Adenosine A2A receptor antagonist

Abstract

The present invention relates to compounds of Formula I shown below, wherein R0, R1, R2, R3, and A are each as defined in this application. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions comprising the same, and their use in the treatment of diseases or conditions involving adenosine A2a receptor activity, such as cancer, for example: [Chemical Formula I]

Description

Technology Field

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

[0002] Numerous immunosuppressive pathways are active in the tumor microenvironment, allowing tumor cells to evade clearance by cytotoxic T cells and potentially reducing patients' clinical response to immunotherapy using anti-checkpoint antibodies. Anti-PD-1 antibodies such as pembrolizumab and nivolumab, and anti-PD-L1 antibodies such as durvalumab, avelumab, and atezolizumab are approved for the treatment of many solid tumors, including non-small cell lung cancer, head and neck squamous carcinoma, and urothelial carcinoma. However, only 20 to 30 percent of patients respond to checkpoint blockade, and the side effects of these therapies are significant (Sukari et al, 2016). Consequently, other approaches to enhance the cytotoxic potential of the tumor microenvironment are being actively investigated. These include agents that can be used as monotherapy or, more likely, in combination with checkpoint inhibitors and cytotoxic agents to enhance efficacy.

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

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

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

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

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

[0008] These findings spurred the development of selective A2a antagonists for use in cancer immunotherapy, and clinical trials are underway for CPI-444, the first selective A2a antagonist evaluated in cancer, which is used both as monotherapy and in combination with the anti-PDL1 antibody atezolizumab. Preliminary data indicated that the compound is well-tolerated and showed early signs of reducing tumor size and improving CD8+T invasion into tumor tissue.

[0009] However, there remains a need for second-generation compounds that are potent adenosine A2a antagonists. Specifically, there is a need for compounds that are potent and selective adenosine A2a antagonists, and in some cases, potent and selective adenosine A2a and A2b antagonists. Additionally, there is a need for compounds that are potent adenosine A2a antagonists or adenosine A2a and A2b antagonists that maintain activity in the presence of high concentrations of adenosine in the tumor microenvironment. means of solving the problem

[0010] According to a first aspect of the present invention, a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof is provided.

[0011] According to a further aspect of the present 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.

[0012] According to a further aspect of the present invention, a method for antagonizing an adenosine A2a receptor (and in some cases, an A2b receptor) in vitro or in vivo is provided, the method comprising the step of contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

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

[0014] According to a further aspect of the present invention, a method for inhibiting cell proliferation in vitro or in vivo is provided, the method comprising the step of 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).

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

[0016] According to a further aspect of the present invention, a method for treating a proliferative disorder in a patient requiring treatment is provided, the method comprising the step of 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).

[0017] According to a further aspect of the present invention, a method for treating cancer in a patient requiring treatment is provided, the method comprising the step of 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).

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

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

[0020] According to a further aspect of the present invention, a compound as defined herein for use in the treatment of cancer, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein is provided. In a specific embodiment, the cancer is 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).

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

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

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

[0024] According to a further aspect of the present invention, the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided in the manufacture of a drug for the treatment of cancer. Suitably, the cancer is 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).

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

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

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

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

[0029] According to a further aspect of the present invention, a novel intermediate as defined in the present specification is provided, suitable for use in any one of the synthesis methods presented in the present specification.

[0030] Features comprising optional, suitable, and desirable features in relation to one aspect of the present invention may also be features comprising optional, suitable, and desirable features in relation to any other aspect of the present invention. Specific details for implementing the invention

[0031] definition

[0032] Unless otherwise specified, the following terms used in the specification and claims have the meanings set forth below.

[0033] It should be understood that references to "treating" or "treatment" include prevention as well as the alleviation of established symptoms of a condition. Accordingly, "treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the onset of clinical symptoms of a condition, disorder, or condition in a human being who has or may have contracted the condition, disorder, or condition but has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition; (2) suppressing the condition, disorder, or condition, i.e., preventing, reducing, or delaying the occurrence of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (3) alleviating or weakening the disease, i.e., causing the regression of at least one of the condition, disorder, or condition or its clinical or subclinical symptoms.

[0034] "Therapeutic effective dose" refers to the amount of a compound sufficient to deliver such treatment for a disease when administered to a mammal for the treatment of the disease. The "therapeutic effective dose" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0035] In this specification, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups, such as "propyl," are specific only to the straight-chain form, and references to individual branched-chain alkyl groups, such as "isopropyl," are specific only to the branched-chain form. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t - Includes butyl. Similar rules apply to other radicals, for example, "phenyl(1-6C)alkyl" includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

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

[0037] An "alkylene," "alkenylene," or "alkynylene" group is an alkyl, alkenyl, or alkynylene group located between two different chemical groups and serving to connect them. Thus, "(1-6C)alkylene" refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc.

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

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

[0040] The term "(m-nC)cycloalkyl" means a hydrocarbon ring containing m to n carbon atoms, for example, "(3-6C)cycloalkyl" means a hydrocarbon ring containing 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term "(m-nC)-cycloalkyl" also includes non-aromatic saturated or partially saturated monocyclic, fused, crosslinked, or spirobicyclic carbocyclic ring system(s). The term "(m-nC)cycloalkyl" includes both monovalent and divalent species. Monocyclic "(m-nC)cycloalkyl" rings contain about 3 to 12 (suitably 3 to 8, most suitably 5 to 6) cyclic carbon atoms. Bicyclic "(m-nC) cycloalkyl" contains 7 to 17 cyclic carbon atoms, suitably 7 to 12 cyclic carbon atoms. Bicyclic "C m-n The -cycloalkyl" ring can be a fused, spiro, or cross-linked ring system.

[0041] "(3-8C)cycloalkyl" means a hydrocarbon ring or crosslinking system containing 3 to 8 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

[0042] "(3-8C)cycloalkenyl" means a hydrocarbon ring containing at least one double bond, e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, e.g., 3-cyclohexene-1-yl, or cyclooctenyl.

[0043] "(3-8C)cycloalkyl-(1-6C)alkylene" means a (3-8C)cycloalkyl group covalently attached to a (1-6C)alkylene group, both of which are defined in this specification.

[0044] The terms "halo" or "halogeno" refer to fluoro, chloro, bromo, and iodo.

[0045] The terms “heterocyclic,” “heterocyclic,” or “heterocycle” refer to non-aromatic saturated or partially saturated monocyclic, fused, crosslinked, or spiro-bicyclic heterocyclic ring systems. A monocyclic heterocyclic ring contains about 3 to 12 (suitably 3 to 7) ring atoms along with 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. A bicyclic heterocycle contains 7 to 17 constituent atoms, suitably 7 to 12 constituent atoms in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or crosslinked ring systems. Examples of heterocyclic groups include cyclic ethers, such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, etc. Conventional sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2 H- Includes thiopyran and hexahydrotiepine. Other heterocycles include dihydrooxathiollyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomofolinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. In the case of heterocycles containing sulfur, oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomofolinyl, such as tetrahydrothiene 1,1-dioxide and thiomofolinyl 1,1-dioxide. Suitable values ​​for heterocyclil groups having one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxomidazolidinyl, 2-thioxomidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxomidazolidinyl, or 2,6-dioxopiperidinyl. A specific heterocyclile group is a saturated monocyclic 3 to 7-membered heterocyclile containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, e.g., azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomomorpholinyl, thiomomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperidinyl. As understood by those skilled in the art, any heterocycle may be connected to another group through any suitable carbon, e.g., through a carbon or nitrogen atom. However, references to piperidino or morpholino in this specification refer to a piperidin-1-yl or morpholin-4-yl ring connected through a ring nitrogen.

[0046] "Carbon-linked heterocyclile" means a heterocycl group as defined above that is linked through carbon atoms rather than heteroatoms such as nitrogen.

[0047] "Spirocyclic ring system" refers to a compound having at least two rings that have only one atom in common and are not connected by a bridge.

[0048] A "fused ring system" refers to a compound in which two rings share two adjacent atoms. In other words, the rings share one covalent bond.

[0049] "Bridged ring system" refers to a ring system in which two rings share more than two atoms, for example, literature[ Advanced Organic Chemistry , by Jerry March, 4 th See [Edition, Wiley Interscience, pages 131-133, 1992]. Examples of cross-linked heterocyclil ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidein.

[0050] "Spiro-bicyclic ring system" means that two ring systems share a common spiro-carbon atom, that is, a heterocyclic ring is connected to an additional carbocyclic or heterocyclic ring through a single common spiro-carbon atom. Examples of spiro-ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0051] "Heterocyclyl (1-6C)alkyl" means a heterocyclyl group covalently attached to a (1-6C)alkylene group, both of which are defined in this specification.

[0052] The terms “heteroaryl” or “heteroaromatic” mean an aromatic mono-, bi-, or polycyclic ring 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 species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 cyclic rings, more generally 5 to 10 cyclic rings. The heteroaryl group may be a bicyclic structure formed, for example, from a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example, a fused 5- and 6-membered ring or two fused 6-membered rings. Each ring may typically contain up to about 4 heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to three heteroatoms, more generally up to two, for example, a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom of the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or may be essentially 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 group substituent of the ring, will be less than five.

[0053] Examples of heteroaryls include furil, pyrrolil, thienyl, oxazolil, isoxazolil, imidazollil, pyrazolil, thiazolil, isothiazollil, oxadiazollil, thiadiazolil, triazolil, tetrazollil, pyridyl, pyridazinil, pyrimidinil, pyrazinil, 1,3,5-triazenil, benzofuranil, indolyl, isoindolyl, benzothienyl, benzoxazolil, benzimidazolil, benzothiazollil, benzothiazollil, indazolil, furinyl, benzofurazanil, quinolyl, isoquinolyl, quinazolinil, quinoxalinil, cinnolinil, pteridinil, naftiridinil, carbazollil, phenazinil, benzisoquinolinil, pyridopirazinil, It includes thieno[2,3b]-furanyl-, 2H-furo[3,2b]-pyranyl-, 5H-pyrido[2,3-d]-oxazolyl-, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, -imidazo[2,1b]thiazolyl, and -imidazo[1,2b][1,2,4]-triazinyl. "Heteroaryl" also includes a partially aromatic non- or polycyclic ring system in which at least one ring is an aromatic ring and one or more other ring(s) 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 partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthiridinyl, 1,2,3,4-tetrahydropyrido[2,3- b ]Pyrazinyl, 3,4-Dihydro-2 H -Pirido[3,2- b Includes ][1,4]oxazinyl and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazinyl.

[0054] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0055] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinil, pyridazinil, pyrimidinil, and triazinil.

[0056] Bicyclic heteroaryl groups, for example,

[0057] A benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 cyclic heteroatoms;

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

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

[0060] A pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 cyclic heteroatoms;

[0061] A pyrazol ring fused to a 5- or 6-membered ring containing 1 or 2 cyclic heteroatoms;

[0062] A pyrazine ring fused to a 5 or 6-membered ring containing 1 or 2 cyclic heteroatoms;

[0063] An imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 cyclic heteroatoms;

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

[0065] A bisoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 cyclic heteroatoms;

[0066] A thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 cyclic heteroatoms;

[0067] An isothiazol ring fused to a 5- or 6-membered ring containing 1 or 2 cyclic heteroatoms;

[0068] A thiophene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 cyclic heteroatoms;

[0069] A furan ring fused to a 5- or 6-membered ring containing 1, 2, or 3 cyclic heteroatoms;

[0070] A cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 cyclic heteroatoms; and

[0071] A cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 cyclic heteroatoms.

[0072] It can be a date selected from.

[0073] Specific examples of a bicyclic heteroaryl group containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisosoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, furinyl (e.g., adeninyl, guaniyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0074] Specific examples of a cyclic heteroaryl group containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthiridinyl, and pteridinyl groups.

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

[0076] The term "aryl" means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc. In certain embodiments, the aryl is phenyl.

[0077] The term "aryl(1-6C)alkyl" means 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 various compound terms to describe groups comprising one or more functionalities. These terms will be understood by those skilled in the art. For example, heterocyclyl (m-nC)alkyl comprises a (m-nC)alkyl group substituted by a heterocyclyl.

[0079] The term "optionally substituted" refers to a substituted group, structure, or molecule, and an unsubstituted group, structure, or molecule. The term "here, R 1 Any CH, CH2, CH3 group or heteroatom (i.e., NH) within the group is optionally substituted" is suitably R 1 This means that one of the hydrogen radicals of the group is replaced by a related specified group.

[0080] Where optional substituents are selected from "one or more" groups, this definition should be understood to include all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

[0081] The phrase "compound of the present invention" generally and specifically means the compound disclosed in this specification.

[0082] Compound of the present invention

[0083] In a first aspect, the present invention relates to a compound having the structural formula I shown below, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0084] [Chemical Formula I]

[0085]

[0086] Here,

[0087] R0 is hydrogen or deuterium;

[0088] R1 is selected from aryl or heteroaryl, and

[0089] Here, R1 is (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , (CH2) q1 OR 1B , (CH2) q1 C(O)R 1B , (CH2) q1 C(O)OR 1B , (CH2) q1 OC(O)R 1B , (CH2) q1 C(O)N(R 1C )R 1B , (CH2) q1 N(R 1C )C(O)R 1B , (CH2) q1 S(O) p R 1B (Here, p is 0, 1, or 2), (CH2) q1 SO2N(R 1C )R 1B , or (CH2) q1 N(R 1C )SO2R 1B One or more Rs independently selected from 1zSelectively substituted by a substituent,

[0090] 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;

[0091] R2 is hydrogen, cyano, halo, (1-4C)alkyl, (1-4C)haloalkyl, C(O)OR 2A , C(O)NR 2A R 2B Selected from , aryl, heteroaryl, (2-6C)alkenyl, (2-6C)alkynyl, or (1-4C)alkanoyl;

[0092] Here, 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, or

[0093] CONR 2A R 2B In the, R 2A and R 2B They are connected to form a heterocyclic ring together with the attached nitrogen atoms, and

[0094] Any alkyl, alkenyl, alkynyl, alkanoyl, aryl, heteroaryl, or heterocyclil group (R 2A and R 2B (Formed by) is (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 (Here, p is 0, 1, or 2), (CH2) q2 SO2N(R 2E )R 2D , or (CH2) q2 N(R 2E )SO2R 2D Optionally substituted by one or more substituents independently selected from, wherein q2 is 0, 1, 2 or 3; R 2D and R 2E Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0095] R3 is selected from hydrogen, halo, cyano, or groups of the following chemical formulas:

[0096] -LYL q -Q

[0097] Here,

[0098] L is an (1-4C)alkylene that is absent or optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0099] Y is absent or 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, but R a and R b Each is independently selected from hydrogen or (1-4C)alkyl and R y is selected from hydrogen, (1-4C)alkyl, nitro, or cyano;

[0100] L q is an (1-4C)alkylene that is absent or optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino, or oxo;

[0101] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-8)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl;

[0102] Q is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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) additionally optionally substituted by one or more substituents independently selected from; 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;

[0103] R c and R d are connected to form a 4 to 7-membered heterocyclic ring selectively 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 hydroxyl, together with the nitrogen atoms to which they are attached;

[0104] Q is optionally substituted by one or more groups of the following chemical formula:

[0105] -L1-L Q1 -W1

[0106] Here,

[0107] L1 is absent or optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo, and is a (1-3C)alkylene;

[0108] L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R) f ), N(R f )C(O), N(R f )C(O)N(R g ), N(R f )C(O)O, OC(O)N(R f ), S(O)2N(R f ), N(R f Selected from )SO2, but R f and R gEach is independently selected from hydrogen or (1-2C)alkyl;

[0109] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclil; W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, aryl, heteroaryl, heterocyclil, (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 Optionally substituted by one or more substituents selected from (where s is 1, 2, or 3); R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0110] Any alkyl, alkoxy, aryl, heteroaryl, heterocyclil, or cycloalkyl moiety among the substituents present in W1 is additionally optionally 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;

[0111] R h and R i are connected to form a 4 to 7-membered heterocyclic ring selectively substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy, together with the nitrogen atoms to which they are attached;

[0112] A is selected from CR4 and N, and

[0113] Here, R4 is hydrogen, halo, or 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 (Here, p is 0, 1, or 2), (CH2) qa SO2N(R 4B )R 4A , or (CH2) qa N(R 4B )SO2R 4A (1-4C)alkyl optionally substituted by one or more substituents selected from, wherein qa is 0, 1, 2 or 3 and R 4A and R 4BEach is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0114] In the compound of formula I, any tertiary amine is optionally in the form of an N-oxide and the nitrogen atom of the pyridine ring is optionally in the form of an N-oxide;

[0115] Any S atom present in the heterocyclic ring is optionally S(=O), S(=O)2, or S(=O)(=NR z Can exist as ), but R z It is selected from hydrogen, (1-3C)alkyl or (2-3C)alkanoyl.

[0116] Specific compounds of the present invention include, for example, compounds of Formula I, or pharmaceutically acceptable salts, hydrates, and / or solvates thereof, and unless otherwise stated herein, R o , R1, R2, R3 and A each have any meaning defined in any of the above or subsequent paragraphs (1) to (55):-

[0117] (1) R0 is hydrogen;

[0118] (2) R0 is deuterium;

[0119] (3) R1 is selected from aryl or heteroaryl, and

[0120] Here, R1 is (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , (CH2) q1 OR 1B , (CH2) q1 C(O)R 1B , (CH2) q1 C(O)OR 1B , (CH2) q1 OC(O)R 1B , (CH2) q1 C(O)N(R 1C )R 1B, (CH2) q1 N(R 1C )C(O)R 1B , (CH2) q1 S(O) p R 1B (Here, p is 0, 1, or 2), (CH2) q1 SO2N(R 1C )R 1B , or (CH2) q1 N(R 1C )SO2R 1B One or more Rs independently selected from R 1z Selectively substituted by a substituent,

[0121] 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;

[0122] (4) R1 is selected from aryl or heteroaryl, and

[0123] Here, R1 is (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , OR 1B , C(O)R 1B , C(O)OR 1B , OC(O)R 1B , C(O)N(R 1C )R 1B , N(R 1C )C(O)R 1B , S(O) p R 1B (Here, p is 0, 1, or 2), SO2N(R 1C )R 1B , or N(R 1C )SO2R 1B One or more Rs independently selected from 1z Selectively substituted by a substituent,

[0124] q1 is 0, 1, or 2, and;

[0125] R 1B and R 1C Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0126] (5) R1 is selected from aryl or heteroaryl, and

[0127] Here, R1 is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , OR 1B , C(O)R 1B , C(O)OR 1B , OC(O)R 1B , C(O)N(R 1C )R 1B , N(R 1C )C(O)R 1B , S(O) p R 1B (Here, p is 0, 1, or 2), SO2N(R 1C )R 1B , or N(R 1C )SO2R 1B One or more Rs independently selected from 1z Selectively substituted by a substituent,

[0128] q1 is 0, 1, or 2, and;

[0129] R 1B and R 1C Each is independently selected from hydrogen, (1-2C)alkyl, or (3-4C)cycloalkyl;

[0130] (5) R1 is selected from aryl or heteroaryl, and

[0131] Here, R1 is (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , (CH2) q1 OR 1B, (CH2) q1 C(O)R 1B , (CH2) q1 C(O)OR 1B , (CH2) q1 OC(O)R 1B , (CH2) q1 C(O)N(R 1C )R 1B , (CH2) q1 N(R 1C )C(O)R 1B , (CH2) q1 S(O) p R 1B (Here, p is 0, 1, or 2), (CH2) q1 SO2N(R 1C )R 1B , or (CH2) q1 N(R 1C )SO2R 1B One or more Rs independently selected from 1z Selectively substituted by a substituent,

[0132] q1 is 0, 1, or 2, and;

[0133] R 1B and R 1C Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0134] (6) R1 is selected from phenyl or 5 or 6-membered heteroaryl, and

[0135] R1 is (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , OR 1B , C(O)R 1B , C(O)OR 1B , OC(O)R 1B , C(O)N(R 1C )R 1B , N(R 1C )C(O)R 1B , S(O) p R 1B(Here, p is 0, 1, or 2), SO2N(R 1C )R 1B , or N(R 1C )SO2R 1B One or more Rs independently selected from 1z Selectively substituted by a substituent,

[0136] q1 is 0, 1, or 2, and;

[0137] R 1B and R 1C Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0138] (7) R1 is selected from aryl or heteroaryl, and

[0139] Here, R1 is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , OR 1B , C(O)R 1B , C(O)OR 1B , OC(O)R 1B , C(O)N(R 1C )R 1B , N(R 1C )C(O)R 1B , S(O) p R 1B (Here, p is 0, 1, or 2), SO2N(R 1C )R 1B , or N(R 1C )SO2R 1B One or more Rs independently selected from 1z Selectively substituted by a substituent,

[0140] q1 is 0, 1, or 2, and;

[0141] R 1B and R 1C Each is independently selected from hydrogen, (1-2C)alkyl, or (3-4C)cycloalkyl;

[0142] (8) R1 is selected from aryl or heteroaryl, and

[0143] Here, R1 is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , (CH2) q1 OR 1B , (CH2) q1 C(O)R 1B , (CH2) q1 C(O)OR 1B , (CH2) q1 OC(O)R 1B , (CH2) q1 C(O)N(R 1C )R 1B , or (CH2) q1 N(R 1C )C(O)R 1B One or more Rs independently selected from 1z Selectively substituted by a substituent,

[0144] q1 is 0, 1, 2 or 3, and R 1B and R 1C Each is independently selected from hydrogen or (1-2C)alkyl;

[0145] (9) R1 is selected from aryl or heteroaryl, and

[0146] Here, R1 is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , (CH2) q1 OR 1B , or (CH2) q1 C(O)R 1B One or more Rs independently selected from 1z Selectively substituted by a substituent,

[0147] q1 is 0, 1, 2 or 3, and R 1B and R 1CEach is independently selected from hydrogen or (1-2C)alkyl;

[0148] (10) R1 is selected from phenyl or 5 or 6-membered heteroaryl, and

[0149] Here, R1 is (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, (CH2) q1 NR 1B R 1C , OR 1B , C(O)R 1B , C(O)OR 1B , OC(O)R 1B , C(O)N(R 1C )R 1B , N(R 1C )C(O)R 1B , S(O) p R 1B (Here, p is 0, 1, or 2), SO2N(R 1C )R 1B , or N(R 1C )SO2R 1B One or more Rs independently selected from 1z Selectively substituted by a substituent,

[0150] q1 is 0, 1, or 2, and;

[0151] R 1B and R 1C Each is independently selected from hydrogen or (1-2C)alkyl;

[0152] (11) R1 is one or more R defined in any one of paragraphs (1) to (10) above. 1z It is a phenyl selectively substituted by a substituent.

[0153] (12) R1 is one or more R defined in any one of paragraphs (1) to (10) above. 1z It is a 5- or 6-membered heteroaryl selectively substituted by a substituent.

[0154] (13) R1 is selected from phenyl, furyl, pyridyl, oxazolyl, thiazolyl, isoxazolyl or oxazolin-2-yl, wherein the phenyl, furyl, pyridyl or oxazolyl ring is optionally substituted by a halo, (1-2C)alkyl, (1-2C)alkoxy or cyano.

[0155] (14) R1 is selected from phenyl, furyl, pyridyl or oxazolyl, wherein the phenyl, furyl, pyridyl or oxazolyl ring is a halo, C 1-2 Optionally substituted by one or more of alkoxy or cyano.

[0156] (15) R1 is selected from phenyl, furyl, pyridyl or oxazolyl, wherein the phenyl, furyl, pyridyl or oxazolyl ring is optionally substituted by a halo or cyano.

[0157] (16) R1 is selected from 3-cyanophenyl, furyl, or oxazolyl, thiazolyl, isoxazolyl or oxazolin-2-yl.

[0158] (17) R1 is 3-cyanophenyl.

[0159] (18) R2 is hydrogen, cyano, halo, (1-4C)alkyl, (1-4C)haloalkyl, C(O)OR 2A , C(O)NR 2A R 2B Selected from , aryl, heteroaryl, (2-6C)alkenyl, (2-6C)alkynyl, or (1-4C)alkanoyl;

[0160] Here, 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, or

[0161] CONR 2A R 2B In the, R 2A and R 2B They are connected to form a 4 to 7-membered heterocyclic ring together with the attached nitrogen atoms, and

[0162] Any alkyl, alkenyl, alkynyl, alkanoyl, aryl, heteroaryl, or heterocyclil group (R 2A and R 2B (Formed by) is (1-4C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, (CH2) q2 NR 2D R 2E , (CH2) q2 OR 2D , (CH2) q2 C(O)R 2D , (CH2) q2 C(O)OR 2D , (CH2) q2 OC(O)R 2D , (CH2) q2 C(O)N(R 2E )R 2D , (CH2) q2 N(R 2E )C(O)R 12D , (CH2) q2 S(O) p R 2D (Here, p is 0, 1, or 2), (CH2) q2 SO2N(R 2E )R 2D , or (CH2) q2 N(R 2E )SO2R 2D Optionally substituted by one or more substituents independently selected from, and

[0163] q2 is 0, 1, or 2 and;

[0164] R 2D and R 2E Each is independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl;

[0165] When R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0166] (19) R2 is hydrogen, cyano, halo, (1-4C)alkyl, (1-4C)haloalkyl, C(O)OR2A , C(O)NR 2A R 2B Selected from , phenyl, 5 or 6-membered heteroaryl, (2-4C)alkenyl or (1-4C)alkanoyl, and

[0167] Here, 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

[0168] Any alkyl, alkenyl, alkanoyl, phenyl, or heteroaryl group is (1-4C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, (CH2) q2 NR 2D R 2E , (CH2) q2 OR 2D , (CH2) q2 C(O)R 2D , (CH2) q2 C(O)OR 2D , (CH2) q2 OC(O)R 2D , (CH2) q2 C(O)N(R 2E )R 2D , (CH2) q2 N(R 2E )C(O)R 12D , (CH2) q2 S(O) p R 2D (Here, p is 0, 1, or 2), (CH2) q2 SO2N(R 2E )R 2D , or (CH2) q2 N(R 2E )SO2R 2D Optionally substituted by one or more substituents independently selected from, and

[0169] q2 is 0, 1, or 2 and;

[0170] R 2D and R 2EEach is independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl;

[0171] When R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0172] (20) R2 is hydrogen, cyano, halo, (1-2C)alkyl, (1-2C)haloalkyl, C(O)OR 2A , C(O)NR 2A R 2B Selected from , phenyl, 5 or 6-membered heteroaryl or (1-4C)alkanoyl, and

[0173] Here, R 2A and R 2B Each is independently selected from hydrogen or (1-4C)alkyl, and

[0174] Any alkyl, alkenyl, alkanoyl, phenyl, or heteroaryl group is (1-4C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, (CH2) q2 NR 2D R 2E , (CH2) q2 OR 2D , (CH2) q2 C(O)R 2D , (CH2) q2 C(O)OR 2D , (CH2) q2 OC(O)R 2D , (CH2) q2 C(O)N(R 2E )R 2D , (CH2) q2 N(R 2E )C(O)R 12D , (CH2) q2 S(O) p R 2D (Here, p is 0, 1, or 2), (CH2) q2 SO2N(R 2E )R 2D , or (CH2)q2N(R 2E )SO2R 2DOptionally substituted by one or more substituents independently selected from, and

[0175] q2 is 0, 1, or 2 and;

[0176] R 2D and R 2E Each is independently selected from hydrogen, (1-2C)alkyl, (3-4C)cycloalkyl, or (3-4C)cycloalkyl(1-2C)alkyl;

[0177] When R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0178] (21) R2 is cyano, halo, methyl, CF3, C(O)OR 2A , C(O)NR 2A R 2B , selected from 5 or 6-membered heteroaryls or (2-4C)alkanoyls, and

[0179] Here, R 2A and R 2B Each is independently selected from hydrogen or (1-4C)alkyl, and

[0180] Any phenyl or heteroaryl group is (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 (Here, p is 0, 1, or 2), SO2N(R 2E )R 2D , or N(R 2E )SO2R 2D Optionally substituted by one or more substituents independently selected from, where q2 is 0 or 1; R2D and R 2E Each is independently selected from hydrogen or (1-2C)alkyl;

[0181] When R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0182] (22) R2 is selected from optionally substituted cyano or 5- or 6-membered heteroaryls as defined in any one of paragraphs (18) to (21);

[0183] Here, when R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0184] (23) R2 is selected from a cyano or 5- or 6-membered heteroaryl selectively substituted by one or more substituents independently selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or cyano; wherein, where R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0185] (24) R2 is a 5- or 6-membered heteroaryl optionally substituted by one or more substituents independently selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or cyano; wherein, where R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0186] (25) R2 is a 5- or 6-membered heteroaryl optionally substituted by one or more substituents independently selected from (1-2C)alkyl or halo; wherein, if R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0187] (26) R2 is a 6-membered heteroaryl optionally substituted by one or more substituents independently selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy or cyano; wherein, if R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0188] (27) R2 is a 6-membered nitrogen-containing heteroaryl optionally substituted by one or more substituents independently selected from (1-2C)alkyl or halo; wherein, if R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0189] (28) R2 is a 6-membered nitrogen-containing heteroaryl optionally substituted by one or more substituents independently selected from methyl or chloro; where, if R2 is a pyridyl, the ring nitrogen atom is optionally in the form of an N-oxide;

[0190] (29) R2 is

[0191]

[0192] (Here,

[0193] (i) R 200 and R 201 Each is independently selected from (1-2C)alkyl, hydroxy(1-2C)alkyl, aminohalo, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (1-2C)alkanoyl, or cyano;

[0194] (ii) R 200 and R 201 Each is independently selected from methyl, hydroxymethyl, halo, di-fluoromethyl, trifluoromethyl, methoxy, acetyl, or cyano;

[0195] (iii) R 200 is methyl or chloro and R 201Selected from methyl, hydroxymethyl, halo, difluoromethyl, trifluoromethyl, methoxy, acetyl, or cyano); or

[0196]

[0197] (Here,

[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, halo, difluoromethyl, trifluoromethyl, methoxy, acetyl, or cyano;

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

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

[0202] (v) R 201 (It is chloro)

[0203] lim;

[0204] (30) R2 is a pyridinyl (e.g., pyridin-4-yl) optionally substituted by one or more substituents independently selected from methyl or chloro;

[0205] (31) R2 is 2-chloro-6-methylpyridine-4-yl or 2,6-dimethylpyridine-4-yl, i.e.

[0206] or lim;

[0207] (32) R3 is selected from hydrogen, halo, cyano or groups of the following chemical formulas:

[0208] -LYL q -Q

[0209] Here,

[0210] L is absent or (1-4C)alkylene;

[0211] Y is absent or 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, but R a and R b Each is independently selected from hydrogen or (1-4C)alkyl and R y is selected from hydrogen, (1-4C)alkyl, nitro, or cyano;

[0212] L q is an (1-4C)alkylene that is absent or optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino, or oxo;

[0213] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-8)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl;

[0214] Q is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, NR c R d , OR c , C(O)Rc , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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) additionally optionally substituted by one or more substituents independently selected from; R c and R d Each is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0215] R c and R d are connected to form a 4 to 7-membered heterocyclic ring selectively 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 hydroxyl, together with the nitrogen atoms to which they are attached;

[0216] Q is optionally substituted by one or more groups of the following chemical formula:

[0217] -L1-L Q1 -W1

[0218] Here,

[0219] L1 is absent or (1-3C)alkylene;

[0220] L Q1 is absent or O, S, SO, SO2, N(R f), C(O), C(O)O, OC(O), C(O)N(R) f ), N(R f )C(O), N(R f )C(O)N(R g ), N(R f )C(O)O, OC(O)N(R f ), S(O)2N(R f ), N(R f Selected from )SO2, but R f and R g Each is independently selected from hydrogen or (1-2C)alkyl;

[0221] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclil; W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, aryl, heteroaryl, heterocyclil, (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 Optionally substituted by one or more substituents selected from (where s is 1, 2, or 3); R h and R iEach is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0222] Any alkyl, alkoxy, aryl, heteroaryl, heterocyclil, or cycloalkyl moiety among the substituents present in W1 is additionally optionally 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;

[0223] R h and R i are connected to form a 4 to 7-membered heterocyclic ring selectively substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy, together with the nitrogen atoms to which they are attached;

[0224] In the R3 group, any tertiary amine or nitrogen atom of the pyridyl ring is optionally in the form of an N-oxide;

[0225] (33) R3 is selected from hydrogen, halo, cyano or groups of the following chemical formulas:

[0226] -LYL q -Q

[0227] Here,

[0228] L is absent or (1-4C)alkylene;

[0229] Y is absent or 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(Ra )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, but R a and R b Each is independently selected from hydrogen or (1-4C)alkyl and R y is selected from hydrogen, (1-4C)alkyl, nitro, or cyano;

[0230] L q is an (1-4C)alkylene that is absent or optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino, or oxo;

[0231] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, (3-8)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclyl;

[0232] Q is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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) additionally optionally substituted by one or more substituents independently selected from; R c and R d Each is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0233] Q is optionally substituted by one or more groups of the following chemical formula:

[0234] -L1-L Q1 -W1

[0235] Here,

[0236] L1 is absent or (1-3C)alkylene;

[0237] L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R) f ), N(R f )C(O), N(R f )C(O)N(R g ), N(R f )C(O)O, OC(O)N(R f ), S(O)2N(R f ), N(R f Selected from )SO2, but R f and R g Each is independently selected from hydrogen or (1-2C)alkyl;

[0238] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, heteroaryl or heterocyclil; W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, aryl, heteroaryl, heterocyclil, (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 Optionally substituted by one or more substituents selected from (where s is 1, 2, or 3); R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0239] In the R3 group, any tertiary amine or nitrogen atom of the pyridyl ring is optionally in the form of an N-oxide;

[0240] (34) R3 is selected from hydrogen, halo, cyano or groups of the following chemical formulas:

[0241] -LYL q -Q

[0242] Here,

[0243] L is absent or (1-2C)alkylene;

[0244] Y is absent or 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, but R a and R b Each is independently selected from hydrogen or (1-4C)alkyl and R y is selected from hydrogen, (1-4C)alkyl, nitro, or cyano;

[0245] L q is an (1-4C)alkylene that is absent or optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino, or oxo;

[0246] Q is hydrogen, (1-6C)alkyl, aryl, (3-8)cycloalkyl, heteroaryl, or heterocyclyl;

[0247] Q is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c, C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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) additionally optionally substituted by one or more substituents independently selected from; R c and R d Each is independently selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;

[0248] Q is optionally substituted by one or more groups of the following chemical formula:

[0249] -L1-L Q1 -W1

[0250] Here,

[0251] L1 is absent or (1-2C)alkylene;

[0252] L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R) f ), N(R f )C(O), N(R f )C(O)N(R g ), N(R f )C(O)O, OC(O)N(R f ), S(O)2N(R f ), N(R f Selected from )SO2, but R f and R g Each is independently selected from hydrogen or (1-2C)alkyl;

[0253] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1, or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h Optionally substituted by one or more substituents selected from (where s is 1, 2, or 3); R h and R i Each is independently selected from hydrogen or (1-4C)alkyl;

[0254] In the R3 group, any tertiary amine or nitrogen atom of the pyridyl ring is optionally in the form of an N-oxide;

[0255] (35) R3 is selected from hydrogen, halo, cyano or groups of the following chemical formulas:

[0256] -LYL q -Q

[0257] Here,

[0258] L is absent or (1-2C)alkylene;

[0259] Y is absent or O, N(R a ), C(O), C(O)O, C(O)N(R a ), N(R a)C(O), C(O)N(R a )O, N(R a )C(O)N(R 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, but R a and R b Each is independently selected from hydrogen or (1-4C)alkyl and R y is selected from hydrogen, (1-4C)alkyl, nitro, or cyano;

[0260] L q is an (1-4C)alkylene that is absent or optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino, or oxo;

[0261] Q is hydrogen, (1-6C)alkyl, aryl, (3-8)cycloalkyl, heteroaryl, or heterocyclyl;

[0262] Q is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c(Here, 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) additionally optionally substituted by one or more substituents independently selected from; R c and R d Each is independently selected from hydrogen or (1-6C)alkyl;

[0263] Q is optionally substituted by one or more groups of the following chemical formula:

[0264] -L1-L Q1 -W1

[0265] Here,

[0266] L1 is absent or (1-2C)alkylene;

[0267] L Q1 is absent;

[0268] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h Optionally substituted by one or more substituents selected from (where r is 0, 1, or 2); R h and R iEach is independently selected from hydrogen or (1-4C)alkyl;

[0269] In the R3 group, any tertiary amine or nitrogen atom of the pyridyl ring is optionally in the form of an N-oxide;

[0270] (35a) R3 is selected from hydrogen, halo, cyano, or groups of the following chemical formulas:

[0271] -LYL q -Q

[0272] Here,

[0273] L is absent or (1-2C)alkylene;

[0274] Y is absent or N(R a ), C(O), C(O)N(R a ), N(R a )C(=NR y )N(R b ), C(O)N(R a )O, or N(R a )C(O)N(R b )become; R a and R b Each is independently selected from hydrogen or (1-4C)alkyl and R y is selected from hydrogen, (1-4C)alkyl or cyano;

[0275] L q is absent or (1-4C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkoxy, halo, cyano, amino, or oxo;

[0276] Q is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (3-8)cycloalkyl, or heterocyclyl;

[0277] Q is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)aminoalkyl, (1-4C)hydroxyalkyl, cyano, NR c R d , OR c , C(O)R c, C(O)OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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) additionally optionally substituted by one or more substituents independently selected from; R c and R d Each is independently selected from hydrogen or (1-6C)alkyl;

[0278] Q is optionally substituted by one or more groups of the following chemical formula:

[0279] -L1-L Q1 -W1

[0280] Here,

[0281] L1 is absent or (1-2C)alkylene;

[0282] L Q1 is absent;

[0283] W1 is hydrogen, (1-6C)alkyl, aryl, aryl(1-2C)alkyl, (3-8C)cycloalkyl, heteroaryl or heterocyclyl; W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, cyano, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O)r R h Optionally substituted by one or more substituents selected from (where r is 0, 1, or 2), and R h and R i Each is independently selected from hydrogen or (1-4C)alkyl;

[0284] In the R3 group, any tertiary amine or nitrogen atom of the pyridyl ring is optionally in the form of an N-oxide;

[0285] (36) R3 is the base of the following chemical formula:

[0286] -LYL q -Q

[0287] Here,

[0288] L is absent;

[0289] Y is N(R a ) or C(O)N(R a ) and;

[0290] L q is absent;

[0291] Q is a (1-6C)alkyl or (3-8)cycloalkyl;

[0292] Q is Halo, Cyano, NR c R d , OR c , C(O)R c , C(O)OR c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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) additionally optionally substituted by one or more substituents independently selected from; Rc and R d Each is independently selected from hydrogen or (1-6C)alkyl;

[0293] (37) R3 is the base of the following chemical formula:

[0294] -LYL q -Q

[0295] Here,

[0296] L is absent;

[0297] Y is N(R a ) or C(O)N(R a ) and;

[0298] L q is absent;

[0299] Q is a (1-6C)alkyl group;

[0300] Q is Halo, Cyano, NR c R d , OR c , C(O)OR c , S(O) p R c (Here, p is 0, 1, or 2), SO2N(R d )R c Further optionally substituted by one or more substituents independently selected from; R c and R d Each is independently selected from hydrogen or (1-6C)alkyl;

[0301] (38) R3 is the base of the following chemical formula:

[0302] -LYL q -Q

[0303] Here,

[0304] L is absent;

[0305] Y is N(R a ) or C(O)N(R a ) and;

[0306] L q is absent;

[0307] Q is a (1-6C)alkyl group;

[0308] Q is one or more OR c Additionally optionally substituted by;

[0309] R c Each is selected from hydrogen or (1-4C)alkyl;

[0310] (39) R3 is the base of the following chemical formula:

[0311] -LYL q -Q

[0312] Here,

[0313] L is absent;

[0314] Y is N(R a ) or C(O)N(R a ) and;

[0315] L q is absent;

[0316] Q is a (1-6C)alkyl group;

[0317] Q is additionally optionally substituted by one or more OH groups;

[0318] (40) R3 is the base of the following chemical formula:

[0319]

[0320] Here, R 3a is hydrogen or methyl;

[0321] (41) R3 is selected from halo or groups of the following chemical formulas:

[0322] -LYQ

[0323] Here,

[0324] L is absent;

[0325] Y is absent or 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(Ra )SO2 or N(R a )SO2N(R b ) but, R a and R b Each is independently selected from hydrogen or (1-2C)alkyl;

[0326] Q is a (1-4C)alkyl, heteroaryl, or heterocyclyl;

[0327] Q is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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) additionally optionally substituted by one or more substituents independently selected from; R c , R d and R e Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0328] R c and R dare connected to form a 4 to 6-membered heterocyclic ring 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 hydroxyl, together with the nitrogen atoms to which they are attached;

[0329] Q is optionally substituted by a group of the following chemical formula:

[0330] -L1-L Q1 -W1

[0331] Here,

[0332] L1 is absent or optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo, and is a (1-3C)alkylene;

[0333] L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R) f ), N(R f )C(O), N(R f )C(O)O, OC(O)N(R f ), S(O)2N(R f ), or N(R f Selected from )SO2, but R f and R g Each is independently selected from hydrogen or (1-2C)alkyl;

[0334] W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl or heterocyclil; W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, cyano, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R i )Rh , 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 Optionally substituted by one or more substituents selected from (where s is 1, 2, or 3); R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0335] Any alkyl, alkoxy, aryl, heteroaryl, heterocyclil, or cycloalkyl moiety among the substituents present in W1 is further optionally 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;

[0336] Any tertiary amine or nitrogen atom of the pyridyl ring present in the R3 group is optionally in the form of an N-oxide;

[0337] (42) R3 is selected from halo or groups of the following chemical formulas:

[0338] -Q

[0339] Here,

[0340] Q is a heteroaryl or heterocyclil;

[0341] Q is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)Rc , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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) additionally optionally substituted by one or more substituents independently selected from; R c , R d and R e Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0342] R c and R d are connected to form a 4 to 6-membered heterocyclic ring 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 hydroxyl, together with the nitrogen atoms to which they are attached;

[0343] Q is optionally substituted by a group of the following chemical formula:

[0344] -L1-L Q1 -W1

[0345] Here,

[0346] L1 is absent or optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo, and is a (1-3C)alkylene;

[0347] L Q1 is absent or O, S, SO, SO2, N(R f), C(O), C(O)O, OC(O), C(O)N(R) f ), N(R f )C(O), N(R f )C(O)O, OC(O)N(R f ), S(O)2N(R f ), or N(R f Selected from )SO2, but R f and R g Each is independently selected from hydrogen or (1-2C)alkyl;

[0348] W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl, or heterocyclyl;

[0349] W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, cyano, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1, or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h Optionally substituted by one or more substituents selected from (where s is 1, 2, or 3); R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0350] R h and R iare connected to form a 4 to 7-membered heterocyclic ring selectively substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy, together with the nitrogen atoms to which they are attached;

[0351] Any alkyl, alkoxy, aryl, heteroaryl, heterocyclil, or cycloalkyl moiety among the substituents present in W1 is further optionally 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;

[0352] Any tertiary amine or nitrogen atom of the pyridyl ring present in the R3 group is optionally in the form of an N-oxide;

[0353] (43) R3 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, p is 0, 1, or 2), SO2N(R d )R c , N(R d )SO2R c , or (CH2) q NR c R dIt is a heterocyclile additionally optionally substituted by one or more substituents independently selected from (where q is 1, 2, or 3); R c , R d and R e Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0354] R c and R d are connected to form a 4 to 6-membered heterocyclic ring 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 hydroxyl, together with the nitrogen atoms to which they are attached;

[0355] R3 is optionally substituted by a group of the following chemical formula:

[0356] -L1-L Q1 -W1

[0357] Here,

[0358] L1 is an (1-3C)alkylene that is absent or optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0359] L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R) f ), N(R f )C(O), N(R f )C(O)O, OC(O)N(R f ), S(O)2N(R f ), or N(R f Selected from )SO2, but R f and R g Each is independently selected from hydrogen or (1-2C)alkyl;

[0360] W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl or heterocyclil; W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, cyano, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1, or 2), SO2N(R i )R h , N(R i )SO2R h or (CH2) s NR i R h Optionally substituted by one or more substituents selected from (where s is 1, 2, or 3); R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0361] R h and R i are connected to form a 4 to 7-membered heterocyclic ring selectively substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy, together with the nitrogen atoms to which they are attached;

[0362] Any alkyl, alkoxy, aryl, heteroaryl, heterocyclil, or cycloalkyl moiety among the substituents present in W1 is further optionally 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;

[0363] Any tertiary amine or nitrogen atom of the pyridyl ring present in the R3 group is optionally in the form of an N-oxide;

[0364] (44) R3 is a nitrogen-linked heterocycle selected from a 4 to 7-membered heterocyclic ring system, a 9 to 15-membered acyclic ring system or a 9 to 15-membered spirocyclic ring system;

[0365] R3 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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) is additionally optionally substituted by one or more substituents independently selected from; R c , R d and R eEach is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0366] R c and R d are connected to form a 4 to 6-membered heterocyclic ring 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 hydroxyl, together with the nitrogen atoms to which they are attached;

[0367] R3 is optionally substituted by a group of the following chemical formula:

[0368] -L1-L Q1 -W1

[0369] Here,

[0370] L1 is an (1-3C)alkylene that is absent or optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0371] L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R) f ), N(R f )C(O), N(R f )C(O)O, OC(O)N(R f ), S(O)2N(R f ), or N(R f Selected from )SO2, but R f and R g Each is independently selected from hydrogen or (1-2C)alkyl;

[0372] W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl or heterocyclil; W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, cyano, NR h R i , ORh , 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 Optionally substituted by one or more substituents selected from (where s is 1, 2, or 3); R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0373] R h and R i are connected to form a 4 to 7-membered heterocyclic ring selectively substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy, together with the nitrogen atoms to which they are attached;

[0374] Any alkyl, alkoxy, aryl, heteroaryl, heterocyclil, or cycloalkyl moiety among the substituents present in W1 is further optionally 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;

[0375] Any tertiary amine or nitrogen atom of the pyridyl ring present in the R3 group is optionally in the form of an N-oxide.

[0376] (45) R3 is a heterocyclile selected from piperazinyl, piperidinyl, pyrrolidinyl, oxetanil, morpholinyl, diazephanyl, azetidinyl, each of which may be additionally optionally substituted by one or more R6 groups; or R3 has one of the following structures:

[0377]

[0378]

[0379] Here, b is an integer selected from 0, 1, 2, 3, or 4;

[0380] Each R6 group is (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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 independently selected from the group of the following formula:

[0381] -L1-L Q1 -W1

[0382] Here, R c , R d and R e is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl, respectively; R c and R dare connected to form a 4 to 6-membered heterocyclic ring, 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, together with the nitrogen atoms to which they are attached;

[0383] L1 is an (1-3C)alkylene that is absent or optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo;

[0384] L Q1 is absent or O, S, SO, SO2, N(R f ), C(O), C(O)O, OC(O), C(O)N(R) f ), N(R f )C(O), N(R f )C(O)O, OC(O)N(R f ), S(O)2N(R f ), or N(R f Selected from )SO2, but R f and R g Each is independently selected from hydrogen or (1-2C)alkyl;

[0385] W1 is hydrogen, (1-4C)alkyl, aryl, heteroaryl or heterocyclil; W1 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, cyano, NR h R i , OR h , C(O)R h , C(O)OR h , OC(O)R h , C(O)N(R i )R h , N(R i )C(O)R h , S(O) r R h (where r is 0, 1, or 2), SO2N(R i )R h, N(R i )SO2R h or (CH2) s NR i R h Optionally substituted by one or more substituents selected from (where s is 1, 2, or 3); R h and R i Each is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl;

[0386] R h and R i are connected to form a 4 to 7-membered heterocyclic ring selectively substituted by one or more substituents selected from oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, amino, cyano, or hydroxy, together with the nitrogen atoms to which they are attached;

[0387] Any alkyl, alkoxy, aryl, heteroaryl, heterocyclil, or cycloalkyl moiety among the substituents present in W1 is further optionally 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;

[0388] Any tertiary amine or nitrogen atom of the pyridyl ring present in the R3 group is optionally in the form of an N-oxide.

[0389] (46) R3 is a heterocyclil selected from piperazinil, piperidinil, pyrrolidinil, oxetanil, morpholinil, diazephanil, azetidinil, or one of the following structures:

[0390]

[0391]

[0392] (47) R3 is a nitrogen-linked heterocycle selected from a heterocyclic ring system of 4 to 7 members, a bicyclic ring system of 9 to 15 members, or a spirocyclic ring system of 9 to 15 members;

[0393] R3 is oxo, (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, 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) is additionally optionally substituted by one or more substituents independently selected from;

[0394] R c , R d and R e is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl, respectively; R c and R d They are connected to form a 4 to 6-membered heterocyclic ring, 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 hydroxyl, together with the attached nitrogen atoms.

[0395] (48) R3 is a heterocyclile selected from piperazinyl, piperidinyl, pyrrolidinyl, oxetanil, morpholinyl, diazephanyl, azetidinyl, each of which may be additionally optionally substituted by one or more R6 groups; or R3 has one of the following structures:

[0396]

[0397] Here, b is an integer selected from 0, 1, 2, 3, or 4;

[0398] Each R6 group is (1-4C)alkyl, halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, NR c R d , OR c , C(O)R c , C(O)OR c , OC(O)R c , C(O)N(R d )R c , N(R d )C(O)R c , S(O) p R c (Here, p is 0, 1, or 2), SO2N(R d )R c , N(R d )SO2R c, or (CH2) q NR c R d Independently selected from (where q is 1, 2, or 3);

[0399] R c and R d is independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl, respectively; R c and R dare connected to form a 4 to 6-membered heterocyclic ring, 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, together with the nitrogen atoms to which they are attached;

[0400] Any tertiary amine present in the R3 group is optionally in the form of an N-oxide.

[0401] (49) R3 is piperazinil, piperidinil, pyrrolidinil, oxetanil, morpholinil, diazephanil, azetidinil, or a heterocyclil selected from one of the following structures:

[0402]

[0403] (50) A is selected from CR4 and N, and

[0404] R4 is hydrogen, halo, or halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, amino, cyano, (CH2) qa NR 4A R 4B , (CH2) qa OR 4A , (CH2) qa C(O)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 (Here, p is 0, 1, or 2), (CH2) qa SO2N(R 4B )R 4A , or (CH2) qa N(R 4B)SO2R 4A (1-2C)alkyl optionally substituted by one or more substituents selected from, wherein 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;

[0405] (51) A is selected from CR4 and N, and

[0406] R4 is a (1-2C)alkyl selectively substituted by one or more substituents selected from hydrogen, halo, or halo;

[0407] (52) A is selected from CR4 and N, and

[0408] R4 is hydrogen, methyl, or a haloim;

[0409] (53) A is derived from CR4, where R4 is hydrogen, methyl, fluoro, or chloro;

[0410] (54) A is CH;

[0411] (55) A is N.

[0412] Suitably, a heteroaryl or heterocyclil group as defined in this specification is a monocyclic heteroaryl or mono, bicyclic or cross-linked heterocyclil group comprising one, two, or three heteroatoms selected from N, O, or S.

[0413] Suitably, the heteroaryl is a 5- or 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from N, O, or S.

[0414] Suitably, the heterocyclil group is a 4, 5, 6, 7, or 8-membered heterocyclil ring comprising 1, 2, or 3 heteroatoms selected from N, O, or S. Most suitably, the heterocyclil group is a 5, 6, or 7-membered ring comprising 1, 2, or 3 heteroatoms selected from N, O, or S [e.g., morpholinyl (e.g., 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl, or pyrrolidinonyl].

[0415] Suitablely, the aryl group is phenyl.

[0416] Suitably, R0 is as defined in paragraph (1) or (2) above. In one embodiment, R0 is hydrogen. In another embodiment, R0 is deuterium.

[0417] Suitably, R1 is as defined in any one of paragraphs (3) through (17). More suitably, R1 is as defined in any one of paragraphs (13) through (17). Most suitably, R1 is as defined in paragraph (13) or (17).

[0418] Suitably, R2 is as defined in any one of paragraphs (18) through (31). More suitably, R2 is cyano or as defined in any one of paragraphs (25) through (31). Most suitably, R2 is as defined in paragraph (25) or (31).

[0419] Suitably, R3 is defined as in any one of paragraphs (32) through (49). More suitably, R3 is defined as in any one of paragraphs (35) through (40) (e.g., any one of paragraphs (35) through (39)). Most suitably, R2 is defined as in paragraph (39) or (40).

[0420] Suitably, A is as defined in any one of paragraphs (50) through (55). Most suitably, A is as defined in paragraphs (51), (54), or (55).

[0421] In a specific group of compounds of the above formula I, R1 is defined as in any one of paragraphs (3), (4), (5), (10), (13) or (17), and R0, R2, R3 and A each have any one of the definitions in this specification.

[0422] In a specific group of compounds of the above formula I, R2 is defined as in any one of paragraphs (18), (19), (20), (25), (29), (30) or (31), and R0, R1, R3 and A each have any one of the definitions in this specification.

[0423] In a specific group of compounds of the above formula I, R3 is defined as in any one of paragraphs (32), (33), (34), (35), (35a), (38), (39) or (40), and R0, R1, R2 and A each have any one of the definitions in this specification.

[0424] In a specific group of compounds of the above formula I, A is defined as in any one of paragraphs (50), (51), (54) or (55), and R0, R1, R2 and R3 each have any one of the definitions in this specification.

[0425] In one embodiment of the compound of the above chemical formula I:

[0426] R0 is as defined in paragraph (1) or (2);

[0427] R1 is as defined in paragraphs (3) through (17) above;

[0428] R2 is as defined in any one of paragraphs (18) to (31) above;

[0429] R3 is as defined in any one of paragraphs (32) to (49) above;

[0430] A is as defined in any one of paragraphs (50) to (55) above.

[0431] In a specific group of compounds of the above chemical formula I:

[0432] R0 is as defined in paragraph (1) or (2);

[0433] R1 is as defined in paragraphs (3) through (17) above;

[0434] R2 is as defined in any one of paragraphs (25) to (31) above;

[0435] R3 is as defined in any one of the above paragraphs (35) to (40);

[0436] A is as defined in any one of the above paragraphs (51), (54), or (55).

[0437] In a specific group of compounds of the above chemical formula I:

[0438] R0 is as defined in paragraph (1) or (2);

[0439] R1 is as defined in paragraph (5) above;

[0440] R2 is as defined in paragraph (19) above;

[0441] R3 is as defined in paragraph (33) above;

[0442] A is as defined in paragraph (51) above.

[0443] In a specific group of compounds of the above chemical formula I:

[0444] R0 is as defined in paragraph (1);

[0445] R1 is as defined in paragraph (10) above;

[0446] R2 is as defined in paragraph (20) above;

[0447] R3 is as defined in paragraph (34) above;

[0448] A is as defined in paragraph (51) above.

[0449] In a specific group of compounds of the above chemical formula I:

[0450] R0 is as defined in paragraph (1);

[0451] R1 is as defined in paragraph (13) above;

[0452] R2 is as defined in paragraph (25) above;

[0453] R3 is as defined in paragraph (35) or (35a) above;

[0454] A is as defined in paragraph (53) above.

[0455] In a specific group of compounds of the above chemical formula I:

[0456] R0 is as defined in paragraph (1);

[0457] R1 is as defined in paragraph (17) above;

[0458] R2 is as defined in paragraph (29) above;

[0459] R3 is as defined in paragraph (38) above;

[0460] A is as defined in paragraph (54) above.

[0461] In a specific group of compounds of the present invention, the compound has the structural formula Ib [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0462] [Chemical Formula Ib]

[0463]

[0464] Here, R0, R1, R2 and R3 are each as defined above, and R4 is hydrogen, methyl, fluoro, or chloro.

[0465] In one embodiment of a compound of chemical formula Ib:

[0466] R0 is as defined in paragraph (1) or (2);

[0467] R1 is as defined in any one of paragraphs (3) to (17) above;

[0468] R2 is as defined in any one of paragraphs (18) to (31) above;

[0469] R3 is as defined in any one of the above paragraphs (32) to (40);

[0470] R4 is hydrogen, methyl, fluoro, or chloro.

[0471] In one embodiment of a compound of chemical formula Ib:

[0472] R0 is as defined in paragraph (1) or (2);

[0473] R1 is as defined in any one of paragraphs (3) to (17) above;

[0474] R2 is as defined in any one of paragraphs (18) to (31) above;

[0475] R3 is as defined in any one of paragraphs (32) to (49) above;

[0476] R4 is hydrogen, methyl, fluoro, or chloro.

[0477] In another embodiment of a compound of chemical formula Ib:

[0478] R0 is as defined in paragraph (1) above;

[0479] R1 is as defined in paragraph (13) above;

[0480] R2 is as defined in paragraph (25) above;

[0481] R3 is as defined in paragraph (25) above;

[0482] R4 is hydrogen.

[0483] In another embodiment of a compound of chemical formula Ib:

[0484] R0 is as defined in paragraph (1) above;

[0485] R1 is as defined in paragraph (17) above;

[0486] R2 is as defined in paragraph (31) above;

[0487] R3 is as defined in paragraphs (38), (39) or (40) above;

[0488] R4 is hydrogen.

[0489] In another embodiment of a compound of chemical formula Ib:

[0490] R0 is as defined in paragraph (1) above;

[0491] R1 is as defined in paragraph (17) above;

[0492] R2 is as defined in paragraph (31) above;

[0493] R3 is as defined in the above paragraph (40);

[0494] R4 is hydrogen.

[0495] In a specific group of compounds of the present invention, the compound has the structural formula Ic [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0496] [Chemical Formula Ic]

[0497]

[0498] Here, R0, R1, R2 and R3 are each as defined above.

[0499] In one embodiment of a compound of chemical formula Ic:

[0500] R0 is as defined in paragraph (1) or (2);

[0501] R1 is as defined in any one of paragraphs (3) to (17) above;

[0502] R2 is as defined in any one of paragraphs (18) to (31) above;

[0503] R3 is as defined in any one of paragraphs (32) to (40) above.

[0504] In another embodiment of a compound of chemical formula Ic:

[0505] R0 is as defined in paragraph (1) or (2);

[0506] R1 is as defined in any one of paragraphs (3) to (17) above;

[0507] R2 is as defined in any one of paragraphs (18) to (31) above;

[0508] R3 is as defined in any one of paragraphs (32) to (49) above.

[0509] In another embodiment of a compound of chemical formula Ic:

[0510] R0 is as defined in paragraph (1) above;

[0511] R1 is as defined in paragraph (13) above;

[0512] R2 is as defined in paragraph (25) above;

[0513] R3 is as defined in paragraph (35) above.

[0514] In another embodiment of a compound of chemical formula Ic:

[0515] R0 is as defined in paragraph (1) above;

[0516] R1 is as defined in paragraph (17) above;

[0517] R2 is as defined in paragraph (31) above;

[0518] R3 is as defined in paragraphs (38), (39), or (40) above.

[0519] In another embodiment of a compound of chemical formula Ic:

[0520] R0 is as defined in paragraph (1) above;

[0521] R1 is as defined in paragraph (17) above;

[0522] R2 is as defined in paragraph (30) above;

[0523] R3 is as defined in paragraph (40) above.

[0524] In a specific group of compounds of the present invention, the compound has the structural formula Id [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0525] [Chemical Formula Id]

[0526]

[0527] Here, A, R1, R2 and R3 are each as defined above.

[0528] In one embodiment of a compound of chemical formula Id:

[0529] R1 is as defined in any one of paragraphs (3) to (17) above;

[0530] R2 is as defined in any one of paragraphs (18) to (31) above;

[0531] R3 is as defined in any one of the above paragraphs (32) to (40);

[0532] A is as defined in any one of paragraphs (50) to (55) above.

[0533] In one embodiment of a compound of chemical formula Id:

[0534] R1 is as defined in any one of paragraphs (3) to (17) above;

[0535] R2 is as defined in any one of paragraphs (18) to (31) above;

[0536] R3 is as defined in any one of paragraphs (32) to (49) above;

[0537] A is as defined in any one of paragraphs (50) to (55) above.

[0538] In another embodiment of a compound of the chemical formula Id:

[0539] R1 is as defined in paragraph (13) above;

[0540] R2 is as defined in paragraph (25) above;

[0541] R3 is as defined in paragraph (35) above;

[0542] A is as defined in paragraph (51) above.

[0543] In another embodiment of a compound of the chemical formula Id:

[0544] R1 is as defined in paragraph (17) above;

[0545] R2 is as defined in paragraph (31) above;

[0546] R3 is as defined in paragraphs (38), (39) or (40) above;

[0547] A is as defined in paragraph (54) or (55) above.

[0548] In another embodiment of a compound of the chemical formula Id:

[0549] R1 is as defined in paragraph (17) above;

[0550] R2 is as defined in paragraph (31) above;

[0551] R3 is as defined in the above paragraph (40);

[0552] A is as defined in paragraph (54) or (55) above.

[0553] In a specific group of compounds of the present invention, the compound has the structural formula Ie [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0554] [Chemical Formula Ie]

[0555]

[0556] Here, R0, R2, R3 and R 1z are as defined above, and m is 0, 1, or 2.

[0557] In one embodiment of a compound of chemical formula Ie:

[0558] R0 is as defined in paragraph (1) or (2) above;

[0559] R 1z is as defined in any one of paragraphs (3) to (10) above;

[0560] m is 0, 1, or 2, and;

[0561] R2 is as defined in any one of paragraphs (18) to (31) above;

[0562] R3 is as defined in any one of the above paragraphs (32) to (40);

[0563] A is as defined in any one of paragraphs (50) to (55) above.

[0564] In one embodiment of a compound of chemical formula Ie:

[0565] R0 is as defined in paragraph (1) or (2) above;

[0566] R 1z is as defined in any one of paragraphs (3) to (10) above;

[0567] m is 0, 1, or 2, and;

[0568] R2 is as defined in any one of paragraphs (18) to (31) above;

[0569] R3 is as defined in any one of paragraphs (31) to (49) above;

[0570] A is as defined in any one of paragraphs (50) to (55) above.

[0571] In another embodiment of a compound of chemical formula Ie:

[0572] R0 is as defined in paragraph (1) above;

[0573] R 1z is halo or cyano;

[0574] m is 0 or 1 and;

[0575] R2 is as defined in paragraph (25) above;

[0576] R3 is as defined in paragraph (35) above;

[0577] A is as defined in paragraph (51) above.

[0578] In another embodiment of a compound of chemical formula Ie:

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

[0580] R 1z is cyano and;

[0581] m is 1 and;

[0582] R1 is as defined in paragraph (17) above;

[0583] R2 is as defined in paragraph (31) above;

[0584] R3 is as defined in paragraphs (38), (39) or (40) above;

[0585] A is as defined in paragraph (54) or (55) above.

[0586] In another embodiment of a compound of chemical formula Ie:

[0587] R0 is as defined in paragraph (1) above;

[0588] R 1z is cyano and;

[0589] m is 1 and;

[0590] R2 is as defined in paragraph (31) above;

[0591] R3 is as defined in the above paragraph (40);

[0592] A is as defined in paragraph (54) or (55) above.

[0593] In a specific group of compounds of the present invention, the compound has the structural formula If [sub-definition of Chemical Formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0594] [Chemical Formula If]

[0595]

[0596] Here, A, R0, R2, R3 and R 1z Each is as defined above.

[0597] In one embodiment of a compound of the chemical formula If:

[0598] R0 is as defined in paragraph (1) or (2) above;

[0599] R 1z is as defined in any one of paragraphs (3) to (10) above;

[0600] R2 is as defined in any one of paragraphs (18) to (31) above;

[0601] R3 is as defined in any one of the above paragraphs (32) to (40);

[0602] A is as defined in any one of paragraphs (50) to (55) above.

[0603] In one embodiment of a compound of the chemical formula If:

[0604] R0 is as defined in paragraph (1) or (2) above;

[0605] R 1z is as defined in any one of paragraphs (3) to (10) above;

[0606] R2 is as defined in any one of paragraphs (18) to (31) above;

[0607] R3 is as defined in any one of paragraphs (32) to (49) above;

[0608] A is as defined in any one of paragraphs (50) to (55) above.

[0609] In another embodiment of the compound of the chemical formula If:

[0610] R0 is as defined in paragraph (1) above;

[0611] R 1z is halo or cyano;

[0612] R2 is as defined in paragraph (25) above;

[0613] R3 is as defined in paragraph (35) above;

[0614] A is as defined in paragraph (51).

[0615] In another embodiment of the compound of the chemical formula If:

[0616] R0 is as defined in paragraph (1) above;

[0617] R 1z is cyano and;

[0618] R2 is as defined in paragraph (31) above;

[0619] R3 is as defined in paragraphs (38), (39) or (40) above;

[0620] A is as defined in paragraph (54) or (55) above.

[0621] In another embodiment of the compound of the chemical formula If:

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

[0623] R 1z is cyano and;

[0624] R2 is as defined in paragraph (31) above;

[0625] R3 is as defined in the above paragraph (40);

[0626] A is as defined in paragraph (54) or (55) above.

[0627] In a specific group of compounds of the present invention, the compound has the structural formula Ig [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0628] [Chemical Formula Ig]

[0629]

[0630] Here, A, R0, R1, and R3 are each as defined above; R 200 and R 201 Each is independently selected from hydrogen, methyl, hydroxymethyl, halo, trifluoromethyl, difluoromethyl, methoxy, or acetyl. Suitably, R 200 and R 201 Each is independently selected from hydrogen, methyl, or halo.

[0631] In one embodiment of a compound of chemical formula Ig:

[0632] R0 is as defined in paragraph (1) or (2) above;

[0633] R1 is as defined in any one of paragraphs (3) to (17) above;

[0634] R3 is as defined in any one of paragraphs (32) to (49) above;

[0635] A is as defined in any one of paragraphs (50) through (55);

[0636] R 200 and R 201 Each is independently selected from hydrogen, methyl, hydroxymethyl, or halo.

[0637] In one embodiment of a compound of chemical formula Ig:

[0638] R0 is as defined in paragraph (1) or (2) above;

[0639] R1 is as defined in any one of paragraphs (3) to (17) above;

[0640] R3 is as defined in any one of the above paragraphs (32) to (40);

[0641] A is as defined in any one of paragraphs (50) through (55);

[0642] R 200 and R 201 Each is independently selected from hydrogen, methyl, hydroxymethyl, or halo.

[0643] In another embodiment of the compound of chemical formula Ig:

[0644] R0 is as defined in paragraph (1) above;

[0645] R1 is as defined in paragraph (13) above;

[0646] R2 is as defined in paragraph (25) above;

[0647] R3 is as defined in paragraph (35) above;

[0648] A is as defined in paragraph (51);

[0649] R 200 and R 201 Each is independently selected from methyl or chloro.

[0650] In another embodiment of the compound of chemical formula Ig:

[0651] R0 is as defined in paragraph (1) above;

[0652] R1 is as defined in paragraph (17) above;

[0653] R2 is as defined in paragraph (31) above;

[0654] R3 is as defined in paragraphs (38), (39) or (40) above;

[0655] A is as defined in paragraph (54) or (55);

[0656] R 200 is methyl and R 201 It is chloro or methyl.

[0657] In another embodiment of the compound of chemical formula Ig:

[0658] R0 is as defined in paragraph (1) above;

[0659] R1 is as defined in paragraph (17) above;

[0660] R2 is as defined in paragraph (31) above;

[0661] R3 is as defined in the above paragraph (40);

[0662] A is as defined in paragraph (54) or (55);

[0663] R 200 is methyl and R 201 It is chloro or methyl.

[0664] In a specific group of compounds of the present invention, the compound has the structural formula Ig2 [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0665] [Chemical Formula Ig2]

[0666]

[0667] Here, A, R0, R1, and R3 are each as defined above, and R 201 It is selected from hydrogen, methyl, halo, trifluoromethyl, difluoromethyl, methoxy, or acetyl.

[0668] In one embodiment of a compound of chemical formula Ig2:

[0669] In one embodiment of a compound of chemical formula Ig2:

[0670] R0 is as defined in paragraph (1) or (2) above;

[0671] R1 is as defined in any one of paragraphs (3) to (17) above;

[0672] R3 is as defined in any one of the above paragraphs (32) to (40);

[0673] A is as defined in any one of paragraphs (50) through (55);

[0674] R 201 It is selected from hydrogen, methyl, or halo.

[0675] In one embodiment of a compound of chemical formula Ig2:

[0676] R0 is as defined in paragraph (1) or (2) above;

[0677] R1 is as defined in any one of paragraphs (3) to (17) above;

[0678] R3 is as defined in any one of paragraphs (32) to (49) above;

[0679] A is as defined in any one of the above paragraphs (50) to (55);

[0680] R 201 It is selected from methyl, methoxy, or halo.

[0681] In another embodiment of the compound of chemical formula Ig2:

[0682] R0 is as defined in paragraph (1) above;

[0683] R1 is as defined in paragraph (13) above;

[0684] R3 is as defined in paragraph (35) above;

[0685] A is as defined in paragraph (51) above;

[0686] R 201 It is selected from methyl or halo.

[0687] In another embodiment of the compound of chemical formula Ig2:

[0688] R0 is as defined in paragraph (1) above;

[0689] R1 is as defined in paragraph (17) above;

[0690] R2 is as defined in paragraph (31) above;

[0691] R3 is as defined in paragraphs (38), (39) or (40) above;

[0692] A is as defined in paragraph (54) or (55) above;

[0693] R 201 It is selected from methyl or chloro.

[0694] In another embodiment of the compound of chemical formula Ig2:

[0695] R0 is as defined in paragraph (1) above;

[0696] R1 is as defined in paragraph (17) above;

[0697] R2 is as defined in paragraph (31) above;

[0698] R3 is as defined in the above paragraph (40);

[0699] A is as defined in paragraph (54) or (55) above;

[0700] R 201 It is selected from methyl or chloro.

[0701] In a specific group of compounds of the present invention, the compound has the structural formula Ih [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0702] [Chemical Formula Ih]

[0703]

[0704] Here, A, R0, R1 and R3 are each as defined above.

[0705] In one embodiment of a compound of chemical formula Ih:

[0706] R0 is as defined in paragraph (1) or (2) above;

[0707] R1 is as defined in any one of paragraphs (3) to (17) above;

[0708] R3 is as defined in any one of the above paragraphs (32) to (40);

[0709] A is as defined in any one of paragraphs (50) to (55).

[0710] In one embodiment of a compound of chemical formula Ih:

[0711] R0 is as defined in paragraph (1) or (2) above;

[0712] R1 is as defined in any one of paragraphs (3) to (17) above;

[0713] R3 is as defined in any one of paragraphs (32) to (49) above;

[0714] A is as defined in any one of paragraphs (50) to (55).

[0715] In another embodiment of a compound of chemical formula Ih:

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

[0717] R1 is as defined in paragraph (13) above;

[0718] R2 is as defined in paragraph (25) above;

[0719] R3 is as defined in paragraph (35) above;

[0720] A is as defined in paragraph (51).

[0721] In another embodiment of a compound of chemical formula Ih:

[0722] R0 is as defined in paragraph (1) above;

[0723] R1 is as defined in paragraph (17) above;

[0724] R2 is as defined in paragraph (31) above;

[0725] R3 is as defined in paragraphs (38), (39) or (40) above;

[0726] A is as defined in paragraph (54) or (55).

[0727] In another embodiment of a compound of chemical formula Ih:

[0728] R0 is as defined in paragraph (1) above;

[0729] R1 is as defined in paragraph (17) above;

[0730] R2 is as defined in paragraph (30) above;

[0731] R3 is as defined in paragraph (39) or (40) above;

[0732] A is as defined in paragraph (52) or (53).

[0733] In a specific group of compounds of the present invention, the compound has the structural formula Ih [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0734] [Chemical Formula Ih2]

[0735]

[0736] Here, A, R0, R1 and R3 are each as defined above.

[0737] In one embodiment of a compound of chemical formula Ih2:

[0738] R0 is as defined in paragraph (1) or (2) above;

[0739] R1 is as defined in any one of paragraphs (3) to (17) above;

[0740] R3 is as defined in any one of the above paragraphs (32) to (40);

[0741] A is as defined in any one of paragraphs (50) to (55) above.

[0742] In one embodiment of a compound of chemical formula Ih2:

[0743] R0 is as defined in paragraph (1) or (2) above;

[0744] R1 is as defined in any one of paragraphs (3) to (17) above;

[0745] R3 is as defined in any one of paragraphs (32) to (49) above;

[0746] A is as defined in any one of paragraphs (50) to (55).

[0747] In another embodiment of a compound of chemical formula Ih2:

[0748] R0 is as defined in paragraph (1) above;

[0749] R1 is as defined in paragraph (13) above;

[0750] R3 is as defined in paragraph (35) above;

[0751] A is as defined in paragraph (51) above.

[0752] In another embodiment of a compound of chemical formula Ih2:

[0753] R0 is as defined in paragraph (1) above;

[0754] R1 is as defined in any one of paragraphs (14) to (17) above;

[0755] R3 is as defined in paragraphs (38), (39) or (40) above;

[0756] A is as defined in paragraph (52) or (53) above.

[0757] In another embodiment of a compound of chemical formula Ih2:

[0758] R0 is as defined in paragraph (1) above;

[0759] R1 is as defined in paragraph (17) above;

[0760] R3 is as defined in paragraphs (38), (39) or (40) above;

[0761] A is as defined in paragraph (52) or (53) above.

[0762] In another embodiment of a compound of chemical formula Ih2:

[0763] R0 is as defined in paragraph (1) above;

[0764] R1 is as defined in paragraph (17) above;

[0765] R2 is as defined in paragraph (31) above;

[0766] R3 is as defined in the above paragraph (40);

[0767] A is as defined in paragraph (52) or (53).

[0768] In a specific group of compounds of the present invention, the compound has the structural formula Ii [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0769] [Chemical Formula II]

[0770]

[0771] Here, A, R0, R3 and R 1z Each is as defined above.

[0772] In one embodiment of a compound of chemical formula IIi:

[0773] R0 is as defined in paragraph (1) or (2) above;

[0774] R 1z is as defined in any one of paragraphs (3) to (10) above;

[0775] R3 is as defined in any one of paragraphs (32) to (49) above;

[0776] A is as defined in any one of paragraphs (50) to (55).

[0777] In one embodiment of a compound of chemical formula IIi:

[0778] R0 is as defined in paragraph (1) or (2) above;

[0779] R 1z is as defined in any one of paragraphs (3) to (10) above;

[0780] R3 is as defined in any one of the above paragraphs (32) to (40);

[0781] A is as defined in any one of paragraphs (50) to (55).

[0782] In another embodiment of the compound of chemical formula Ii:

[0783] R0 is as defined in paragraph (1) above;

[0784] R 1z is halo or cyano;

[0785] R3 is as defined in paragraph (35) above;

[0786] A is as defined in paragraph (51) above.

[0787] In another embodiment of the compound of chemical formula Ii:

[0788] R0 is as defined in paragraph (1) above;

[0789] R1z is cyano and;

[0790] R3 is as defined in paragraphs (38), (39) or (40) above;

[0791] A is as defined in paragraph (54) or (55) above.

[0792] In another embodiment of the compound of chemical formula Ii:

[0793] R0 is as defined in paragraph (1) above;

[0794] R 1z is cyano and;

[0795] R3 is as defined in the above paragraph (40);

[0796] A is as defined in paragraph (54) or (55) above.

[0797] In a specific group of compounds of the present invention, the compound has the structural formula Ii2 [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0798] [Chemical Formula II2]

[0799]

[0800] Here, A, R0, R3 and R 1z Each is as defined above.

[0801] In one embodiment of a compound of chemical formula Ii2:

[0802] R0 is as defined in paragraph (1) or (2) above;

[0803] R 1z is as defined in any one of paragraphs (3) to (10) above;

[0804] R3 is as defined in any one of the above paragraphs (32) to (40);

[0805] A is as defined in any one of paragraphs (50) to (55).

[0806] In one embodiment of a compound of chemical formula Ii2:

[0807] R0 is as defined in paragraph (1) or (2) above;

[0808] R 1z is as defined in any one of paragraphs (3) to (10) above;

[0809] R3 is as defined in any one of paragraphs (32) to (49) above;

[0810] A is as defined in any one of paragraphs (50) to (55).

[0811] In another embodiment of a compound of chemical formula Ii2:

[0812] R0 is as defined in paragraph (1) above;

[0813] R 1z is halo or cyano;

[0814] R3 is as defined in paragraph (35) above;

[0815] A is as defined in paragraph (51) above.

[0816] In another embodiment of a compound of chemical formula Ii2:

[0817] R0 is as defined in paragraph (1) above;

[0818] R 1z is cyano and;

[0819] R3 is as defined in paragraphs (38), (39) or (40) above;

[0820] A is as defined in paragraph (54) or (55) above.

[0821] In another embodiment of a compound of chemical formula Ii2:

[0822] R0 is as defined in paragraph (1) above;

[0823] R 1z is cyano and;

[0824] R3 is as defined in the above paragraph (40);

[0825] A is as defined in paragraph (54) or (55) above.

[0826] In a specific group of compounds of the present invention, the compound has the structural formula Ii3 [sub-definition of chemical formula I] shown below, or a pharmaceutically acceptable salt, hydrate, and / or solvate thereof:

[0827] [Chemical Formula Ii3]

[0828]

[0829] Here, A, R0, R3 and R 1z are each as defined above, and R 201 It is selected from hydrogen, methyl, hydroxymethyl, halo, trifluoromethyl, difluoromethyl, methoxy, or acetyl.

[0830] In one embodiment of a compound of chemical formula Ii2:

[0831] R0 is as defined in paragraph (1) or (2) above;

[0832] R 1z is as defined in any one of paragraphs (3) to (10) above;

[0833] R3 is as defined in any one of the above paragraphs (32) to (40);

[0834] A is as defined in any one of the above paragraphs (50) to (55);

[0835] R 201 It is selected from methyl, hydroxymethyl, halo, trifluoromethyl, difluoromethyl, methoxy, or acetyl.

[0836] In one embodiment of a compound of chemical formula Ii3:

[0837] R0 is as defined in paragraph (1) or (2) above;

[0838] R 1z is as defined in any one of paragraphs (3) to (10) above;

[0839] R3 is as defined in any one of paragraphs (32) to (49) above;

[0840] A is as defined in any one of the above paragraphs (50) to (55);

[0841] R 201 It is selected from methyl, hydroxymethyl, halo, trifluoromethyl, difluoromethyl, methoxy, or acetyl.

[0842] In another embodiment of the compound of chemical formula Ii3:

[0843] R0 is as defined in paragraph (1) above;

[0844] R 1z is halo or cyano;

[0845] R3 is as defined in paragraph (35) above;

[0846] A is as defined in the above paragraph (50);

[0847] R 201 It is selected from methyl, hydroxymethyl, halo, or methoxy.

[0848] In another embodiment of the compound of chemical formula Ii3:

[0849] R0 is as defined in paragraph (1) above;

[0850] R 1z is cyano and;

[0851] R3 is as defined in paragraphs (38), (39) or (40) above;

[0852] A is as defined in paragraph (54) or (55) above;

[0853] R 201 It is selected from methyl or chloro.

[0854] In another embodiment of the compound of chemical formula Ii3:

[0855] R0 is as defined in paragraph (1) above;

[0856] R 1z is cyano and;

[0857] R3 is as defined in the above paragraph (40);

[0858] A is as defined in paragraph (54) or (55) above;

[0859] R 201 It is selected from methyl or chloro.

[0860] Specific compounds of the present invention include any of the compounds described in the Examples section of this application, or pharmaceutically acceptable salts or solvates thereof, and specifically any of the following:

[0861] 3-[5-amino-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0862] 3-[5-amino-3-(1H-pyrazole-4-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[0863] 3-(5-amino-3-pyridazine-4-yl-pyrazolo[1,5-a]pyrimidine-2-yl)benzonitrile;

[0864] 3-[5-amino-3-(2-ethylpyrazole-3-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

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

[0866] 3-[5-amino-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0867] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0868] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-1-bicyclo[1.1.1]fentanyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0869] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0870] (3S)-4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]morpholine-3-carboxylic acid;

[0871] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-ethyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0872] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

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

[0874] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[3-(hydroxymethyl)-4-methyl-piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0875] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0876] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0877] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

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

[0879] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0880] 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]-2,2-dimethyl-propanoic acid;

[0881] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0882] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1,2-dimethyl-propyl]amino] pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0883] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3R,4R)-4-hydroxytetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

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

[0885] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0886] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-morpholinoethylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0887] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1,2-dimethyl-propyl]amino] pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0888] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[2-[2-(dimethylamino)ethyl]morpholine-4-yl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0889] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0890] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4H-1,2,4-triazole-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0891] (2R)-4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]morpholine-2-carboxylic acid;

[0892] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0893] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazolo [1,5-a]pyrimidine-2-yl]benzonitrile;

[0894] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1,1-dioxotian-4-yl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0895] 2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]acetamide;

[0896] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-piperazine-1-yl-pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0897] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[2-(dimethylamino)-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0898] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-hydroxy-pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0899] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1H-imidazole-2-ylmethylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0900] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-morpholino-pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0901] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]azetidine-2-carboxylic acid;

[0902] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]azetidine-3-carboxylic acid;

[0903] (3R)-1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]pyrrolidine-3-carboxylic acid;

[0904] 4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]piperazine-1-sulfonamide;

[0905] 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]bicyclo[1.1.1]pentane-1-carboxylic acid;

[0906] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2R)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0907] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0908] 3-[5-( tert- Butylamino)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0909] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0910] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-hydroxycyclopropyl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0911] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0912] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-morpholine-3-yl]methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0913] tert- Butyl (3R)-3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]morpholine-4-carboxylate;

[0914] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0915] tert- Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]piperidine-1-carboxylate;

[0916] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0917] tert- Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]pyrrolidine-1-carboxylate;

[0918] 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]oxazine-6-yl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0919] tert- Butyl rac-(4aS,7aS)-6-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate;

[0920] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-morpholine-3-yl]methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0921] tert- Butyl (3S)-3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]morpholine-4-carboxylate;

[0922] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[0923] tert- Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]pyrrolidine-1-carboxylate;

[0924] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0925] tert- Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]piperidine-1-carboxylate;

[0926] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]fentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

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

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

[0929] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

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

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

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

[0933] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholine-4-carbonyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0934] 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;

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

[0936] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

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

[0938] 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;

[0939] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

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

[0941] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxyoxetane-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

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

[0943] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

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

[0945] 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;

[0946] N-(4-aminonorbornan-1-yl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0947] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2S)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0948] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0949] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0950] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(1-methylazetidin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0951] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0952] 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;

[0953] N -(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo [1,5-a]pyrimidine-5-carboxamide;

[0954] N -(3-amino-1-bicyclo[1.1.1]fentanyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0955] tert- Butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-1-bicyclo[1.1.1]fentanyl]carbamate;

[0956] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[cis-(3S,4R)-4-hydroxypyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0957] tert- Butyl (3S,4R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate;

[0958] N -(2-amino-1,1-dimethyl-ethyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0959] tert- Butyl N -[2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-2-methyl-propyl]carbamate;

[0960] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0961] tert- Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]piperidine-1-carboxylate;

[0962] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[trans-(3S,4S)-4-hydroxypyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0963] tert- Butyl trans-(3S,4S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl) pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate;

[0964] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxypyrrolidin-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0965] tert- Butyl 3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]methyl]-3-hydroxy-pyrrolidine-1-carboxylate;

[0966] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0967] tert- Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]piperidine-1-carboxylate;

[0968] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-methylpyrrolidine-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0969] tert- Butyl 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-3-methyl-pyrrolidine-1-carboxylate;

[0970] 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;

[0971] 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;

[0972] 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;

[0973] tert- Butyl N-[1-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]methyl]-3,3-difluoro-cyclobutyl]carbamate;

[0974] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(morpholine-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0975] tert- Butyl 2-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino] methyl]morpholine-4-carboxylate;

[0976] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(piperazine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0977] tert- Butyl 4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]piperazine-1-carboxylate;

[0978] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0979] tert- Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]pyrrolidine-1-carboxylate;

[0980] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0981] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid;

[0982] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0983] 2-(3-cyanophenyl)-3-(2-ethylpyrazole-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazole[1,5-a]pyrimidine-5-carboxamide;

[0984] 2-(3-cyanophenyl)-3-(2-ethyl-5-methyl-pyrazole-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazole[1,5-a]pyrimidine-5-carboxamide;

[0985] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0986] 2-(3-cyanophenyl)-3-(2-ethyl-4-methyl-pyrazole-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazole[1,5-a]pyrimidine-5-carboxamide;

[0987] 2-(3-cyanophenyl)-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0988] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methylpyrazole-3-yl)pyrazole[1,5-a]pyrimidine-5-carboxamide;

[0989] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-pyrimidine-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0990] 3-cyano-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[0991] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0992] N -[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]methanesulfonamide;

[0993] ( 2S )-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]propanoic acid;

[0994] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile formate;

[0995] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0996] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0997] 3-[5-(aminomethyl)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0998] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[0999] 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1000] 3-[5-[(2-hydroxy-2-methyl-propyl)amino]-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1001] 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1002] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1003] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(dimethylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1004] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidyloxy)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1005] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-3-piperidyl]oxy]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1006] tert-Butyl (3R)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]oxypiperidin-1-carboxylate;

[1007] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3S)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1008] tert- Butyl (3S)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]oxypyrrolidin-1-carboxylate;

[1009] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-3-piperidyl]oxy]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1010] tert- Butyl (3S)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]oxypiperidin-1-carboxylate;

[1011] 3-[5-amino-3-(6-amino-5-methyl-3-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1012] 3-[5-amino-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1013] 3-[5-amino-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1014] 4-[5-amino-2-(3-cyanophenyl)pyrazolo [1,5-a]pyrimidine-3-yl]-6-methyl-pyridine-2-carbonitrile;

[1015] 3-[5-amino-3-(2-fluoro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1016] 3-[5-amino-3-(1-methylpyrazole-4-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1017] 3-[5-amino-3-(2,6-dimethyl-1-oxydo-pyridin-1-ium-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1018] 3-[5-amino-3-(2-amino-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1019] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-yl]-6-methyl-pyridine-2-carboxamide;

[1020] N -[4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-yl]-6-methyl-2-pyridyl]acetamide;

[1021] 3-[5-amino-3-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1022] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-yl]-6-methyl-pyridine-2-carboxylic acid;

[1023] 3-[5-amino-3-[2-(dimethylamino)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1024] [3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]urea;

[1025] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-(2-hydroxy-2-methyl-propyl)urea;

[1026] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-(1-ethyl-4-piperidyl)urea;

[1027] N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]piperazine-1-carboxamide;

[1028] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-[(3S)-pyrrolidin-3-yl]urea;

[1029] 1-(2-aminoethyl)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]urea;

[1030] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-[(3R)-pyrrolidine-3-yl]urea;

[1031] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-cyano-guanidine;

[1032] 3-[3-(2-ethylpyrazole-3-yl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1033] 3-[3-(2-ethylpyrazole-3-yl)-5-[3-(hydroxymethyl)-4-methyl-piperazine-1-yl]pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1034] 3-[3-(2-ethylpyrazole-3-yl)-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1035] 3-[3-(2-ethylpyrazole-3-yl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1036] 3-[3-(2-ethylpyrazole-3-yl)-5-(4-methylsulfonylpiperazine-1-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1037] 3-[3-(2-ethylpyrazole-3-yl)-5-(4H-1,2,4-triazole-3-ylmethylamino)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1038] 3-[3-(2-ethylpyrazole-3-yl)-5-piperazine-1-yl-pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1039] 3-[3-(2-ethylpyrazole-3-yl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1040] 5-(benzylamino)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1041] N-benzyl-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1042] 2-(2-furyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1043] tert- Butyl (2S)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]morpholine-4-carboxylate;

[1044] tert- Butyl (2R)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]pyrrolidine-1-carboxylate;

[1045] 5-[4-(2-fluoroethyl)piperazine-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1046] tert- Butyl (2S)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]pyrrolidine-1-carboxylate;

[1047] tert- Butyl (2R)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]morpholine-4-carboxylate;

[1048] 2-(2-furyl)-5-[4-(2-phenylethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1049] 2-(2-furyl)-5-[4-(2-pyridylmethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1050] 2-(2-furyl)-5-(4-methylpiperazine-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1051] 5-[(1-benzyl-4-piperidyl)methylamino]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1052] tert- Butyl (2R)-4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-methyl-piperazine-1-carboxylate;

[1053] tert- Butyl (2S)-4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-methyl-piperazine-1-carboxylate;

[1054] 5-[2-(4-benzylpiperazine-1-yl)ethylamino]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1055] 2-(2-furyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1056] 5-[4-(2-fluoroethyl)piperazine-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1057] 5-[3-(dimethylamino)azetidine-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1058] tert- Butyl 4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate;

[1059] 2-(2-furyl)-5-piperazine-1-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1060] 2-(2-furyl)-5-[[(2S)-morpholine-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1061] 2-(2-furyl)-5-[[(2R)-morpholine-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1062] 5-(4-benzylpiperazine-1-yl)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1063] N-benzyl-3-bromo-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1064] 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1065] 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1066] 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde;

[1067] N-benzyl-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1068] 5-amino-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1069] 3-Bromo-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1070] 2-(2-furyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1071] 2-(2-furyl)-5-[4-[(2,4,6-trifluorophenyl)methyl]piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1072] 2-(2-furyl)-5-[4-[(1-methylimidazole-2-yl)methyl]piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1073] 2-(2-furyl)-5-[4-(2-hydroxyethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1074] N-benzyl-2-(2-furyl)-3-(1-methylpyrazole-4-yl)pyrazole[1,5-a]pyrimidine-5-amine;

[1075] N-benzyl-2-(2-furyl)-3-(2-methylpyrazole-3-yl)pyrazole[1,5-a]pyrimidine-5-amine;

[1076] Methyl (E)-3-[5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-yl]prop-2-enoate;

[1077] (E)-3-[5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-yl]prop-2-enic acid;

[1078] 2-(2-furyl)-5-(4-phenylpiperazine-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1079] 2-(2-furyl)-5-(3-hydroxypropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1080] 2-(2-furyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1081] 2-(2-furyl)-5-(3-piperidylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile hydrochloride;

[1082] 5-(benzylamino)-2-oxazole-2-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1083] 5-(benzylamino)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1084] 2-(3-cyanophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1085] 2-(3-fluorophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1086] 5-[4-(2-fluoroethyl)piperazine-1-yl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1087] 5-[4-(2-fluoroethyl)piperazine-1-yl]-2-oxazole-5-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1088] 5-(benzylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1089] 5-(benzylamino)-2-(5-methyl-2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1090] 5-[4-[(3-methyl-2-pyridyl)methyl]piperazine-1-yl]-2-oxazole-5-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1091] N-benzyl-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1092] 2-(3-fluorophenyl)-N-[(3-methyl-2-pyridyl)methyl]pyrazolo[1,5-a]pyrimidine-5-amine;

[1093] 2-(3-fluorophenyl)-N-(2-phenylethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1094] N-(1H-benzimidazole-2-ylmethyl)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1095] 2-(3-fluorophenyl)-N-(2-isoindolin-2-ylethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1096] N-benzyl-3-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1097] 3-Bromo-5-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine;

[1098] N-benzyl-3-bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1099] 5-(benzylamino)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1100] 3-Bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1101] 5-amino-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1102] 2-(2-furyl)-N-(thiazole-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1103] [5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-yl]methanol;

[1104] 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;

[1105] N -Benzyl-2-(2-furyl)-3-iodo-pyrazolo[1,5-a]pyrimidine-5-amine;

[1106] 2-(2-furyl)-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1107] 2-(2-furyl)-5-[[(2R)-pyrrolidin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1108] 2-(2-furyl)-5-[[(2R)-1-methylpyrrolidine-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1109] 2-(2-furyl)-5-[(3R)-3-methylpiperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile hydrochloride;

[1110] tert- Butyl 4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]piperidine-1-carboxylate;

[1111] N-benzyl-7-(2-furyl)pyrazolo[1,5-a][1,3,5]triazine-2-amine;

[1112] N-benzyl-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1113] 2-(3-cyanophenyl)-5-[4-(2-fluoroethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1114] 2-(3-cyanophenyl)-5-[2-(4-phenylpiperazine-1-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1115] 3-(2-chloro-6-methyl-4-pyridyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1116] N- tert- Butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamidine;

[1117] 3-(2-amino-6-methyl-4-pyridyl)-N- tert- Butyl-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1118] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1119] 2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1120] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-1-bicyclo[1.1.1]fentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1121] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-5-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine;

[1122] N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-hydroxy-2-methyl-propanamide;

[1123] N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2,2-dimethyl-propanamide;

[1124] N-(3-amino-3-methyl-butyl)-2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide.

[1125] Additional compounds of the present invention, or pharmaceutical salts thereof, comprise the following:

[1126] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1127] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-[2-methyl-6-(trifluoromethyl)-4-pyridyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1128] 3-(2-chloro-6-methyl-4-pyridyl)-N-(1-cyano-1-methyl-ethyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1129] 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;

[1130] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-cyano-3-isopropyl-guanidine;

[1131] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1132] 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;

[1133] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxycyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1134] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1135] 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;

[1136] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1-methyl-2-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1137] 2-(3-cyanophenyl)-N-[(1S)-1,2-dimethylallyl]-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1138] N-(2-acetamido-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1139] N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1140] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1141] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1142] 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;

[1143] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1144] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1145] 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1146] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2-oxo-oxazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1147] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-methyl-5-oxo-pyrrolidin-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1148] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[1-(3-hydroxyoxetane-3-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1149] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-methyl-6-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1150] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-cyano-3-(2-hydroxy-2-methyl-propyl)guanidine;

[1151] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]fentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1152] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1153] 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;

[1154] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1155] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-methyl-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1156] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1157] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1158] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1159] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-3-methyl-cyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1160] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3R)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1161] 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;

[1162] N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-hydroxy-3-methyl-butanamide;

[1163] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1164] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[1-(2-hydroxyethyl)-4-piperidyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1165] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1166] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]guanidine;

[1167] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamidine;

[1168] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1169] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1170] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3S)-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1171] 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(1-methyl-2-oxo-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1172] N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-hydroxy-3-methyl-butanamide;

[1173] N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]acetamide

[1174] [2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-yl]urea;

[1175] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-hydroxyoxetane-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1176] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1177] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1178] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S,3S)-3-aminocyclopentyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1179] m-{4-[({[(3S)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1.5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraene-8-yl}benzonitrile;

[1180] 3-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1181] 3-(2-cyano-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1182] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(1R)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1183] N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-hydroxy-2-methyl-propanamide;

[1184] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(3S)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1185] 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1186] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-4-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1187] 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1188] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(5-oxopyrrolidine-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1189] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1190] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1191] m-[7-(2,6-dimethyl-4-pyridyl)-4-({[(5-oxo-3-pyrrolidinyl)methyl]amino}carbonyl)-1.5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraene-8-yl]benzonitrile;

[1192] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1193] m-{4-[({[(3R)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1.5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraene-8-yl}benzonitrile;

[1194] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazetidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1195] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-yl]-6-methyl-pyridine-2-carbonitrile;

[1196] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1197] 3-[5-[(1-acetyl-4-piperidyl)amino]-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1198] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(5-oxomorpholine-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1199] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1200] 1-(2-amino-2-methyl-propyl)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]urea.

[1201] Specific compounds of the present invention include any of the compounds described in the Examples section of this application, or pharmaceutically acceptable salts or solvates thereof, and specifically any of the following:

[1202] 3-[5-amino-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1203] 3-[5-amino-3-(1H-pyrazole-4-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1204] 3-(5-amino-3-pyridazine-4-yl-pyrazolo[1,5-a]pyrimidine-2-yl)benzonitrile;

[1205] 3-[5-amino-3-(2-ethylpyrazole-3-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1206] 3-[5-amino-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1207] 3-[5-amino-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1208] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1209] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-1-bicyclo[1.1.1]fentanyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1210] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1211] (3S)-4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]morpholine-3-carboxylic acid;

[1212] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-ethyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1213] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1214] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1215] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[3-(hydroxymethyl)-4-methyl-piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1216] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1217] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1218] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1219] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methylsulfonyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1220] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1221] 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]-2,2-dimethyl-propanoic acid;

[1222] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1223] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1,2-dimethyl-propyl]amino] pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1224] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3R,4R)-4-hydroxytetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1225] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(quinuclidin-3-ylamino)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1226] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxycyclobutyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1227] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-morpholinoethylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1228] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1,2-dimethyl-propyl]amino] pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1229] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[2-[2-(dimethylamino)ethyl]morpholine-4-yl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1230] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1231] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4H-1,2,4-triazole-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1232] (2R)-4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]morpholine-2-carboxylic acid;

[1233] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-tetrahydrofuran-3-yl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1234] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazolo [1,5-a]pyrimidine-2-yl]benzonitrile;

[1235] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1,1-dioxotian-4-yl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1236] 2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]acetamide;

[1237] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-piperazine-1-yl-pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1238] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[2-(dimethylamino)-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1239] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-hydroxy-pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1240] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1H-imidazole-2-ylmethylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1241] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-morpholino-pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1242] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]azetidine-2-carboxylic acid;

[1243] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]azetidine-3-carboxylic acid;

[1244] (3R)-1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]pyrrolidine-3-carboxylic acid;

[1245] 4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]piperazine-1-sulfonamide;

[1246] 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]bicyclo[1.1.1]pentane-1-carboxylic acid;

[1247] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2R)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1248] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1249] 3-[5-( tert- Butylamino)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1250] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1251] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-hydroxycyclopropyl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1252] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1253] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-morpholine-3-yl]methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1254] tert- Butyl (3R)-3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]morpholine-4-carboxylate;

[1255] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1256] tert- Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]piperidine-1-carboxylate;

[1257] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1258] tert- Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]pyrrolidine-1-carboxylate;

[1259] 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]oxazine-6-yl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1260] tert- Butyl rac-(4aS,7aS)-6-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2,3,4a,5,7,7a-hexahydropyrrolo[3,4-b][1,4]oxazine-4-carboxylate;

[1261] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-morpholine-3-yl]methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1262] tert-Butyl (3S)-3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]morpholine-4-carboxylate;

[1263] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1264] tert- Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]pyrrolidine-1-carboxylate;

[1265] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1266] tert- Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]piperidine-1-carboxylate;

[1267] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]fentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1268] N- tert- Butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1269] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1270] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1271] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[2-(4-phenylpiperazine-1-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1272] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(oxetane-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1273] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1274] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholine-4-carbonyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1275] 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;

[1276] N-(2-amino-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1277] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclopropyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1278] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1-hydroxycyclobutyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1279] 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;

[1280] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1281] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R)-2-hydroxy-1-methyl-ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1282] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxyoxetane-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1283] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-methylsulfonyl-pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1284] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1285] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxycyclobutyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1286] 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;

[1287] N-(4-aminonorbornan-1-yl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1288] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2S)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1289] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1290] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(2R)-2,3-dihydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1291] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(1-methylazetidin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1292] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1293] 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;

[1294] N -(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo [1,5-a]pyrimidine-5-carboxamide;

[1295] N -(3-amino-1-bicyclo[1.1.1]fentanyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1296] tert- Butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-1-bicyclo[1.1.1]fentanyl]carbamate;

[1297] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[cis-(3S,4R)-4-hydroxypyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1298] tert-Butyl (3S,4R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate;

[1299] N -(2-amino-1,1-dimethyl-ethyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1300] tert- Butyl N -[2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-2-methyl-propyl]carbamate;

[1301] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3S)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1302] tert- Butyl (3S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]piperidine-1-carboxylate;

[1303] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[trans-(3S,4S)-4-hydroxypyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1304] tert- Butyl trans-(3S,4S)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl) pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-4-hydroxy-pyrrolidine-1-carboxylate;

[1305] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-hydroxypyrrolidin-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1306] tert-Butyl 3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]methyl]-3-hydroxy-pyrrolidine-1-carboxylate;

[1307] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1308] tert- Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]piperidine-1-carboxylate;

[1309] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-methylpyrrolidine-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1310] tert- Butyl 3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-3-methyl-pyrrolidine-1-carboxylate;

[1311] 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;

[1312] 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;

[1313] 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;

[1314] tert-Butyl N-[1-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]methyl]-3,3-difluoro-cyclobutyl]carbamate;

[1315] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(morpholine-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1316] tert- Butyl 2-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino] methyl]morpholine-4-carboxylate;

[1317] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(piperazine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1318] tert- Butyl 4-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]piperazine-1-carboxylate;

[1319] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3R)-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1320] tert- Butyl (3R)-3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]pyrrolidine-1-carboxylate;

[1321] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1322] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid;

[1323] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1324] 2-(3-cyanophenyl)-3-(2-ethylpyrazole-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazole[1,5-a]pyrimidine-5-carboxamide;

[1325] 2-(3-cyanophenyl)-3-(2-ethyl-5-methyl-pyrazole-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazole[1,5-a]pyrimidine-5-carboxamide;

[1326] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1327] 2-(3-cyanophenyl)-3-(2-ethyl-4-methyl-pyrazole-3-yl)-N-(2-hydroxy-2-methyl-propyl)pyrazole[1,5-a]pyrimidine-5-carboxamide;

[1328] 2-(3-cyanophenyl)-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1329] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methylpyrazole-3-yl)pyrazole[1,5-a]pyrimidine-5-carboxamide;

[1330] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-pyrimidine-4-yl-pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1331] 3-cyano-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1332] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1333] N -[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]methanesulfonamide;

[1334] ( 2S )-2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]propanoic acid;

[1335] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile formate;

[1336] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1337] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(morpholinomethyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1338] 3-[5-(aminomethyl)-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1339] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(3-hydroxy-3-methyl-butyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1340] 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1341] 3-[5-[(2-hydroxy-2-methyl-propyl)amino]-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1342] 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1343] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1344] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(dimethylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1345] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidyloxy)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1346] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3R)-3-piperidyl]oxy]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1347] tert- Butyl (3R)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]oxypiperidin-1-carboxylate;

[1348] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3S)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1349] tert- Butyl (3S)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]oxypyrrolidin-1-carboxylate;

[1350] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(3S)-3-piperidyl]oxy]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1351] tert- Butyl (3S)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]oxypiperidin-1-carboxylate;

[1352] 3-[5-amino-3-(6-amino-5-methyl-3-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1353] 3-[5-amino-3-[2-(difluoromethyl)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1354] 3-[5-amino-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1355] 4-[5-amino-2-(3-cyanophenyl)pyrazolo [1,5-a]pyrimidine-3-yl]-6-methyl-pyridine-2-carbonitrile;

[1356] 3-[5-amino-3-(2-fluoro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1357] 3-[5-amino-3-(1-methylpyrazole-4-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1358] 3-[5-amino-3-(2,6-dimethyl-1-oxydo-pyridin-1-ium-4-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1359] 3-[5-amino-3-(2-amino-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1360] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-yl]-6-methyl-pyridine-2-carboxamide;

[1361] N -[4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-yl]-6-methyl-2-pyridyl]acetamide;

[1362] 3-[5-amino-3-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1363] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-yl]-6-methyl-pyridine-2-carboxylic acid;

[1364] 3-[5-amino-3-[2-(dimethylamino)-6-methyl-4-pyridyl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1365] [3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]urea;

[1366] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-(2-hydroxy-2-methyl-propyl)urea;

[1367] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-(1-ethyl-4-piperidyl)urea;

[1368] N -[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]piperazine-1-carboxamide;

[1369] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-[(3S)-pyrrolidin-3-yl]urea;

[1370] 1-(2-aminoethyl)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]urea;

[1371] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-[(3R)-pyrrolidine-3-yl]urea;

[1372] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-cyano-guanidine;

[1373] 3-[3-(2-ethylpyrazole-3-yl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1374] 3-[3-(2-ethylpyrazole-3-yl)-5-[3-(hydroxymethyl)-4-methyl-piperazine-1-yl]pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1375] 3-[3-(2-ethylpyrazole-3-yl)-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1376] 3-[3-(2-ethylpyrazole-3-yl)-5-(8-methyl-3,8-diazabicyclo[3.2.1]octane-3-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1377] 3-[3-(2-ethylpyrazole-3-yl)-5-(4-methylsulfonylpiperazine-1-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1378] 3-[3-(2-ethylpyrazole-3-yl)-5-(4H-1,2,4-triazole-3-ylmethylamino)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1379] 3-[3-(2-ethylpyrazole-3-yl)-5-piperazine-1-yl-pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1380] 3-[3-(2-ethylpyrazole-3-yl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazole[1,5-a]pyrimidine-2-yl]benzonitrile;

[1381] 5-(benzylamino)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1382] N-benzyl-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1383] 2-(2-furyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1384] tert- Butyl (2S)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]morpholine-4-carboxylate;

[1385] tert- Butyl (2R)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]pyrrolidine-1-carboxylate;

[1386] 5-[4-(2-fluoroethyl)piperazine-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1387] tert- Butyl (2S)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]pyrrolidine-1-carboxylate;

[1388] tert- Butyl (2R)-2-[[[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]morpholine-4-carboxylate;

[1389] 2-(2-furyl)-5-[4-(2-phenylethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1390] 2-(2-furyl)-5-[4-(2-pyridylmethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1391] 2-(2-furyl)-5-(4-methylpiperazine-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1392] 5-[(1-benzyl-4-piperidyl)methylamino]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1393] tert- Butyl (2R)-4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-methyl-piperazine-1-carboxylate;

[1394] tert- Butyl (2S)-4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-methyl-piperazine-1-carboxylate;

[1395] 5-[2-(4-benzylpiperazine-1-yl)ethylamino]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1396] 2-(2-furyl)-5-[(3-methyl-2-pyridyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1397] 5-[4-(2-fluoroethyl)piperazine-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1398] 5-[3-(dimethylamino)azetidine-1-yl]-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1399] tert- Butyl 4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate;

[1400] 2-(2-furyl)-5-piperazine-1-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1401] 2-(2-furyl)-5-[[(2S)-morpholine-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1402] 2-(2-furyl)-5-[[(2R)-morpholine-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1403] 5-(4-benzylpiperazine-1-yl)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1404] N-benzyl-3-bromo-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1405] 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1406] 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

[1407] 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde;

[1408] N-benzyl-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1409] 5-amino-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1410] 3-Bromo-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1411] 2-(2-furyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1412] 2-(2-furyl)-5-[4-[(2,4,6-trifluorophenyl)methyl]piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1413] 2-(2-furyl)-5-[4-[(1-methylimidazole-2-yl)methyl]piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1414] 2-(2-furyl)-5-[4-(2-hydroxyethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1415] N-benzyl-2-(2-furyl)-3-(1-methylpyrazole-4-yl)pyrazole[1,5-a]pyrimidine-5-amine;

[1416] N-benzyl-2-(2-furyl)-3-(2-methylpyrazole-3-yl)pyrazole[1,5-a]pyrimidine-5-amine;

[1417] Methyl (E)-3-[5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-yl]prop-2-enoate;

[1418] (E)-3-[5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-yl]prop-2-enic acid;

[1419] 2-(2-furyl)-5-(4-phenylpiperazine-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1420] 2-(2-furyl)-5-(3-hydroxypropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1421] 2-(2-furyl)-5-(2-hydroxyethylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1422] 2-(2-furyl)-5-(3-piperidylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile hydrochloride;

[1423] 5-(benzylamino)-2-oxazole-2-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1424] 5-(benzylamino)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1425] 2-(3-cyanophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1426] 2-(3-fluorophenyl)-5-[4-[(3-methyl-2-pyridyl)methyl]piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1427] 5-[4-(2-fluoroethyl)piperazine-1-yl]-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1428] 5-[4-(2-fluoroethyl)piperazine-1-yl]-2-oxazole-5-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1429] 5-(benzylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1430] 5-(benzylamino)-2-(5-methyl-2-furyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1431] 5-[4-[(3-methyl-2-pyridyl)methyl]piperazine-1-yl]-2-oxazole-5-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1432] N-benzyl-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1433] 2-(3-fluorophenyl)-N-[(3-methyl-2-pyridyl)methyl]pyrazolo[1,5-a]pyrimidine-5-amine;

[1434] 2-(3-fluorophenyl)-N-(2-phenylethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1435] N-(1H-benzimidazole-2-ylmethyl)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1436] 2-(3-fluorophenyl)-N-(2-isoindolin-2-ylethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1437] N-benzyl-3-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1438] 3-Bromo-5-chloro-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine;

[1439] N-benzyl-3-bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1440] 5-(benzylamino)-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1441] 3-Bromo-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1442] 5-amino-2-(3-fluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1443] 2-(2-furyl)-N-(thiazole-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1444] [5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-yl]methanol;

[1445] 5-(benzylamino)-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid;

[1446] N-Benzyl-2-(2-furyl)-3-iodo-pyrazolo[1,5-a]pyrimidine-5-amine;

[1447] 2-(2-furyl)-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1448] 2-(2-furyl)-5-[[(2R)-pyrrolidin-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1449] 2-(2-furyl)-5-[[(2R)-1-methylpyrrolidine-2-yl]methylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1450] 2-(2-furyl)-5-[(3R)-3-methylpiperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile hydrochloride;

[1451] tert- Butyl 4-[3-cyano-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-yl]piperidine-1-carboxylate;

[1452] N-benzyl-7-(2-furyl)pyrazolo[1,5-a][1,3,5]triazine-2-amine;

[1453] N-benzyl-2-(2-furyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1454] 2-(3-cyanophenyl)-5-[4-(2-fluoroethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1455] 2-(3-cyanophenyl)-5-[2-(4-phenylpiperazine-1-yl)ethylamino]pyrazolo[1,5-a]pyrimidine-3-carbonitrile;

[1456] 3-(2-chloro-6-methyl-4-pyridyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-5-amine;

[1457] N- tert- Butyl-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamidine;

[1458] 3-(2-amino-6-methyl-4-pyridyl)-N- tert- Butyl-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1459] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1460] 2-(3-cyanophenyl)-N-(2,3-dihydroxy-2-methyl-propyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1461] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-1-bicyclo[1.1.1]fentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1462] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-5-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine;

[1463] N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-hydroxy-2-methyl-propanamide;

[1464] N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2,2-dimethyl-propanamide;

[1465] N-(3-amino-3-methyl-butyl)-2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1466] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-1,1-dimethyl-ethyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1467] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-[2-methyl-6-(trifluoromethyl)-4-pyridyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1468] 3-(2-chloro-6-methyl-4-pyridyl)-N-(1-cyano-1-methyl-ethyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1469] 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;

[1470] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-cyano-3-isopropyl-guanidine;

[1471] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1472] 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;

[1473] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxycyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1474] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1475] 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;

[1476] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1-methyl-2-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1477] 2-(3-cyanophenyl)-N-[(1S)-1,2-dimethylallyl]-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1478] N-(2-acetamido-2-methyl-propyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1479] N-(3-amino-3-methyl-butyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1480] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(1-methyl-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1481] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1482] 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;

[1483] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1484] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(4-hydroxy-4-methyl-cyclohexyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1485] 3-[3-[2-(difluoromethyl)-6-methyl-4-pyridyl]-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1486] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2-oxo-oxazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1487] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-methyl-5-oxo-pyrrolidin-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1488] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[1-(3-hydroxyoxetane-3-yl)ethyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1489] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-methyl-6-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1490] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-cyano-3-(2-hydroxy-2-methyl-propyl)guanidine;

[1491] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]fentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1492] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1493] 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;

[1494] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3S,4S)-4-methoxy-1-methyl-pyrrolidin-3-yl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1495] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(3-methyl-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1496] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-(2-methoxy-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1497] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1498] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1499] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(3-hydroxy-3-methyl-cyclobutyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1500] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(3R)-3-piperidyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1501] 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;

[1502] N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-hydroxy-3-methyl-butanamide;

[1503] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyoxetane-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1504] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[1-(2-hydroxyethyl)-4-piperidyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1505] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxy-3-methyl-butyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1506] 1-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]guanidine;

[1507] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamidine;

[1508] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1509] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(5-oxopyrrolidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1510] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3S)-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1511] 3-[3-(2,6-dimethyl-4-pyridyl)-5-[(1-methyl-2-oxo-4-piperidyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1512] N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3-hydroxy-3-methyl-butanamide;

[1513] N-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]acetamide

[1514] [2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-yl]urea;

[1515] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3-hydroxyoxetane-3-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1516] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1517] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(2S)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1518] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S,3S)-3-aminocyclopentyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1519] m-{4-[({[(3S)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1.5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraene-8-yl}benzonitrile;

[1520] 3-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1521] 3-(2-cyano-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1522] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[rac-(1R)-2-hydroxy-1,2-dimethyl-propyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1523] N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-hydroxy-2-methyl-propanamide;

[1524] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[rac-(3S)-3-piperidyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1525] 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1526] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(2-oxo-4-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1527] 2-(3-cyanophenyl)-3-(3-fluoro-2,6-dimethyl-4-pyridyl)-N-[(4-methyl-2,5-dioxo-imidazolidin-4-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1528] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(5-oxopyrrolidine-3-yl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1529] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1530] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-3-(1-hydroxy-1-methyl-ethyl)piperazine-1-yl]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1531] m-[7-(2,6-dimethyl-4-pyridyl)-4-({[(5-oxo-3-pyrrolidinyl)methyl]amino}carbonyl)-1.5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraene-8-yl]benzonitrile;

[1532] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2-hydroxycyclobutyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1533] m-{4-[({[(3R)-5-oxo-3-pyrrolidinyl]methyl}amino)carbonyl]-7-(2,6-dimethyl-4-pyridyl)-1.5.9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraene-8-yl}benzonitrile;

[1534] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazetidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1535] 4-[5-amino-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-3-yl]-6-methyl-pyridine-2-carbonitrile;

[1536] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-imino-1-oxo-1,4-thiazinan-4-yl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1537] 3-[5-[(1-acetyl-4-piperidyl)amino]-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1538] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(5-oxomorpholine-2-yl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1539] 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3R)-pyrrolidin-3-yl]oxy-pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile;

[1540] 1-(2-amino-2-methyl-propyl)-3-[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]urea;

[1541] 3-[3-(2,6-dimethyl-4-pyridyl)-5-(2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1542] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1543] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[[(2R)-5-oxopyrrolidine-2-yl]methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1544] 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

[1545] 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;

[1546] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(6-oxo-3-piperidyl)methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1547] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1548] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1549] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1550] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3R,4R)-4-hydroxy-1-methyl-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1551] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[[(2S)-5-oxopyrrolidine-2-yl]methyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1552] 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(3S,4R)-4-hydroxy-1-methyl-pyrrolidin-3-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1553] 2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)-3-thiazole-5-yl-pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1554] 3-[5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1555] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(4-piperidyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1556] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(4-cyano-4-piperidyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1557] N-(4-carbamoyl-4-piperidyl)-3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide;

[1558] 3-[3-(2,6-dimethyl-4-pyridyl)-5-(piperazine-1-ylmethyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1559] 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;

[1560] 3-[3-(2,6-dimethyl-4-pyridyl)-5-(3-oxo-2,8-diazaspiro[4.5]decane-8-yl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1561] 3-[3-(2,6-dimethyl-4-pyridyl)-5-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile;

[1562] (2S)-N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propanamide;

[1563] N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide; and

[1564] 4-cyano-N-[2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-yl]-4-methyl-piperidine-1-carboxamide.

[1565] The various functional groups and substituents constituting the compound of Formula I are typically selected so that the molecular weight of the compound of Formula I does not exceed 1000. More generally, the molecular weight of the compound will be less than 900, e.g., less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, e.g., 550 or less.

[1566] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, for example, acid addition salts with inorganic acids or organic acids, for example, hydrochloric acid, hydrobromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonate or maleic acid. Additionally, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[1567] Compounds that have the same molecular formula but differ in the bonding properties or order of atoms, or in the arrangement of atoms in space, are called "isomers." Isomers that differ in the arrangement of atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereoisomers," and those whose mirror images do not overlap are called "enantiomers." If a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of the asymmetric center, described by Cahn and Prelog's R and S sequencing rules, or by the rotation of the molecule's plane of polarization, and are designated as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[1568] The compounds of the present invention may have one or more asymmetric centers; thus, such compounds may be produced as individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise indicated, the description or designation of a particular compound in the specification and claims is intended to include individual enantiomers and mixtures thereof, racemics, or anything else. Methods for the stereochemical determination and separation of stereoisomers, for example, by synthesis from optically active starting materials or by decomposition in racemic forms, are well known in the art (see the discussion in Chapter 4 of the literature ["Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001]). Some of the compounds of the present invention may have geometric isomer centers (E and Z isomers). The present invention should be understood to include all optical, diastereomers and geometric isomers and mixtures thereof having anti-inflammatory activity.

[1569] The present invention also comprises compounds of the present invention as defined herein, comprising one or more isotopic substitutions. For example, H may be any isotopic form including 1H, 2H(D), and 3H(T); C may be any isotopic form including 12C, 13C, and 14C; O may be any isotopic form including 16O and 18O, etc.

[1570] It should also be understood that a specific compound of Formula I may exist not only in a solvated form but also in a non-solvated form, e.g., a hydrated form. The present invention should be understood to include all such solvated forms having antiproliferative activity.

[1571] Specific compounds of Formula I may exhibit polymorphism, and the present invention should be understood to include all such forms having antiproliferative activity.

[1572] The compound of Formula I may exist in a number of different tautomeric forms, and references to the compound of Formula I include all of these forms. To avoid doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or indicated, all others are nevertheless included in Formula I. Examples of tautomeric forms include the keto-, enol-, and enolate- forms, as in tautomeric pairs such as keto / enol (described below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acine-nitro:

[1573]

[1574] Compounds of Formula I containing amine functional groups may also form N-oxides. References to compounds of Formula I containing amine functional groups in this specification also include N-oxides. If a compound contains multiple amine functional groups, one or more nitrogen atoms may be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of nitrogen atoms in tertiary amines or nitrogen-containing heterocycles. N-oxides may be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or pericylic acid (e.g., peroxycarboxylic acid), for example, see the literature [Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages]. More specifically, N-oxide can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent, such as dichloromethane.

[1575] The compound of Formula I may be administered in the form of a prodrug that decomposes in the human or animal body to release the compound of the present invention. The prodrug may be used to modify the physical and / or pharmacokinetic properties of the compound of the present invention. The prodrug may be formed when the compound of the present invention contains a suitable group or substituent to which a characteristic-modifier can be attached. Examples of prodrugs include an in vivo cleavable ester derivative that may be formed at the carboxyl or hydroxyl group of the compound of Formula I, and an in vivo cleavable amide derivative that may be formed at the carboxyl or amino group of the compound of Formula I.

[1576] Accordingly, the present invention comprises a compound of Formula I as defined above when made available by organic synthesis and when made available within the human or animal body through the cleavage of a prodrug. Accordingly, the present invention comprises a compound of Formula I produced by means of organic synthesis and also such a compound produced in the human or animal body through the metabolism of a precursor compound, that is, the compound of Formula I may be a compound produced by synthesis or a compound produced by metabolism.

[1577] A suitable pharmaceutically acceptable prodrug of the compound of Formula I is one that is suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity, based on reasonable medical judgment.

[1578] Various forms of prodrugs are listed below, for example:

[1579] document:-

[1580] a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

[1581] b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);

[1582] c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “and Application of Pro-drugs”91 (1991);

[1583] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[1584] e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

[1585] f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);

[1586] g) T. Higuchi and V. Stella, “as Novel Delivery Systems” and

[1587] h) E. Roche (editor), “Carriers in Drug Design”

[1588] Suitable pharmaceutically acceptable prodrugs for compounds of Formula I containing a carboxyl group are, for example, their in vivo cleavable esters. In vivo cleavable esters of compounds of Formula I containing a carboxyl group are, for example, pharmaceutically acceptable esters that are cleaved in the human or animal body to produce a parent acid. Suitable pharmaceutically acceptable esters for carboxyl are C1-6 alkyl esters, such as methyl, ethyl, and tert- Includes butyl, C1-6 alkoxymethyl esters, e.g., methoxymethyl ester, C1-6 alkanoyloxymethyl ester, e.g., pivaloyloxymethyl ester, 3-phthalidyl ester, C3-8 cycloalkylcarbonyloxy-C1-6 alkyl esters, e.g., cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolenylmethyl ester, e.g., 5-methyl-2-oxo-1,3-dioxolene-4-ylmethyl ester, and C1-6 alkoxycarbonyloxy-C1-6 alkyl esters, e.g., methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl ester.

[1589] Suitable pharmaceutically acceptable prodrugs of the compound of Formula I having a hydroxyl group are, for example, its in vivo cleavable esters or ethers. The in vivo cleavable esters or ethers of the compound of Formula I containing a hydroxyl group are, for example, pharmaceutically acceptable esters that are cleaved in the human or animal body to produce a parent hydroxyl compound. Pharmaceutically acceptable ester-forming groups suitable for the hydroxyl group include inorganic esters, such as phosphate esters (including phosphoramidic cyclic esters). Additional suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include C1-10 alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, and C1-10 alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C1-6)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-4alkyl)piperazine-1-ylmethyl. Pharmaceutically acceptable ether-forming groups suitable for the hydroxyl group include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl groups.

[1590] Suitable pharmaceutically acceptable prodrugs of a compound of formula I having a carboxyl group are, for example, amides that can be cleaved in vivo, for example, amines, e.g., ammonia; C1-4 alkylamines, e.g., methylamine; (C1-4 alkyl)2 amines, e.g., dimethylamine; N-ethyl-N-methylamine or diethylamine; C1-4 alkoxy-C2-4 alkylamines, e.g., 2-methoxyethylamine; phenyl-C1-4 alkylamines, e.g., benzylamine; and amides formed from amino acids, e.g., glycine or esters thereof.

[1591] Suitable pharmaceutically acceptable prodrugs of compounds of Formula I having amino groups are, for example, amide derivatives that can be cleaved in vivo. Suitable pharmaceutically acceptable amides from amino groups include, for example, amides formed from C1-10 alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-4alkyl)piperazine-1-ylmethyl.

[1592] The in vivo effect of the compound of Formula I may be partially exerted by one or more metabolites formed within the human or animal body after administration of the compound of Formula I. As mentioned above, the in vivo effect of the compound of Formula I may also be exerted through the metabolism of a precursor compound (prodrug).

[1593] The present invention may relate to any compound or a specific group of compounds defined herein by means of optional, preferred, or suitable features or otherwise in terms of specific embodiments, but the present invention may also relate to any compound or a specific group of compounds that specifically excludes said optional, preferred, or suitable features or specific embodiments.

[1594] Suitably, the present invention excludes any individual compound that does not have biological activity as defined herein.

[1595] synthesis

[1596] 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 following Examples section, and reaction schemes for preparing such compounds are shown in FIGS. 1 to 18. Referring to the attached drawings:

[1597] Figure 1 shows a reaction scheme for the preparation of a compound of formula I, wherein A is CH, R1 is 3-cyanophenyl; R2 is 2-chloro-6-methylpyridine-4-yl; and R3 is an amide linkage substituent represented by the formula -C(O)NRR (where each R is hydrogen or a substituent).

[1598] FIG. 2 shows the reaction scheme for the preparation of intermediate B (described in the attached Examples section).

[1599] Figure 3 shows a reaction scheme for the preparation of a compound of formula I, in which A is CH, R1 is 3-cyanophenyl; R2 is 2-chloro-6-methylpyridine-4-yl; and R3 is an amine linkage substituent represented by the formula -NH-R.

[1600] FIG. 4 shows a reaction scheme for the preparation of a compound of formula I, wherein A is CH, R1 is 3-cyanophenyl; R2 is a group as defined herein; and R3 is an amine group (which may further react to form an amine-linked substituent).

[1601] Figure 5 shows a reaction scheme for the preparation of a compound of formula I, in which A is CH, R1 is 3-cyanophenyl; R2 is 2-chloro-6-methylpyridine-4-yl; and R3 is a urea moiety of formula -NH-C(O)-NH2.

[1602] FIG. 6 shows the reaction scheme for the preparation of intermediate G (described in the attached Examples section).

[1603] FIG. 7 shows the reaction scheme for the preparation of the compounds of Examples 35 and 36 of the present specification.

[1604] Figure 8 shows the reaction scheme for the preparation of the compound of formula I, in addition to the intermediate compounds T, P, and R, where A is CH, R1 is furan-2-yl; R2 is cyano, and R3 is an amine linkage substituent represented by the formula -NH-R.

[1605] Figure 9 shows a reaction scheme for the preparation of a compound of formula I, in addition to the intermediate Q, where A is CH, R1 is furan-2-yl; R2 is Br, cyano or -C(O)NH2, and R3 is benzylamino.

[1606] FIG. 10 shows a reaction scheme for the preparation of a compound of formula I, in addition to the intermediate S, where A is CH, R1 is furan-2-yl; R2 is a group as defined in this specification; and R3 is benzylamino.

[1607] Figure 11 shows a reaction scheme for the preparation of a compound of formula I through intermediate X, in which A is CH, R1 is furan-2-yl; R2 is hydrogen; and R3 is benzylamino.

[1608] FIG. 12 shows a reaction scheme for the preparation of a compound of formula I, in addition to the intermediate U, where A is CH, R1 is as defined in this specification; R2 is cyano, and R3 is benzylamino.

[1609] Figure 13 shows a reaction scheme for the preparation of the compound of formula I, in addition to the intermediate compounds V and W, where A is CH, R1 is 3-fluorophenyl, R2 is cyano or bromo, and R3 is an amine linkage substituent represented by the formula -NHR.

[1610] FIG. 14 shows a reaction scheme for the preparation of a compound of Formula I, wherein A is CH, R1 is 4-fluorophenyl, R2 is as defined in this specification, and R3 is an amine linkage substituent represented by the formula "-NRR" (where each R is hydrogen or a substituent).

[1611] FIG. 15 shows a reaction scheme for the preparation of a compound of Formula I, in which A is CH, R1 is 3-cyanophenyl, R2 is 2,6-dimethylpyridine-4-yl, and R3 is an amide linkage substituent represented by the formula -C(O)-NRR (where each R is hydrogen or a substituent).

[1612] Figure 16 shows the reaction scheme for the preparation of intermediate compound Y.

[1613] Figure 17 shows the reaction scheme for the preparation of intermediate compound Z.

[1614] Figure 18 shows the reaction scheme for the preparation of the intermediate compound AB.

[1615] It should be understood that in the description of the synthesis method and any referenced synthesis method used to prepare the starting material described herein, all proposed reaction conditions, including the selection of solvent, reaction atmosphere, reaction temperature, duration of experiment, and post-treatment procedure, may be selected by those skilled in the art.

[1616] Those skilled in the art of organic synthesis understand that functional groups present in various parts of a molecule must be compatible with the reagents and reaction conditions used.

[1617] It will be understood that during the synthesis of the compounds of the present invention or during the synthesis of specific starting materials in the processes defined herein, it may be desirable to protect specific substituents to prevent their undesirable reactions. A skilled chemist will understand when such protection is necessary and how to place and later remove such protecting groups.

[1618] For examples of protecting groups, refer to one of the many general texts on the subject, for instance, 'Protective Groups in Organic Synthesis' by Theodora Green (Publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to a skilled chemist as appropriate for their removal, and such methods are selected to affect the removal of the protecting group while minimizing disturbance to groups elsewhere in the molecule.

[1619] Accordingly, if the reactant contains a group such as, for example, an amino, carboxyl, or hydroxyl group, it may be desirable to protect the group in some reactions mentioned herein.

[1620] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, for example, alkanoyyl groups, such as acetyl; alkoxycarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups, for example, benzyloxycarbonyl; or aroyl groups, for example, benzoyl. The conditions for deprotection of the protecting group inevitably vary depending on the choice of protecting group. Thus, acyl groups, such as alkanoyyl or alkoxycarbonyl groups or aroyl groups, for example, can be removed by hydrolysis using a suitable base, such as an alkali metal hydroxide, for example, lithium hydroxide or sodium hydroxide. Alternatively, tertAcyl groups such as butoxycarbonyl groups can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed by hydrogenation on a catalyst such as palladium carbonate, for example, or by treatment with a Lewis acid, for example, boron tris(trifluoroacetate). A suitable alternative protecting group for the primary amino group is a phthaloyl group, which can be removed by treatment with an alkylamine, for example, dimethylaminopropylamine, or hydrazine.

[1621] Suitable protecting groups for the hydroxyl group are, for example, acyl groups, for example, alkanoyyl groups, such as acetyl; aroyl groups, for example, benzoyl; or arylmethyl groups, for example, benzyl. The conditions for deprotection of the protecting group will inevitably vary depending on the choice of protecting group. Thus, for example, acyl groups, such as alkanoyyl or aroyl groups, can be removed by hydrolysis using a suitable base, such as an alkali metal hydroxide, for example, lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed by hydrogenation on a catalyst, for example, palladium carbonate.

[1622] Suitable protecting groups for the carboxyl group are, for example, esterifying groups, such as methyl or ethyl groups that can be removed by hydrolysis with a base such as sodium hydroxide, for example, or t-butyl groups that can be removed by treatment with an acid, for example, an organic acid such as trifluoroacetic acid, for example, or benzyl groups that can be removed by hydrogenation on a catalyst such as palladium carbonate.

[1623] Resin can also be used as a protector.

[1624] The methodology used to synthesize the compounds of Formula I will vary depending on the properties of A, R1, R2, and R3 and any associated substituents. Processes suitable for their preparation are further described in the attached examples.

[1625] When a compound of Formula I is synthesized by any one of the processes defined herein, the process may further include one or more of the following additional steps:

[1626] (i) Step to remove existing protectors;

[1627] (ii) a step of converting a compound of formula I into another compound of formula I;

[1628] (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate of the compound of formula I; and / or

[1629] (iv) A step of forming a precursor drug of the compound of chemical formula I.

[1630] The example of (ii) above provides a compound of formula I that is synthesized, and then one or more of the groups of A, R1, R2, or R3 are further reacted to change the properties of the groups and provide an alternative compound of formula I.

[1631] The compound of chemical formula I produced can be separated and purified using techniques well known in the art.

[1632] A specific compound of Formula I defined in this specification can be prepared by the following:

[1633] (i) Step of reacting the compound of formula IIa

[1634] [Chemical Formula IIa]

[1635]

[1636] (where A, R0, R1 and R2 are each as defined above, and X1 is a suitable leaving group (e.g., bromo, chloro, iodo, -SMe, -S(O)Me or -S(O)2Me);

[1637] Step of reacting with [R3-X2]-H (where X2 is N, S, or O and [R3-X2] represents an R3 group as defined above connected together through X2 atoms).

[1638] It can be manufactured by;

[1639] Optionally, thereafter, the above process may further include one or more of the following additional steps:

[1640] (i) a step of removing any possible protectors;

[1641] (ii) a step of converting the compound of Formula I into another compound of Formula I (e.g., converting an R3 substituent to another R3 substituent as defined herein);

[1642] (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate of the compound of formula I; and / or

[1643] (iv) A step of forming a precursor drug of the compound of chemical formula I.

[1644] To avoid any doubt, the X2 atom is a heteroatom existing in the R3 group, that is, [R3-X2] is the R3 group containing the X2 heteroatom.

[1645] In the above reaction, it will be understood that when the compound of formula II reacts with the [R3-X2]-H group, the X1 group is replaced along with the atom of the [R3-X2]-H group, and the R3 substituent is bonded to the compound of formula II through the X2 atom.

[1646] A person skilled in the art will be able to easily select reaction conditions suitable for the reaction between the compound of Formula II and the [R3-X2]-H group. Examples of suitable reaction conditions are described in the appended Examples section of this specification.

[1647] The compound of Formula II can be prepared by suitable techniques known in the art, as will be apparent from the attached Examples section. Specific examples of the preparation of the compound of Formula II are described in the attached Examples section of this specification.

[1648] Compounds of Formula I can also be prepared by Suzuki-Miyaura or Stille coupling reactions. For example, specific compounds of Formula I defined herein can also be prepared by the following:

[1649] (i) Compound of Chemical Formula III

[1650] [Chemical Formula III]

[1651]

[1652] (Here, A, R0, R2, and R3 are each as defined above, and X3 is a halo atom (e.g., bromo, chloro, or iodine);

[1653] The formula of the following chemical formula

[1654] R1-M

[1655] (Here, M is a coupling reagent (e.g., a boron coupling agent or a tin coupling agent as defined herein) and R1 is as defined above)

[1656] A step of reacting with; or

[1657] (ii) Compound of Chemical Formula IV

[1658] [Chemical Formula IV]

[1659]

[1660] (Here, A, R0, R1, and R3 are each as defined above, and X3 is a halo atom (e.g., bromo, chloro, or iodine);

[1661] The formula of the following chemical formula

[1662] R2-M

[1663] (Here, M is a coupling reagent (e.g., a boron coupling agent or a tin coupling agent as defined herein) and R2 is as defined above)

[1664] A step of reacting with; or

[1665] (iii) Compound of formula V

[1666] [Chemical Formula V]

[1667]

[1668] (Here, A, R0, R1, and R2 are each as defined above, and X3 is a halo atom (e.g., bromo, chloro, or iodine);

[1669] The formula of the following chemical formula

[1670] R3-M

[1671] (Here, M is a coupling reagent (e.g., a boron coupling agent or a tin coupling agent as defined herein) and R3 is as defined above)

[1672] The step of reacting with

[1673] It can be manufactured by;

[1674] Optionally, thereafter, the above process may further include one or more of the following additional steps:

[1675] (i) a step of removing any possible protectors;

[1676] (ii) a step of converting a compound of formula I into another compound of formula I;

[1677] (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate of the compound of formula I; and / or

[1678] (iv) A step of forming a precursor drug of the compound of chemical formula I.

[1679] The M group may be a suitable boron coupling reagent known in the art for the Suzuki-Miyaura coupling reaction. Examples of suitable boron agents include boric acid, boric acid esters (e.g., catechol boric acid ester, pinacol boric acid ester, triisopropyl boronate, MIDA boronate, cyclic triol boronate), borane (e.g., 9-BBN boran), organotrifluoroborate, or boronamide (e.g., 1,8-daaminonaphthyl boronamide). Specific examples include -B(OH)2 or -B(OCH3)2.

[1680] The Suzuki-Miyaura coupling reaction is well known, and those skilled in the art will be able to easily select reaction conditions suitable for this reaction.

[1681] In the Stille coupling reaction, M is a tin coupling agent, suitably a tin coupling agent of the chemical formula -Sn[(1-6C)alkyl]3, e.g. -Sn(butyl)3.

[1682] The Stille coupling reaction is well known, and those skilled in the art will be able to easily select reaction conditions suitable for this reaction. Such reactions are typically carried out in the presence of a palladium catalyst.

[1683] biological activity

[1684] The pharmacological effects of the compounds of the present invention can be measured using the biological analysis described in the Examples section (Biological Examples 1 to 3).

[1685] Although the pharmacological properties of the compound of Formula I vary depending on structural changes, as expected, the compound of the present invention was found to be active in the analysis described in biological Examples 1, 2, and 3.

[1686] Generally, regarding adenosine A2a antagonism, the compound of the present invention has an IC50 of 1 μM or less in the analysis described in Biological Example 1. 50 Representing, the preferred compound of the present invention has an IC of 200 nM or less. 50 It indicates that the most preferred compound of the present invention has an IC of 50 nM or less. 50 It represents.

[1687] Suitably, the IC50 of the compound of the present invention at adenosine A1, A2b, or A3 receptors in the analysis described in Biological Example 1. 50 IC at adenosine A2a receptors 50 At least 2 times higher than, more appropriately at least 5 times higher, and much more appropriately at least 10 times higher.

[1688] Pharmaceutical composition

[1689] According to a further aspect of the present invention, a pharmaceutical composition is provided comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, together with a pharmaceutically acceptable diluent or carrier.

[1690] The composition of the present invention may be in a form suitable for oral use (e.g., as a tablet, lozenge, hard or soft capsule, aqueous or oily suspension, emulsion, dispersible powder or granule, syrup or elixir), topical use (e.g., as a cream, ointment, gel, or aqueous or oily solution or suspension), administration by inhalation (e.g., as a fine powder or liquid aerosol), administration by aspiration (e.g., as a fine powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[1691] The composition of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Accordingly, a composition intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[1692] An effective amount of the compound of the present invention for use in treatment is sufficient to treat or prevent the proliferative pathological condition mentioned herein and / or slow its progression and / or reduce symptoms associated with said pathological condition.

[1693] The amount of active ingredient combined with one or more excipients to produce a single dosage form will inevitably vary depending on the individual being treated and the specific route of administration. For example, a formulation intended for oral administration to humans will generally contain 0.5 mg to 0.5 g (more suitably 0.5 to 100 mg, e.g., 1 to 30 mg) of active ingredient combined with appropriate and convenient amounts of excipients, which may vary from about 5 to about 98 weight percent of the total composition.

[1694] The dosage of the compound of Formula I for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the pathological condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[1695] When the compounds of the present invention are used for therapeutic or prophylactic purposes, they will generally be administered at a daily dose, for example, in the range of 0.1 mg / kg to 75 mg / kg body weight, and provided in divided doses if necessary. Generally, lower doses will be administered when a parenteral route is used. Thus, for example, in the case of intravenous or intraperitoneal administration, doses in the range of 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, in the case of administration by inhalation, doses in the range of 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration in the form of tablets may also be particularly suitable. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compounds of the present invention.

[1696] Therapeutic Uses and Applications

[1697] The present invention provides a compound that functions as an antagonist to an adenosine A2 receptor, particularly an adenosine A2a receptor.

[1698] According to a further aspect of the present invention, a method for antagonizing an adenosine A2a receptor in vitro or in vivo is provided, the method comprising the step of contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1699] According to a further aspect of the present invention, a method for selectively antagonizing an adenosine A2a receptor in vitro or in vivo is provided, the method comprising the step of contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1700] According to a further aspect of the present invention, a method for inhibiting cell proliferation in vitro or in vivo is provided, the method comprising the step of contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 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).

[1701] According to a further aspect of the present invention, a method for treating a disease or disorder involving adenosine A2a receptor activity in a patient requiring treatment is provided, the method comprising the step of 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.

[1702] According to a further aspect of the present invention, a method for treating a proliferative disorder in a patient requiring treatment is provided, the method comprising the step of 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).

[1703] According to a further aspect of the present invention, a method for treating cancer in a patient requiring treatment is provided, the method comprising the step of 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).

[1704] According to a further aspect of the present invention, a compound as defined herein for therapeutic use, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition is provided.

[1705] According to a further aspect of the present invention, a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein is provided for use in the treatment of proliferative conditions. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1706] According to a further aspect of the present invention, a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition is provided for use in the treatment of cancer. In a specific embodiment, the cancer is 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).

[1707] According to a further aspect of the present invention, a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided for use as an adenosine A2a antagonist. In one embodiment, the compound of the present invention is a selective adenosine A2a antagonist. In an alternative embodiment, a specific compound of the present invention is a selective adenosine A2a and adenosine A2b antagonist.

[1708] According to a further aspect of the present invention, a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided for use in the treatment of a disease or disorder associated with adenosine A2a.

[1709] According to a further aspect of the present invention, the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided in the preparation of a drug for the treatment of proliferative conditions. Suitably, the compound or pharmaceutical composition is administered in combination with one or more additional antiproliferative agents (e.g., checkpoint inhibitors and / or cytotoxic agents).

[1710] According to a further aspect of the present invention, the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided in the manufacture of a drug for the treatment of cancer. Suitably, the cancer is 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).

[1711] According to a further aspect of the present invention, the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided in the preparation of a drug for use as an adenosine A2a antagonist.

[1712] According to a further aspect of the present invention, the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is provided in the preparation of a drug for the treatment of a disease or disorder associated with adenosine A2a receptor activity.

[1713] The term “proliferative disorder” is used interchangeably herein and relates to unwanted or uncontrolled cell proliferation of undesirable, excessive, or abnormal cells, such as neoplasms or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cell proliferation, including but not limited to malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., connective tissue), and atherosclerosis. Any type of cell, including but not limited to the lungs, colon, breast, ovary, prostate, liver, pancreas, brain, and skin, may be treated.

[1714] The antiproliferative effect of the compound of the present invention is particularly applicable to the treatment of human cancer (due to its adenosine A2a antagonist activity).

[1715] More specifically, a compound of general formula I is provided for use in the treatment of cancer, particularly solid tumors, e.g., non-small cell or small cell lung cancer, head and neck squamous carcinoma and urothelial carcinoma.

[1716] More specifically, a compound of general formula I is provided for use in the treatment of cancer, for example, lung cancer, such as small cell lung cancer or non-small cell lung cancer.

[1717] In addition, the use of a compound of general formula I is provided in the manufacture of a drug for the treatment of cancer, particularly solid tumors, e.g., non-small cell or small cell lung cancer, head and neck squamous carcinoma, and urothelial carcinoma.

[1718] The present invention further provides a method for treating cancer, particularly solid tumors, e.g., non-small cell or small cell lung cancer, head and neck squamous carcinoma and urothelial carcinoma, the method comprising the step of administering an effective amount of a compound of general formula I to a patient requiring such treatment.

[1719] The patient to be treated is, suitablely, a mammal, and more suitablely, a human.

[1720] Route of administration

[1721] The compounds of the present invention or pharmaceutical compositions comprising these compounds can be administered to a subject by any convenient route of administration, regardless of whether it is systemic, peripheral, or local (i.e., desired site of action).

[1722] Routes of administration include, but are not limited to: oral (e.g., ingestion); buccal; sublingual; transdermal (e.g., via patches, plasters, etc.); transmucosal (e.g., via patches, plasters, etc.); intranasal (e.g., via nasal sprays); ocular (e.g., via eye drops); pulmonary (e.g., via aerosols, e.g., via inhalation or ventilation therapy used through the mouth or nose); rectal (e.g., via suppositories or enemas); vaginal (e.g., via pessaries); parenteral, e.g., by injection including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, intrasternal, and intratumoral; e.g., by implantation of a depot or reservoir subcutaneously or intramuscularly.

[1723] The compounds of the present invention or pharmaceutical compositions containing these compounds can be administered by intratumoral delivery.

[1724] Combination therapy

[1725] Compounds of Formula I are useful for the treatment and / or prevention of proliferative disorders, such as cancer, for example. Compounds of Formula I as defined herein may be used in combination with one or more additional antiproliferative / anticancer therapies, such as chemotherapy using one or more additional antiproliferative / anticancer agents, radiation therapy, and / or conventional surgery, for example.

[1726] An additional antiproliferative / anticancer agent may be included in the pharmaceutical composition together with the compound of Formula I as defined herein, or alternatively, it may be administered separately, either simultaneously with or earlier than the compound of Formula I.

[1727] Accordingly, in a further aspect of the present invention, a product is provided comprising a compound of general formula I and an additional agent useful for the treatment or prevention of cancer as a combination formulation for simultaneous, sequential, or separate use in the treatment of cancer.

[1728] The present invention also provides a compound of general formula I combined with one or more additional antiproliferative / anticancer agents for use in cancer treatment as a combination formulation for simultaneous, sequential, or separate use in the treatment of cancer.

[1729] Specifically, the combination therapy defined in this specification is suitable for the treatment of solid tumors, for example, non-small cell or small cell lung cancer, head and neck squamous carcinoma, and urothelial carcinoma.

[1730] Suitable additional antiproliferative / anticancer agents that may be used in combination with the compound of Formula I defined herein [separately, or as part of a combined pharmaceutical composition or a formulation in combination with a compound of Formula I] include the following:

[1731] 1) Other forms of cancer immunotherapy and anticancer chemotherapy agents;

[1732] 2) Adenosine pathway modulators including, but not limited to, A2b antagonists, CD73 inhibitors, and CD39 inhibitors;

[1733] 3) Anti-PD-1 and PDL-1 antibodies including, but not limited to, setrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab; and

[1734] 4) Anti-CTLA4 antibodies including, but not limited to, ipilimumab.

[1735] The compound of Formula I defined in this specification is particularly suitable for use in combination with anti-PD-1 and PDL-1 antibodies, including but not limited to setrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab.

[1736] Suitably, the anti-PD1 antibody is one of the antibodies disclosed in U.S. Publication No. 2019 / 0225689 or U.S. Publication No. 2017 / 0121409 (in its entirety incorporated herein by reference), such as setrelimab. Setrelimab (JNJ-63723283, CET) is a fully human immunoglobulin (Ig) G4 kappa monoclonal antibody that binds to programmed death receptor-1 (PD-1) with high affinity and specificity. Setrelimab has demonstrated activity in solid tumors. Rutkowski P, et al. Journal of Clinical Oncology. 2019;37(8):31.

[1737] The compound of Formula I defined in this specification is particularly suitable for use in combination with adenosine pathway modulators, including but not limited to A2b antagonists, CD73 inhibitors, and CD39 inhibitors.

[1738] A2a antagonists of general chemical formula I can also be used in combination with cell-based immunotherapies and cancer vaccines, including but not limited to CAR-T cell therapy.

[1739] Examples of additional antiproliferative / anticancer chemotherapy agents include, but are not limited to, any one or more of the following:

[1740] MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1 120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD3 18088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosourea, nitrogen mustard (e.g., mechloroethamine, cyclophosphamide, Chlorambucil, Mayphalan), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozosin), triagens (decarbazine)), anti-metabolites (e.g., 5-azathiophrine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexid, raltitrexid, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, fluorouridine, cytarabine), purine analogs (e.g., mercaptopurines, thioguanine, pentostatin) etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindecin, Podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrin, etoposide (VP16), etoposide phosphate, tenifoside, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds, platinum-based compounds or platinum-containing agents (e.g., cisplatin, oxaloplatin, arboplatin), anthracendiones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyureas), methylhydrazine derivatives (e.g.,Procarbazine), adrenocorticosteroids (e.g., mitothan, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, bortmannine, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossypol, genasense, polyphenol E, chlorofusin, all trans-retinoic acid (ATRA), Bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycitidine, alltransretinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamasin, 17-N-allylamino-17-demethoxygeldanamasin (17-AAG), flavopyridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-l, 25-dihydroxyvitamin D3; 5-ethinyluracil; abiraterone; aclarubicin; Acylfulben; Adesiphenol; Adozelesin; Aldesleukin; ALL-TK antagonist; Altretamine; Ambamustine; Amidox; Amifostine; Aminlevulinic acid; Amrubicin; Amsacrin; Anagrelide; Anastrozole; Andrographolide; Angiogenesis inhibitor; Antagonist D; Antagonist G; Antarelix; Anti-dorsalizing morphogenetic protein-1; Antiandrogen, prostate carcinoma; Antiestrogen; Antineoplaston; Antisense oligonucleotide; Apidicholine glycinate; Apoptosis gene regulator; Apoptosis regulator; Apuric acid;Ara-CDP-DL-PTBA; Arginine deaminase; Asulacrine; Atamestan; Atrimustine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azasetron; Azatoxin; Azatyrosine; Vacatin III derivatives; Balanol; Vatimastat; BCR / ABL antagonists; Benzochlorine; Benzoylstaurosporine; Beta-lactam derivatives; Beta-Alletin; Beta-Clamycin B; Betulinic acid; bFGF inhibitors; Bicalutamide; Bisantren; Bisaziridinylspermine; Bisnafid; Bistraten A; Bizelesin; Breplate; Bropyrimin; Budotitan; Butionine Sulfoximine; Calcipotriol; Carfostin C; Camptothecin derivatives; Canarifox IL-2; Capecitabine; Carboxamide-amino-triazole; Carboxamidotriazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermin; cecropin B; cetrorelix; chlorine; chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; clomiphene analog; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analog; conagenine; crembecidin 816; crinatol; cryptophysin 8; cryptophysin A derivative; curacin A; cyclopentanthraquinone; cycloplatam; cyfemycin; cytarabine oxphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; desrorelin; dexamethasone; Dexifosfamide; Dexrazoxic acid; Dexverapamil; Diaziquone; Didemnin B; Didox; Diethylnospermine; Dihydro-5-Azacitidine; 9-Dioxamycin; Diphenylspiromustine; Docosanol; Dolasetron; Doxyfluridine; Droloxifene; Dronabinol; Duocamycin SA; Epselen; Ecomustine; Edelfosin; Edrecolomab; Eflonitine; Elemen; Emitefur; Epirubicin; Ephristeride; Estramustine analogs; Estrogen agonists; Estrogen antagonists; Ethanidazole; Etoposide phosphate; Exemestane; Padrozol; Fazarabine; Fenretinide; Filgrastim;Finasteride; Flavopyridol; Flegelastin; Fluasterone; Piudarabine; Fluorodaurounisin Hydrochloride; Porfenimex; Formestane; Postriesin; Potemustine; Gadolinium Texapyrin; Gallium Nitrate; Galocitabine; Ganirelix; Gelatinase Inhibitor; Gemcitabine; Glutathione Inhibitor; Hepsulfame; Heregulin; Hexamethylene Bisacetamide; Hypericin; Ibandronate; Idarubicin; Idoxifen; Idramanton; Ilmofosin; Ilomastert; Imidazoacridone; Imiquimod; Immunostimulating Peptide; Insulin-like Growth Factor-1 Receptor Inhibitor; Interferon Agonist; Interferon; Interleukin; Iobenguan; Iododoxorubicin; Ipomenol, 4-; Iroplact; Irsogladin; Isobengazole; Isohomohalicondrin B; Itasetron; Jasflaquinolide; Cahalilide F; Lamellarin-N Triacetate; Lanreotide; Reinamycin; Lenograstim; Lentinan Sulfate; Leptolstatin; Letrozole; Leukemia Suppressor Factor; Leukocyte Alpha Interferon; Leuprolide + Estrogen + Progesterone; Leuprorelin; Levamisole; Riarozole; Linear Polyamine Analogue; Lipophilic Disaccharide Peptide; Lipophilic Platinum Compound; Lysoclinamide 7; Lovaplatin; Lombricin; Rometrexole; Ronidamine; Rosoxantrone; Lovastatin; Loxoribine; Lutotecan; Lutetium Texapyrin; Lysophylline; Soluble Peptide; Meitansine; Mannostatin A; Marimastat; Masoprocol; Maspin; Matrylicin inhibitors; Matrix metalloproteinase inhibitors; Menogaril; Mervaron; Mederellin; Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosin; Myrimostim; Mismatched double-stranded RNA; Mitoguazone; Mitoractol; Mitomycin analogs; Mitonapid; Mitotoxin; Fibroblast growth factor-Saporin; Mitoxantrone; Moparotene; Molgramostim; Monoclonal antibody, Human chorionic gonadotropin; Monophosphoryl lipid A+ Myobacterium cell wall sk; Morphidamol; Multidrug resistance gene inhibitors; Multidrug tumor inhibitor 1-based therapy; Mustard anticancer agent; MycaperoxideB; Mycobacterial cell wall extract; Myriaporone; N-acetyldinaline; N-substituted benzamide; Naparelin; Nagrestip; Naloxone + Pentazosine; Nafavin; Naphterpin; Nartograstim; Nedaplatin; Nemolubicin; Neridronic acid; Neutral endopeptidase; Nilutamide; Nisamycin; Nitric oxide modulator; Nitroxide antioxidant; Nitrulline; O6-Benzylguanine; Octreotide; Oxenone; Oligonucleotide; Onapriston; Ondansetron; Ondansetron; Oracin; Oral cytokine inducer; Ormaplatin; Osateron; Oxaliplatin; Oxaunomycin; Palauamine; Palmitoylisoxin; Pamidronic acid; Panaxitriol; Panomiphene; Parabacterin; Fazeliptin; Pegylasparaginase; Feldecin; Sodium pentosan polysulfate; Pentostatin; Pentrozol; Perflubrone; Perphosphamide; Perillyl alcohol; Phenazinomycin; Phenylacetate; Phosphatase inhibitors; Pisibanil; Pilocarpine hydrochloride; Pirarubicin; Pyritrexime; Placetin A; Placetin B; Plasminogen activator inhibitors; Platinum complex; Platinum compound; Platinum-triamine complex; Sodium porfimer; Porphyromycin; Prednisone; Propyl bis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A-based immunomodulators; Protein kinase C inhibitors; Protein kinase C inhibitors, microalgae; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Furpurin; Pyrazoloacridin; Pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonist; raltitrexid; ramosetron; ras farnesil protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; reteliptin demethylation; rhenium Re 186 etidronate; lyzoxin; ribozyme; RII retinamide; regletimide; rohitukin; romulotide; roquinimex; rubiginone B1; luboxil; saffingol; syntopin; SarCNU; sarcopitol A; salgramostim; Sdi 1 mimic; semustine; aging-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transductionModifiers; Single-chain antigen-binding proteins; Sizofuran; Sobuzoate; Sodium borocoptate; Sodium phenylacetate; Sorverol; Somatomedin binding protein; Sonermin sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; Spongestatin 1; Squalamine; Stem cell inhibitors; Stem cell division inhibitors; Stipiamide; Stromelisin inhibitors; Sulfinosine; Superactive vasoactive intestinal peptide antagonists; Suradista; Suramine; Swainsonine; Synthetic glycosaminoglycans; Talimustine; Tamoxifen methiodide; Tauromustine; Tazarotene; Tecogalan sodium; Tegafur; Talurapyrillium; Telomerase inhibitors; Temopopin; Temozolomide; Tenifoside; Tetrachlorodecaoxide; Tetrazomin; Taliblastine; Thiocoraline; Thrombopoietin; Thrombopoietin mimic; Timalfacine; Thymopoietin receptor agonist; Timotrinan; Thyroid-stimulating hormone; Tin ethyl thiofurpurine; Tirapazamine; Titanocene bichloride; Topcentin; Toremifene; Pluripotent stem cell factor; Translation inhibitor; Tretinoin; Triacetyluridine; Trisyribin; Trimetrexate; Triptorelin; Trophisetron; Turosteride; Tyrosine kinase inhibitor; Tirfostine; UBC inhibitor; Uvenimex; Genitourinary-derived growth inhibitor; Urokinase receptor antagonist; Baprootide; Valiolin B; Vector system, erythrocyte gene therapy; Bellaresol; Veramin; Verdins; Verteporfin; Vinorelbine; Vinzaltin; Vitaxin; Borozol; Zanoteron; Geniplatin; Zilascov; Gynostatin, Stimalamer, Adriamycin, D-Actinomycin, Bleomycin, Vinblastine, Cisplatin, Ashibicin; Aclarubicin; Acodazole Hydrochloride; Acronin; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutecimide; Amsacrine; Anastrozole; Antramycin; Asparaginase; Aperline; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantren Hydrochloride; Bisnafid Dimethicate; Bizelesin; Bleomycin Sulfate; BrequinarSodium; Bropyrimin; Busulfan; Cactinomycin; Calosterone; Carasemide; Carvetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Sedepingol; Chlorambucil; Sirolemycin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Desaguanine; Desaguanine Mesylate; Diaziquone; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflonitine Hydrochloride; Elsamitrusin; Enroplatin; Enpromate; Epipropidine; Epirubicin hydrochloride; erbulozol; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; padrozol hydrochloride; fazarabine; fenretinide; floruridine; fludarabine phosphate; fluorouracil; fluorocitabine; phosquidone; postriesin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; eimorphosin; interleukin 2 (including recombinant interleukin 2, or rlL.sub.2), interferon alpha-2a; interferon alpha-2b; interferon alpha-nl; interferon alpha-n3; Interferon beta-la; Interferon gamma-lb; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Riarozole hydrochloride; Lometrexole sodium; Lomustine; Rosoxantrone hydrochloride; Masoprocol; Meitansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogyline; Mitomalcin; Mitomycin; Mitosper; Mitotan; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazoy;Nogalamycin; Ormaplatin; Oxysuran; Pegyasparaginase; Peliomycin; Pentamustine; Peflomycin Sulfate; Perphosphamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Floremestane; Porfimer Sodium; Porphyromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazopurine; Ribophrine; Regletimide; Safingol; Safingol Hydrochloride; Semustine; Simtrazen; Sparphosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigreen; Streptozin; Sulofenur; Thalisomycin; Tecogalan Sodium; Tegafur; Teloxantrone hydrochloride; Temoporfin; Tenifoside; Teroxylon; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Thiazopurine; Tirapazamine; Toremifene citrate; Trestolon acetate; Trisiribin phosphate; Trimetrexate; Trimetrexate glucuronate; Triptorelin; Tubulozol hydrochloride; Uracil mustard; Uredepa; Baprootide; Verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindecin; Vindecin sulfate; Vinepidine sulfate; Vinglycinate sulfate; Vinryurosin sulfate; Vinorelbine tartrate; Vinrosidine sulfate; Vinzolidine sulfate; Borozol; Geniplatin; Gynostatin; Zorbicin hydrochloride, agents that inhibit cells in the G2-M phase and / or regulate the formation or stability of microtubules (e.g., Taxol™ (i.e., paclitaxel), Taxotere™, compounds containing a taxane backbone, erbulozol (i.e., R-55104), dolastatin 10 (i.e., DLS-10 and NSC-376128), mibobulin isethionate (i.e., CI-980), vincristine, NSC-639829, discodermolid (i.e., NVP-XX-A-296), ABT-751 (Abbott, i.e., E-7010), altohytin (e.g., altohytin A and altohytin C), spongestatins (e.g., spongestatin 1,Spongestatin 2, Spongestatin 3, Spongestatin 4, Spongestatin 5, Spongestatin 6, Spongestatin 7, Spongestatin 8, and Spongestatin 9), Semadotine hydrochloride (i.e., LU-103793 and NSC-D-669356), Epotillon (e.g., Epotillon A, Epotillon B, Epotillon C (i.e., Desoxiepotillon A or dEpoA), Epotillon D (i.e., KOS-862, dEpoB, and Desoxiepotillon B), Epotillon E, Epotillon F, Epotillon B N-oxide, Epotillon A N-oxide, 16-Aza-Epotillon B, 21-Aminoepotillon B (i.e., BMS-3 10705), 21-Hydroxypotillon D (i.e., desoxiepotillon F and dEpoF), 26-fluoroepotillon, auristatin PE (i.e., NSC-654663), soblidotin (i.e., TZT-1027), vincristine sulfate, cryptophysin 52 (i.e., LY-355703), betilebuamide, tubulisin A, canadensol, centaureidin (i.e., NSC-106969), oncocidin Al (i.e., BTO-956 and DF E), pyzianolid B, raulimalide, narcosin (also known as NSC-5366), nascapine, hemiasterin, vanadocene acetylacetonate, monsatrol, inanosine (i.e., NSC-698666), eleuterobin (e.g., desmethyleleuterobin, Desaethyl eleuterobin, isoeleuterobin A, and Z-eleuterobin), caribaoside, caribaolin, halicondrin B, diazonamide A, tacalonoride A, diozostatin, (-)-phenylahistine (i.e., NSCL-96F037), myoseverin B, resverasatin phosphate sodium, steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), e.g., goserelin or leuprolide, adrenal cortical steroids (e.g., prednisone), progestins (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., Bacillus calmette-Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-F£ER2, anti-CD52, anti-ULA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calichiamycin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to ln, OY, or I, etc.), triptolide, homoharingtonin, dactinomycin, doxorubicin, Epirubicin, Topotecan, Itraconazole, Vindesin, Cerivastatin, Vincristine, Deoxyadenosine, Sertraline, Pitavastatin, Irinotecan, Clofazimine, 5-Nonyloxytriptamine, Vemurafenib, Dabrafenib, Erlotinib, Gefitinib, EGFR inhibitors, Epidermal Growth Factor Receptor (EGFR)-targeted therapies or treatments (e.g., Gefitinib (Iressa), Erlotinib (Tarceva), Cetuximab (Erbitux), Lafatinib (Tykerb), Panitumumab (Vectibix), Vandetanib (Caprelsa), Apatinib / BIBW2992, CI-1033 / Canertinib, Neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib / PF299804, OSI-420 / desmethyl erlotinib, AZD8931, AEE788, felitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, hormone therapy, etc.

[1741] As indicated above, the combination therapy of the present invention can be achieved by simultaneous, sequential, or individual administration of the individual components of the treatment. Such combination products utilize the compounds of the present invention within the dosage ranges described above and other pharmaceutical active agents within the approved dosage ranges.

[1742] According to this aspect of the present invention, a combination for use in the treatment of cancer (e.g., cancer involving a solid tumor) is provided, comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and one or more additional antiproliferative / anticancer agents.

[1743] According to this aspect of the present invention, a combination for use in the treatment of a proliferative condition, e.g., cancer (e.g., cancer involving a solid tumor), is also provided, comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and one or more additional antiproliferative / anticancer agents selected from those listed above.

[1744] In a further aspect of the present invention, a compound of the present invention or a pharmaceutically acceptable salt, hydrate, or solvate thereof is provided for use in the treatment of cancer in combination with another antitumor agent optionally selected from those listed above in this specification.

[1745] In this specification, where the term “combination” is used, it should be understood to refer to simultaneous, individual, or sequential administration. In one aspect of the invention, “combination” refers to simultaneous administration. In another aspect of the invention, “combination” refers to individual administration. In a further aspect of the invention, “combination” refers to sequential administration. Where administration is sequential or individual, the delay in administration of the second component must not be such that the beneficial effect of the combination is lost.

[1746] According to a further aspect of the present invention, a pharmaceutical composition is provided comprising a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with an antitumor agent (optionally selected from those listed above) together with a pharmaceutically acceptable diluent or carrier.

[1747] Examples

[1748] General conditions:

[1749] Mass spectra were executed on an LC-MS system using electron spray ionization. This was performed using a Waters Acquity H-Class UPLC with PDA and QDa mass detectors, an Acquity UPLC (binary pump / PDA detector) + ZQ mass spectrometer or an Acquity i-Class (quarter 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 a single isotope.

[1750] NMR spectra were performed on a Bruker Ultrashield 500 MHz NMR spectrometer, Bruker Avance III HD 400 MHz NMR spectrometer, Bruker Avance DPX 300 MHz NMR spectrometer, Bruker Avance III HD 500 MHz, or Bruker Avance III HD 250 MHz. Spectra were recorded at 298 K and referenced using the solvent peak.

[1751] The following examples are intended to illustrate the invention and should not be construed as limiting the invention. Temperatures are provided in degrees Celsius. Unless otherwise noted, all evaporation is performed under vacuum, preferably between about 15 mm Hg and 100 mm Hg (= 20 to 133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods, e.g., MS and NMR. Abbreviations used are common in the art. Where not defined, terms have their generally accepted meanings.

[1752] abbreviation

[1753] app obvious

[1754] br wide

[1755] d double line

[1756] dd double line double line

[1757] DABCO (1,4-diazabicyclo[2.2.2]octane)

[1758] DBU 1,8-Diazabicyclo[5.4.0]undek-7-en

[1759] DCM dichloromethane

[1760] DIPEA Diisopropylethylamine

[1761] DMA Dimethylacetamide

[1762] DMF N,N-dimethylformamide

[1763] EtOAc ethyl acetate

[1764] HPLC High Performance Liquid Chromatography

[1765] HBTU, hexafluorophosphate, benzotriazole, tetramethyl uranium

[1766] IMS Industrial Methylated Alcohol

[1767] LC-MS Liquid Chromatography and Mass Spectrometer

[1768] mCPBA 3-chloroperbenzoic acid

[1769] MeOH methanol

[1770] MeCN Acetonitrile

[1771] MS Mass Spectrometer

[1772] m multiline

[1773] min minutes

[1774] mL milliliters

[1775] m / z mass-to-charge ratio

[1776] NBS N - Bromosimide

[1777] NMR Nuclear Magnetic Resonance

[1778] Pd(amphos)2Cl2bis(di- tert -Butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)

[1779] Pd(tBu3P)2bis(tri-tert-butylphosphine)palladium(0)

[1780] ppm parts per million

[1781] PS polymer support

[1782] Rt holding time

[1783] s single line

[1784] t triple line

[1785] T3P propanephosphonic acid anhydride

[1786] TFA trifluoroacetic acid

[1787] THF Tetrahydrofuran

[1788] With reference to the following examples, a compound of a preferred embodiment was synthesized using the method described herein or other methods known in the art.

[1789] Various starting materials, intermediates, and compounds of the preferred embodiment may be separated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise noted, all starting materials are obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt formation procedures.

[1790] It should be understood that an organic compound according to a preferred embodiment may exhibit tautomerism. Since the chemical structure described herein may represent only one of the possible tautomer forms, it should be understood that a preferred embodiment includes any tautomer form of the illustrated structure.

[1791] Unless otherwise indicated, the analytical HPLC conditions are as follows:

[1792] Method 2A

[1793] Column: Kinetex Core-Shell C18 2.1 × 50 mm 5 μm

[1794] Column temperature 40℃

[1795] Eluent: A: H2O + 0.1% formic acid, B: MeCN + 0.1% formic acid

[1796] Flow rate: 1.2 mL / min

[1797] Gradient: 0 to 1.83 min 5 to 100 B, 1.83 to 2.25 min 100% B, 2.25 to 2.26 min 100 to 5% B

[1798] Method 2.5B

[1799] Column: Phenomenex Gemini-NX C18 2 × 50 mm 3 μm

[1800] Column temperature 40℃

[1801] Eluent: A: 2 mM ammonium bicarbonate, buffered to pH 10, B: MeCN

[1802] Flow rate: 1 mL / min

[1803] Gradient: 0 to 1.80 min 1 to 100% B, 1.80 to 2.10 min 100% B, 2.10 to 2.30 min 100 to 1% B

[1804] Method 3A

[1805] Column: Acquity UPLC CSH C18 2.1 × 50 mm, 1.7 μm

[1806] Column temperature 50℃

[1807] Eluent: A: H2O, B: MeCN, 0.1% formic acid

[1808] Flow rate: 1 mL / min

[1809] Gradient: 0.2 to 2.5 min 2 to 98% B, 2.5 to 3.0 min 98% B

[1810] Method 3B

[1811] Column: Acquity UPLC BEH C18 2.1 × 50 mm, 1.7 μm

[1812] Column temperature 50℃

[1813] Eluent: A: H2O, B: MeCN, 0.1% ammonia

[1814] Flow rate: 1 mL / min

[1815] Gradient: 0.2 to 2.5 min 2 to 98% B, 2.5 to 3.0 min 98% B

[1816] Method 5A

[1817] Column: YMC-Triart C18 2 × 50 mm, 5 μm.

[1818] Flow rate: 0.8 mL / min.

[1819] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% formic acid

[1820] Gradient: 0.0 to 4.0 min 0 to 95% B, 5% C; 4.0 to 4.4 min 95% B, 5% C; 4.4 to 4.5 min 95% A, 5% B

[1821] Method 5B

[1822] Column: YMC-Triart C18 2 × 50 mm, 5 μm.

[1823] Flow rate: 0.8 mL / min.

[1824] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% Ammonia (Aqueous)

[1825] Gradient: 0.0 to 4.0 min 0 to 95% B, 5% C; 4.0 to 4.4 min 95% B, 5% C; 4.4 to 4.5 min 95% A, 5% B

[1826] Method 7A

[1827] Column: Phenomenex Kinetix-XB C18 2.1 × 100 mm, 1.7 μm

[1828] Column temperature 40℃

[1829] Eluent: A: H2O 0.1% formic acid, B: MeCN, 0.1% formic acid

[1830] Flow rate: 0.6 mL / min

[1831] Gradient: 0 to 5.3.0 min 5 to 100% B, 5.3 to 5.8 min 100% B, 5.8 to 5.82 min 100 to 5% B, 5.82 to 7.00 min 5% B

[1832] Method 7B

[1833] Column: Waters UPLC® BEH TM C18, 2.1 mm × 100 mm, 1.7 μm column

[1834] Column temperature 40℃

[1835] Eluent: A: 2 mM ammonium bicarbonate buffered to pH 10, B: MeCN

[1836] Flow rate: 0.6 mL / min

[1837] Gradient: 0 to 5.3.0 min 5 to 100% B, 5.3 to 5.8 min 100% B, 5.8 to 5.82 min 100 to 5% B, 5.82 to 7.00 min 5% B

[1838] Method 8A

[1839] Column: Acquity UPLC CSH C18 2.1 × 100 mm, 1.7 μm

[1840] Column temperature 50℃

[1841] Eluent: A: H2O, B: MeCN, 0.1% formic acid

[1842] Flow rate: 0.6 mL / min

[1843] Gradient: 0.5 to 6.5 mins 2 to 98% B 6.5 to 7.5 mins 98% B

[1844] Method 8B

[1845] Column: Acquity UPLC BEH C18 2.1 × 100 mm, 1.7 μm

[1846] Column temperature 50℃

[1847] Eluent: A: H2O, B: MeCN, 0.1% ammonia

[1848] Flow rate: 0.6 mL / min

[1849] Gradient: 0.5 to 6.5 mins 2 to 98% B 6.5 to 7.5 mins 98% B

[1850] Method 15A

[1851] Column: YMC-Triart C18 2 × 50 mm, 5 μm.

[1852] Flow rate: 0.8 mL / min.

[1853] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% formic acid

[1854] Gradient: 0.0 to 12.0 min 0 to 95% B, 5% C; 12.0 to 14.0 min 95% B, 5% C; 14.0 to 14.2 min 95% A, 5% B

[1855] Method 15B

[1856] Column: YMC-Triart C18 50 × 2 mm, 5 μm.

[1857] Flow rate: 0.8 mL / min.

[1858] Eluent: A: H2O, B: MeCN, C: 50% H2O / 50% MeCN + 1.0% Ammonia (Aqueous)

[1859] Gradient: 0.0 to 12.0 min 0 to 95% B, 5% C; 12.0 to 14.0 min 95% B, 5% C; 14.0 to 14.2 min 95% A, 5% B

[1860] Example 1 - 3-[5-amino-3-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile

[1861]

[1862] A mixture of 3-(5-amino-3-bromo-pyrazolo[1,5-a]pyrimidine-2-yl)benzonitrile (intermediate E) (89 mg, 0.28 mmol), 4-pyridylboronic acid (52 mg, 0.42 mmol), and K2CO3 (78 mg, 0.57 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was degassed under a stream of N2. Pd(tBu3P)2 (14 mg, 0.03 mmol) was added, and the reaction mixture was heated to 120°C (in a preheated bath) for 1 hour. The resulting mixture was cooled to room temperature and added dropwise to stirring water (50 mL). The precipitate was collected by filtration, and purification was performed by chromatography on silica eluted by a 5 to 10% MeOH gradient in DCM. The generated material was triturated with MeOH (3 mL) followed by EtOAc (5 mL) to obtain the title compound as a beige solid.

[1863] LC-MS (Method 15A): Rt 5.14 min; MS m / z 313.2 = [M+H]+

[1864] 1 H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 7.5 Hz, 1H), 8.44 (d, J = 5.5 Hz, 2H), 7.91 (t, J = 3.3 Hz, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 5.2 Hz, 2H), 7.25 (s, 2H), 6.39 (d, J = 7.5 Hz, 1H).

[1865] The compounds of the example (Table Ex1) prepared in the table below were prepared similarly to Example 1 from 3-(5-amino-3-bromo-pyrazolo[1,5-a]pyrimidine-2-yl)benzonitrile (intermediate E) and a suitable boronic acid or boronate ester.

[1866] Table Ex1

[1867]

[1868]

[1869]

[1870] Example 2 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(2-hydroxy-2-methyl-propyl)amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile

[1871]

[1872] A suspension of 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidin-2-yl]benzonitrile (intermediate C) (900 mg, 2.37 mmol), 1-amino-2-methyl-propan-2-ol (316 mg, 3.55 mmol), and DIPEA (2.06 mL, 11.83 mmol) in NMP (15 mL) was heated to 50°C for 3 hours. After cooling to room temperature, the mixture was distributed between a 90% saline solution (100 mL) and EtOAc (100 mL). The organic layer was washed with a 50% saline solution (3 × 50 mL), dried over MgSO4, and then concentrated under vacuum. The title compound was obtained as a colorless solid by purifying the crude material by silica phase chromatography eluted with a gradient of 0 to 5% MeOH in DCM.

[1873] LC-MS (Method 8B): Rt 4.24 min; MS m / z 431.2 / 433.2 = [MH]-

[1874] 1 ¹H NMR (500 MHz, DMSO- d 6) δ 8.57 (d, J = 7.6 Hz, 1H), 8.01 - 7.90 (m, 3H), 7.83 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.27 (s, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.63 (s, 1H), 3.44 (d, J = 5.8 Hz, 2H), 2.33 (s, 3H), 1.19 (s, 6H).

[1875] The compound of the example (Table Ex2) prepared in the table below was prepared similarly to Example 2 from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile (intermediate C) and a suitable amine.

[1876] Table Ex2

[1877]

[1878]

[1879]

[1880]

[1881]

[1882]

[1883]

[1884]

[1885]

[1886]

[1887]

[1888]

[1889]

[1890] Example 3 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(2R)-2-hydroxypropyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile

[1891]

[1892] (2 R)-1-aminopropan-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 minutes. The resulting mixture was cooled to room temperature and added dropwise to stirring 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 then concentrated under vacuum. The title compound was obtained as a colorless solid by purifying the crude material by reverse-phase chromatography eluted with 40% to 50% MeCN in water, followed by purifying it by silica-phase chromatography eluted with a gradient of 0% to 8% MeOH in DCM.

[1893] LC-MS (Method 15B): Rt 7.23 min; MS m / z 419.2 / 421.1 = [M+H]+

[1894] 1 ¹H NMR (500 MHz, DMSO- d 6) δ 8.59 (d, J = 7.5 Hz, 1H), 8.05 (s, 1H), 8.00 - 7.94 (m, 2H), 7.84 (dt, J = 7.9, 1.4 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 6.53 (d, J = 7.6 Hz, 1H), 4.83 (d, J = 4.8 Hz, 1H), 4.01 - 3.92 (m, 1H), 3.56 - 3.45 (m, 1H), 3.22 (dt, J = 13.0, 6.1 Hz, 1H), 2.34 (s, 3H), 1.16 (d, J = 6.2 Hz, 3H).

[1895] The compound of the example (Table Ex3) prepared in the table below was prepared similarly to Example 3 from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile (intermediate C) and a suitable amine.

[1896] Table Ex3

[1897]

[1898]

[1899] Example 4 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile

[1900]

[1901] Step 1: tert- Butyl 4-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]piperidine-1-carboxylate

[1902]

[1903] 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 stirring water (20 mL), the resulting precipitate was collected by filtration and washed with water (2 × 5 mL). The solid was azeotropically purified in acetone (20 mL) by reverse phase elution with a gradient of 40 to 65% MeCN in water (+0.1 wt% NH4OH) to obtain the title compound as a colorless solid.

[1904] LC-MS (Method 5B): Rt 3.89 min; MS m / z 544.2 = [M+H]+

[1905] 1¹H NMR (500 MHz, DMSO- d 6) δ 8.63 (d, J = 7.6 Hz, 1H), 8.03 - 7.93 (m, 3H), 7.86 (dt, J = 8.0, 1.5 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 6.45 (d, J = 7.6 Hz, 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).

[1906] Step 2: 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(4-piperidylamino)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile

[1907] 4 M HCl (0.55 mL, 2.19 mmol) in 1,4-dioxane in MeOH (0.50 mL) tert- Butyl 4-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]piperidine-1-carboxylate (step 1) (119 mg, 0.22 mmol) was added to a suspension and stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum and purified by reverse phase elution in water (+0.1 wt% NH4OH) with a gradient of 5 to 60% MeCN to obtain the title compound as a colorless solid.

[1908] LC-MS (Method 8B): Rt 4.78 min; MS m / z 444.2 / 446.2 = [M+H]+

[1909] 1 ¹H NMR (500 MHz, DMSO- d 6) 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.

[1910] The compound of the example (Table Ex4) prepared in the table below was prepared similarly to Example 4 by starting from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile (intermediate C) and a suitable amine (step 1), followed by deprotection using 4 M HCl / dioxane (step 2).

[1911] Table Ex4

[1912]

[1913]

[1914]

[1915]

[1916]

[1917]

[1918]

[1919] 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]pyrimidine-2-yl]benzonitrile

[1920]

[1921] 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]pyrimidine-2-yl]benzonitrile

[1922]

[1923] The title compound was prepared from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile (intermediate C) and (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethanolamine in a manner similar to Step 1 of Example 4.

[1924] LC-MS (Method 5B): Rt 3.84 min; MS m / z 489.2 / 491.1 = [M+H]+

[1925] 1H NMR (500 MHz, DMSO-d6) δ 8.60 (d,J= 7.6 Hz, 1H), 8.02 - 7.93 (m, 2H), 7.89 - 7.80 (m, 2H), 7.69 (t,J= 7.8 Hz, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 6.50 (d,J= 7.6 Hz, 1H), 4.29 (s, 2H), 4.03 (dd,J= 8.2, 6.2 Hz, 1H), 3.72 (dd,J= 8.2, 6.2 Hz, 1H), 2.35 (s, 3H), 1.36 (s, 3H), 1.30 (s, 3H), 1.21 (d,J= 6.0 Hz, 3H).

[1926] Step 2 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1R,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile

[1927] 2 M aqueous HCl (0.5 mL, 1 mmol) was added 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]pyrimidine-2-yl]benzonitrile (Step 1) (49.1 mg, 0.1000 mmol) in THF (1 mL), and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was distributed between ethyl acetate (15 mL) and water (15 mL). The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate (2 × 10 mL). The combined organic layer was washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The title compound was obtained as a colorless solid by purification by silica phase chromatography eluted with a gradient of 2 to 10% MeOH in DCM.

[1928] LC-MS (Method 8B): Rt 4.06 min; MS m / z 449.2 / 451.2 = [M+H]+

[1929] 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d,J= 7.6 Hz, 1H), 7.99 - 7.93 (m, 2H), 7.83 (d,J= 8.1, 1.5 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.38 (s, 1H), 7.31 (s, 1H), 6.62 (d,J= 7.6 Hz, 1H), 5.03 (d,J= 4.7 Hz, 1H), 4.56 (t,J= 5.5 Hz, 1H), 4.40 - 4.26 (m, 1H), 3.65 - 3.54 (m, 1H), 3.38 (t,J= 6.0 Hz, 2H), 2.34 (s, 3H), 1.26 (d,J= 6.7 Hz, 3H).

[1930] 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]pyrimidine-2-yl]benzonitrile

[1931]

[1932] 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]pyrimidine-2-yl]benzonitrile

[1933]

[1934] The title compound was prepared from 3-[5-chloro-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile (intermediate C) and (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]ethanolamine in a manner similar to Step 1 of Example 4.

[1935] LC-MS (Method 5B): Rt 2.29 min; MS m / z 489.4 / 491.1 = [M+H]+

[1936] 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d,J= 7.5 Hz, 1H), 8.00 - 7.93 (m, 2H), 7.92 (d,J= 8.0 Hz, 1H), 7.83 (d,J= 8.0 Hz, 1H), 7.69 (t,J= 7.8 Hz, 1H), 7.34 (s, 1H), 7.28 (s, 1H), 6.45 (d,J= 7.6 Hz, 1H), 4.25 (q,J= 7.1 Hz, 1H), 4.15 (q,J= 6.2 Hz, 1H), 4.04 (dd,J= 8.4, 6.5 Hz, 1H), 3.85 (dd,J= 8.4, 5.5 Hz, 1H), 2.34 (s, 3H), 1.40 (s, 3H), 1.30 (s, 3H), 1.24 (d,J= 6.6 Hz, 3H).

[1937] Step 2 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[[(1S,2S)-2,3-dihydroxy-1-methyl-propyl]amino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile

[1938] 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]pyrimidine-2-yl]benzonitrile (Step 1) and 2 M aqueous HCl in a manner similar to Step 2 of Example 4.8.

[1939] LC-MS (Method 8B): Rt 4.01 min; MS m / z 449.2 / 451.2 = [M+H]+

[1940] 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d,J= 7.5 Hz, 1H), 8.00 - 7.93 (m, 2H), 7.88 - 7.79 (m, 2H), 7.70 (t,J= 7.7 Hz, 1H), 7.44 (s, 1H), 7.22 (s, 1H), 6.52 (d,J= 7.6 Hz, 1H), 4.86 (d,J= 5.3 Hz, 1H), 4.60 (t,J= 5.4 Hz, 1H), 4.30 - 4.17 (m, 1H), 3.75 - 3.66 (m, 1H), 3.43 (t,J= 5.9 Hz, 2H), 2.36 (s, 3H), 1.18 (d,J= 6.7 Hz, 3H).

[1941] Example 4.10 - [5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile trifluoroacetate

[1942]

[1943] Step 1 - tert-butyl N-[2-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]-1,1-dimethyl-ethyl]carbamate:

[1944]

[1945] 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 in a manner similar to Step 1 of Example 4.

[1946] LC-MS (Method 5B): Rt 3.34 min; MS m / z 530.3 / 532.3 = [MH]-

[1947] 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d,J= 7.6 Hz, 1H), 8.02 - 7.92 (m, 3H), 7.83 (d,J= 7.8 Hz, 1H), 7.70 (t,J= 7.8 Hz, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 6.67 (s, 1H), 6.57 (d,J= 7.6 Hz, 1H), 3.65 (d,J= 6.1 Hz, 2H), 2.37 (s, 3H), 1.32 - 1.24 (m, 15H).

[1948] Step 2 - [5-[(2-amino-2-methyl-propyl)amino]-3-(2-chloro-6-methyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile trifluoroacetate

[1949] 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]pyrimidine-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 hours. The mixture was concentrated under vacuum, and the solid residue was ground with diethyl ether (2 mL) and acetonitrile (2 mL) to obtain the title compound as a grayish-white solid.

[1950] LC-MS (Method 8B): Rt 4.51 min; MS m / z 432.2 / 434.2 = [MH]+

[1951] 1H NMR (500 MHz, DMSO-d6) δ 8.69 (d,J= 7.6 Hz, 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= 8.0 Hz, 1H), 7.34 (s, 1H), 7.27 (s, 1H), 6.55 (d,J= 7.7 Hz, 1H), 3.62 (d,J= 6.2 Hz, 2H), 2.37 (s, 3H), 1.33 (s, 6H).

[1952] Example 4.11 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazetidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile trifluoroacetate

[1953]

[1954] Step 1 - tert-butyl 3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]-3-hydroxy-azetidine-1-carboxylate

[1955]

[1956] 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 3-(aminomethyl)-3-hydroxy-azetidine-1-carboxylate in a manner similar to Step 1 of Example 4.

[1957] LC-MS (Method 5B): Rt 3.15 min; MS m / z 546.2 = [M+H]+

[1958] 1 ¹H NMR (500 MHz, DMSO- d 6) δ 8.62 (d, J= 7.5 Hz, 1H), 8.16 - 8.06 (m, 1H), 8.01 - 7.92 (m, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.24 (s, 1H), 6.57 (d, J = 7.6 Hz, 1H), 6.07 (s, 1H), 3.91 (s, 2H), 3.81 - 3.66 (m, 4H), 2.35 (s, 3H), 1.34 (s, 9H).

[1959] Step 2 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-[(3-hydroxyazetidine-3-yl)methylamino]pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile trifluoroacetate

[1960] The title compound was prepared from tert-butyl 3-[[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-yl]amino]methyl]-3-hydroxy-azetidine-1-carboxylate (Step 1) and TFA in a manner similar to Step 2 of Example 4.10.

[1961] LC-MS (Method 15B): Rt 8.34 min; MS m / z 446.1 = [M + H]+

[1962] 1 ¹H NMR (500 MHz, DMSO- d 6) δ 8.84 (s, 1H), 8.75 - 8.60 (m, 2H), 8.11 (s, 1H), 8.02 - 7.91 (m, 2H), 7.81 (d, J = 7.9 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.26 (s, 1H), 6.58 (d, J = 7.6 Hz, 1H), 6.47 (s, 1H), 4.12 - 4.00 (m, 2H), 3.86 (dd, J= 11.4, 5.8 Hz, 2H), 3.68 (d, J = 5.5 Hz, 2H), 2.38 (s, 3H).

[1963] Example 5 - 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(3-hydroxy-1-bicyclo[1.1.1]fentanyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide

[1964]

[1965] DMF (1 drop) was added 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), then oxalyl chloride (33 μL, 0.38 mmol) was added dropwise, and the mixture was stirred at room temperature for 5 minutes. Additional DCM (1 mL) and oxalyl chloride (0.02 mL, 0.26 mmol) were added, and the mixture was stirred for an additional 5 minutes, after which the resulting mixture was concentrated under vacuum to obtain acid chloride.

[1966] A suspension of acid chloride in DCM (1 mL) was added dropwise to a solution of 3-aminobicyclo[1.1.1]pentan-1-ol hydrochloride (26 mg, 0.19 mmol) and DIPEA (89 μL, 0.51 mmol) in DCM (1 mL), and the mixture was stirred for 45 minutes. Additionally, 3-aminobicyclo[1.1.1]pentan-1-ol hydrochloride (9 mg, 0.06 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The resulting mixture was distributed between H2O (10 mL) and DCM (10 mL), and the organic fraction was separated. The aqueous material was further extracted with DCM (2 × 10 mL), and the combined organic extract was washed with brine (10 mL), dried over MgSO4, and the solvent removed under vacuum. The title compound was obtained as a yellow solid by purification by silica phase chromatography eluted with a gradient of 0 to 2% MeOH in DCM.

[1967] LC-MS (Method 8B): Rt 4.32 min; MS m / z 471.2 / 473.1 = [M+H]+

[1968] 1 H NMR (500 MHz, DMSO-d6) δ 9.41 (d, J= 7.2 Hz, 1H), 9.24 (s, 1H), 8.05 (s, 1H), 7.99 (d, J= 7.8 Hz, 1H), 7.87 (d, J= 7.8 Hz, 1H), 7.71 (t, J= 7.8 Hz, 1H), 7.65 (d, J= 7.2 Hz, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 6.30 (s, 1H), 2.46 (s, 3H), 2.18 (s, 6H).

[1969] The compound of the example (Table Ex5) prepared in the table below was prepared similarly to Example 5 from 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (intermediate A), oxalyl chloride, and a suitable amine.

[1970] Table Ex5

[1971]

[1972]

[1973]

[1974] Example 5.8 - 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide

[1975]

[1976] The title compound was prepared similarly to Example 5 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.

[1977] LC-MS (Method 8B): Rt 3.74 min; MS m / z 369.2 = [M+H]+

[1978] 1H NMR (500 MHz, DMSO-d6) δ 9.37 (d,J= 7.2 Hz, 1H), 8.12 (s, 1H), 8.04 - 8.00 (m, 1H), 7.99 - 7.94 (m, 2H), 7.86 (d,J= 7.9 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.18 (s, 2H), 2.41 (s, 6H).

[1979] 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

[1980]

[1981] 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 (3 S After adding DIPEA (89 μL, 0.51 mmol) to a mixture of )-3-amino-2-methyl-butan-2-ol hydrochloride (21 mg, 0.15 mmol), T3P ® (50% of DMF) (0.14 mL, 0.21 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. 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 × 10 mL). The combined organic layer was washed with 50% brine (3 × 10 mL), dried over MgSO4, filtered, and concentrated under vacuum. The title compound was obtained as a yellow solid by purification by silica-phase chromatography eluted with a gradient of 0 to 3% MeOH in DCM.

[1982] LC-MS (Method 8B): Rt 4.57 min; MS m / z 475.2 / 477.2 = [M+H]+

[1983] 1 ¹H NMR (500 MHz, DMSO- d 6) δ 9.45 (d, J = 7.1 Hz, 1H), 8.27 (d,J = 9.0 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 8.0 Hz, 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).

[1984] The compound of the example (Table Ex6) prepared in the table below is 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (intermediate A), T3P ® It was prepared similarly to Example 6 from DIPEA and a suitable amine.

[1985] Table Ex6

[1986]

[1987]

[1988]

[1989]

[1990]

[1991]

[1992]

[1993]

[1994]

[1995]

[1996] 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

[1997]

[1998] Step 1: tert-Butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-1,1-dimethyl-propyl]carbamate

[1999]

[2000] 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (intermediate A) (50 mg, 0.13 mmol), T3P in DMF (1 mL). ® (50 wt% of EtOAc (91 μL, 0.26 mmol), DIPEA (112 μL, 0.64 mmol) and tert- A solution of butyl N-(3-amino-1,1-dimethyl-propyl)carbamate (38.92 mg, 0.19 mmol) was stirred at 60°C for 4 hours. The mixture was diluted with water (5 ml) and the resulting precipitate was collected under vacuum filtration. The solid was dissolved in DCM (20 ml), filtered through a phase separation cartridge, and then concentrated under vacuum to obtain the title compound as a yellow solid.

[2001] LC-MS (Method 2A): Rt 1.37 min; MS m / z 574.3 / 576.3 = [M+H]+

[2002] 1H NMR (400 MHz, DMSO-d6) δ 9.41 (d, J = 7.2 Hz, 1H), 8.70 (t, J = 5.8 Hz, 1H), 8.06 (t, J = 1.4 Hz, 1H), 8.00 (dt, J = 7.7, 1.3 Hz, 1H), 7.88 (dt, J = 7.9, 1.3 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.51 (s, 1H), 7.32 (s, 1H), 6.43 (s, 1H), 2.47 (s, 3H), 1.91 (t, J = 7.5 Hz, 2H), 1.35 (s, 9H), 1.24 (s, 6H). As shown in HSQC, there is 1 x CH2 signal below the water peak.

[2003] 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

[2004] In DCM (2 mL) tert- A solution of butyl N-[3-[[3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carbonyl]amino]-1,1-dimethyl-propyl]carbamate (Step 1) (62 mg, 0.10 mmol) and 1,4-dioxane (251 μL, 1 mmol) in 4 M HCl was stirred at room temperature for 18 hours. The resulting mixture was concentrated under vacuum, and then 1 g Isolute eluted with 7 M NH3 in MeOH was prepared. ® Purification was performed using an SCX cartridge. The filtrate was concentrated under vacuum and freeze-dried to obtain the title compound as a yellow powder.

[2005] LC-MS (Method 7A): Rt 2.09 min; MS m / z 474.2 / 476.2 = [M+H]+

[2006] 1H NMR (500 MHz, DMSO-d6) δ 9.57 - 9.51 (m, 1H), 9.41 (d, J = 7.2 Hz, 1H), 8.06 (t, J = 1.4 Hz, 1H), 8.00 (dt, J = 7.8, 1.3 Hz, 1H), 7.87 (dt, J = 7.9, 1.3 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.38 (d, J = 12.1 Hz, 2H), 3.45 (q, J = 6.4 Hz, 2H), 2.44 (s, 3H), 1.61 (t, J = 6.8 Hz, 2H), 1.12 (s, 6H). No NH2 protons were observed.

[2007] The compound of the example (Table Ex7) prepared in the table below is 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid (intermediate A), T3P ® It was prepared similarly to Example 7 by deprotection using 4 M HCl in 1,4-dioxane (Step 2) from , DIPEA and a suitable amine (Step 1).

[2008] Table Ex7

[2009]

[2010]

[2011]

[2012]

[2013]

[2014]

[2015]

[2016]

[2017]

[2018]

[2019]

[2020]

[2021]

[2022]

[2023]

[2024]

[2025]

[2026] 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

[2027]

[2028] 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

[2029]

[2030] 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]ethanolamine in a manner similar to Step 1 of Example 7.

[2031] LC-MS (Method 5B): Rt 3.08 min; MS m / z 517.2 / 519.2 = [M+H]+

[2032] 1H NMR (500 MHz, DMSO-d6) δ 9.44 (d,J= 7.2 Hz, 1H), 8.50 (d,J= 8.8 Hz, 1H), 8.09 (s, 1H), 8.01 (d,J= 7.9 Hz, 1H), 7.91 (d,J= 7.9 Hz, 1H), 7.73 (t,J= 7.9 Hz, 1H), 7.70 (d,J= 7.2 Hz, 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, 6.6 Hz, 1H), 3.90 (dd,J= 8.7, 5.3 Hz, 1H), 2.46 (s, 3H), 1.33 - 1.20 (m, 9H)

[2033] 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

[2034] 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 2 M aqueous HCl in a manner similar to Step 2 of Example 4.8.

[2035] LC-MS (Method 8B): Rt 3.99 min; MS m / z 477.2 = [M+H]+

[2036] 1H NMR (500 MHz, DMSO-d6) δ 9.44 (d, J = 7.2 Hz, 1H), 8.57 (d, J = 8.8 Hz, 1H), 8.09 (t, J = 1.7 Hz, 1H), 8.01 (dt, J = 7.8, 1.4 Hz, 1H), 7.91 (dt, J = 8.1, 1.4 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.58 (s, 1H), 7.25 (s, 1H), 5.02 (d, J = 5.2 Hz, 1H), 4.73 (t, J = 5.5 Hz, 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 = 6.7 Hz, 3H).

[2037] Example 8 - 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile

[2038]

[2039] Step 1: 3-[3-bromo-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile

[2040]

[2041] MeMgCl (3 M in THF) (0.2 mL, 0.60 mmol) was added dropwise 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, and the reaction mixture was stirred for 1.5 hours. The resulting mixture was diluted with DCM (40 mL) and washed with NH4Cl (2 × 20 mL). The organic phase was dried on MgSO4 and concentrated under vacuum. The title compound was obtained as a colorless solid by purification by silica phase chromatography eluted with a gradient of 0 to 2% MeOH in DCM.

[2042] LC-MS (Method 5B): Rt 3.80 min; MS m / z 357.0 / 359.0 = [M+H]+

[2043] 1H NMR (500 MHz, DMSO-d6) δ 9.16 (d, J = 7.2 Hz, 1H), 8.39 - 8.36 (m, 1H), 8.35 - 8.30 (m, 1H), 8.01 - 7.98 (m, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 5.61 (s, 1H), 1.52 (s, 6H).

[2044] Step 2: 3-[3-(2-chloro-6-methyl-4-pyridyl)-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile

[2045] A mixture of 3-[3-bromo-5-(1-hydroxy-1-methyl-ethyl)pyrazolo[1,5-a]pyrimidine-2-yl]benzonitrile (step 1) (65 mg, 0.18 mmol), 2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (62 mg, 0.24 mmol) and K2CO3 (75 mg, 0.55 mmol) was degassed under a stream of N2 in 1,4-dioxane (3 mL) and water (0.75 mL). Pd(tBu3P)2 (9 mg, 0.02 mmol) was added, and the reaction mixture was heated to 80°C for 15 minutes. The resulting mixture was cooled to room temperature, water (30 mL) was added, and then extracted with DCM (2 × 30 mL). The organic extract was dried on an MgSO4 phase and concentrated under vacuum. The title compound was obtained as a colorless solid by silica phase chromatography eluted with a gradient of 0 to 10% MeOH in DCM, followed by purification by C18 reverse phase chromatography eluted with a gradient of 40 to 80% MeCN in water (+0.1 wt% NH4OH), and final purification on a silica phase eluted with a gradient of 0 to 10% MeOH in DCM.

[2046] LC-MS (Method 15B): Rt 7.79 min; MS m / z 404.1 / 406.0 = [M+H]+

[2047] 1H NMR (500 MHz, DMSO-d6) δ 9.23 (d, J = 7.3 Hz, 1H), 8.05 (s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 5.64 (s, 1H), 2.39 (s, 3H), 1.54 (s, 6H).

[2048] Example 9 (= Intermediate A) - 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid

[2049]

[2050] A solution of lithium hydroxide (273 mg, 11.42 mmol) in water (20 mL) was added to a stirred partial 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 hour. The resulting mixture was distributed between H2O (100 mL) and Et2O (100 mL). The organic fraction was removed, and the aqueous portion was acidified with 2 M HCl. The resulting solid was collected by filtration and azeotropically mixed with MeOH (×2) to obtain the title compound as a yellow solid.

[2051] LC-MS (Method 3B): Rt 1.09 min; MS m / z 390.1 = [M+H]+

[2052] 1H NMR (500 MHz, DMSO-d6) δ 9.37 (d, J = 7.2 Hz, 1H), 8.06 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 2.42 (s, 3H). No OH protons were observed.

[2053] Example 10 - 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide

[2054]

[2055] 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 hour. Additional (2,6-dimethyl-4-pyridyl)boronic acid (46 mg, 0.31 mmol) was added in 2 portions at 30-minute intervals, and the reaction mixture was heated to 50°C for an additional 30 minutes. 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (48 mg, 0.21 mmol), Pd(tBu3P)2 (5 mg, 0.01 mmol), and K2CO3 (57 mg, 0.41 mmol) were added to the water, and the mixture was heated to 50°C for an additional 1 hour, after which the reaction mixture was cooled to room temperature. The resulting mixture was distributed between H2O (15 mL) and EtOAc (20 mL), the organic portion was separated, and the aqueous portion was further extracted with EtOAc (2 × 25 mL). The combined organic extract was dried over Na2SO4 and concentrated under vacuum. The title compound was obtained as a yellow solid by purification by silica-phase c...

Claims

Claim 1 Compound having the structural formula Ii3 shown below, or a pharmaceutically acceptable salt thereof: [Structural formula Ii3] Here, A is CH or N; R0 is hydrogen; and R3 is the group of the following chemical formula: Here, R 3a is hydrogen or methyl; R 1z is cyano and; R 201 It is selected from methyl or chloro. Claim 2 In claim 1, a compound or a pharmaceutically acceptable salt thereof selected from any one of the following: 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1R )-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide; 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide; or 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide. Claim 3 As a compound, or a pharmaceutically acceptable salt thereof, the compound is: A compound that is 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt thereof. Claim 4 As a compound, or a pharmaceutically acceptable salt thereof, the compound is: A compound that is 3-(2-chloro-6-methyl-4-pyridyl)-2-(3-cyanophenyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt thereof. Claim 5 As a compound, or a pharmaceutically acceptable salt thereof, 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; a compound, or a pharmaceutically acceptable salt thereof. Claim 6 As a compound, or a pharmaceutically acceptable salt thereof, the compound is: A compound that is 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-(2-hydroxy-2-methyl-propyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt thereof. Claim 7 As a compound, or a pharmaceutically acceptable salt thereof, the compound is: A compound that is 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1S)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt thereof. Claim 8 As a compound, or a pharmaceutically acceptable salt thereof, the compound is: A compound that is 2-(3-cyanophenyl)-3-(2,6-dimethyl-4-pyridyl)-N-[(1R)-2-hydroxy-1,2-dimethyl-propyl]pyrazolo[1,5-a]pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt thereof. Claim 9 A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable diluent or carrier. as, (i) treatment of proliferative conditions; (ii) treatment of cancer; (iii) treatment of cancer in which a compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents; (iv) a pharmaceutical composition for use in the treatment of cancer in which a compound or pharmaceutical composition is administered in combination with one or more additional anticancer agents selected from the group consisting of 1) other forms of cancer immunotherapy and anticancer chemotherapy agents; 2) adenosine pathway modulators; 3) anti-PD-1 and PDL-1 antibodies; and 4) anti-CTLA4 antibodies. Claim 10 A pharmaceutical composition for use in the treatment of cancer in combination with one or more adenosine pathway modulators according to claim 9, wherein the adenosine pathway modulator is selected from A2b antagonists, CD73 inhibitors, and CD39 inhibitors. Claim 11 A pharmaceutical composition for use in the treatment of cancer in combination with one or more anti-PD-1 or PDL-1 antibodies according to claim 9, wherein the anti-PD-1 or PDL-1 antibody is selected from setrelimab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolizumab. Claim 12 A pharmaceutical composition for use in the treatment of cancer in combination with an anti-CTLA4 antibody according to claim 9, wherein the anti-CTLA4 antibody is ipilimumab. Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete

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