiazolyl, isoxazolyl or oxazolin-2-yl. (17) R1 is 3-cyanophenyl. (18) R2 is hydrogen, cyano, halo, (1-4C) alkyl, (1-4C) haloalkyl, C(O)OR 2A , C(O)NR 2A R 2B , aryl, heteroaryl, (2-6C)alkenyl, (2-6C)alkynyl or (1-4C)alkanoyl (where R 2A and R 2Bare each independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or CONR 2A R 2B In the group, R 2A and R 2B are linked together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle, alkyl, alkenyl, alkynyl, alkanoyl, aryl, heteroaryl or heterocyclyl group (R 2A and R 2B (formed by) is (1-4C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, (CH2) q2 NR 2D R 2E , (CH2) q2 OR 2D , (CH2) q2 C(O)R 2D , (CH2) q2 C(O)OR 2D , (CH2) q2 OC(O)R 2D , (CH2)q2C(O)N(R 2E )R 2D , (CH2) q2 N(R 2E )C(O)R 12D , (CH2) q2 S(O)pR 2D (wherein p is 0, 1 or 2), (CH2) q2 SO2N(R 2E )R 2D or (CH2) q2 N(R 2E )SO2R 2D and optionally substituted by one or more substituents independently selected from q2 is 0, 1 or 2; R 2D and R 2E are each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; When R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide; (19) R2 is hydrogen, cyano, halo, (1-4C) alkyl, (1-4C) haloalkyl, C(O)OR 2A , C(O)NR 2A R 2B , phenyl, 5- or 6-membered heteroaryl, (2-4C)alkenyl or (1-4C)alkanoyl (where R 2A and R 2B are each independently selected from hydrogen, (1-4C) alkyl or (3-6C) cycloalkyl or (3-6C) cycloalkyl(1-2C) alkyl; The alkyl, alkenyl, alkanoyl, phenyl or heteroaryl group is selected from the group consisting of (1-4C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, (CH2) q2 NR 2D R 2E , (CH2) q2 OR 2D , (CH2) q2 C(O)R 2D , (CH2) q2 C(O)OR 2D , (CH2) q2 OC(O)R 2D , (CH2)q 2C (O)N(R 2E )R 2D , (CH2) q2 N(R 2E )C(O)R 12D , (CH2) q2 S(O)pR 2D (wherein p is 0, 1 or 2), (CH2) q2 SO2N(R 2E )R 2D or (CH2) q2 N(R 2E )SO2R 2D and optionally substituted by one or more substituents independently selected from q2 is 0, 1 or 2; R 2D and R 2Eare each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; When R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide; (20) R2 is hydrogen, cyano, halo, (1-2C) alkyl, (1-2C) haloalkyl, C(O)OR 2A , C(O)NR 2A R 2B , phenyl, 5- or 6-membered heteroaryl, or (1-4C)alkanoyl (where R 2A and R 2B are each independently selected from hydrogen or (1-4C)alkyl; The alkyl, alkenyl, alkanoyl, phenyl or heteroaryl group is selected from the group consisting of (1-4C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, (CH2) q2 NR 2D R 2E , (CH2) q2 OR 2D , (CH2) q2 C(O)R 2D , (CH2) q2 C(O)OR 2D , (CH2) q2 OC(O)R 2D , (CH2)q2C(O)N(R 2E )R 2D , (CH2) q2 N(R 2E )C(O)R 12D , (CH2) q2 S(O)pR 2D (wherein p is 0, 1 or 2), (CH2) q2 SO2N(R 2E )R 2D or (CH2) q2 N(R 2E )SO2R 2D and optionally substituted by one or more substituents independently selected from q2 is 0, 1 or 2; R 2D and R 2Eare each independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; When R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide; (21) R2 is cyano, halo, methyl, CF3, C(O)OR 2A , C(O)NR 2A R 2B , 5- or 6-membered heteroaryl or (2-4C)alkanoyl (where R 2A and R 2B are each independently selected from hydrogen or (1-4C)alkyl; The phenyl or heteroaryl group may be (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano, (CH2) q2 NR 2D R 2E , OR 2D , C(O)R 2D , C(O)OR 2D ,OC(O)R 2D , C(O)N(R 2E )R 2D , N(R 2E )C(O)R 12D , S(O)pR 2D (wherein p is 0, 1 or 2), SO2N(R 2E )R 2D or N(R 2E )SO2R 2D and q2 is 0 or 1; and R 2D and R 2E are each independently selected from hydrogen or (1-2C) alkyl; When R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide; (22) R2 is selected from cyano or a 5- or 6-membered heteroaryl optionally substituted as defined above in any one of paragraphs (18) to (21). (wherein when R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide); (23) R2 is selected from cyano or a 5- or 6-membered heteroaryl optionally substituted with one or more substituents independently selected from (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy, or cyano (wherein, when R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide); (24) R2 is a 5- or 6-membered heteroaryl optionally substituted with one or more substituents independently selected from (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy, or cyano (wherein, when R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide); (25) R2 is a 5- or 6-membered heteroaryl optionally substituted with one or more substituents independently selected from (1-2C) alkyl or halo (wherein, when R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide); (26) R2 is a 6-membered heteroaryl optionally substituted with one or more substituents independently selected from (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy, or cyano (wherein, when R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide); (27) R2 is a nitrogen-containing 6-membered heteroaryl optionally substituted with one or more substituents independently selected from (1-2C) alkyl or halo (wherein, when R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide); (28) R2 is a nitrogen-containing 6-membered heteroaryl optionally substituted with one or more substituents independently selected from methyl or chloro (wherein, when R2 is pyridyl, the ring nitrogen atom may be in the form of an N-oxide); (29)R2 is [ka] (In the formula, (i)R 200 and R 201 are each independently selected from (1-2C)alkyl, hydroxy(1-2C)alkyl, aminohalo, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkanoyl or cyano; (ii)R 200 and R 201 are each independently selected from methyl, hydroxymethyl, halo, difluoromethyl, trifluoromethyl, methoxy, acetyl, or cyano; (iii)R 200 is methyl or chloro, and R 201 is selected from methyl, hydroxymethyl, halo, difluoromethyl, trifluoromethyl, methoxy, acetyl or cyano; or [ka] (In the formula, (i)R 201 is (1-2C)alkyl, halo, (1-2C)haloalkyl, hydroxy(1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkanoyl or cyano; (ii)R 201 is methyl, hydroxymethyl, halo, difluoromethyl, trifluoromethyl, methoxy, acetyl or cyano; (iii)R 201 is methyl, hydroxymethyl or chloro; (iv)R 201 is methyl; (v)R 201 is chloro) is; (30) R2 is pyridinyl (e.g., pyridin-4-yl) optionally substituted with one or more substituents independently selected from methyl or chloro; (31) R2 is 2-chloro-6-methylpyridin-4-yl or 2,6-dimethylpyridin-4-yl, i.e., [ka] is; (32) R3 is hydrogen, halo, cyano or a group of the formula: -LYL q -Q (In the formula, L is absent or (1-4C)alkylene; Y is absent or is O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), C(O)N(R a )O,N(R a )C(O),N(R a )C(O)N(R b ), N(R a )C(O)O,OC(O)N(R a ), C(=NR y )N(R a ), N(R a )C(=NRy), N(R a )C(=NR y )N(R b ), S(O)2N(R a ), N(Ra)SO2, N(R a )SO2N(R b ) or C(O)N(R a )SO2 (where R a and R b are each independently selected from hydrogen or (1-4C) alkyl; R y is selected from hydrogen, (1-4C) alkyl, nitro or cyano, L q is absent or is a (1-4C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino or oxo, Q is hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-8) cycloalkyl, (3-8C) cycloalkenyl, heteroaryl, or heterocyclyl (wherein Q is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, NR c R d , OR c , C(O)R c , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3), and R c and R d are each independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or R c and R d are linked together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle optionally substituted with one or more substituents selected from (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy; and / or Q is a group having the formula: -L1-L Q1 -W1 (In the formula, L1 is absent or (1-3C) alkylene; L Q1 is absent or O, S, SO, SO2, N(R f), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O),N(R f )C(O)N(R g ), N(R f )C(O)O,OC(O)N(R f ), S(O)2N(R f ), N(R f )SO2 (where R f and R g are each independently selected from hydrogen or (1-2C) alkyl, W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl, or heterocyclyl, where W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1 or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h (where s is 1, 2, or 3), and R h and R i are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl; The alkyl, alkoxy, aryl, heteroaryl, heterocyclyl or cycloalkyl moieties in the substituents present in W1 may be further substituted by one or more halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano or hydroxy groups; or R h and R i are linked together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocycle optionally substituted with one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy. and optionally substituted with one or more groups of is selected from the group The nitrogen atom in the tertiary amine or pyridyl ring in the R3 group may be in the form of an N-oxide; (33) R3 is hydrogen, halo, cyano or a group of the formula: -LYL q -Q (In the formula, L is absent or (1-4C)alkylene; Y is absent or is O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), C(O)N(R a )O,N(R a )C(O),N(R a )C(O)N(R b ), N(R a )C(O)O,OC(O)N(R a ), C(=NR y )N(R a ), N(R a )C(=NRy), N(R a )C(=NR y )N(R b ), S(O)2N(R a), N(Ra)SO2, N(R a )SO2N(R b ) or C(O)N(R a )SO2 (where R a and R b are each independently selected from hydrogen or (1-4C) alkyl; R y is selected from hydrogen, (1-4C) alkyl, nitro or cyano, L q is absent or is a (1-4C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino or oxo, Q is hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl, aryl, (3-8) cycloalkyl, (3-8C) cycloalkenyl, heteroaryl, or heterocyclyl (wherein Q is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, NR c R d , OR c , C(O)R c , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3), and R c and R dare each independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; and / or Q is a group having the formula: -L1-L Q1 -W1 (In the formula, L1 is absent or (1-3C) alkylene; L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O),N(R f )C(O)N(R g ), N(R f )C(O)O,OC(O)N(R f ), S(O)2N(R f ), N(R f )SO2 (where R f and R g are each independently selected from hydrogen or (1-2C) alkyl, W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl, or heterocyclyl, where W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, aryl, heteroaryl, heterocyclyl, (3-6C)cycloalkyl, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1 or 2), SO2N(R i )R h, N(R i )SO2R h or (CH2) s NR i R h (where s is 1, 2, or 3), and R h and R i are each independently selected from hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, or (3-6C) cycloalkyl(1-2C) alkyl). and optionally substituted with one or more groups of is selected from the group The nitrogen atom in the tertiary amine or pyridyl ring in the R3 group may be in the form of an N-oxide; (34) R3 is hydrogen, halo, cyano or a group of the formula: -LYL q -Q (In the formula, L is absent or (1-2C) alkylene; Y is absent or is O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), C(O)N(R a )O,N(R a )C(O),N(R a )C(O)N(R b ), N(R a )C(O)O,OC(O)N(R a ), C(=NR y )N(R a ), N(R a )C(=NR y ), N(R a )C(=NR y )N(R b ), S(O)2N(R a ), N(Ra)SO2, N(R a )SO2N(R b ) or C(O)N(R a )SO2 (where R a and R b are each independently selected from hydrogen or (1-4C) alkyl; Ry is selected from hydrogen, (1-4C) alkyl, nitro or cyano, L q is absent or is a (1-4C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino or oxo, Q is hydrogen, (1-6C) alkyl, aryl, (3-8) cycloalkyl, heteroaryl, or heterocyclyl (wherein Q is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, NR c R d , OR c , C(O)R c , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3), and R c and R d are each independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; and / or Q is a group having the formula: -L1-L Q1 -W1 (In the formula, L1 is absent or (1-2C) alkylene; L Q1 is absent or O, S, SO, SO2, N(R f), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O),N(R f )C(O)N(R g ), N(R f )C(O)O,OC(O)N(R f ), S(O)2N(R f ), N(R f )SO2 and R f and R g are each independently selected from hydrogen or (1-2C) alkyl; W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl, and W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1 or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h (where s is 1, 2, or 3), and R h and R i are each independently selected from hydrogen or (1-4C) alkyl. and optionally substituted with one or more groups of is selected from the group The nitrogen atom in the tertiary amine or pyridyl ring in the R3 group may be in the form of an N-oxide; (35) R3 is hydrogen, halo, cyano or a group of the formula: -LYL q -Q (In the formula, L is absent or (1-2C) alkylene; Y is absent or O, N(R a ), C(O), C(O)O, C(O)N(R a ), N(R a )C(O), C(O)N(R a )O,N(R a )C(O),N(R a )C(O)N(R b ), N(R a )C(O)O,OC(O)N(R a ), C(=NR y )N(R a ), N(R a )C(=NRy), N(R a )C(=NR y )N(R b ), S(O)2N(R a ), N(Ra)SO2, N(R a )SO2N(R b ) or C(O)N(R a )SO2 (where R a and R b are each independently selected from hydrogen or (1-4C) alkyl; R y is selected from hydrogen, (1-4C) alkyl, nitro or cyano, L q is absent or is a (1-4C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino or oxo, Q is hydrogen, (1-6C) alkyl, aryl, (3-8) cycloalkyl, heteroaryl, or heterocyclyl (wherein Q is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, NR c R d , OR c , C(O)Rc , C(O)OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3), and R c and R d are each independently selected from hydrogen or (1-6C) alkyl, and / or Q is a group having the formula: -L1-L Q1 -W1 (In the formula, L1 is absent or (1-2C) alkylene; L Q1 does not exist, W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl, and W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (wherein r is 0, 1 or 2), and R h and R iare each independently selected from hydrogen or (1-4C) alkyl. and optionally substituted with one or more groups of is selected from the group The nitrogen atom in the tertiary amine or pyridyl ring in the R3 group may be in the form of an N-oxide; (35a) R3 is hydrogen, halo, cyano or a group of the formula: -LYL q -Q (In the formula, L is absent or (1-2C) alkylene; Y is absent or N(R a ), C(O), C(O)N(R a ), N(R a )C(=NR y )N(R b ), C(O)N(R a )O or N(R a )C(O)N(R b ) (where R a and R b are each independently selected from hydrogen or (1-4C) alkyl; R y is selected from hydrogen, (1-4C) alkyl or cyano, L q is absent or is a (1-4C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino or oxo, Q is hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (3-8) cycloalkyl, or heterocyclyl (wherein Q is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, C(O)R c , C(O)OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c(wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3), and R c and R d are each independently selected from hydrogen or (1-6C) alkyl, and / or Q is a group having the formula: -L1-L Q1 -W1 (In the formula, L1 is absent or (1-2C) alkylene; L Q1 does not exist, W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl, and W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (wherein r is 0, 1 or 2), and R h and R i are each independently selected from hydrogen or (1-4C) alkyl. and optionally substituted with one or more groups of is selected from the group The nitrogen atom in the tertiary amine or pyridyl ring in the R3 group may be in the form of an N-oxide; (36) R3 is a group represented by the formula: -LYL q -Q (In the formula, L does not exist, Y is N(R a ) or C(O)N(R a ) and L q does not exist, Q is (1-6C) alkyl or (3-8) cycloalkyl (where Q is halo, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3), and R c and R d are each independently selected from hydrogen or (1-6C) alkyl. is the basis of; (37) R3 is a group represented by the formula: -LYL q -Q (In the formula, L does not exist, Y is N(R a ) or C(O)N(R a ) and L q does not exist, Q is (1-6C) alkyl (where Q is halo, cyano, NR c R d , ORc , C(O)OR c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c and R c and R d are each independently selected from hydrogen or (1-6C) alkyl. is the basis of; (38) R3 is a group represented by the formula: -LYL q -Q (In the formula, L does not exist, Y is N(R a ) or C(O)N(R a ) and L q does not exist, Q is (1-6C) alkyl (where Q is one or more OR c and R c is selected from hydrogen or (1-4C) alkyl) is the basis of; (39) R3 is a group represented by the formula: -LYL q -Q (In the formula, L does not exist, Y is N(R a ) or C(O)N(R a ) and L q does not exist, Q is (1-6C) alkyl (wherein Q may be further substituted with one or more OH). is the basis of; (40) R3 is a group represented by the formula: [ka] (In the formula, R 3a is hydrogen or methyl) is the basis of; (41) R3 is halo or a group of the formula: -LYQ (In the formula, L does not exist, Y is absent or is O, S, SO, SO2, N(R a ), C(O), C(O)O, OC(O), C(O)N(R a ), C(O)N(R a )O,N(R a )C(O), S(O)2N(R a ), N(R a )SO2 or N(R a )SO2N(R b ) (where R a and R b are each independently selected from hydrogen or (1-2C) alkyl, Q is (1-4C) alkyl, heteroaryl, or heterocyclyl (wherein Q is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3), and may be further substituted with one or more substituents independently selected from c , R d and R e are each independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; Rc and R d are linked together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, amino, cyano, or hydroxy), and / or Q is a group having the formula: -L1-L Q1 -W1 (In the formula, L1 is absent or is a (1-3C)alkylene optionally substituted with one or more substituents selected from a (1-2C)alkyl or an oxo; L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O),N(R f )C(O)O,OC(O)N(R f ), S(O)2N(R f ) or N(R f )SO2 (where R f and R g are each independently selected from hydrogen or (1-2C) alkyl, W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl, or heterocyclyl, where W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, cyano, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h(where r is 0, 1 or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h (where s is 1, 2, or 3), and R h and R i are each independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl, and the alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, or cycloalkyl moiety in the substituent present in W1 may be further substituted with one or more halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy groups. and optionally substituted with a group is selected from the group A nitrogen atom in a tertiary amine or pyridyl ring present in an R3 group may be in the form of an N-oxide; (42) R3 is halo or a group of the formula: -Q (In the formula, Q is heteroaryl or heterocyclyl (wherein Q is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2Rc or (CH2) q NR c R d (wherein q is 1, 2, or 3), and may be further substituted with one or more substituents independently selected from c , R d and R e are each independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; R c and R d are linked together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy), and / or Q is a group having the formula: -L1-L Q1 -W1 (In the formula, L1 is absent or is a (1-3C)alkylene optionally substituted with one or more substituents selected from a (1-2C)alkyl or an oxo; L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O),N(R f )C(O)O,OC(O)N(R f ), S(O)2N(R f ) or N(R f )SO2 and R f and R g are each independently selected from hydrogen or (1-2C) alkyl; W1 is hydrogen, (1-4C) alkyl, aryl, heteroaryl or heterocyclyl; W1 is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, cyano, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1 or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h (where s is 1, 2, or 3), and R h and R i are each independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; or R h and R i are linked together with the nitrogen atom to which they are attached so as to form a 4- to 7-membered heterocycle optionally substituted with one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy; The alkyl, alkoxy, aryl, heteroaryl, heterocyclyl or cycloalkyl moieties in the substituents present in W1 may be further substituted with one or more halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano or hydroxy groups. and optionally substituted with a group is selected from the group A nitrogen atom in a tertiary amine or pyridyl ring present in an R3 group may be in the form of an N-oxide; (43) R3 is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3) c , R d and R e are each independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; R c and R d are linked together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, amino, cyano, or hydroxy), and / or R3 has the formula: -L1-L Q1 -W1 (In the formula, L1 is absent or is a (1-3C)alkylene optionally substituted with one or more substituents selected from a (1-2C)alkyl or an oxo; L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O),N(R f )C(O)O,OC(O)N(R f ), S(O)2N(R f ) or N(R f )SO2 and R f and R g are each independently selected from hydrogen or (1-2C) alkyl; W1 is hydrogen, (1-4C) alkyl, aryl, heteroaryl or heterocyclyl, and W1 is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, cyano, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1 or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h (where s is 1, 2, or 3), and R h and R i are each independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; or R h and R iare linked together with the nitrogen atom to which they are attached so as to form a 4- to 7-membered heterocycle optionally substituted with one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy; The alkyl, alkoxy, aryl, heteroaryl, heterocyclyl or cycloalkyl moieties in the substituents present in W1 may be further substituted with one or more halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano or hydroxy groups. and optionally substituted with a group A nitrogen atom in a tertiary amine or pyridyl ring present in an R3 group may be in the form of an N-oxide; (44) R3 is a nitrogen-bonded heterocycle selected from a 4- to 7-membered heterocyclic ring, a 9- to 15-membered bicyclic ring, or a 9- to 15-membered spirocyclic ring. (wherein R3 is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3), and may be further substituted with one or more substituents independently selected fromc , R d and R e are each independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; R c and R d are linked together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, amino, cyano, or hydroxy), and / or R3 has the formula: -L1-L Q1 -W1 (In the formula, L1 is absent or is a (1-3C)alkylene optionally substituted with one or more substituents selected from a (1-2C)alkyl or an oxo; L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O),N(R f )C(O)O,OC(O)N(R f ), S(O)2N(R f ) or N(R f )SO2 and R f and R g are each independently selected from hydrogen or (1-2C) alkyl; W1 is hydrogen, (1-4C) alkyl, aryl, heteroaryl or heterocyclyl, and W1 is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, cyano, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i)R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1 or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h (where s is 1, 2, or 3), and R h and R i are each independently selected from hydrogen, (1-4C) alkyl or (3-6C) cycloalkyl; or R h and R i are linked together with the nitrogen atom to which they are attached so as to form a 4- to 7-membered heterocycle optionally substituted with one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy; The alkyl, alkoxy, aryl, heteroaryl, heterocyclyl or cycloalkyl moieties in the substituents present in W1 may be further substituted with one or more halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano or hydroxy groups. and optionally substituted with a group A nitrogen atom in a tertiary amine or pyridyl ring present in an R3 group may be in the form of an N-oxide. (45) R3 is a heterocyclyl selected from piperazinyl, piperidinyl, pyrrolidinyl, oxetanyl, morpholinyl, diazepanyl, azetidinyl (each of which may be further substituted with one or more R6 groups), or R3 has one of the following structures: [ka] where b is an integer selected from 0, 1, 2, 3, or 4; Each R group is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(R d )SO2R c or (CH2) q NR c R d where q is 1, 2 or 3, or a compound of the formula: -L1-L Q1 -W1 are independently selected from the group R c , R d and R e are each independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl, or R c and R d are linked together with the nitrogen atom to which they are attached so as to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, amino, cyano, or hydroxy; where: L1 is absent or is a (1-3C)alkylene optionally substituted with one or more substituents selected from a (1-2C)alkyl or an oxo; L Q1is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R f ), N(R f )C(O),N(R f )C(O)O,OC(O)N(R f ), S(O)2N(R f ) or N(R f )SO2 and R f and R g are each independently selected from hydrogen or (1-2C) alkyl; W1 is hydrogen, (1-4C) alkyl, aryl, heteroaryl or heterocyclyl, and W1 is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxy, cyano, NR h R i , OR h , C(O)R h , C(O)OR h ,OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1 or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h (where s is 1, 2, or 3), and R h and R i are each independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; or R h and R iare linked together with the nitrogen atom to which they are attached so as to form a 4- to 7-membered heterocycle optionally substituted with one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy; The alkyl, alkoxy, aryl, heteroaryl, heterocyclyl or cycloalkyl moieties in the substituents present in W1 may be further substituted by one or more halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano or hydroxy groups; A nitrogen atom in a tertiary amine or pyridyl ring present in an R3 group may be in the form of an N-oxide. (46) R3 is piperazinyl, piperidinyl, pyrrolidinyl, oxetanyl, morpholinyl, diazepanyl, azetidinyl, or a heterocyclyl selected from one of the following structures: [ka] . (47) R3 is a nitrogen-linked heterocycle selected from a 4- to 7-membered heterocyclic ring system, a 9- to 15-membered bicyclic ring system, or a 9- to 15-membered spirocyclic ring system; where R3 is oxo, (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c , N(Rd )SO2R c or (CH2) q NR c R d (wherein q is 1, 2, or 3), R c , R d and R e are each independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl, or R c and R d are linked together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, amino, cyano, or hydroxy. (48) R3 is a heterocyclyl selected from piperazinyl, piperidinyl, pyrrolidinyl, oxetanyl, morpholinyl, diazepanyl, azetidinyl (each of which may be further substituted with one or more R6 groups), or R3 has one of the following structures: [ka] where b is an integer selected from 0, 1, 2, 3, or 4; Each R group is (1-4C) alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c ,OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (wherein p is 0, 1 or 2), SO2N(R d )R c, N(R d )SO2R c or (CH2) q NR c R d where q is 1, 2, or 3; R c and R d are each independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl, or R c and R d are linked together with the nitrogen atom to which they are attached so as to form a 4- to 6-membered heterocycle optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-2C)alkylamino, di-[(1-2C)alkyl]amino, amino, cyano, or hydroxy; wherein the tertiary amine present in the R3 group may be in the form of an N-oxide. (49) R3 is piperazinyl, piperidinyl, pyrrolidinyl, oxetanyl, morpholinyl, diazepanyl, azetidinyl, or a heterocyclyl selected from one of the following structures: [ka] . (50) A is selected from CR4 and N; where R4 is hydrogen, halo, or halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, amino, cyano, (CH2) qa NR 4A R 4B , (CH2) qa OR 4A , (CH2) qa C(O)Rc 4A , (CH2) qa C(O)OR 4A , (CH2) qa OC(O)R 4A , (CH2) qa C(O)N(R 4B )R 4A , (CH2) qa N(R4B )C(O)R 4A , (CH2) qa S(O) p R 4A (wherein p is 0, 1 or 2), (CH2) qa SO2N(R 4B )R 4A or (CH2) qa N(R 4B )SO2R 4A and qa is 0, 1, 2, or 3; and R 4A and R 4B are each independently selected from hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl; (51) A is selected from CR4 and N; wherein R4 is hydrogen, halo, or (1-2C)alkyl optionally substituted with one or more substituents selected from halo; (52) A is selected from CR4 and N; where R4 is hydrogen, methyl or halo; (53) A is CR4, where R4 is hydrogen, methyl, fluoro, or chloro; (54) A is CH; (55)A is N.

[0067] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or a monocyclic, bicyclic or bridged heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0068] Suitably, the heteroaryl is a 5 or 6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0069] Preferably, the heterocyclyl group is a 4-, 5-, 6-, 7-, or 8-membered heterocyclyl ring containing 1, 2, or 3 heteroatoms selected from N, O, or S. Most preferably, the heterocyclyl group is a 5-, 6-, or 7-membered ring containing 1, 2, or 3 heteroatoms selected from N, O, or S (e.g., morpholinyl (e.g., 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl, or pyrrolidinonyl).

[0070] Preferably, the aryl group is phenyl.

[0071] Suitably, R is as defined in paragraph (1) or (2) above. In one embodiment, R is hydrogen. In another embodiment, R is deuterium.

[0072] Preferably, R1 is as defined in any one of paragraphs (3) to (17) above. More preferably, R1 is as defined in any one of paragraphs (13) to (17) above. Most preferably, R1 is as defined in paragraphs (13) or (17) above.

[0073] Preferably, R2 is as defined in any one of paragraphs (18) to (31). More preferably, R2 is cyano or as defined in any one of paragraphs (25) to (31). Most preferably, R2 is as defined in paragraphs (25) or (31).

[0074] Preferably, R3 is as defined in any one of paragraphs (32) to (49). More preferably, R3 is as defined in any one of paragraphs (35) to (40) (e.g., any one of paragraphs (35) to (39)). Most preferably, R2 is as defined in paragraph (39) or (40).

[0075] Preferably, A is as defined in any one of paragraphs (50) to (55). Most preferably, A is as defined in paragraphs (51), (54) or (55).

[0076] In certain groups of compounds of formula I above, R1 is as defined in any one of paragraphs (3), (4), (5), (10), (13) or (17), and R0, R2, R3 and A each have any one of the definitions herein.

[0077] In certain groups of compounds of formula I above, R2 is as defined in any one of paragraphs (18), (19), (20), (25), (29), (30) or (31), and R0, R1, R3 and A each have any one of the definitions herein.

[0078] In certain groups of compounds of formula I above, R3 is as defined in any one of paragraphs (32), (33), (34), (35), (35a), (38), (39) or (40), and R0, R1, R2 and A each have any one of the definitions herein.

[0079] In certain groups of compounds of formula I above, A is as defined in any one of paragraphs (50), (51), (54) or (55), and R0, R1, R2 and R3 each have any one of the definitions herein.

[0080] In one embodiment of the compound of formula I above, R0 is as defined in paragraph (1) or (2); R1 is as defined in paragraphs (3) through (17) above; R2 is as defined in any one of paragraphs (18) to (31) above; R3 is as defined in any one of paragraphs (32) to (49) above, and A is as defined in any one of paragraphs (50) to (55) above.

[0081] In a particular group of compounds of formula I above, R0 is as defined in paragraph (1) or (2); R1 is as defined in paragraphs (13)-(17) above; R2 is as defined in any one of paragraphs (25) to (31) above; R3 is as defined in any one of paragraphs (35) to (40) above, and A is as defined in any one of paragraphs (51), (54) or (55) above.

[0082] In a particular group of compounds of formula I above, R0 is as defined in paragraph (1) or (2); R1 is as defined in paragraph (5) above; R2 is as defined in paragraph (19) above; R3 is as defined in paragraph (33) above, and A is as defined in paragraph (51) above.

[0083] In a particular group of compounds of formula I above, R0 is as defined in paragraph (1); R1 is as defined in paragraph (10) above; R2 is as defined in paragraph (20) above; R3 is as defined in paragraph (34) above, and A is as defined in paragraph (51) above.

[0084] In a particular group of compounds of formula I above, R0 is as defined in paragraph (1); R1 is as defined in paragraph (13) above; R2 is as defined in paragraph (25) above; R3 is as defined in paragraph (35) or (35a) above, and A is as defined in paragraph (53) above.

[0085] In a particular group of compounds of formula I above, R0 is as defined in paragraph (1); R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (29) above; R3 is as defined in paragraph (38) above, and A is as defined in paragraph (54) above.

[0086] In a particular group of compounds of the invention, the compounds have the structural formula Ib [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (wherein R0, R1, R2 and R3 are each as defined above, and R4 is hydrogen, methyl, fluoro or chloro).

[0087] In one embodiment of the compound of formula Ib: R0 is as defined in paragraph (1) or (2); R1 is as defined in any one of paragraphs (3) through (17) above; R2 is as defined in any one of paragraphs (18) to (31) above; R3 is as defined in any one of paragraphs (32) to (40) above, and R4 is hydrogen, methyl, fluoro or chloro.

[0088] In one embodiment of the compound of formula Ib: R0 is as defined in paragraph (1) or (2); R1 is as defined in any one of paragraphs (3) through (17) above; R2 is as defined in any one of paragraphs (18) to (31) above; R3 is as defined in any one of paragraphs (32) to (49) above, and R4 is hydrogen, methyl, fluoro or chloro.

[0089] In another embodiment of the compound of formula Ib, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (13) above; R2 is as defined in paragraph (25) above; R3 is as defined in paragraph (35) above, and R4 is hydrogen.

[0090] In another embodiment of the compound of formula Ib, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (38), (39) or (40) above, and R4 is hydrogen.

[0091] In another embodiment of the compound of formula Ib, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (40) above, and R4 is hydrogen.

[0092] In a particular group of compounds of the invention, the compounds have the structural formula Ic [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (wherein R0, R1, R2 and R3 are each as defined above).

[0093] In one embodiment of the compound of formula Ic: R0 is as defined in paragraph (1) or (2); R1 is as defined in any one of paragraphs (3) through (17) above; R2 is as defined in any one of paragraphs (18) to (31) above, and R3 is as defined in any one of paragraphs (32) to (40) above.

[0094] In another embodiment of the compound of formula Ic, R0 is as defined in paragraph (1) or (2); R1 is as defined in any one of paragraphs (3) through (17) above; R2 is as defined in any one of paragraphs (18) to (31) above, and R3 is as defined in any one of paragraphs (32) to (49) above.

[0095] In another embodiment of the compound of formula Ic, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (13) above; R2 is as defined in paragraph (25) above, and R3 is as defined in paragraph (35) above.

[0096] In another embodiment of the compound of formula Ic, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above, and R3 is as defined in paragraphs (38), (39) or (40) above.

[0097] In another embodiment of the compound of formula Ic, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (30) above, and R3 is as defined in paragraph (40) above.

[0098] In a particular group of compounds of the invention, the compounds have the structural formula Id [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (wherein A, R1, R2 and R3 are each as defined above).

[0099] In one embodiment of the compound of formula Id, R1 is as defined in any one of paragraphs (3) through (17) above; R2 is as defined in any one of paragraphs (18) to (31) above; R3 is as defined in any one of paragraphs (32) to (40) above, and A is as defined in any one of paragraphs (50) to (55) above.

[0100] In one embodiment of the compound of formula Id, R1 is as defined in any one of paragraphs (3) through (17) above; R2 is as defined in any one of paragraphs (18) to (31) above; R3 is as defined in any one of paragraphs (32) to (49) above, and A is as defined in any one of paragraphs (50) to (55) above.

[0101] In another embodiment of the compound of formula Id, R1 is as defined in paragraph (13) above; R2 is as defined in paragraph (25) above; R3 is as defined in paragraph (35) above, and A is as defined in paragraph (51) above.

[0102] In another embodiment of the compound of formula Id, R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above, and R3 is as defined in paragraph (38), (39) or (40) above, and A is as defined in paragraph (54) or (55) above.

[0103] In another embodiment of the compound of formula Id, R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above, and R3 is as defined in paragraph (40) above, and A is as defined in paragraph (54) or (55) above.

[0104] In a particular group of compounds of the invention, the compounds have the structural formula Ie [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (Wherein A, R0, R2, R3 and R 1Z are each as defined above, and m is 0, 1, or 2).

[0105] In one embodiment of the compound of formula Ie: R0 is as defined in paragraph (1) or (2) above; R 1Z is as defined in any one of paragraphs (3) through (10) above; m is 0, 1 or 2; R2 is as defined in any one of paragraphs (18) to (31) above; R3 is as defined in any one of paragraphs (32) to (40) above, and A is as defined in any one of paragraphs (50) to (55) above.

[0106] In one embodiment of the compound of formula Ie: R0 is as defined in paragraph (1) or (2) above; R 1Z is as defined in any one of paragraphs (3) through (10) above; m is 0, 1 or 2; R2 is as defined in any one of paragraphs (18) to (31) above; R3 is as defined in any one of paragraphs (31) to (49) above, and A is as defined in any one of paragraphs (50) to (55) above.

[0107] In another embodiment of the compound of formula Ie, R0 is as defined in paragraph (1) above; R 1z is halo or cyano; m is 0 or 1; R2 is as defined in paragraph (25) above; R3 is as defined in paragraph (35) above, and A is as defined in paragraph (51) above.

[0108] In another embodiment of the compound of formula Ie, R0 is as defined in paragraph (1) above; R 1z is cyano, m is 1, R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (38), (39) or (40) above, and A is as defined in paragraph (54) or (55) above.

[0109] In another embodiment of the compound of formula Ie, R0 is as defined in paragraph (1) above; R 1z is cyano, m is 1, R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (40) above, and A is as defined in paragraph (54) or (55) above.

[0110] In a particular group of compounds of the invention, the compound has the structural formula If [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (Wherein A, R0, R2, R3 and R 1Z are as defined above).

[0111] In one embodiment of the compound of formula If: R0 is as defined in paragraph (1) or (2) above; R 1Z is as defined in any one of paragraphs (3) through (10) above; R2 is as defined in any one of paragraphs (18) to (31) above; R3 is as defined in any one of paragraphs (32) to (40) above, and A is as defined in any one of paragraphs (50) to (55) above.

[0112] In one embodiment of the compound of formula If: R0 is as defined in paragraph (1) or (2) above; R 1Zis as defined in any one of paragraphs (3) through (10) above; R2 is as defined in any one of paragraphs (18) to (31) above; R3 is as defined in any one of paragraphs (32) to (49) above, and A is as defined in any one of paragraphs (50) to (55) above.

[0113] In another embodiment of the compound of formula If, R0 is as defined in paragraph (1) above; R 1z is halo or cyano; R2 is as defined in paragraph (25) above; R3 is as defined in paragraph (35) above, and A is as defined in paragraph (51).

[0114] In another embodiment of the compound of formula If, R0 is as defined in paragraph (1) above; R 1z is cyano, R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (38), (39) or (40) above, and A is as defined in paragraph (54) or (55) above.

[0115] In another embodiment of the compound of formula If, R0 is as defined in paragraph (1) above; R 1z is cyano, R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (40) above, and A is as defined in paragraph (54) or (55) above.

[0116] In a particular group of compounds of the invention, the compounds have the structural formula Ig [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (wherein A, R0, R1 and R3 are as defined above, and R 200 and R 201 are each independently selected from hydrogen, methyl, hydroxymethyl, halo, trifluoromethyl, difluoromethyl, methoxy or acetyl. 200 and R 201 are each independently selected from hydrogen, methyl, or halo.

[0117] In one embodiment of the compound of formula Ig: R0 is as defined in paragraph (1) or (2) above; R1 is as defined in any one of paragraphs (3) through (17) above; R3 is as defined in any one of paragraphs (32) to (49) above; A is as defined in any one of paragraphs (50) to (55); and R 200 and R 201 are each independently selected from hydrogen, methyl, hydroxymethyl, or halo.

[0118] In one embodiment of the compound of formula Ig: R0 is as defined in paragraph (1) or (2) above; R1 is as defined in any one of paragraphs (3) through (17) above; R3 is as defined in any one of paragraphs (32) to (40) above; A is as defined in any one of paragraphs (50) to (55); and R 200 and R 201 are each independently selected from hydrogen, methyl, hydroxymethyl, or halo.

[0119] In another embodiment of the compound of formula Ig, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (13) above; R2 is as defined in paragraph (25) above; R3 is as defined in paragraph (35) above; A is as defined in paragraph (51), and R 200 and R 201 are each independently selected from methyl or chloro.

[0120] In another embodiment of the compound of formula Ig, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (38), (39) or (40) above; A is as defined in paragraph (54) or (55) above, and R 200 is methyl and R 201 is chloro or methyl.

[0121] In another embodiment of the compound of formula Ig, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (40) above; A is as defined in paragraph (54) or (55) above, and R 200 is methyl and R 201 is chloro or methyl.

[0122] In a particular group of compounds of the invention, the compounds have the structural formula Ig2 [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (Wherein A, R0, R1 and R3 are as defined above, R 201 is selected from hydrogen, methyl, halo, trifluoromethyl, difluoromethyl, methoxy or acetyl).

[0123] In one embodiment of the compound of formula Ig2,

[0124] In one embodiment of the compound of formula Ig2, R0 is as defined in paragraph (1) or (2) above; R1 is as defined in any one of paragraphs (3) through (17) above; R3 is as defined in any one of paragraphs (32) to (40) above; A is as defined in any one of paragraphs (50) to (55); and R 201 is selected from hydrogen, methyl or halo.

[0125] In one embodiment of the compound of formula Ig2, R0 is as defined in paragraph (1) or (2) above; R1 is as defined in any one of paragraphs (3) through (17) above; R3 is as defined in any one of paragraphs (32) to (49) above; A is as defined in any one of paragraphs (50) to (55) above, and R 201 is selected from methyl, methoxy or halo.

[0126] In another embodiment of the compound of formula Ig2, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (13) above; R3 is as defined in paragraph (35) above; A is as defined in paragraph (51) above, and R 201 is selected from methyl or halo.

[0127] In another embodiment of the compound of formula Ig2, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (38), (39) or (40) above, and A is as defined in paragraph (54) or (55) above, and R 201 is selected from methyl or chloro.

[0128] In another embodiment of the compound of formula Ig2, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (40) above; A is as defined in paragraph (54) or (55) above, and R 201 is selected from methyl or chloro.

[0129] In a particular group of compounds of the invention, the compounds have the structural formula Ih [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (wherein A, R0, R1 and R3 are each as defined above).

[0130] In one embodiment of the compound of formula Ih: R0 is as defined in paragraph (1) or (2) above; R1 is as defined in any one of paragraphs (3) through (17) above; R3 is as defined in any one of paragraphs (32) to (40) above, and A is as defined in any one of paragraphs (50) to (55).

[0131] In one embodiment of the compound of formula Ih: R0 is as defined in paragraph (1) or (2) above; R1 is as defined in any one of paragraphs (3) through (17) above; R3 is as defined in any one of paragraphs (32) to (49) above, and A is as defined in any one of paragraphs (50) to (55).

[0132] In another embodiment of the compound of formula Ih, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (13) above; R2 is as defined in paragraph (25) above; R3 is as defined in paragraph (35) above, and A is as defined in paragraph (51).

[0133] In another embodiment of the compound of formula Ih, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (38), (39) or (40) above, and A is as defined in paragraph (54) or (55).

[0134] In another embodiment of the compound of formula Ih, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (30) above; R3 is as defined in paragraph (39) or (40) above, and A is as defined in (52) or (53).

[0135] In a particular group of compounds of the invention, the compounds have the structural formula Ih [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (wherein A, R0, R1 and R3 are each as defined above).

[0136] In one embodiment of the compound of formula Ih2, R0 is as defined in paragraph (1) or (2) above; R1 is as defined in any one of paragraphs (3) through (17) above; R3 is as defined in any one of paragraphs (32) to (40) above, and A is as defined in any one of paragraphs (50) to (55) above.

[0137] In one embodiment of the compound of formula Ih2, R0 is as defined in paragraph (1) or (2) above; R1 is as defined in any one of paragraphs (3) through (17) above; R3 is as defined in any one of paragraphs (32) to (49) above, and A is as defined in any one of paragraphs (50) to (55).

[0138] In another embodiment of the compound of formula Ih2, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (13) above; R3 is as defined in paragraph (35) above, and A is as defined in paragraph (51) above.

[0139] In another embodiment of the compound of formula Ih2, R0 is as defined in paragraph (1) above; R1 is as defined in any one of paragraphs (14) to (17) above; R3 is as defined in paragraph (38), (39) or (40) above, and A is as defined in (52) or (53).

[0140] In another embodiment of the compound of formula Ih2, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R3 is as defined in paragraph (38), (39) or (40) above, and A is as defined in (52) or (53).

[0141] In another embodiment of the compound of formula Ih2, R0 is as defined in paragraph (1) above; R1 is as defined in paragraph (17) above; R2 is as defined in paragraph (31) above; R3 is as defined in paragraph (40) above, and A is as defined in (52) or (53).

[0142] In a particular group of compounds of the invention, the compounds have the structural formula Ii [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (Wherein A, R0, R3 and R 1Z are as defined above).

[0143] In one embodiment of the compound of formula Ii: R0 is as defined in paragraph (1) or (2) above; R 1Z is as defined in any one of paragraphs (3) through (10) above; R3 is as defined in any one of paragraphs (32) to (49) above, and A is as defined in any one of paragraphs (50) to (55).

[0144] In one embodiment of the compound of formula Ii: R0 is as defined in paragraph (1) or (2) above; R 1Z is as defined in any one of paragraphs (3) through (10) above; R3 is as defined in any one of paragraphs (32) to (40) above, and A is as defined in any one of paragraphs (50) to (55).

[0145] In another embodiment of the compound of formula Ii, R0 is as defined in paragraph (1) above; R 1z is halo or cyano; R3 is as defined in paragraph (35) above, and A is as defined in paragraph (51) above.

[0146] In another embodiment of the compound of formula Ii, R0 is as defined in paragraph (1) above; R 1z is cyano, R3 is as defined in paragraph (38), (39) or (40) above, and A is as defined in paragraph (54) or (55) above.

[0147] In another embodiment of the compound of formula Ii, R0 is as defined in paragraph (1) above; R 1z is cyano, R3 is as defined in paragraph (40) above, and A is as defined in paragraph (54) or (55) above.

[0148] In a particular group of compounds of the invention, the compounds have the structural formula Ii2 [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (Wherein A, R0, R3 and R 1Z are as defined above).

[0149] In one embodiment of the compound of formula Ii2, R0 is as defined in paragraph (1) or (2) above; R 1Z is as defined in any one of paragraphs (3) through (10) above; R3 is as defined in any one of paragraphs (32) to (40) above, and A is as defined in any one of paragraphs (50) to (55).

[0150] In one embodiment of the compound of formula Ii2, R0 is as defined in paragraph (1) or (2) above; R 1Zis as defined in any one of paragraphs (3) through (10) above; R3 is as defined in any one of paragraphs (32) to (49) above, and A is as defined in any one of paragraphs (50) to (55).

[0151] In another embodiment of the compound of formula Ii2, R0 is as defined in paragraph (1) above; R 1z is halo or cyano; R3 is as defined in paragraph (35) above, and A is as defined in paragraph (51) above.

[0152] In another embodiment of the compound of formula Ii2, R0 is as defined in paragraph (1) above; R 1z is cyano, R3 is as defined in paragraph (38), (39) or (40) above, and A is as defined in paragraph (54) or (55) above.

[0153] In another embodiment of the compound of formula Ii2, R0 is as defined in paragraph (1) above; R 1z is cyano, R3 is as defined in paragraph (40) above, and A is as defined in paragraph (54) or (55) above.

[0154] In a particular group of compounds of the invention, the compounds have the structural formula Ii3 [subdefinition of formula (I)] shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] (Wherein A, R0, R3 and R 1Zare as defined above, and R 201 is selected from hydrogen, methyl, hydroxymethyl, halo, trifluoromethyl, difluoromethyl, methoxy or acetyl).

[0155] In one embodiment of the compound of formula Ii2, R0 is as defined in paragraph (1) or (2) above; R 1Z is as defined in any one of paragraphs (3) through (10) above; R3 is as defined in any one of paragraphs (32) to (40) above; A is as defined in any one of paragraphs (50) to (55) above, and R 201 is selected from methyl, hydroxymethyl, halo, trifluoromethyl, difluoromethyl, methoxy or acetyl.

[0156] In one embodiment of the compound of formula Ii3, R0 is as defined in paragraph (1) or (2) above; R 1Z is as defined in any one of paragraphs (3) through (10) above; R3 is as defined in any one of paragraphs (32) to (49) above; A is as defined in any one of paragraphs (50) to (55) above, and R 201 is selected from methyl, hydroxymethyl, halo, trifluoromethyl, difluoromethyl, methoxy or acetyl.

[0157] In another embodiment of the compound of formula Ii3, R0 is as defined in paragraph (1) above; R 1z is halo or cyano; R3 is as defined in paragraph (35) above; A is as defined in paragraph (50) above, and R 201 is selected from methyl, hydroxymethyl, halo, or methoxy.

[0158] In another embodiment of the compound of formula Ii3, R0 is as defined in paragraph (1) above; R 1z is cyano, R3 is as defined in paragraph (38), (39) or (40) above; A is as defined in paragraph (54) or (55) above, and R 201 is selected from methyl or chloro.

[0159] In another embodiment of the compound of formula Ii3, R0 is as defined in paragraph (1) above; R 1z is cyano, R3 is as defined in paragraph (40) above; A is as defined in paragraph (54) or (55) above, and R 201 is selected from methyl or chloro.

[0160] Particular compounds of the present invention include any of the compounds described in the Examples section of this application, or a pharmaceutically acceptable salt or solvate thereof, particularly any of the following: 3-[5-amino-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(5-amino-3-pyridazin-4-yl-pyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile; 3-[5-amino-3-(2-ethylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-1-bicyclo[1.1.1]pentanyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; (3S)-4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]morpholine-3-carboxylic acid; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-ethyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[3-(hydroxymethyl)-4-methyl-piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetan-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methylsulfonyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]-2,2-dimethyl-propanoic acid; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidin-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3R,4R)-4-hydroxytetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(quinuclidin-3-ylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-morpholinoethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[2-[2-(dimethylamino)ethyl]morpholin-4-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4H-1,2,4-triazol-3-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; (2R)-4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]morpholine-2-carboxylic acid; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1,1-dioxothian-4-yl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]acetamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[2-(dimethylamino)-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-hydroxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1H-imidazol-2-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]azetidine-2-carboxylic acid; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]azetidine-3-carboxylic acid; (3R)-1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidine-3-carboxylic acid; 4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-sulfonamide; 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]bicyclo[1.1.1]pentane-1-carboxylic acid; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2R)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-(tert-butylamino)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-hydroxycyclopropyl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-morpholin-3-yl]methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3R)-3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]piperidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]pyrrolidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[rac-(4aS,7aS)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl rac-(4aS,7aS)-6-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-morpholin-3-yl]methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3S)-3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]pyrrolidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]piperidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-tert-butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[2-(4-phenylpiperazin-1-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholine-4-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(2-amino-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1-methyl-ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxyoxetan-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-methylsulfonyl-pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxycyclobutyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-N-(1-cyano-2-methoxy-1-methyl-ethyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(4-aminonorbornan-1-yl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2S)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(1-methylazetidin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-N-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(3-amino-1-bicyclo[1.1.1]pentanyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-1-bicyclo[1.1.1]pentanyl]carbamate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[cis-(3S,4R)-4-hydroxypyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl (3S,4R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate; N-(2-amino-1,1-dimethyl-ethyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl N-[2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-2-methyl-propyl]carbamate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]piperidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[trans-(3S,4S)-4-hydroxypyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl trans-(3S,4S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxypyrrolidin-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl 3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]methyl]-3-hydroxy-pyrrolidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]piperidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-methylpyrrolidin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-3-methyl-pyrrolidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R,2S)-2,3-dihydroxy-1-methyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-[(1-amino-3,3-difluoro-cyclobutyl)methyl]-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl N-[1-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]methyl]-3,3-difluoro-cyclobutyl]carbamate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(morpholin-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl 2-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]methyl]morpholine-4-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(piperazine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl 4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]piperazine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]pyrrolidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2-ethylpyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2-ethyl-5-methyl-pyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2-ethyl-4-methyl-pyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-cyano-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methanesulfonamide; (2S)-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]propanoic acid; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile formate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-(aminomethyl)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-[(2-hydroxy-2-methyl-propyl)amino]-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidyloxy)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-3-piperidyl]oxy]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3R)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypiperidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3S)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3S)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypyrrolidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-3-piperidyl]oxy]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3S)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypiperidine-1-carboxylate; 3-[5-amino-3-(6-amino-5-methyl-3-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-pyridine-2-carbonitrile; 3-[5-amino-3-(2-fluoro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(2-amino-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-pyridine-2-carboxamide; N-[4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-2-pyridyl]acetamide; 3-[5-amino-3-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-pyridine-2-carboxylic acid; 3-[5-amino-3-[2-(dimethylamino)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; [3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-(2-hydroxy-2-methyl-propyl)urea; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-(1-ethyl-4-piperidyl)urea; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxamide; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-[(3S)-pyrrolidin-3-yl]urea; 1-(2-aminoethyl)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-[(3R)-pyrrolidin-3-yl]urea; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-cyano-guanidine; 3-[3-(2-ethylpyrazol-3-yl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-[3-(hydroxymethyl)-4-methyl-piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-(4-methylsulfonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-(4H-1,2,4-triazol-3-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 5-(benzylamino)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; N-benzyl-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 2-(2-Furyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; tert-Butyl (2S)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate; tert-Butyl (2R)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]pyrrolidine-1-carboxylate; 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; tert-Butyl (2S)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]pyrrolidine-1-carboxylate; tert-Butyl (2R)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate; 2-(2-Furyl)-5-[4-(2-phenylethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[4-(2-pyridylmethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-[(1-benzyl-4-piperidyl)methylamino]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; tert-Butyl (2R)-4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-methyl-piperazine-1-carboxylate; tert-Butyl (2S)-4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-methyl-piperazine-1-carboxylate; 5-[2-(4-benzylpiperazin-1-yl)ethylamino]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 5-[3-(dimethylamino)azetidin-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; tert-Butyl 4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate; 2-(2-Furyl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[[(2S)-morpholin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[[(2R)-morpholin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-(4-benzylpiperazin-1-yl)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; N-benzyl-3-bromo-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-amine; 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde; N-benzyl-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-amine; 5-Amino-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 3-Bromo-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-amine; 2-(2-Furyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[4-[(2,4,6-trifluorophenyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[4-[(1-methylimidazol-2-yl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[4-(2-hydroxyethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; N-benzyl-2-(2-furyl)-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine; N-benzyl-2-(2-furyl)-3-(2-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine; Methyl (E)-3-[5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoate; (E)-3-[5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoic acid; 2-(2-Furyl)-5-(4-phenylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-(3-hydroxypropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-(3-piperidylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile hydrochloride; 5-(benzylamino)-2-oxazol-2-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-(benzylamino)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(3-cyanophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(3-fluorophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-oxazol-5-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-(benzylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-(benzylamino)-2-(5-methyl-2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]-2-oxazol-5-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile; N-benzyl-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 2-(3-fluorophenyl)-N-[(3-methyl-2-pyridyl)methyl]pyrazolo[1,5-a]pyrimidin-5-amine; 2-(3-fluorophenyl)-N-(2-phenylethyl)pyrazolo[1,5-a]pyrimidin-5-amine; N-(1H-benzoimidazol-2-ylmethyl)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 2-(3-fluorophenyl)-N-(2-isoindolin-2-ylethyl)pyrazolo[1,5-a]pyrimidin-5-amine; N-benzyl-3-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 3-Bromo-5-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine; N-benzyl-3-bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 5-(benzylamino)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 3-Bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 5-amino-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-N-(thiazol-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-5-amine; [5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol; 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid; N-benzyl-2-(2-furyl)-3-iodo-pyrazolo[1,5-a]pyrimidin-5-amine; 2-(2-Furyl)-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine; 2-(2-Furyl)-5-[[(2R)-pyrrolidin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[[(2R)-1-methylpyrrolidin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[(3R)-3-methylpiperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile hydrochloride; tert-Butyl 4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperidine-1-carboxylate; N-benzyl-7-(2-furyl)pyrazolo[1,5-a][1,3,5]triazin-2-amine; N-Benzyl-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-5-[4-(2-fluoroethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(3-cyanophenyl)-5-[2-(4-phenylpiperazin-1-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; N-tert-butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamidine; 3-(2-amino-6-methyl-4-pyridyl)-N-tert-butyl-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-5-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-hydroxy-2-methyl-propanamide; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2,2-dimethyl-propanamide; N-(3-amino-3-methyl-butyl)-2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide.

[0161] Further compounds of the present invention, or pharmaceutically acceptable salts thereof, include: 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-[2-methyl-6-(trifluoromethyl)-4-pyridyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-N-(1-cyano-1-methyl-ethyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-cyano-3-isopropyl-guanidine; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyano-2-methyl-phenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxycyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-1,1,2-trimethyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1-methyl-2-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-[(1S)-1,2-dimethylallyl]-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(2-acetamido-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2-oxo-oxazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-methyl-5-oxo-pyrrolidin-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[1-(3-hydroxyoxetan-3-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-methyl-6-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-cyano-3-(2-hydroxy-2-methyl-propyl)guanidine; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyano-2-methyl-phenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-methyl-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-3-methyl-cyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3R)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyano-2-methyl-phenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-hydroxy-3-methyl-butanamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetan-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[1-(2-hydroxyethyl)-4-piperidyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]guanidine; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamidine; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidin-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3S)-3-(1-hydroxy-1-methyl-ethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(1-methyl-2-oxo-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-hydroxy-3-methyl-butanamide; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]acetamide [2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-hydroxyoxetan-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S,3S)-3-aminocyclopentyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; m-{4-[({[(3S)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1.5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-8-yl}benzonitrile; 3-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-cyano-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(1R)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-hydroxy-2-methyl-propanamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(3S)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-4-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(5-oxopyrrolidin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-3-(1-hydroxy-1-methyl-ethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; m-[7-(2,6-dimethyl-4-pyridyl)-4-({[(5-oxo-3-pyrrolidinyl)methyl]amino}carbonyl)-1,5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-8-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; m-{4-[({[(3R)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1.5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-8-yl}benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazetidin-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-pyridine-2-carbonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-[(1-acetyl-4-piperidyl)amino]-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(5-oxomorpholin-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 1-(2-Amino-2-methyl-propyl)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea.

[0162] Particular compounds of the present invention include any of the compounds described in the Examples section of this application, or a pharmaceutically acceptable salt or solvate thereof, particularly any of the following: 3-[5-amino-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(5-amino-3-pyridazin-4-yl-pyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile; 3-[5-amino-3-(2-ethylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-1-bicyclo[1.1.1]pentanyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; (3S)-4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]morpholine-3-carboxylic acid; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-ethyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[3-(hydroxymethyl)-4-methyl-piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetan-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methylsulfonyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]-2,2-dimethyl-propanoic acid; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidin-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3R,4R)-4-hydroxytetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(quinuclidin-3-ylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-morpholinoethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[2-[2-(dimethylamino)ethyl]morpholin-4-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4H-1,2,4-triazol-3-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; (2R)-4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]morpholine-2-carboxylic acid; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1,1-dioxothian-4-yl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]acetamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[2-(dimethylamino)-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-hydroxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1H-imidazol-2-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]azetidine-2-carboxylic acid; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]azetidine-3-carboxylic acid; (3R)-1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidine-3-carboxylic acid; 4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-sulfonamide; 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]bicyclo[1.1.1]pentane-1-carboxylic acid; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2R)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-(tert-butylamino)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-hydroxycyclopropyl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-morpholin-3-yl]methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3R)-3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]piperidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]pyrrolidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[rac-(4aS,7aS)-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazin-6-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl rac-(4aS,7aS)-6-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-morpholin-3-yl]methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3S)-3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]pyrrolidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]piperidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-tert-butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[2-(4-phenylpiperazin-1-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholine-4-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(2-amino-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1-methyl-ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxyoxetan-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-methylsulfonyl-pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxycyclobutyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-N-(1-cyano-2-methoxy-1-methyl-ethyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(4-aminonorbornan-1-yl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2S)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(1-methylazetidin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-N-methyl-pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(3-amino-1-bicyclo[1.1.1]pentanyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-1-bicyclo[1.1.1]pentanyl]carbamate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[cis-(3S,4R)-4-hydroxypyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl (3S,4R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate; N-(2-amino-1,1-dimethyl-ethyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl N-[2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-2-methyl-propyl]carbamate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]piperidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[trans-(3S,4S)-4-hydroxypyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl trans-(3S,4S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxypyrrolidin-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl 3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]methyl]-3-hydroxy-pyrrolidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]piperidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-methylpyrrolidin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-3-methyl-pyrrolidine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R,2S)-2,3-dihydroxy-1-methyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-[(1-amino-3,3-difluoro-cyclobutyl)methyl]-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl N-[1-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]methyl]-3,3-difluoro-cyclobutyl]carbamate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(morpholin-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl 2-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]methyl]morpholine-4-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(piperazine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl 4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]piperazine-1-carboxylate; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; tert-Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]pyrrolidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2-ethylpyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2-ethyl-5-methyl-pyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2-ethyl-4-methyl-pyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-cyano-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methanesulfonamide; (2S)-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]propanoic acid; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile formate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-(aminomethyl)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-[(2-hydroxy-2-methyl-propyl)amino]-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidyloxy)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-3-piperidyl]oxy]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3R)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypiperidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3S)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3S)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypyrrolidine-1-carboxylate; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-3-piperidyl]oxy]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; tert-Butyl (3S)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypiperidine-1-carboxylate; 3-[5-amino-3-(6-amino-5-methyl-3-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-pyridine-2-carbonitrile; 3-[5-amino-3-(2-fluoro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(2,6-dimethyl-1-oxide-pyridin-1-ium-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-amino-3-(2-amino-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-pyridine-2-carboxamide; N-[4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-2-pyridyl]acetamide; 3-[5-amino-3-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-pyridine-2-carboxylic acid; 3-[5-amino-3-[2-(dimethylamino)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; [3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-(2-hydroxy-2-methyl-propyl)urea; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-(1-ethyl-4-piperidyl)urea; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxamide; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-[(3S)-pyrrolidin-3-yl]urea; 1-(2-aminoethyl)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-[(3R)-pyrrolidin-3-yl]urea; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-cyano-guanidine; 3-[3-(2-ethylpyrazol-3-yl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-[3-(hydroxymethyl)-4-methyl-piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-(4-methylsulfonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-(4H-1,2,4-triazol-3-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-ethylpyrazol-3-yl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 5-(benzylamino)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; N-benzyl-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 2-(2-Furyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; tert-Butyl (2S)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate; tert-Butyl (2R)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]pyrrolidine-1-carboxylate; 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; tert-Butyl (2S)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]pyrrolidine-1-carboxylate; tert-Butyl (2R)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate; 2-(2-Furyl)-5-[4-(2-phenylethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[4-(2-pyridylmethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-[(1-benzyl-4-piperidyl)methylamino]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; tert-Butyl (2R)-4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-methyl-piperazine-1-carboxylate; tert-Butyl (2S)-4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-methyl-piperazine-1-carboxylate; 5-[2-(4-benzylpiperazin-1-yl)ethylamino]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carboxamide; 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 5-[3-(dimethylamino)azetidin-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; tert-Butyl 4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate; 2-(2-Furyl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[[(2S)-morpholin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[[(2R)-morpholin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-(4-benzylpiperazin-1-yl)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; N-benzyl-3-bromo-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-amine; 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde; N-benzyl-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-amine; 5-Amino-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 3-Bromo-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-amine; 2-(2-Furyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[4-[(2,4,6-trifluorophenyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[4-[(1-methylimidazol-2-yl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[4-(2-hydroxyethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; N-benzyl-2-(2-furyl)-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine; N-benzyl-2-(2-furyl)-3-(2-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine; Methyl (E)-3-[5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoate; (E)-3-[5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoic acid; 2-(2-Furyl)-5-(4-phenylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-(3-hydroxypropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-(3-piperidylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile hydrochloride; 5-(benzylamino)-2-oxazol-2-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-(benzylamino)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(3-cyanophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(3-fluorophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-oxazol-5-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-(benzylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-(benzylamino)-2-(5-methyl-2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]-2-oxazol-5-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile; N-benzyl-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 2-(3-fluorophenyl)-N-[(3-methyl-2-pyridyl)methyl]pyrazolo[1,5-a]pyrimidin-5-amine; 2-(3-fluorophenyl)-N-(2-phenylethyl)pyrazolo[1,5-a]pyrimidin-5-amine; N-(1H-benzoimidazol-2-ylmethyl)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 2-(3-fluorophenyl)-N-(2-isoindolin-2-ylethyl)pyrazolo[1,5-a]pyrimidin-5-amine; N-benzyl-3-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 3-Bromo-5-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine; N-benzyl-3-bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 5-(benzylamino)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 3-Bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; 5-amino-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-N-(thiazol-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-5-amine; [5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol; 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid; N-benzyl-2-(2-furyl)-3-iodo-pyrazolo[1,5-a]pyrimidin-5-amine; 2-(2-Furyl)-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine; 2-(2-Furyl)-5-[[(2R)-pyrrolidin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[[(2R)-1-methylpyrrolidin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(2-Furyl)-5-[(3R)-3-methylpiperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile hydrochloride; tert-Butyl 4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperidine-1-carboxylate; N-benzyl-7-(2-furyl)pyrazolo[1,5-a][1,3,5]triazin-2-amine; N-Benzyl-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-5-[4-(2-fluoroethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 2-(3-cyanophenyl)-5-[2-(4-phenylpiperazin-1-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine; N-tert-butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamidine; 3-(2-amino-6-methyl-4-pyridyl)-N-tert-butyl-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-5-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-hydroxy-2-methyl-propanamide; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2,2-dimethyl-propanamide; N-(3-amino-3-methyl-butyl)-2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-[2-methyl-6-(trifluoromethyl)-4-pyridyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-N-(1-cyano-1-methyl-ethyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-cyano-3-isopropyl-guanidine; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyano-2-methyl-phenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxycyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-1,1,2-trimethyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1-methyl-2-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-[(1S)-1,2-dimethylallyl]-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(2-acetamido-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyano-2-methyl-phenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2-oxo-oxazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-methyl-5-oxo-pyrrolidin-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[1-(3-hydroxyoxetan-3-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-methyl-6-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-cyano-3-(2-hydroxy-2-methyl-propyl)guanidine; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyano-2-methyl-phenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-methyl-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-3-methyl-cyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3R)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyano-2-methyl-phenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-hydroxy-3-methyl-butanamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetan-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[1-(2-hydroxyethyl)-4-piperidyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]guanidine; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamidine; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidin-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3S)-3-(1-hydroxy-1-methyl-ethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(1-methyl-2-oxo-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-hydroxy-3-methyl-butanamide; N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]acetamide [2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-hydroxyoxetan-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S,3S)-3-aminocyclopentyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; m-{4-[({[(3S)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1.5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-8-yl}benzonitrile; 3-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-cyano-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(1R)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-hydroxy-2-methyl-propanamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(3S)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-4-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(5-oxopyrrolidin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-3-(1-hydroxy-1-methyl-ethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; m-[7-(2,6-dimethyl-4-pyridyl)-4-({[(5-oxo-3-pyrrolidinyl)methyl]amino}carbonyl)-1,5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-8-yl]benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; m-{4-[({[(3R)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1.5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-8-yl}benzonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazetidin-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-pyridine-2-carbonitrile; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[5-[(1-acetyl-4-piperidyl)amino]-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(5-oxomorpholin-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 1-(2-amino-2-methyl-propyl)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea; 3-[3-(2,6-dimethyl-4-pyridyl)-5-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[[(2R)-5-oxopyrrolidin-2-yl]methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4R)-4-hydroxy-4-methyl-tetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4S)-4-hydroxy-4-methyl-tetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(6-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4R)-4-hydroxy-1-methyl-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[[(2S)-5-oxopyrrolidin-2-yl]methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3S,4R)-4-hydroxy-1-methyl-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-thiazol-5-yl-pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(4-piperidyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(4-cyano-4-piperidyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; N-(4-carbamoyl-4-piperidyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2,6-dimethyl-4-pyridyl)-5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]-3-[2-(hydroxymethyl)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-[3-(2,6-dimethyl-4-pyridyl)-5-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; 3-[3-(2,6-dimethyl-4-pyridyl)-5-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile; (2S)-N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propanamide; N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide; and 4-Cyano-N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-4-methyl-piperidine-1-carboxamide.

[0163] The various functional groups and substituents comprising the compound of formula (I) are generally selected so that the molecular weight of the compound of formula (I) does not exceed 1000. More generally, the molecular weight of the compound is less than 900, for example, less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, for example, 550 or less.

[0164] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of compounds of the present invention that are sufficiently basic, for example, acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0165] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0166] The compounds of the present invention may have one or more asymmetric centers, and such compounds can therefore be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers, e.g., by synthesis from optically active starting materials or by resolution of racemates, are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomeric centers (E and Z isomers). It is understood that the present invention encompasses all optical, diastereomeric, and geometric isomers, and mixtures thereof, that possess antiproliferative activity.

[0167] The present invention also encompasses compounds of the present invention as defined herein that contain one or more isotopic substitutions. For example, H can be in any isotopic form, including 1H, 2H (D), and 3H (T), C can be in any isotopic form, including 12C, 13C, and 14C, and O can be in any isotopic form, including 16O and 18O.

[0168] It is also to be understood that certain compounds of formula (I) can exist in solvated as well as unsolvated forms, for example, hydrated forms, and it is to be understood that the present invention encompasses all such solvated forms that possess antiproliferative activity.

[0169] It will also be understood that certain compounds of formula I may exhibit polymorphism and that the invention encompasses all such forms which possess antiproliferative activity.

[0170] Compounds of Formula I can exist in many different tautomeric forms, and reference to a compound of Formula I includes all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all others are nevertheless encompassed by Formula I. Examples of tautomeric forms include keto, enol, and enolate forms, such as, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. [ka]

[0171] Compounds of Formula I containing an amine functional group can also form N-oxides. Reference herein to compounds of Formula I containing an amine functional group also includes N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid). See, for example, Jerry March, Advanced Organic Chemistry, 4th Edition, Wiley Interscience, pages 1977-1989. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0172] The compounds of formula (I) can be administered in the form of prodrugs, which are broken down in the human or animal body to release the compounds of the present invention. Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at a carboxy or hydroxy group in the compounds of formula (I), and in vivo cleavable amide derivatives that can be formed at a carboxy or amino group in the compounds of formula (I).

[0173] Thus, the present invention includes compounds of formula (I) as defined above when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present invention includes compounds of formula I produced by organic synthetic means as well as such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., compounds of formula (I) can be synthetically produced compounds or metabolically produced compounds.

[0174] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) are those that, based on sound medical judgment, have no undesirable pharmacological activity, are not excessively toxic, and are suitable for administration to the human or animal body.

[0175] Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, H. Bundgaard p.113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0176] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a carboxy group are, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula I containing a carboxy group are, for example, pharmaceutically acceptable esters which are cleaved in the human or animal body to yield the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C1-6 alkyl esters such as methyl, ethyl and tert-butyl, C1-6 alkoxymethyl esters such as methoxymethyl ester, C1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl ester, C3-8 cycloalkylcarbonyloxy-C1-6 alkyl esters such as pivaloyloxymethyl ester, 3-phthalidyl ester, cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and C1-6 alkoxycarbonyloxyC1-6 alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl ester.

[0177] Suitable pharmaceutically acceptable prodrugs of a compound of formula (I) having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. An in vivo cleavable ester or ether of a compound of formula (I) containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramido cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include C1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, and C1-10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-6)2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0178] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having a carboxy group are, for example, in vivo cleavable amides thereof, for example amides formed with amines such as ammonia, C1-4 alkylamines such as methylamine, (C1-4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-4 alkoxy-C2-4 alkylamines such as 2-methoxyethylamine, phenyl-C1-4 alkylamines such as benzylamine, and amino acids such as glycine or its esters.

[0179] Suitable pharmaceutically acceptable prodrugs of compounds of formula I having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, amides formed with C1-10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-4 alkyl)piperazin-1-ylmethyl.

[0180] The in vivo effects of the compounds of formula (I) may be exerted in part by one or more metabolic products formed in the human or animal body following administration of the compounds of formula (I). As noted above, the in vivo effects of the compounds of formula (I) may also be exerted by metabolism of precursor compounds (prodrugs).

[0181] The present invention may relate to any compound or particular group of compounds defined herein by any preferred or suitable feature or with respect to a particular embodiment, but the present invention may also relate to any compound or particular group of compounds that specifically excludes said any preferred or suitable feature or particular embodiment.

[0182] Preferably, the present invention excludes any individual compound that does not have biological activity as defined herein.

[0183] synthesis The compounds of the present invention can be prepared by any suitable technique known in the art. Specific processes for preparing the compounds of the present invention are described in the Examples section below, and reaction schemes for preparing such compounds are shown in Figures 1-18. [Brief explanation of the drawings]

[0184] [Figure 1]FIG. 1 shows a reaction scheme for preparing compounds of formula I, where A is CH, R1 is 3-cyanophenyl, R2 is 2-chloro-6-methylpyridin-4-yl, and R3 is an amide-linked substituent of formula —C(O)NRR, where each R is hydrogen or a substituent. [Figure 2] FIG. 2 shows a reaction scheme for preparing intermediate B (described in the accompanying Examples section). [Figure 3] FIG. 3 shows a reaction scheme for preparing compounds of Formula I, where A is CH, R1 is 3-cyanophenyl, R2 is 2-chloro-6-methylpyridin-4-yl, and R3 is an amine-linked substituent represented by the formula —NH—R. [Figure 4] FIG. 4 shows a reaction scheme for preparing compounds of formula I, where A is CH, R1 is 3-cyanophenyl, R2 is a group as defined herein, and R3 is an amine group (which can be further reacted to form an amine-linked substituent). [Figure 5] FIG. 5 shows a reaction scheme for preparing a compound of formula I, where A is CH, R1 is 3-cyanophenyl, R2 is 2-chloro-6-methylpyridin-4-yl, and R3 is a urea moiety of formula —NH—C(O)NH2. [Figure 6] FIG. 6 shows a reaction scheme for preparing intermediate G (described in the accompanying Examples section). [Figure 7] FIG. 7 shows a reaction scheme for preparing the compounds of Examples 35 and 36 herein. [Figure 8] FIG. 8 shows intermediate compounds T, P, and R, as well as a reaction scheme for preparing compounds of formula I, where A is CH, R1 is furan-2-yl, R2 is cyano, and R3 is an amine-linked substituent of formula —NH—R. [Figure 9] FIG. 9 shows intermediate Q and a reaction scheme for preparing compounds of formula I, where A is CH, R1 is furan-2-yl, R2 is Br, cyano, or —C(O)NH2, and R3 is benzylamino. [Figure 10] FIG. 10 shows a reaction scheme for preparing intermediate S and compounds of formula I, where A is CH, R is furan-2-yl, R is a group defined herein, and R is benzylamino. [Figure 11] FIG. 11 shows a reaction scheme for preparing compounds of formula I via intermediate X, where A is CH, R1 is furan-2-yl, R2 is hydrogen, and R3 is benzylamino. [Figure 12] FIG. 12 shows intermediate U and a reaction scheme for preparing compounds of formula I, where A is CH, R is a group defined herein, R is cyano, and R is benzylamino. [Figure 13] FIG. 13 shows the reaction scheme for preparing intermediate compounds V and W, as well as compounds of formula I, where A is CH, R1 is 3-fluorophenyl, R2 is cyano or bromo, and R3 is an amine-linked substituent represented by the formula -NHR. [Figure 14] FIG. 14 shows a reaction scheme for preparing a compound of formula I, wherein A is CH, R1 is 4-fluorophenyl, R2 is a group as defined herein, and R3 is an amine-linked substituent represented by the formula "-NRR" (where each R is hydrogen or a substituent). [Figure 15] FIG. 15 shows the reaction scheme for preparing the intermediate compounds shown in Steps 2a and 2b of Example 92, as well as compounds of Formula I, where A is CH, R1 is 3-cyanophenyl, R2 is 2,6-dimethylpyridin-4-yl, and R3 is an amide-linked substituent represented by the formula —C(O)—NRR, where each R is hydrogen or a substituent. [Figure 16] FIG. 16 shows a reaction scheme for preparing intermediate compound Y. [Figure 17] FIG. 17 shows a reaction scheme for preparing intermediate compound Z. [Figure 18] FIG. 18 shows a reaction scheme for preparing intermediate compound AB. DETAILED DESCRIPTION OF THE INVENTION

[0185] In the descriptions of synthetic methods described herein, and in any reference synthetic methods used to prepare starting materials, it is understood that all suggested reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, can be selected by one of ordinary skill in the art.

[0186] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0187] It will be appreciated that during the synthesis of the compounds of the invention, or of particular starting materials in the processes defined herein, it may be desirable to protect certain substituents to prevent their undesired reactions. The skilled chemist will understand when such protection is required and how such protecting groups may be put in place and subsequently removed.

[0188] For examples of protecting groups, see one of the many general texts on the subject, for example, "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such method being chosen so as to remove the protecting group with minimal interference with groups elsewhere in the molecule.

[0189] Thus, where reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0190] For example, suitable protecting groups for amino or alkylamino groups include acyl groups, such as alkanoyl groups (e.g., acetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl). The deprotection conditions for the above-mentioned protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, e.g., lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, such as t-butoxycarbonyl groups, can be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups, can be removed by hydrogenation with a catalyst, e.g., palladium on carbon, or by treatment with a Lewis acid, e.g., borontris (trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0191] Suitable protecting groups for hydroxy groups are, for example, acyl groups, e.g., alkanoyl groups such as acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed by hydrolysis with a suitable base such as, for example, an alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation over a catalyst such as, for example, palladium on carbon.

[0192] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group which may be removed by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed by treatment with an acid, for example an organic acid, such as trifluoroacetic acid, or for example a benzyl group which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0193] Resins can also be used as protecting groups.

[0194] The methodology used to synthesize compounds of formula (I) will vary depending on the nature of A, R1, R2 and R3, and any substituents associated therewith. Suitable processes for their preparation are further described in the accompanying Examples.

[0195] Once a compound of formula (I) has been synthesised by any one of the processes defined herein, the process may then further comprise one or more of the following additional steps: (i) removing any protecting groups present; (ii) converting a compound of formula (I) into another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate of a compound of formula I; and / or (iv) forming a prodrug of a compound of formula I.

[0196] An example of (ii) above is where a compound of formula (I) is synthesised and then one or more of the groups A, R1, R2 or R3 are further reacted to change the nature of the group to provide an alternative compound of formula (I).

[0197] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0198] Certain compounds of formula I as defined herein are (i) a compound of formula IIa [ka] wherein A, R, R, and R are each as defined above, and X is a suitable leaving group (e.g., bromo, chloro, iodo, —SMe, —S(O)Me, or —S(O)Me). with a group [R3-X2]-H, where X2 is N, S or O and [R3-X2] together represent a group R3 as defined above linked via the X2 atom. can be prepared by Optionally, the process can then further comprise one or more of the following additional steps: (i) removing any protecting groups that may be present; (ii) converting a compound of formula (I) into another compound of formula (I) (e.g., converting an R3 substituent into another R3 substituent as defined herein); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate of a compound of formula I; and / or (iv) forming a prodrug of a compound of formula I.

[0199] For the avoidance of any doubt, the X2 atom is a heteroatom present in the group R3, ie, [R3-X2] is an R3 group including the X2 heteroatom.

[0200] In the above reaction, it will be understood that when a compound of formula II is reacted with a [R3-X2]-H group, the X1 group is replaced with the H atom of the [R3-X2]-H group, and the R3 substituent is attached to the compound of formula II via the X2 atom.

[0201] Those skilled in the art will be able to readily select suitable reaction conditions for the reaction between a compound of formula II and the [R-X]-H group. Examples of suitable reaction conditions are described in the accompanying Examples section of this specification.

[0202] Compounds of formula II may be prepared by any suitable technique known in the art, as will be apparent from the accompanying Examples section. Specific examples of the preparation of compounds of formula II are described in the accompanying Examples section herein.

[0203] Compounds of formula I can also be prepared by Suzuki-Miyaura coupling or Stille coupling reactions. For example, certain compounds of formula I defined herein can also be prepared by (i) a compound of formula III [ka] wherein A, R, R, and R are each as defined above, and X is a halo atom (e.g., bromo, chloro, or iodo). in the group of the following formula: R1-M wherein M is a coupling reagent (e.g., a boron coupling agent or a tin coupling agent as defined herein) and R1 is as defined above; or (ii) a compound of formula IV [ka] wherein A, R, R, and R are each as defined above, and X is a halo atom (e.g., bromo, chloro, or iodo). in the group of the following formula: R2-M wherein M is a coupling reagent (e.g., a boron coupling agent or a tin coupling agent as defined herein) and R2 is as defined above; or (iii) a compound of formula V [ka] (wherein A, R0, R1, and R2 are each as defined above, and X3 is a halo atom (e.g., bromo, chloro, or iodo). in the group of the following formula: R3-M wherein M is a coupling reagent (e.g., a boron coupling agent or a tin coupling agent as defined herein) and R3 is as defined above. can be prepared by Optionally, the process can then further comprise one or more of the following additional steps: (i) removing any protecting groups that may be present; (ii) converting a compound of formula (I) into another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate of a compound of formula I; and / or (iv) forming a prodrug of a compound of formula I.

[0204] The group M can be a suitable boron coupling reagent known in the art for the Suzuki-Miyaura coupling reaction. Examples of suitable boron reagents include boronic acids, boronic esters (e.g., catechol boronic ester, pinacol boronic ester, triisopropyl boronate, MIDA boronate, cyclic triol boronate), boranes (e.g., 9-BBN borane), organic trifluoroborates, or boronic amides (e.g., 1,8-diaminonaphthylboronamide). A specific example is -B(OH)2 or B(OCH3)2.

[0205] The Suzuki-Miyaura coupling reaction is well known, and one skilled in the art would be able to readily select suitable reaction conditions for this reaction.

[0206] In a Stille coupling reaction, M is a tin coupling agent, suitably of the formula -Sn[(1-6C)alkyl]3, for example -Sn(butyl)3.

[0207] The Stille coupling reaction is well known, and one skilled in the art would be able to easily select suitable reaction conditions for this reaction. Such reactions are usually carried out in the presence of a palladium catalyst.

[0208] biological activity The biological assays described in the Examples section (Biological Examples 1-3) can be used to measure the pharmacological effects of the compounds of the present invention.

[0209] Although the pharmacological properties of compounds of formula I vary, as would be expected, with structural changes, the compounds of the invention were found to be active in the assays described in Biological Examples 1, 2 and 3.

[0210] Generally, with respect to adenosine A2a antagonism, compounds of the present invention have an IC2A activity of 1 μM or less in the assay described in Biological Example 1. 50 and preferred compounds of the present invention exhibit an IC 50 and the most preferred compounds of the present invention exhibit an IC of 50 nM or less. 50 Shows.

[0211] Suitably, the compounds of the invention have an IC50 at adenosine A1, A2b or A3 receptors in the assay described in Biological Example 1. 50 IC at adenosine A2a receptors 50 Preferably, the ion exchange rate is at least two times higher, more preferably at least five times higher, and even more preferably at least ten times higher.

[0212] Pharmaceutical Composition According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0213] Compositions of the invention may be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0214] The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0215] An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the proliferative conditions referred to herein.

[0216] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g of active agent (more preferably, 0.5 to 100 mg, e.g., 1 to 30 mg), mixed with an appropriate and convenient amount of excipient, which may vary from about 5 to about 98% by weight of the total composition.

[0217] The magnitude of a dose of a compound of formula I for therapeutic or prophylactic purposes will, of course, vary with the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0218] When used for therapeutic or prophylactic purposes, the compounds of the present invention are generally administered at a daily dose ranging, for example, from 0.1 mg / kg to 75 mg / kg of body weight, given in divided doses if necessary. Generally, when parenteral administration is used, lower doses are administered. Thus, for example, for intravenous or intraperitoneal administration, doses ranging, for example, from 0.1 mg / kg to 30 mg / kg of body weight are generally used. Similarly, for administration by inhalation, doses ranging, for example, from 0.05 mg / kg to 25 mg / kg of body weight are used. Oral administration, particularly in tablet form, may also be suitable. Typically, a unit dosage form contains about 0.5 mg to 0.5 g of a compound of the present invention.

[0219] Therapeutic Uses and Applications The present invention provides compounds that function as antagonists of adenosine A2 receptors, particularly adenosine A2a receptors.

[0220] According to a further aspect of the present invention there is provided a method of antagonizing adenosine A2a receptors in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0221] According to a further aspect of the present invention there is provided a method of selectively antagonizing adenosine A2a receptors in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0222] According to a further aspect of the present invention there is provided a method of inhibiting proliferation of a cell in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0223] According to a further aspect of the present invention there is provided a method of treating a disease or disorder associated with adenosine A2a receptor activity in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0224] According to a further aspect of the present invention there is provided a method of treating a cell proliferative disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0225] According to a further aspect of the present invention there is provided a method of treating cancer in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., a checkpoint inhibitor and / or a cytotoxic agent).

[0226] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

[0227] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a cell proliferative condition. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0228] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer. In certain embodiments, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0229] According to a further aspect of the present invention, there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use as an adenosine A2a antagonist. In one embodiment, the compound of the present invention is a selective adenosine A2a antagonist. In an alternative embodiment, certain compounds of the present invention are selective adenosine A2a antagonists and adenosine A2b antagonists.

[0230] According to a further aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which adenosine A2a is involved.

[0231] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a cell proliferative condition. Suitably the compound or pharmaceutical composition is administered in combination with one or more additional anti-proliferative agents (e.g. checkpoint inhibitors and / or cytotoxic agents).

[0232] According to a further aspect of the present invention, there is provided the use of a compound defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of cancer. Preferably, the cancer is a human cancer. Preferably, the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0233] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use as an adenosine A2a antagonist.

[0234] According to a further aspect of the invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use as an adenosine A2a antagonist.

[0235] According to a further aspect of the present invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which adenosine A2a receptor activity is implicated.

[0236] The term "proliferative disorder" is used interchangeably herein and refers to unwanted or uncontrolled cell proliferation of unwanted, excessive, or abnormal cells, such as neoplastic or hyperplastic growth, in vitro or in vivo. Examples of cell proliferative conditions include, but are not limited to, premalignant and malignant cell proliferation, including, but not limited to, malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis. Any type of cell can be treated, including, but not limited to, lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

[0237] The antiproliferative effects of the compounds of the present invention have particular application in the treatment of human cancers (due to their adenosine A2a antagonist activity).

[0238] More particularly, there is provided compounds of general formula (I) for use in the treatment of cancer, in particular solid tumors such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma.

[0239] More particularly, there is provided a compound of general formula (I) for use in the treatment of cancer, for example lung cancer, such as small cell lung cancer or non-small cell lung cancer.

[0240] There is also provided the use of a compound of general formula (I) in the manufacture of a medicament for use in the treatment of cancer, in particular solid tumours such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma.

[0241] The present invention further provides a method for the treatment of cancer, in particular solid tumors such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma, which comprises administering to a patient in need of such treatment an effective amount of a compound of general formula (I).

[0242] The patient to be treated is preferably a mammal, more preferably a human.

[0243] Administration route The compounds of the present invention or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, to the desired site of action).

[0244] Routes of administration include, but are not limited to, oral (e.g., by ingestion), buccal, sublingual, transdermal (e.g., by patch, plaster, etc.), transmucosal (e.g., by patch, plaster, etc.), intranasal (e.g., by nasal spray), intraocular (e.g., by eye drops), pulmonary (e.g., by aerosol, e.g., by inhalation or insufflation therapy through the mouth or nose), rectal (e.g., by suppository or enema), vaginal (e.g., by pessary), parenteral (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intrathecal, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, substernal, and intratumoral, and by implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly).

[0245] The compounds of the present invention or pharmaceutical compositions containing these compounds can be administered by intratumoral delivery.

[0246] Combination therapy The compounds of formula I are useful for the treatment and / or prevention of cell proliferative disorders, such as, for example, cancer. The compounds of formula I as defined herein may be used in combination with one or more additional anti-proliferative / anti-cancer therapies, such as, for example, chemotherapy with one or more additional anti-proliferative / anti-cancer agents, radiation therapy, and / or conventional surgery.

[0247] The additional anti-proliferative / anti-cancer agent may be included in a pharmaceutical composition together with a compound of formula (I) as defined herein or may be administered separately, either simultaneously with, earlier or later than, a compound of formula (I).

[0248] Thus, in a further aspect of the present invention there is provided a product comprising a compound of general formula (I) and an additional agent useful in the treatment or prevention of cancer as a combined preparation for simultaneous, sequential or separate use in the treatment of cancer.

[0249] The present invention also provides compounds of general formula (I) in combination with one or more additional anti-proliferative / anti-cancer agents for use in the treatment of cancer, as a combined preparation for simultaneous, sequential or separate use in the treatment of cancer.

[0250] In particular, the combination therapy defined herein is suitable for the treatment of solid tumors, such as non-small cell lung cancer or small cell lung cancer, head and neck squamous cell carcinoma and urothelial carcinoma.

[0251] Suitable additional antiproliferative / anticancer agents that may be used in combination with compounds of formula I as defined herein (either separately or as part of a pharmaceutical composition combined with a compound of general formula (I) or as part of a combined preparation) include: 1) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents; 2) adenosine pathway modulators (including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors); 3) anti-PD-1 and PDL-1 antibodies (including, but not limited to, cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab); and 4) Anti-CTLA4 antibodies (including but not limited to ipilimumab).

[0252] The compounds of formula I as defined herein are particularly suitable for use in combination with anti-PD-1 antibodies and anti-PDL-1 antibodies, including but not limited to cetrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab.

[0253] Preferably, the anti-PD1 antibody is one of the antibodies disclosed in U.S. Patent Application Publication No. 2019 / 0225689 or U.S. Patent Application Publication No. 2017 / 0121409 (incorporated herein by reference in their entireties), such as cetrelimab. Cetrelimab (JNJ-63723283, CET) is a fully human immunoglobulin (Ig) G4 kappa monoclonal antibody that binds to programmed death receptor-1 (PD-1) with high affinity and specificity. Cetrelimab has demonstrated activity in solid tumors. Rutkowski P, et al. Journal of Clinical Oncology. 2019;37(8):31.

[0254] 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.

[0255] The A2a antagonists of general formula (I) may also be used in combination with cell-based immunotherapies, including but not limited to CAR-T cell therapy, and cancer vaccines.

[0256] Examples of additional anti-proliferative / anti-cancer chemotherapeutic agents include, but are not limited to, any one or more of the following: Tauromustine; Tazarotene; Tecogalan sodium; Tegafur; Terlapyrylium; Telomerase inhibitors; Temoporfin; Temozolomide; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Taliblastine; Thiocoraline; Thrombopoietin; Thrombopoietin mimetics; Thymalfadine; Thymopoietin receptor agonists; Thymotrin; Thyroid-stimulating hormone; Tin ethyl etiopurpurin; Tirapazamine; Titanocene dichloride; Topsentin; Toremifene; Totipotent stem cell factor; Translation inhibitors; Tretinoin; Triacetyluridine; Triciribine; Toxin Rimetrexate; Triptorelin; Tropisetron; Turosteride; Tyrosine kinase inhibitors; Tyrphostin; UBC inhibitors; Ubenimex; Urogenital sinus-derived growth inhibitor; Urokinase receptor antagonists; Vapreotide; Variolin B; Vector systems, erythrocyte gene therapy drugs; Veraresol; Veramine; Verdine; Verteporfin; Vinorelbine; Vinoxacin; Vitaxin; Vorozole; Zanoterone; Zeniplatin; Zilascorub; Zinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin,Acivicin; Aclarubicin; Acodazole hydrochloride; Acronine; Adzelesin; Aldesleukin; Altretamine; Ambomycin; Amethantrone acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene hydrochloride; Bisnafide dimesylate; Bizeresin; Sulfate Bleomycin;Brequinar sodium;Bropirimine;Busulfan;Cactinomycin;Calsterone;Caracemide;Carbetimer;Carboplatin;Carmustine;Carubicin hydrochloride;Carzelcin;Cedefingol;Chlorambucil;Ciloremycin;Cladribine;Crisnatol mesylate;Cyclophosphamide;Cytarabine;Dacarbazine;Daunorubicin hydrochloride;Decitabine;Dexolomaplatin;Dezaguamine;De Zaguamine mesylate; Diazicon; Doxorubicin; Doxorubicin hydrochloride; Droloxifene; Droloxifene citrate; Dromostanolone propionate; Duazomycin; Edatrexate; Eflornithine hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropizin; Epirubicin hydrochloride; Elbrozole; Esorubicin hydrochloride; Estramustine; Estramustine phosphate sodium; Ethanidazole ru; etoposide; etoposide phosphate; etopurine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; foscidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin 2 or rlL.sub.2),Interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-la; interferon gamma-lb; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; Methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocalcin; mitochromin; mitogillin; mitomarcine; mitomycin; mitosperm; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisulan; pegaspargase; periomycin; pentamstine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; promestane; porfimer sodium; Porfiromycin;Prednimustine;Procarbazine hydrochloride;Puromycin;Puromycin hydrochloride;Pyrazofurin;Rivopurin;Rogletimide;Safingol;Safingol hydrochloride;Semustine;Simtrazene;Sparfosate sodium;Sparsomycin;Spirogermanium hydrochloride;Spiromustine;Spiroplatin;Streptonigrin;Streptozocin;Sulofenur;Tallysomycin;Tecogalan sodium;Tegafur;Teloxantrone hydrochloride;Temoporfin;Teniposide;Teroxylon;Testolactone;Thiamiprine;Thiaminoprine Oguanine; Thiotepa; Tiazofurin; Tirapazamine; Toremifene citrate; Trestrone acetate; Trisibirine phosphate; Trimetrexate; Trimetrexate glucuronate; Triptorelin; Tubrozole hydrochloride; Uracil mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Binepidine sulfate; Vingrisinate sulfate; Vinleurosine sulfate; Vinorelbine tartrate; Vinrocidine sulfate; Vinzoquidine sulfate; Vorozole; Zeniplatin; Zinostatin; Zorubicin hydrochloride,Agents that arrest cells in the G2-M phase and / or modulate the formation or stability of microtubules (e.g., Taxol™ (i.e., paclitaxel)), Taxotere™ (compounds containing a taxane skeleton), elbrozole (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobulin isethionate (i.e., as CI-980), vincristine, NSC-639829, discodermolide (i.e., as NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), altritol (e.g., Altritol), altritin A and altritin C), spongistatins (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9), cemadotin hydrochloride (i.e., LU-103793 and NSC-D-669356), epothilones (e.g., epothilone A, epothilone B, epothilone C (i.e., desoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and desoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-3-10705), 21-hydroxyepothilone D (i.e., desoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), vincristine sulfate, cryptophycin 52 (i.e., LY-355703), bitilebamide, tublysin A, canadensol, sendaureidin (i.e., NSC-106969), oncocidin A1 (i.e., BTO-956 and DF-106969), E), Physianolide B, Laulimalide, Narcosine (also known as NSC-5366), Nascapine, Hemiasterin, Vanadocene acetylacetonate, Monsatrol, Inanosin (i.e., NSC-698666), Eleutherobin (Desmethyleleutherobin, Desaetyleleutherobin,leuruterobin A and Z), caribeoside, caribaeolin, halichondrin B, diazonamide A, taccalonolide A, diozostatin, (-)-phenylahistine (i.e., NSCL-96F037), myoseverin B, resberastatin sodium phosphate, steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-Fc anti-ER2, anti-CD52, anti-ULA-DR and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapeutic agents (e.g., anti-CD20 monoclonal antibody conjugated to ln, 0Y or I), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine , sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib / BIBW2992,CI-1033 / canertinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or hormone therapy, etc.

[0257] As noted above, combination therapies of the present invention may be achieved by the simultaneous, sequential, or separate administration of the individual components of the treatment. Such combination products utilize the compounds of this invention within the dosage ranges described above and the other pharmaceutically active agent(s) within their approved dosage ranges.

[0258] According to this aspect of the invention there is provided a combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more further anti-proliferative / anti-cancer agents for use in the treatment of cancer (e.g. cancer involving solid tumours).

[0259] According to this aspect of the invention there is also provided a combination for use in the treatment of a cell proliferative condition such as cancer (e.g. cancer involving solid tumours), comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional anti-proliferative / anti-cancer agents selected from those listed above.

[0260] In a further aspect of the present invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of cancer in combination with another anti-tumour agent selected from any of those listed hereinabove.

[0261] When the term "combination" is used herein, it should be understood to refer to simultaneous, separate or sequential administration. In one aspect of the present invention, "combination" refers to simultaneous administration. In another aspect of the present invention, "combination" refers to separate administration. In a further aspect of the present invention, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such that the beneficial effect of the combination is lost.

[0262] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumor agent (selected from any of those listed herein above), in combination with a pharmaceutically acceptable diluent or carrier. [Example]

[0263] General conditions: Mass spectra were performed on an LC-MS system using electrospray ionization. These were performed using a Waters Acquity H-Class UPLC with PDA and QDa mass detection, an Acquity UPLC (binary pump / PDA detector) + ZQ mass spectrometer, or an Acquity i-Class (quaternary pump / PDA detector) + Quattro Micro mass spectrometer, a Waters Acquity uPLC system equipped with Waters PDA and ELS detectors, or a Shimadzu LC-MS-2010EV system. [M+H]+ refers to the monoisotopic molecular weight.

[0264] NMR spectra were performed on a Bruker Ultrashield 500 MHz NMR spectrometer, a Bruker Avance III HD 400 MHz NMR spectrometer, a Bruker Avance DPX 300 MHz NMR spectrometer, a Bruker Avance III HD 500 MHz, or a Bruker Avance III HD 250 MHz. Spectra were recorded at 298 K and referenced to the solvent peak.

[0265] The following examples illustrate the present invention, but are not intended to be limiting. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporations are carried out under vacuum, preferably at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, such as MS and NMR. Abbreviations used are conventional in the art. Unless defined, these terms have their generally accepted meanings.

[0266] Abbreviation Appearance br Broad d double line dd compound double line DABCO (1,4-diazabicyclo[2.2.2]octane) DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIPEA Diisopropylethylamine DMA Dimethylacetamide DMF N,N-dimethylformamide EtOAc ethyl acetate HPLC High-Performance Liquid Chromatography HBTU Hexafluorophosphate Benzotriazole Tetramethyluranium IMS Industrial Denatured Alcohol LC-MS Liquid Chromatography Mass Spectrometry mCPBA 3-chloroperbenzoic acid MeOH Methanol MeCN acetonitrile MS mass spectrometry m multiplet min mL milliliter m / z mass-to-charge ratio NBS N-Bromosuccinimide NMR nuclear magnetic resonance Pd(amphos)2Cl2 Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd(tBu3P)2 Bis(tri-tert-butylphosphine)palladium(0) ppm parts per million PS polymer support Rt retention time s single line t triple line T3P Propanephosphonic Anhydride TFA trifluoroacetic acid THF tetrahydrofuran.

[0267] For the examples that follow, compounds of preferred embodiments were synthesized using methods described herein or other methods known in the art.

[0268] The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified, if necessary, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purification. Salts can be prepared from compounds by known salt-forming procedures.

[0269] It is understood that organic compounds according to the preferred embodiments may exhibit the phenomenon of tautomerism, and since the chemical structures within this specification can represent only one of the possible tautomeric forms, it is understood that the preferred embodiments encompass any tautomeric form of the depicted structure.

[0270] Unless otherwise stated, analytical HPLC conditions were as follows:

[0271] Method 2A Column: Kinetex Core-Shell C18 2.1 x 50 mm 5 μm Column temperature: 40°C Eluent: A: H2O + 0.1% formic acid, B: MeCN + 0.1% formic acid Flow rate: 1.2mL / min Gradient: 0-1.83 min 5-100% B, 1.83-2.25 min 100% B, 2.25-2.26 min 100-5% B

[0272] Method 2.5B Column: Phenomenex Gemini-NX C18 2 x 50 mm 3 μm Column temperature: 40℃ Eluents: A: 2 mM ammonium bicarbonate buffered to pH 10, B: MeCN Flow rate: 1mL / min Gradient: 0-1.80 min 1-100% B, 1.80-2.10 min 100% B, 2.10-2.30 min 100-1% B

[0273] Method 3A Column: Acquity UPLC CSH C18 2.1 x 50 mm, 1.7 μm Column temperature: 50℃ Eluent: A: HO, B: MeCN, 0.1% formic acid Flow rate: 1mL / min Gradient: 0.2-2.5 min 2-98%B, 2.5-3.0 min 98%B

[0274] Method 3B Column: Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 μm Column temperature: 50℃ Eluent: A: HO, B: MeCN, 0.1% ammonia Flow rate: 1mL / min Gradient: 0.2-2.5 min 2-98%B, 2.5-3.0 min 98%B

[0275] Method 5A Column: YMC-Triart C18 2 x 50 mm, 5 μm Flow rate: 0.8mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% formic acid Gradient: 0.0–4.0 min 0–95% B, 5% C; 4.0–4.4 min 95% B, 5% C; 4.4–4.5 min 95% A, 5% B

[0276] Method 5B Column: YMC-Triart C18 2 x 50 mm, 5 μm Flow rate: 0.8mL / min Eluents: A: HO, B: MeCN, C: 50% HO / 50% MeCN + 1.0% ammonia (aqueous) Gradient: 0.0–4.0 min 0–95% B, 5% C; 4.0–4.4 min 95% B, 5% C; 4.4–4.5 min 95% A, 5% B

[0277] Method 7A Column: Phenomenex Kinetix-XB C18 2.1 x 100 mm, 1.7 μm Column temperature: 40℃ Eluent: A: HO + 0.1% formic acid, B: MeCN + 0.1% formic acid Flow rate: 0.6mL / min Gradient: 0-5.3.0 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82-7.00 min 5% B

[0278] Method 7B Column: Waters UPLC® BEH™ C18, 2.1 mm x 100 mm, 1.7 μm column Column temperature: 40℃ Eluents: A: 2 mM ammonium bicarbonate buffered to pH 10, B: MeCN Flow rate: 0.6mL / min Gradient: 0-5.3.0 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100-5% B, 5.82-7.00 min 5% B

[0279] Method 8A Column: Acquity UPLC CSH C18 2.1 x 100 mm, 1.7 μm Column temperature: 50℃ Eluent: A: HO, B: MeCN, 0.1% formic acid Flow rate: 0.6mL / min Gradient: 0.5-6.5 min 2-98%B, 6.5-7.5 min 98%B

[0280] Method 8B Column: Acquity UPLC BEH C18 2.1 x 100 mm, 1.7 μm Column temperature: 50℃ Eluent: A: HO, B: MeCN, 0.1% ammonia Flow rate: 0.6mL / min Gradient: 0.5-6.5 min 2-98%B, 6.5-7.5 min 98%B

[0281] Method 15A Column: YMC-Triart C18 2 x 50 mm, 5 μm Flow rate: 0.8mL / min Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% formic acid Gradient: 0.0–12.0 min 0–95% B, 5% C; 12.0–14.0 min 95% B, 5% C; 14.0–14.2 min 95% A, 5% B

[0282] Method 15B Column: YMC-Triart C18 50 x 2 mm, 5 μm Flow rate: 0.8mL / min Eluents: A: HO, B: MeCN, C: 50% HO / 50% MeCN + 1.0% ammonia (aqueous) Gradient: 0.0–12.0 min 0–95% B, 5% C; 12.0–14.0 min 95% B, 5% C; 14.0–14.2 min 95% A, 5% B

[0283] Example 1 - 3-[5-amino-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] A mixture of 3-(5-amino-3-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile (Intermediate E) (89 mg, 0.28 mmol), 4-pyridylboronic acid (52 mg, 0.42 mmol), and K2CO3 (78 mg, 0.57 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was degassed under a stream of N2. Pd(tBu3P)2 (14 mg, 0.03 mmol) was added, and the reaction mixture was heated to 120 °C (preheated bath) for 1 h. The resulting mixture was cooled to room temperature and added dropwise to stirred water (50 mL). The precipitate was collected by filtration and purified by silica chromatography eluting with a gradient of 5–10% MeOH / DCM. The resulting material was triturated with MeOH (3 mL) followed by EtOAc (5 mL) to give the title compound as a beige solid. LC-MS (Method 15A): Rt5.14 min; MS m / z313.2=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 8.62(d,J=7.5Hz,1H),8.44(d,J=5.5Hz,2H),7.91(t,J=3.3Hz,2H),7.78(d,J=7.9Hz, 1H),7.65(t,J=8.0Hz,1H),7.40(d,J=5.2Hz,2H),7.25(s,2H),6.39(d,J=7.5Hz,1H).

[0284] The compounds of the examples shown in the table below (Table Ex1) were prepared in analogy to Example 1 from 3-(5-amino-3-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile (Intermediate E) and the appropriate boronic acid or boronic ester.

[0285] [Table 1]

[0286] [Table 2]

[0287] [Table 3]

[0288] Example 2 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] A suspension of 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) (900 mg, 2.37 mmol), 1-amino-2-methyl-propan-2-ol (316 mg, 3.55 mmol), and DIPEA (2.06 mL, 11.83 mmol) in NMP (15 mL) was heated at 50 °C for 3 h. After cooling to room temperature, the mixture was partitioned between 90% brine solution (100 mL) and EtOAc (100 mL). The organic layer was washed with 50% brine solution (3 × 50 mL), dried over MgSO4, and concentrated in vacuo. The crude material was purified by silica chromatography eluting with a gradient of 0–5% MeOH / DCM to give the title compound as a colorless solid. LC-MS (Method 8B): Rt4.24 min; MS m / z431.2 / 433.2=[MH]- 1 H NMR(500MHz,DMSO-d6)δ 8.57(d,J=7.6Hz,1H),8.01-7.90(m,3H),7.83(d,J=7.8Hz,1H),7.68(t,J=7.8Hz,1H),7.41(s,1H) ,7.27(s,1H),6.61(d,J=7.6Hz,1H),4.63(s,1H),3.44(d,J=5.8Hz,2H),2.33(s,3H),1.19(s,6H).

[0289] The compounds of the examples shown in the table below (Table Ex2) were prepared in a similar manner to Example 2 from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) and the appropriate amine.

[0290]

Table 4

[0291]

Table 5

[0292]

Table 6

[0293]

Table 7

[0294]

Table 8

[0295]

Table 9

[0296]

Table 10

[0297]

Table 11

[0298]

Table 12

[0299]

Table 13

[0300] [Table 14]

[0301] [Table 15]

[0302] [Table 16]

[0303] Example 3 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2R)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] To 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) (100 mg, 0.26 mmol) in DMF (1 mL) was added (2R)-1-aminopropan-2-ol (0.08 mL, 1.05 mmol) and stirred at 60 °C for 45 min. The resulting mixture was cooled to room temperature and added dropwise to stirred water (20 mL). EtOAc (50 mL) was added and the aqueous layer was separated. The organic layer was washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The crude material was purified by reverse-phase chromatography eluting with 40–50% MeCN / water (+0.1% NHOH by weight), followed by silica chromatography eluting with a gradient of 0–8% MeOH / DCM to give the title compound as a colorless solid. LC-MS (Method 15B): Rt7.23 min; MS m / z419.2 / 421.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 8.59(d,J=7.5Hz,1H),8.05(s,1H),8.00-7.94(m,2H),7.84(dt,J=7.9,1.4Hz,1H),7.70(t,J=7.7Hz,1H),7.38(s,1H),7.29(s,1H),6.53(d, J=7.6Hz,1H),4.83(d,J=4.8Hz,1H),4.01-3.92(m,1H),3.56-3.45(m,1H),3.22(dt,J=13.0,6.1Hz,1H),2.34(s,3H),1.16(d,J=6.2Hz,3H).

[0304] The compounds of the examples shown in the table below (Table Ex3) were prepared in a similar manner to Example 3 from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) and the appropriate amine.

[0305] [Table 17]

[0306] [Table 18]

[0307] Example 4 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] Step 1: tert-butyl 4-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]piperidine-1-carboxylate [ka] tert-Butyl 4-aminopiperidine-1-carboxylate (69 mg, 0.34 mmol) was added to a suspension of DIPEA (0.06 mL, 0.34 mmol) and 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) (100 mg, 0.26 mmol) in DMF (1 mL) and stirred at 60 °C overnight. After cooling to room temperature, the mixture was added dropwise to stirred water (20 mL), and the resulting precipitate was collected by filtration and washed with water (2 × 5 mL). The solid was azeotroped from acetone (20 mL) and purified by reverse phase elution with a gradient of 40–65% MeCN / water (+0.1 wt% NH4OH) to give the title compound as a colorless solid. LC-MS (Method 5B): Rt3.89 min; MS m / z544.2=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 8.63(d,J=7.6Hz,1H),8.03-7.93(m,3H),7.86(dt,J=8.0,1.5Hz,1H),7.72(t,J=7.8 Hz,1H),7.43(s,1H),7.30(s,1H),6.45(d,J=7.6Hz,1H),4.06-3.94(m,3H),2.97(br s,2H),2.36(s,3H),2.15-2.03(m,2H),1.48-1.34(m,11H).

[0308] Step 2: 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile 4 M HCl in 1,4-dioxane (0.55 mL, 2.19 mmol) was added to a suspension of tert-butyl 4-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]piperidine-1-carboxylate (Step 1) (119 mg, 0.22 mmol) in MeOH (0.50 mL) and stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo and purified by reverse phase elution with a gradient of 5-60% MeCN / water (+0.1 wt% NH4OH) to give the title compound as a colorless solid. LC-MS (Method 8B): Rt4.78 min; MS m / z444.2 / 446.2=[M+H]+ 1 H NMR (500 MHz, DMSO-d6) δ 8.58 (d, J = 7.6 Hz, 1H), 8.02-7.94 (m, 2H), 7.92 (d, J = 6.8 Hz, 1H), 7.85 (dt, J = 7.9, 1.5 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.28 (s, 1H), 6.43 (d, J = 7.6 Hz, 1H), 3.94-3.82 (m, 1H), 3.07-2.97 (m, 2H), 2.64-2.55 (m, 2H), 2.33 (s, 3H), 2.06-1.96 (m, 2H), 1.45-1.29 (m, 2H). No NH protons were observed.

[0309] The compounds of the examples shown in the table below (Table Ex4) were prepared in analogy to Example 4 from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) and the appropriate amine (Step 1) followed by deprotection using 4M HCl / dioxane (Step 2).

[0310] [Table 19]

[0311] [Table 20]

[0312] [Table 21]

[0313] [Table 22]

[0314] [Table 23]

[0315] [Table 24]

[0316] [Table 25]

[0317] Example 4. 8-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] Step 1-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] The title compound was prepared in a similar manner to Step 1 of Example 4 from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) and (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamine. LC-MS (Method 5B): Rt3.84 min; MS m / z489.2 / 491.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 8.60(d,J=7.6Hz,1H),8.02-7.93(m,2H),7.89-7.80(m,2H),7.69(t,J=7.8Hz,1H),7.34(s,1H),7.31(s,1H),6.50(d,J=7.6Hz,1H), 4.29(s,2H),4.03(dd,J=8.2,6.2Hz,1H),3.72(dd,J=8.2,6.2Hz,1H),2.35(s,3H),1.36(s,3H),1.30(s,3H),1.21(d,J=6.0Hz,3H).

[0318] Step 2-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile To a suspension of 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Step 1) (49.1 mg, 0.1000 mmol) in THF (1 mL) was added 2 M aqueous HCl (0.5 mL, 1 mmol), and the reaction mixture was stirred at room temperature for 16 h. The resulting mixture was partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (15 mL), dried over NaSO, filtered, and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 2–10% MeOH / DCM afforded the title compound as a white solid. LC-MS (Method 8B): Rt4.06 min; MS m / z449.2 / 451.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 8.56(d,J=7.6Hz,1H),7.99-7.93(m,2H),7.83(d,J=8.1,1.5Hz,1H),7.73-7.62(m,2H),7.38(s,1H),7.31(s,1H),6.62(d,J=7.6Hz,1H),5. 03(d,J=4.7Hz,1H),4.56(t,J=5.5Hz,1H),4.40-4.26(m,1H),3.65-3.54(m,1H),3.38(t,J=6.0Hz,2H),2.34(s,3H),1.26(d,J=6.7Hz,3H).

[0319] Example 4. 9-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] Step 1-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] The title compound was prepared in a similar manner to Step 1 of Example 4 from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) and (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamine. LC-MS (Method 5B): Rt2.29 min; MS m / z489.4 / 491.1=[M+H]+ 1H NMR (500MHz, DMSO-d6) δ 8.61(d,J=7.5Hz,1H),8.00-7.93(m,2H),7.92(d,J=8.0Hz,1H),7.83(d,J=8.0H z,1H),7.69(t,J=7.8Hz,1H),7.34(s,1H),7.28(s,1H),6.45(d,J=7.6Hz,1H),4. 25(q,J=7.1Hz,1H),4.15(q,J=6.2Hz,1H),4.04(dd,J=8.4,6.5Hz,1H),3.85(dd, J=8.4,5.5Hz,1H),2.34(s,3H),1.40(s,3H),1.30(s,3H),1.24(d,J=6.6Hz,3H).

[0320] Step 2-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile The title compound was prepared in analogy to Step 2 of Example 4.8 from 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Step 1) and 2M aqueous HCl. LC-MS (Method 8B): Rt4.01 min; MS m / z449.2 / 451.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 8.57(d,J=7.5Hz,1H),8.00-7.93(m,2H),7.88-7.79(m,2H),7.70(t,J=7.7Hz,1H),7.44(s,1H),7.22(s,1H),6.52(d,J=7.6Hz,1H),4.86 (d,J=5.3Hz,1H),4.60(t,J=5.4Hz,1H),4.30-4.17(m,1H),3.75-3.66(m,1H),3.43(t,J=5.9Hz,2H),2.36(s,3H),1.18(d,J=6.7Hz,3H).

[0321] Example 4.10-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile trifluacetate [ka] Step 1 - tert-Butyl N-[2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]-1,1-dimethyl-ethyl]carbamate: [ka] The title compound was prepared in a similar manner to Step 1 of Example 4 from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) and tert-butyl N-(2-amino-1,1-dimethyl-ethyl)carbamate. LC-MS (Method 5B): Rt3.34 min; MS m / z530.3 / 532.3=[MH]- 1H NMR(500MHz,DMSO-d6)δ 8.61(d,J=7.6Hz,1H),8.02-7.92(m,3H),7.83(d,J=7.8Hz,1H),7.70(t,J=7.8Hz,1H),7.41(s,1H),7. 32(s,1H),6.67(s,1H),6.57(d,J=7.6Hz,1H),3.65(d,J=6.1Hz,2H),2.37(s,3H),1.32-1.24(m,15H).

[0322] Step 2-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile trifluoroacetate Trifluoroacetic acid (0.14 mL, 1.84 mmol) was added to a suspension of tert-butyl N-[2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]-1,1-dimethyl-ethyl]carbamate (Step 1) (65.4 mg, 0.1200 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, and the solid residue was then triturated with diethyl ether (2 mL) and acetonitrile (2 mL) to give the title compound as an off-white solid. LC-MS (Method 8B): Rt4.51 min; MS m / z432.2 / 434.2=[MH]+ 1H NMR(500MHz,DMSO-d6)δ 8.69(d,J=7.6Hz,1H),8.03(s,1H),7.99-7.94(m,2H),7.90(br s,3H),7.84-7.78(m,1H),7.69(t,J=8.0Hz,1H),7.34(s,1H),7.27(s,1H) ),6.55(d,J=7.7Hz,1H),3.62(d,J=6.2Hz,2H),2.37(s,3H),1.33(s,6H).

[0323] Example 4.11-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazetidin-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile trifluoroacetate [ka] Step 1-tert-Butyl 3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]-3-hydroxy-azetidine-1-carboxylate [ka] The title compound was prepared in a similar manner to Step 1 of Example 4 from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) and tert-butyl 3-(aminomethyl)-3-hydroxy-azetidine-1-carboxylate. LC-MS (Method 5B): Rt3.15 min; MS m / z546.2=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 8.62(d,J=7.5Hz,1H),8.16-8.06(m,1H),8.01-7.92(m,2H),7.84(d,J=7.9Hz,1H),7.70(t,J=7.8Hz,1H),7.41(s ,1H),7.24(s,1H),6.57(d,J=7.6Hz,1H),6.07(s,1H),3.91(s,2H),3.81-3.66(m,4H),2.35(s,3H),1.34(s,9H).

[0324] Step 2-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazetidin-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile trifluoroacetate The title compound was prepared in analogy to Step 2 of Example 4.10 from tert-butyl 3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]-3-hydroxy-azetidine-1-carboxylate (Step 1) and TFA. LC-MS (Method 15B): Rt8.34 min; MS m / z446.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 8.84(s,1H),8.75-8.60(m,2H),8.11(s,1H),8.02-7.91(m,2H),7.81(d,J=7.9Hz,1H),7.69(t,J=7.9Hz,1H),7.33(s,1H),7.26 (s,1H),6.58(d,J=7.6Hz,1H),6.47(s,1H),4.12-4.00(m,2H),3.86(dd,J=11.4,5.8Hz,2H),3.68(d,J=5.5Hz,2H),2.38(s,3H).

[0325] Example 5 - 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide [ka] To a suspension of 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-A]pyrimidine-5-carboxylic acid (Intermediate A) (50 mg, 0.13 mmol) in DCM (1 mL) was added DMF (1 drop) followed by oxalyl chloride (33 μL, 0.38 mmol), and the mixture was stirred at room temperature for 5 min. Additional DCM (1 mL) and oxalyl chloride (0.02 mL, 0.26 mmol) were added, and the mixture was stirred for an additional 5 min. The resulting mixture was concentrated in vacuo to give the acid chloride.

[0326] To a solution of 3-aminobicyclo[1.1.1]pentan-1-ol hydrochloride (26 mg, 0.19 mmol) and DIPEA (89 μL, 0.51 mmol) in DCM (1 mL) was added dropwise a suspension of the acid chloride in DCM (1 mL), and the mixture was stirred for 45 min. Further 3-aminobicyclo[1.1.1]pentan-1-ol hydrochloride (9 mg, 0.06 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The resulting mixture was partitioned between HO (10 mL) and DCM (10 mL), and the organic portion was separated. The aqueous solution was further extracted with DCM (2 × 10 mL), and the combined organic extracts were washed with brine (10 mL), dried over MgSO, and the solvent was removed in vacuo. Purification by silica chromatography eluting with a gradient of 0–2% MeOH / DCM afforded the title compound as a yellow solid. LC-MS (Method 8B): Rt4.32 min; MS m / z471.2 / 473.1=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 9.41(d,J=7.2Hz,1H),9.24(s,1H),8.05(s,1H),7.99(d,J=7.8Hz,1H),7.87(d,J=7.8Hz,1H),7.71(t, J=7.8Hz,1H),7.65(d,J=7.2Hz,1H),7.52(s,1H),7.33(s,1H),6.30(s,1H),2.46(s,3H),2.18(s,6H).

[0327] The compounds of the following table (Table Ex5) were prepared in analogy to Example 5 from 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (Intermediate A), oxalyl chloride and the appropriate amine.

[0328] [Table 26]

[0329] [Table 27]

[0330] [Table 28]

[0331] Example 5.8-2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide [ka] 2-(3-Cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (Step 2b of Example 92) The title compound was prepared in a manner analogous to Example 5 from oxalyl chloride and ammonium hydroxide. LC-MS (Method 8B): Rt3.74 min; MS m / z369.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 9.37(d,J=7.2Hz,1H),8.12(s,1H),8.04-8.00(m,1H),7.99-7.94(m,2H),7.86(d,J=7.9Hz,1H),7.71-7.65(m,2H),7.18(s,2H),2.41(s,6H).

[0332] Example 6 - 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide [ka] To a mixture of 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-A]pyrimidine-5-carboxylic acid (Intermediate A) (40 mg, 0.10 mmol) and (3S)-3-amino-2-methyl-butan-2-ol hydrochloride (21 mg, 0.15 mmol) in DMF (2 mL), DIPEA (89 μL, 0.51 mmol) was added dropwise, followed by T3P® (50% in DMF) (0.14 mL, 0.21 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with EtOAc (10 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with 50% brine (3 × 10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 0-3% MeOH / DCM gave the title compound as a yellow solid. LC-MS (Method 8B): Rt4.57 min; MS m / z475.2 / 477.2=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 9.45(d,J=7.1Hz,1H),8.27(d,J=9.0Hz,1H),8.10(s,1H),8.02(d,J=7.8Hz,1H),7.93(d,J=8.0Hz,1H),7. 77-7.69(m,2H),7.55(s,1H),7.30(s,1H),4.73(s,1H),3.95-3.83(m,1H),2.45(s,3H),1.22-1.13(m,9H).

[0333] The compounds of the following table (Table Ex6) were prepared in analogy to Example 6 from 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (Intermediate A), T3P®, DIPEA and the appropriate amine.

[0334] [Table 29]

[0335] [Table 30]

[0336] [Table 31]

[0337] [Table 32]

[0338] [Table 33]

[0339] [Table 34]

[0340] [Table 35]

[0341] [Table 36]

[0342] [Table 37]

[0343] [Table 38]

[0344] Example 7 - N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide [ka] Step 1-tert-Butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-1,1-dimethyl-ethyl]carbamate [ka] A solution of 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-A]pyrimidine-5-carboxylic acid (Intermediate A) (50 mg, 0.13 mmol), T3P® (50 wt % in EtOAc) (91 μL, 0.26 mmol), DIPEA (112 μL, 0.64 mmol), and tert-butyl N-(3-amino-1,1-dimethyl-propyl)carbamate (38.92 mg, 0.19 mmol) in DMF (1 mL) was stirred at 60° C. for 4 hours. The mixture was diluted with water (5 mL), and the resulting precipitate was collected by vacuum filtration. The solid was dissolved in DCM (20 mL), filtered through a phase separation cartridge, and concentrated in vacuo to give the title compound as a yellow solid. LC-MS (Method 2A): Rt1.37 min; MS m / z574.3 / 576.3=[M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 7.2 Hz, 1H), 8.70 (t, J = 5.8 Hz, 1H), 8.06 (t, J = 1.4 Hz, 1H), 8.00 (dt, J = 7.7, 1.3 Hz, 1H), 7.88 (dt, J = 7.9, 1.3 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.51 (s, 1H), 7.32 (s, 1H), 6.43 (s, 1H), 2.47 (s, 3H), 1.91 (t, J = 7.5 Hz, 2H), 1.35 (s, 9H), 1.24 (s, 6H). HSQC showed a 1× CH signal below the water peak.

[0345] Step 2: N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide A solution of tert-butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-1,1-dimethyl-propyl]carbamate (Step 1) (62 mg, 0.10 mmol) in DCM (2 mL) and 4 M HCl in 1,4-dioxane (251 μL, 1 mmol) was stirred at room temperature for 18 h. The resulting mixture was concentrated in vacuo and then purified using a 1 g Isolute® SCX cartridge eluting with 7 M NH3 in MeOH. The filtrate was concentrated in vacuo and lyophilized to give the title compound as a yellow powder. LC-MS (Method 7A): Rt2.09 min; MS m / z474.2 / 476.2=[M+H]+ 1 H NMR (500 MHz, DMSO-d₆) δ 9.57-9.51 (m, 1H), 9.41 (d, J = 7.2 Hz, 1H), 8.06 (t, J = 1.4 Hz, 1H), 8.00 (dt, J = 7.8, 1.3 Hz, 1H), 7.87 (dt, J = 7.9, 1.3 Hz, 1H), 7.75-7.68 (m, 2H), 7.38 (d, J = 12.1 Hz, 2H), 3.45 (q, J = 6.4 Hz, 2H), 2.44 (s, 3H), 1.61 (t, J = 6.8 Hz, 2H), 1.12 (s, 6H). No NH₂ protons were observed.

[0346] The compounds of the following table of examples (Table Ex7) were prepared in analogy to Example 7 from 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (Intermediate A), T3P®, DIPEA and the appropriate amine (Step 1), followed by deprotection using 4M HCl in 1,4-dioxane (Step 2).

[0347] [Table 39]

[0348] [Table 40]

[0349] Table 41

[0350] Table 42

[0351] Table 43

[0352] Table 44

[0353] Table 45

[0354] Table 46

[0355] Table 47

[0356] Table 48

[0357] Table 49

[0358]

Table 50

[0359] [Table 51]

[0360] [Table 52]

[0361] [Table 53]

[0362] [Table 54]

[0363] [Table 55]

[0364] Example 7. 19-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide [ka] Step 1: 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide [ka] The title compound was prepared in a similar manner to Step 1 of Example 7 from 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (Intermediate A) and (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamine. LC-MS (Method 5B): Rt3.08 min; MS m / z517.2 / 519.2=[M+H]+ 1H NMR (500MHz, DMSO-d6) δ 9.44(d,J=7.2Hz,1H),8.50(d,J=8.8Hz,1H),8.09(s,1H),8.01(d,J=7.9Hz ,1H),7.91(d,J=7.9Hz,1H),7.73(t,J=7.9Hz,1H),7.70(d,J=7.2Hz,1H),7 .54(s,1H),7.33(s,1H),4.23-4.17(m,1H),4.14-4.08(m,1H),4.03(dd,J= 8.7,6.6Hz,1H),3.90(dd,J=8.7,5.3Hz,1H),2.46(s,3H),1.33-1.20(m,9H)

[0365] Step 2-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide The title compound was prepared in analogy to Step 2 of Example 4.8 from 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide (Step 1) and 2M aqueous HCl. LC-MS (Method 8B): Rt3.99 min; MS m / z477.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 9.44(d,J=7.2Hz,1H),8.57(d,J=8.8Hz,1H),8.09(t,J=1.7Hz,1H),8.01(dt,J=7 .8,1.4Hz,1H),7.91(dt,J=8.1,1.4Hz,1H),7.77-7.71(m,2H),7.58(s,1H),7.25( s,1H),5.02(d,J=5.2Hz,1H),4.73(t,J=5.5Hz,1H),4.20-4.10(m,1H),3.65-3.57 (m,1H),3.53-3.47(m,1H),3.44-3.39(m,1H),2.47(s,3H),1.15(d,J=6.7Hz,3H).

[0366] Example 8 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] Step 1: 3-[3-bromo-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] To a mixture of ethyl 3-bromo-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (Intermediate A5) (96 mg, 0.26 mmol) in THF (5 mL) at 0 °C, MeMgCl (3 M in THF) (0.2 mL, 0.60 mmol) was added dropwise, and the reaction mixture was stirred for 1.5 h. The resulting mixture was diluted with DCM (40 mL) and washed with NH4Cl (2 × 20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 0–2% MeOH / DCM afforded the title compound as a colorless solid. LC-MS (Method 5B): Rt3.80 min; MS m / z357.0 / 359.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 9.16(d,J=7.2Hz,1H),8.39-8.36(m,1H),8.35-8.30(m,1H),8.01-7.98(m, 1H),7.79(t,J=7.9Hz,1H),7.46(d,J=7.2Hz,1H),5.61(s,1H),1.52(s,6H).

[0367] Step 2: 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile A mixture of 3-(3-bromo-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile (Step 1) (65 mg, 0.18 mmol), 2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (62 mg, 0.24 mmol), and K2CO3 (75 mg, 0.55 mmol) in 1,4-dioxane (3 mL) and water (0.75 mL) was degassed under a N2 flow. Pd(tBu3P)2 (9 mg, 0.02 mmol) was added, and the reaction mixture was heated to 80 °C for 15 min. The resulting mixture was cooled to room temperature, added to water (30 mL), and extracted with DCM (2 × 30 mL). The organic extract was dried over MgSO4 and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 0-10% MeOH / DCM followed by C18 reverse phase chromatography eluting with a gradient of 40-80% MeCN / water (+0.1 wt% NH4OH) and a final re-purification by silica eluting with a gradient of 0-10% MeOH / DCM gave the title compound as a colorless solid. LC-MS (Method 15B): Rt7.79 min; MS m / z404.1 / 406.0=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 9.23(d,J=7.3Hz,1H),8.05(s,1H),8.00(d,J=7.7Hz,1H),7.89(d,J=7.8Hz,1H),7.72(t,J=7.8 Hz,1H),7.52(d,J=7.3Hz,1H),7.42(s,1H),7.35(s,1H),5.64(s,1H),2.39(s,3H),1.54(s,6H).

[0368] Example 9 (= Intermediate A) - 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid [ka] A solution of lithium hydroxide (273 mg, 11.42 mmol) in water (20 mL) was added to a stirred, portion-wise suspension of ethyl 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-A]pyrimidine-5-carboxylate (Intermediate A6) (1.59 g, 3.81 mmol) in 1,4-dioxane (50 mL), and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was partitioned between HO (100 mL) and EtO (100 mL). The organic fraction was removed, and the aqueous portion was acidified with 2 M HCl. The resulting solid was collected by filtration and azeotroped from MeOH (×2) to give the title compound as a yellow solid. LC-MS (Method 3B): Rt1.09 min; MS m / z390.1=[M+H]+ 1H NMR (500 MHz, DMSO-d6) δ 9.37 (d, J = 7.2 Hz, 1H), 8.06 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 2.42 (s, 3H). No OH protons were observed.

[0369] Example 10 - 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide [ka] A solution of 3-bromo-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide (Intermediate B) (85 mg, 0.21 mmol) in 1,4-dioxane (2 mL) and water (0.40 mL) was degassed with N and treated with (2,6-dimethyl-4-pyridyl)boronic acid (46 mg, 0.31 mmol), KCO (57 mg, 0.41 mmol), and Pd(tBuP) (5 mg, 0.01 mmol). The resulting mixture was heated to 50 °C for 1 h. Additional (2,6-dimethyl-4-pyridyl)boronic acid (46 mg, 0.31 mmol), KCO (57 mg, 0.41 mmol), and Pd(tBuP) (5 mg, 0.01 mmol) were added, and the reaction mixture was heated to 50° C. for an additional 1 h. Additional (2,6-dimethyl-4-pyridyl)boronic acid (46 mg, 0.31 mmol) was added in two portions 30 min apart, and the reaction mixture was heated to 50° C. for an additional 30 min. Additional 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (48 mg, 0.21 mmol), Pd(tBuP) (5 mg, 0.01 mmol), and KCO (57 mg, 0.41 mmol) in water (0.2 mL) were added, and the mixture was heated to 50 °C for an additional 1 h, after which the reaction was cooled to room temperature. The resulting mixture was partitioned between HO (15 mL) and EtOAc (20 mL), the organic portion was separated, and the aqueous solution was further extracted with EtOAc (2 × 25 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 2–5% MeOH / DCM afforded the title compound as a yellow solid. LC-MS (Method 8B): Rt4.06 min; MS m / z441.3=[M+H]+ 1H NMR (500 MHz, DMSO-d₆) δ 9.42 (d, J = 7.1 Hz, 1H), 8.37 (t, J = 6.1 Hz, 1H), 8.06 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.70 (t, J = 7.1 Hz, 1H), 7.22 (s, 2H), 4.75 (s, 1H), 2.40 (s, 6H), 1.16 (s, 6H). No CH₂ signal was observed.

[0370] Example 12 - 2-(3-cyanophenyl)-3-(2-ethylpyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide [ka] A mixture of 3-bromo-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-A]pyrimidine-5-carboxamide (Intermediate B) (60 mg, 0.14 mmol), (2-ethylpyrazol-3-yl)boronic acid (22 mg, 0.16 mmol), and K2CO3 (40 mg, 0.29 mmol) in 1,4-dioxane (1 mL) and water (0.20 mL) was degassed under a N2 flow. Pd(tBu3P)2 (4 mg, 0.01 mmol) was added, and the reaction mixture was heated to 50 °C for 2 h. Additional (2-ethylpyrazol-3-yl)boronic acid (11 mg, 0.08 mmol) was added, and the mixture was heated for an additional 1 h. After cooling to room temperature, the resulting mixture was partitioned between HO (15 mL) and EtOAc (20 mL), the organic portion was separated, and the aqueous liquid was further extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over NaSO and concentrated in vacuo. Purification by silica chromatography eluting with 3% MeOH / DCM gave the title compound as a yellow solid. LC-MS (Method 8B): Rt3.95 min; MS m / z430.3=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 9.44(d,J=7.2Hz,1H),8.21(t,J=6.2Hz,1H),7.94-7.90(m,2H),7.84(d,J=8.0Hz,1H),7.73(d,J=7.2Hz,1H),7.67(t,J=8.0Hz,1H),7.6 3(d,J=1.7Hz,1H),6.33(d,J=1.7Hz,1H),4.69(s,1H),3.94(q,J=7.2Hz,2H),3.29(d,J=6.2Hz,2H),1.20(t,J=7.2Hz,3H),1.09(s,6H).

[0371] The compounds of the examples shown in the table below (Table Ex12) were prepared in analogy to Example 12 from 3-bromo-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide (Intermediate B) and the appropriate boronic acid or boronic ester.

[0372] [Table 56]

[0373] [Table 57]

[0374] [Table 58]

[0375] Example 13 - 2-(3-Cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxamide [ka] To a degassed solution of 3-bromo-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide (Intermediate B) (50 mg, 0.12 mmol) in THF (2 mL) was added tributyl(pyrimidin-4-yl)stannane (0.04 mL, 0.13 mmol), copper(I) chloride (14 mg, 0.14 mmol), lithium chloride (6 mg, 0.14 mmol), and Pd(PPh) (14 mg, 0.01 mmol), and the mixture was heated to 90 °C for 3 h. After the mixture was cooled to room temperature and further degassed, additional tributyl(pyrimidin-4-yl)stannane (89 mg, 0.24 mmol) and Pd(PPh) (14 mg, 0.01 mmol) were added, and the mixture was heated for 1 h. The resulting mixture was cooled to room temperature and partitioned between EtOAc (15 mL) and HO (15 mL). The organic portion was separated and the aqueous liquid was further extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with 5% aqueous KF (2 × 20 mL), brine (2 × 20 mL), dried over NaSO, and the solvent was removed in vacuo. Purification by silica chromatography eluting with a gradient of 2–4% MeOH / DCM gave a yellow solid. This solid was suspended in hexane, filtered, washed with EtO, and dried to give the title compound as a yellow solid. LC-MS (Method 8B): Rt3.61 min; MS m / z414.2=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 9.49(d,J=7.1Hz,1H),9.02(s,1H),8.86(d,J=5.3Hz,1H),8.61(t,J=6.2Hz,1H),8.44(d,J=5.3Hz,1H),8.16(s,1H),8.04(d,J= 7.8Hz,1H),7.96(d,J=7.8Hz,1H),7.79(d,J=7.1Hz,1H),7.70(t,J=7.8Hz,1H),4.77(s,1H),3.36(d,J=6.2Hz,2H),1.17(s,6H).

[0376] Example 14 - 3-Cyano-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide [ka] To a degassed solution of 3-bromo-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide (Intermediate B) (50 mg, 0.12 mmol) in DMA (2 mL) was added zinc dust (16 mg, 0.24 mmol), zinc cyanide (34 mg, 0.29 mmol), and Pd(dppf)Cl₂·CHCl₂ (10 mg, 0.01 mmol), and the mixture was heated to 120 °C for 2 h. The mixture was cooled to room temperature, Pd(tBuP)₂ (6 mg, 0.01 mmol) was added, and stirring was continued for 1.5 h. The resulting mixture was diluted with EtOAc (5 mL) and filtered through cotton wool. The mixture was diluted with 25 mL of EtOAc and 20 mL of HO. The organic portion was separated, and the aqueous solution was further extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (4 x 20 mL), dried over NaSO, and the solvent was removed in vacuo. Purification by silica chromatography eluting with 2% MeOH / DCM gave a colorless solid. This solid was suspended in EtO, collected by filtration, and dried to give the title compound as a colorless solid. LC-MS (Method 8B): Rt3.84 min; MS m / z359.2=[MH]- 1 H NMR(500MHz,DMSO-d6)δ 9.58(d,J=7.1Hz,1H),8.62(t,J=6.2Hz,1H),8.46(s,1H),8.42(d,J=7.9Hz,1H),8.12(d,J=7.9Hz,1H),7.90(t,J=7.9Hz,Overlap d,J=7.1Hz,2H),4.79(s,1H),3.36(d,J=6.2Hz,2H),1.16(s,6H).

[0377] Example 15-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] A 1 M solution of LiHMDS (0.24 mL, 0.24 mmol) in THF was added to a solution of 2-methylpropane-1,2-diol (0.02 mL, 0.24 mmol) in THF (1 mL), and the mixture was stirred at room temperature for 15 minutes. 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) (70 mg, 0.18 mmol) was added, and stirring was continued at room temperature overnight. The resulting mixture was partitioned between EtOAc (5 mL) and water (3 mL), and the organic portion was separated. The aqueous layer was further extracted with EtOAc (2 × 5 mL), and the combined organic extracts were dried over NaSO and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 2–6% MeOH / DCM afforded the title compound as a colorless solid. LC-MS (Method 8B): Rt4.70 min; MS m / z434.2 / 436.2=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 9.07(d,J=7.5Hz,1H),8.02(s,1H),7.99(d,J=7.8Hz,1H),7.86(d,J=7.8Hz,1H),7.71(t,J=7.8Hz,1H) ,7.35(s,1H),7.31(s,1H),6.80(d,J=7.5Hz,1H),4.77(s,1H),4.24(s,2H),2.39(s,3H),1.24(s,6H).

[0378] Example 16-N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methanesulfonamide [ka] DBU (0.03 mL, 0.22 mmol) was added to a solution of 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) (70 mg, 0.18 mmol) and methanesulfonamide (21 mg, 0.22 mmol) in NMP (1 mL), and the reaction mixture was stirred at 40° C. for 90 min. Additional methanesulfonamide (21 mg, 0.22 mmol) was added, and stirring was continued at 40° C. for 1 h. Additional methanesulfonamide (21 mg, 0.22 mmol) and DBU (0.03 mL, 0.22 mmol) were added, and the reaction mixture was stirred at 40° C. overnight. The resulting mixture was diluted with MeOH (2 mL) and water (0.5 mL), and the crude product was purified sequentially under the following conditions: C18 reverse-phase chromatography eluting with a gradient of 5-25% MeCN / water (+0.1 wt% NH4OH), followed by silica chromatography eluting with a gradient of 0-8% MeOH / DCM. This material was then purified by C18 reverse-phase chromatography with a gradient of 30-45% MeCN / water (+0.1 wt% formic acid), reverse-phase purification eluting with a gradient of 5-25% MeCN / water (+0.1 wt% NH4OH), and finally silica chromatography eluting with a gradient of 0-8% MeOH / DCM to give the title compound as an off-white solid. LC-MS (Method 8B): Rt3.08 min; MS m / z439.1 / 441.1=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 11.64(s,1H),9.05(d,J=7.4Hz,1H),8.04(s,1H),8.00(d,J=7.8Hz,1H),7.88(d,J=7.9Hz,1H),7 .72(t,J=7.8Hz,1H),7.42(s,1H),7.34(s,1H),6.69(d,J=7.4Hz,1H),3.46(s,3H),2.38(s,3H).

[0379] Example 16. 1-1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]guanidine [ka] The title compound was prepared in a similar manner to Example 16 from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C), guanidine hydrochloride, and DBU (5 equivalents) at 100° C. LC-MS (Method 8B): Rt4.05 min; MS m / z403.2=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 8.63(d,J=7.5Hz,1H),7.98(t,J=1.7Hz,1H),7.94(dt,J=7.7,1.4Hz,1H),7.83(dt,J=8.0,1.5Hz,1H), 7.68(t,J=7.8Hz,1H),7.54-7.27(m,4H),7.24(s,1H),7.15(s,1H),6.36(d,J=7.4Hz,1H),2.39(s,3H).

[0380] Example 17-(2S)-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]propanoic acid [ka] Step 1: Methyl (2S)-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]propanoate [ka] Methyl (2S)-2-aminopropanoate (25 mg, 0.24 mmol) was added to a suspension of DIPEA (0.1 mL, 0.55 mmol) and 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) (70 mg, 0.18 mmol) in DMF (1 mL), and the mixture was stirred at 50° C. overnight and then at 70° C. for 1 hour. Additional methyl (2S)-2-aminopropanoate (25 mg, 0.24 mmol) and DIPEA (0.1 mL, 0.55 mmol) were added, and the mixture was stirred at 70° C. overnight. After cooling to room temperature, the resulting mixture was partitioned between EtOAc (20 mL) and water (20 mL). The aqueous layer was separated and the organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica chromatography eluting with a gradient of 2-10% MeOH / DCM gave the title compound as an orange oil. LC-MS (Method 5A): Rt2.96 min; MS m / z447.2=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 8.68(d,J=7.5Hz,1H),8.40(d,J=6.0Hz,1H),7.99-7.95(m,2H),7.83(dt,J=7.9,1.5Hz,1H),7.70(t,J=7.8Hz,1H),7.30 (d,J=1.2Hz,1H),7.18(s,1H),6.55(d,J=7.5Hz,1H),4.53-4.44(m,1H),3.63(s,3H),2.37(s,3H),1.48(d,J=7.2Hz,3H).

[0381] Step 2: (2S)-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]propanoic acid A solution of LiOH (11 mg, 0.46 mmol) in water (1 mL) was added to a solution of methyl (2S)-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-A]pyrimidin-5-yl]amino]propanoate (Step 1) (82 mg, 0.18 mmol) in THF (2 mL), and the mixture was stirred at room temperature for 30 min. The resulting mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, and the aqueous portion was acidified to approximately pH 1 with 2 M HCl (aq). The mixture was extracted with EtOAc (20 mL), and the organic portion was dried over NaSO, filtered, and concentrated in vacuo. Purification by C18 reverse-phase chromatography eluting with a gradient of 20–45% MeCN / water (+0.1% formic acid by weight) afforded the title compound as an off-white solid. LC-MS (Method 8A): Rt4.29 min; MS m / z433.3 / 435.2=[M+H]+ 1 H NMR (500 MHz, DMSO-d₆) δ 8.63 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 8.00-7.92 (m, 2H), 7.84 (d, J = 7.8 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.47 (s, 1H), 7.15 (s, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.36-4.24 (m, 1H), 2.38 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H). No OH protons were observed.

[0382] Example 18 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile formate [ka] Step 1: tert-butyl (3R)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypyrrolidine-1-carboxylate [ka] NaH (10 mg, 0.24 mmol) was added to a solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (45 mg, 0.24 mmol) in THF (1 mL), and the mixture was stirred at room temperature for 45 minutes. To this mixture was added 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Intermediate C) (70 mg, 0.18 mmol), and stirring was continued at room temperature overnight. The resulting mixture was partitioned between EtOAc (5 mL) and water (3 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 × 5 mL). The organic layers were combined, dried over NaSO, and concentrated in vacuo to give the title compound as an orange gum. LC-MS (Method 3B): Rt2.96 min; MS m / z531.2=[M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 9.15(d,J=7.4Hz,1H),8.10-8.07(m,1H),8.05(dt,J=7.7,1.4Hz,1H),7.9 2(dt,J=7.9,1.4Hz,1H),7.77(t,J=7.8Hz,1H),7.42-7.33(m,2H),6.87(d, J=7.5Hz,1H),5.61(s,1H),3.88-3.71(m,1H),3.59-3.51(m,1H),3.20-3. 10(m,1H),2.46(s,3H),2.37-2.26(m,2H),1.84-1.72(m,1H),1.45(s,9H).

[0383] Step 2: 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile formate 4M HCl in 1,4-dioxane (0.46 mL, 1.84 mmol) was added to a suspension of tert-butyl (3R)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypyrrolidine-1-carboxylate (Step 1) (98 mg, 0.18 mmol) in MeOH (0.50 mL), and the mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo and purified by C18 reverse phase eluting with a gradient of 5-90% MeCN / water (+0.1 wt% NH4OH) followed by 5-60% MeCN / water (+0.1 wt% formic acid) to give the title compound as a brown solid. LC-MS (Method 15B): Rt8.86 min; MS m / z431.1 / 433.0=[MH]+ 1 H NMR(500MHz,DMSO-d6)δ 9.07(d,J=7.5Hz,1H),8.35(s,1H),8.02(d,J=1.9Hz,1H),7.99(d,J=7.8Hz,1H),7.86( d,J=7.9Hz,1H),7.72(t,J=7.8Hz,1H),7.35(s,1H),7.31(s,1H),6.75(d,J=7.4Hz,1H) , 5.47 (t, J = 6.0 Hz, 1H), 3.28 (dd, J = 12.9, 5.5 Hz, 1H), 3.17-3.11 (m, 1H), 2.99 (dd, J = 20.9, 12.9 Hz, 2H), 2.40 (s, 3H), 2.25-2.11 (m, 1H), 2.07-1.96 (m, 1H). No NH protons were observed.

[0384] Example 19 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] Step 1: 3-[3-bromo-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] 2-Aminoethanol (0.09 mL, 1.5 mmol) was added to a suspension of 3-(3-bromo-5-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile (Intermediate E1) (100 mg, 0.30 mmol) in DMF (1 mL) and stirred at 90° C. for 30 minutes. The resulting mixture was cooled to room temperature and added dropwise to stirred water (20 mL). The precipitate was collected by filtration and washed with water (2×5 mL). The solid was azeotroped from acetone (30 ml) to give the title compound as an off-white solid. LC-MS (Method 5A): Rt2.31 min; MS m / z358.0 / 360.1=[M+2+H]+ 1 H NMR(500MHz,DMSO-d6)δ 8.53(d,J=7.5Hz,1H),8.31-8.29(m,1H),8.26(dt,J=7.9,1.4Hz,1H),7.93(dt,J=7.7,1.4Hz,1H),7.86(br s,1H),7.74(t,J=7.8Hz,1H),6.46(d,J=7.6Hz,1H),4.83(t,J=5.1Hz,1H),3.62(q,J=5.7Hz,2H),3.52-3.45(m,2H).

[0385] Step 2: 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile A solution of 3-[3-bromo-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Step 1) (107 mg, 0.30 mmol), (2-chloro-6-methyl-4-pyridyl)boronic acid (77 mg, 0.45 mmol), and KCO (83 mg, 0.60 mmol) in water (1 mL) and 1,4-dioxane (4 mL) was degassed under a N flow and treated with Pd(BuP) (23 mg, 0.04 mmol). The reaction mixture was stirred at 100 °C for 45 min and then cooled to room temperature. The reaction mixture was adsorbed onto silica and purified by silica chromatography eluting with a gradient of 2-10% MeOH / DCM followed by C18 reverse-phase chromatography eluting with a gradient of 20-50% MeCN / water (+0.1 wt % NHOH) to give the title compound as a colorless solid. LC-MS (Method 8A): Rt6.88 min; MS m / z405.1 / 407.0=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 8.58(d,J=7.6Hz,1H),8.05-7.99(m,1H),8.00-7.95(m,2H),7.82(dt,J=7.9,1.4Hz,1H),7.69(td,J=7.8,0.8Hz,1H),7. 37-7.30(m,2H),6.51(d,J=7.6Hz,1H),4.83(t,J=5.2Hz,1H),3.67(q,J=5.6Hz,2H),3.49(q,J=5.6Hz,2H),2.34(s,3H).

[0386] Example 20 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] Step 1: 3-[5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] A suspension of 3-(5-chloropyrazolo[1,5-A]pyrimidin-2-yl)benzonitrile (Intermediate C2) (200 mg, 0.79 mmol), potassium (morpholin-4-yl)methyltrifluoroborate (195 mg, 0.94 mmol), and cesium carbonate (640 mg, 1.96 mmol) in a mixture of water (0.50 mL) and 1,4-dioxane (5 mL) was treated with Pd(tBuP) (40 mg, 0.08 mmol) under nitrogen and stirred at 90 °C for 1 h. After cooling to room temperature, the resulting mixture was diluted with water (50 mL), and the precipitate was collected by filtration and washed with water (2 × 5 mL). The solid was suspended in acetone, filtered, and washed with acetone (2 × 5 mL). The filtrate was concentrated in vacuo to give the title compound as an off-white solid. LC-MS (Method 3A): Rt1.14 min; MS m / z320.2=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 9.08(dd,J=7.2,0.9Hz,1H),8.47(t,J=1.7Hz,1H),8.37(dt,J=8.0,1.4Hz,1H),7.90(dt,J=7.6,1.4Hz,1H),7.72 (t,J=7.8Hz,1H),7.32(d,J=0.9Hz,1H),7.16(d,J=7.2Hz,1H),3.65(s,2H),3.64-3.61(m,4H),2.49-2.45(m,4H).

[0387] Step 2: 3-[3-iodo-5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] A suspension of 3-[5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Step 1) (203 mg, 0.64 mmol), N-iodosuccinimide (157 mg, 0.70 mmol) in MeCN (6 mL) and DMF (3 mL) was stirred at room temperature for 1.5 hours. Additional N-iodosuccinimide (157 mg, 0.70 mmol) was added, and the reaction mixture was stirred at room temperature for 45 minutes. The resulting mixture was added dropwise to stirred water (50 mL), and the precipitate was collected by filtration and washed with water (2 x 5 mL). The solid was azeotroped from acetone (20 ml) to give the title compound as a brown solid. LC-MS (Method 5B): Rt2.99 min; MS m / z446.0=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 9.40(d,J=7.1Hz,1H),8.46-8.27(m,2H),8.07-7.98(m,1H),7.88-7.75(m,1H),7.29(d,J =7.1Hz,1H),4.77-4.60(m,2H),4.14-3.96(m,2H),3.89-3.67(m,4H),3.70-3.52(m,2H).

[0388] Step 3: 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile A mixture of 3-[3-iodo-5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (Step 2) (170 mg, 0.24 mmol), (2-chloro-6-methyl-4-pyridyl)boronic acid (61 mg, 0.36 mmol), and potassium carbonate (65 mg, 0.47 mmol) in water (1 mL) and 1,4-dioxane (4 mL) was degassed with N and treated with Pd(tBuP) (18 mg, 0.04 mmol). After stirring at 80 °C for 2 h 30 min, additional (2-chloro-6-methyl-4-pyridyl)boronic acid (61 mg, 0.36 mmol) and Pd(tBuP) (18 mg, 0.04 mmol) were added, and stirring was continued at 80 °C for 45 min. The resulting mixture was cooled to room temperature, and the crude mixture was adsorbed onto silica. Purification by silica chromatography eluting with a gradient of 2-10% MeOH / DCM followed by C18 reverse phase chromatography eluting with a gradient of 35-55% MeCN / water (+0.1 wt% NH4OH) gave the title compound as a yellow solid. LC-MS (Method 15B): Rt7.75 min; MS m / z445.1 / 447.0=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 9.21(d,J=7.1Hz,1H),8.05-8.03(m,1H),7.99(dt,J=7.8,1.4Hz,1H),7.86(dt,J=8.0,1.4Hz,1H),7.71(t,J=7.8Hz,1H) ,7.39(s,1H),7.34(d,J=7.2Hz,1H),7.33-7.31(m,1H),3.74(s,2H),3.67-3.60(m,4H),2.54-2.49(m,4H),2.41(s,3H).

[0389] Example 20. 1-3-[3-(2,6-dimethyl-4-pyridyl)-5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile trifluoroacetate [ka] Step 1: tert-butyl 4-[[2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methyl]piperazine-1-carboxylate [ka] The title compound was prepared in analogy to Step 1 of Example 20 from 3-(5-chloropyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile (Intermediate C2) and potassium (4-tert-butoxycarbonylpiperazin-1-yl)methyltrifluoroborate. LC-MS (Method 5B): Rt3.04 min; MS m / z419.6=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 9.08(d,J=7.2Hz,1H),8.47(t,J=1.7Hz,1H),8.37(dt,J=7.9,1.5Hz,1H),7.90(dt,J=7.7,1.4Hz,1H),7.72(t,J=7.8 Hz,1H),7.36-7.27(m,1H),7.16(d,J=7.2Hz,1H),3.67(s,2H),3.38-3.33(m,4H),2.43(t,J=5.1Hz,4H),1.40(s,9H).

[0390] Step 2: tert-butyl 4-[[2-(3-cyanophenyl)-3-iodo-pyrazolo[1,5-a]pyrimidin-5-yl]methyl]piperazine-1-carboxylate [ka] The title compound was prepared in a similar manner to Step 2 of Example 20 from tert-butyl 4-[[2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methyl]piperazine-1-carboxylate (Step 1) and N-iodosuccinimide. LC-MS (Method 5B): Rt3.42 min; MS m / z545.1=[M+H]+ 1H NMR(500MHz,DMSO-d6)δ 9.13(d,J=7.2Hz,1H),8.34(d,J=1.7Hz,1H),8.32-8.26(m,1H),7.99(dt,J=7.9,1.5Hz,1H),7.80(t,J =7.8Hz,1H),7.26(d,J=7.1Hz,1H),3.73(s,2H),3.41-3.35(m,4H),2.45(t,J=5.1Hz,4H),1.41(s,9H).

[0391] Step 3: tert-butyl 4-[[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]methyl]piperazine-1-carboxylate [ka] The title compound was prepared in a similar manner to Step 3 of Example 20 from tert-butyl 4-[[2-(3-cyanophenyl)-3-iodo-pyrazolo[1,5-a]pyrimidin-5-yl]methyl]piperazine-1-carboxylate (Step 2) and bis(tri-tert-butylphosphine)palladium(0). LC-MS (Method 5B): Rt3.09 min; MS m / z522.4=[MH]- 1H NMR(500MHz,DMSO-d6)δ 9.18(d,J=7.3Hz,1H),7.99(t,J=1.7Hz,1H),7.95(d,J=7.7Hz,1H),7.87-7.80(m,1H),7.68(t,J=7.8Hz,1H),7.2 8(d,J=7.1Hz,1H),7.12(s,2H),3.74(s,2H),3.39-3.35(m,4H),2.47(t,J=4.9Hz,4H),2.39(s,6H),1.40(s,9H).

[0392] Step 4: 3-[3-(2,6-dimethyl-4-pyridyl)-5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile trifluoroacetate Trifluoroacetic acid (0.15 mL, 1.91 mmol) was added to a suspension of tert-butyl 4-[[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]methyl]piperazine-1-carboxylate (Step 3) (67 mg, 0.13 mmol) in DCM (1 mL) and stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, and the solid residue was triturated with diethyl ether (2 mL) and acetonitrile (2 mL) to give the title compound as a yellow solid. LC-MS (Method 8B): Rt4.17 min; MS m / z424.3=[M#H]+ 1H NMR(500MHz,DMSO-d6)δ 9.35(d,J=7.2Hz,1H),8.59(s,2H),8.09-8.02(m,2H),7.90(d,J=7.9Hz,1H),7.78-7.64( m,3H),7.44(d,J=7.2Hz,1H),3.89(s,2H),3.18(s,4H),2.75(t,J=4.8Hz,4H),2.60(s,6H)

[0393] Example 21 - 3-[5-(aminomethyl)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] Step 1: tert-butyl N-[[2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methyl]carbamate [ka] A mixture of 3-(5-chloropyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile (Intermediate C2) (200 mg, 0.79 mmol), potassium (tert-butoxycarbonylamino)methyltrifluoroborate (223 mg, 0.94 mmol), and cesium carbonate (640 mg, 1.96 mmol) in water (0.50 mL) and 1,4-dioxane (5 mL) was degassed with N and treated with Pd(PPh)Cl (56 mg, 0.08 mmol). After stirring overnight at 90 °C, additional Pd(PPh)Cl (56 mg, 0.08 mmol) was added, and stirring was continued at 100 °C for 3 h. Additional potassium (tert-butoxycarbonylamino)methyltrifluoroborate (93 mg, 0.39 mmol) and Pd(tBuP) (40 mg, 0.08 mmol) were added sequentially, and the mixture was stirred at 100° C. for 3 h. The resulting mixture was partitioned between EtOAc (50 mL) and water (50 mL), the mixture was filtered, and the recovered material was washed with EtOAc (10 mL). The organic layer was separated, washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to provide the title compound as a black oil. LC-MS (Method 5A): Rt 2.85 min; MS m / z250.1[M-Boc+H]+ 1H NMR(500MHz,DMSO-d6)δ 9.09(d,J=7.2Hz,1H),8.48(s,1H),8.42-8.33(m,1H),7.90(dt,J=7.6,1.3Hz,1H),7.72(t,J=7.8 Hz,1H),7.67-7.60(m,1H),7.31(s,1H),7.05(d,J=7.6Hz,1H),4.28(d,J=6.2Hz,2H),1.37(s,9H).

[0394] Step 2: tert-butyl N-[[2-(3-cyanophenyl)-3-iodo-pyrazolo[1,5-a]pyrimidin-5-yl]methyl]carbamate [ka] A solution of tert-butyl N-[[2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methyl]carbamate (Step 1) (274 mg, 0.79 mmol), N-iodosuccinimide (265 mg, 1.18 mmol), and MeCN (7 mL) was stirred at room temperature for 3 h. The resulting mixture was adsorbed onto silica and purified by chromatography eluting with a gradient of 1-3% MeOH / DCM to give the title compound as a brown oil. LC-MS (Method 5A): Rt3.18 min; MS m / z376.0=[M-Boc+H]+ 1 H NMR(500MHz,DMSO-d6)δ 9.13(d,J=7.1Hz,1H),8.35(t,J=1.7Hz,1H),8.33-8.27(m,1H),8.03-7.97(m,1H),7.80(t,J=7. 9Hz,1H),7.61(t,J=6.2Hz,1H),7.05(d,J=7.2Hz,1H),4.33(dd,J=6.4,3.1Hz,2H),1.37(s,9H).

[0395] Step 3: tert-butyl N-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methyl]carbamate [ka] A mixture of tert-butyl N-[[2-(3-cyanophenyl)-3-iodo-pyrazolo[1,5-a]pyrimidin-5-yl]methyl]carbamate (Step 2) (65 mg, 0.14 mmol), (2-chloro-6-methyl-4-pyridyl)boronic acid (35 mg, 0.21 mmol), and potassium carbonate (38 mg, 0.27 mmol) in water (0.50 mL) and 1,4-dioxane (2 mL) was degassed with N and treated with Pd(tBuP) (11 mg, 0.02 mmol). After stirring at 80 °C for 45 min, the resulting mixture was cooled to room temperature and adsorbed onto silica. Purification by silica chromatography eluting with a gradient of 1–8% MeOH / DCM afforded the title compound as a brown solid. LC-MS (Method 5A): Rt3.31 min; MS m / z475.0=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 9.22(d,J=7.2Hz,1H),8.05(d,J=1.9Hz,1H),7.99(dt,J=7.8,1.4Hz,1H),7.87(d,J=7.9Hz,1H),7.71(t,J=7.8Hz,1H), 7.60(t,J=6.1Hz,1H),7.39(s,1H),7.34(s,1H),7.15(d,J=7.2Hz,1H),4.35(d,J=6.2Hz,2H),2.41(s,3H),1.41(s,9H).

[0396] Step 4: 3-[5-(aminomethyl)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile 4 M HCl in 1,4-dioxane (0.34 mL, 1.37 mmol) was added to a suspension of tert-butyl N-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methyl]carbamate (Step 3) (65 mg, 0.14 mmol) in MeOH (0.50 mL), and the mixture was stirred at room temperature for 2 h. The crude reaction mixture was concentrated in vacuo and purified by C18 reverse-phase chromatography eluting with a gradient of 5-45% MeCN / water (+0.1 wt% NH4OH) to give the title compound as an off-white solid. LC-MS (Method 8B): Rt4.01 min; MS m / z375.2 / 377.2=[M+H]+ 1 H NMR(500MHz,DMSO-d6)δ 9.21(d,J=7.2Hz,1H),8.04(t,J=1.7Hz,1H),7.99(dt,J=7.7,1.4Hz,1H),7.87(dt,J=7.9,1.4Hz,1 H),7.71(t,J=7.8Hz,1H),7.39-7.37(m,2H),7.37-7.35(m,1H),3.92(s,2H),2.41(s,3H),2.20(br s,2H).

[0397] Example 22-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] Step 1: 3-[5-(3-hydroxy-3-methyl-but-1-ynyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile [ka] A mixture of 2...

Claims

1. A compound having the structural formula li3 shown below, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the formula, R ０ is hydrogen, R １ｚ is cyano, R ３ is a group of the formula: 【Chemistry 2】 (In the formula, R ３ａ is hydrogen or methyl), A is CH or N; R ２０１ is selected from methyl or chloro).

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from any one of the following: 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; or 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide.

3. A compound which is 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

4. A compound which is 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

5. A compound which is 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

6. A compound which is 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

7. A compound which is 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

8. A compound which is 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.

10. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for use in therapy.

11. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9, for use in therapy in combination with at least one additional therapeutic agent.

12. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, (i) treatment of cell proliferative conditions; (ii) the treatment of cancer; (iii) the treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more additional anti-cancer agents; (iv) the treatment of cancer, wherein said compound or pharmaceutical composition is 1) other forms of cancer immunotherapy and anti-cancer chemotherapeutic agents; 2) Adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors; 3) anti-PD-1 and PDL-1 antibodies; and 4) Anti-CTLA4 antibody and (iii) administering the compound in combination with one or more additional anti-cancer agents selected from the group consisting of:

2. A compound or pharmaceutical composition for use in

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