Antagonists of the adenosine a2a receptor

Abstract

The present invention relates to compounds having the formula I: wherein R0, R1, R2, R3 and A are each as defined in the application. The invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or conditions associated with adenosine A2a receptor activity, such as cancer.

Description

[0001] introduction

[0002] This invention relates to certain compounds used as antagonists of adenosine A2a receptors. Furthermore, some of these compounds are also antagonists of A2b receptors. The invention also relates to methods for preparing these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or conditions (e.g., cancer) associated with adenosine A2a receptor activity. Background Technology

[0003] Many immunosuppressive pathways are active in the tumor microenvironment, enabling tumor cells to evade elimination by cytotoxic T cells and reducing clinical response to anti-checkpoint antibody immunotherapy. Anti-PD-1 antibodies pembrolizumab and nivolumab, as well as anti-PD-L1 antibodies durvalumab, avelumab, and atezolizumab, are approved for the treatment of various solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma. However, only 20%–30% of patients respond to checkpoint blockade, and the side effects of such treatments are significant (Sukari et al., 2016). Therefore, other approaches to enhance the cytotoxic potential of the tumor microenvironment are being actively investigated. This includes agents that can be used as monotherapy, or agents that are more likely to be used in combination with checkpoint inhibitors and cytotoxic agents to enhance their efficacy.

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

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

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

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

[0008] The effects of A2a gene deficiency in mouse models are modeled through pharmacological blockade of A2a. A2a antagonists have been shown to enhance cytotoxic CD8+ T cells and improve the ability of NK cells to prevent metastasis of CD73-expressing tumors (Beavis et al., 2013). Importantly, A2a antagonists enhance the efficacy of anti-PD1 antibodies (Beavis et al., 2015).

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

[0010] However, there is still a need for second-generation compounds that are effective adenosine A2a antagonists. In particular, there is a need for compounds that are both effective and selective adenosine A2a antagonists, and in some cases, compounds that are both effective and selective adenosine A2a and A2b antagonists. There is also a need for compounds that are effective adenosine A2a antagonists or adenosine A2a and A2b antagonists, and that remain active in the presence of high concentrations of adenosine in the tumor microenvironment. Summary of the Invention

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

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

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

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

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

[0016] According to another aspect of the invention, a method is provided for treating a disease or disorder related to adenosine A2a receptor activity in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

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

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

[0019] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions thereof, are provided for use in therapy.

[0020] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, are provided for use in the treatment of proliferative disorders. Suitably, the compounds or pharmaceutical compositions are administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0021] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions thereof, are provided for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[0022] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided for use as adenosine A2a antagonists. In examples, the compounds of the invention are selective adenosine A2a antagonists. In alternative examples, certain compounds of the invention are selective adenosine A2a and adenosine A2b antagonists.

[0023] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided for use in the treatment of diseases or disorders associated with adenosine A2a.

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

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

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

[0027] According to another aspect of the invention, the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the manufacture of a medicament for treating diseases or disorders associated with adenosine A2a is provided.

[0028] According to another aspect of the invention, a method is provided for preparing compounds as defined herein or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0029] According to another aspect of the invention, there are provided compounds or pharmaceutically acceptable salts, hydrates or solvates thereof that are obtainable by, or obtained by, or directly obtained by methods for preparing compounds as defined herein.

[0030] According to another aspect of the invention, novel intermediates as defined herein are provided that are suitable for any of the synthetic methods described herein.

[0031] Features relating to one aspect of the invention (including optional, suitable, and preferred features) can also be features relating to any other aspect of the invention (including optional, suitable, and preferred features). Detailed Implementation

[0032] definition

[0033] Unless otherwise stated, the following terms used in the specification and claims have the same meanings as stated below.

[0034] It should be understood that the term “treating” as used here includes prevention and relief of established symptoms of a condition. “Treating” of a state, disorder, or symptom includes: (1) preventing or delaying the onset of clinical symptoms of a state, disorder, or symptom that develops in a person who may have or is susceptible to the state, disorder, or symptom but has not yet experienced or shown clinical or subclinical symptoms of the state, disorder, or symptom; (2) suppressing the state, disorder, or symptom, i.e., preventing, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance therapy) or at least one of its clinical or subclinical symptoms; or (3) alleviating or slowing the disease, i.e. causing the disappearance of the state, disorder, or symptom or at least one of its clinical or subclinical symptoms.

[0035] "Therapeutic effective dose" refers to the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to achieve the desired therapeutic effect. The "therapeutic effective dose" varies depending on the compound, the disease and its severity, and the age and weight of the mammal being treated.

[0036] In this specification, the term "alkyl" includes both straight-chain and branched alkyl groups. References to a single alkyl group, such as "propyl," are specific only to the straight-chain form, and references to a single branched alkyl group, such as "isopropyl," are specific only to the branched form. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl. Similar convention applies to other groups; for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

[0037] The terms “(m-nC)” or “(m-nC) group” used alone or as a prefix refer to any group having m to n carbon atoms.

[0038] "alkylene", "alkenylene", or "alkynylene" groups are alkyl, alkenyl, or alkynyl groups located between two other chemical groups and used to connect these two other chemical groups. Therefore, "(1-6C)alkylene" means a straight-chain saturated divalent hydrocarbon group having one to six carbon atoms or a branched saturated divalent hydrocarbon group having three to six carbon atoms, such as methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc.

[0039] "(2-6C)-olefin" refers to a straight-chain divalent hydrocarbon group with two to six carbon atoms containing at least one double bond, or a branched divalent hydrocarbon group with three to six carbon atoms, such as vinylidene, 2,4-pentadienylidene, etc.

[0040] "(2-6C)-ynyl" refers to a straight-chain divalent hydrocarbon group with two to six carbon atoms containing at least one triple bond, or a branched divalent hydrocarbon group with three to six carbon atoms, such as ynylene, ynylene, and ynylene.

[0041] The term "(m-nC)cycloalkyl" refers to a hydrocarbon ring containing m to n carbon atoms. For example, "(3-6C)cycloalkyl" refers to a hydrocarbon ring containing 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "(m-nC)cycloalkyl" also encompasses one or more non-aromatic, saturated or partially saturated monocyclic, fused, bridged, or spirobicyclic carbocyclic systems. The term "(m-nC)cycloalkyl" includes both monovalent and divalent substances. A monocyclic "(m-nC)cycloalkyl" ring contains about 3 to 12 (suitably 3 to 8, most suitable 5 to 6) cyclic carbon atoms. A bicyclic "(m-nC)cycloalkyl" ring contains 7 to 17 cyclic carbon atoms, suitably 7 to 12 cyclic carbon atoms. m-n The cycloalkyl ring can be a fused, spirocyclic, or bridged ring system.

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

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

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

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

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

[0047] "Carbon-linked heterocyclic groups" refers to heterocyclic groups as defined above that are linked via carbon atoms rather than heteroatoms such as nitrogen.

[0048] A "spirocyclic system" refers to a compound in which at least two rings share only one common atom and are not connected by a bridge.

[0049] A "fused ring system" is a compound in which two rings share two adjacent atoms. In other words, the rings share a single covalent bond.

[0050] “Bridged ring system” refers to a ring system in which two rings share more than two atoms, see, for example, *Advanced Organic Chemistry*, edited by Jerry March, 4th edition, Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclic ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, and quinine rings.

[0051] A “spirobicyclic system” refers to a system in which two rings share a common spirocarbon atom, meaning that a heterocycle is connected to another carbon ring or heterocycle through a single common spirocarbon atom. Examples of spirocyclic systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0052] "Heterocyclic (1-6C)alkyl" refers to a heterocyclic group covalently attached to a (1-6C)alkylene group, both of which are defined herein.

[0053] The term "heteroaryl" or "heteroaromatic" refers to a monocyclic, bicyclic, or polycyclic aromatic group containing one or more (e.g., 14, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes both monovalent and divalent substances. Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic, such as a bicyclic structure formed by fused 5- and 6-membered rings or two fused 6-membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents in the ring) will be less than five.

[0054] Examples of heteroaryl groups include furanyl, pyrroleyl, thiophenyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenoyl, benzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, benzothiazolyl, indolyl, purinyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxolinyl, and quinoxolinyl. The terms "heteroaryl" also encompass partially aromatic bicyclic or polycyclic systems, wherein at least one ring is an aromatic ring and one or more other rings are non-aromatic, saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of some aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxacyclopentenyl, 2,2-dioxo-1,3-dihydro-2-benzothiophene, 4,5,6,7-tetrahydrobenzofuranyl, dihydroindolyl, 1,2,3,4-tetrahydro-1,8-naphthidyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl.

[0055] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, furazonyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0056] Examples of six-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl.

[0057] The bicyclic heteroaryl group can be, for example, selected from the following groups:

[0058] A benzene ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

[0059] A pyridine ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

[0060] A pyrimidine ring fused with a 5- or 6-membered ring containing one or two heteroatoms;

[0061] Pyrrole rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0062] A pyrazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0063] Pyrazine rings fused with 5- or 6-membered rings containing 1 or 2 heteroatoms;

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

[0065] Oxazole rings fused with 5- or 6-membered rings containing 1 or 2 heteroatoms;

[0066] An isoxazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

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

[0068] An isothiazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0069] Thiophene rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0070] Furan rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0071] Cyclohexyl rings fused with 5- or 6-membered heteroaromatic rings containing 1, 2, or 3 cyclic heteroatoms; and

[0072] A cyclopentyl ring fused with a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms.

[0073] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused with a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, inazinyl, dihydroindolyl, isodihydroindolyl, purine (e.g., adenine, guanine), indolyl, benzodioxanepentenyl, and pyrazolopyridyl groups.

[0074] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxane, quinazinyl, benzooxazinyl, benzodiazinyl, pyridinylpyridinyl, quinoxolinyl, quinazolinyl, terpineyl, phthalazinyl, naphthidyl, and pteridylyl groups.

[0075] "Heteroaryl(1-6C)alkyl" refers to a heteroaryl group covalently attached to a (1-6C)alkylene group, both of which are defined herein. Examples of heteroarylalkyl groups include pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, etc.

[0076] The term "aryl" refers to a ring or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent substances. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In a specific embodiment, the aryl group is phenyl.

[0077] The term “aryl(1-6C)alkyl” refers to an aryl group covalently attached to a (1-6C)alkylene group, both of which are defined herein. Examples of aryl-(1-6C)alkyl groups include benzyl, phenylethyl, etc.

[0078] This specification also uses several compound terms to describe groups containing more than one functionality. Such terms will be understood by those skilled in the art. For example, heterocyclic (m-nC) alkyl includes (m-nC) alkyl groups substituted with heterocyclic groups.

[0079] The term "optionally substituted" refers to both the substituted group, structure, or molecule and the unsubstituted group, structure, or molecule. The term "wherein R..." 1 "One or any CH, CH2, CH3 group or heteroatom (i.e., NH) within the group is optionally substituted" properly means R 1 Any one of the hydrogen groups in the group is replaced by a group specified in the relevant regulations.

[0080] When the optional substituent is selected from "one or more" groups, it should be understood that the definition includes all substituents selected from one of the specified groups or substituents selected from two or more specified groups.

[0081] The phrase “compounds of the present invention” means those compounds disclosed herein, both generally and specifically.

[0082] The compounds of the present invention

[0083] In a first aspect, the present invention relates to compounds having the following structural formula I, or pharmaceutically acceptable salts, hydrates, or solvates thereof:

[0084]

[0085] in:

[0086] R0 is hydrogen or deuterium;

[0087] R1 is selected from aryl or heteroaryl.

[0088] R1 is optionally and independently selected from one or more of the following R 1z Substituents: (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 (where p is 0, 1, or 2), (CH2) q1 SO2N(R 1C )R 1B Or (CH2) q1 N(R 1C SO2R 1B ,

[0089] And where q1 is 0, 1, 2 or 3 and R 1B and R 1C Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;

[0090] R2 is selected from hydrogen, cyano, halogen, (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) alkylyl;

[0091] Where R 2A and R 2B Each is independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl.

[0092] Or, in CONR 2A R2B In the group, R 2A and R 2B They are linked together, causing them to form heterocycles together with the nitrogen atoms to which they are attached, and

[0093] Any alkyl, alkenyl, alkynyl, alkylyl, aryl, heteroaryl, or heterocyclic group (as defined by R) 2A and R 2B The group (forming) may optionally be substituted independently by one or more substituents selected from the following: (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) q2 C(O)N(R 2E )R 2D (CH2) q2 N(R 2E )C(O)R 2D (CH2) q2 S(O) p R 2D (where p is 0, 1, or 2), (CH2) q2 SO2N(R 2E )R 2D Or (CH2) q2 N(R 2E SO2R 2D Where q2 is 0, 1, 2, or 3; and where R 2D and R 2E Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;

[0094] R3 is selected from hydrogen, halo, cyano, or groups having the following formula:

[0095] -LYL q -Q

[0096] in:

[0097] L is absent or optionally substituted with one or more (1-4C) alkylene groups selected from (1-2C) alkyl or oxo groups;

[0098] Y does not exist, or it 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(R a SO2, N(R) a SO2N(R) b ) or C(O)N(R a SO2, where R a and R b Each is independently selected from hydrogen or (1-4C) alkyl and R y Selected from hydrogen, (1-4C)alkyl, nitro, or cyano;

[0099] L q (1-4C) alkylene groups that are absent or optionally substituted with one or more substituents selected from (1-2C)alkoxy, halogen, cyano, amino, or oxo groups; and

[0100] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)ynyl, aryl, (3-8)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclic;

[0101] Q may optionally be further substituted by one or more substituents independently selected from the following: oxo, (1-4C)alkyl, halogen, (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 (where 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); where R c R d and R e Each is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or

[0102] R c and R d They are linked together such that they, together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycle, which is optionally substituted by 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

[0103] Q may be optionally substituted by one or more groups having the following formula:

[0104] -L1-L Q1 -W1

[0105] in:

[0106] L1 is absent or optionally substituted with one or more (1-3C) alkylene groups selected from (1-2C) alkyl or oxo substituents;

[0107] L Q1 It does not exist or is selected from 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 Each is independently selected from hydrogen or (1-2C) alkyl; and

[0108] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl, or heterocyclic; wherein W1 is optionally substituted by one or more substituents selected from: oxo, (1-4C)alkyl, halogenated, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, aryl, heteroaryl, heterocyclic, (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); where R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;

[0109] And any alkyl, alkoxy, aryl, heteroaryl, heterocyclic, or cycloalkyl moiety present on W1 is optionally 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 hydroxyl groups; or

[0110] R h and R i They are linked together such that they together with the nitrogen atom to which they are attached form a 4-7 membered heterocycle, which is optionally substituted by one or more substituents selected from the following: 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;

[0111] A is selected from CR4 and N.

[0112] R4 is hydrogen, halo, or (1-4C)alkyl, which is optionally substituted by one or more substituents selected from the following: halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, cyano, (CH2). qa NR 4A R 4B (CH2) qa OR 4A (CH2) qa C(O)R c4A (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) p R 4A (where p is 0, 1, or 2), (CH2) qa SO2N(R 4B )R 4A Or (CH2) qa N(R 4B SO2R 4A Where qa is 0, 1, 2 or 3 and R 4A and R 4B Each is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;

[0113] Furthermore, any tertiary amine in the compound of formula I is optionally in the form of an N-oxide and the nitrogen atom in the pyridine ring is optionally in the form of an N-oxide;

[0114] Furthermore, any S atom present in the heterocycle may optionally be S(=O), S(=O)2, or S(=O)(=NR). z ) exists, where R z It is selected from hydrogen, (1-3C)alkyl or (2-3C)alkylyl.

[0115] Specific compounds of the present invention include, for example, compounds having Formula I or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise specified, R oEach of R1, R2, R3, and A has any meaning as defined above or as defined in any of paragraphs (1) to (55) below:

[0116] (1) R0 is hydrogen;

[0117] (2) R0 is deuterium;

[0118] (3) R1 is selected from aryl or heteroaryl.

[0119] R1 is optionally and independently selected from one or more of the following R 1z Substituents: (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 (where p is 0, 1, or 2), (CH2) q1 SO2N(R 1C )R 1B Or (CH2) q1 N(R 1C SO2R 1B ,

[0120] And where q1 is 0, 1, 2 or 3 and R 1B and R 1C Each is independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl;

[0121] (4) R1 is selected from aryl or heteroaryl.

[0122] R1 is optionally and independently selected from one or more of the following R 1z Substituents: (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 (where p is 0, 1, or 2), SO2N(R) 1C )R 1B or N(R) 1C SO2R 1B And among them:

[0123] q1 is 0, 1, or 2; and

[0124] R 1B and R 1C Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;

[0125] (5) R1 is selected from aryl or heteroaryl.

[0126] R1 is optionally and independently selected from one or more of the following R 1z Substituents: (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 (where p is 0, 1, or 2), SO2N(R) 1C )R 1B or N(R) 1C SO2R 1B And among them:

[0127] q1 is 0, 1, or 2; and

[0128] R 1B and R 1CEach is independently selected from hydrogen, (1-2C)alkyl, or (3-4C)cycloalkyl;

[0129] (5) R1 is selected from aryl or heteroaryl.

[0130] R1 is optionally and independently selected from one or more of the following R 1z Substituents: (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 (where p is 0, 1, or 2), (CH2) q1 SO2N(R 1C )R 1B Or (CH2) q1 N(R 1C SO2R 1B And among them:

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

[0132] R 1B and R 1C Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;

[0133] (6) R1 is selected from phenyl or 5- or 6-membered heteroaryl groups.

[0134] R1 is optionally and independently selected from one or more of the following R 1z Substituents: (1-4C)alkyl, halo, (1-4C) haloalkyl, (1-4C) haloalkoxy, cyano, (CH2) q1 NR 1B R 1C OR 1BC(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 (where p is 0, 1, or 2), SO2N(R) 1C )R 1B or N(R) 1C SO2R 1B And among them:

[0135] q1 is 0, 1, or 2; and

[0136] R 1B and R 1C Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;

[0137] (7) R1 is selected from aryl or heteroaryl.

[0138] R1 is optionally and independently selected from one or more of the following R 1z Substituents: (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 (where p is 0, 1, or 2), SO2N(R) 1C )R 1B or N(R) 1C SO2R 1B And among them:

[0139] q1 is 0, 1, or 2; and

[0140] R 1B and R 1C Each is independently selected from hydrogen, (1-2C)alkyl, or (3-4C)cycloalkyl;

[0141] (8) R1 is selected from aryl or heteroaryl.

[0142] R1 is optionally and independently selected from one or more of the following R 1z Substituents: (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 ,

[0143] And where q1 is 0, 1, 2 or 3 and R 1B and R 1C Each is independently selected from hydrogen or (1-2C) alkyl;

[0144] (9) R1 is selected from aryl or heteroaryl.

[0145] R1 is optionally and independently selected from one or more of the following R 1z Substituents: (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 ,

[0146] And where q1 is 0, 1, 2 or 3 and R 1B and R 1C Each is independently selected from hydrogen or (1-2C) alkyl;

[0147] (10) R1 is selected from phenyl or 5- or 6-membered heteroaryl groups.

[0148] R1 is optionally and independently selected from one or more of the following R 1zSubstituents: (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 (where p is 0, 1, or 2), SO2N(R) 1C )R 1B or N(R) 1C SO2R 1B And among them:

[0149] q1 is 0, 1, or 2; and

[0150] R 1B and R 1C Each is independently selected from hydrogen or (1-2C) alkyl;

[0151] (11) R1 is a phenyl group, which is optionally defined by one or more R groups as defined in any one of paragraphs (1) to (10) above. 1z Substituent substitution.

[0152] (12) R1 is a 5- or 6-membered heteroaryl group, which is optionally defined by one or more R groups as defined in any one of paragraphs (1) to (10) above. 1z Substituent substitution.

[0153] (13) R1 is selected from phenyl, furanyl, pyridyl, oxazolyl, thiazolyl, isoxazolyl or oxazolin-2-yl, wherein the phenyl, furanyl, pyridyl or oxazolyl ring is optionally substituted by a halogen, (1-2C)alkyl, (1-2C)alkoxy or cyano.

[0154] (14) R1 is selected from phenyl, furanyl, pyridyl or oxazolyl, wherein the phenyl, furanyl, pyridyl or oxazolyl ring is optionally halogenated or C-substituted. 1-2 One or more substitutions of alkoxy or cyano groups.

[0155] (15) R1 is selected from phenyl, furanyl, pyridyl or oxazolyl, wherein the phenyl, furanyl, pyridyl or oxazolyl ring is optionally substituted with a halogen or cyano group.

[0156] (16) R1 is selected from 3-cyanophenyl, furanyl, or oxazolyl, thiazolyl, isoxazolyl or oxazolin-2-yl.

[0157] (17) R1 is 3-cyanophenyl.

[0158] (18) R2 is selected from hydrogen, cyano, halogen, (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) alkylyl;

[0159] Where R 2A and R 2B Each is independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl.

[0160] Or, in CONR 2A R 2B In the group, R 2A and R 2B They are linked together, forming 4-7 membered heterocycles together with the nitrogen atoms to which they are attached, and

[0161] Any alkyl, alkenyl, alkynyl, alkylyl, aryl, heteroaryl, or heterocyclic group (as defined by R) 2A and R 2B The group (forming) may optionally be substituted independently by one or more substituents selected from the following: (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) q2 C(O)N(R 2E )R 2D (CH2) q2 N(R 2E )C(O)R 12D (CH2) q2 S(O) p R 2D (where p is 0, 1, or 2), (CH2) q2SO2N(R 2E )R 2D Or (CH2) q2 N(R 2E SO2R 2D ,

[0162] Where q2 is 0, 1, or 2; and

[0163] Where R 2D and R 2E Each is independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl;

[0164] Furthermore, when R2 is a pyridinyl group, the cyclic nitrogen atom may optionally be in the form of an N-oxide.

[0165] (19) R2 is selected from hydrogen, cyano, halogen, (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) alkylyl,

[0166] Where R 2A and R 2B Each is independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl, and

[0167] Any alkyl, alkenyl, alkanoyl, phenyl, or heteroaryl group may optionally be substituted independently by one or more substituents selected from the following: (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) q2 C(O)N(R 2E )R 2D (CH2) q2 N(R 2E )C(O)R 12D (CH2) q2 S(O) p R 2D(where p is 0, 1, or 2), (CH2) q2 SO2N(R 2E )R 2D Or (CH2) q2 N(R 2E SO2R 2D ,

[0168] Where q2 is 0, 1, or 2;

[0169] And R 2D and R 2E Each is independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl;

[0170] Furthermore, when R2 is a pyridinyl group, the cyclic nitrogen atom may optionally be in the form of an N-oxide.

[0171] (20) R2 is selected from hydrogen, cyano, halogen, (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) alkylyl,

[0172] Where R 2A and R 2B Each is independently selected from hydrogen or (1-4C) alkyl, and

[0173] Any alkyl, alkenyl, alkanoyl, phenyl, or heteroaryl group may optionally be substituted independently by one or more substituents selected from the following: (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) q2 C(O)N(R 2E )R 2D (CH2) q2 N(R 2E )C(O)R 12D (CH2) q2 S(O) p R 2D(where p is 0, 1, or 2), (CH2) q2 SO2N(R 2E )R 2D or (CH2)q2N(R) 2E SO2R 2D ,

[0174] Where q2 is 0, 1, or 2; and

[0175] Where R 2D and R 2E Each is independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl;

[0176] Furthermore, when R2 is a pyridinyl group, the cyclic nitrogen atom may optionally be in the form of an N-oxide.

[0177] (21) R2 is selected from cyano, halogen, methyl, CF3, C(O)OR 2A C(O)NR 2A R 2B 5 or 6-membered heteroaryl or (2-4C) alkylyl,

[0178] Where R 2A and R 2B Each is independently selected from hydrogen or (1-4C) alkyl groups.

[0179] Any phenyl or heteroaryl group may optionally be substituted independently by one or more substituents selected from the following: (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) p R 2D (where p is 0, 1, or 2), SO2N(R) 2E )R 2D or N(R) 2E SO2R 2D , where q2 is 0 or 1; and where R 2D and R 2E Each is independently selected from hydrogen or (1-2C) alkyl;

[0180] Furthermore, when R2 is a pyridinyl group, the cyclic nitrogen atom may optionally be in the form of an N-oxide.

[0181] (22) R2 is selected from cyano or 5 or 6 heteroaryl, which may optionally be substituted as defined above in any of paragraphs (18) to (21);

[0182] Furthermore, when R2 is a pyridinyl group, the cyclic nitrogen atom may optionally be in the form of an N-oxide.

[0183] (23) R2 is selected from cyano or 5- or 6-membered heteroaryl, which is optionally substituted independently by one or more substituents selected from the following: (1-2C)alkyl, halo, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or cyano; and wherein when R2 is pyridyl, the cyclic nitrogen atom is optionally in the form of an N-oxide;

[0184] (24) R2 is a 5- or 6-membered heteroaryl group, which is optionally substituted independently by one or more substituents selected from the following: (1-2C)alkyl, halo, (1-2C) haloalkyl, (1-2C) alkoxy, (1-2C) haloalkoxy or cyano; and wherein when R2 is pyridyl, the cyclic nitrogen atom is optionally in the form of an N-oxide;

[0185] (25) R2 is a 5- or 6-membered heteroaryl group, which is optionally substituted independently by one or more substituents selected from the following: (1-2C) alkyl or halogenated; and wherein when R2 is pyridyl, the cyclic nitrogen atom is optionally in the form of an N-oxide;

[0186] (26) R2 is a 6-membered heteroaryl group, which is optionally substituted independently by one or more substituents selected from the following: (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or cyano; and wherein when R2 is pyridyl, the cyclic nitrogen atom is optionally in the form of an N-oxide.

[0187] (27) R2 is a 6-membered nitrogen-containing heteroaryl group, which is optionally substituted independently by one or more substituents selected from the following: (1-2C) alkyl or halogenated; and wherein when R2 is pyridyl, the cyclic nitrogen atom is optionally in the form of an N-oxide;

[0188] (28) R2 is a 6-membered nitrogen-containing heteroaryl group, which is optionally substituted independently by one or more substituents selected from the group consisting of methyl or chlorine; and wherein when R2 is pyridyl, the cyclic nitrogen atom is optionally in the form of an N-oxide.

[0189] (29) R2 is:

[0190]

[0191] in:

[0192] (i)R 200 and R 201 Each is independently selected from (1-2C)alkyl, hydroxy(1-2C)alkyl, amino, halogen, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkanoyl or cyano;

[0193] (ii)R 200 and R 201 Each is independently selected from methyl, hydroxymethyl, halogenated, di-fluoromethyl, trifluoromethyl, methoxy, acetyl, or cyano;

[0194] (iii)R 200 It is methyl or chlorine and R 201 Selected from methyl, hydroxymethyl, halogenated, di-fluoromethyl, trifluoromethyl, methoxy, acetyl, or cyano;

[0195] or

[0196]

[0197] in:

[0198] (i)R 201 It is (1-2C)alkyl, halo, (1-2C)haloalkyl, hydroxy(1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkanoyl or cyano;

[0199] (ii)R 201 It is methyl, hydroxymethyl, halogenated, di-fluoromethyl, trifluoromethyl, methoxy, acetyl, or cyano;

[0200] (iii)R 201 It is methyl, hydroxymethyl, or chlorine;

[0201] (iv)R 201 It is methyl;

[0202] (v)R 201 It is chlorine;

[0203] (30) R2 is a pyridinyl group (e.g., pyridin-4-yl), which is optionally substituted independently by one or more substituents selected from the group consisting of methyl or chlorine;

[0204] (31) R2 is 2-chloro-6-methylpyridin-4-yl or 2,6-dimethylpyridin-4-yl, i.e.

[0205]

[0206] (32) R3 is selected from hydrogen, halo, cyano, or groups having the following formula:

[0207] -LYL q -Q

[0208] in:

[0209] L is absent or is a (1-4C) alkylene group;

[0210] Y does not exist, or it 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(R a SO2, N(R) a SO2N(R) b ) or C(O)N(R a SO2, where R a and R b Each is independently selected from hydrogen or (1-4C) alkyl and R y Selected from hydrogen, (1-4C)alkyl, nitro, or cyano;

[0211] L q (1-4C) alkylene groups that are absent or optionally substituted with one or more substituents selected from (1-2C)alkoxy, halogen, cyano, amino, or oxo groups; and

[0212] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)ynyl, aryl, (3-8)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclic;

[0213] Q may optionally be further substituted by one or more substituents independently selected from the following: oxo, (1-4C)alkyl, halogen, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) aminoalkyl, (1-4C) hydroxyalkyl, cyano, NRc 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 (where 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); where R c and R d Each is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or

[0214] R c and R d They are linked together such that they, together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycle, which is optionally substituted by 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

[0215] Q may be optionally substituted by one or more groups having the following formula:

[0216] -L1-L Q1 -W1

[0217] in:

[0218] L1 is absent or is a (1-3C) alkylene group;

[0219] L Q1 It does not exist or is selected from 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 Each is independently selected from hydrogen or (1-2C) alkyl; and

[0220] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl, or heterocyclic; wherein W1 is optionally substituted by one or more substituents selected from: oxo, (1-4C)alkyl, halogenated, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, aryl, heteroaryl, heterocyclic, (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); where R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;

[0221] And any alkyl, alkoxy, aryl, heteroaryl, heterocyclic, or cycloalkyl moiety present on W1 is optionally 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 hydroxyl groups; or

[0222] R h and R iThey are linked together such that they together with the nitrogen atom to which they are attached form a 4-7 membered heterocycle, which is optionally substituted by one or more substituents selected from the following: 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;

[0223] Furthermore, any tertiary amine or nitrogen atom in the pyridine ring of the R3 group is optionally in the form of an N-oxide;

[0224] (33) R3 is selected from hydrogen, halo, cyano, or groups having the following formula:

[0225] -LYL q -Q

[0226] in:

[0227] L is absent or is a (1-4C) alkylene group;

[0228] Y does not exist, or it 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(R a SO2, N(R) a SO2N(R) b ) or C(O)N(R a SO2, where R a and R b Each is independently selected from hydrogen or (1-4C) alkyl and R y Selected from hydrogen, (1-4C)alkyl, nitro, or cyano;

[0229] L q(1-4C) alkylene groups that are absent or optionally substituted with one or more substituents selected from (1-2C)alkoxy, halogen, cyano, amino, or oxo groups; and

[0230] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)ynyl, aryl, (3-8)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclic;

[0231] Q may optionally be further substituted by one or more substituents independently selected from the following: oxo, (1-4C)alkyl, halogen, (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 (where 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); where R c and R d Each is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; and / or

[0232] Q may be optionally substituted by one or more groups having the following formula:

[0233] -L1-L Q1 -W1

[0234] in:

[0235] L1 is absent or is a (1-3C) alkylene group;

[0236] L Q1 It does not exist or is selected from 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 Each is independently selected from hydrogen or (1-2C) alkyl; and

[0237] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl, or heterocyclic; wherein W1 is optionally substituted by one or more substituents selected from: oxo, (1-4C)alkyl, halogenated, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, aryl, heteroaryl, heterocyclic, (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); where R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;

[0238] Furthermore, any tertiary amine or nitrogen atom in the pyridine ring of the R3 group is optionally in the form of an N-oxide;

[0239] (34) R3 is selected from hydrogen, halo, cyano, or groups having the following formula:

[0240] -LYL q -Q

[0241] in:

[0242] L is absent or is a (1-2C) alkylene group;

[0243] Y does not exist, or it 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(R a SO2, N(R) a SO2N(R) b ) or C(O)N(R a SO2, where R a and R b Each is independently selected from hydrogen or (1-4C) alkyl and R y Selected from hydrogen, (1-4C)alkyl, nitro, or cyano;

[0244] L q (1-4C) alkylene groups that are absent or optionally substituted with one or more substituents selected from (1-2C)alkoxy, halogen, cyano, amino, or oxo groups; and

[0245] Q is hydrogen, (1-6C)alkyl, aryl, (3-8)cycloalkyl, heteroaryl, or heterocyclic;

[0246] Q may optionally be further substituted by one or more substituents independently selected from the following: oxo, (1-4C)alkyl, halogen, (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(Rd )C(O)R c S(O) p R c (where 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); where R c and R d Each is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; and / or

[0247] Q may be optionally substituted by one or more groups having the following formula:

[0248] -L1-L Q1 -W1

[0249] in:

[0250] L1 is absent or is a (1-2C) alkylene group;

[0251] L Q1 It does not exist or is selected from 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 Each is independently selected from hydrogen or (1-2C) alkyl; and

[0252] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl, or heterocyclic; wherein W1 is optionally substituted by one or more substituents selected from: oxo, (1-4C)alkyl, halogenated, (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)ORh 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); where R h and R i Each is independently selected from hydrogen or (1-4C) alkyl;

[0253] Furthermore, any tertiary amine or nitrogen atom in the pyridine ring of the R3 group is optionally in the form of an N-oxide;

[0254] (35) R3 is selected from hydrogen, halo, cyano, or groups having the following formula:

[0255] -LYL q -Q

[0256] in:

[0257] L is absent or is a (1-2C) alkylene group;

[0258] Y does not exist or is 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 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(R a SO2, N(R) a SO2N(R) b ) or C(O)N(R aSO2, where R a and R b Each is independently selected from hydrogen or (1-4C) alkyl and R y Selected from hydrogen, (1-4C)alkyl, nitro, or cyano;

[0259] L q (1-4C) alkylene groups that are absent or optionally substituted with one or more substituents selected from (1-2C)alkoxy, halogen, cyano, amino, or oxo groups; and

[0260] Q is hydrogen, (1-6C)alkyl, aryl, (3-8)cycloalkyl, heteroaryl, or heterocyclic;

[0261] Q may optionally be further substituted by one or more substituents independently selected from the following: oxo, (1-4C)alkyl, halogen, (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 C(O)N(R) d )R c 、N(R d )C(O)R c S(O) p R c (where 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); where R c and R d Each is independently selected from hydrogen or (1-6C) alkyl; and / or

[0262] Q may be optionally substituted by one or more groups having the following formula:

[0263] -L1-L Q1 -W1

[0264] in:

[0265] L1 is absent or is a (1-2C) alkylene group;

[0266] L Q1 It does not exist; and

[0267] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl, or heterocyclic; wherein W1 is optionally substituted by one or more substituents selected from: oxo, (1-4C)alkyl, halogenated, (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), where R h and R i Each is independently selected from hydrogen or (1-4C) alkyl;

[0268] Furthermore, any tertiary amine or nitrogen atom in the pyridine ring of the R3 group is optionally in the form of an N-oxide;

[0269] (35a) R3 is selected from hydrogen, halo, cyano, or groups having the following formula:

[0270] -LYL q -Q

[0271] in:

[0272] L is absent or is a (1-2C) alkylene group;

[0273] Y does not exist 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 Each is independently selected from hydrogen or (1-4C) alkyl and R y Selected from hydrogen, (1-4C)alkyl, or cyano;

[0274] L q(1-4C) alkylene groups that are absent or optionally substituted with one or more substituents selected from (1-2C)alkoxy, halogen, cyano, amino, or oxo groups; and

[0275] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (3-8)cycloalkyl or heterocyclic group;

[0276] Q may optionally be further substituted by one or more substituents independently selected from the following: oxo, (1-4C)alkyl, halogen, (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 C(O)N(R) d )R c 、N(R d )C(O)R c S(O) p R c (where 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); where R c and R d Each is independently selected from hydrogen or (1-6C) alkyl; and / or

[0277] Q may be optionally substituted by one or more groups having the following formula:

[0278] -L1-L Q1 -W1

[0279] in:

[0280] L1 is absent or is a (1-2C) alkylene group;

[0281] L Q1 It does not exist; and

[0282] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl, or heterocyclic; wherein W1 is optionally substituted by one or more substituents selected from: oxo, (1-4C)alkyl, halogenated, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, NR hR 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), where R h and R i Each is independently selected from hydrogen or (1-4C) alkyl;

[0283] Furthermore, any tertiary amine or nitrogen atom in the pyridine ring of the R3 group is optionally in the form of an N-oxide;

[0284] (36) R3 is a group having the following formula:

[0285] -LYL q -Q

[0286] in:

[0287] L does not exist;

[0288] Y is N(R) a ) or C(O)N(R a );

[0289] L q It does not exist; and

[0290] Q is (1-6C) alkyl or (3-8) cycloalkyl;

[0291] Q may optionally be further substituted by one or more substituent groups independently selected from the following: halogenated, 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 (where p is 0, 1, or 2), SO2N(R) d )R c 、N(R d SO2R c Or (CH2) q NR c Rd (where q is 1, 2, or 3); where R c and R d Each is independently selected from hydrogen or (1-6C) alkyl;

[0292] (37) R3 is a group having the following formula:

[0293] -LYL q -Q

[0294] in:

[0295] L does not exist;

[0296] Y is N(R) a ) or C(O)N(R a );

[0297] L q It does not exist; and

[0298] Q is a (1-6C) alkyl group;

[0299] Q may optionally be further substituted by one or more substituent groups independently selected from the following: halogenated, cyano, NR c R d OR c C(O)OR c S(O) p R c (where p is 0, 1, or 2), SO2N(R) d )R c ;where R c and R d Each is independently selected from hydrogen or (1-6C) alkyl;

[0300] (38) R3 is a group having the following formula:

[0301] -LYL q -Q

[0302] in:

[0303] L does not exist;

[0304] Y is N(R) a ) or C(O)N(R a );

[0305] L q It does not exist; and

[0306] Q is a (1-6C) alkyl group;

[0307] Q is optionally further subjected to one or more ORs c Replace; where R cSelected from hydrogen or (1-4C) alkyl;

[0308] (39) R3 is a group having the following formula:

[0309] -LYL q -Q

[0310] in:

[0311] L does not exist;

[0312] Y is N(R) a ) or C(O)N(R a );

[0313] L q It does not exist; and

[0314] Q is a (1-6C) alkyl group;

[0315] Q may be further replaced by one or more OH groups;

[0316] (40) R3 is a group having the following formula:

[0317]

[0318] Where R 3a It is hydrogen or methyl;

[0319] (41) R3 is selected from halogenated groups or groups having the following formula:

[0320] -LYQ

[0321] in:

[0322] L does not exist;

[0323] Y does not exist, or it 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 Each is independently selected from hydrogen or (1-2C) alkyl; and

[0324] Q is a (1-4C) alkyl, heteroaryl, or heterocyclic group;

[0325] Q may optionally be further substituted by one or more substituents independently selected from the following: oxo, (1-4C)alkyl, halogen, (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 (where 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); where R c R d and R e Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl; or

[0326] R c and R d They are linked together such that they, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocycle, which is optionally substituted by 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

[0327] Q may be optionally substituted by a group having the following formula:

[0328] -L1-L Q1 -W1

[0329] in:

[0330] L1 is absent or optionally substituted with one or more (1-3C) alkylene groups selected from (1-2C) alkyl or oxo substituents;

[0331] L Q1 It does not exist or is selected from O, S, SO, SO2, N(R) f ), C(O), C(O)O, OC(O), C(O)N(R f ), N(Rf 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 Each is independently selected from hydrogen or (1-2C) alkyl; and

[0332] W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl, or heterocyclic; wherein W1 is optionally substituted by one or more substituents selected from: oxo, (1-4C)alkyl, halogenated, (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); where R h and R i Each is independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; and any alkyl, alkoxy, aryl, heteroaryl, heterocyclic or cycloalkyl portion of the substituent group present on W1 is optionally 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 group;

[0333] Furthermore, any tertiary amine or nitrogen atom present in the pyridine ring of the R3 group is optionally in the form of an N-oxide;

[0334] (42) R3 is selected from halogenated groups or groups having the following formula:

[0335] -Q

[0336] in:

[0337] Q is a heteroaryl or heterocyclic group;

[0338] Q may optionally be further substituted by one or more substituents independently selected from the following: oxo, (1-4C)alkyl, halogen, (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 (where 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); where R c R d and R e Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl; or

[0339] R c and R d They are linked together such that they, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocycle, which is optionally substituted by 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

[0340] Q may be optionally substituted by a group having the following formula:

[0341] -L1-L Q1 -W1

[0342] in:

[0343] L1 is absent or optionally substituted with one or more (1-3C) alkylene groups selected from (1-2C) alkyl or oxo substituents;

[0344] L Q1 It does not exist or is selected from 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 Each is independently selected from hydrogen or (1-2C) alkyl; and

[0345] W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl, or heterocyclic;

[0346] W1 is optionally substituted by one or more substituents selected from the following: oxo, (1-4C)alkyl, halogenated, (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); where R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0347] Or R h and R i They are linked together such that they together with the nitrogen atom to which they are attached form a 4-7 membered heterocycle, which is optionally substituted by one or more substituents selected from the following: 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;

[0348] Furthermore, any alkyl, alkoxy, aryl, heteroaryl, heterocyclic, or cycloalkyl moiety present on W1 may optionally 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 hydroxyl groups;

[0349] Furthermore, any tertiary amine or nitrogen atom present in the pyridine ring of the R3 group is optionally in the form of an N-oxide;

[0350] (43) R3 is a heterocyclic group, which is optionally further substituted independently by one or more substituents selected from the following: oxo, (1-4C)alkyl, halogenated, (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 (where 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); where R c R d and R e Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl; or

[0351] R c and R d They are linked together such that they, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocycle, which is optionally substituted by 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

[0352] R3 may be optionally substituted with a group having the following formula:

[0353] -L1-LQ1 -W1

[0354] in:

[0355] L1 is absent or optionally substituted with one or more (1-3C) alkylene groups selected from (1-2C) alkyl or oxo substituents;

[0356] L Q1 It does not exist or is selected from 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 Each is independently selected from hydrogen or (1-2C) alkyl; and

[0357] W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl, or heterocyclic; wherein W1 is optionally substituted by one or more substituents selected from: oxo, (1-4C)alkyl, halogenated, (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); where R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0358] Or R h and R iThey are linked together such that they together with the nitrogen atom to which they are attached form a 4-7 membered heterocycle, which is optionally substituted by one or more substituents selected from the following: 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;

[0359] Furthermore, any alkyl, alkoxy, aryl, heteroaryl, heterocyclic, or cycloalkyl moiety present on W1 may optionally 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 hydroxyl groups;

[0360] Furthermore, any tertiary amine or nitrogen atom present in the pyridine ring of the R3 group is optionally in the form of an N-oxide;

[0361] (44) R3 is a nitrogen-linked heterocycle, which is selected from a 4-7 member heterocycle system, a 9-15 member bicyclic system or a 9-15 member spirocyclic system;

[0362] R3 may optionally be further substituted by one or more substituents independently selected from the following: oxo, (1-4C)alkyl, halogen, (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 (where 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); where R c R d and R e Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl; or

[0363] R c and Rd They are linked together such that they, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocycle, which is optionally substituted by 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

[0364] R3 may be optionally substituted with a group having the following formula:

[0365] -L1-L Q1 -W1

[0366] in:

[0367] L1 is absent or optionally substituted with one or more (1-3C) alkylene groups selected from (1-2C) alkyl or oxo substituents;

[0368] L Q1 It does not exist or is selected from 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 Each is independently selected from hydrogen or (1-2C) alkyl; and

[0369] W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl, or heterocyclic; wherein W1 is optionally substituted by one or more substituents selected from: oxo, (1-4C)alkyl, halogenated, (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(Ri SO2R h Or (CH2) s NR i R h (where s is 1, 2, or 3); where R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0370] Or R h and R i They are linked together such that they together with the nitrogen atom to which they are attached form a 4-7 membered heterocycle, which is optionally substituted by one or more substituents selected from the following: 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;

[0371] Furthermore, any alkyl, alkoxy, aryl, heteroaryl, heterocyclic, or cycloalkyl moiety present on W1 may optionally 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 hydroxyl groups;

[0372] Furthermore, any tertiary amine or nitrogen atom present in the pyridine ring of the R3 group is optionally in the form of an N-oxide.

[0373] (45) R3 is a heterocyclic group selected from piperazinyl, piperidinyl, pyrrolidinyl, oxetyl, morpholinyl, diazacycloheptyl, and azirbolyl, each of which may optionally be further substituted by one or more R6 groups; or R3 has one of the following structures:

[0374]

[0375] Where b is an integer selected from 0, 1, 2, 3 or 4;

[0376] Each R6 group is independently selected from (1-4C)alkyl, halogen, (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 (where 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 groups having the following formula:

[0377] -L1-L Q1 -W1

[0378] Where R c R d and R e Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl; or R c and R d They are linked together such that they, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocycle, which is optionally substituted by 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

[0379] in:

[0380] L1 is absent or optionally substituted with one or more (1-3C) alkylene groups selected from (1-2C) alkyl or oxo substituents;

[0381] L Q1 It does not exist or is selected from 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 Each is independently selected from hydrogen or (1-2C) alkyl; and

[0382] W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl, or heterocyclic; wherein W1 is optionally substituted by one or more substituents selected from: oxo, (1-4C)alkyl, halogenated, (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); where R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0383] Or R h and R i They are linked together such that they together with the nitrogen atom to which they are attached form a 4-7 membered heterocycle, which is optionally substituted by one or more substituents selected from the following: 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;

[0384] Furthermore, any alkyl, alkoxy, aryl, heteroaryl, heterocyclic, or cycloalkyl moiety present on W1 may optionally 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 hydroxyl groups;

[0385] Furthermore, any tertiary amine or nitrogen atom present in the pyridine ring of the R3 group is optionally in the form of an N-oxide.

[0386] (46) R3 is a heterocyclic group selected from piperazinyl, piperidinyl, pyrrolidinyl, oxetyl, morpholinyl, diazacycloheptyl, aziridine, or one of the following structures:

[0387]

[0388] (47) R3 is a nitrogen-linked heterocycle, which is selected from a 4-7 member heterocycle system, a 9-15 member bicyclic system or a 9-15 member spirocyclic system;

[0389] R3 may optionally be further substituted by one or more substituents independently selected from the following: oxo, (1-4C)alkyl, halogen, (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 (where 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);

[0390] Where R c R d and R e Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl; or R c and R d They are linked together such that they, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocycle, which is optionally substituted by one or more substituents selected from the following: (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.

[0391] (48) R3 is a heterocyclic group selected from piperazinyl, piperidinyl, pyrrolidinyl, oxetyl, morpholinyl, diazacycloheptyl, and azirbolyl, each of which may optionally be further substituted by one or more R6 groups; or R3 has one of the following structures:

[0392]

[0393] Where b is an integer selected from 0, 1, 2, 3 or 4;

[0394] Each R6 group is independently selected from (1-4C)alkyl, halogen, (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 (where 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);

[0395] Where R c and R d Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl; or R c and R d They are linked together such that they together with the nitrogen atom to which they are attached form a 4-6 membered heterocycle, which is optionally substituted by one or more substituents selected from the following: (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;

[0396] Furthermore, any tertiary amine present in the R3 group may optionally be in the form of an N-oxide.

[0397] (49) R3 is a heterocyclic group selected from piperazinyl, piperidinyl, pyrrolidinyl, oxetyl, morpholinyl, diazacycloheptyl, aziryl, or one of the following structures:

[0398]

[0399] (50)A is selected from CR4 and N.

[0400] R4 is hydrogen, halo, or (1-2C)alkyl, which is optionally substituted by one or more substituents selected from: halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, amino, cyano, (CH2). qa NR 4A R 4B (CH2) qa OR 4A (CH2) qa C(O)R c4A (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) p R 4A (where p is 0, 1, or 2), (CH2) qa SO2N(R 4B )R 4A Or (CH2) qa N(R 4B SO2R 4A Where qa is 0, 1, 2 or 3 and R 4A and R 4B Each is independently selected from hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl or (3-4C)cycloalkyl(1-2C)alkyl;

[0401] (51) A is selected from CR4 and N.

[0402] R4 is a (1-2C) alkyl group that is hydrogen-, halo-, or optionally substituted with one or more substituents selected from halo-;

[0403] (52) A is selected from CR4 and N.

[0404] R4 is hydrogen, methyl, or halogenated;

[0405] (53) A comes from CR4 and R4 is hydrogen, methyl, fluorine or chlorine;

[0406] (54) A is CH;

[0407] (55) A is N.

[0408] Appropriately, a heteroaryl or heterocyclic group as defined herein is a monocyclic heteroaryl or a monocyclic, bicyclic or bridged heterocyclic group containing one, two or three heteroatoms selected from N, O or S.

[0409] Appropriately, a heteroaryl is a 5- or 6-membered heteroaryl ring containing one, two, or three heteroatoms selected from N, O, or S.

[0410] Suitablely, the heterocyclic group is a 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring containing one, two, or three heteroatoms selected from N, O, or S. Most suitablely, the heterocyclic group is a 5-, 6-, or 7-membered ring containing one, two, or three heteroatoms selected from N, O, or S [e.g., morpholino (e.g., 4-morpholino), pyridino, piperazino, homopiperazino, or pyrrolidone].

[0411] Appropriately, the aryl group is phenyl.

[0412] Appropriately, R0 is as defined in paragraph (1) or (2) above. In one embodiment, R0 is hydrogen. In another embodiment, R0 is deuterium.

[0413] Appropriately, R1 is defined as in any of paragraphs (3) to (17) above. More appropriately, R1 is defined as in any of paragraphs (13) to (17) above. Most appropriately, R1 is defined as in paragraph (13) or (17) above.

[0414] Appropriately, R2 is as defined in any of paragraphs (18) to (31). More appropriately, R2 is cyano or as defined in any of paragraphs (25) to (31). Most appropriately, R2 is as defined in paragraph (25) or (31).

[0415] Appropriately, R3 is as defined in any of paragraphs (32) through (49). More appropriately, R3 is as defined in any of paragraphs (35) through (40) (e.g., any of paragraphs (35) through (39)). Most appropriately, R2 is as defined in paragraph (39) or (40).

[0416] Appropriately, A is as defined in any of paragraphs (50) through (55). Most appropriately, A is as defined in paragraphs (51), (54), or (55).

[0417] In a specific set of compounds having Formula I, R1 is as defined in any of paragraphs (3), (4), (5), (10), (13) or (17), and R0, R2, R3 and A each have any of the definitions herein.

[0418] In a specific set of compounds having Formula I, R2 is as defined in any of paragraphs (18), (19), (20), (25), (29), (30) or (31), and R0, R1, R3 and A each have any one of the definitions herein.

[0419] In a specific set of compounds having Formula I, R3 is as defined in any 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.

[0420] In a specific set of compounds having Formula I, A is as defined in any of paragraphs (50), (51), (54) or (55), and R0, R1, R2 and R3 each have any of the definitions herein.

[0421] In the examples of compounds having Formula I described above:

[0422] R0 is as defined in paragraph (1) or (2);

[0423] R1 is as defined in paragraphs (3) to (17) above;

[0424] R2 is as defined in any of the paragraphs (18) to (31) above;

[0425] R3 is as defined in any of paragraphs (32) to (49) above; and

[0426] A is as defined in any of paragraphs (50) to (55) above.

[0427] In a specific set of the above-mentioned compounds having Formula I:

[0428] R0 is as defined in paragraph (1) or (2);

[0429] R1 is defined as described in paragraphs (13) to (17) above;

[0430] R2 is as defined in any of the paragraphs (25) to (31) above;

[0431] R3 is as defined in any of paragraphs (35) to (40) above; and

[0432] A is as defined in any of the paragraphs (51), (54) or (55) above.

[0433] In a specific set of the above-mentioned compounds having Formula I:

[0434] R0 is as defined in paragraph (1) or (2);

[0435] R1 is as defined in paragraph (5) above;

[0436] R2 is as defined in paragraph (19) above;

[0437] R3 is as defined in paragraph (33) above; and

[0438] A is as defined in paragraph (51) above.

[0439] In a specific set of the above-mentioned compounds having Formula I:

[0440] R0 is as defined in paragraph (1);

[0441] R1 is as defined in paragraph (10) above;

[0442] R2 is as defined in paragraph (20) above;

[0443] R3 is as defined in paragraph (34) above; and

[0444] A is as defined in paragraph (51) above.

[0445] In a specific set of the above-mentioned compounds having Formula I:

[0446] R0 is as defined in paragraph (1);

[0447] R1 is as defined in paragraph (13) above;

[0448] R2 is as defined in paragraph (25) above;

[0449] R3 is as defined in paragraph (35) or (35a) above; and

[0450] A is as defined in paragraph (53) above.

[0451] In a specific set of the above-mentioned compounds having Formula I:

[0452] R0 is as defined in paragraph (1);

[0453] R1 is as defined in paragraph (17) above;

[0454] R2 is as defined in paragraph (29) above;

[0455] R3 is as defined in paragraph (38) above; and

[0456] A is as defined in paragraph (54) above.

[0457] In a specific set of compounds of the present invention, these compounds have the following structural formula Ib (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0458]

[0459] R0, R1, R2 and R3 are each as defined above, and R4 is hydrogen, methyl, fluorine or chlorine.

[0460] In examples of compounds having formula Ib:

[0461] R0 is as defined in paragraph (1) or (2);

[0462] R1 is defined as in any of the paragraphs (3) to (17) above;

[0463] R2 is as defined in any of the paragraphs (18) to (31) above;

[0464] R3 is as defined in any of paragraphs (32) to (40) above; and

[0465] R4 is hydrogen, methyl, fluorine, or chlorine.

[0466] In examples of compounds having formula Ib:

[0467] R0 is as defined in paragraph (1) or (2);

[0468] R1 is defined as in any of the paragraphs (3) to (17) above;

[0469] R2 is as defined in any of the paragraphs (18) to (31) above;

[0470] R3 is as defined in any of paragraphs (32) to (49) above; and

[0471] R4 is hydrogen, methyl, fluorine, or chlorine.

[0472] In another embodiment of the compound having formula Ib:

[0473] R0 is as defined in paragraph (1) above;

[0474] R1 is as defined in paragraph (13) above;

[0475] R2 is as defined in paragraph (25) above;

[0476] R3 is as defined in paragraph (35) above; and

[0477] R4 is hydrogen.

[0478] In another embodiment of the compound having formula Ib:

[0479] R0 is as defined in paragraph (1) above;

[0480] R1 is as defined in paragraph (17) above;

[0481] R2 is as defined in paragraph (31) above;

[0482] R3 is as defined in paragraphs (38), (39) or (40) above; and

[0483] R4 is hydrogen.

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

[0485] R0 is as defined in paragraph (1) above;

[0486] R1 is as defined in paragraph (17) above;

[0487] R2 is as defined in paragraph (31) above;

[0488] R3 is as defined in paragraph (40) above; and

[0489] R4 is hydrogen.

[0490] In a specific set of compounds of the present invention, these compounds have the following structural formula Ic (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0491]

[0492] R0, R1, R2 and R3 are each defined as above.

[0493] In examples of compounds having formula Ic:

[0494] R0 is as defined in paragraph (1) or (2);

[0495] R1 is defined as in any of the paragraphs (3) to (17) above;

[0496] R2 is as defined in any of paragraphs (18) to (31) above; and

[0497] R3 is defined as in any of paragraphs (32) to (40) above.

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

[0499] R0 is as defined in paragraph (1) or (2);

[0500] R1 is defined as in any of the paragraphs (3) to (17) above;

[0501] R2 is as defined in any of paragraphs (18) to (31) above; and

[0502] R3 is defined as in any of paragraphs (32) to (49) above.

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

[0504] R0 is as defined in paragraph (1) above;

[0505] R1 is as defined in paragraph (13) above;

[0506] R2 is as defined in paragraph (25) above; and

[0507] R3 is defined as described in paragraph (35) above.

[0508] In another embodiment of the compound having formula Ic:

[0509] R0 is as defined in paragraph (1) above;

[0510] R1 is as defined in paragraph (17) above;

[0511] R2 is as defined in paragraph (31) above; and

[0512] R3 is defined as in paragraphs (38), (39) or (40) above.

[0513] In another embodiment of the compound having formula Ic:

[0514] R0 is as defined in paragraph (1) above;

[0515] R1 is as defined in paragraph (17) above;

[0516] R2 is as defined in paragraph (30) above; and

[0517] R3 is defined as in paragraph (40) above.

[0518] In a specific set of compounds of the present invention, these compounds have the following structural formula Id (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0519]

[0520] A, R1, R2, and R3 are each defined as described above.

[0521] In examples of compounds having formula Id:

[0522] R1 is defined as in any of the paragraphs (3) to (17) above;

[0523] R2 is as defined in any of the paragraphs (18) to (31) above;

[0524] R3 is as defined in any of paragraphs (32) to (40) above; and

[0525] A is as defined in any of paragraphs (50) to (55) above.

[0526] In examples of compounds having formula Id:

[0527] R1 is defined as in any of the paragraphs (3) to (17) above;

[0528] R2 is as defined in any of the paragraphs (18) to (31) above;

[0529] R3 is as defined in any of paragraphs (32) to (49) above; and

[0530] A is as defined in any of paragraphs (50) to (55) above.

[0531] In another embodiment of the compound having formula Id:

[0532] R1 is as defined in paragraph (13) above;

[0533] R2 is as defined in paragraph (25) above;

[0534] R3 is as defined in paragraph (35) above; and

[0535] A is as defined in paragraph (51) above.

[0536] In another embodiment of the compound having formula Id:

[0537] R1 is as defined in paragraph (17) above;

[0538] R2 is as defined in paragraph (31) above; and

[0539] R3 is as defined in paragraphs (38), (39) or (40) above; and

[0540] A is as defined in paragraphs (54) or (55) above.

[0541] In another embodiment of the compound having formula Id:

[0542] R1 is as defined in paragraph (17) above;

[0543] R2 is as defined in paragraph (31) above; and

[0544] R3 is as defined in paragraph (40) above; and

[0545] A is as defined in paragraphs (54) or (55) above.

[0546] In a specific set of compounds of the present invention, these compounds have the following structural formula Ie (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0547]

[0548] Where A, R0, R2, R3 and R 1z Each is as defined above, and m is 0, 1, or 2.

[0549] In examples of compounds having formula Ie:

[0550] R0 is as defined in paragraph (1) or (2) above;

[0551] R 1z It is as defined in any of paragraphs (3) to (10) above;

[0552] m is 0, 1, or 2;

[0553] R2 is as defined in any of the paragraphs (18) to (31) above;

[0554] R3 is as defined in any of paragraphs (32) to (40) above; and

[0555] A is as defined in any of paragraphs (50) to (55) above.

[0556] In examples of compounds having formula Ie:

[0557] R0 is as defined in paragraph (1) or (2) above;

[0558] R 1z It is as defined in any of paragraphs (3) to (10) above;

[0559] m is 0, 1, or 2;

[0560] R2 is as defined in any of the paragraphs (18) to (31) above;

[0561] R3 is as defined in any of paragraphs (31) to (49) above; and

[0562] A is as defined in any of paragraphs (50) to (55) above.

[0563] In another embodiment of the compound having formula Ie:

[0564] R0 is as defined in paragraph (1) above;

[0565] R 1z It is either halogenated or cyano-based;

[0566] m is 0 or 1;

[0567] R2 is as defined in paragraph (25) above;

[0568] R3 is as defined in paragraph (35) above; and

[0569] A is as defined in paragraph (51) above.

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

[0571] R0 is as defined in paragraph (1) above;

[0572] R 1z It is cyano;

[0573] m is 1;

[0574] R1 is as defined in paragraph (17) above;

[0575] R2 is as defined in paragraph (31) above;

[0576] R3 is as defined in paragraphs (38), (39) or (40) above; and

[0577] A is as defined in paragraphs (54) or (55) above.

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

[0579] R0 is as defined in paragraph (1) above;

[0580] R 1z It is cyano;

[0581] m is 1;

[0582] R2 is as defined in paragraph (31) above;

[0583] R3 is as defined in paragraph (40) above; and

[0584] A is as defined in paragraphs (54) or (55) above.

[0585] In a specific set of compounds of the present invention, these compounds have the following structural formula If (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0586]

[0587] Where A, R0, R2, R3 and R 1z Each as defined above.

[0588] In embodiments of compounds having the formula If:

[0589] R0 is as defined in paragraph (1) or (2) above;

[0590] R 1z It is as defined in any of paragraphs (3) to (10) above;

[0591] R2 is as defined in any of the paragraphs (18) to (31) above;

[0592] R3 is as defined in any of paragraphs (32) to (40) above; and

[0593] A is as defined in any of paragraphs (50) to (55) above.

[0594] In embodiments of compounds having the formula If:

[0595] R0 is as defined in paragraph (1) or (2) above;

[0596] R 1z It is as defined in any of paragraphs (3) to (10) above;

[0597] R2 is as defined in any of the paragraphs (18) to (31) above;

[0598] R3 is as defined in any of paragraphs (32) to (49) above; and

[0599] A is as defined in any of paragraphs (50) to (55) above.

[0600] In another embodiment of the compound having the formula If:

[0601] R0 is as defined in paragraph (1) above;

[0602] R 1z It is either halogenated or cyano-based;

[0603] R2 is as defined in paragraph (25) above;

[0604] R3 is as defined in paragraph (35) above; and

[0605] A is as defined in paragraph (51).

[0606] In another embodiment of the compound having the formula If:

[0607] R0 is as defined in paragraph (1) above;

[0608] R 1z It is cyano;

[0609] R2 is as defined in paragraph (31) above;

[0610] R3 is as defined in paragraphs (38), (39) or (40) above; and

[0611] A is as defined in paragraphs (54) or (55) above.

[0612] In another embodiment of the compound having the formula If:

[0613] R0 is as defined in paragraph (1) above;

[0614] R 1z It is cyano;

[0615] R2 is as defined in paragraph (31) above;

[0616] R3 is as defined in paragraph (40) above; and

[0617] A is as defined in paragraphs (54) or (55) above.

[0618] In a specific set of compounds of the present invention, these compounds have the following structural formula Ig (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0619]

[0620] A, R0, R1, and R3 are each defined as described above; and R 200 and R 201 Each is independently selected from hydrogen, methyl, hydroxymethyl, halogenated, trifluoromethyl, difluoromethyl, methoxy, or acetyl. Appropriately, R200 and R 201 Each is independently selected from hydrogen, methyl, or halogenated.

[0621] In examples of compounds having formula Ig:

[0622] R0 is as defined in paragraph (1) or (2) above;

[0623] R1 is defined as in any of the paragraphs (3) to (17) above;

[0624] R3 is as defined in any of the paragraphs (32) to (49) above;

[0625] A is as defined in any of paragraphs (50) to (55); and

[0626] R 200 and R 201 Each is independently selected from hydrogen, methyl, hydroxymethyl, or halogenated.

[0627] In examples of compounds having formula Ig:

[0628] R0 is as defined in paragraph (1) or (2) above;

[0629] R1 is defined as in any of the paragraphs (3) to (17) above;

[0630] R3 is as defined in any of paragraphs (32) to (40) above;

[0631] A is as defined in any of paragraphs (50) to (55); and

[0632] R 200 and R 201 Each is independently selected from hydrogen, methyl, hydroxymethyl, or halogenated.

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

[0634] R0 is as defined in paragraph (1) above;

[0635] R1 is as defined in paragraph (13) above;

[0636] R2 is as defined in paragraph (25) above;

[0637] R3 is as defined in paragraph (35) above;

[0638] A is as defined in paragraph (51); and

[0639] R 200 and R 201Each is independently selected from methyl or chlorine.

[0640] In another embodiment of the compound having formula Ig:

[0641] R0 is as defined in paragraph (1) above;

[0642] R1 is as defined in paragraph (17) above;

[0643] R2 is as defined in paragraph (31) above;

[0644] R3 is as defined in paragraphs (38), (39) or (40) above;

[0645] A is as defined in paragraphs (54) or (55); and

[0646] R 200 It is methyl and R 201 It is chlorine or methyl.

[0647] In another embodiment of the compound having formula Ig:

[0648] R0 is as defined in paragraph (1) above;

[0649] R1 is as defined in paragraph (17) above;

[0650] R2 is as defined in paragraph (31) above;

[0651] R3 is as defined in paragraph (40) above;

[0652] A is as defined in paragraphs (54) or (55) above; and

[0653] R 200 It is methyl and R 201 It is chlorine or methyl.

[0654] In a specific set of compounds of the present invention, these compounds have the following structural formula Ig2 (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0655]

[0656] Where A, R0, R1, and R3 are each defined as above, and R 201 It is selected from hydrogen, methyl, halogen, trifluoromethyl, difluoromethyl, methoxy, or acetyl.

[0657] In examples of compounds having the formula Ig2:

[0658] In examples of compounds having the formula Ig2:

[0659] R0 is as defined in paragraph (1) or (2) above;

[0660] R1 is defined as in any of the paragraphs (3) to (17) above;

[0661] R3 is as defined in any of paragraphs (32) to (40) above;

[0662] A is as defined in any of paragraphs (50) to (55); and

[0663] R 201 Selected from hydrogen, methyl, or halogenated.

[0664] In examples of compounds having the formula Ig2:

[0665] R0 is as defined in paragraph (1) or (2) above;

[0666] R1 is defined as in any of the paragraphs (3) to (17) above;

[0667] R3 is as defined in any of the paragraphs (32) to (49) above;

[0668] A is as defined in any of paragraphs (50) to (55) above; and

[0669] R 201 Selected from methyl, methoxy, or halogenated.

[0670] In another embodiment of the compound having the formula Ig2:

[0671] R0 is as defined in paragraph (1) above;

[0672] R1 is as defined in paragraph (13) above;

[0673] R3 is as defined in paragraph (35) above;

[0674] A is as defined in paragraph (51) above; and

[0675] R 201 Selected from methyl or halogenated.

[0676] In another embodiment of the compound having the formula Ig2:

[0677] R0 is as defined in paragraph (1) above;

[0678] R1 is as defined in paragraph (17) above;

[0679] R2 is as defined in paragraph (31) above;

[0680] R3 is as defined in paragraphs (38), (39) or (40) above;

[0681] A is as defined in paragraphs (54) or (55) above; and

[0682] R 201 Selected from methyl or chlorine.

[0683] In another embodiment of the compound having the formula Ig2:

[0684] R0 is as defined in paragraph (1) above;

[0685] R1 is as defined in paragraph (17) above;

[0686] R2 is as defined in paragraph (31) above;

[0687] R3 is as defined in paragraph (40) above;

[0688] A is as defined in paragraphs (54) or (55) above; and

[0689] R 201 Selected from methyl or chlorine.

[0690] In a specific set of compounds of the present invention, these compounds have the following structural formula Ih (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0691]

[0692] A, R0, R1, and R3 are each defined as described above.

[0693] In examples of compounds having formula Ih:

[0694] R0 is as defined in paragraph (1) or (2) above;

[0695] R1 is defined as in any of the paragraphs (3) to (17) above;

[0696] R3 is as defined in any of paragraphs (32) to (40) above; and

[0697] A is as defined in any of paragraphs (50) to (55).

[0698] In examples of compounds having formula Ih:

[0699] R0 is as defined in paragraph (1) or (2) above;

[0700] R1 is defined as in any of the paragraphs (3) to (17) above;

[0701] R3 is as defined in any of paragraphs (32) to (49) above; and

[0702] A is as defined in any of paragraphs (50) to (55).

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

[0704] R0 is as defined in paragraph (1) above;

[0705] R1 is as defined in paragraph (13) above;

[0706] R2 is as defined in paragraph (25) above;

[0707] R3 is as defined in paragraph (35) above; and

[0708] A is as defined in paragraph (51).

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

[0710] R0 is as defined in paragraph (1) above;

[0711] R1 is as defined in paragraph (17) above;

[0712] R2 is as defined in paragraph (31) above;

[0713] R3 is as defined in paragraphs (38), (39) or (40) above; and

[0714] A is as defined in paragraphs (54) or (55).

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

[0716] R0 is as defined in paragraph (1) above;

[0717] R1 is as defined in paragraph (17) above;

[0718] R2 is as defined in paragraph (30) above;

[0719] R3 is as defined in paragraphs (39) or (40) above; and

[0720] A is as defined in paragraphs (52) or (53).

[0721] In a specific set of compounds of the present invention, these compounds have the following structural formula Ih (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0722]

[0723] A, R0, R1, and R3 are each defined as described above.

[0724] In examples of compounds having the formula Ih2:

[0725] R0 is as defined in paragraph (1) or (2) above;

[0726] R1 is defined as in any of the paragraphs (3) to (17) above;

[0727] R3 is as defined in any of paragraphs (32) to (40) above; and

[0728] A is as defined in any of paragraphs (50) to (55) above.

[0729] In examples of compounds having the formula Ih2:

[0730] R0 is as defined in paragraph (1) or (2) above;

[0731] R1 is defined as in any of the paragraphs (3) to (17) above;

[0732] R3 is as defined in any of paragraphs (32) to (49) above; and

[0733] A is as defined in any of paragraphs (50) to (55).

[0734] In another embodiment of the compound having formula Ih2:

[0735] R0 is as defined in paragraph (1) above;

[0736] R1 is as defined in paragraph (13) above;

[0737] R3 is as defined in paragraph (35) above; and

[0738] A is as defined in paragraph (51) above.

[0739] In another embodiment of the compound having formula Ih2:

[0740] R0 is as defined in paragraph (1) above;

[0741] R1 is as defined in any of paragraphs (14) to (17) above;

[0742] R3 is as defined in paragraphs (38), (39) or (40) above; and

[0743] A is as defined in paragraphs (52) or (53) above.

[0744] In another embodiment of the compound having formula Ih2:

[0745] R0 is as defined in paragraph (1) above;

[0746] R1 is as defined in paragraph (17) above;

[0747] R3 is as defined in paragraphs (38), (39) or (40) above; and

[0748] A is as defined in paragraphs (52) or (53) above.

[0749] In another embodiment of the compound having formula Ih2:

[0750] R0 is as defined in paragraph (1) above;

[0751] R1 is as defined in paragraph (17) above;

[0752] R2 is as defined in paragraph (31) above;

[0753] R3 is as defined in paragraph (40) above; and

[0754] A is as defined in paragraphs (52) or (53).

[0755] In a specific set of compounds of the present invention, these compounds have the following structural formula Ii (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0756]

[0757] Where A, R0, R3 and R 1z Each as defined above.

[0758] In examples of compounds having formula Ii:

[0759] R0 is as defined in paragraph (1) or (2) above;

[0760] R 1z It is as defined in any of paragraphs (3) to (10) above;

[0761] R3 is as defined in any of paragraphs (32) to (49) above; and

[0762] A is as defined in any of paragraphs (50) to (55).

[0763] In examples of compounds having formula Ii:

[0764] R0 is as defined in paragraph (1) or (2) above;

[0765] R 1z It is as defined in any of paragraphs (3) to (10) above;

[0766] R3 is as defined in any of paragraphs (32) to (40) above; and

[0767] A is as defined in any of paragraphs (50) to (55).

[0768] In another embodiment of the compound having formula Ii:

[0769] R0 is as defined in paragraph (1) above;

[0770] R 1z It is either halogenated or cyano-based;

[0771] R3 is as defined in paragraph (35) above; and

[0772] A is as defined in paragraph (51) above.

[0773] In another embodiment of the compound having formula Ii:

[0774] R0 is as defined in paragraph (1) above;

[0775] R 1z It is cyano;

[0776] R3 is as defined in paragraphs (38), (39) or (40) above; and

[0777] A is as defined in paragraphs (54) or (55) above.

[0778] In another embodiment of the compound having formula Ii:

[0779] R0 is as defined in paragraph (1) above;

[0780] R 1z It is cyano;

[0781] R3 is as defined in paragraph (40) above;

[0782] A is as defined in paragraphs (54) or (55) above.

[0783] In a specific set of compounds of the present invention, these compounds have the following structural formula Ii2 (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0784]

[0785] Where A, R0, R3 and R 1z Each as defined above.

[0786] In examples of compounds having formula Ii2:

[0787] R0 is as defined in paragraph (1) or (2) above;

[0788] R 1z It is as defined in any of paragraphs (3) to (10) above;

[0789] R3 is as defined in any of paragraphs (32) to (40) above; and

[0790] A is as defined in any of paragraphs (50) to (55).

[0791] In examples of compounds having formula Ii2:

[0792] R0 is as defined in paragraph (1) or (2) above;

[0793] R 1z It is as defined in any of paragraphs (3) to (10) above;

[0794] R3 is as defined in any of paragraphs (32) to (49) above; and

[0795] A is as defined in any of paragraphs (50) to (55).

[0796] In another embodiment of the compound having formula Ii2:

[0797] R0 is as defined in paragraph (1) above;

[0798] R 1z It is either halogenated or cyano-based;

[0799] R3 is as defined in paragraph (35) above; and

[0800] A is as defined in paragraph (51) above.

[0801] In another embodiment of the compound having formula Ii2:

[0802] R0 is as defined in paragraph (1) above;

[0803] R 1z It is cyano;

[0804] R3 is as defined in paragraphs (38), (39) or (40) above; and

[0805] A is as defined in paragraphs (54) or (55) above.

[0806] In another embodiment of the compound having formula Ii2:

[0807] R0 is as defined in paragraph (1) above;

[0808] R 1z It is cyano;

[0809] R3 is as defined in paragraph (40) above; and

[0810] A is as defined in paragraphs (54) or (55) above.

[0811] In a specific set of compounds of the present invention, these compounds have the following structural formula Ii3 (a sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0812]

[0813] Where A, R0, R3 and R 1z Each as defined above and R 201 It is selected from hydrogen, methyl, hydroxymethyl, halogen, trifluoromethyl, difluoromethyl, methoxy, or acetyl.

[0814] In examples of compounds having formula Ii2:

[0815] R0 is as defined in paragraph (1) or (2) above;

[0816] R 1z It is as defined in any of paragraphs (3) to (10) above;

[0817] R3 is as defined in any of paragraphs (32) to (40) above;

[0818] A is as defined in any of paragraphs (50) to (55) above; and

[0819] R 201It is selected from methyl, hydroxymethyl, halogenated, trifluoromethyl, difluoromethyl, methoxy, or acetyl.

[0820] In examples of compounds having formula Ii3:

[0821] R0 is as defined in paragraph (1) or (2) above;

[0822] R 1z It is as defined in any of paragraphs (3) to (10) above;

[0823] R3 is as defined in any of the paragraphs (32) to (49) above;

[0824] A is as defined in any of paragraphs (50) to (55) above; and

[0825] R 201 It is selected from methyl, hydroxymethyl, halogenated, trifluoromethyl, difluoromethyl, methoxy, or acetyl.

[0826] In another embodiment of the compound having formula Ii3:

[0827] R0 is as defined in paragraph (1) above;

[0828] R 1z It is either halogenated or cyano-based;

[0829] R3 is as defined in paragraph (35) above;

[0830] A is as defined in paragraph (50) above; and

[0831] R 201 Selected from methyl, hydroxymethyl, halogenated or methoxylated.

[0832] In another embodiment of the compound having formula Ii3:

[0833] R0 is as defined in paragraph (1) above;

[0834] R 1z It is cyano;

[0835] R3 is as defined in paragraphs (38), (39) or (40) above;

[0836] A is as defined in paragraphs (54) or (55) above; and

[0837] R 201 Selected from methyl or chlorine.

[0838] In another embodiment of the compound having formula Ii3:

[0839] R0 is as defined in paragraph (1) above;

[0840] R 1z It is cyano;

[0841] R3 is as defined in paragraph (40) above;

[0842] A is as defined in paragraphs (54) or (55) above; and

[0843] R 201 Selected from methyl or chlorine.

[0844] Specific compounds of this invention include any compound described in the Examples section of this application or a pharmaceutically acceptable salt or solvate thereof, particularly any of the following compounds:

[0845] 3-[5-amino-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0846] 3-[5-amino-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0847] 3-(5-amino-3-pyridazin-4-yl-pyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile;

[0848] 3-[5-amino-3-(2-ethylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0849] 3-[5-amino-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0850] 3-[5-amino-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0851] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0852] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-1-bicyclo[1.1.1]pentyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0853] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0854] (3S)-4-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]morpholin-3-carboxylic acid;

[0855] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-ethyl-4-piperidinyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0856] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S,4S)-4-methoxy-1-methyl-pyrrolidine-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0857] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0858] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[3-(hydroxymethyl)-4-methyl-piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0859] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0860] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0861] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0862] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methylsulfonyl-4-piperidinyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0863] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0864] 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]-2,2-dimethyl-propionic acid;

[0865] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0866] 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;

[0867] 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;

[0868] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(quininecyclo-3-ylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0869] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0870] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-morpholinoethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0871] 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;

[0872] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[2-[2-(dimethylamino)ethyl]morpholin-4-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0873] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0874] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4H-1,2,4-triazol-3-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0875] (2R)-4-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]morpholin-2-carboxylic acid;

[0876] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0877] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazin-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0878] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1,1-dioxothio-4-yl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0879] 2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]acetamide;

[0880] 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0881] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[2-(dimethylamino)-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0882] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-hydroxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0883] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1H-imidazol-2-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0884] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0885] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]azacyclobutane-2-carboxylic acid;

[0886] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]azacyclobutane-3-carboxylic acid;

[0887] (3R)-1-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidine-3-carboxylic acid;

[0888] 4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-sulfonamide;

[0889] 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;

[0890] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2R)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0891] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0892] 3-[5-(tert-butylamino)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0893] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0894] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-hydroxycyclopropyl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0895] 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-(4-piperidinylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0896] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-morpholin-3-yl]methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0897] 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;

[0898] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-3-piperidinyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0899] 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;

[0900] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-pyrrolidine-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0901] tert-butyl(3R)-3-[[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]pyrrolidine-1-carboxylate;

[0902] 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;

[0903] tert-butylrac-(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;

[0904] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-morpholin-3-yl]methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0905] 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;

[0906] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-pyrrolidine-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0907] tert-butyl(3S)-3-[[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]pyrrolidine-1-carboxylate;

[0908] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-3-piperidinyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0909] tert-butyl(3S)-3-[[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]piperidine-1-carboxylate;

[0910] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0911] N-tert-butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0912] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0913] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0914] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[2-(4-phenylpiperazin-1-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0915] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(oxetane-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0916] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0917] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholin-4-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0918] 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;

[0919] N-(2-amino-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0920] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0921] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0922] 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;

[0923] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0924] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1-methyl-ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0925] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxyoxetane-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0926] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-methylsulfonyl-pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0927] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0928] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxycyclobutyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0929] 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;

[0930] N-(4-aminonorborne-1-yl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0931] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2S)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0932] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-methoxy-1-methyl-pyrrolidine-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0933] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0934] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(1-methylazacyclobutane-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0935] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0936] 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;

[0937] N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0938] N-(3-amino-1-bicyclo[1.1.1]pentyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0939] tert-butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-1-bicyclo[1.1.1]pentyl]carbamate;

[0940] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[cis-(3S,4R)-4-hydroxypyrrolidine-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0941] tert-butyl(3S,4R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-4-hydroxypyrrolidine-1-carboxylate;

[0942] N-(2-amino-1,1-dimethyl-ethyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0943] tert-butyl N-[2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-2-methyl-propyl]carbamate;

[0944] 3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)-N-[(3S)-3-piperidinyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0945] tert-butyl(3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]piperidine-1-carboxylate;

[0946] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[trans-(3S,4S)-4-hydroxypyrrolidine-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0947] tert-butyltrans-(3S,4S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-4-hydroxypyrrolidine-1-carboxylate;

[0948] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxypyrrolidine-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0949] tert-butyl 3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]methyl]-3-hydroxy-pyrrolidine-1-carboxylate;

[0950] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-3-piperidinyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0951] tert-butyl(3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]piperidine-1-carboxylate;

[0952] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-methylpyrrolidine-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0953] tert-butyl 3-[[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-3-methyl-pyrrolidine-1-carboxylate;

[0954] 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;

[0955] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0956] 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;

[0957] tert-butyl N-[1-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]methyl]-3,3-difluoro-cyclobutyl]carbamate;

[0958] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(morpholin-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0959] tert-butyl 2-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]methyl]morpholine-4-carboxylate;

[0960] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(piperazin-1-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0961] tert-butyl 4-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]piperazine-1-carboxylate;

[0962] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-pyrrolidine-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0963] tert-butyl(3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]pyrrolidine-1-carboxylate;

[0964] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0965] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid;

[0966] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0967] 2-(3-cyanophenyl)-3-(2-ethylpyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0968] 2-(3-cyanophenyl)-3-(2-ethyl-5-methylpyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0969] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0970] 2-(3-cyanophenyl)-3-(2-ethyl-4-methylpyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0971] 2-(3-cyanophenyl)-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0972] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0973] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-5-carboxamide;

[0974] 3-Cyano-2-(3-Cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0975] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0976] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methanesulfonamide;

[0977] (2S)-2-[[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]propionic acid;

[0978] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidine-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile carbamate;

[0979] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0980] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0981] 3-[5-(aminomethyl)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0982] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0983] 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0984] 3-[5-[(2-hydroxy-2-methyl-propyl)amino]-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0985] 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0986] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0987] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0988] 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-(4-piperidinyloxy)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0989] 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-[[(3R)-3-piperidinyl]oxy]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0990] tert-butyl(3R)-3-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypiperidine-1-carboxylate;

[0991] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3S)-pyrrolidine-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0992] tert-butyl(3S)-3-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypyrrolidine-1-carboxylate;

[0993] 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-[[(3S)-3-piperidinyl]oxy]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0994] tert-butyl(3S)-3-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypiperidine-1-carboxylate;

[0995] 3-[5-amino-3-(6-amino-5-methyl-3-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0996] 3-[5-amino-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0997] 3-[5-amino-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0998] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methylpyridin-2-carboxynitrile;

[0999] 3-[5-amino-3-(2-fluoro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1000] 3-[5-amino-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1001] 3-[5-amino-3-(2,6-dimethyl-1-oxy-pyridin-1-onthium-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1002] 3-[5-amino-3-(2-amino-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1003] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methylpyridine-2-carboxamide;

[1004] N-[4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-2-pyridyl]acetamide;

[1005] 3-[5-amino-3-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1006] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methylpyridin-2-carboxylic acid;

[1007] 3-[5-amino-3-[2-(dimethylamino)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1008] [3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea;

[1009] 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;

[1010] 1-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-(1-ethyl-4-piperidinyl)urea;

[1011] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxamide;

[1012] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-[(3S)-pyrrolidine-3-yl]urea;

[1013] 1-(2-aminoethyl)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea;

[1014] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-[(3R)-pyrrolidine-3-yl]urea;

[1015] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-cyano-guanidine;

[1016] 3-[3-(2-ethylpyrazol-3-yl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1017] 3-[3-(2-ethylpyrazol-3-yl)-5-[3-(hydroxymethyl)-4-methyl-piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1018] 3-[3-(2-ethylpyrazol-3-yl)-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1019] 3-[3-(2-ethylpyrazol-3-yl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1020] 3-[3-(2-ethylpyrazol-3-yl)-5-(4-methylsulfonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1021] 3-[3-(2-ethylpyrazol-3-yl)-5-(4H-1,2,4-triazol-3-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1022] 3-[3-(2-ethylpyrazol-3-yl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1023] 3-[3-(2-ethylpyrazol-3-yl)-5-(1-imino-1-oxo-1,4-thiazin-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1024] 5-(benzylamino)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1025] N-Benzyl-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1026] 2-(2-furanyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carboxylonitrile;

[1027] tert-butyl(2S)-2-[[[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate;

[1028] tert-butyl(2R)-2-[[[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]pyrrolidine-1-carboxylate;

[1029] 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1030] tert-butyl(2S)-2-[[[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]pyrrolidine-1-carboxylate;

[1031] tert-butyl(2R)-2-[[[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate;

[1032] 2-(2-furanyl)-5-[4-(2-phenylethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1033] 2-(2-furanyl)-5-[4-(2-pyridylmethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1034] 2-(2-furanyl)-5-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1035] 5-[(1-benzyl-4-piperidinyl)methylamino]-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1036] tert-butyl(2R)-4-[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-methyl-piperazine-1-carboxylate;

[1037] tert-butyl(2S)-4-[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-methyl-piperazine-1-carboxylate;

[1038] 5-[2-(4-benzylpiperazin-1-yl)ethylamino]-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1039] 2-(2-furanyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1040] 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1041] 5-[3-(dimethylamino)azacyclobutane-1-yl]-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1042] tert-butyl 4-[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate;

[1043] 2-(2-furanyl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1044] 2-(2-furanyl)-5-[[(2S)-morpholin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1045] 2-(2-furanyl)-5-[[(2R)-morpholin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1046] 5-(4-benzylpiperazin-1-yl)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1047] N-Benzyl-3-bromo-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1048] 5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1049] 5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1050] 5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxaldehyde;

[1051] N-Benzyl-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1052] 5-Amino-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1053] 3-Bromo-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1054] 2-(2-furanyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1055] 2-(2-furanyl)-5-[4-[(2,4,6-trifluorophenyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1056] 2-(2-furanyl)-5-[4-[(1-methylimidazol-2-yl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1057] 2-(2-furanyl)-5-[4-(2-hydroxyethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1058] N-Benzyl-2-(2-furanyl)-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1059] N-Benzyl-2-(2-furanyl)-3-(2-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1060] Methyl(E)-3-[5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoate;

[1061] (E)-3-[5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoic acid;

[1062] 2-(2-furanyl)-5-(4-phenylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1063] 2-(2-furanyl)-5-(3-hydroxypropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1064] 2-(2-furanyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1065] 2-(2-furanyl)-5-(3-piperidinylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylonitrile hydrochloride;

[1066] 5-(benzylamino)-2-oxazol-2-yl-pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1067] 5-(benzylamino)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1068] 2-(3-cyanophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1069] 2-(3-fluorophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1070] 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylonitrile;

[1071] 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-oxazol-5-yl-pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1072] 5-(benzylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1073] 5-(benzylamino)-2-(5-methyl-2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1074] 5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]-2-oxazol-5-yl-pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1075] N-Benzyl-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1076] 2-(3-fluorophenyl)-N-[(3-methyl-2-pyridyl)methyl]pyrazolo[1,5-a]pyrimidin-5-amine;

[1077] 2-(3-fluorophenyl)-N-(2-phenylethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1078] N-(1H-benzimidazol-2-ylmethyl)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1079] 2-(3-Fluorophenyl)-N-(2-isoindoline-2-ylethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1080] N-Benzyl-3-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1081] 3-Bromo-5-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine;

[1082] N-Benzyl-3-bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1083] 5-(benzylamino)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1084] 3-Bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1085] 5-Amino-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1086] 2-(2-furanyl)-N-(thiazolyl-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1087] [5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol;

[1088] 5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;

[1089] N-Benzyl-2-(2-furanyl)-3-iodopyrazolo[1,5-a]pyrimidine-5-amine;

[1090] 2-(2-furanyl)-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1091] 2-(2-furanyl)-5-[[(2R)-pyrrolidone-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1092] 2-(2-furanyl)-5-[[(2R)-1-methylpyrrolidone-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1093] 2-(2-furanyl)-5-[(3R)-3-methylpiperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylonitrile hydrochloride;

[1094] tert-butyl 4-[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperidine-1-carboxylate;

[1095] N-Benzyl-7-(2-furanyl)pyrazolo[1,5-a][1,3,5]triazine-2-amine;

[1096] N-Benzyl-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1097] 2-(3-cyanophenyl)-5-[4-(2-fluoroethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1098] 2-(3-cyanophenyl)-5-[2-(4-phenylpiperazin-1-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1099] 3-(2-chloro-6-methyl-4-pyridyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1100] N-tert-butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-formamidinium;

[1101] 3-(2-amino-6-methyl-4-pyridyl)-N-tert-butyl-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1102] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1103] 2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1104] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1105] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-5-(aminosulfonylamino)pyrazolo[1,5-a]pyrimidine;

[1106] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-hydroxy-2-methylpropionamide;

[1107] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2,2-dimethylpropionamide;

[1108] N-(3-amino-3-methyl-butyl)-2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide.

[1109] Other compounds of the present invention or their pharmaceutical salts include:

[1110] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1111] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-[2-methyl-6-(trifluoromethyl)-4-pyridyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1112] 3-(2-chloro-6-methyl-4-pyridyl)-N-(1-cyano-1-methyl-ethyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1113] 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;

[1114] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-cyano-3-isopropyl-guanidine;

[1115] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1116] 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;

[1117] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxycyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1118] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-3-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1119] 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;

[1120] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1-methyl-2-oxo-3-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1121] 2-(3-cyanophenyl)-N-[(1S)-1,2-dimethylallyl]-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1122] N-(2-acetamido-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1123] N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1124] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methyl-4-piperidinyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1125] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1126] 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;

[1127] 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;

[1128] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1129] 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1130] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2-oxo-oxazolidine-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1131] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-methyl-5-oxo-pyrrolidine-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1132] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[1-(3-hydroxyoxetane-3-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1133] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-methyl-6-oxo-3-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1134] 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;

[1135] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1136] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1137] 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;

[1138] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3S,4S)-4-methoxy-1-methyl-pyrrolidine-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1139] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-methyl-3-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1140] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1141] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolone-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1142] 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;

[1143] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-3-methyl-cyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1144] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3R)-3-piperidinyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1145] 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;

[1146] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-hydroxy-3-methyl-butyramide;

[1147] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1148] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[1-(2-hydroxyethyl)-4-piperidinyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1149] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1150] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]guanidine;

[1151] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-formamidinium;

[1152] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1153] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1154] 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;

[1155] 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(1-methyl-2-oxo-4-piperidinyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1156] N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-hydroxy-3-methyl-butyramide;

[1157] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]acetamide

[1158] [2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea;

[1159] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-hydroxyoxetane-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1160] 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;

[1161] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1162] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S,3S)-3-aminocyclopentyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1163] m-{4-[({[(3S)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1,5,9-triazabicyclo[4.3.0]non-2,4,6,8-tetraen-8-yl}benzonitrile;

[1164] 3-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1165] 3-(2-cyano-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1166] 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;

[1167] N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-hydroxy-2-methylpropionamide;

[1168] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(3S)-3-piperidinyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1169] 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1170] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-4-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1171] 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolone-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1172] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(5-oxopyrrolidone-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1173] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1174] 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;

[1175] m-[7-(2,6-dimethyl-4-pyridyl)-4-({[(5-oxo-3-pyrrolidinyl)methyl]amino}carbonyl)-1,5,9-triazabicyclo[4,3,0]non-2,4,6,8-tetraen-8-yl]benzonitrile;

[1176] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1177] m-{4-[({[(3R)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1,5,9-triazabicyclo[4.3.0]non-2,4,6,8-tetraen-8-yl}benzonitrile;

[1178] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazacyclobutane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1179] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methylpyridin-2-carboxynitrile;

[1180] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazin-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1181] 3-[5-[(1-acetyl-4-piperidinyl)amino]-3-(2,6-dimethyl-4-pyridinyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1182] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(5-oxomorpholin-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1183] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidine-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1184] 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.

[1185] Specific compounds of this invention include any compound described in the Examples section of this application or a pharmaceutically acceptable salt or solvate thereof, particularly any of the following compounds:

[1186] 3-[5-amino-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1187] 3-[5-amino-3-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1188] 3-(5-amino-3-pyridazin-4-yl-pyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile;

[1189] 3-[5-amino-3-(2-ethylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1190] 3-[5-amino-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1191] 3-[5-amino-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1192] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1193] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-1-bicyclo[1.1.1]pentyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1194] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1195] (3S)-4-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]morpholin-3-carboxylic acid;

[1196] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-ethyl-4-piperidinyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1197] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S,4S)-4-methoxy-1-methyl-pyrrolidine-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1198] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1199] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[3-(hydroxymethyl)-4-methyl-piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1200] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1201] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1202] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1203] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methylsulfonyl-4-piperidinyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1204] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1205] 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]-2,2-dimethyl-propionic acid;

[1206] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1207] 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;

[1208] 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;

[1209] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(quininecyclo-3-ylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1210] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1211] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-morpholinoethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1212] 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;

[1213] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[2-[2-(dimethylamino)ethyl]morpholin-4-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1214] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1215] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4H-1,2,4-triazol-3-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1216] (2R)-4-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]morpholin-2-carboxylic acid;

[1217] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1218] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazin-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1219] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1,1-dioxothio-4-yl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1220] 2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]acetamide;

[1221] 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1222] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[2-(dimethylamino)-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1223] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-hydroxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1224] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1H-imidazol-2-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1225] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-morpholino-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1226] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]azacyclobutane-2-carboxylic acid;

[1227] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]azacyclobutane-3-carboxylic acid;

[1228] (3R)-1-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]pyrrolidine-3-carboxylic acid;

[1229] 4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-sulfonamide;

[1230] 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;

[1231] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2R)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1232] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1233] 3-[5-(tert-butylamino)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1234] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1235] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-hydroxycyclopropyl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1236] 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-(4-piperidinylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1237] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-morpholin-3-yl]methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1238] 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;

[1239] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-3-piperidinyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1240] 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;

[1241] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-pyrrolidine-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1242] tert-butyl(3R)-3-[[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]pyrrolidine-1-carboxylate;

[1243] 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;

[1244] tert-butylrac-(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;

[1245] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-morpholin-3-yl]methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1246] 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;

[1247] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-pyrrolidine-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1248] tert-butyl(3S)-3-[[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]pyrrolidine-1-carboxylate;

[1249] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-3-piperidinyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1250] tert-butyl(3S)-3-[[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]piperidine-1-carboxylate;

[1251] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1252] N-tert-butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1253] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1254] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1255] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[2-(4-phenylpiperazin-1-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1256] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(oxetane-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1257] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1258] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholin-4-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1259] 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;

[1260] N-(2-amino-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1261] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1262] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1263] 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;

[1264] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1265] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1-methyl-ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1266] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxyoxetane-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1267] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-methylsulfonyl-pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1268] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1269] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxycyclobutyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1270] 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;

[1271] N-(4-aminonorborne-1-yl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1272] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2S)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1273] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-methoxy-1-methyl-pyrrolidine-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1274] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1275] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(1-methylazacyclobutane-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1276] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1277] 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;

[1278] N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1279] N-(3-amino-1-bicyclo[1.1.1]pentyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1280] tert-butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-1-bicyclo[1.1.1]pentyl]carbamate;

[1281] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[cis-(3S,4R)-4-hydroxypyrrolidine-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1282] tert-butyl(3S,4R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-4-hydroxypyrrolidine-1-carboxylate;

[1283] N-(2-amino-1,1-dimethyl-ethyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1284] tert-butyl N-[2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-2-methyl-propyl]carbamate;

[1285] 3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)-N-[(3S)-3-piperidinyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1286] tert-butyl(3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]piperidine-1-carboxylate;

[1287] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[trans-(3S,4S)-4-hydroxypyrrolidine-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1288] tert-butyltrans-(3S,4S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-4-hydroxypyrrolidine-1-carboxylate;

[1289] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxypyrrolidine-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1290] tert-butyl 3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]methyl]-3-hydroxy-pyrrolidine-1-carboxylate;

[1291] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-3-piperidinyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1292] tert-butyl(3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]piperidine-1-carboxylate;

[1293] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-methylpyrrolidine-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1294] tert-butyl 3-[[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-3-methyl-pyrrolidine-1-carboxylate;

[1295] 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;

[1296] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1297] 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;

[1298] tert-butyl N-[1-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]methyl]-3,3-difluoro-cyclobutyl]carbamate;

[1299] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(morpholin-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1300] tert-butyl 2-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]methyl]morpholine-4-carboxylate;

[1301] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(piperazin-1-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1302] tert-butyl 4-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]piperazine-1-carboxylate;

[1303] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-pyrrolidine-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1304] tert-butyl(3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]pyrrolidine-1-carboxylate;

[1305] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1306] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid;

[1307] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1308] 2-(3-cyanophenyl)-3-(2-ethylpyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1309] 2-(3-cyanophenyl)-3-(2-ethyl-5-methylpyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1310] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1311] 2-(3-cyanophenyl)-3-(2-ethyl-4-methylpyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1312] 2-(3-cyanophenyl)-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1313] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1314] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-5-carboxamide;

[1315] 3-Cyano-2-(3-Cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1316] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1317] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methanesulfonamide;

[1318] (2S)-2-[[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]propionic acid;

[1319] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidine-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile carbamate;

[1320] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1321] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1322] 3-[5-(aminomethyl)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1323] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1324] 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1325] 3-[5-[(2-hydroxy-2-methyl-propyl)amino]-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1326] 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1327] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1328] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1329] 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-(4-piperidinyloxy)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1330] 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-[[(3R)-3-piperidinyl]oxy]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1331] tert-butyl(3R)-3-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypiperidine-1-carboxylate;

[1332] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3S)-pyrrolidine-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1333] tert-butyl(3S)-3-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypyrrolidine-1-carboxylate;

[1334] 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-[[(3S)-3-piperidinyl]oxy]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1335] tert-butyl(3S)-3-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]oxypiperidine-1-carboxylate;

[1336] 3-[5-amino-3-(6-amino-5-methyl-3-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1337] 3-[5-amino-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1338] 3-[5-amino-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1339] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methylpyridin-2-carboxynitrile;

[1340] 3-[5-amino-3-(2-fluoro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1341] 3-[5-amino-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1342] 3-[5-amino-3-(2,6-dimethyl-1-oxy-pyridin-1-onthium-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1343] 3-[5-amino-3-(2-amino-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1344] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methylpyridine-2-carboxamide;

[1345] N-[4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methyl-2-pyridyl]acetamide;

[1346] 3-[5-amino-3-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1347] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methylpyridin-2-carboxylic acid;

[1348] 3-[5-amino-3-[2-(dimethylamino)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1349] [3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea;

[1350] 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;

[1351] 1-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-(1-ethyl-4-piperidinyl)urea;

[1352] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxamide;

[1353] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-[(3S)-pyrrolidine-3-yl]urea;

[1354] 1-(2-aminoethyl)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea;

[1355] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-[(3R)-pyrrolidine-3-yl]urea;

[1356] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-cyano-guanidine;

[1357] 3-[3-(2-ethylpyrazol-3-yl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1358] 3-[3-(2-ethylpyrazol-3-yl)-5-[3-(hydroxymethyl)-4-methyl-piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1359] 3-[3-(2-ethylpyrazol-3-yl)-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1360] 3-[3-(2-ethylpyrazol-3-yl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1361] 3-[3-(2-ethylpyrazol-3-yl)-5-(4-methylsulfonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1362] 3-[3-(2-ethylpyrazol-3-yl)-5-(4H-1,2,4-triazol-3-ylmethylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1363] 3-[3-(2-ethylpyrazol-3-yl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1364] 3-[3-(2-ethylpyrazol-3-yl)-5-(1-imino-1-oxo-1,4-thiazin-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1365] 5-(benzylamino)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1366] N-Benzyl-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1367] 2-(2-furanyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carboxylonitrile;

[1368] tert-butyl(2S)-2-[[[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate;

[1369] tert-butyl(2R)-2-[[[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]pyrrolidine-1-carboxylate;

[1370] 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1371] tert-butyl(2S)-2-[[[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]pyrrolidine-1-carboxylate;

[1372] tert-butyl(2R)-2-[[[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]morpholine-4-carboxylate;

[1373] 2-(2-furanyl)-5-[4-(2-phenylethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1374] 2-(2-furanyl)-5-[4-(2-pyridylmethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1375] 2-(2-furanyl)-5-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1376] 5-[(1-benzyl-4-piperidinyl)methylamino]-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1377] tert-butyl(2R)-4-[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-methyl-piperazine-1-carboxylate;

[1378] tert-butyl(2S)-4-[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-methyl-piperazine-1-carboxylate;

[1379] 5-[2-(4-benzylpiperazin-1-yl)ethylamino]-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1380] 2-(2-furanyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1381] 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1382] 5-[3-(dimethylamino)azacyclobutane-1-yl]-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1383] tert-butyl 4-[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate;

[1384] 2-(2-furanyl)-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1385] 2-(2-furanyl)-5-[[(2S)-morpholin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1386] 2-(2-furanyl)-5-[[(2R)-morpholin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1387] 5-(4-benzylpiperazin-1-yl)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1388] N-Benzyl-3-bromo-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1389] 5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1390] 5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1391] 5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxaldehyde;

[1392] N-Benzyl-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1393] 5-Amino-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1394] 3-Bromo-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1395] 2-(2-furanyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1396] 2-(2-furanyl)-5-[4-[(2,4,6-trifluorophenyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1397] 2-(2-furanyl)-5-[4-[(1-methylimidazol-2-yl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1398] 2-(2-furanyl)-5-[4-(2-hydroxyethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1399] N-Benzyl-2-(2-furanyl)-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1400] N-Benzyl-2-(2-furanyl)-3-(2-methylpyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1401] Methyl(E)-3-[5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoate;

[1402] (E)-3-[5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-3-yl]prop-2-enoic acid;

[1403] 2-(2-furanyl)-5-(4-phenylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1404] 2-(2-furanyl)-5-(3-hydroxypropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1405] 2-(2-furanyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1406] 2-(2-furanyl)-5-(3-piperidinylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylonitrile hydrochloride;

[1407] 5-(benzylamino)-2-oxazol-2-yl-pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1408] 5-(benzylamino)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1409] 2-(3-cyanophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1410] 2-(3-fluorophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1411] 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylonitrile;

[1412] 5-[4-(2-fluoroethyl)piperazin-1-yl]-2-oxazol-5-yl-pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1413] 5-(benzylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1414] 5-(benzylamino)-2-(5-methyl-2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1415] 5-[4-[(3-methyl-2-pyridyl)methyl]piperazin-1-yl]-2-oxazol-5-yl-pyrazolo[1,5-a]pyrimidin-3-carboxylonitrile;

[1416] N-Benzyl-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1417] 2-(3-fluorophenyl)-N-[(3-methyl-2-pyridyl)methyl]pyrazolo[1,5-a]pyrimidin-5-amine;

[1418] 2-(3-fluorophenyl)-N-(2-phenylethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1419] N-(1H-benzimidazol-2-ylmethyl)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1420] 2-(3-Fluorophenyl)-N-(2-isoindoline-2-ylethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1421] N-Benzyl-3-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1422] 3-Bromo-5-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine;

[1423] N-Benzyl-3-bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine;

[1424] 5-(benzylamino)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1425] 3-Bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1426] 5-Amino-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxynitrile;

[1427] 2-(2-furanyl)-N-(thiazolyl-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1428] [5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanol;

[1429] 5-(benzylamino)-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;

[1430] N-Benzyl-2-(2-furanyl)-3-iodopyrazolo[1,5-a]pyrimidine-5-amine;

[1431] 2-(2-furanyl)-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1432] 2-(2-furanyl)-5-[[(2R)-pyrrolidone-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1433] 2-(2-furanyl)-5-[[(2R)-1-methylpyrrolidone-2-yl]methylamino]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1434] 2-(2-furanyl)-5-[(3R)-3-methylpiperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylonitrile hydrochloride;

[1435] tert-butyl 4-[3-cyano-2-(2-furanyl)pyrazolo[1,5-a]pyrimidin-5-yl]piperidine-1-carboxylate;

[1436] N-Benzyl-7-(2-furanyl)pyrazolo[1,5-a][1,3,5]triazine-2-amine;

[1437] N-Benzyl-2-(2-furanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1438] 2-(3-cyanophenyl)-5-[4-(2-fluoroethyl)piperazin-1-yl]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1439] 2-(3-cyanophenyl)-5-[2-(4-phenylpiperazin-1-yl)ethylamino]pyrazolo[1,5-a]pyrimidin-3-carboxynitrile;

[1440] 3-(2-chloro-6-methyl-4-pyridyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1441] N-tert-butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-formamidinium;

[1442] 3-(2-amino-6-methyl-4-pyridyl)-N-tert-butyl-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1443] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1444] 2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1445] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1446] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-5-(aminosulfonylamino)pyrazolo[1,5-a]pyrimidine;

[1447] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-hydroxy-2-methylpropionamide;

[1448] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2,2-dimethylpropionamide;

[1449] N-(3-amino-3-methyl-butyl)-2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1450] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1451] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-[2-methyl-6-(trifluoromethyl)-4-pyridyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1452] 3-(2-chloro-6-methyl-4-pyridyl)-N-(1-cyano-1-methyl-ethyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1453] 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;

[1454] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-cyano-3-isopropyl-guanidine;

[1455] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1456] 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;

[1457] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxycyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1458] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-3-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1459] 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;

[1460] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1-methyl-2-oxo-3-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1461] 2-(3-cyanophenyl)-N-[(1S)-1,2-dimethylallyl]-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1462] N-(2-acetamido-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1463] N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1464] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methyl-4-piperidinyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1465] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1466] 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;

[1467] 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;

[1468] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1469] 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1470] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2-oxo-oxazolidine-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1471] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-methyl-5-oxo-pyrrolidine-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1472] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[1-(3-hydroxyoxetane-3-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1473] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-methyl-6-oxo-3-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1474] 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;

[1475] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1476] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1477] 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;

[1478] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3S,4S)-4-methoxy-1-methyl-pyrrolidine-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1479] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-methyl-3-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1480] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1481] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolone-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1482] 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;

[1483] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-3-methyl-cyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1484] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3R)-3-piperidinyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1485] 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;

[1486] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-hydroxy-3-methyl-butyramide;

[1487] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1488] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[1-(2-hydroxyethyl)-4-piperidinyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1489] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1490] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]guanidine;

[1491] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-formamidinium;

[1492] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1493] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1494] 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;

[1495] 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(1-methyl-2-oxo-4-piperidinyl)amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1496] N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-3-hydroxy-3-methyl-butyramide;

[1497] N-[3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]acetamide

[1498] [2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]urea;

[1499] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-hydroxyoxetane-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1500] 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;

[1501] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1502] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S,3S)-3-aminocyclopentyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1503] m-{4-[({[(3S)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1,5,9-triazabicyclo[4.3.0]non-2,4,6,8-tetraen-8-yl}benzonitrile;

[1504] 3-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1505] 3-(2-cyano-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1506] 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;

[1507] N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-hydroxy-2-methylpropionamide;

[1508] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(3S)-3-piperidinyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1509] 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1510] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-4-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1511] 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolone-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1512] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(5-oxopyrrolidone-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1513] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1514] 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;

[1515] m-[7-(2,6-dimethyl-4-pyridyl)-4-({[(5-oxo-3-pyrrolidinyl)methyl]amino}carbonyl)-1,5,9-triazabicyclo[4,3,0]non-2,4,6,8-tetraen-8-yl]benzonitrile;

[1516] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1517] m-{4-[({[(3R)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1,5,9-triazabicyclo[4.3.0]non-2,4,6,8-tetraen-8-yl}benzonitrile;

[1518] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazacyclobutane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1519] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-6-methylpyridin-2-carboxynitrile;

[1520] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazin-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1521] 3-[5-[(1-acetyl-4-piperidinyl)amino]-3-(2,6-dimethyl-4-pyridinyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1522] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(5-oxomorpholin-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1523] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidine-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1524] 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;

[1525] 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;

[1526] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1527] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[[(2R)-5-oxopyrrolidine-2-yl]methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1528] 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

[1529] 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;

[1530] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(6-oxo-3-piperidinyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1531] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1532] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1533] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1534] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4R)-4-hydroxy-1-methyl-pyrrolidine-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1535] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[[(2S)-5-oxopyrrolidine-2-yl]methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1536] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3S,4R)-4-hydroxy-1-methyl-pyrrolidine-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1537] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-thiazolyl-5-yl-pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1538] 3-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1539] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(4-piperidinyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1540] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(4-cyano-4-piperidinyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1541] N-(4-carbamoyl-4-piperidinyl)-3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1542] 3-[3-(2,6-dimethyl-4-pyridyl)-5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1543] 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;

[1544] 3-[3-(2,6-dimethyl-4-pyridyl)-5-(3-oxo-2,8-diazaspiro[4.5]decane-8-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1545] 3-[3-(2,6-dimethyl-4-pyridyl)-5-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidinyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1546] (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-methylpropionamide;

[1547] 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

[1548] 4-Cyano-N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-5-yl]-4-methyl-piperidine-1-carboxamide.

[1549] Typically, various functional groups and substituents constituting a compound having formula (I) are selected such that the molecular weight of the compound having formula (I) does not exceed 1000. More generally, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, and for example 550 or less.

[1550] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of sufficiently basic compounds of the present invention, such as acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of sufficiently acidic compounds of the present invention are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations (e.g., salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tri-(2-hydroxyethyl)amine).

[1551] Compounds with the same molecular formula but different atomic bonding properties or sequences, or different spatial arrangements of atoms, are called "isomers." The term "stereoisomer" refers to isomers whose atoms differ in spatial arrangement. Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, that asymmetric center is bonded to four different groups, there may be a pair of enantiomers. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)- isomers, respectively) by the Cahn and Prelog R and S sequencing rules, or by the method of rotating the plane of polarized light. Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[1552] The compounds of this invention may have one or more asymmetric centers; therefore, such compounds may be generated as individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise stated, the description or naming of specific compounds in the specification and claims is intended to include individual enantiomers and their racemic mixtures or other mixtures. Methods for stereochemical determination and stereoisomer separation are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolving racemic forms. Some compounds of this invention may have geometric isomer centers (E and Z isomers). It should be understood that this invention covers all optical, diastereomers, and geometric isomers and mixtures thereof with antiproliferative activity.

[1553] This invention also covers compounds of the invention containing one or more isotopic substitutions as defined herein. For example, H may be in any isotopic form, including 1H, 2H(D), and 3H(T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 16O and 18O; and so on.

[1554] It should also be understood that some compounds having formula (I) can exist in both solvated and non-solvated forms, such as hydrated forms. It should be understood that this invention covers all such solvated forms exhibiting antiproliferative activity.

[1555] It should also be understood that some compounds having Formula I can exhibit polymorphism, and the present invention covers all such forms having antiproliferative activity.

[1556] Compounds having Formula I can exist in many different tautomer forms, and references to compounds having Formula I include all such forms. To avoid ambiguity, Formula I still includes all other forms even when a compound can exist in one of several tautomer forms, and only one is specifically described or shown. Examples of tautomer forms include ketone, enol, and enolate forms, for example, as in the following tautomer pairs: ketone / enol (shown below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[1557]

[1558] Compounds of Formula I containing amine functional groups can also form N-oxides. The compounds of Formula I containing amine functional groups mentioned herein also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are tertiary amines containing nitrogen heterocycles or N-oxides of nitrogen atoms. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, *Advanced Organic Chemistry*, edited by Jerry March, 4th ed., Wiley Interscience, p. More specifically, N-oxides can be prepared by the procedure in LWDeady (Syn.Comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[1559] Compounds having formula (I) can be administered as prodrugs, which decompose in humans or animals to release the compounds of the present invention. Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain suitable groups or substituents to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxyl or hydroxyl group in a compound having formula (I) and in vivo cleavable amide derivatives that can be formed at the carboxyl or amino group in a compound having formula (I).

[1560] Therefore, the present invention includes those compounds having formula (I) as defined above, when they are obtainable by organic synthesis and when they are obtainable in humans or animals by cleaving their prodrugs. Thus, the present invention includes those compounds having formula I produced by organic synthesis, and also includes such compounds produced in humans or animals by metabolizing precursor compounds, i.e., compounds having formula (I) that are either synthetically produced or metabolically produced.

[1561] A suitable pharmaceutically acceptable prodrug of a compound having formula (I) is based on reasonable medical judgment as a pharmaceutically acceptable prodrug suitable for administration to humans or animals without undesirable pharmacological activity and without abnormal toxicity.

[1562] For example, various forms of prodrugs have been described in the following literature:

[1563] a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985);

[1564] b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985);

[1565] c) A Textbook of Drug Design and Development, by Krogsgaard-Larsen and

[1566] H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, edited by H. Bundgaard, pp. 113-191 (1991);

[1567] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[1568] e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

[1569] f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984);

[1570] g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems,” ACS Symposium Series, Volume 14; and

[1571] h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[1572] Suitable pharmaceutically acceptable prodrugs of compounds having Formula I (which have a carboxyl group) are, for example, esters that are cleavable in vivo. Cleavable esters of compounds having Formula I containing a carboxyl group are, for example, pharmaceutically acceptable esters that are cleaved in humans or animals to produce a parent acid. Suitable pharmaceutically acceptable esters with a carboxyl group include C1-6 alkyl esters such as methyl, ethyl, and tert-butyl esters; C1-6 alkoxymethyl esters such as methoxymethyl esters; C1-6 alkyloxymethyl esters such as neopentyloxymethyl esters; 3-phthalyl esters; C3-8 cycloalkylcarbonyloxy-C1-6 alkyl esters such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester; 2-oxo-1,3-dioxopentenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxopententen-4-ylmethyl ester; and C1-6 alkoxycarbonyloxy-C1-6 alkyl esters such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester.

[1573] Suitable pharmaceutically acceptable prodrugs of compounds having formula (I) (which have a hydroxyl group) are, for example, esters or ethers that are cleavable in vivo. Cleavable esters or ethers of compounds of formula I containing a hydroxyl group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in a human or animal body to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include inorganic esters, such as phosphate esters (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include C1-10 alkyl acyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, and C1-10 alkoxy carbonyl groups such as ethoxy carbonyl, N,N-(C1-6)2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include α-acyloxyalkyl groups such as acetoxymethyl and neopentyloxymethyl groups.

[1574] Suitable pharmaceutically acceptable prodrugs having a carboxyl group of a compound having formula (I) are, for example, amides that are cleavable in vivo, such as amides or esters thereof formed with amines such as ammonia, C1-4 alkylamines such as methylamine, (C1-4 alkyl)2-amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-4 alkoxy-C2-4 alkylamines such as 2-methoxyethylamine, phenyl-C1-4 alkylamines such as benzylamine, and amino acids such as glycine.

[1575] Suitable pharmaceutically acceptable prodrugs (having an amino group) of compounds having Formula I are, for example, amide derivatives of which are capable of being cleaved in vivo. Suitable pharmaceutically acceptable amides derived from the amino group include, for example, amides formed with C1-10 alkyl acyl groups (such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups). Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-4 alkyl)piperazine-1-ylmethyl.

[1576] The in vivo effects of compounds having formula (I) can be exerted in part through one or more metabolites formed in humans or animals following administration of the compound having formula (I). As described above, the in vivo effects of compounds having formula (I) can also be exerted by metabolizing prodrugs (prodrugs).

[1577] While the invention may relate to any compound or particular group of compounds as defined herein by means of optional, preferred or suitable features or otherwise for particular embodiments, the invention may also relate to any compound or particular group of compounds that specifically excludes the optional, preferred or suitable features or particular embodiments.

[1578] Appropriately, this invention excludes any single compound that does not have the biological activity defined herein.

[1579] synthesis

[1580] The compounds of the present invention can be prepared by any suitable technique known in the art. Specific methods for preparing the compounds of the present invention are described in the Examples section below, and the reaction schemes for preparing such compounds are as follows: Figures 1 to 18 As shown in the attached diagram:

[1581] Figure 1 A reaction scheme for preparing a compound having formula I is shown, wherein A is CH, R1 is 3-cyanophenyl; R2 is 2-chloro-6-methylpyridin-4-yl and R3 is an amide-linked substituent group represented by formula -C(O)NRR, wherein each R is a hydrogen or substituent group.

[1582] Figure 2 The reaction scheme for preparing intermediate B is shown (described in the accompanying Examples section).

[1583] Figure 3 A reaction scheme for preparing a compound having formula I is shown, wherein A is CH, R1 is 3-cyanophenyl, R2 is 2-chloro-6-methylpyridin-4-yl, and R3 is an amine-linked substituent group represented by the formula -NH-R.

[1584] Figure 4 A reaction scheme for preparing compounds having formula I is shown, wherein A is CH, R1 is 3-cyanophenyl; R2 is a group as defined herein, and R3 is an amino group (which is capable of further reaction to form an amine-linked substituent group).

[1585] Figure 5 A reaction scheme for preparing a compound having formula I is shown, wherein A is CH, R1 is 3-cyanophenyl; R2 is 2-chloro-6-methylpyridin-4-yl and R3 is the urea moiety of formula -NH-C(O)-NH2.

[1586] Figure 6 The reaction scheme for preparing intermediate G is shown (described in the accompanying Examples section).

[1587] Figure 7The reaction schemes used to prepare the compounds of Examples 35 and 36 of this article are shown.

[1588] Figure 8 The reaction schemes for preparing intermediate compounds T, P and R, as well as compounds having formula I, are shown, where A is CH, R1 is furan-2-yl, R2 is cyano, and R3 is an amine-linked substituent group represented by the formula -NH-R.

[1589] Figure 9 The reaction scheme for preparing intermediate Q and compounds having formula I is shown, wherein A is CH, R1 is furan-2-yl; R2 is Br, cyano or -C(O)NH2, and R3 is benzylamino.

[1590] Figure 10 The reaction schemes for preparing intermediate S and compounds having formula I are shown, wherein A is CH, R1 is furan-2-yl; R2 is a group as defined herein, and R3 is benzylamino.

[1591] Figure 11 A reaction scheme for preparing a compound having formula I via intermediate X is shown, wherein A is CH, R1 is furan-2-yl; R2 is hydrogen, and R3 is benzylamino.

[1592] Figure 12 The reaction scheme for preparing intermediate U and compounds having formula I is shown, wherein A is CH, R1 is a group as defined herein; R2 is a cyano group, and R3 is a benzylamino group.

[1593] Figure 13 The reaction schemes for preparing intermediate compounds V and W, as well as compounds having formula I, are shown, where A is CH, R1 is 3-fluorophenyl, R2 is cyano or bromine, and R3 is an amine-linked substituent group represented by formula -NHR.

[1594] Figure 14 A reaction scheme for preparing compounds having formula I is shown, wherein A is CH, R1 is 4-fluorophenyl, R2 is a group as defined herein, and R3 is an amine-linked substituent group, denoted by the formula "-NRR", wherein each R is a hydrogen or substituent group.

[1595] Figure 15 The reaction schemes for preparing the intermediate compounds shown in steps 2a and 2b of Example 92, as well as compounds having formula I, are shown, where A is CH, R1 is 3-cyanophenyl, R2 is 2,6-dimethylpyridin-4-yl, and R3 is an amide-linked substituent group represented by formula -C(O)-NRR, where each R is a hydrogen or substituent group.

[1596] Figure 16 The reaction scheme for preparing intermediate compound Y is shown.

[1597] Figure 17 The reaction scheme for preparing intermediate compound Z is shown.

[1598] Figure 18 The reaction scheme for preparing intermediate compound AB is shown.

[1599] In the description of the synthetic methods described herein, and in any reference synthetic methods used to prepare the starting materials, it should be understood that those skilled in the art can choose all the proposed reaction conditions, including the selection of solvent, reaction atmosphere, reaction temperature, experimental duration, and post-treatment procedures.

[1600] Those skilled in the field of organic synthesis should understand that the functionality present in each part of a molecule must be compatible with the reagents and reaction conditions used.

[1601] It should be understood that during the synthesis of the compounds of the present invention in the process defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituent groups to prevent undesirable reactions. Skilled chemists will understand when such protection is needed, and how such protecting groups can be placed in the appropriate position and subsequently removed.

[1602] For examples of protecting groups, see one of the many general texts on the subject, such as Theodora Green’s “Protective Groups in Organic Synthesis” (John Wiley & Sons). Protecting groups can be removed by any convenient method suitable for removing the protecting groups in question, as described in the literature or known to a skilled chemist, chosen so as to achieve the removal of the protecting groups with minimal perturbation to groups elsewhere in the molecule.

[1603] Therefore, if the reactants include, for example, groups such as amino, carboxyl, or hydroxyl groups, it may be necessary to protect those groups in some of the reactions mentioned herein.

[1604] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups like acetyl, alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl groups, arylmethoxycarbonyl groups, such as benzyloxycarbonyl, or aromatic acyl groups, such as benzoyl. The deprotection conditions for these protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl, alkoxycarbonyl, or aromatic acyl groups can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide (e.g., lithium hydroxide or sodium hydroxide). Alternatively, acyl groups such as tert-butoxycarbonyl groups can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed, for example, by hydrogenation with a catalyst such as palladium on carbon, or by treatment with a Lewis acid such as boron tris(trifluoroacetate). Suitable alternative protecting groups for the primary amino group are, for example, phthaloyl groups, which can be removed by treatment with alkylamines (e.g., dimethylaminopropylamine) or with hydrazine.

[1605] Suitable protecting groups for hydroxyl groups are, for example, acyl groups (e.g., alkanoyl groups such as acetyl, aromatic acyl groups such as benzoyl) or arylmethyl groups (e.g., benzyl). The deprotection conditions for these protecting groups will necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or aromatic acyl groups can be removed by hydrolysis with a suitable base (e.g., an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or ammonia). Alternatively, arylmethyl groups such as benzyl groups can be removed, for example, by hydrogenation with a catalyst such as palladium on carbon.

[1606] Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl groups (which can be removed, for example, by hydrolysis with a base such as sodium hydroxide), or tert-butyl groups (which can be removed, for example, by treatment with an acid such as an organic acid such as trifluoroacetic acid), or benzyl groups (which can be removed, for example, by hydrogenation with a catalyst such as palladium on carbon).

[1607] Resins can also be used as protecting groups.

[1608] The methods for synthesizing compounds having formula (I) will vary depending on the nature of A, R1, R2, and R3, as well as any associated substituent groups. Suitable methods for their preparation are further described in the accompanying examples.

[1609] Once a compound having formula (I) has been synthesized using any of the methods defined herein, the method may further include one or more of the following additional steps:

[1610] (i) Remove any protecting groups present;

[1611] (ii) Converting a compound having formula (I) into another compound having formula (I);

[1612] (iii) Forming a pharmaceutically acceptable salt, hydrate, or solvate of a compound having Formula I; and / or

[1613] (iv) Forming a prodrug of a compound having formula I.

[1614] An example of (ii) above is when a compound having formula (I) is synthesized and then one or more of groups A, R1, R2 or R3 can be further reacted to change the properties of the group and provide an alternative compound having formula (I).

[1615] The obtained compound having formula (I) can be separated and purified using techniques well known in the art.

[1616] Certain compounds having formula I as defined in this article can be prepared by the following:

[1617] (i) making compounds having formula IIa

[1618]

[1619] Where A, R0, R1 and R2 are each defined above, and X1 is a suitable leaving group (e.g., bromine, chlorine, iodine, -SMe, -S(O)Me or -S(O)2Me);

[1620] It reacts with the group [R3-X2]-H, where X2 is N, S, or O and [R3-X2] together represents the group R3 as defined above, which is connected through the X2 atom;

[1621] Optionally, the process may further include one or more additional steps thereafter:

[1622] (i) Remove any protecting groups that may be present;

[1623] (ii) Converting a compound having formula (I) into another compound having formula (I) (e.g., converting an R3 substituent into another R3 substituent group as defined herein);

[1624] (iii) Forming a pharmaceutically acceptable salt, hydrate, or solvate of a compound having Formula I; and / or

[1625] (iv) Forming a prodrug of a compound having formula I.

[1626] To avoid any doubt, the X2 atom is a heteroatom present on the group R3, that is, [R3-X2] is the R3 group containing the X2 heteroatom.

[1627] It should be understood that in the above reaction, if a compound having formula II reacts with a [R3-X2]-H group, the X1 group is replaced together with the H atom of the [R3-X2]-H group, and the R3 substituent group is combined with the compound having formula II via the X2 atom.

[1628] Those skilled in the art will be able to readily select suitable reaction conditions for the reaction between a compound having formula II and a [R3-X2]-H group. Examples of suitable reaction conditions are described in the Examples section appended herein.

[1629] Compounds having Formula II can be prepared by suitable techniques known in the art, as will be apparent from the appended Examples section. Specific examples of the preparation of compounds having Formula II are described in the appended Examples section.

[1630] Compounds having Formula I can also be prepared by Suzuki-Miyaura or Stille coupling reactions. For example, some compounds having Formula I as defined herein can also be prepared by the following:

[1631] (i) making compounds having formula III

[1632]

[1633] Where A, R0, R2 and R3 are each as defined above and X3 is a halogenated atom (e.g., bromine, chlorine or iodine);

[1634] Reacts with groups having the following formula:

[1635] R1-M

[1636] Where M is a coupling agent (e.g., a boron coupling agent or a tin coupling agent as defined herein) and R1 is as defined above; or

[1637] (ii) To make compounds having formula IV:

[1638]

[1639] Where A, R0, R1 and R3 are each as defined above and X3 is a halogenated atom (e.g., bromine, chlorine or iodine);

[1640] Reacts with groups having the following formula:

[1641] R2-M

[1642] Where M is a coupling agent (e.g., a boron coupling agent or a tin coupling agent as defined herein) and R2 is as defined above; or

[1643] (iii) To make compounds having formula V:

[1644]

[1645] Where A, R0, R1 and R2 are each as defined above and X3 is a halogenated atom (e.g., bromine, chlorine or iodine);

[1646] Reacts with groups having the following formula:

[1647] R3-M

[1648] Where M is a coupling agent (e.g., a boron coupling agent or a tin coupling agent as defined herein) and R3 is as defined above; or

[1649] Optionally, the process may further include one or more additional steps thereafter:

[1650] (i) Remove any protecting groups that may be present;

[1651] (ii) Converting a compound having formula (I) into another compound having formula (I);

[1652] (iii) Forming a pharmaceutically acceptable salt, hydrate, or solvate of a compound having Formula I; and / or

[1653] (iv) Forming a prodrug of a compound having formula I.

[1654] The M group can be a suitable boron coupling agent known in the art for the Suzuki-Miyaura coupling reaction. Examples of suitable boron reagents include: boric acids, borate esters (e.g., catechol borate, pinacol borate, triisopropyl borate, MIDA borate, cyclotriol borate), boranes (e.g., 9-BBN borane), organofluoroborates, or borate amides (e.g., 1,8-diaminonaphthylboramide). Specific examples are -B(OH)2 or -B(OCH3)2.

[1655] The Suzuki-Miyaura coupling reaction is well known, and those skilled in the art will be able to readily select suitable reaction conditions for it.

[1656] In the Stieler coupling reaction, M is a tin coupling agent, preferably a tin coupling agent having the formula -Sn[(1-6C)alkyl]3 (e.g., -Sn(butyl)3).

[1657] Stieler coupling reactions are well known, and those skilled in the art will be able to readily select suitable reaction conditions for this reaction. Such reactions are typically carried out in the presence of a palladium catalyst.

[1658] Bioactivity

[1659] The bioassays described in the Examples section (Biological Examples 1 to 3) can be used to measure the pharmacological effects of the compounds of the present invention.

[1660] Although the pharmacological properties of compounds having Formula I vary with structural changes, as expected, the compounds of the present invention were found to be active in the assays described in biological Examples 1, 2 and 3.

[1661] Generally, regarding the antagonistic effect of adenosine A2a, the compounds of the present invention showed an IC50 of 1 μM or lower in the assay described in Biological Example 1. 50 The preferred compounds of the present invention exhibit IC50 values ​​of 200 nM or lower. 50 Furthermore, the most preferred compound of the present invention exhibits an IC50 concentration of 50 nM or lower. 50 .

[1662] Suitable, the IC50 of the adenosine A1, A2b, or A3 receptor of the compounds of the present invention is determined in the manner described in Biological Example 1. 50 IC50 of adenosine A2a receptor 50 At least twice as high, more appropriately, at least five times as high, or even more appropriately at least ten times as high.

[1663] Pharmaceutical Composition

[1664] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention as defined above, in combination with a pharmaceutically acceptable diluent or carrier, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1665] The compositions of the present invention may be in forms suitable for use in the following ways: oral administration (e.g., as tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical administration (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as fine powders or liquid aerosols), administration by blowing (e.g., as fine powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[1666] The compositions of the present invention can use conventional pharmaceutical excipients and are obtained through conventional procedures well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[1667] An effective amount of the compound of the invention used in a therapy is sufficient to treat or prevent the proliferative disease mentioned herein, slow its progression, and / or alleviate the symptoms associated with the disease.

[1668] The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual being treated and the specific route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, from 0.5 mg to 0.5 g of active ingredient (more appropriately from 0.5 to 100 mg, e.g., from 1 to 30 mg), which is compounded with an appropriate and convenient amount of excipients, the amount of which can vary from about 5% by weight to about 98% by weight of the total composition.

[1669] Based on well-known medical principles, the dosage of a compound with chemical formula I for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the ailment, the age and sex of the animal or patient, and the route of administration.

[1670] When using the compounds of the present invention for therapeutic or preventative purposes, they are typically administered such that, if fractionation is required, a daily dose ranging from, for example, 0.1 mg / kg to 75 mg / kg body weight is received. Generally, a lower dose is administered when administered via a parenteral route. Thus, for example, for intravenous or intraperitoneal administration, a dose ranging from, for example, 0.1 mg / kg body weight to 30 mg / kg body weight will typically be used. Similarly, for administration by inhalation, a dose ranging from, for example, 0.05 mg / kg body weight to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compounds of the present invention.

[1671] Therapeutic uses and applications

[1672] The present invention provides compounds that function as antagonists of adenosine A2 receptors, particularly adenosine A2a receptors.

[1673] According to another aspect of the invention, a method for antagonizing adenosine A2a receptors in vitro or in vivo is provided, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[1674] According to another aspect of the invention, a method for selectively antagonizing adenosine A2a receptors in vitro or in vivo is provided, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[1675] According to another aspect of the invention, a method for inhibiting cell proliferation in vitro or in vivo is provided, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1676] According to another aspect of the invention, a method is provided for treating a disease or disorder related to adenosine A2a receptor activity in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[1677] According to another aspect of the invention, a method for treating a patient requiring such treatment for a proliferative disorder is provided, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1678] According to another aspect of the invention, a method for treating cancer in a patient requiring such treatment is provided, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1679] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions thereof, are provided for use in therapy.

[1680] According to another aspect of the invention, compounds as defined herein or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, are provided for use in the treatment of proliferative disorders. Suitably, the compounds or pharmaceutical compositions are administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1681] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions thereof, are provided for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1682] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided for use as adenosine A2a antagonists. In examples, the compounds of the invention are selective adenosine A2a antagonists. In alternative examples, certain compounds of the invention are selective adenosine A2a and adenosine A2b antagonists.

[1683] According to another aspect of the invention, compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided for use in the treatment of diseases or disorders associated with adenosine A2a.

[1684] According to another aspect of the invention, use is provided in the manufacture of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvation thereof, for the treatment of proliferative disorders. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1685] According to another aspect of the invention, use is provided in the manufacture of a medicament for treating cancer, as defined herein, of a compound or a pharmaceutically acceptable salt, hydrate, or solvation thereof. Suitably, the cancer is a human cancer. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1686] According to another aspect of the invention, use is provided in the manufacture of a medicament for use as an adenosine A2a antagonist, in a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1687] According to another aspect of the invention, use is provided in the manufacture of a medicament for use as an adenosine A2a antagonist, in a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1688] According to another aspect of the invention, the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvation thereof, in the manufacture of a medicament for treating diseases or disorders associated with adenosine A2a receptor activity is provided.

[1689] The term "proliferative disorder" is used interchangeably throughout this document and refers to unwanted or uncontrolled cell proliferation (whether in vitro or in vivo) of an undesirable excess or abnormal number of cells, such as vesicular or proliferative growth. Examples of proliferative disorders include, but are not limited to, premalignant and malignant cell proliferation, including but not limited to malignant growths and tumors, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., fibroproliferative disorders of connective tissue), and atherosclerosis. Treatment can be administered to any type of cell, including but not limited to those in the lungs, colon, breast, ovaries, prostate, liver, pancreas, brain, and skin.

[1690] The antiproliferative effects of the compounds of the present invention are particularly suitable for the treatment of human cancers (due to their adenosine A2a antagonist activity).

[1691] More specifically, compounds having the general formula (I) are provided for use in the treatment of cancer, particularly solid tumors such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma.

[1692] More specifically, compounds having the general formula (I) are provided for use in the treatment of cancers, such as lung cancer, including small cell lung cancer or non-small cell lung cancer.

[1693] It also provides the use of compounds having general formula (I) in the manufacture of drugs for treating cancer, particularly solid tumors such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma.

[1694] The present invention further provides a method for treating cancer, particularly solid tumors such as non-small cell or small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma, the method comprising administering an effective amount of a compound having the general formula (I) to a patient in need of such treatment.

[1695] The patient to be treated is appropriately a mammal, and more appropriately a human.

[1696] Application route

[1697] The compounds of the present invention or pharmaceutical compositions comprising these compounds may be administered to a subject via any convenient route of administration, whether systemic, peripheral, or local (i.e., at the site of desired action).

[1698] Routes of administration include, but are not limited to, oral (e.g., by swallowing); buccal; sublingual; percutaneous (including, for example, by patches, plasters, etc.); mucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, via aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by a pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcorneal, intra-articular, subarachnoid, intrasternal, and intratumoral; and implantation into a reservoir or depository, such as subcutaneous or intramuscular.

[1699] The compounds of the present invention or pharmaceutical compositions comprising these compounds may be administered via intratumoral delivery.

[1700] Combination therapy

[1701] Compounds having Formula I can be used to treat and / or prevent proliferative disorders, such as cancer. Compounds having Formula I as defined herein can be used in combination with one or more other antiproliferative / anticancer therapies, such as chemotherapy with one or more other antiproliferative / anticancer agents, radiation therapy, and / or conventional surgery.

[1702] Additionally, antiproliferative / anticancer agents may be included in pharmaceutical compositions containing compounds having formula (I) as defined herein, or alternatively, may be administered alone, or simultaneously, earlier, or later than compounds having formula (I).

[1703] Therefore, in another aspect of the invention, a product comprising a compound having general formula (I) and additional pharmaceutical agents for treating or preventing cancer is provided, which is used as a combination formulation for simultaneous, sequential or individual use in the treatment of cancer.

[1704] The present invention also provides compounds having general formula (I) in combination with one or more additional antiproliferative / anticancer agents for the treatment of cancer, wherein the combination formulation is used simultaneously, sequentially or alone in the treatment of cancer.

[1705] In particular, the combination therapies defined in this article are suitable for the treatment of solid tumors, such as non-small cell or small cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial carcinoma.

[1706] Suitable additional antiproliferative / anticancer agents that can be used in combination with compounds of formula I as defined herein [alone or as part of a combination pharmaceutical composition or a combination formulation with a compound of general formula (I)] include:

[1707] 1) Other forms of cancer immunotherapy and anticancer chemotherapy;

[1708] 2) Adenosine pathway regulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors;

[1709] 3) Anti-PD-1 and PDL-1 antibodies, including but not limited to cilimatumab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab; and

[1710] 4) Anti-CTLA4 antibodies, including but not limited to ipilimumab.

[1711] Compounds of Formula I as defined herein are particularly suitable for use in combination with anti-PD-1 and PDL-1 antibodies, including but not limited to cilimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab.

[1712] Appropriately, anti-PD1 antibodies are those disclosed in U.S. Publication No. 2019 / 0225689 or U.S. Publication No. 2017 / 0121409 (incorporated herein by reference in its entirety), such as cilimab. Cilimab (JNJ-63723283, CET) is a fully human immunoglobulin (Ig) G4κ monoclonal antibody that binds to programmed death receptor-1 (PD-1) with high affinity and specificity. Cilimab has shown activity in solid tumors. Rutkowski P et al. Journal of Clinical Oncology. 2019; 37(8):31.

[1713] Compounds of Formula I as defined herein are particularly suitable for use in combination with adenosine pathway regulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors.

[1714] A2a antagonists with general formula (I) can also be used in combination with cell-based immunotherapies and cancer vaccines (including but not limited to CAR-T cell therapy).

[1715] Other examples of antiproliferative / anticancer chemotherapeutic agents include, but are not limited to, any one or more of the following:

[1716]

[1717] Metansine; Nitrogen mustard hydrochloride; Medroxyprogesterone acetate; Melenoprogesterone acetate; Melphalan; Minoril; Mercaptopurine; Methotrexate; Methotrexate sodium; Chlorpheniramine; Metotepazole; Mildolidomide; Mitoxin; Mitocelin; Mitomarcin; Mitosperidin; Mitosperidone; Mitosperidone hydrochloride; Mycophenolic acid; Nocodazoie; Nopramine; Omaplatin; Oxyssuron; Pegaspargase; peribacic acid; pendimethalin; pepromycin sulfate; pephosphatamide; piperobromidine; pipesoven; pyroanthraquinone hydrochloride; procainamide; propranolol; porphyrin sodium; methylmitromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofuranoline; lipoadenosine; rogulam; safungolate; safungolate hydrochloride; semustine; cintracin; sparfosate sodium sodium); Sparmycin; Germanium spiroamine hydrochloride; Spiromustin; Spiroplatin; Streptomycin; Streptozotocin; Sulfonamide; Tarimycin; Tecogallan sodium; Tegafur; Teloanthraquinone hydrochloride; Temopofen; Teniposide; Tiroxicon; Testrolide; Thiomipurine; Thioguanine; Thiotepa; Thiazofuranoline; Tirazamine; Toremifen citrate; Tritoprolone acetate; Tricerebroside phosphate; Trimethotraxa; Trimethotraxa glucuronide; Triptorelin; Tobradex hydrochloride; Uramustin; Uretepa; Vapotetide; Vertepofen; Vincristine sulfate; Sulfuric acid Vincristine; vindesine; vindesine sulfate; vinpidin sulfate; vinblastine sulfate; vinorelbine sulfate; vinorelbine tartrate; vinrodin sulfate; vinorelbine sulfate; vorticazole; zeniplatin; fentostatin; zorubicin hydrochloride; agents that arrest cells in the G2-M phase and / or regulate microtubule formation or stability (e.g., Taxol™ (paclitaxel), Taxotere™); compounds containing a taxane skeleton; irbuproazole (R-55104); sulphurin 10 (DLS-10 and NSC-376128); mivobulin ethanesulfonate. isethionate (i.e., CI-980); vincristine; NSC-639829; Discodermolide (i.e., NVP-XX-A-296); ABT-751 (Abbott, i.e., E-7010); Altorhyrtin (e.g., Altorhyrtin A and Altorhyrtin C); Spongistatin (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9); Cimadolicin hydrochloride (i.e., LU-103793 and NSC-D-669356);Epothilones (such as epothilone A, epothilone B, epothilone C (i.e., deoxyepothilone A or dEpoA), epothilone D (i.e., KOS-862, dEpoB, and deoxyepothilone B), epothilone E, epothilone F, and epothilone B) N-oxide, epothilone AN-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., deoxyepothilone F and dEpoF), 26-fluoroepothilone); auratestatin PE (i.e., NSC-654663); soblidotin (i.e., TZT-1027); vincristine sulfate; cyclopeptide 52 (e.g., LY-355703); vitilevuamide; tubulin inhibitor (tubulysin) A; canadensol; centaureidin (i.e., NSC-106969), oncocidin A1 (i.e., BTO-956 and DFE); Fijianolide B; Laulimalide; Nascapine (also known as NSC-5366); Nascapine; Hammetrine; Vanadyl acetylacetonate; Monsatrol; lnanocine (i.e., NSC-698666); Eleutherobin (such as desmethyleleutherobin, desaetyleleutherobin, isoeleutherobin A, and Z-eleutherobin)); Caribaeolin; Halichondrin B; Diazonamide A; arrowroot lactone A; Diozostatin; (-)-phenylalanine (i.e., NSCL-96F037); myoglobin B; Resverastatin sodium phosphate; steroids (e.g., dexamethasone); finasteride; aromatase inhibitors; gonadotropin-releasing hormone agonists (GnRH) (e.g., goserelin or leuprorelin); corticosteroids (e.g., prednisone); progesterone (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate); estrogens (e.g., diethylstilbestrol, ethinylestradiol); anti-estrogens (e.g., tamoxifen); androgens (e.g., testosterone propionate, fluoxymesterone); anti-androgens (e.g., flutamide); immunostimulants (e.g., BCG, levamisole, interleukin-2, alpha-interferon, etc.);Monoclonal antibodies (e.g., anti-CD20, anti-FLER2, anti-CD52, anti-ULA-DR, and anti-VEGF monoclonal antibodies); immunotoxins (e.g., anti-CD33 monoclonal antibody-acrylosporin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.); radioimmunotherapy (e.g., anti-CD20 monoclonal antibody, conjugated to ln, OY, or I, etc.); triptolide; homoharringtonine; styromycin; doxorubicin; epirubicin; topotecan; itraconazole; vinblastine; cerivastatin; vincristine; deoxyadenosine; sertraline; pitavastatin; irinotecan; clofazimine; 5-nonoxytryptamine; vemurafenib; dabrafenib; erlotinib; gefitinib; EGFR inhibitors; epidermal growth factor receptor (EGFR) targeted therapy or therapeutic agents (e.g., gefitinib (Iressa); TM ), Erlotinib (Tarceva) TM ), cetuximab (Erbitux) TM Lapatinib (Tykerb) TM Panitumumab (Vectibix) TM ), Caprelsa TM (Afatinib / BIBW2992, CI-1033 / canenatinib, neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethylerlotinib, AZD8931, AEE788, peritinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626); sorafenib; imatinib; sunitinib; dasatinib; hormone therapy, etc.

[1718] As indicated above, the combination therapies of the present invention can be achieved by administering the individual components of the treatment simultaneously, sequentially, or individually. Such combination products utilize compounds of the present invention within the dosage range described above, as well as other pharmaceutically active agents within their approved dosage ranges.

[1719] According to this aspect of the invention, a combination for treating cancer (e.g., cancer involving solid tumors) is provided, comprising a compound of the invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more additional antiproliferative / anticancer agents.

[1720] According to this aspect of the invention, a combination for treating proliferative conditions such as cancer (e.g., cancer involving solid tumors) is also provided, comprising the compounds of the invention as defined above, or pharmaceutically acceptable salts, hydrates or solvates thereof, and one or more additional antiproliferative / anticancer agents selected from those listed above.

[1721] In another aspect of the invention, the compounds of the invention or their pharmaceutically acceptable salts, hydrates or solvates are provided in combination with another antitumor agent for the treatment of cancer, the other antitumor agent optionally selected from one of the antitumor agents listed above.

[1722] In this document, the term "combination" is understood to mean simultaneous, individual, or sequential application. In one aspect of the invention, "combination" means simultaneous application. In another aspect of the invention, "combination" means individual application. In yet another aspect of the invention, "combination" means sequential application. In the case of sequential or individual application, delaying the application of the second component should not result in the loss of the beneficial effects of the combination.

[1723] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with an antitumor agent (optionally selected from one of the antitumor agents listed above), in conjunction with a pharmaceutically acceptable diluent or carrier.

[1724] Example

[1725] General conditions:

[1726] Mass spectrometry was performed on an LC-MS system using electrospray ionization. These were performed using a Waters Acquity H-Class UPLC (with PDA and QDa mass spectrometry detection), an Acquity UPLC (binary pump / PDA detector) + ZQ mass spectrometer, an Acquityi-Class (quaternary pump / PDA detector) + Quattro Micro mass spectrometer, a Waters Acquity uPLC system (with Waters PDA and ELS detectors), or a Shimadzu LC-MS-2010EV system. [M+H]+ refers to the molecular weight of the single isotope.

[1727] NMR spectra were run on a Bruker Ultrashield 500MHz NMR spectrometer, a Bruker Avance III HD 400MHz NMR spectrometer, a Bruker Avance DPX 300MHz NMR spectrometer, a Bruker Avance III HD 500MHz, or a Bruker Avance III HD 250MHz. Spectra were recorded at 298 K, with the solvent peak used as a reference.

[1728] The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporation is carried out in a vacuum, preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods, such as MS and NMR. Abbreviations used are conventional abbreviations in the art. Unless otherwise defined, these terms have their generally accepted meanings.

[1729] abbreviation

[1730] app appearance

[1731] br wide peak

[1732] d double peak

[1733] dd Double peak

[1734] DABCO (1,4-diazabicyclo[2.2.2]octane)

[1735] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[1736] DCM dichloromethane

[1737] DIPEA (diisopropylethylamine)

[1738] DMA dimethylacetamide

[1739] DMF N,N-dimethylformamide

[1740] EtOAc (ethyl acetate)

[1741] HPLC (High Performance Liquid Chromatography)

[1742] HBTU Benzotriazole hexafluorophosphate tetramethylurea

[1743] IMS Industrial Methylated Alcohol

[1744] LC-MS (Liquid Chromatography and Mass Spectrometry)

[1745] mCPBA 3-chloroperoxybenzoic acid

[1746] MeOH (methanol)

[1747] MeCN Acetonitrile

[1748] MS mass spectrometry

[1749] m multiplet

[1750] min(s) minutes

[1751] mL

[1752] m / z mass-to-charge ratio

[1753] NBS N-bromosuccinimide

[1754] NMR (Nuclear Magnetic Resonance)

[1755] Pd(amphos)₂Cl₂ bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride

[1756] Pd(tBu3P)2 bis(tri-tert-butylphosphine)palladium(0)

[1757] ppm (parts per million)

[1758] PS Polymer Support

[1759] Rt retention time

[1760] s single peak

[1761] t triple peak

[1762] T3P propionic anhydride

[1763] TFA (trifluoroacetic acid)

[1764] THF Tetrahydrofuran

[1765] Referring to the following examples, the compounds of the preferred embodiments were synthesized using the methods described herein or other methods known in the art.

[1766] Various starting materials, intermediates, and compounds of the preferred embodiments can be separated and purified using conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, where appropriate. Unless otherwise stated, all starting materials are obtained from commercial suppliers and are ready for use without further purification. Salts can be prepared from the compounds using known salt-forming procedures.

[1767] It should be understood that the organic compounds according to the preferred embodiments may exhibit tautomerism. Since the chemical structures in this specification represent only one possible tautomer, it should be understood that the preferred embodiments cover any tautomer of the drawn structures.

[1768] Unless otherwise specified, the analytical HPLC conditions are as follows:

[1769] Method 2A

[1770] Pillar: Kinetex Core-Shell C18 2.1 x 50 mm 5μm

[1771] Column temperature 40℃

[1772] Eluent: A: H2O + 0.1% formic acid, B: MeCN + 0.1% formic acid

[1773] Flow rate: 1.2 mL / min

[1774] Gradient: 0-1.83 min 5-100% B, 1.83-2.25 min 100% B, 2.25-2.26 min 100-5% B

[1775] Method 2.5B

[1776] Column: Phenomenex Gemini-NX C18 2 x 50mm 3μm

[1777] Column temperature: 40℃

[1778] Eluent: A: 2mM ammonium bicarbonate, buffered to pH 10; B: MeCN

[1779] Flow rate: 1 mL / min

[1780] Gradient: 0-1.80 min 1-100% B, 1.80-2.10 min 100% B, 2.10-2.30 min 100-1% B

[1781] Method 3A

[1782] Column: Acquity UPLC CSH C18 2.1x 50mm, 1.7μm

[1783] Column temperature: 50℃

[1784] Eluent: A: H2O, B: MeCN, 0.1% formic acid

[1785] Flow rate: 1 mL / min

[1786] Gradient: 0.2-2.5 min 2-98% B, 2.5-3.0 min 98% B

[1787] Method 3B

[1788] Column: Acquity UPLC BEH C18 2.1x 50mm, 1.7μm

[1789] Column temperature: 50℃

[1790] Eluent: A: H2O, B: MeCN, 0.1% ammonia

[1791] Flow rate: 1 mL / min

[1792] Gradient: 0.2-2.5 min 2-98% B, 2.5-3.0 min 98% B

[1793] Method 5A

[1794] Column: YMC-Triart C18 2x 50mm, 5μm.

[1795] Flow rate: 0.8 mL / min.

[1796] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% Formic Acid

[1797] 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

[1798] Method 5B

[1799] Column: YMC-Triart C18 2x 50mm, 5μm.

[1800] Flow rate: 0.8 mL / min.

[1801] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% ammonia (aqueous)

[1802] 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

[1803] Method 7A

[1804] Column: Phenomenex Kinetix-XB C18 2.1 x 100 mm, 1.7 μm

[1805] Column temperature: 40℃

[1806] Eluent: A: H2O 0.1% formic acid, B: MeCN 0.1% formic acid

[1807] Flow rate: 0.6 mL / min

[1808] Gradient: 0-5.3.0 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100% B, 5.82-7.00 min 5% B

[1809] Method 7B

[1810] Column: Waters BEH TM C18, 2.1mm x 100mm, 1.7μm column

[1811] Column temperature: 40℃

[1812] Eluent: A: 2mM ammonium bicarbonate, buffered to pH 10; B: MeCN

[1813] Flow rate: 0.6 mL / min

[1814] Gradient: 0-5.3.0 min 5-100% B, 5.3-5.8 min 100% B, 5.8-5.82 min 100% B, 5.82-7.00 min 5% B

[1815] Method 8A

[1816] Column: Acquity UPLC CSH C18 2.1x 100mm, 1.7μm

[1817] Column temperature: 50℃

[1818] Eluent: A: H2O, B: MeCN, 0.1% formic acid

[1819] Flow rate: 0.6 mL / min

[1820] Gradient: 0.5-6.5 min 2-98% B 6.5-7.5 min 98% B

[1821] Method 8B

[1822] Column: Acquity UPLC BEH C18 2.1x 100mm, 1.7μm

[1823] Column temperature: 50℃

[1824] Eluent: A: H2O, B: MeCN, 0.1% ammonia

[1825] Flow rate: 0.6 mL / min

[1826] Gradient: 0.5-6.5 min 2-98% B 6.5-7.5 min 98% B

[1827] Method 15A

[1828] Column: YMC-Triart C18 2x 50mm, 5μm.

[1829] Flow rate: 0.8 mL / min.

[1830] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% Formic Acid

[1831] 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

[1832] Method 15B

[1833] Column: YMC-Triart C18 50x 2mm, 5μm.

[1834] Flow rate: 0.8 mL / min.

[1835] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% ammonia (aqueous)

[1836] 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

[1837] Example 1 - 3-[5-amino-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile

[1838]

[1839] 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 N₂. Pd(tBu₃P)₂ (14 mg, 0.03 mmol) was added, and the reaction mixture was heated to 120 °C (preheating 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 gel chromatography (eluting with a gradient of 5% to 10% MeOH in DCM). The resulting material was ground with MeOH (3 mL) followed by EtOAc (5 mL) to give the title compound as a beige solid.

[1840] LC-MS (Method 15A): Rt 5.14 min; MS m / z 313.2 = [M + H] +

[1841] 1 H NMR (500MHz, DMSO-d6) δ8.62(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).

[1842] Similar to Example 1, compounds of the examples listed below (Table Ex1) were prepared from 3-(5-amino-3-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)benzonitrile (intermediate E) and suitable boric acid or borate ester.

[1843] Table Ex1

[1844]

[1845]

[1846] 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

[1847]

[1848] 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-prop-2-ol (316 mg, 3.55 mmol), and DIPEA (2.06 mL, 11.83 mmol) in NMP (15 mL) was heated to 50 °C for 3 h. After cooling to room temperature, the mixture was partitioned between 90% saline solution (100 mL) and EtOAc (100 mL). The organic layer was washed with 50% saline solution (3 x 50 mL), dried over MgSO4, and concentrated under vacuum. The crude material was purified by silica gel chromatography (eluting with a gradient of 0 to 5% MeOH in DCM) to provide the title compound as a colorless solid.

[1849] LC-MS (Method 8B): Rt 4.24 min; MS m / z 431.2 / 433.2 = [MH]-

[1850] 1 H NMR(500MHz,DMSO-d6)δ8.57(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).

[1851] Similar to Example 2, compounds of the examples listed below (Table Ex2) were prepared from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (intermediate C) and a suitable amine.

[1852] Table Ex2

[1853]

[1854]

[1855]

[1856]

[1857]

[1858]

[1859]

[1860]

[1861]

[1862]

[1863]

[1864]

[1865]

[1866]

[1867]

[1868]

[1869] Example 3 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2R)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile

[1870]

[1871] (2R)-1-aminoprop-2-ol (0.08 mL, 1.05 mmol) was added 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) 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 Na2SO4, and concentrated under vacuum. The crude material was purified by reversed-phase chromatography (eluting with a gradient of 40% to 50% MeCN in water (+0.1 wt% NH4OH)) followed by silica gel chromatography (eluting with a gradient of 0% to 8% MeOH in DCM) to provide the title compound as a colorless solid.

[1872] LC-MS (Method 15B): Rt 7.23 min; MS m / z 419.2 / 421.1=[M+H]+

[1873] 1H NMR(500MHz,DMSO-d6)δ8.59(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,1 H),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).

[1874] Similar to Example 3, compounds of the examples listed below (Table Ex3) were prepared from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (intermediate C) and a suitable amine.

[1875] Table Ex3

[1876]

[1877]

[1878] Example 4 - 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-(4-piperidinylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile

[1879]

[1880] 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

[1881]

[1882] tert-butyl 4-aminopiperidin-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 overnight at 60 °C. 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 x 5 mL). The solid was azeotropically treated with acetone (20 mL) and purified by reverse-phase chromatography (elution with a gradient of 40% to 65% MeCN in water (+0.1 wt% NH4OH) to provide the title compound as a colorless solid.

[1883] LC-MS (Method 5B): Rt 3.89 min; MS m / z 544.2 = [M + H] +

[1884] 1 H NMR(500MHz,DMSO-d6)δ8.63(d,J=7.6Hz,1H),8.03-7.93(m,3H),7.86(dt,J=8.0,1.5Hz,1H),7. 72(t,J=7.8Hz,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).

[1885] Step 2: 3-[3-(2-chloro-6-methyl-4-pyridinyl)-5-(4-piperidinylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile

[1886] 4M 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 under vacuum and purified by reverse-phase chromatography (elution with a gradient of 5%–60% MeCN in water (+0.1 wt% NH4OH)) to provide the title compound as a colorless solid.

[1887] LC-MS (Method 8B): Rt 4.78 min; MS m / z 444.2 / 446.2=[M+H]+

[1888] 1 ¹H NMR (500MHz, 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.

[1889] Similar to Example 4, compounds of the examples listed below (Table Ex4) were prepared from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (intermediate C) and a suitable amine (step 1), followed by deprotection with 4M HCl / dioxane (step 2).

[1890] TableEx4

[1891]

[1892]

[1893]

[1894]

[1895]

[1896]

[1897]

[1898] 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

[1899]

[1900] Step 1-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile

[1901]

[1902] Similar to step 1 in Example 4, the title compound was prepared 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-dioxolane-4-yl]ethanethiamine.

[1903] LC-MS (Method 5B): Rt 3.84 min; MS m / z 489.2 / 491.1=[M+H]+

[1904] 1H NMR (500MHz, DMSO-d6) δ8.60(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).

[1905] 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

[1906] To a suspension of 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (step 1) (49.1 mg, 0.1000 mmol) in THF (1 mL), 2 M aqueous HCl (0.5 mL, 1 mmol) was added 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 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with a gradient of 2% to 10% MeOH in DCM) provided the title compound as a white solid.

[1907] LC-MS (Method 8B): Rt 4.06 min; MS m / z 449.2 / 451.2=[M+H]+

[1908] 1H NMR(500MHz,DMSO-d6)δ8.56(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).

[1909] 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

[1910]

[1911] Step 1 -3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile

[1912]

[1913] Similar to step 1 in Example 4, the title compound was prepared 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-dioxolane-4-yl]ethanethiamine.

[1914] LC-MS (Method 5B): Rt 2.29 min; MS m / z 489.4 / 491.1=[M+H]+

[1915] 1H NMR(500MHz,DMSO-d6)δ8.61(d,J=7.5Hz,1H),8.00-7.93(m,2H),7.92(d,J=8.0Hz,1H ),7.83(d,J=8.0Hz,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),3.8 5(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).

[1916] 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

[1917] Similar to step 2 in Example 4.8, the title compound was prepared from 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (step 1) and 2M aqueous HCl.

[1918] LC-MS (Method 8B): Rt 4.01 min; MS m / z 449.2 / 451.2 = [M+H]+

[1919] 1H NMR (500MHz, DMSO-d6) δ8.57 (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=7.6H z,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).

[1920] 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 trifluoroacetate

[1921]

[1922] 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:

[1923]

[1924] Similar to step 1 in Example 4, the title compound was prepared 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.

[1925] LC-MS (Method 5B): Rt 3.34 min; MS m / z 530.3 / 532.3 = [MH]-

[1926] 1H NMR (500MHz, DMSO-d6) δ8.61(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),7.4 1(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).

[1927] 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

[1928] 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 under vacuum, and the solid residue was then ground with diethyl ether (2 mL) and acetonitrile (2 mL) to give the title compound as a grayish-white solid.

[1929] LC-MS (Method 8B): Rt 4.51 min; MS m / z 432.2 / 434.2 = [MH]+

[1930] 1H NMR(500MHz,DMSO-d6)δ8.69(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).

[1931] Example 4.11-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazacyclobutane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile trifluoroacetate

[1932]

[1933] Step 1 -tert-butyl3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]-3-hydroxy-azacyclobutane-1-carboxylate

[1934]

[1935] Similar to step 1 in Example 4, the title compound was prepared from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (intermediate C) and tert-butyl3-(aminomethyl)-3-hydroxy-azacyclobutane-1-carboxylate.

[1936] LC-MS (Method 5B): Rt 3.15 min; MS m / z 546.2 = [M + H] +

[1937] 1 H NMR (500MHz, DMSO-d6) δ8.62(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).

[1938] Step 2 -3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazacyclobutane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile trifluoroacetate

[1939] Similar to step 2 in Example 4.10, the title compound was prepared 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-azacyclobutane-1-carboxylate (step 1) and TFA.

[1940] LC-MS (Method 15B): Rt 8.34 min; MS m / z 446.1 = [M+H]+

[1941] 1H NMR (500MHz, DMSO-d6) δ8.84(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).

[1942] Example 5 - 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]pentyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide

[1943]

[1944] DMF (1 drop) was added dropwise 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), 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 again for 5 min. The resulting mixture was then concentrated under vacuum to obtain the acyl chloride.

[1945] A suspension of the acyl chloride in DCM (1 mL) was added dropwise to a solution of 3-aminobicyclo[1.1.1]pentane-1-ol hydrochloride (26 mg, 0.19 mmol) and DIPEA (89 μL, 0.51 mmol) in DCM (1 mL), and the mixture was stirred for 45 min. Additional 3-aminobicyclo[1.1.1]pentane-1-ol hydrochloride (9 mg, 0.06 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The resulting mixture was partitioned between H₂O (10 mL) and DCM (10 mL), and the organic fraction was separated. The aqueous fraction was further extracted with DCM (2 x 10 mL), and the combined organic extracts were washed with brine (10 mL), dried over MgSO₄, and the solvent was removed under vacuum. Purification by silica gel chromatography (eluting with a gradient of 0 to 2% MeOH in DCM) yielded the title compound as a yellow solid.

[1946] LC-MS (Method 8B): Rt 4.32 min; MS m / z 471.2 / 473.1 = [M+H]+

[1947] 1 H NMR (500MHz, DMSO-d6) δ9.41(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,1 H),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).

[1948] Similar to Example 5, compounds of the examples listed below (Table Ex5) were prepared from 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (intermediate A), oxalyl chloride and a suitable amine.

[1949] Table Ex5

[1950]

[1951]

[1952]

[1953] Example 5.8-2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide

[1954]

[1955] Similar to Example 5, the title compound was prepared from 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (Step 2b of Example 92), oxalyl chloride, and ammonium hydroxide.

[1956] LC-MS (Method 8B): Rt 3.74 min; MS m / z 369.2 = [M + H] +

[1957] 1H NMR(500MHz,DMSO-d6)δ9.37(d,J=7.2Hz,1H),8.12(s,1H),8.04-8.00(m,1H),7.9 9-7.94(m,2H),7.86(d,J=7.9Hz,1H),7.71-7.65(m,2H),7.18(s,2H),2.41(s,6H).

[1958] 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

[1959]

[1960] DIPEA (89 μL, 0.51 mmol) was added dropwise 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-butane-2-ol hydrochloride (21 mg, 0.15 mmol) in DMF (2 mL), followed by the addition of... (50% in DMF) (0.14 mL, 0.21 mmol), and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted in EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 50% brine (3 x 10 mL), dried over MgSO4, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with a gradient of 0 to 3% MeOH in DCM) provided the title compound as a yellow solid.

[1961] LC-MS (Method 8B): Rt 4.57 min; MS m / z 475.2 / 477.2=[M+H]+

[1962] 1 H NMR (500MHz, DMSO-d6) δ9.45(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).

[1963] Similar to Example 6, from 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (intermediate A), The following list of examples of compounds were prepared from DIPEA and appropriate amines (Table Ex6).

[1964] Table Ex6

[1965]

[1966]

[1967]

[1968]

[1969]

[1970]

[1971]

[1972]

[1973]

[1974] 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

[1975]

[1976] Step 1: tert-butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-1,1-dimethyl-propyl]carbamate

[1977]

[1978] 3-(2-chloro-6-methyl-4-pyridinyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (intermediate A) (50 mg, 0.13 mmol), A solution of (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 h. The mixture was diluted with water (5 mL) and the resulting precipitate was collected by filtration under vacuum. The solid was dissolved in DCM (20 mL), filtered through a phase separation column, and concentrated under vacuum to give the title compound as a yellow solid.

[1979] LC-MS (Method 2A): Rt 1.37 min; MS m / z 574.3 / 576.3=[M+H]+

[1980] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.41 (d, J = 7.2Hz, 1H), 8.70 (t, J = 5.8Hz, 1H), 8.06 (t, J = 1.4Hz, 1H), 8.00 (dt, J = 7.7, 1.3Hz, 1H), 7.88 (dt, J = 7.9, 1.3Hz, 1H), 7.73 (t, J = 7.8Hz, 1H), 7.69 (d, J = 7.2Hz, 1H), 7.51 (s, 1H), 7.32 (s, 1H), 6.43 (s, 1H), 2.47 (s, 3H), 1.91 (t, J = 7.5Hz, 2H), 1.35 (s, 9H), 1.24 (s, 6H). The 1x CH₂ signal is below the water peak, as shown in HSQC.

[1981] 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

[1982] A solution of tert-butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-carbonyl]amino]-1,1-dimethyl-propyl]carbamate (step 1) (62 mg, 0.10 mmol) in DCM (2 mL) and 1,4-dioxane (251 μL, 1 mmol) in 4 M HCl was stirred at room temperature for 18 h. The resulting mixture was concentrated under vacuum and then 1 g was used. Purification was performed using an SCX column (eluting with 7M NH3 in MeOH). The filtrate was concentrated under vacuum and lyophilized to give the title compound as a yellow powder.

[1983] LC-MS (Method 7A): Rt 2.09 min; MS m / z 474.2 / 476.2=[M+H]+

[1984] 1¹H NMR (500MHz, 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.

[1985] Similar to Example 7, from 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (intermediate A), The following list of examples of compounds were prepared using DIPEA and appropriate amines (Table Ex7). (Step 1) Deprotection was then performed using 4M HCl in 1,4-dioxane (Step 2).

[1986] Table Ex7

[1987]

[1988]

[1989]

[1990]

[1991]

[1992]

[1993]

[1994]

[1995]

[1996]

[1997]

[1998]

[1999]

[2000]

[2001]

[2002]

[2003] 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

[2004]

[2005] Step 1 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide

[2006]

[2007] Similar to step 1 in Example 7, the title compound was prepared 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-dioxolane-4-yl]ethanemine.

[2008] LC-MS (Method 5B): Rt 3.08 min; MS m / z 517.2 / 519.2=[M+H]+

[2009] 1H NMR(500MHz,DMSO-d6)δ9.44(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)

[2010] 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

[2011] Similar to step 2 in Example 4.8, the title compound was prepared from 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide (step 1) and 2M aqueous HCl.

[2012] LC-MS (Method 8B): Rt 3.99 min; MS m / z 477.2 = [M + H] +

[2013] 1H NMR (500MHz, DMSO-d6) δ9.44(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).

[2014] Example 8 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile

[2015]

[2016] Step 1: 3-[3-bromo-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile

[2017]

[2018] 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 x 20 mL). The organic phase was dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (eluting with a gradient of 0 to 2% MeOH in DCM) provided the title compound as a colorless solid.

[2019] LC-MS (Method 5B): Rt 3.80 min; MS m / z 357.0 / 359.0 = [M+H]+

[2020] 1H NMR(500MHz,DMSO-d6)δ9.16(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).

[2021] Step 2: 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile

[2022] 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-dioxane-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 nitrogen stream. 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 x 30 mL). The organic extract was dried over MgSO₄ and concentrated under vacuum. The title compound was purified by silica gel chromatography (eluting with a gradient of 0 to 10% MeOH in DCM), followed by C18 reversed-phase chromatography (eluting with a gradient of 40% to 80% MeCN in water (+0.1 wt% NH4OH), and finally purified again by silica gel chromatography (eluting with a gradient of 0 to 10% MeOH in DCM) to provide a colorless solid.

[2023] LC-MS (Method 15B): Rt 7.79 min; MS m / z 404.1 / 406.0 = [M+H]+

[2024] 1H NMR (500MHz, DMSO-d6) δ9.23(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=7.8Hz,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).

[2025] Example 9 (Intermediate A)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid

[2026]

[2027] A solution of lithium hydroxide (273 mg, 11.42 mmol) in water (20 mL) was added to a partially stirred 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 H₂O (100 mL) and Et₂O (100 mL). The organic fraction was removed, and the aqueous fraction was acidified with 2 M HCl. The resulting solid was collected by filtration and azeotropically reacted with MeOH (x₂) to give the title compound as a yellow solid.

[2028] LC-MS (Method 3B): Rt 1.09 min; MS m / z 390.1 = [M + H] +

[2029] ¹H NMR (500MHz, DMSO-d⁶) δ 9.37 (d, J = 7.2Hz, ¹H), 8.06 (s, ¹H), 7.99 (d, J = 7.8Hz, ¹H), 7.87 (d, J = 7.8Hz, ¹H), 7.71 (t, J = 7.8Hz, ¹H), 7.66 (d, J = 7.2Hz, ¹H), 7.43 (s, ¹H), 7.33 (s, ¹H), 2.42 (s, ³H). No OH protons were observed.

[2030] Example 10-2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide

[2031]

[2032] 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 N2 and treated with (2,6-dimethyl-4-pyridyl)boronic acid (46 mg, 0.31 mmol), K2CO3 (57 mg, 0.41 mmol), and Pd(tBu3P)2 (5 mg, 0.01 mmol). The resulting mixture was heated to 50 °C for 1 h. Further addition of (2,6-dimethyl-4-pyridyl)boronic acid (46 mg, 0.31 mmol), K2CO3 (57 mg, 0.41 mmol), and Pd(tBu3P)2 (5 mg, 0.01 mmol) was made, and the reaction mixture was heated to 50 °C for another 1 h. Two fractions of (2,6-dimethyl-4-pyridyl)boronic acid (46 mg, 0.31 mmol) were added at 30-min intervals, and the reaction mixture was heated to 50 °C for another 30 min. Then, 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine (48 mg, 0.21 mmol), Pd(tBu3P)2 (5 mg, 0.01 mmol), and K2CO3 (57 mg, 0.41 mmol) in water (0.2 mL) were added, and the mixture was heated to 50 °C for another 1 h, after which the reaction was cooled to room temperature. The resulting mixture was partitioned between H2O (15 mL) and EtOAc (20 mL), separating the organic fraction and further extracting the aqueous fraction with EtOAc (2 x 25 mL). The combined organic extracts were dried over Na2SO4 and concentrated under vacuum. The title compound was purified by silica gel chromatography (eluting with a gradient of 2% to 5% MeOH in DCM) to provide a yellow solid.

[2033] LC-MS (Method 8B): Rt 4.06 min; MS m / z 441.3 = [M + H] +

[2034] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 9.42 (d, J = 7.1Hz, 1H), 8.37 (t, J = 6.1Hz, 1H), 8.06 (s, 1H), 7.99 (d, J = 7.8Hz, 1H), 7.91 (d, J = 7.8Hz, 1H), 7.71 (t, J = 7.8Hz, 1H), 7.70 (t, J = 7.1Hz, 1H), 7.22 (s, 2H), 4.75 (s, 1H), 2.40 (s, 6H), 1.16 (s, 6H). No CH₂ signal was observed.

[2035] Example 12-2-(3-cyanophenyl)-3-(2-ethylpyrazol-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide

[2036]

[2037] 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 nitrogen stream. Pd(tBu₃P)₂ (4 mg, 0.01 mmol) was added, and the reaction mixture was heated to 50 °C for 2 h. Further addition of (2-ethylpyrazol-3-yl)boronic acid (11 mg, 0.08 mmol) was made, and the mixture was heated again for one hour. After cooling to room temperature, the resulting mixture was partitioned between H₂O (15 mL) and EtOAc (20 mL) to separate the organic fraction, and the aqueous fraction was further extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under vacuum. Purification by silica gel chromatography (eluting with 3% MeOH in DCM) provided the title compound as a yellow solid.

[2038] LC-MS (Method 8B): Rt 3.95 min; MS m / z 430.3 = [M + H] +

[2039] 1 H NMR (500MHz, DMSO-d6) δ9.44(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=8.0 Hz,1H),7.63(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).

[2040] Similar to Example 12, compounds of the examples listed below (Table Ex 12) were prepared from 3-bromo-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide (intermediate B) and suitable boric acid or borate ester.

[2041] Table Ex12

[2042]

[2043]

[2044]

[2045]

[2046] Example 13-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-pyrimidin-4-yl-pyrazolo[1,5-a]pyrimidin-5-carboxamide

[2047]

[2048] Tributyl(pyrimidin-4-yl)stanane (0.04 mL, 0.13 mmol), cuprous chloride (14 mg, 0.14 mmol), lithium chloride (6 mg, 0.14 mmol), and Pd(PPh3)4 (14 mg, 0.01 mmol) were added to a degassed solution of 3-bromo-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidin-5-carboxamide (intermediate B) (50 mg, 0.12 mmol) in THF (2 mL), and the mixture was heated to 90 °C for 3 h. The mixture was cooled to room temperature, and after further degassed, additional tributyl(pyrimidin-4-yl)stanane (89 mg, 0.24 mmol) and Pd(PPh3)4 (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 H2O (15 mL). The organic fraction was separated, and the aqueous fraction was further extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with 5% aqueous KF solution (2 x 20 mL), brine (2 x 20 mL), dried over Na2SO4, and the solvent was removed under vacuum. Purification by silica gel chromatography (eluting with a gradient of 2% to 4% MeOH in DCM) provided a yellow solid. The solid was suspended in hexane, filtered, washed with Et2O, and dried to give the title compound as a yellow solid.

[2049] LC-MS (Method 8B): Rt 3.61 min; MS m / z 414.2 = [M + H] +

[2050] 1H NMR(500MHz,DMSO-d6)δ9.49(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).

[2051] Example 14-3-Cyano-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide

[2052]

[2053] 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), zinc powder (16 mg, 0.24 mmol), zinc cyanide (34 mg, 0.29 mmol), and Pd(dppf)Cl2.CH2Cl2 (10 mg, 0.01 mmol) were added, and the mixture was heated to 120 °C for 2 h. The mixture was cooled to room temperature, and Pd(tBu3P)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 further diluted with EtOAc (25 mL) and H2O (20 mL) to separate the organic fraction, and the aqueous fraction was further extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine (4 x 20 mL), dried over Na₂SO₄, and the solvent was removed under vacuum. Purification by silica gel chromatography (eluting with 2% MeOH in DCM) provided a colorless solid. The solid was suspended in Et₂O, collected by filtration, and dried to give the title compound as a colorless solid.

[2054] LC-MS (Method 8B): Rt 3.84 min; MS m / z 359.2 = [MH]-

[2055] 1H NMR (500MHz, DMSO-d6) δ9.58(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,with overlapping, J=7.1Hz, 2H), 4.79 (s, 1H), 3.36 (d, J= 6.2Hz, 2H), 1.16 (s, 6H).

[2056] Example 15 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile

[2057]

[2058] A 1M 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 min. 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 continued overnight at room temperature. The resulting mixture was partitioned between EtOAc (5 mL) and water (3 mL), and the organic fraction was separated. The aqueous layer was further extracted with EtOAc (2 x 5 mL), and the combined organic extracts were dried over Na₂SO₄ and concentrated under vacuum. Purification by silica gel chromatography (eluting with a gradient of 2% to 6% MeOH in DCM) provided the title compound as a colorless solid.

[2059] LC-MS (Method 8B): Rt 4.70 min; MS m / z 434.2 / 436.2 = [M+H]+

[2060] 1 H NMR (500MHz, DMSO-d6) δ9.07(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).

[2061] Example 16-N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]methanesulfonamide

[2062]

[2063] 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 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 reversed-phase chromatography (eluting with a gradient of 5% to 25% MeCN in water (+0.1 wt% NH4OH), followed by silica gel chromatography (eluting with a gradient of 0-8% MeOH in DCM). The material was then further purified by C18 reversed-phase chromatography (eluting with a gradient of 30% to 45% MeCN in water (+0.1 wt% formic acid), by reversed-phase chromatography (eluting with a gradient of 5% to 25% MeCN in water (+0.1 wt% NH4OH), and finally by silica gel chromatography (eluting with a gradient of 0-8% MeOH in DCM), providing the title compound as a grayish-white solid.

[2064] LC-MS (Method 8B): Rt 3.08 min; MS m / z 439.1 / 441.1=[M+H]+

[2065] 1 H NMR (500MHz, DMSO-d6) δ11.64(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).

[2066] Example 16.1-1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]guanidine

[2067]

[2068] Similar to Example 16, the title compound was prepared at 100 °C 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).

[2069] LC-MS (Method 8B): Rt 4.05 min; MS m / z 403.2 = [M + H] +

[2070] 1H NMR (500MHz, DMSO-d6) δ8.63(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).

[2071] Example 17-(2S)-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]propionic acid

[2072]

[2073] Step 1: Methyl(2S)-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]propionate

[2074]

[2075] Methyl (2S)-2-aminopropionate (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 overnight at 50 °C and then stirred at 70 °C for 1 h. Additional methyl (2S)-2-aminopropionate (25 mg, 0.24 mmol) and DIPEA (0.1 mL, 0.55 mmol) were added, and the mixture was stirred overnight at 70 °C. 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 under vacuum. The title compound, which is provided as an orange oil, was purified by silica gel chromatography (eluting with a gradient of 2% to 10% MeOH in DCM).

[2076] LC-MS (Method 5A): Rt 2.96 min; MS m / z 447.2 = [M + H] +

[2077] 1 H NMR (500MHz, DMSO-d6) δ8.68(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=7.8H z,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).

[2078] Step 2: (2S)-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]propionic acid

[2079] 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]propionate (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 fraction was acidified to approximately pH 1 with 2 M HCl (aqueous). The mixture was extracted with EtOAc (20 mL), and the organic fraction was dried over Na2SO4, filtered, and concentrated under vacuum. Purification by C18 reversed-phase chromatography (eluting with a gradient of 20% to 45% MeCN in water (+0.1 wt% formic acid) provided the title compound as an off-white solid.

[2080] LC-MS (Method 8A): Rt 4.29 min; MS m / z 433.3 / 435.2=[M+H]+

[2081] 1 ¹H NMR (500MHz, 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.

[2082] Example 18-3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidine-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile carboxylate

[2083]

[2084] 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

[2085]

[2086] 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 min. 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 to the mixture, and stirring was continued overnight at room temperature. The resulting mixture was partitioned between EtOAc (5 mL) and water (3 mL). The organic layers were separated, and the aqueous layer was further extracted with EtOAc (2 x 5 mL). The organic layers were combined, dried over Na₂SO₄, and concentrated under vacuum to give the title compound as an orange gel.

[2087] LC-MS (Method 3B): Rt 2.96 min; MS m / z 531.2 = [M + H] +

[2088] 1 H NMR (400MHz, DMSO-d6) δ9.15 (d, J = 7.4Hz, 1H), 8.10-8.07 (m, 1H), 8.05 (dt, J = 7. 7,1.4Hz,1H),7.92(dt,J=7.9,1.4Hz,1H),7.77(t,J=7.8Hz,1H),7.42-7.33(m,2 H),6.87(d,J=7.5Hz,1H),5.61(s,1H),3.88-3.71(m,1H),3.59-3.51...

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, having the following structural formula: Ii3: in A is CH or N; R0 is hydrogen; R3 is a group in the following formula: Where R 3a It is hydrogen or methyl; R 1z It is cyano; and R 201 Selected from methyl or chlorine; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is 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, or a pharmaceutically acceptable salt thereof, wherein the compound is: 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide.

4. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound 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.

5. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound 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.

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

7. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound 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.

8. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound 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.

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

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

11. Use of the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for use in: (i) Treatment of proliferative diseases; (ii) Treating cancer; (iii) Treating cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more other anticancer agents; (iv) Treatment of cancer, wherein the compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents selected from the group consisting of: 1) Other forms of cancer immunotherapy and anticancer chemotherapy; 2) Adenosine pathway regulators, 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.

12. The use according to claim 11, wherein the anti-PD-1 and PDL-1 antibody is selected from cilimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab.

13. The use according to claim 11, wherein the anti-CTLA4 antibody is ipilimumab.

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